Christos Evangelou, MSc, PhD

The combination of atezolizumab plus sacituzumab govitecan as first-line treatment showed encouraging anti-tumor activity in previously untreated patients with triple-negative breast cancer (TNBC), in an ongoing phase 1b/2 trial.

MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.

The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
 

Rationale for Combining Antibody-Drug Conjugates with Immunotherapy

Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.

TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.

Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.

“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
 

Study Design

The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.

“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.

During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.

“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.

Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
 

Promising Anti-tumor Activity

The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.

“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.

The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.

Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”

She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
 

Encouraging survival trends

Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.

During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”

These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
 

Relationship between biomarker expression and response

The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).

“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.

Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
 

Safety of combination treatment

The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.

All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).

The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.

“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.
 

Looking Ahead

Dr. Tolaney highlighted that the cohort size of this study was small and the follow-up time was insufficient to draw conclusions about survival outcomes. Larger studies with long-term follow-up are needed to confirm the efficacy of first-line atezolizumab plus sacituzumab govitecan, she said.

“While this was a small study, the response data is very intriguing, with 17% of patients experiencing complete responses. The PFS data are also impressive, and there seems to be an interesting trend towards better response in patients with high Trop-2 expression and those with high levels of stromal TILs,” she added.

Dr. Tolaney also noted that the response rates and PFS data presented are similar to those of one of the treatment arms in the BEGONIA trial (NCT03742102), which investigated different combinations of immunotherapy in patients with metastatic TNBC. Like MORPHEUS-pan BC (NCT03424005), this study evaluated the efficacy of a different antibody-drug conjugate with chemotherapy. Patients in the study arm of the BEGONIA trial she was referring to received durvalumab (an anti-PD-L1 agent) and datopotamab deruxtecan (an antibody-drug conjugate).

Dr. Schmid said that biomarker analyses are ongoing to assess whether there is a correlation between Trop-2 expression levels and the benefits of sacituzumab govitecan. Studies are also needed to determine whether this combination can improve pathologic complete response rates in early-stage TNBC.

Dr. Tolaney echoed the importance of evaluating the efficacy of antibody-drug conjugates plus immune checkpoint inhibitors in different settings, including patients with PD-L1–negative or immunologically cold tumors and those with early-stage disease. “Ultimately, we want this combination treatment to move forward to early-stage TNBC to see if we could cure more patients,” she said, during the discussion.

Dr. Schmid reported financial relationships with Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (consulting or advisory roles); Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (honoraria); and AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas, and Medivation (research funding). Dr. Tolaney reported financial relationships with Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., Beyond Spring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, and Jazz Pharmaceuticals (consulting or advisory roles); Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Nanostring, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, Cyclacel, Sanofi, and Seattle Genetics (research funding).

The combination of atezolizumab plus sacituzumab govitecan as first-line treatment showed encouraging anti-tumor activity in previously untreated patients with triple-negative breast cancer (TNBC), in an ongoing phase 1b/2 trial.

MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.

The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
 

Rationale for Combining Antibody-Drug Conjugates with Immunotherapy

Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.

TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.

Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.

“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
 

Study Design

The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.

“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.

During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.

“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.

Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
 

Promising Anti-tumor Activity

The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.

“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.

The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.

Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”

She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
 

Encouraging survival trends

Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.

During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”

These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
 

Relationship between biomarker expression and response

The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).

“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.

Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
 

Safety of combination treatment

The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.

All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).

The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.

“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.
 

Looking Ahead

Dr. Tolaney highlighted that the cohort size of this study was small and the follow-up time was insufficient to draw conclusions about survival outcomes. Larger studies with long-term follow-up are needed to confirm the efficacy of first-line atezolizumab plus sacituzumab govitecan, she said.

“While this was a small study, the response data is very intriguing, with 17% of patients experiencing complete responses. The PFS data are also impressive, and there seems to be an interesting trend towards better response in patients with high Trop-2 expression and those with high levels of stromal TILs,” she added.

Dr. Tolaney also noted that the response rates and PFS data presented are similar to those of one of the treatment arms in the BEGONIA trial (NCT03742102), which investigated different combinations of immunotherapy in patients with metastatic TNBC. Like MORPHEUS-pan BC (NCT03424005), this study evaluated the efficacy of a different antibody-drug conjugate with chemotherapy. Patients in the study arm of the BEGONIA trial she was referring to received durvalumab (an anti-PD-L1 agent) and datopotamab deruxtecan (an antibody-drug conjugate).

Dr. Schmid said that biomarker analyses are ongoing to assess whether there is a correlation between Trop-2 expression levels and the benefits of sacituzumab govitecan. Studies are also needed to determine whether this combination can improve pathologic complete response rates in early-stage TNBC.

Dr. Tolaney echoed the importance of evaluating the efficacy of antibody-drug conjugates plus immune checkpoint inhibitors in different settings, including patients with PD-L1–negative or immunologically cold tumors and those with early-stage disease. “Ultimately, we want this combination treatment to move forward to early-stage TNBC to see if we could cure more patients,” she said, during the discussion.

Dr. Schmid reported financial relationships with Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (consulting or advisory roles); Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (honoraria); and AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas, and Medivation (research funding). Dr. Tolaney reported financial relationships with Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., Beyond Spring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, and Jazz Pharmaceuticals (consulting or advisory roles); Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Nanostring, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, Cyclacel, Sanofi, and Seattle Genetics (research funding).

The combination of atezolizumab plus sacituzumab govitecan as first-line treatment showed encouraging anti-tumor activity in previously untreated patients with triple-negative breast cancer (TNBC), in an ongoing phase 1b/2 trial.

MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.

The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
 

Rationale for Combining Antibody-Drug Conjugates with Immunotherapy

Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.

TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.

Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.

“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
 

Study Design

The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.

“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.

During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.

“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.

Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
 

Promising Anti-tumor Activity

The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.

“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.

The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.

Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”

She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
 

Encouraging survival trends

Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.

During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”

These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
 

Relationship between biomarker expression and response

The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).

“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.

Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
 

Safety of combination treatment

The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.

All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).

The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.

“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.
 

Looking Ahead

Dr. Tolaney highlighted that the cohort size of this study was small and the follow-up time was insufficient to draw conclusions about survival outcomes. Larger studies with long-term follow-up are needed to confirm the efficacy of first-line atezolizumab plus sacituzumab govitecan, she said.

“While this was a small study, the response data is very intriguing, with 17% of patients experiencing complete responses. The PFS data are also impressive, and there seems to be an interesting trend towards better response in patients with high Trop-2 expression and those with high levels of stromal TILs,” she added.

Dr. Tolaney also noted that the response rates and PFS data presented are similar to those of one of the treatment arms in the BEGONIA trial (NCT03742102), which investigated different combinations of immunotherapy in patients with metastatic TNBC. Like MORPHEUS-pan BC (NCT03424005), this study evaluated the efficacy of a different antibody-drug conjugate with chemotherapy. Patients in the study arm of the BEGONIA trial she was referring to received durvalumab (an anti-PD-L1 agent) and datopotamab deruxtecan (an antibody-drug conjugate).

Dr. Schmid said that biomarker analyses are ongoing to assess whether there is a correlation between Trop-2 expression levels and the benefits of sacituzumab govitecan. Studies are also needed to determine whether this combination can improve pathologic complete response rates in early-stage TNBC.

Dr. Tolaney echoed the importance of evaluating the efficacy of antibody-drug conjugates plus immune checkpoint inhibitors in different settings, including patients with PD-L1–negative or immunologically cold tumors and those with early-stage disease. “Ultimately, we want this combination treatment to move forward to early-stage TNBC to see if we could cure more patients,” she said, during the discussion.

Dr. Schmid reported financial relationships with Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (consulting or advisory roles); Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (honoraria); and AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas, and Medivation (research funding). Dr. Tolaney reported financial relationships with Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., Beyond Spring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, and Jazz Pharmaceuticals (consulting or advisory roles); Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Nanostring, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, Cyclacel, Sanofi, and Seattle Genetics (research funding).

For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However, results from a large international study presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress provide reassuring evidence that ART, such as in vitro fertilization, can be safely used by BRCA1/2 mutation carriers previously treated for breast cancer.

“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
 

Unmet Fertility Needs for Women With Breast Cancer

With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.

According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.

“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
 

Study Design and Patient Population

The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.

Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.

Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
 

No Increased Risks for Pregnancy and Fetal Outcomes

Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.

Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.

“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
 

No Adverse Effects on Breast Cancer Prognosis

At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).

“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.

Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.

“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
 

Clinical Implications and Future Work

According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.

“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”

During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.

“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.

She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”

Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”

Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).

For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However, results from a large international study presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress provide reassuring evidence that ART, such as in vitro fertilization, can be safely used by BRCA1/2 mutation carriers previously treated for breast cancer.

“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
 

Unmet Fertility Needs for Women With Breast Cancer

With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.

According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.

“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
 

Study Design and Patient Population

The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.

Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.

Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
 

No Increased Risks for Pregnancy and Fetal Outcomes

Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.

Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.

“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
 

No Adverse Effects on Breast Cancer Prognosis

At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).

“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.

Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.

“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
 

Clinical Implications and Future Work

According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.

“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”

During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.

“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.

She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”

Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”

Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).

For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However, results from a large international study presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress provide reassuring evidence that ART, such as in vitro fertilization, can be safely used by BRCA1/2 mutation carriers previously treated for breast cancer.

“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
 

Unmet Fertility Needs for Women With Breast Cancer

With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.

According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.

“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
 

Study Design and Patient Population

The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.

Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.

Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
 

No Increased Risks for Pregnancy and Fetal Outcomes

Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.

Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.

“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
 

No Adverse Effects on Breast Cancer Prognosis

At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).

“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.

Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.

“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
 

Clinical Implications and Future Work

According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.

“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”

During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.

“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.

She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”

Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”

Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).

SAN DIEGO — A new cell-free DNA (cfDNA)-based blood test shows promising performance in detecting colorectal cancer and advanced precancerous lesions, say the authors of new research.

Rachel B. Issaka, MD, MAS, of the Fred Hutchinson Cancer Center, Seattle, presented the clinical data, which was published in The New England Journal of Medicine, at the American Association for Cancer Research annual meeting.

Issaka_Rachel_WASH_web.jpg

The authors of the study evaluated the performance of a cfDNA blood-based test in a population eligible for colorectal cancer screening. The researchers found that the test had high sensitivity for the detection of colorectal cancer and high specificity for advanced precancerous lesions.

This novel blood test could improve screening adherence and, ultimately, reduce colorectal cancer-related mortality, Dr. Issaka said during her presentation.

“This test has the potential to help us reach the 80% screening target in colorectal cancer. However, this will depend on many factors, including access, implementation, follow-up colonoscopy, and characteristics of the test,” Dr. Issaka said in an interview.

She added that, when approved for broader use, anyone who wants to use this blood test for colorectal cancer screening should have a frank conversation with their healthcare provider.

“Considering the person’s age, medical history, family history, and any potential symptoms, and how the test performs will dictate if it’s the right test for that person versus another screening strategy,” Dr. Issaka explained.
 

The Blood Test Detects Colorectal Cancer With High Accuracy

The investigators of the observational ECLIPSE trial evaluated the performance of the cfDNA-based blood test in 7861 individuals who were eligible for colorectal cancer screening. The study population included people from more than 200 rural and urban sites across 34 states, including community hospitals, private practices, gastroenterology clinics, and academic centers. “The study enrolled a diverse cohort that is reflective of the demographics of the intended use population in the US,” Dr. Issaka said during her talk.

The co-primary outcomes of the study were the test’s sensitivity for detecting colorectal cancer and its specificity for identifying advanced neoplasia.

In her presentation, Dr. Issaka highlighted that the test had 83.1% (95% confidence interval [CI], 72.2%-90.3%) sensitivity for the detection of colorectal cancer, meaning that it was able to correctly identify most participants with the disease. The test’s sensitivity was even higher (87.5%; 95% CI, 75.3%-94.1%) for stage I, II, or III colorectal cancer. “These are the stages at which early intervention can have the greatest impact on patient prognosis,” Dr. Issaka said.

Moreover, the blood test showed 89.6% (95% CI, 88.8%-90.3%) specificity for advanced neoplasia, including colorectal cancer and advanced precancerous lesions. The specificity of the test for negative colonoscopy results (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0%-90.7%).

Dr. Issaka highlighted that this cfDNA assay is the first blood-based test with performance comparable to current guideline-recommended noninvasive options for CRC.
 

The Blood Test Shows Limited Ability To Detect Advanced Precancerous Lesions

During her presentation, Dr. Issaka acknowledged that the cfDNA-based blood test had a lower sensitivity (13.2%; 95% CI, 11.3%-15.3%) for the detection of advanced precancerous lesions, suggesting that it may be more effective at identifying established cancers than early-stage precancerous changes. Low sensitivity was also observed for high-grade dysplasia (22.6%; 95% CI, 11.4%-39.8%). However, she emphasized that the test could still play a valuable role in a comprehensive screening approach, potentially serving as a first-line tool to identify individuals who would then undergo follow-up colonoscopy.

“Although blood-based tests perform well at finding cancers, they do not do so well at finding precancerous polyps. This is relevant because colorectal cancer is one of the few cancers that we can prevent by finding and removing precancerous polyps,” Folasade P. May, MD, PhD, MPhil, said in an interview.

“Users must also understand that if the test result is abnormal, a colonoscopy is required to look for cancers and polyps that might have caused the abnormal result,” added Dr. May, associate professor at UCLA. She was not involved in the study.
 

Clinical Implications and Future Steps

According to the study published in the NEJM, colorectal cancer is the third most commonly diagnosed cancer in the United States, and early detection is crucial for effective treatment. However, over a third of eligible individuals are not up to date with recommended screening.

During her talk, Dr. Issaka noted that colonoscopy is the most commonly used screening method for colorectal cancer. What contributes to the low adherence to getting a colonoscopy among the eligible population is that some find it inconvenient, and the test is invasive, she added.

According to Dr. May, the key advantage of cfDNA-based screening is that many people will find it easier to complete a blood test than the currently available screening tests.

“This option may allow us to screen individuals that we have previously struggled to convince to get screened for colorectal cancer,” she said.

In an interview, Dr. Issaka acknowledged that the potential public health impact of any noninvasive screening test depends on how many people with abnormal results complete a follow-up colonoscopy. “This is an important quality metric to track,” she said.

In an interview, Dr. Issaka emphasized that comparing this cfDNA blood test with emerging blood tests and other noninvasive screening strategies will empower patients and clinicians to select the right test at the right time for the right patient.

She added that the study was conducted in an average-risk screening population and that further research is needed to evaluate the test’s performance in higher-risk groups and to assess its real-world impact on screening adherence and colorectal cancer-related outcomes.

Commenting on potential challenges with implementing this cfDNA blood test in clinical practice, Dr. May said, “As we consider incorporating blood-based tests into clinical practice, some challenges include cost, equitable access to tests and follow-up, performance in young adults who are newly eligible for screening, and follow-up after abnormal results.”

She added that, if there is uptake of these tests, it will be important to track how that impacts colorectal cancer screening rates, stage at diagnosis, and whether there is stage migration, incidence, and mortality.

“At this time, I feel that these tests are appropriate for individuals who will not or cannot participate in one of the currently recommended screening tests. These include colonoscopy and stool-based tests, like FIT and FIT-DNA,” Dr. May concluded.

Dr. Issaka reported financial relationships with the National Institutes of Health/National Cancer Institute, American College of Gastroenterology, and Guardant Health Inc. Dr. May reported financial relationships with Takeda, Medtronic, Johnson & Johnson, Saint Supply, Exact Sciences, Freenome, Geneoscopy, Guardant Health, InterVenn, Natura, National Institutes of Health/National Cancer Institute, Veterans Affairs HSR&D, Broad Institute, Stand up to Cancer, and NRG Oncology.

SAN DIEGO — A new cell-free DNA (cfDNA)-based blood test shows promising performance in detecting colorectal cancer and advanced precancerous lesions, say the authors of new research.

Rachel B. Issaka, MD, MAS, of the Fred Hutchinson Cancer Center, Seattle, presented the clinical data, which was published in The New England Journal of Medicine, at the American Association for Cancer Research annual meeting.

Issaka_Rachel_WASH_web.jpg

The authors of the study evaluated the performance of a cfDNA blood-based test in a population eligible for colorectal cancer screening. The researchers found that the test had high sensitivity for the detection of colorectal cancer and high specificity for advanced precancerous lesions.

This novel blood test could improve screening adherence and, ultimately, reduce colorectal cancer-related mortality, Dr. Issaka said during her presentation.

“This test has the potential to help us reach the 80% screening target in colorectal cancer. However, this will depend on many factors, including access, implementation, follow-up colonoscopy, and characteristics of the test,” Dr. Issaka said in an interview.

She added that, when approved for broader use, anyone who wants to use this blood test for colorectal cancer screening should have a frank conversation with their healthcare provider.

“Considering the person’s age, medical history, family history, and any potential symptoms, and how the test performs will dictate if it’s the right test for that person versus another screening strategy,” Dr. Issaka explained.
 

The Blood Test Detects Colorectal Cancer With High Accuracy

The investigators of the observational ECLIPSE trial evaluated the performance of the cfDNA-based blood test in 7861 individuals who were eligible for colorectal cancer screening. The study population included people from more than 200 rural and urban sites across 34 states, including community hospitals, private practices, gastroenterology clinics, and academic centers. “The study enrolled a diverse cohort that is reflective of the demographics of the intended use population in the US,” Dr. Issaka said during her talk.

The co-primary outcomes of the study were the test’s sensitivity for detecting colorectal cancer and its specificity for identifying advanced neoplasia.

In her presentation, Dr. Issaka highlighted that the test had 83.1% (95% confidence interval [CI], 72.2%-90.3%) sensitivity for the detection of colorectal cancer, meaning that it was able to correctly identify most participants with the disease. The test’s sensitivity was even higher (87.5%; 95% CI, 75.3%-94.1%) for stage I, II, or III colorectal cancer. “These are the stages at which early intervention can have the greatest impact on patient prognosis,” Dr. Issaka said.

Moreover, the blood test showed 89.6% (95% CI, 88.8%-90.3%) specificity for advanced neoplasia, including colorectal cancer and advanced precancerous lesions. The specificity of the test for negative colonoscopy results (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0%-90.7%).

Dr. Issaka highlighted that this cfDNA assay is the first blood-based test with performance comparable to current guideline-recommended noninvasive options for CRC.
 

The Blood Test Shows Limited Ability To Detect Advanced Precancerous Lesions

During her presentation, Dr. Issaka acknowledged that the cfDNA-based blood test had a lower sensitivity (13.2%; 95% CI, 11.3%-15.3%) for the detection of advanced precancerous lesions, suggesting that it may be more effective at identifying established cancers than early-stage precancerous changes. Low sensitivity was also observed for high-grade dysplasia (22.6%; 95% CI, 11.4%-39.8%). However, she emphasized that the test could still play a valuable role in a comprehensive screening approach, potentially serving as a first-line tool to identify individuals who would then undergo follow-up colonoscopy.

“Although blood-based tests perform well at finding cancers, they do not do so well at finding precancerous polyps. This is relevant because colorectal cancer is one of the few cancers that we can prevent by finding and removing precancerous polyps,” Folasade P. May, MD, PhD, MPhil, said in an interview.

“Users must also understand that if the test result is abnormal, a colonoscopy is required to look for cancers and polyps that might have caused the abnormal result,” added Dr. May, associate professor at UCLA. She was not involved in the study.
 

Clinical Implications and Future Steps

According to the study published in the NEJM, colorectal cancer is the third most commonly diagnosed cancer in the United States, and early detection is crucial for effective treatment. However, over a third of eligible individuals are not up to date with recommended screening.

During her talk, Dr. Issaka noted that colonoscopy is the most commonly used screening method for colorectal cancer. What contributes to the low adherence to getting a colonoscopy among the eligible population is that some find it inconvenient, and the test is invasive, she added.

According to Dr. May, the key advantage of cfDNA-based screening is that many people will find it easier to complete a blood test than the currently available screening tests.

“This option may allow us to screen individuals that we have previously struggled to convince to get screened for colorectal cancer,” she said.

In an interview, Dr. Issaka acknowledged that the potential public health impact of any noninvasive screening test depends on how many people with abnormal results complete a follow-up colonoscopy. “This is an important quality metric to track,” she said.

In an interview, Dr. Issaka emphasized that comparing this cfDNA blood test with emerging blood tests and other noninvasive screening strategies will empower patients and clinicians to select the right test at the right time for the right patient.

She added that the study was conducted in an average-risk screening population and that further research is needed to evaluate the test’s performance in higher-risk groups and to assess its real-world impact on screening adherence and colorectal cancer-related outcomes.

Commenting on potential challenges with implementing this cfDNA blood test in clinical practice, Dr. May said, “As we consider incorporating blood-based tests into clinical practice, some challenges include cost, equitable access to tests and follow-up, performance in young adults who are newly eligible for screening, and follow-up after abnormal results.”

She added that, if there is uptake of these tests, it will be important to track how that impacts colorectal cancer screening rates, stage at diagnosis, and whether there is stage migration, incidence, and mortality.

“At this time, I feel that these tests are appropriate for individuals who will not or cannot participate in one of the currently recommended screening tests. These include colonoscopy and stool-based tests, like FIT and FIT-DNA,” Dr. May concluded.

Dr. Issaka reported financial relationships with the National Institutes of Health/National Cancer Institute, American College of Gastroenterology, and Guardant Health Inc. Dr. May reported financial relationships with Takeda, Medtronic, Johnson & Johnson, Saint Supply, Exact Sciences, Freenome, Geneoscopy, Guardant Health, InterVenn, Natura, National Institutes of Health/National Cancer Institute, Veterans Affairs HSR&D, Broad Institute, Stand up to Cancer, and NRG Oncology.

SAN DIEGO — A new cell-free DNA (cfDNA)-based blood test shows promising performance in detecting colorectal cancer and advanced precancerous lesions, say the authors of new research.

Rachel B. Issaka, MD, MAS, of the Fred Hutchinson Cancer Center, Seattle, presented the clinical data, which was published in The New England Journal of Medicine, at the American Association for Cancer Research annual meeting.

Issaka_Rachel_WASH_web.jpg

The authors of the study evaluated the performance of a cfDNA blood-based test in a population eligible for colorectal cancer screening. The researchers found that the test had high sensitivity for the detection of colorectal cancer and high specificity for advanced precancerous lesions.

This novel blood test could improve screening adherence and, ultimately, reduce colorectal cancer-related mortality, Dr. Issaka said during her presentation.

“This test has the potential to help us reach the 80% screening target in colorectal cancer. However, this will depend on many factors, including access, implementation, follow-up colonoscopy, and characteristics of the test,” Dr. Issaka said in an interview.

She added that, when approved for broader use, anyone who wants to use this blood test for colorectal cancer screening should have a frank conversation with their healthcare provider.

“Considering the person’s age, medical history, family history, and any potential symptoms, and how the test performs will dictate if it’s the right test for that person versus another screening strategy,” Dr. Issaka explained.
 

The Blood Test Detects Colorectal Cancer With High Accuracy

The investigators of the observational ECLIPSE trial evaluated the performance of the cfDNA-based blood test in 7861 individuals who were eligible for colorectal cancer screening. The study population included people from more than 200 rural and urban sites across 34 states, including community hospitals, private practices, gastroenterology clinics, and academic centers. “The study enrolled a diverse cohort that is reflective of the demographics of the intended use population in the US,” Dr. Issaka said during her talk.

The co-primary outcomes of the study were the test’s sensitivity for detecting colorectal cancer and its specificity for identifying advanced neoplasia.

In her presentation, Dr. Issaka highlighted that the test had 83.1% (95% confidence interval [CI], 72.2%-90.3%) sensitivity for the detection of colorectal cancer, meaning that it was able to correctly identify most participants with the disease. The test’s sensitivity was even higher (87.5%; 95% CI, 75.3%-94.1%) for stage I, II, or III colorectal cancer. “These are the stages at which early intervention can have the greatest impact on patient prognosis,” Dr. Issaka said.

Moreover, the blood test showed 89.6% (95% CI, 88.8%-90.3%) specificity for advanced neoplasia, including colorectal cancer and advanced precancerous lesions. The specificity of the test for negative colonoscopy results (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0%-90.7%).

Dr. Issaka highlighted that this cfDNA assay is the first blood-based test with performance comparable to current guideline-recommended noninvasive options for CRC.
 

The Blood Test Shows Limited Ability To Detect Advanced Precancerous Lesions

During her presentation, Dr. Issaka acknowledged that the cfDNA-based blood test had a lower sensitivity (13.2%; 95% CI, 11.3%-15.3%) for the detection of advanced precancerous lesions, suggesting that it may be more effective at identifying established cancers than early-stage precancerous changes. Low sensitivity was also observed for high-grade dysplasia (22.6%; 95% CI, 11.4%-39.8%). However, she emphasized that the test could still play a valuable role in a comprehensive screening approach, potentially serving as a first-line tool to identify individuals who would then undergo follow-up colonoscopy.

“Although blood-based tests perform well at finding cancers, they do not do so well at finding precancerous polyps. This is relevant because colorectal cancer is one of the few cancers that we can prevent by finding and removing precancerous polyps,” Folasade P. May, MD, PhD, MPhil, said in an interview.

“Users must also understand that if the test result is abnormal, a colonoscopy is required to look for cancers and polyps that might have caused the abnormal result,” added Dr. May, associate professor at UCLA. She was not involved in the study.
 

Clinical Implications and Future Steps

According to the study published in the NEJM, colorectal cancer is the third most commonly diagnosed cancer in the United States, and early detection is crucial for effective treatment. However, over a third of eligible individuals are not up to date with recommended screening.

During her talk, Dr. Issaka noted that colonoscopy is the most commonly used screening method for colorectal cancer. What contributes to the low adherence to getting a colonoscopy among the eligible population is that some find it inconvenient, and the test is invasive, she added.

According to Dr. May, the key advantage of cfDNA-based screening is that many people will find it easier to complete a blood test than the currently available screening tests.

“This option may allow us to screen individuals that we have previously struggled to convince to get screened for colorectal cancer,” she said.

In an interview, Dr. Issaka acknowledged that the potential public health impact of any noninvasive screening test depends on how many people with abnormal results complete a follow-up colonoscopy. “This is an important quality metric to track,” she said.

In an interview, Dr. Issaka emphasized that comparing this cfDNA blood test with emerging blood tests and other noninvasive screening strategies will empower patients and clinicians to select the right test at the right time for the right patient.

She added that the study was conducted in an average-risk screening population and that further research is needed to evaluate the test’s performance in higher-risk groups and to assess its real-world impact on screening adherence and colorectal cancer-related outcomes.

Commenting on potential challenges with implementing this cfDNA blood test in clinical practice, Dr. May said, “As we consider incorporating blood-based tests into clinical practice, some challenges include cost, equitable access to tests and follow-up, performance in young adults who are newly eligible for screening, and follow-up after abnormal results.”

She added that, if there is uptake of these tests, it will be important to track how that impacts colorectal cancer screening rates, stage at diagnosis, and whether there is stage migration, incidence, and mortality.

“At this time, I feel that these tests are appropriate for individuals who will not or cannot participate in one of the currently recommended screening tests. These include colonoscopy and stool-based tests, like FIT and FIT-DNA,” Dr. May concluded.

Dr. Issaka reported financial relationships with the National Institutes of Health/National Cancer Institute, American College of Gastroenterology, and Guardant Health Inc. Dr. May reported financial relationships with Takeda, Medtronic, Johnson & Johnson, Saint Supply, Exact Sciences, Freenome, Geneoscopy, Guardant Health, InterVenn, Natura, National Institutes of Health/National Cancer Institute, Veterans Affairs HSR&D, Broad Institute, Stand up to Cancer, and NRG Oncology.

SAN DIEGO — Monitoring a patient’s circulating tumor DNA (ctDNA) can provide valuable insights on early response to targeted therapies among patients with HER2-positive cancers.

This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.

“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.

Kurzrock_Razelle_WISC_web.jpg

Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.

“Such monitoring may be useful in clinical trials and eventually in practice,” she added.
 

Need for new methods to predict early tumor response

Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.

During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.

“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.

Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.

“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.

In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.
 

Design of patient-specific ctDNA assays

In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).

By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).

During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.

Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.
 

Changes in ctDNA levels predict patient survival

The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = 0.04).

Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).

“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.

Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”

The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.

In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”

Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.
 

Implementation of ctDNA monitoring in clinical trials

Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.

“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.

He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.

“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.

Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — Monitoring a patient’s circulating tumor DNA (ctDNA) can provide valuable insights on early response to targeted therapies among patients with HER2-positive cancers.

This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.

“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.

Kurzrock_Razelle_WISC_web.jpg

Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.

“Such monitoring may be useful in clinical trials and eventually in practice,” she added.
 

Need for new methods to predict early tumor response

Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.

During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.

“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.

Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.

“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.

In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.
 

Design of patient-specific ctDNA assays

In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).

By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).

During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.

Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.
 

Changes in ctDNA levels predict patient survival

The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = 0.04).

Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).

“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.

Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”

The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.

In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”

Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.
 

Implementation of ctDNA monitoring in clinical trials

Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.

“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.

He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.

“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.

Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — Monitoring a patient’s circulating tumor DNA (ctDNA) can provide valuable insights on early response to targeted therapies among patients with HER2-positive cancers.

This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.

“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.

Kurzrock_Razelle_WISC_web.jpg

Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.

“Such monitoring may be useful in clinical trials and eventually in practice,” she added.
 

Need for new methods to predict early tumor response

Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.

During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.

“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.

Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.

“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.

In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.
 

Design of patient-specific ctDNA assays

In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).

By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).

During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.

Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.
 

Changes in ctDNA levels predict patient survival

The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = 0.04).

Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).

“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.

Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”

The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.

In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”

Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.
 

Implementation of ctDNA monitoring in clinical trials

Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.

“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.

He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.

“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.

Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — A novel multicancer early detection (MCED) blood test has demonstrated promising real-world results in detecting new cancers, including several cases of early-stage disease.

This was the conclusion of recent data presented by Ora Karp Gordon, MD, MS, during a session at the American Association for Cancer Research annual meeting.

The MCED test, known as Galleri, was made clinically available in the United States in April 2021. Developed by GRAIL LLC, the test analyzes cell-free DNA in the blood using targeted methylation analysis and machine learning to detect the presence of a cancer signal and determine its organ of origin or cancer signal origin. The initial screening of over 53,000 individuals with the Galleri test detected a cancer signal in 1.1% of participants.

The new real-world analysis examines the outcomes of repeat MCED testing in 5,794 individuals.

The study looked at individuals who initially received a ‘no cancer signal detected’ result and then underwent a second Galleri test. Over 80% of participants received their follow-up test 10-18 months after the first, with a median interval between blood draws of 12.9 months.

“The repeat tests detect those cancer cases that have reached the detection threshold since their last MCED test, which should be less than one year of incidence,” Dr. Gordon, professor at Saint John’s Cancer Institute, Santa Monica, California, said in an interview. “We are just now starting to see results from patients who get their second and even third round of screening.”

“Galleri is recommended to be used annually in addition to USPSTF [US Preventive Services Task Force]–recommended cancer screening tests, like mammography and colonoscopy,” she said.

This recommendation is based on a modeling study suggesting that annual screening would improve stage shift, diagnostic yield, and potentially mortality when compared to biennial screening, although biennial screening was still favorable compared with no screening, she explained.
 

Early Real-World Evidence of Repeat Testing

Among the cohort of 5,794 individuals who received repeat testing, 26 received a positive cancer signal on their second test, yielding a cancer signal detection rate of 0.45% (95% CI: 0.31%-0.66%). The cancer signal detection rate was slightly higher in men. The rate was 0.50% (95% CI: 0.32%-0.81%; 17 of 3367) in men versus 0.37% (95% CI: 0.2%-0.7%; 9 of 2427) in women.

During her presentation, Dr. Gordon highlighted that the repeat testing signal detection rate was lower than the initial 0.95% rate (95% CI: 0.87-1.0; 510 of 53,744) seen in the previous larger cohort of patients who were retested at 1 year.

She acknowledged that the lower cancer signal detection rate of repeat testing may indicate some degree of ‘early adopter’ bias, where those who return for a second test are systematically different from the general screening population. This could suggest that broader population-level screening may yield different results, she continued.
 

Shift Toward Unscreened Cancers

The top cancer types identified in the second round of testing were lymphoid, head and neck, bladder/urothelial, colorectal, and anal cancers. Clinicians were able to confirm clinical outcomes in 12 of 26 cases, in which cancer signals were detected. Of those 12 cases, 8 individuals received a cancer diagnosis and 4 did not have cancer. The remaining 14 of 26 cases in which cancer signals were detected are still under investigation.

“We found a shift away from USPSTF screen-detected cancers, like breast, lung, and prostate, and relative increase in unscreened urinary, head and neck, and lymphoid cancers, with 75% of cancers being those without any screening guidelines,” Dr. Gordon said in an interview.

She added that patients who choose to retest may have different cancer rates for several reasons, including bias toward a population that is health conscious and adhered to all recommended cancer screening.

“So the shift toward unscreened cancers is not unexpected and highlights the value of Galleri,” she said, but also acknowledged that “continued monitoring is needed to see if this translates in a persistent finding over time and tests.”
 

Shift Toward Early-Stage Cancers

Staging information was available for five cases, and Dr. Gordon highlighted in her talk that four of these confirmed cancers were stage I, including cancers of the anus, head and neck, bladder, and lymphoma. The fifth confirmed cancer with staging information was stage IV ovarian cancer.

“It is still early, and the numbers are very small, but the detection of early-stage cancers with second annual testing is very encouraging as these are the cases where MCED testing could have the greatest impact in improving outcomes through earlier treatment,” Dr. Gordon told this publication.

During an interview after the talk, Kenneth L. Kehl, MD, MPH, echoed that data must be confirmed in larger cohorts.

“The shift toward earlier stage cancers that are less detectable by standard screening methods is an interesting result, but we need to be cautious since the numbers were relatively small, and we do not have data on cancers that were diagnosed among patients whose second MCED test was also negative,” said Dr. Kehl, a medical oncologist at Dana-Farber Cancer Institute, Boston.
 

MCED Results Could Help Direct Diagnostic Workup

The test’s ability to predict the organ of origin was highly accurate, correctly identifying the cancer type in all eight confirmed cases. Among the eight cases with a confirmed cancer diagnosis, the accuracy of the first prediction was 100%, and diagnoses included invasive cancers across multiple tissues and organs, including anus, colon, head and neck, urothelial tract, ovary, and the lymphatic system.

“The fact that the site of origin for 100% of confirmed cancers was accurately predicted with GRAIL’s CSO by Galleri test confirms the promise that this can guide workup when a cancer signal is detected,” Dr. Gordon noted in the interview.
 

Looking Ahead

Dr. Kehl, who was not involved in the MCED study, noted in an interview that “further data on test characteristics beyond positive predictive value, including the sensitivity, specificity, and negative predictive value, as well as demonstration of clinical benefit — ideally in a randomized trial — will likely be required for MCED testing to become a standard public health recommendation.”

He added that challenges associated with implementing annual screening with MCED tests include the risks of both false positives and false negatives as testing becomes more widely available.

“False positives cause anxiety and lead to additional testing that may carry its own risks, and we need to understand if potentially false negative tests will be associated with less uptake of established screening strategies,” Dr. Kehl said in an interview. However, he noted that serial testing could lead to more frequent diagnoses of early-stage cancers that may be less detectable by standard methods.

Dr. Gordon reported financial relationships with GRAIL LLC and Genetic Technologies Corporation. Dr. Kehl reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — A novel multicancer early detection (MCED) blood test has demonstrated promising real-world results in detecting new cancers, including several cases of early-stage disease.

This was the conclusion of recent data presented by Ora Karp Gordon, MD, MS, during a session at the American Association for Cancer Research annual meeting.

The MCED test, known as Galleri, was made clinically available in the United States in April 2021. Developed by GRAIL LLC, the test analyzes cell-free DNA in the blood using targeted methylation analysis and machine learning to detect the presence of a cancer signal and determine its organ of origin or cancer signal origin. The initial screening of over 53,000 individuals with the Galleri test detected a cancer signal in 1.1% of participants.

The new real-world analysis examines the outcomes of repeat MCED testing in 5,794 individuals.

The study looked at individuals who initially received a ‘no cancer signal detected’ result and then underwent a second Galleri test. Over 80% of participants received their follow-up test 10-18 months after the first, with a median interval between blood draws of 12.9 months.

“The repeat tests detect those cancer cases that have reached the detection threshold since their last MCED test, which should be less than one year of incidence,” Dr. Gordon, professor at Saint John’s Cancer Institute, Santa Monica, California, said in an interview. “We are just now starting to see results from patients who get their second and even third round of screening.”

“Galleri is recommended to be used annually in addition to USPSTF [US Preventive Services Task Force]–recommended cancer screening tests, like mammography and colonoscopy,” she said.

This recommendation is based on a modeling study suggesting that annual screening would improve stage shift, diagnostic yield, and potentially mortality when compared to biennial screening, although biennial screening was still favorable compared with no screening, she explained.
 

Early Real-World Evidence of Repeat Testing

Among the cohort of 5,794 individuals who received repeat testing, 26 received a positive cancer signal on their second test, yielding a cancer signal detection rate of 0.45% (95% CI: 0.31%-0.66%). The cancer signal detection rate was slightly higher in men. The rate was 0.50% (95% CI: 0.32%-0.81%; 17 of 3367) in men versus 0.37% (95% CI: 0.2%-0.7%; 9 of 2427) in women.

During her presentation, Dr. Gordon highlighted that the repeat testing signal detection rate was lower than the initial 0.95% rate (95% CI: 0.87-1.0; 510 of 53,744) seen in the previous larger cohort of patients who were retested at 1 year.

She acknowledged that the lower cancer signal detection rate of repeat testing may indicate some degree of ‘early adopter’ bias, where those who return for a second test are systematically different from the general screening population. This could suggest that broader population-level screening may yield different results, she continued.
 

Shift Toward Unscreened Cancers

The top cancer types identified in the second round of testing were lymphoid, head and neck, bladder/urothelial, colorectal, and anal cancers. Clinicians were able to confirm clinical outcomes in 12 of 26 cases, in which cancer signals were detected. Of those 12 cases, 8 individuals received a cancer diagnosis and 4 did not have cancer. The remaining 14 of 26 cases in which cancer signals were detected are still under investigation.

“We found a shift away from USPSTF screen-detected cancers, like breast, lung, and prostate, and relative increase in unscreened urinary, head and neck, and lymphoid cancers, with 75% of cancers being those without any screening guidelines,” Dr. Gordon said in an interview.

She added that patients who choose to retest may have different cancer rates for several reasons, including bias toward a population that is health conscious and adhered to all recommended cancer screening.

“So the shift toward unscreened cancers is not unexpected and highlights the value of Galleri,” she said, but also acknowledged that “continued monitoring is needed to see if this translates in a persistent finding over time and tests.”
 

Shift Toward Early-Stage Cancers

Staging information was available for five cases, and Dr. Gordon highlighted in her talk that four of these confirmed cancers were stage I, including cancers of the anus, head and neck, bladder, and lymphoma. The fifth confirmed cancer with staging information was stage IV ovarian cancer.

“It is still early, and the numbers are very small, but the detection of early-stage cancers with second annual testing is very encouraging as these are the cases where MCED testing could have the greatest impact in improving outcomes through earlier treatment,” Dr. Gordon told this publication.

During an interview after the talk, Kenneth L. Kehl, MD, MPH, echoed that data must be confirmed in larger cohorts.

“The shift toward earlier stage cancers that are less detectable by standard screening methods is an interesting result, but we need to be cautious since the numbers were relatively small, and we do not have data on cancers that were diagnosed among patients whose second MCED test was also negative,” said Dr. Kehl, a medical oncologist at Dana-Farber Cancer Institute, Boston.
 

MCED Results Could Help Direct Diagnostic Workup

The test’s ability to predict the organ of origin was highly accurate, correctly identifying the cancer type in all eight confirmed cases. Among the eight cases with a confirmed cancer diagnosis, the accuracy of the first prediction was 100%, and diagnoses included invasive cancers across multiple tissues and organs, including anus, colon, head and neck, urothelial tract, ovary, and the lymphatic system.

“The fact that the site of origin for 100% of confirmed cancers was accurately predicted with GRAIL’s CSO by Galleri test confirms the promise that this can guide workup when a cancer signal is detected,” Dr. Gordon noted in the interview.
 

Looking Ahead

Dr. Kehl, who was not involved in the MCED study, noted in an interview that “further data on test characteristics beyond positive predictive value, including the sensitivity, specificity, and negative predictive value, as well as demonstration of clinical benefit — ideally in a randomized trial — will likely be required for MCED testing to become a standard public health recommendation.”

He added that challenges associated with implementing annual screening with MCED tests include the risks of both false positives and false negatives as testing becomes more widely available.

“False positives cause anxiety and lead to additional testing that may carry its own risks, and we need to understand if potentially false negative tests will be associated with less uptake of established screening strategies,” Dr. Kehl said in an interview. However, he noted that serial testing could lead to more frequent diagnoses of early-stage cancers that may be less detectable by standard methods.

Dr. Gordon reported financial relationships with GRAIL LLC and Genetic Technologies Corporation. Dr. Kehl reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — A novel multicancer early detection (MCED) blood test has demonstrated promising real-world results in detecting new cancers, including several cases of early-stage disease.

This was the conclusion of recent data presented by Ora Karp Gordon, MD, MS, during a session at the American Association for Cancer Research annual meeting.

The MCED test, known as Galleri, was made clinically available in the United States in April 2021. Developed by GRAIL LLC, the test analyzes cell-free DNA in the blood using targeted methylation analysis and machine learning to detect the presence of a cancer signal and determine its organ of origin or cancer signal origin. The initial screening of over 53,000 individuals with the Galleri test detected a cancer signal in 1.1% of participants.

The new real-world analysis examines the outcomes of repeat MCED testing in 5,794 individuals.

The study looked at individuals who initially received a ‘no cancer signal detected’ result and then underwent a second Galleri test. Over 80% of participants received their follow-up test 10-18 months after the first, with a median interval between blood draws of 12.9 months.

“The repeat tests detect those cancer cases that have reached the detection threshold since their last MCED test, which should be less than one year of incidence,” Dr. Gordon, professor at Saint John’s Cancer Institute, Santa Monica, California, said in an interview. “We are just now starting to see results from patients who get their second and even third round of screening.”

“Galleri is recommended to be used annually in addition to USPSTF [US Preventive Services Task Force]–recommended cancer screening tests, like mammography and colonoscopy,” she said.

This recommendation is based on a modeling study suggesting that annual screening would improve stage shift, diagnostic yield, and potentially mortality when compared to biennial screening, although biennial screening was still favorable compared with no screening, she explained.
 

Early Real-World Evidence of Repeat Testing

Among the cohort of 5,794 individuals who received repeat testing, 26 received a positive cancer signal on their second test, yielding a cancer signal detection rate of 0.45% (95% CI: 0.31%-0.66%). The cancer signal detection rate was slightly higher in men. The rate was 0.50% (95% CI: 0.32%-0.81%; 17 of 3367) in men versus 0.37% (95% CI: 0.2%-0.7%; 9 of 2427) in women.

During her presentation, Dr. Gordon highlighted that the repeat testing signal detection rate was lower than the initial 0.95% rate (95% CI: 0.87-1.0; 510 of 53,744) seen in the previous larger cohort of patients who were retested at 1 year.

She acknowledged that the lower cancer signal detection rate of repeat testing may indicate some degree of ‘early adopter’ bias, where those who return for a second test are systematically different from the general screening population. This could suggest that broader population-level screening may yield different results, she continued.
 

Shift Toward Unscreened Cancers

The top cancer types identified in the second round of testing were lymphoid, head and neck, bladder/urothelial, colorectal, and anal cancers. Clinicians were able to confirm clinical outcomes in 12 of 26 cases, in which cancer signals were detected. Of those 12 cases, 8 individuals received a cancer diagnosis and 4 did not have cancer. The remaining 14 of 26 cases in which cancer signals were detected are still under investigation.

“We found a shift away from USPSTF screen-detected cancers, like breast, lung, and prostate, and relative increase in unscreened urinary, head and neck, and lymphoid cancers, with 75% of cancers being those without any screening guidelines,” Dr. Gordon said in an interview.

She added that patients who choose to retest may have different cancer rates for several reasons, including bias toward a population that is health conscious and adhered to all recommended cancer screening.

“So the shift toward unscreened cancers is not unexpected and highlights the value of Galleri,” she said, but also acknowledged that “continued monitoring is needed to see if this translates in a persistent finding over time and tests.”
 

Shift Toward Early-Stage Cancers

Staging information was available for five cases, and Dr. Gordon highlighted in her talk that four of these confirmed cancers were stage I, including cancers of the anus, head and neck, bladder, and lymphoma. The fifth confirmed cancer with staging information was stage IV ovarian cancer.

“It is still early, and the numbers are very small, but the detection of early-stage cancers with second annual testing is very encouraging as these are the cases where MCED testing could have the greatest impact in improving outcomes through earlier treatment,” Dr. Gordon told this publication.

During an interview after the talk, Kenneth L. Kehl, MD, MPH, echoed that data must be confirmed in larger cohorts.

“The shift toward earlier stage cancers that are less detectable by standard screening methods is an interesting result, but we need to be cautious since the numbers were relatively small, and we do not have data on cancers that were diagnosed among patients whose second MCED test was also negative,” said Dr. Kehl, a medical oncologist at Dana-Farber Cancer Institute, Boston.
 

MCED Results Could Help Direct Diagnostic Workup

The test’s ability to predict the organ of origin was highly accurate, correctly identifying the cancer type in all eight confirmed cases. Among the eight cases with a confirmed cancer diagnosis, the accuracy of the first prediction was 100%, and diagnoses included invasive cancers across multiple tissues and organs, including anus, colon, head and neck, urothelial tract, ovary, and the lymphatic system.

“The fact that the site of origin for 100% of confirmed cancers was accurately predicted with GRAIL’s CSO by Galleri test confirms the promise that this can guide workup when a cancer signal is detected,” Dr. Gordon noted in the interview.
 

Looking Ahead

Dr. Kehl, who was not involved in the MCED study, noted in an interview that “further data on test characteristics beyond positive predictive value, including the sensitivity, specificity, and negative predictive value, as well as demonstration of clinical benefit — ideally in a randomized trial — will likely be required for MCED testing to become a standard public health recommendation.”

He added that challenges associated with implementing annual screening with MCED tests include the risks of both false positives and false negatives as testing becomes more widely available.

“False positives cause anxiety and lead to additional testing that may carry its own risks, and we need to understand if potentially false negative tests will be associated with less uptake of established screening strategies,” Dr. Kehl said in an interview. However, he noted that serial testing could lead to more frequent diagnoses of early-stage cancers that may be less detectable by standard methods.

Dr. Gordon reported financial relationships with GRAIL LLC and Genetic Technologies Corporation. Dr. Kehl reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

SAN DIEGO — First-line treatment with a combination of cadonilimab, a PD-1/CTLA-4 bispecific immune checkpoint inhibitor, and standard chemotherapy provides a survival advantage over placebo plus chemotherapy in patients with locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma,, according to a new study.

Jiafu Ji, MD, PhD, presented this and other findings of the randomized, double-blind, placebo-controlled phase 3 COMPASSION-15 trial at the annual meeting of the American Association for Cancer Research (AACR).

“The consistent survival benefits across all prespecified PD-L1 expression cutoffs, particularly in patients with low PD-L1 expression, have significant implications for clinical practice by expanding treatment options, improving outcomes for patients with PD-L1–low tumors, influencing guidelines, and stimulating further research in advanced G/GEJ adenocarcinoma treatment,” said Dr. Ji, a principal investigator of this trial, in an interview.

Unmet Need

The incidence of gastric cancer is particularly high in China, but as Dr. Ji discussed in his talk, the treatment options for patients with advanced disease remain limited. Although the Food and Drug Administration (FDA) has approved the combination of PD-L1 inhibitors with chemotherapy for the first-line treatment of advanced gastric cancer, not all patients respond to the treatment, explained Dr. Ji, who is a professor of gastrointestinal surgery and president of Peking University Cancer Hospital and Beijing Institute for Cancer Research in China.

He added that the combination of PD-L1 inhibitors and chemotherapy has not yet been approved for the treatment of advanced gastric cancer in China, leaving chemotherapy as the only treatment option for Chinese patients.

Study Design

To evaluate the efficacy and safety of first-line cadonilimab plus standard chemotherapy in patients with advanced or metastatic gastric cancer, the authors of the COMPASSION-15 trial enrolled 610 patients with unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma who had not received any prior treatments. PD-L1 expression status was not used to exclude patients from the trial.

In a press conference held at AACR 2024, Dr. Ji explained the study rationale, design, and endpoints. He said that patients with tumors without PD-L1 expression typically show little to no benefit from anti–PD-1/PD-L1 inhibitors, and their treatment options are limited to chemotherapy.

“Testing the efficacy of this bispecific antibody in this patient population could provide an alternative treatment approach for them,” he added.

Patients were randomized 1:1 to receive either cadonilimab (10 mg/kg every 3 weeks) plus chemotherapy or placebo plus chemotherapy. The primary endpoint of the study was overall survival (OS) in the intent-to-treat (ITT) population, and secondary efficacy endpoints included OS, progression-free survival (PFS), and objective response rate (ORR) in the ITT population, as well as in patients stratified by PD-L1 expression.

Cadonilimab Plus Standard Chemotherapy Improves OS

Interim analysis, conducted with a median follow-up of 18.69 months, showed a significant improvement in OS for the cadonilimab plus chemotherapy group compared with the chemotherapy-alone group, according to data presented at the press conference. The median OS was 15.0 months in the cadonilimab group versus 10.8 months in the placebo group, representing a 38% reduction in the risk of death (hazard ratio [HR], 0.62; 95% CI, 0.50-0.78, P < .001).

Yelena Y. Janjigian, MD, who not involved in COMPASSION-15, provided critique of the study, during another session at the meeting, in which she discussed the CheckMate 649 trial. She noted that, although the median OS of 15 months in the COMPASSION-15 study was slightly higher than the OS in the CheckMate 649 trial (approximately 14 months), comparing the results of two studies is challenging.

“In the COMPASSION-15 trial, chemotherapy was stopped after [4.5 months], and only 50% of patients received chemotherapy with subsequent treatment — this is not standard and may limit the comparison with other immunotherapy trials,” explained Dr. Janjigian, who is a gastrointestinal oncologist and was a principal investigator in the phase 3 CheckMate 649 immunotherapy trial for advanced gastric cancer.

Importantly, survival benefit with cadonilimab plus chemotherapy was observed across all prespecified PD-L1 expression levels, including in patients with low PD-L1 expression (PD-L1 combined positive score [CPS] less than 5%). In the low PD-L1 expression group (CPS less than 5%), the median OS was 14.8 months in the cadonilimab group compared with 11.8 months in the placebo group (HR, 0.70; 95% CI, 0.51-0.95; P = .011).

“These positive survival outcomes when cadonilimab was combined with chemotherapy may be attributed to synergistic mechanisms of action, enhanced immune responses, modulation of the tumor microenvironment, and careful patient selection based on biomarker assessments,” noted Dr. Ji, during an interview. “Targeting multiple pathways using bispecific antibodies provides potential synergistic effects, enhancing anti-tumor activity and improving treatment outcomes.”

Cadonilimab Plus Standard Chemotherapy Reduces the Risk of Tumor Progression

In addition to prolonging OS, cadonilimab plus chemotherapy also provided superior PFS and ORR compared to placebo plus chemotherapy.

The median PFS was 7.0 months in the cadonilimab plus chemotherapy group, versus 5.3 months in the chemotherapy-only group (HR, 0.53; 95% CI, 0.44-0.65, P < .001), and the ORR was 65.2% versus 48.9%, respectively. Furthermore, the duration of response was longer with cadonilimab plus chemotherapy than with placebo plus chemotherapy (8.8 versus 4.4 months, respectively).

Toxicities Associated With Cadonilimab Plus Standard Chemotherapy Are Manageable

The safety profile of the cadonilimab plus chemotherapy regimen was manageable, with grade 3 or higher treatment-related adverse events occurring in 71.8% of patients in the cadonilimab group and 60.5% of patients in the placebo group. No new safety signals were observed.

During an interview, Dr. Ji said that the most common adverse events were endocrine toxicity, skin toxicity, and lung toxicity. “These adverse events were managed through close monitoring, symptom management, and appropriate interventions based on the severity and nature of the toxicity experienced by patients,” he explained. He added that this toxicity profile of cadonilimab is similar to the toxicity profiles of approved PD-1 and CTLA-4 inhibitors.

Implications — A New Treatment Paradigm for Advanced Gastric Cancer?

According to Dr. Ji, the interim results from the cadonilimab study suggest that this novel PD-1/CTLA-4 bispecific antibody, in combination with chemotherapy, could become a new standard first-line treatment option for patients with advanced G/GEJ adenocarcinoma, offering a significant survival advantage over chemotherapy alone, regardless of PD-L1 status.

“The ability of cadonilimab to improve survival outcomes, regardless of PD-L1 status, is a significant advancement, as we have struggled to find effective treatments for patients with low PD-L1 expression in this setting,” he said, during the interview.

Despite these promising findings, Dr. Janjigian highlighted that patient stratification in the COMPASSION-15 study is currently lacking. She explained that biomarkers such as MSI status, T-reg signatures, and HER-2 are important to consider according to data from the CheckMate 649 trial.

“Hazard ratios for patients with T-reg–high tumors were almost 0.6, independent of inflammatory status. These data suggest that we can maybe even cure some patients with PD-1/CTLA-4 inhibitors,” she noted.

She added that knowing the status of MSI and HER-2 is clinically important as it can inform clinicians whether they can avoid chemotherapy or add trastuzumab.

“Despite the suboptimal comparator arm, the study is very important and offers a rationale for dual PD-1/CTLA-4 blockade,” Dr. Janjigian concluded.

COMPASSION-15 was funded by Akeso Biopharma, Inc. Dr. Ji reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients. Dr. Janjigian lists relationships with AbbVie, AmerisourceBergen Drug Corporation, Arcus Biosciences, Ask-Gene Pharma, Inc., Astellas Pharma, AstraZeneca, Basilea Pharmaceutica Ltd., Bayer, Bristol Myers, Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck, Pfizer, and many other companies, as well as the U.S. Department of Defense, National Cancer Institute, and others.

SAN DIEGO — First-line treatment with a combination of cadonilimab, a PD-1/CTLA-4 bispecific immune checkpoint inhibitor, and standard chemotherapy provides a survival advantage over placebo plus chemotherapy in patients with locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma,, according to a new study.

Jiafu Ji, MD, PhD, presented this and other findings of the randomized, double-blind, placebo-controlled phase 3 COMPASSION-15 trial at the annual meeting of the American Association for Cancer Research (AACR).

“The consistent survival benefits across all prespecified PD-L1 expression cutoffs, particularly in patients with low PD-L1 expression, have significant implications for clinical practice by expanding treatment options, improving outcomes for patients with PD-L1–low tumors, influencing guidelines, and stimulating further research in advanced G/GEJ adenocarcinoma treatment,” said Dr. Ji, a principal investigator of this trial, in an interview.

Unmet Need

The incidence of gastric cancer is particularly high in China, but as Dr. Ji discussed in his talk, the treatment options for patients with advanced disease remain limited. Although the Food and Drug Administration (FDA) has approved the combination of PD-L1 inhibitors with chemotherapy for the first-line treatment of advanced gastric cancer, not all patients respond to the treatment, explained Dr. Ji, who is a professor of gastrointestinal surgery and president of Peking University Cancer Hospital and Beijing Institute for Cancer Research in China.

He added that the combination of PD-L1 inhibitors and chemotherapy has not yet been approved for the treatment of advanced gastric cancer in China, leaving chemotherapy as the only treatment option for Chinese patients.

Study Design

To evaluate the efficacy and safety of first-line cadonilimab plus standard chemotherapy in patients with advanced or metastatic gastric cancer, the authors of the COMPASSION-15 trial enrolled 610 patients with unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma who had not received any prior treatments. PD-L1 expression status was not used to exclude patients from the trial.

In a press conference held at AACR 2024, Dr. Ji explained the study rationale, design, and endpoints. He said that patients with tumors without PD-L1 expression typically show little to no benefit from anti–PD-1/PD-L1 inhibitors, and their treatment options are limited to chemotherapy.

“Testing the efficacy of this bispecific antibody in this patient population could provide an alternative treatment approach for them,” he added.

Patients were randomized 1:1 to receive either cadonilimab (10 mg/kg every 3 weeks) plus chemotherapy or placebo plus chemotherapy. The primary endpoint of the study was overall survival (OS) in the intent-to-treat (ITT) population, and secondary efficacy endpoints included OS, progression-free survival (PFS), and objective response rate (ORR) in the ITT population, as well as in patients stratified by PD-L1 expression.

Cadonilimab Plus Standard Chemotherapy Improves OS

Interim analysis, conducted with a median follow-up of 18.69 months, showed a significant improvement in OS for the cadonilimab plus chemotherapy group compared with the chemotherapy-alone group, according to data presented at the press conference. The median OS was 15.0 months in the cadonilimab group versus 10.8 months in the placebo group, representing a 38% reduction in the risk of death (hazard ratio [HR], 0.62; 95% CI, 0.50-0.78, P < .001).

Yelena Y. Janjigian, MD, who not involved in COMPASSION-15, provided critique of the study, during another session at the meeting, in which she discussed the CheckMate 649 trial. She noted that, although the median OS of 15 months in the COMPASSION-15 study was slightly higher than the OS in the CheckMate 649 trial (approximately 14 months), comparing the results of two studies is challenging.

“In the COMPASSION-15 trial, chemotherapy was stopped after [4.5 months], and only 50% of patients received chemotherapy with subsequent treatment — this is not standard and may limit the comparison with other immunotherapy trials,” explained Dr. Janjigian, who is a gastrointestinal oncologist and was a principal investigator in the phase 3 CheckMate 649 immunotherapy trial for advanced gastric cancer.

Importantly, survival benefit with cadonilimab plus chemotherapy was observed across all prespecified PD-L1 expression levels, including in patients with low PD-L1 expression (PD-L1 combined positive score [CPS] less than 5%). In the low PD-L1 expression group (CPS less than 5%), the median OS was 14.8 months in the cadonilimab group compared with 11.8 months in the placebo group (HR, 0.70; 95% CI, 0.51-0.95; P = .011).

“These positive survival outcomes when cadonilimab was combined with chemotherapy may be attributed to synergistic mechanisms of action, enhanced immune responses, modulation of the tumor microenvironment, and careful patient selection based on biomarker assessments,” noted Dr. Ji, during an interview. “Targeting multiple pathways using bispecific antibodies provides potential synergistic effects, enhancing anti-tumor activity and improving treatment outcomes.”

Cadonilimab Plus Standard Chemotherapy Reduces the Risk of Tumor Progression

In addition to prolonging OS, cadonilimab plus chemotherapy also provided superior PFS and ORR compared to placebo plus chemotherapy.

The median PFS was 7.0 months in the cadonilimab plus chemotherapy group, versus 5.3 months in the chemotherapy-only group (HR, 0.53; 95% CI, 0.44-0.65, P < .001), and the ORR was 65.2% versus 48.9%, respectively. Furthermore, the duration of response was longer with cadonilimab plus chemotherapy than with placebo plus chemotherapy (8.8 versus 4.4 months, respectively).

Toxicities Associated With Cadonilimab Plus Standard Chemotherapy Are Manageable

The safety profile of the cadonilimab plus chemotherapy regimen was manageable, with grade 3 or higher treatment-related adverse events occurring in 71.8% of patients in the cadonilimab group and 60.5% of patients in the placebo group. No new safety signals were observed.

During an interview, Dr. Ji said that the most common adverse events were endocrine toxicity, skin toxicity, and lung toxicity. “These adverse events were managed through close monitoring, symptom management, and appropriate interventions based on the severity and nature of the toxicity experienced by patients,” he explained. He added that this toxicity profile of cadonilimab is similar to the toxicity profiles of approved PD-1 and CTLA-4 inhibitors.

Implications — A New Treatment Paradigm for Advanced Gastric Cancer?

According to Dr. Ji, the interim results from the cadonilimab study suggest that this novel PD-1/CTLA-4 bispecific antibody, in combination with chemotherapy, could become a new standard first-line treatment option for patients with advanced G/GEJ adenocarcinoma, offering a significant survival advantage over chemotherapy alone, regardless of PD-L1 status.

“The ability of cadonilimab to improve survival outcomes, regardless of PD-L1 status, is a significant advancement, as we have struggled to find effective treatments for patients with low PD-L1 expression in this setting,” he said, during the interview.

Despite these promising findings, Dr. Janjigian highlighted that patient stratification in the COMPASSION-15 study is currently lacking. She explained that biomarkers such as MSI status, T-reg signatures, and HER-2 are important to consider according to data from the CheckMate 649 trial.

“Hazard ratios for patients with T-reg–high tumors were almost 0.6, independent of inflammatory status. These data suggest that we can maybe even cure some patients with PD-1/CTLA-4 inhibitors,” she noted.

She added that knowing the status of MSI and HER-2 is clinically important as it can inform clinicians whether they can avoid chemotherapy or add trastuzumab.

“Despite the suboptimal comparator arm, the study is very important and offers a rationale for dual PD-1/CTLA-4 blockade,” Dr. Janjigian concluded.

COMPASSION-15 was funded by Akeso Biopharma, Inc. Dr. Ji reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients. Dr. Janjigian lists relationships with AbbVie, AmerisourceBergen Drug Corporation, Arcus Biosciences, Ask-Gene Pharma, Inc., Astellas Pharma, AstraZeneca, Basilea Pharmaceutica Ltd., Bayer, Bristol Myers, Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck, Pfizer, and many other companies, as well as the U.S. Department of Defense, National Cancer Institute, and others.

SAN DIEGO — First-line treatment with a combination of cadonilimab, a PD-1/CTLA-4 bispecific immune checkpoint inhibitor, and standard chemotherapy provides a survival advantage over placebo plus chemotherapy in patients with locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma,, according to a new study.

Jiafu Ji, MD, PhD, presented this and other findings of the randomized, double-blind, placebo-controlled phase 3 COMPASSION-15 trial at the annual meeting of the American Association for Cancer Research (AACR).

“The consistent survival benefits across all prespecified PD-L1 expression cutoffs, particularly in patients with low PD-L1 expression, have significant implications for clinical practice by expanding treatment options, improving outcomes for patients with PD-L1–low tumors, influencing guidelines, and stimulating further research in advanced G/GEJ adenocarcinoma treatment,” said Dr. Ji, a principal investigator of this trial, in an interview.

Unmet Need

The incidence of gastric cancer is particularly high in China, but as Dr. Ji discussed in his talk, the treatment options for patients with advanced disease remain limited. Although the Food and Drug Administration (FDA) has approved the combination of PD-L1 inhibitors with chemotherapy for the first-line treatment of advanced gastric cancer, not all patients respond to the treatment, explained Dr. Ji, who is a professor of gastrointestinal surgery and president of Peking University Cancer Hospital and Beijing Institute for Cancer Research in China.

He added that the combination of PD-L1 inhibitors and chemotherapy has not yet been approved for the treatment of advanced gastric cancer in China, leaving chemotherapy as the only treatment option for Chinese patients.

Study Design

To evaluate the efficacy and safety of first-line cadonilimab plus standard chemotherapy in patients with advanced or metastatic gastric cancer, the authors of the COMPASSION-15 trial enrolled 610 patients with unresectable, locally advanced, or metastatic G/GEJ adenocarcinoma who had not received any prior treatments. PD-L1 expression status was not used to exclude patients from the trial.

In a press conference held at AACR 2024, Dr. Ji explained the study rationale, design, and endpoints. He said that patients with tumors without PD-L1 expression typically show little to no benefit from anti–PD-1/PD-L1 inhibitors, and their treatment options are limited to chemotherapy.

“Testing the efficacy of this bispecific antibody in this patient population could provide an alternative treatment approach for them,” he added.

Patients were randomized 1:1 to receive either cadonilimab (10 mg/kg every 3 weeks) plus chemotherapy or placebo plus chemotherapy. The primary endpoint of the study was overall survival (OS) in the intent-to-treat (ITT) population, and secondary efficacy endpoints included OS, progression-free survival (PFS), and objective response rate (ORR) in the ITT population, as well as in patients stratified by PD-L1 expression.

Cadonilimab Plus Standard Chemotherapy Improves OS

Interim analysis, conducted with a median follow-up of 18.69 months, showed a significant improvement in OS for the cadonilimab plus chemotherapy group compared with the chemotherapy-alone group, according to data presented at the press conference. The median OS was 15.0 months in the cadonilimab group versus 10.8 months in the placebo group, representing a 38% reduction in the risk of death (hazard ratio [HR], 0.62; 95% CI, 0.50-0.78, P < .001).

Yelena Y. Janjigian, MD, who not involved in COMPASSION-15, provided critique of the study, during another session at the meeting, in which she discussed the CheckMate 649 trial. She noted that, although the median OS of 15 months in the COMPASSION-15 study was slightly higher than the OS in the CheckMate 649 trial (approximately 14 months), comparing the results of two studies is challenging.

“In the COMPASSION-15 trial, chemotherapy was stopped after [4.5 months], and only 50% of patients received chemotherapy with subsequent treatment — this is not standard and may limit the comparison with other immunotherapy trials,” explained Dr. Janjigian, who is a gastrointestinal oncologist and was a principal investigator in the phase 3 CheckMate 649 immunotherapy trial for advanced gastric cancer.

Importantly, survival benefit with cadonilimab plus chemotherapy was observed across all prespecified PD-L1 expression levels, including in patients with low PD-L1 expression (PD-L1 combined positive score [CPS] less than 5%). In the low PD-L1 expression group (CPS less than 5%), the median OS was 14.8 months in the cadonilimab group compared with 11.8 months in the placebo group (HR, 0.70; 95% CI, 0.51-0.95; P = .011).

“These positive survival outcomes when cadonilimab was combined with chemotherapy may be attributed to synergistic mechanisms of action, enhanced immune responses, modulation of the tumor microenvironment, and careful patient selection based on biomarker assessments,” noted Dr. Ji, during an interview. “Targeting multiple pathways using bispecific antibodies provides potential synergistic effects, enhancing anti-tumor activity and improving treatment outcomes.”

Cadonilimab Plus Standard Chemotherapy Reduces the Risk of Tumor Progression

In addition to prolonging OS, cadonilimab plus chemotherapy also provided superior PFS and ORR compared to placebo plus chemotherapy.

The median PFS was 7.0 months in the cadonilimab plus chemotherapy group, versus 5.3 months in the chemotherapy-only group (HR, 0.53; 95% CI, 0.44-0.65, P < .001), and the ORR was 65.2% versus 48.9%, respectively. Furthermore, the duration of response was longer with cadonilimab plus chemotherapy than with placebo plus chemotherapy (8.8 versus 4.4 months, respectively).

Toxicities Associated With Cadonilimab Plus Standard Chemotherapy Are Manageable

The safety profile of the cadonilimab plus chemotherapy regimen was manageable, with grade 3 or higher treatment-related adverse events occurring in 71.8% of patients in the cadonilimab group and 60.5% of patients in the placebo group. No new safety signals were observed.

During an interview, Dr. Ji said that the most common adverse events were endocrine toxicity, skin toxicity, and lung toxicity. “These adverse events were managed through close monitoring, symptom management, and appropriate interventions based on the severity and nature of the toxicity experienced by patients,” he explained. He added that this toxicity profile of cadonilimab is similar to the toxicity profiles of approved PD-1 and CTLA-4 inhibitors.

Implications — A New Treatment Paradigm for Advanced Gastric Cancer?

According to Dr. Ji, the interim results from the cadonilimab study suggest that this novel PD-1/CTLA-4 bispecific antibody, in combination with chemotherapy, could become a new standard first-line treatment option for patients with advanced G/GEJ adenocarcinoma, offering a significant survival advantage over chemotherapy alone, regardless of PD-L1 status.

“The ability of cadonilimab to improve survival outcomes, regardless of PD-L1 status, is a significant advancement, as we have struggled to find effective treatments for patients with low PD-L1 expression in this setting,” he said, during the interview.

Despite these promising findings, Dr. Janjigian highlighted that patient stratification in the COMPASSION-15 study is currently lacking. She explained that biomarkers such as MSI status, T-reg signatures, and HER-2 are important to consider according to data from the CheckMate 649 trial.

“Hazard ratios for patients with T-reg–high tumors were almost 0.6, independent of inflammatory status. These data suggest that we can maybe even cure some patients with PD-1/CTLA-4 inhibitors,” she noted.

She added that knowing the status of MSI and HER-2 is clinically important as it can inform clinicians whether they can avoid chemotherapy or add trastuzumab.

“Despite the suboptimal comparator arm, the study is very important and offers a rationale for dual PD-1/CTLA-4 blockade,” Dr. Janjigian concluded.

COMPASSION-15 was funded by Akeso Biopharma, Inc. Dr. Ji reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients. Dr. Janjigian lists relationships with AbbVie, AmerisourceBergen Drug Corporation, Arcus Biosciences, Ask-Gene Pharma, Inc., Astellas Pharma, AstraZeneca, Basilea Pharmaceutica Ltd., Bayer, Bristol Myers, Squibb, Eli Lilly and Company, GlaxoSmithKline, Merck, Pfizer, and many other companies, as well as the U.S. Department of Defense, National Cancer Institute, and others.

SAN DIEGO – Gout is one of the most poorly managed diseases and is mostly treated by primary care providers, said a presenter at the annual meeting of the American College of Physicians. Failure to understand the disease process and goals of urate-lowering therapy (ULT) is a key barrier to achieving optimal gout therapy.

“There’s too much focus on the flare and too little focus on the urate burden of the disease. Regardless of the clinical setting, the goal should be to manage [high] serum uric acid levels,” said Lawrence Edwards, MD, professor at the University of Florida, Gainesville, during his talk.

Dr. Edwards, who specializes in treating patients with gout and rheumatoid arthritis, discussed the role of primary care providers in the treatment of gout. “We can and must do better,” he said.
 

Understanding the pathology of gout is key to effective treatment

Knowledge of the molecular pathology of gout has advanced drastically over the last few years. “The improved understanding of the molecules involved in disease initiation and progression can help us make better treatment decisions depending on the stage of the disease,” Dr. Edwards said.

Gout is caused by the deposition of monosodium urate (MSU) crystals, which starts as asymptomatic hyperuricemia, he said. Inflammatory responses to MSU crystals are responsible for gout flares, the frequency of which increases as the disease progresses.

Innate immune responses driven by macrophages and neutrophils play a crucial role in acute gout attacks. In the molecular pathway, proinflammatory cytokines IL-1 beta and IL-6 are the mediators of gout flares, whereas IL-8 accumulates over time and contributes to disease progression and systemic illness. If left untreated or undertreated, the repeated inflammatory reaction leads to advanced gout. The urate burden also increases with disease progression.

“Physicians need to better educate themselves on the destructive nature of this inflammatory arthritis and the need for effective urate-lowering therapy in the management of gout,” Dr. Edwards said.
 

Management of acute gout attacks

The management of gout flares involves the use of pharmacological agents to control pain and inflammation. The three most common anti-inflammatory therapies are colchicine, NSAIDs, and corticosteroids (either oral or intramuscular).

The choice of which of these should be used alone or in combination for a flare is based on previous tolerance of the medication or the presence of diabetes, kidney disease, heart disease, or a history of upper gastrointestinal bleeding. Dr. Edwards referred internists to the 2020 American College of Rheumatology gout management guideline.

“Regardless of which therapy is chosen, the more important consideration is how quickly the patients can start treatment after the flare begins,” said Dr. Edwards when asked about priorities in the management of gout flares. “This means that the patient should have ready access to whichever the chosen approach is. We call this the ‘pill-in-the-pocket’ approach,” he added.

Reducing the urate burden is also important for effective treatment. The serum urate level is the primary marker of how well a patient’s gout is being managed. ULT should be initiated in patients with subcutaneous tophi, gout-related radiographic damage, or frequent flares (≥ 2 per year). Allopurinol is typically the first-line ULT of choice.

Dr. Edwards noted that far too much focus is placed on flare treatment rather than addressing the underlying sources of gouty symptoms – the elevated serum levels of urate.
 

Management of advanced gout

“The management of advanced gout is challenging, and the dissolution of MSU is slow unless you take an aggressive approach,” Dr. Edwards said.

Switching to pegloticase is recommended for patients with frequent flares, nonresolving tophi, or high serum urate levels that persist despite treatment with xanthine oxidase inhibitors or other ULT agents.

“The frequency and severity of gout flares are what patients focus on, but if that’s the only focus of the treating physicians, then they are leaving the job less than halfway done. Getting the serum urate to below a level of 6.0 mg/dL is the most important aspect in the lifelong management of gout,” said Dr. Edwards.
 

Barriers to effective gout treatment

When asked during an interview after the session about the most important barriers to successful gout management, Allison M. Mays, MD, a geriatric medicine subspecialist at Cedars-Sinai Medical Center, Los Angeles, said that “the fact that gout mostly impacts quality of life and not necessarily mortality means that other things may take precedent.” She explained that gout typically coexists with other comorbidities, often multiple ones. Patients may also defer taking an additional medication for a disease like gout, which has only episodic discomfort.

She added that gout management involves shared decision-making between patients and the medical team – including the primary care physician, rheumatologist, orthopedist, and emergency physician. Following a visit to the urgent care or the ED for an acute flare of gout, the patient may not follow up with their primary care doctor or bring it up at their next visit for chronic management, she noted.

Dr. Edwards serves as a consultant to Horizon Pharmaceuticals, Atom Biosciences, Shanton Biosciences, and Aclaris Therapeutics. Horizon marketed pegloticase up until last month when Amgen bought the drug. Dr. Edwards is also president of Gout Education Society, and he has no financial agreement with any of the multiple companies that produce colchicine and allopurinol. Dr. Mays reported no conflicts.

SAN DIEGO – Gout is one of the most poorly managed diseases and is mostly treated by primary care providers, said a presenter at the annual meeting of the American College of Physicians. Failure to understand the disease process and goals of urate-lowering therapy (ULT) is a key barrier to achieving optimal gout therapy.

“There’s too much focus on the flare and too little focus on the urate burden of the disease. Regardless of the clinical setting, the goal should be to manage [high] serum uric acid levels,” said Lawrence Edwards, MD, professor at the University of Florida, Gainesville, during his talk.

Dr. Edwards, who specializes in treating patients with gout and rheumatoid arthritis, discussed the role of primary care providers in the treatment of gout. “We can and must do better,” he said.
 

Understanding the pathology of gout is key to effective treatment

Knowledge of the molecular pathology of gout has advanced drastically over the last few years. “The improved understanding of the molecules involved in disease initiation and progression can help us make better treatment decisions depending on the stage of the disease,” Dr. Edwards said.

Gout is caused by the deposition of monosodium urate (MSU) crystals, which starts as asymptomatic hyperuricemia, he said. Inflammatory responses to MSU crystals are responsible for gout flares, the frequency of which increases as the disease progresses.

Innate immune responses driven by macrophages and neutrophils play a crucial role in acute gout attacks. In the molecular pathway, proinflammatory cytokines IL-1 beta and IL-6 are the mediators of gout flares, whereas IL-8 accumulates over time and contributes to disease progression and systemic illness. If left untreated or undertreated, the repeated inflammatory reaction leads to advanced gout. The urate burden also increases with disease progression.

“Physicians need to better educate themselves on the destructive nature of this inflammatory arthritis and the need for effective urate-lowering therapy in the management of gout,” Dr. Edwards said.
 

Management of acute gout attacks

The management of gout flares involves the use of pharmacological agents to control pain and inflammation. The three most common anti-inflammatory therapies are colchicine, NSAIDs, and corticosteroids (either oral or intramuscular).

The choice of which of these should be used alone or in combination for a flare is based on previous tolerance of the medication or the presence of diabetes, kidney disease, heart disease, or a history of upper gastrointestinal bleeding. Dr. Edwards referred internists to the 2020 American College of Rheumatology gout management guideline.

“Regardless of which therapy is chosen, the more important consideration is how quickly the patients can start treatment after the flare begins,” said Dr. Edwards when asked about priorities in the management of gout flares. “This means that the patient should have ready access to whichever the chosen approach is. We call this the ‘pill-in-the-pocket’ approach,” he added.

Reducing the urate burden is also important for effective treatment. The serum urate level is the primary marker of how well a patient’s gout is being managed. ULT should be initiated in patients with subcutaneous tophi, gout-related radiographic damage, or frequent flares (≥ 2 per year). Allopurinol is typically the first-line ULT of choice.

Dr. Edwards noted that far too much focus is placed on flare treatment rather than addressing the underlying sources of gouty symptoms – the elevated serum levels of urate.
 

Management of advanced gout

“The management of advanced gout is challenging, and the dissolution of MSU is slow unless you take an aggressive approach,” Dr. Edwards said.

Switching to pegloticase is recommended for patients with frequent flares, nonresolving tophi, or high serum urate levels that persist despite treatment with xanthine oxidase inhibitors or other ULT agents.

“The frequency and severity of gout flares are what patients focus on, but if that’s the only focus of the treating physicians, then they are leaving the job less than halfway done. Getting the serum urate to below a level of 6.0 mg/dL is the most important aspect in the lifelong management of gout,” said Dr. Edwards.
 

Barriers to effective gout treatment

When asked during an interview after the session about the most important barriers to successful gout management, Allison M. Mays, MD, a geriatric medicine subspecialist at Cedars-Sinai Medical Center, Los Angeles, said that “the fact that gout mostly impacts quality of life and not necessarily mortality means that other things may take precedent.” She explained that gout typically coexists with other comorbidities, often multiple ones. Patients may also defer taking an additional medication for a disease like gout, which has only episodic discomfort.

She added that gout management involves shared decision-making between patients and the medical team – including the primary care physician, rheumatologist, orthopedist, and emergency physician. Following a visit to the urgent care or the ED for an acute flare of gout, the patient may not follow up with their primary care doctor or bring it up at their next visit for chronic management, she noted.

Dr. Edwards serves as a consultant to Horizon Pharmaceuticals, Atom Biosciences, Shanton Biosciences, and Aclaris Therapeutics. Horizon marketed pegloticase up until last month when Amgen bought the drug. Dr. Edwards is also president of Gout Education Society, and he has no financial agreement with any of the multiple companies that produce colchicine and allopurinol. Dr. Mays reported no conflicts.

SAN DIEGO – Gout is one of the most poorly managed diseases and is mostly treated by primary care providers, said a presenter at the annual meeting of the American College of Physicians. Failure to understand the disease process and goals of urate-lowering therapy (ULT) is a key barrier to achieving optimal gout therapy.

“There’s too much focus on the flare and too little focus on the urate burden of the disease. Regardless of the clinical setting, the goal should be to manage [high] serum uric acid levels,” said Lawrence Edwards, MD, professor at the University of Florida, Gainesville, during his talk.

Dr. Edwards, who specializes in treating patients with gout and rheumatoid arthritis, discussed the role of primary care providers in the treatment of gout. “We can and must do better,” he said.
 

Understanding the pathology of gout is key to effective treatment

Knowledge of the molecular pathology of gout has advanced drastically over the last few years. “The improved understanding of the molecules involved in disease initiation and progression can help us make better treatment decisions depending on the stage of the disease,” Dr. Edwards said.

Gout is caused by the deposition of monosodium urate (MSU) crystals, which starts as asymptomatic hyperuricemia, he said. Inflammatory responses to MSU crystals are responsible for gout flares, the frequency of which increases as the disease progresses.

Innate immune responses driven by macrophages and neutrophils play a crucial role in acute gout attacks. In the molecular pathway, proinflammatory cytokines IL-1 beta and IL-6 are the mediators of gout flares, whereas IL-8 accumulates over time and contributes to disease progression and systemic illness. If left untreated or undertreated, the repeated inflammatory reaction leads to advanced gout. The urate burden also increases with disease progression.

“Physicians need to better educate themselves on the destructive nature of this inflammatory arthritis and the need for effective urate-lowering therapy in the management of gout,” Dr. Edwards said.
 

Management of acute gout attacks

The management of gout flares involves the use of pharmacological agents to control pain and inflammation. The three most common anti-inflammatory therapies are colchicine, NSAIDs, and corticosteroids (either oral or intramuscular).

The choice of which of these should be used alone or in combination for a flare is based on previous tolerance of the medication or the presence of diabetes, kidney disease, heart disease, or a history of upper gastrointestinal bleeding. Dr. Edwards referred internists to the 2020 American College of Rheumatology gout management guideline.

“Regardless of which therapy is chosen, the more important consideration is how quickly the patients can start treatment after the flare begins,” said Dr. Edwards when asked about priorities in the management of gout flares. “This means that the patient should have ready access to whichever the chosen approach is. We call this the ‘pill-in-the-pocket’ approach,” he added.

Reducing the urate burden is also important for effective treatment. The serum urate level is the primary marker of how well a patient’s gout is being managed. ULT should be initiated in patients with subcutaneous tophi, gout-related radiographic damage, or frequent flares (≥ 2 per year). Allopurinol is typically the first-line ULT of choice.

Dr. Edwards noted that far too much focus is placed on flare treatment rather than addressing the underlying sources of gouty symptoms – the elevated serum levels of urate.
 

Management of advanced gout

“The management of advanced gout is challenging, and the dissolution of MSU is slow unless you take an aggressive approach,” Dr. Edwards said.

Switching to pegloticase is recommended for patients with frequent flares, nonresolving tophi, or high serum urate levels that persist despite treatment with xanthine oxidase inhibitors or other ULT agents.

“The frequency and severity of gout flares are what patients focus on, but if that’s the only focus of the treating physicians, then they are leaving the job less than halfway done. Getting the serum urate to below a level of 6.0 mg/dL is the most important aspect in the lifelong management of gout,” said Dr. Edwards.
 

Barriers to effective gout treatment

When asked during an interview after the session about the most important barriers to successful gout management, Allison M. Mays, MD, a geriatric medicine subspecialist at Cedars-Sinai Medical Center, Los Angeles, said that “the fact that gout mostly impacts quality of life and not necessarily mortality means that other things may take precedent.” She explained that gout typically coexists with other comorbidities, often multiple ones. Patients may also defer taking an additional medication for a disease like gout, which has only episodic discomfort.

She added that gout management involves shared decision-making between patients and the medical team – including the primary care physician, rheumatologist, orthopedist, and emergency physician. Following a visit to the urgent care or the ED for an acute flare of gout, the patient may not follow up with their primary care doctor or bring it up at their next visit for chronic management, she noted.

Dr. Edwards serves as a consultant to Horizon Pharmaceuticals, Atom Biosciences, Shanton Biosciences, and Aclaris Therapeutics. Horizon marketed pegloticase up until last month when Amgen bought the drug. Dr. Edwards is also president of Gout Education Society, and he has no financial agreement with any of the multiple companies that produce colchicine and allopurinol. Dr. Mays reported no conflicts.

SAN DIEGO – Primary care providers can draw from a wide range of diets to give patients evidence-based advice on how to lose weight, prevent diabetes, and achieve other health goals, according to a speaker at the annual meeting of the American College of Physicians.

“Evidence from studies can help clinicians and their patients develop a successful dietary management plan and achieve optimal health,” said internist Michelle Hauser, MD, clinical associate professor at Stanford (Calif.) University. She also discussed evidence-based techniques to support patients in maintaining dietary modifications.
 

Predominantly plant‐based diets

Popular predominantly plant‐based diets include a Mediterranean diet, healthy vegetarian diet, predominantly whole-food plant‐based (WFPB) diet, and a dietary approach to stop hypertension (DASH).

The DASH diet was originally designed to help patients manage their blood pressure, but evidence suggests that it also can help adults with obesity lose weight. In contrast to the DASH diet, the Mediterranean diet is not low-fat and not very restrictive. Yet the evidence suggests that the Mediterranean diet is not only helpful for losing weight but also can reduce the risk of various chronic diseases, including obesity, type 2 diabetes, cardiovascular disease (CVD), and cancer, Dr. Hauser said. In addition, data suggest that the Mediterranean diet may reduce the risk of all-cause mortality and lower the levels of cholesterol.

“I like to highlight all these protective effects to my patients, because even if their goal is to lose weight, knowing that hard work pays off in additional ways can keep them motivated,” Dr. Hauser stated.

A healthy vegetarian diet and a WFPB diet are similar, and both are helpful in weight loss and management of total cholesterol and LDL‐C levels. Furthermore, healthy vegetarian and WFPB diets may reduce the risk of type 2 diabetes, CVD, and some cancers. Cohort study data suggest that progressively more vegetarian diets are associated with lower BMIs.

“My interpretation of these data is that predominantly plant-based diets rich in whole foods are healthful and can be done in a way that is sustainable for most,” said Dr. Hauser. However, this generally requires a lot of support at the outset to address gaps in knowledge, skills, and other potential barriers.

For example, she referred one obese patient at risk of diabetes and cardiovascular disease to a registered dietitian to develop a dietary plan. The patient also attended a behavioral medicine weight management program to learn strategies such as using smaller plates, and his family attended a healthy cooking class together to improve meal planning and cooking skills.
 

Time‐restricted feeding

There are numerous variations of time-restricted feeding, commonly referred to as intermittent fasting, but the principles are similar – limiting food intake to a specific window of time each day or week.

Although some studies have shown that time-restricted feeding may help patients reduce adiposity and improve lipid markers, most studies comparing time-restricted feeding to a calorie-restricted diet have shown little to no difference in weight-related outcomes, Dr. Hauser said.

These data suggest that time-restricted feeding may help patients with weight loss only if time restriction helps them reduce calorie intake. She also warned that time-restrictive feeding might cause late-night cravings and might not be helpful in individuals prone to food cravings.
 

Low‐carbohydrate and ketogenic diets

Losing muscle mass can prevent some people from dieting, but evidence suggests that a high-fat, very low-carbohydrate diet – also called a ketogenic diet – may help patients reduce weight and fat mass while preserving fat‐free mass, Dr. Hauser said.

The evidence regarding the usefulness of a low-carbohydrate (non-keto) diet is less clear because most studies compared it to a low-fat diet, and these two diets might lead to a similar extent of weight loss.
 

Rating the level of scientific evidence behind different diet options

Nutrition studies do no provide the same level of evidence as drug studies, said Dr. Hauser, because it is easier to conduct a randomized controlled trial of a drug versus placebo. Diets have many more variables, and it also takes much longer to observe most outcomes of a dietary change.

In addition, clinical trials of dietary interventions are typically short and focus on disease markers such as serum lipids and hemoglobin A1c levels. To obtain reliable information on the usefulness of a diet, researchers need to collect detailed health and lifestyle information from hundreds of thousands of people over several decades, which is not always feasible. “This is why meta-analyses of pooled dietary study data are more likely to yield dependable findings,” she noted.
 

Getting to know patients is essential to help them maintain diet modifications

When developing a diet plan for a patient, it is important to consider the sustainability of a dietary pattern. “The benefits of any healthy dietary change will only last as long as they can be maintained,” said Dr. Hauser. “Counseling someone on choosing an appropriate long-term dietary pattern requires getting to know them – taste preferences, food traditions, barriers, facilitators, food access, and time and cost restrictions.”

In an interview after the session, David Bittleman, MD, an internist at Veterans Affairs San Diego Health Care System, agreed that getting to know patients is essential for successfully advising them on diet.

“I always start developing a diet plan by trying to find out what [a patient’s] diet is like and what their goals are. I need to know what they are already doing in order to make suggestions about what they can do to make their diet healthier,” he said.

When asked about her approach to supporting patients in the long term, Dr. Hauser said that she recommends sequential, gradual changes. Dr. Hauser added that she suggests her patients prioritize implementing dietary changes that they are confident they can maintain.

Dr. Hauser and Dr. Bittleman report no relevant financial relationships.

SAN DIEGO – Primary care providers can draw from a wide range of diets to give patients evidence-based advice on how to lose weight, prevent diabetes, and achieve other health goals, according to a speaker at the annual meeting of the American College of Physicians.

“Evidence from studies can help clinicians and their patients develop a successful dietary management plan and achieve optimal health,” said internist Michelle Hauser, MD, clinical associate professor at Stanford (Calif.) University. She also discussed evidence-based techniques to support patients in maintaining dietary modifications.
 

Predominantly plant‐based diets

Popular predominantly plant‐based diets include a Mediterranean diet, healthy vegetarian diet, predominantly whole-food plant‐based (WFPB) diet, and a dietary approach to stop hypertension (DASH).

The DASH diet was originally designed to help patients manage their blood pressure, but evidence suggests that it also can help adults with obesity lose weight. In contrast to the DASH diet, the Mediterranean diet is not low-fat and not very restrictive. Yet the evidence suggests that the Mediterranean diet is not only helpful for losing weight but also can reduce the risk of various chronic diseases, including obesity, type 2 diabetes, cardiovascular disease (CVD), and cancer, Dr. Hauser said. In addition, data suggest that the Mediterranean diet may reduce the risk of all-cause mortality and lower the levels of cholesterol.

“I like to highlight all these protective effects to my patients, because even if their goal is to lose weight, knowing that hard work pays off in additional ways can keep them motivated,” Dr. Hauser stated.

A healthy vegetarian diet and a WFPB diet are similar, and both are helpful in weight loss and management of total cholesterol and LDL‐C levels. Furthermore, healthy vegetarian and WFPB diets may reduce the risk of type 2 diabetes, CVD, and some cancers. Cohort study data suggest that progressively more vegetarian diets are associated with lower BMIs.

“My interpretation of these data is that predominantly plant-based diets rich in whole foods are healthful and can be done in a way that is sustainable for most,” said Dr. Hauser. However, this generally requires a lot of support at the outset to address gaps in knowledge, skills, and other potential barriers.

For example, she referred one obese patient at risk of diabetes and cardiovascular disease to a registered dietitian to develop a dietary plan. The patient also attended a behavioral medicine weight management program to learn strategies such as using smaller plates, and his family attended a healthy cooking class together to improve meal planning and cooking skills.
 

Time‐restricted feeding

There are numerous variations of time-restricted feeding, commonly referred to as intermittent fasting, but the principles are similar – limiting food intake to a specific window of time each day or week.

Although some studies have shown that time-restricted feeding may help patients reduce adiposity and improve lipid markers, most studies comparing time-restricted feeding to a calorie-restricted diet have shown little to no difference in weight-related outcomes, Dr. Hauser said.

These data suggest that time-restricted feeding may help patients with weight loss only if time restriction helps them reduce calorie intake. She also warned that time-restrictive feeding might cause late-night cravings and might not be helpful in individuals prone to food cravings.
 

Low‐carbohydrate and ketogenic diets

Losing muscle mass can prevent some people from dieting, but evidence suggests that a high-fat, very low-carbohydrate diet – also called a ketogenic diet – may help patients reduce weight and fat mass while preserving fat‐free mass, Dr. Hauser said.

The evidence regarding the usefulness of a low-carbohydrate (non-keto) diet is less clear because most studies compared it to a low-fat diet, and these two diets might lead to a similar extent of weight loss.
 

Rating the level of scientific evidence behind different diet options

Nutrition studies do no provide the same level of evidence as drug studies, said Dr. Hauser, because it is easier to conduct a randomized controlled trial of a drug versus placebo. Diets have many more variables, and it also takes much longer to observe most outcomes of a dietary change.

In addition, clinical trials of dietary interventions are typically short and focus on disease markers such as serum lipids and hemoglobin A1c levels. To obtain reliable information on the usefulness of a diet, researchers need to collect detailed health and lifestyle information from hundreds of thousands of people over several decades, which is not always feasible. “This is why meta-analyses of pooled dietary study data are more likely to yield dependable findings,” she noted.
 

Getting to know patients is essential to help them maintain diet modifications

When developing a diet plan for a patient, it is important to consider the sustainability of a dietary pattern. “The benefits of any healthy dietary change will only last as long as they can be maintained,” said Dr. Hauser. “Counseling someone on choosing an appropriate long-term dietary pattern requires getting to know them – taste preferences, food traditions, barriers, facilitators, food access, and time and cost restrictions.”

In an interview after the session, David Bittleman, MD, an internist at Veterans Affairs San Diego Health Care System, agreed that getting to know patients is essential for successfully advising them on diet.

“I always start developing a diet plan by trying to find out what [a patient’s] diet is like and what their goals are. I need to know what they are already doing in order to make suggestions about what they can do to make their diet healthier,” he said.

When asked about her approach to supporting patients in the long term, Dr. Hauser said that she recommends sequential, gradual changes. Dr. Hauser added that she suggests her patients prioritize implementing dietary changes that they are confident they can maintain.

Dr. Hauser and Dr. Bittleman report no relevant financial relationships.

SAN DIEGO – Primary care providers can draw from a wide range of diets to give patients evidence-based advice on how to lose weight, prevent diabetes, and achieve other health goals, according to a speaker at the annual meeting of the American College of Physicians.

“Evidence from studies can help clinicians and their patients develop a successful dietary management plan and achieve optimal health,” said internist Michelle Hauser, MD, clinical associate professor at Stanford (Calif.) University. She also discussed evidence-based techniques to support patients in maintaining dietary modifications.
 

Predominantly plant‐based diets

Popular predominantly plant‐based diets include a Mediterranean diet, healthy vegetarian diet, predominantly whole-food plant‐based (WFPB) diet, and a dietary approach to stop hypertension (DASH).

The DASH diet was originally designed to help patients manage their blood pressure, but evidence suggests that it also can help adults with obesity lose weight. In contrast to the DASH diet, the Mediterranean diet is not low-fat and not very restrictive. Yet the evidence suggests that the Mediterranean diet is not only helpful for losing weight but also can reduce the risk of various chronic diseases, including obesity, type 2 diabetes, cardiovascular disease (CVD), and cancer, Dr. Hauser said. In addition, data suggest that the Mediterranean diet may reduce the risk of all-cause mortality and lower the levels of cholesterol.

“I like to highlight all these protective effects to my patients, because even if their goal is to lose weight, knowing that hard work pays off in additional ways can keep them motivated,” Dr. Hauser stated.

A healthy vegetarian diet and a WFPB diet are similar, and both are helpful in weight loss and management of total cholesterol and LDL‐C levels. Furthermore, healthy vegetarian and WFPB diets may reduce the risk of type 2 diabetes, CVD, and some cancers. Cohort study data suggest that progressively more vegetarian diets are associated with lower BMIs.

“My interpretation of these data is that predominantly plant-based diets rich in whole foods are healthful and can be done in a way that is sustainable for most,” said Dr. Hauser. However, this generally requires a lot of support at the outset to address gaps in knowledge, skills, and other potential barriers.

For example, she referred one obese patient at risk of diabetes and cardiovascular disease to a registered dietitian to develop a dietary plan. The patient also attended a behavioral medicine weight management program to learn strategies such as using smaller plates, and his family attended a healthy cooking class together to improve meal planning and cooking skills.
 

Time‐restricted feeding

There are numerous variations of time-restricted feeding, commonly referred to as intermittent fasting, but the principles are similar – limiting food intake to a specific window of time each day or week.

Although some studies have shown that time-restricted feeding may help patients reduce adiposity and improve lipid markers, most studies comparing time-restricted feeding to a calorie-restricted diet have shown little to no difference in weight-related outcomes, Dr. Hauser said.

These data suggest that time-restricted feeding may help patients with weight loss only if time restriction helps them reduce calorie intake. She also warned that time-restrictive feeding might cause late-night cravings and might not be helpful in individuals prone to food cravings.
 

Low‐carbohydrate and ketogenic diets

Losing muscle mass can prevent some people from dieting, but evidence suggests that a high-fat, very low-carbohydrate diet – also called a ketogenic diet – may help patients reduce weight and fat mass while preserving fat‐free mass, Dr. Hauser said.

The evidence regarding the usefulness of a low-carbohydrate (non-keto) diet is less clear because most studies compared it to a low-fat diet, and these two diets might lead to a similar extent of weight loss.
 

Rating the level of scientific evidence behind different diet options

Nutrition studies do no provide the same level of evidence as drug studies, said Dr. Hauser, because it is easier to conduct a randomized controlled trial of a drug versus placebo. Diets have many more variables, and it also takes much longer to observe most outcomes of a dietary change.

In addition, clinical trials of dietary interventions are typically short and focus on disease markers such as serum lipids and hemoglobin A1c levels. To obtain reliable information on the usefulness of a diet, researchers need to collect detailed health and lifestyle information from hundreds of thousands of people over several decades, which is not always feasible. “This is why meta-analyses of pooled dietary study data are more likely to yield dependable findings,” she noted.
 

Getting to know patients is essential to help them maintain diet modifications

When developing a diet plan for a patient, it is important to consider the sustainability of a dietary pattern. “The benefits of any healthy dietary change will only last as long as they can be maintained,” said Dr. Hauser. “Counseling someone on choosing an appropriate long-term dietary pattern requires getting to know them – taste preferences, food traditions, barriers, facilitators, food access, and time and cost restrictions.”

In an interview after the session, David Bittleman, MD, an internist at Veterans Affairs San Diego Health Care System, agreed that getting to know patients is essential for successfully advising them on diet.

“I always start developing a diet plan by trying to find out what [a patient’s] diet is like and what their goals are. I need to know what they are already doing in order to make suggestions about what they can do to make their diet healthier,” he said.

When asked about her approach to supporting patients in the long term, Dr. Hauser said that she recommends sequential, gradual changes. Dr. Hauser added that she suggests her patients prioritize implementing dietary changes that they are confident they can maintain.

Dr. Hauser and Dr. Bittleman report no relevant financial relationships.

SAN DIEGO – A COVID-19 combination antiviral is the most important new drug primary care physicians have prescribed in recent years – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.

Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.

Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
 

Understanding the mechanism of action

Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.

“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.

“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.

Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.

Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.

Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.

When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.

Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.

“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.

Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
 

Effective in real world, but less so than in clinical trials

The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.

A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
 

Many drug-drug interactions, but they can be managed

Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.

To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.

This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.

To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:

• Prescribe an alternative COVID therapy.
• Temporarily withhold concomitant medication if clinically appropriate.
• Adjust the dose of concomitant medication and monitor for adverse effects.

Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
 

Important considerations

Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.

He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.

Dr. Smetana and Dr. Kiefl reported no disclosures.

SAN DIEGO – A COVID-19 combination antiviral is the most important new drug primary care physicians have prescribed in recent years – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.

Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.

Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
 

Understanding the mechanism of action

Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.

“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.

“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.

Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.

Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.

Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.

When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.

Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.

“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.

Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
 

Effective in real world, but less so than in clinical trials

The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.

A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
 

Many drug-drug interactions, but they can be managed

Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.

To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.

This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.

To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:

• Prescribe an alternative COVID therapy.
• Temporarily withhold concomitant medication if clinically appropriate.
• Adjust the dose of concomitant medication and monitor for adverse effects.

Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
 

Important considerations

Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.

He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.

Dr. Smetana and Dr. Kiefl reported no disclosures.

SAN DIEGO – A COVID-19 combination antiviral is the most important new drug primary care physicians have prescribed in recent years – plus it has helped keep many patients out of the hospital, according to a presenter at the annual meeting of the American College of Physicians.

Nirmatrelvir-ritonavir was granted emergency use authorization by the FDA late in 2021 to prevent progression to severe disease when COVID-19 cases and deaths were surging, and the Delta and Omicron variants started to spread.

Gerald Smetana, MD, an internist at Beth Israel Deaconess Medical Center in Boston, discussed nirmatrelvir-ritonavir as an example of how new drugs relevant to primary care can have a profound impact on public health.
 

Understanding the mechanism of action

Nirmatrelvir is the active agent of this combination and inhibits the SARS-CoV-2 main protease (Mpro), which is required for viral replication. In contrast to the SARS-CoV-2 spike protein, Mpro is highly conserved in coronaviruses and rarely acquires mutations. Therefore, unlike monoclonal antibodies targeting the spike protein, nirmatrelvir is active against known Omicron variants and is predicted to remain active against new variants that may emerge. The HIV1 protease inhibitor ritonavir has no activity against SARS-CoV-2. It can help increase the serum concentration of nirmatrelvir by inhibiting its metabolization.

“Although the details are not important for prescribing internists, having a basic understanding of the mechanism of action can help [doctors] better understand for which patients the drugs are indicated,” said Dr. Smetana, also a professor of medicine at Harvard Medical School, Boston. This is particularly important for newly approved drugs with a lot of new information to digest.

“Knowing the mechanisms of action of new drugs can help us predict their efficacy and potential side effects,” said Hubertus Kiefl, MD, an internist at Beth Israel Deaconess Medical Center and a lecturer at Harvard Medical School, during an interview after the session.

Understanding how drugs work also can help clinicians make better decisions, such as avoiding the use of a monoclonal antibody during a surge of a new variant with mutations in surface proteins or carefully managing the use of nirmatrelvir-ritonavir in patients who take certain medications that would cause potentially serious drug-drug interactions, Dr. Kiefl added.

Nirmatrelvir-ritonavir reduces the risk of hospitalization – but only in high-risk patients.

Dr. Smetana presented published data from the EPIC-HR study, a pivotal phase 2-3 clinical trial in 2,246 adult patients with COVID-19, all of whom were unvaccinated. Additionally, all patients had at least one risk factor for progression to severe disease.

When initiated 5 days after symptom onset or earlier, treatment with 300 mg nirmatrelvir plus 100 mg ritonavir twice a day for 5 days led to an 89% relative risk reduction in COVID-19–related hospitalization or death through day 28, compared with placebo.

Subgroup analyses showed that some patients benefited more than others. The highest risk reduction after treatment with nirmatrelvir-ritonavir was observed in patients at least 65 years old.

“It is important to remember that all the patients of this study were unvaccinated and [had] not had prior SARS-CoV-2 infection. This study population isn’t representative of most patients we are seeing today,” said Dr. Smetana.

Unpublished data from a study of standard-risk patients showed a nonsignificant reduction in the risk of hospitalization or death, he said. The study was stopped because of the low rates of hospitalization and death.
 

Effective in real world, but less so than in clinical trials

The fact that the patient cohort in the EPIC-HR trial was different from the patients internists see today makes real-world data critical for determining the usefulness of nirmatrelvir-ritonavir in everyday practice, Dr. Smetana said.

A real-world study from Israel conducted during the first Omicron wave (January to March 2022) showed that treatment with nirmatrelvir alone substantially reduced the relative risk of hospitalization in adults older than 65, with no evidence of benefit in adults aged 40-65. Dr. Smetana highlighted that, unlike the EPIC-HR cohort, most patients in the Israeli study had prior immunity due to vaccination or prior SARS-CoV-2 infection.
 

Many drug-drug interactions, but they can be managed

Nirmatrelvir-ritonavir interacts with many drugs, some of which are commonly used by primary care patients.

To help internists identify drug-drug interactions, Dr. Smetana proposed the use of the Liverpool COVID-19 Drug Interactions Checker, an intuitive tool that can help prescribers identify potential drug-drug interactions, categorize them based on severity, and identify management strategies.

This tool is specific to COVID-19 drugs. The Liverpool group also offers online drug interaction checkers for HIV, hepatitis, and cancer. “We need more tools like this to help improve the safe use of new drugs,” Dr. Smetana said.

To manage drug interactions, according to Dr. Smetana, U.S. treatment guidelines offer the following three options:

• Prescribe an alternative COVID therapy.
• Temporarily withhold concomitant medication if clinically appropriate.
• Adjust the dose of concomitant medication and monitor for adverse effects.

Medication doses that are withheld or modified should be continued through 3 days after completing nirmatrelvir-ritonavir, he added.
 

Important considerations

Commenting on things to consider for patients with COVID-19, Dr. Smetana said that there is a short window after symptom onset when nirmatrelvir-ritonavir can be prescribed, and safety in pregnancy is not known. There is also uncertainty regarding funding of nirmatrelvir-ritonavir prescriptions after the state of emergency is lifted. He reminded attendees that, although nirmatrelvir-ritonavir is the preferred first-line treatment for high-risk patients, another antiviral agent, molnupiravir, is also available and might be more appropriate for some patients.

He also cautioned about prescribing new drugs off label for indications that are not yet FDA-approved. “We are often stewards of limited resources when new drugs first become available but are not yet in sufficient supply to meet demand. Limiting our prescribing to FDA-approved indications helps to ensure equitable access,” he said.

Dr. Smetana and Dr. Kiefl reported no disclosures.

SAN DIEGO – For patients with obesity, surgery, lifestyle changes, and pharmacologic interventions are all treatment options, but antiobesity medications provide a better risk-to-benefit ratio, according to a presenter at the annual meeting of the American College of Physicians.

Lifestyle changes result in the least weight loss and may be safest, while surgery provides the most weight loss and has the greatest risk. Antiobesity medications, especially the newer ones used in combination with lifestyle changes, can provide significant and sustained weight loss with manageable side effects, said Daniel Bessesen, MD, a professor in the endocrinology, diabetes, and metabolism at University of Colorado at Denver, Aurora.

New and more effective antiobesity medications have given internists more potential options to discuss with their patients, Dr. Bessesen said. He reviewed the pros and cons of the different options.

Medications are indicated for patients with a body mass index greater than 30, including those with a weight-related comorbidity, Dr. Bessesen said. The average weight loss is 5%-15% over 3-6 months but may vary greatly. Insurance often does not cover the medication costs.
 

Older FDA-approved antiobesity medications

Phentermine is the most widely prescribed antiobesity medication, partly because it is the only option most people can afford out of pocket. Dr. Bessesen presented recent data showing that long-term use of phentermine was associated with greater weight loss and that patients continuously taking phentermine for 24 months lost 7.5% of their weight.

Phentermine suppresses appetite by increasing norepinephrine production. Dr. Bessesen warned that internists should be careful when prescribing it to patients with mental conditions, because it acts as a stimulant. Early studies raised concerns about the risk of cardiovascular disease (CVD) in patients taking phentermine. However, analysis of data from over 13,000 individuals showed no evidence of a relationship between phentermine exposure and CVD events.

“These data provide some reassurance that it could be used in patients with CVD risk,” he noted. Phentermine can also be combined with topiramate extended release, a combination that provides greater efficacy (up to 10% weight loss) with fewer side effects. However, this combination is less effective in patients with diabetes than in those without.

Additional treatment options included orlistat and naltrexone sustained release/bupropion SR. Orlistat is a good treatment alternative for patients with constipation and is the safest option among older anti-obesity medications, whereas naltrexone SR/bupropion SR may be useful in patients with food cravings. However, there is more variability in the individual-level benefit from these agents compared to phentermine and phentermine/topiramate ER, Dr. Bessesen said.
 

Newer anti‐obesity medications

Liraglutide, an agent used for the management of type 2 diabetes, has recently been approved for weight loss. Liraglutide causes moderate weight loss, and it may reduce the risk of CVD. However, there are tolerability issues, such as nausea and other risks, and Dr. Bessesen advises internists to “start at low doses and increase slowly.”

Semaglutide is the newest and most effective antiobesity drug approved by the Food and Drug Administration, providing sustained weight loss of 8% for up to 48 weeks after starting treatment. Although its efficacy is lower in patients with diabetes, Dr. Bessesen noted that “this is common for antiobesity agents, and clinicians should not refrain from prescribing it in this population.”

Setmelanotide is another new medication approved for chronic weight management in patients with monogenic obesity. This medication can be considered for patients with early-onset severe obesity with abnormal feeding behavior.

Commenting on barriers to access to new antiobesity medications, Dr. Bessesen said that “the high cost of these medications is a substantial problem, but as more companies become involved and products are on the market for a longer period of time, I am hopeful that prices will come down.”
 

Emerging antiobesity medications

Dr. Bessesen presented recent phase 3 data showing that treatment with tirzepatide provided sustained chronic loss and improved cardiometabolic measures with no diet. Tirzepatide, which targets receptors for glucagonlike peptide–1 and glucose-dependent insulinotropic polypeptide, is used for the management of type 2 diabetes and is expected to be reviewed soon by the FDA for its use in weight management.

A semaglutide/cagrilintide combination may also provide a new treatment option for patients with obesity. In a phase 1b trial, semaglutide/cagrilintide treatment resulted in up to 17% weight loss in patients with obesity who were otherwise healthy; however, phase 2 and 3 data are needed to confirm its efficacy.
 

A ‘holistic approach’

When deciding whether to prescribe antiobesity medications, Dr. Bessesen noted that medications are better than exercise alone. Factors to consider when deciding whether to prescribe drugs, as well as which ones, include costs, local regulatory guidelines, requirement for long-term use, and patient comorbidities.

He also stated that lifestyle changes, such as adopting healthy nutrition and exercising regularly, are also important and can enhance weight loss when combined with medications.

Richele Corrado, DO, MPH, agreed that lifestyle management in combination with medications may provide greater weight loss than each of these interventions alone.

“If you look at the data, exercise doesn’t help you lose much weight,” said Dr. Corrado, a staff internist and obesity medicine specialist at Walter Reed National Military Medical Center in Bethesda, Md., who spoke at the same session. She added that she has many patients who struggle to lose weight despite having a healthy lifestyle. “It’s important to discuss with these patients about medications and surgery.”

Dr. Bessesen noted that management of mental health and emotional well-being should also be an integral part of obesity management. “Treatment for obesity may be more successful when underlying psychological conditions such as depression, childhood sexual trauma, or anxiety are addressed and treated,” he said.

Dr. Bessesen was involved in the study of the efficacy of semaglutide/cagrilintide. He does not have any financial conflicts with the companies that make other mentioned medications. He has received research grants or contracts from Novo Nordisk, honoraria from Novo Nordisk, and consultantship from Eli Lilly. Dr. Corrado reported no relevant financial conflicts.

SAN DIEGO – For patients with obesity, surgery, lifestyle changes, and pharmacologic interventions are all treatment options, but antiobesity medications provide a better risk-to-benefit ratio, according to a presenter at the annual meeting of the American College of Physicians.

Lifestyle changes result in the least weight loss and may be safest, while surgery provides the most weight loss and has the greatest risk. Antiobesity medications, especially the newer ones used in combination with lifestyle changes, can provide significant and sustained weight loss with manageable side effects, said Daniel Bessesen, MD, a professor in the endocrinology, diabetes, and metabolism at University of Colorado at Denver, Aurora.

New and more effective antiobesity medications have given internists more potential options to discuss with their patients, Dr. Bessesen said. He reviewed the pros and cons of the different options.

Medications are indicated for patients with a body mass index greater than 30, including those with a weight-related comorbidity, Dr. Bessesen said. The average weight loss is 5%-15% over 3-6 months but may vary greatly. Insurance often does not cover the medication costs.
 

Older FDA-approved antiobesity medications

Phentermine is the most widely prescribed antiobesity medication, partly because it is the only option most people can afford out of pocket. Dr. Bessesen presented recent data showing that long-term use of phentermine was associated with greater weight loss and that patients continuously taking phentermine for 24 months lost 7.5% of their weight.

Phentermine suppresses appetite by increasing norepinephrine production. Dr. Bessesen warned that internists should be careful when prescribing it to patients with mental conditions, because it acts as a stimulant. Early studies raised concerns about the risk of cardiovascular disease (CVD) in patients taking phentermine. However, analysis of data from over 13,000 individuals showed no evidence of a relationship between phentermine exposure and CVD events.

“These data provide some reassurance that it could be used in patients with CVD risk,” he noted. Phentermine can also be combined with topiramate extended release, a combination that provides greater efficacy (up to 10% weight loss) with fewer side effects. However, this combination is less effective in patients with diabetes than in those without.

Additional treatment options included orlistat and naltrexone sustained release/bupropion SR. Orlistat is a good treatment alternative for patients with constipation and is the safest option among older anti-obesity medications, whereas naltrexone SR/bupropion SR may be useful in patients with food cravings. However, there is more variability in the individual-level benefit from these agents compared to phentermine and phentermine/topiramate ER, Dr. Bessesen said.
 

Newer anti‐obesity medications

Liraglutide, an agent used for the management of type 2 diabetes, has recently been approved for weight loss. Liraglutide causes moderate weight loss, and it may reduce the risk of CVD. However, there are tolerability issues, such as nausea and other risks, and Dr. Bessesen advises internists to “start at low doses and increase slowly.”

Semaglutide is the newest and most effective antiobesity drug approved by the Food and Drug Administration, providing sustained weight loss of 8% for up to 48 weeks after starting treatment. Although its efficacy is lower in patients with diabetes, Dr. Bessesen noted that “this is common for antiobesity agents, and clinicians should not refrain from prescribing it in this population.”

Setmelanotide is another new medication approved for chronic weight management in patients with monogenic obesity. This medication can be considered for patients with early-onset severe obesity with abnormal feeding behavior.

Commenting on barriers to access to new antiobesity medications, Dr. Bessesen said that “the high cost of these medications is a substantial problem, but as more companies become involved and products are on the market for a longer period of time, I am hopeful that prices will come down.”
 

Emerging antiobesity medications

Dr. Bessesen presented recent phase 3 data showing that treatment with tirzepatide provided sustained chronic loss and improved cardiometabolic measures with no diet. Tirzepatide, which targets receptors for glucagonlike peptide–1 and glucose-dependent insulinotropic polypeptide, is used for the management of type 2 diabetes and is expected to be reviewed soon by the FDA for its use in weight management.

A semaglutide/cagrilintide combination may also provide a new treatment option for patients with obesity. In a phase 1b trial, semaglutide/cagrilintide treatment resulted in up to 17% weight loss in patients with obesity who were otherwise healthy; however, phase 2 and 3 data are needed to confirm its efficacy.
 

A ‘holistic approach’

When deciding whether to prescribe antiobesity medications, Dr. Bessesen noted that medications are better than exercise alone. Factors to consider when deciding whether to prescribe drugs, as well as which ones, include costs, local regulatory guidelines, requirement for long-term use, and patient comorbidities.

He also stated that lifestyle changes, such as adopting healthy nutrition and exercising regularly, are also important and can enhance weight loss when combined with medications.

Richele Corrado, DO, MPH, agreed that lifestyle management in combination with medications may provide greater weight loss than each of these interventions alone.

“If you look at the data, exercise doesn’t help you lose much weight,” said Dr. Corrado, a staff internist and obesity medicine specialist at Walter Reed National Military Medical Center in Bethesda, Md., who spoke at the same session. She added that she has many patients who struggle to lose weight despite having a healthy lifestyle. “It’s important to discuss with these patients about medications and surgery.”

Dr. Bessesen noted that management of mental health and emotional well-being should also be an integral part of obesity management. “Treatment for obesity may be more successful when underlying psychological conditions such as depression, childhood sexual trauma, or anxiety are addressed and treated,” he said.

Dr. Bessesen was involved in the study of the efficacy of semaglutide/cagrilintide. He does not have any financial conflicts with the companies that make other mentioned medications. He has received research grants or contracts from Novo Nordisk, honoraria from Novo Nordisk, and consultantship from Eli Lilly. Dr. Corrado reported no relevant financial conflicts.

SAN DIEGO – For patients with obesity, surgery, lifestyle changes, and pharmacologic interventions are all treatment options, but antiobesity medications provide a better risk-to-benefit ratio, according to a presenter at the annual meeting of the American College of Physicians.

Lifestyle changes result in the least weight loss and may be safest, while surgery provides the most weight loss and has the greatest risk. Antiobesity medications, especially the newer ones used in combination with lifestyle changes, can provide significant and sustained weight loss with manageable side effects, said Daniel Bessesen, MD, a professor in the endocrinology, diabetes, and metabolism at University of Colorado at Denver, Aurora.

New and more effective antiobesity medications have given internists more potential options to discuss with their patients, Dr. Bessesen said. He reviewed the pros and cons of the different options.

Medications are indicated for patients with a body mass index greater than 30, including those with a weight-related comorbidity, Dr. Bessesen said. The average weight loss is 5%-15% over 3-6 months but may vary greatly. Insurance often does not cover the medication costs.
 

Older FDA-approved antiobesity medications

Phentermine is the most widely prescribed antiobesity medication, partly because it is the only option most people can afford out of pocket. Dr. Bessesen presented recent data showing that long-term use of phentermine was associated with greater weight loss and that patients continuously taking phentermine for 24 months lost 7.5% of their weight.

Phentermine suppresses appetite by increasing norepinephrine production. Dr. Bessesen warned that internists should be careful when prescribing it to patients with mental conditions, because it acts as a stimulant. Early studies raised concerns about the risk of cardiovascular disease (CVD) in patients taking phentermine. However, analysis of data from over 13,000 individuals showed no evidence of a relationship between phentermine exposure and CVD events.

“These data provide some reassurance that it could be used in patients with CVD risk,” he noted. Phentermine can also be combined with topiramate extended release, a combination that provides greater efficacy (up to 10% weight loss) with fewer side effects. However, this combination is less effective in patients with diabetes than in those without.

Additional treatment options included orlistat and naltrexone sustained release/bupropion SR. Orlistat is a good treatment alternative for patients with constipation and is the safest option among older anti-obesity medications, whereas naltrexone SR/bupropion SR may be useful in patients with food cravings. However, there is more variability in the individual-level benefit from these agents compared to phentermine and phentermine/topiramate ER, Dr. Bessesen said.
 

Newer anti‐obesity medications

Liraglutide, an agent used for the management of type 2 diabetes, has recently been approved for weight loss. Liraglutide causes moderate weight loss, and it may reduce the risk of CVD. However, there are tolerability issues, such as nausea and other risks, and Dr. Bessesen advises internists to “start at low doses and increase slowly.”

Semaglutide is the newest and most effective antiobesity drug approved by the Food and Drug Administration, providing sustained weight loss of 8% for up to 48 weeks after starting treatment. Although its efficacy is lower in patients with diabetes, Dr. Bessesen noted that “this is common for antiobesity agents, and clinicians should not refrain from prescribing it in this population.”

Setmelanotide is another new medication approved for chronic weight management in patients with monogenic obesity. This medication can be considered for patients with early-onset severe obesity with abnormal feeding behavior.

Commenting on barriers to access to new antiobesity medications, Dr. Bessesen said that “the high cost of these medications is a substantial problem, but as more companies become involved and products are on the market for a longer period of time, I am hopeful that prices will come down.”
 

Emerging antiobesity medications

Dr. Bessesen presented recent phase 3 data showing that treatment with tirzepatide provided sustained chronic loss and improved cardiometabolic measures with no diet. Tirzepatide, which targets receptors for glucagonlike peptide–1 and glucose-dependent insulinotropic polypeptide, is used for the management of type 2 diabetes and is expected to be reviewed soon by the FDA for its use in weight management.

A semaglutide/cagrilintide combination may also provide a new treatment option for patients with obesity. In a phase 1b trial, semaglutide/cagrilintide treatment resulted in up to 17% weight loss in patients with obesity who were otherwise healthy; however, phase 2 and 3 data are needed to confirm its efficacy.
 

A ‘holistic approach’

When deciding whether to prescribe antiobesity medications, Dr. Bessesen noted that medications are better than exercise alone. Factors to consider when deciding whether to prescribe drugs, as well as which ones, include costs, local regulatory guidelines, requirement for long-term use, and patient comorbidities.

He also stated that lifestyle changes, such as adopting healthy nutrition and exercising regularly, are also important and can enhance weight loss when combined with medications.

Richele Corrado, DO, MPH, agreed that lifestyle management in combination with medications may provide greater weight loss than each of these interventions alone.

“If you look at the data, exercise doesn’t help you lose much weight,” said Dr. Corrado, a staff internist and obesity medicine specialist at Walter Reed National Military Medical Center in Bethesda, Md., who spoke at the same session. She added that she has many patients who struggle to lose weight despite having a healthy lifestyle. “It’s important to discuss with these patients about medications and surgery.”

Dr. Bessesen noted that management of mental health and emotional well-being should also be an integral part of obesity management. “Treatment for obesity may be more successful when underlying psychological conditions such as depression, childhood sexual trauma, or anxiety are addressed and treated,” he said.

Dr. Bessesen was involved in the study of the efficacy of semaglutide/cagrilintide. He does not have any financial conflicts with the companies that make other mentioned medications. He has received research grants or contracts from Novo Nordisk, honoraria from Novo Nordisk, and consultantship from Eli Lilly. Dr. Corrado reported no relevant financial conflicts.