TBD Meeting (3035-19)

CHICAGO – High baseline C-reactive protein (CRP) and interleuken-6 (IL-6) levels are prognostic for checkpoint inhibition in patients with melanoma, according to post hoc analyses of data from three randomized CheckMate studies.

In 70 treatment-naive patients from the randomized phase 2 CheckMate 064 study who received sequential treatment with the programmed death-1 (PD-1) checkpoint inhibitor nivolumab (NIVO) followed by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab (IPI), best overall response was modestly associated with lower baseline serum IL-6 (P = .087) and significantly associated with on-treatment IL-6 (P = .006). In 70 patients who received IPI then NIVO, best overall response was associated only with on-treatment IL-6 (P = .043), Jeffrey S. Weber, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

“This stimulated us to look at associations with survival ... and there apparently was a significant association with high IL-6 levels in the serum both pretreatment and on treatment in both arms, whether they got NIVO then IPI followed by NIVO maintenance, or IPI then NIVO, also followed by NIVO maintenance,” he said.

After adjusting for covariates, the hazard ratios for survival for baseline IL-6 below versus above the median were 7.81 and 1.07, in the groups, respectively. No deaths occurred in the NIVO-IPI group (thus, no HR), but the HR for survival based on on-treatment IL-6 below versus above the median in the IPI-NIVO group was 1.92.

“So initial conclusions: High baseline and on-treatment IL-6 levels in the serum were associated with poor survival,” said Dr. Weber, deputy director of the Perlmutter Cancer Center, New York University Langone Medical Center.

This finding prompted evaluation of additional samples from the randomized CheckMate 066 study, which compared dacarbazine chemotherapy (the standard of care at the time) and NIVO in 400 treatment-naive patients with BRAF wild-type disease.

Again, baseline IL-6 levels (nondetectable vs. detectable) were associated with better overall survival (OS) in both groups (adjusted HRs, 1.79 and 1.54).

“So this is not a predictive marker, this is a baseline prognostic marker,” he said.

In the international, three-arm, randomized phase 3 CheckMate 067 study, which compared IPI, NIVO, and IPI+NIVO in 945 treatment-naive patients with either BRAF wild-type or BRAF mutated disease, baseline IL-6 levels (nondetectable vs. detectable) again were associated with better OS in all 3 arms (adjusted HRs, 3.13 for NIVO, 2.67 for NIVO+IPI, and 4.06 for IPI alone).

A multivariate analysis of data from the CheckMate 066 and 067 studies, with controlling for lactic acid deydrogenase, performance status, and disease stage, provided additional “impressive evidence” of IL-6 as a potent prognostic factor, Dr. Weber said.

“We then looked at CRP. I’ve always been interested in CRP because in a recent publication CRP was found to be associated with outcomes in patients who got PD-1, and the higher the CRP, the worse they did,” he said.

In CheckMate 064 there was modest association between lower baseline CRP and best overall response in both the NIVO-IPI and IPI-NIVO groups (P = .069 and 0.009, respectively), and on treatment, the association was really only seen in the IPI-NIVO group (P = .210 for NIVO-IPI and 0.015 for IPI-NIVO), in which the higher CRP levels were associated with progression or stability.

For survival, however, both baseline and on-treatment CRP levels were associated with OS; baseline serum CRP above the median was associated with shorter OS (HRs, 7.25 for NIVO-IPI and 1.53 for IPI-NIVO), and a similar trend was seen for on-treatment CRP (HRs, 1.60 and 2.0, respectively).

In CheckMate 066, the association between CRP and OS was also apparent, but not as impressive for NIVO alone (HR, 0.996) as it was for dacarbazine (HR, 1.90), and similar to CheckMate 064, higher baseline CRP levels were associated with shorter survival and were prognostic, he said.

In CheckMate 067, similar trends were seen across the treatment arms, and they were similar to those seen for IL-6, with higher baseline CRP levels (at or above median versus below) associated with shorter OS (HRs, 1.46 for NIVO, 1.26 for NIVO+IPI, and 1.48 for IPI alone).

To better understand how CRP might inhibit the effects of PD-1 and how it could have an immune effect – as also indicated by some prior data – Dr. Weber and colleagues conducted additional in vitro studies to examine the impact of exogenous CRP on T-cell function; they found that CRP affected the earliest steps in T-cell signaling and activation, thereby dampening antitumor immune responses.

Acute phase reactants such as CRP and chronic inflammatory proteins including IL-6 (which induces production of CRP from the liver) have been associated with poor prognosis in a variety of cancers, as well as with poor outcomes after anti–PD-1 or programmed death-ligand 1 (PD-L1) therapy in melanoma and other cancers, Dr. Weber said.

“In murine models of melanoma and pancreatic cancer, combined treatment with anti-IL-6 blockade and anti–PD-1/PD-L1 antibodies enhances antitumor immune responses and efficacy,” he explained, noting that the current analyses were undertaken based on those findings and on “a significant body of data” from other groups and from his own lab.

The current findings suggest that IL-6 and CRP may be prognostic for immune checkpoint inhibitor therapies in patients with melanoma, he said, adding that “blockade of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint therapies may enhance responses and survival rates in patients with different cancers, including melanomas.”

To that end, an investigator-sponsored trial looking at IPI-NIVO with the IL-6–blocking antibody tocilizumab has been approved and will start accruing patients in the next few months, he said.

During a discussion of the findings at the meeting, Charles G. Drake, MD, PhD, associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at Columbia University, New York, said that “Dr. Weber and his colleagues should be commended for really trying to show what CRP does to T-cell activation, and in the studies he showed us, it’s clearly negative.”

“But IL-6 is a pleiotropic cytokine. It will be very interesting to see what happens in the prospective clinical trial that he mentioned, in terms of all the other effects on CD-4 cells, neutrophils, and macrophages,” said Dr. Drake, who also is codirector of Columbia’s Cancer Immunotherapy Program. “Nevertheless, I think the data were clear that IL-6 and CRP are negative prognostic biomarkers in melanoma.”

Of note, the development of a biomarker identified in a trial typically takes many steps, but in the case of IL-6 – and perhaps even more so for CRP – the pathway is relatively short, Dr. Drake said.

“That’s because CRP is a validated and [Food and Drug Administration]–approved test; you can order it to assess cardiovascular risk in almost any hospital in the United States, and so the analyte – this part of the qualification – is done,” he explained. “I think if this was validated prospectively we could have CRP as a negative prognostic – not predictive – biomarker in melanoma, actually.”

Dr. Weber and Dr. Drake each reported relationships with numerous companies, including stock and other ownership interests and patents, consulting or advisory roles and/or receipt of honoraria, research funding to their respective institutions, and payment for travel, accommodations, and expenses

SOURCE: Weber J et al. ASCO 2019, Abstract 100.

CHICAGO – High baseline C-reactive protein (CRP) and interleuken-6 (IL-6) levels are prognostic for checkpoint inhibition in patients with melanoma, according to post hoc analyses of data from three randomized CheckMate studies.

In 70 treatment-naive patients from the randomized phase 2 CheckMate 064 study who received sequential treatment with the programmed death-1 (PD-1) checkpoint inhibitor nivolumab (NIVO) followed by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab (IPI), best overall response was modestly associated with lower baseline serum IL-6 (P = .087) and significantly associated with on-treatment IL-6 (P = .006). In 70 patients who received IPI then NIVO, best overall response was associated only with on-treatment IL-6 (P = .043), Jeffrey S. Weber, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

“This stimulated us to look at associations with survival ... and there apparently was a significant association with high IL-6 levels in the serum both pretreatment and on treatment in both arms, whether they got NIVO then IPI followed by NIVO maintenance, or IPI then NIVO, also followed by NIVO maintenance,” he said.

After adjusting for covariates, the hazard ratios for survival for baseline IL-6 below versus above the median were 7.81 and 1.07, in the groups, respectively. No deaths occurred in the NIVO-IPI group (thus, no HR), but the HR for survival based on on-treatment IL-6 below versus above the median in the IPI-NIVO group was 1.92.

“So initial conclusions: High baseline and on-treatment IL-6 levels in the serum were associated with poor survival,” said Dr. Weber, deputy director of the Perlmutter Cancer Center, New York University Langone Medical Center.

This finding prompted evaluation of additional samples from the randomized CheckMate 066 study, which compared dacarbazine chemotherapy (the standard of care at the time) and NIVO in 400 treatment-naive patients with BRAF wild-type disease.

Again, baseline IL-6 levels (nondetectable vs. detectable) were associated with better overall survival (OS) in both groups (adjusted HRs, 1.79 and 1.54).

“So this is not a predictive marker, this is a baseline prognostic marker,” he said.

In the international, three-arm, randomized phase 3 CheckMate 067 study, which compared IPI, NIVO, and IPI+NIVO in 945 treatment-naive patients with either BRAF wild-type or BRAF mutated disease, baseline IL-6 levels (nondetectable vs. detectable) again were associated with better OS in all 3 arms (adjusted HRs, 3.13 for NIVO, 2.67 for NIVO+IPI, and 4.06 for IPI alone).

A multivariate analysis of data from the CheckMate 066 and 067 studies, with controlling for lactic acid deydrogenase, performance status, and disease stage, provided additional “impressive evidence” of IL-6 as a potent prognostic factor, Dr. Weber said.

“We then looked at CRP. I’ve always been interested in CRP because in a recent publication CRP was found to be associated with outcomes in patients who got PD-1, and the higher the CRP, the worse they did,” he said.

In CheckMate 064 there was modest association between lower baseline CRP and best overall response in both the NIVO-IPI and IPI-NIVO groups (P = .069 and 0.009, respectively), and on treatment, the association was really only seen in the IPI-NIVO group (P = .210 for NIVO-IPI and 0.015 for IPI-NIVO), in which the higher CRP levels were associated with progression or stability.

For survival, however, both baseline and on-treatment CRP levels were associated with OS; baseline serum CRP above the median was associated with shorter OS (HRs, 7.25 for NIVO-IPI and 1.53 for IPI-NIVO), and a similar trend was seen for on-treatment CRP (HRs, 1.60 and 2.0, respectively).

In CheckMate 066, the association between CRP and OS was also apparent, but not as impressive for NIVO alone (HR, 0.996) as it was for dacarbazine (HR, 1.90), and similar to CheckMate 064, higher baseline CRP levels were associated with shorter survival and were prognostic, he said.

In CheckMate 067, similar trends were seen across the treatment arms, and they were similar to those seen for IL-6, with higher baseline CRP levels (at or above median versus below) associated with shorter OS (HRs, 1.46 for NIVO, 1.26 for NIVO+IPI, and 1.48 for IPI alone).

To better understand how CRP might inhibit the effects of PD-1 and how it could have an immune effect – as also indicated by some prior data – Dr. Weber and colleagues conducted additional in vitro studies to examine the impact of exogenous CRP on T-cell function; they found that CRP affected the earliest steps in T-cell signaling and activation, thereby dampening antitumor immune responses.

Acute phase reactants such as CRP and chronic inflammatory proteins including IL-6 (which induces production of CRP from the liver) have been associated with poor prognosis in a variety of cancers, as well as with poor outcomes after anti–PD-1 or programmed death-ligand 1 (PD-L1) therapy in melanoma and other cancers, Dr. Weber said.

“In murine models of melanoma and pancreatic cancer, combined treatment with anti-IL-6 blockade and anti–PD-1/PD-L1 antibodies enhances antitumor immune responses and efficacy,” he explained, noting that the current analyses were undertaken based on those findings and on “a significant body of data” from other groups and from his own lab.

The current findings suggest that IL-6 and CRP may be prognostic for immune checkpoint inhibitor therapies in patients with melanoma, he said, adding that “blockade of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint therapies may enhance responses and survival rates in patients with different cancers, including melanomas.”

To that end, an investigator-sponsored trial looking at IPI-NIVO with the IL-6–blocking antibody tocilizumab has been approved and will start accruing patients in the next few months, he said.

During a discussion of the findings at the meeting, Charles G. Drake, MD, PhD, associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at Columbia University, New York, said that “Dr. Weber and his colleagues should be commended for really trying to show what CRP does to T-cell activation, and in the studies he showed us, it’s clearly negative.”

“But IL-6 is a pleiotropic cytokine. It will be very interesting to see what happens in the prospective clinical trial that he mentioned, in terms of all the other effects on CD-4 cells, neutrophils, and macrophages,” said Dr. Drake, who also is codirector of Columbia’s Cancer Immunotherapy Program. “Nevertheless, I think the data were clear that IL-6 and CRP are negative prognostic biomarkers in melanoma.”

Of note, the development of a biomarker identified in a trial typically takes many steps, but in the case of IL-6 – and perhaps even more so for CRP – the pathway is relatively short, Dr. Drake said.

“That’s because CRP is a validated and [Food and Drug Administration]–approved test; you can order it to assess cardiovascular risk in almost any hospital in the United States, and so the analyte – this part of the qualification – is done,” he explained. “I think if this was validated prospectively we could have CRP as a negative prognostic – not predictive – biomarker in melanoma, actually.”

Dr. Weber and Dr. Drake each reported relationships with numerous companies, including stock and other ownership interests and patents, consulting or advisory roles and/or receipt of honoraria, research funding to their respective institutions, and payment for travel, accommodations, and expenses

SOURCE: Weber J et al. ASCO 2019, Abstract 100.

CHICAGO – High baseline C-reactive protein (CRP) and interleuken-6 (IL-6) levels are prognostic for checkpoint inhibition in patients with melanoma, according to post hoc analyses of data from three randomized CheckMate studies.

In 70 treatment-naive patients from the randomized phase 2 CheckMate 064 study who received sequential treatment with the programmed death-1 (PD-1) checkpoint inhibitor nivolumab (NIVO) followed by the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor ipilimumab (IPI), best overall response was modestly associated with lower baseline serum IL-6 (P = .087) and significantly associated with on-treatment IL-6 (P = .006). In 70 patients who received IPI then NIVO, best overall response was associated only with on-treatment IL-6 (P = .043), Jeffrey S. Weber, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

“This stimulated us to look at associations with survival ... and there apparently was a significant association with high IL-6 levels in the serum both pretreatment and on treatment in both arms, whether they got NIVO then IPI followed by NIVO maintenance, or IPI then NIVO, also followed by NIVO maintenance,” he said.

After adjusting for covariates, the hazard ratios for survival for baseline IL-6 below versus above the median were 7.81 and 1.07, in the groups, respectively. No deaths occurred in the NIVO-IPI group (thus, no HR), but the HR for survival based on on-treatment IL-6 below versus above the median in the IPI-NIVO group was 1.92.

“So initial conclusions: High baseline and on-treatment IL-6 levels in the serum were associated with poor survival,” said Dr. Weber, deputy director of the Perlmutter Cancer Center, New York University Langone Medical Center.

This finding prompted evaluation of additional samples from the randomized CheckMate 066 study, which compared dacarbazine chemotherapy (the standard of care at the time) and NIVO in 400 treatment-naive patients with BRAF wild-type disease.

Again, baseline IL-6 levels (nondetectable vs. detectable) were associated with better overall survival (OS) in both groups (adjusted HRs, 1.79 and 1.54).

“So this is not a predictive marker, this is a baseline prognostic marker,” he said.

In the international, three-arm, randomized phase 3 CheckMate 067 study, which compared IPI, NIVO, and IPI+NIVO in 945 treatment-naive patients with either BRAF wild-type or BRAF mutated disease, baseline IL-6 levels (nondetectable vs. detectable) again were associated with better OS in all 3 arms (adjusted HRs, 3.13 for NIVO, 2.67 for NIVO+IPI, and 4.06 for IPI alone).

A multivariate analysis of data from the CheckMate 066 and 067 studies, with controlling for lactic acid deydrogenase, performance status, and disease stage, provided additional “impressive evidence” of IL-6 as a potent prognostic factor, Dr. Weber said.

“We then looked at CRP. I’ve always been interested in CRP because in a recent publication CRP was found to be associated with outcomes in patients who got PD-1, and the higher the CRP, the worse they did,” he said.

In CheckMate 064 there was modest association between lower baseline CRP and best overall response in both the NIVO-IPI and IPI-NIVO groups (P = .069 and 0.009, respectively), and on treatment, the association was really only seen in the IPI-NIVO group (P = .210 for NIVO-IPI and 0.015 for IPI-NIVO), in which the higher CRP levels were associated with progression or stability.

For survival, however, both baseline and on-treatment CRP levels were associated with OS; baseline serum CRP above the median was associated with shorter OS (HRs, 7.25 for NIVO-IPI and 1.53 for IPI-NIVO), and a similar trend was seen for on-treatment CRP (HRs, 1.60 and 2.0, respectively).

In CheckMate 066, the association between CRP and OS was also apparent, but not as impressive for NIVO alone (HR, 0.996) as it was for dacarbazine (HR, 1.90), and similar to CheckMate 064, higher baseline CRP levels were associated with shorter survival and were prognostic, he said.

In CheckMate 067, similar trends were seen across the treatment arms, and they were similar to those seen for IL-6, with higher baseline CRP levels (at or above median versus below) associated with shorter OS (HRs, 1.46 for NIVO, 1.26 for NIVO+IPI, and 1.48 for IPI alone).

To better understand how CRP might inhibit the effects of PD-1 and how it could have an immune effect – as also indicated by some prior data – Dr. Weber and colleagues conducted additional in vitro studies to examine the impact of exogenous CRP on T-cell function; they found that CRP affected the earliest steps in T-cell signaling and activation, thereby dampening antitumor immune responses.

Acute phase reactants such as CRP and chronic inflammatory proteins including IL-6 (which induces production of CRP from the liver) have been associated with poor prognosis in a variety of cancers, as well as with poor outcomes after anti–PD-1 or programmed death-ligand 1 (PD-L1) therapy in melanoma and other cancers, Dr. Weber said.

“In murine models of melanoma and pancreatic cancer, combined treatment with anti-IL-6 blockade and anti–PD-1/PD-L1 antibodies enhances antitumor immune responses and efficacy,” he explained, noting that the current analyses were undertaken based on those findings and on “a significant body of data” from other groups and from his own lab.

The current findings suggest that IL-6 and CRP may be prognostic for immune checkpoint inhibitor therapies in patients with melanoma, he said, adding that “blockade of IL-6 and CRP synthesis and/or activity in combination with immune checkpoint therapies may enhance responses and survival rates in patients with different cancers, including melanomas.”

To that end, an investigator-sponsored trial looking at IPI-NIVO with the IL-6–blocking antibody tocilizumab has been approved and will start accruing patients in the next few months, he said.

During a discussion of the findings at the meeting, Charles G. Drake, MD, PhD, associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at Columbia University, New York, said that “Dr. Weber and his colleagues should be commended for really trying to show what CRP does to T-cell activation, and in the studies he showed us, it’s clearly negative.”

“But IL-6 is a pleiotropic cytokine. It will be very interesting to see what happens in the prospective clinical trial that he mentioned, in terms of all the other effects on CD-4 cells, neutrophils, and macrophages,” said Dr. Drake, who also is codirector of Columbia’s Cancer Immunotherapy Program. “Nevertheless, I think the data were clear that IL-6 and CRP are negative prognostic biomarkers in melanoma.”

Of note, the development of a biomarker identified in a trial typically takes many steps, but in the case of IL-6 – and perhaps even more so for CRP – the pathway is relatively short, Dr. Drake said.

“That’s because CRP is a validated and [Food and Drug Administration]–approved test; you can order it to assess cardiovascular risk in almost any hospital in the United States, and so the analyte – this part of the qualification – is done,” he explained. “I think if this was validated prospectively we could have CRP as a negative prognostic – not predictive – biomarker in melanoma, actually.”

Dr. Weber and Dr. Drake each reported relationships with numerous companies, including stock and other ownership interests and patents, consulting or advisory roles and/or receipt of honoraria, research funding to their respective institutions, and payment for travel, accommodations, and expenses

SOURCE: Weber J et al. ASCO 2019, Abstract 100.

CHICAGO – Ovarian cancer diagnoses – and treatment within 30 days of diagnosis – occur earlier under the Affordable Care Act, according to a comparison of National Cancer Database surveys from 2006-2009 and 2011-2014.

During the post-Affordable Care Act (ACA) years of 2011-2014, compared with the pre-ACA years of 2004-2009, a treatment group of women aged 21-64 years with ovarian cancer was more likely to be diagnosed at an early stage, compared with a control group of women aged 65 years and older (difference-in-differences [DD]=1.7%), Anna Jo Smith, MD, reported at the annual meeting of the American Society of Clinical Oncology.

Also, the ACA was associated with more women aged 21-64 receiving treatment within 30 days of diagnosis (DD = 1.6%), said Dr. Smith, a 4th-year resident at Johns Hopkins University, Baltimore.

Among women with public insurance, the ACA was associated with even greater improvement in early-stage diagnosis and treatment within 30 days in the treatment group vs. the controls (DD = 2.5% for each), she said, noting that the improvements were seen across race, income, and education groups.

The findings are based on pre-ACA surveys from 35,842 women aged 21-64 years and 28,895 women aged 65 years, and from post-ACA surveys from 37,145 women and 30,604 women in those age groups, respectively, and were adjusted for patient race, living in a rural area, area-level household income and education level, Charlson comorbidity score, distance traveled for care, Census region, and care at an academic center.

The 2010 ACA expanded access to insurance and care for many Americans, and the objective of this study was to evaluate the impact of that access on women with ovarian cancer, Dr. Smith explained.

“Under the 2010 Affordable Care Act, women with ovarian cancer were more likely to be diagnosed at an early stage and receive treatment within 30 days of diagnosis,” she said. “As stage and treatment are the major determinants of survival advantage, these gains under the ACA may have long-term impacts on the survival, health, and well-being of women with ovarian cancer.”

Dr. Smith reported having no disclosures.

SOURCE: Smith A et al., ASCO 2019. Abstract LBA5563.

CHICAGO – Ovarian cancer diagnoses – and treatment within 30 days of diagnosis – occur earlier under the Affordable Care Act, according to a comparison of National Cancer Database surveys from 2006-2009 and 2011-2014.

During the post-Affordable Care Act (ACA) years of 2011-2014, compared with the pre-ACA years of 2004-2009, a treatment group of women aged 21-64 years with ovarian cancer was more likely to be diagnosed at an early stage, compared with a control group of women aged 65 years and older (difference-in-differences [DD]=1.7%), Anna Jo Smith, MD, reported at the annual meeting of the American Society of Clinical Oncology.

Also, the ACA was associated with more women aged 21-64 receiving treatment within 30 days of diagnosis (DD = 1.6%), said Dr. Smith, a 4th-year resident at Johns Hopkins University, Baltimore.

Among women with public insurance, the ACA was associated with even greater improvement in early-stage diagnosis and treatment within 30 days in the treatment group vs. the controls (DD = 2.5% for each), she said, noting that the improvements were seen across race, income, and education groups.

The findings are based on pre-ACA surveys from 35,842 women aged 21-64 years and 28,895 women aged 65 years, and from post-ACA surveys from 37,145 women and 30,604 women in those age groups, respectively, and were adjusted for patient race, living in a rural area, area-level household income and education level, Charlson comorbidity score, distance traveled for care, Census region, and care at an academic center.

The 2010 ACA expanded access to insurance and care for many Americans, and the objective of this study was to evaluate the impact of that access on women with ovarian cancer, Dr. Smith explained.

“Under the 2010 Affordable Care Act, women with ovarian cancer were more likely to be diagnosed at an early stage and receive treatment within 30 days of diagnosis,” she said. “As stage and treatment are the major determinants of survival advantage, these gains under the ACA may have long-term impacts on the survival, health, and well-being of women with ovarian cancer.”

Dr. Smith reported having no disclosures.

SOURCE: Smith A et al., ASCO 2019. Abstract LBA5563.

CHICAGO – Ovarian cancer diagnoses – and treatment within 30 days of diagnosis – occur earlier under the Affordable Care Act, according to a comparison of National Cancer Database surveys from 2006-2009 and 2011-2014.

During the post-Affordable Care Act (ACA) years of 2011-2014, compared with the pre-ACA years of 2004-2009, a treatment group of women aged 21-64 years with ovarian cancer was more likely to be diagnosed at an early stage, compared with a control group of women aged 65 years and older (difference-in-differences [DD]=1.7%), Anna Jo Smith, MD, reported at the annual meeting of the American Society of Clinical Oncology.

Also, the ACA was associated with more women aged 21-64 receiving treatment within 30 days of diagnosis (DD = 1.6%), said Dr. Smith, a 4th-year resident at Johns Hopkins University, Baltimore.

Among women with public insurance, the ACA was associated with even greater improvement in early-stage diagnosis and treatment within 30 days in the treatment group vs. the controls (DD = 2.5% for each), she said, noting that the improvements were seen across race, income, and education groups.

The findings are based on pre-ACA surveys from 35,842 women aged 21-64 years and 28,895 women aged 65 years, and from post-ACA surveys from 37,145 women and 30,604 women in those age groups, respectively, and were adjusted for patient race, living in a rural area, area-level household income and education level, Charlson comorbidity score, distance traveled for care, Census region, and care at an academic center.

The 2010 ACA expanded access to insurance and care for many Americans, and the objective of this study was to evaluate the impact of that access on women with ovarian cancer, Dr. Smith explained.

“Under the 2010 Affordable Care Act, women with ovarian cancer were more likely to be diagnosed at an early stage and receive treatment within 30 days of diagnosis,” she said. “As stage and treatment are the major determinants of survival advantage, these gains under the ACA may have long-term impacts on the survival, health, and well-being of women with ovarian cancer.”

Dr. Smith reported having no disclosures.

SOURCE: Smith A et al., ASCO 2019. Abstract LBA5563.

CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.

In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).

The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.

“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).

Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.

Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.

The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).

The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.

Treatment

Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.

The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.

At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.

Safety

Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).

Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).

Efficacy

One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.

The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.

The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.

Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).

Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.

“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.

The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.

The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.

jensmith@mdedge.com

SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.

CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.

In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).

The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.

“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).

Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.

Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.

The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).

The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.

Treatment

Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.

The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.

At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.

Safety

Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).

Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).

Efficacy

One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.

The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.

The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.

Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).

Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.

“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.

The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.

The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.

jensmith@mdedge.com

SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.

CHICAGO – Subcutaneous (SC) daratumumab is noninferior to intravenous (IV) daratumumab for patients with relapsed or refractory multiple myeloma (MM), according findings from a phase 3 trial.

In the COLUMBA trial, SC daratumumab proved noninferior to IV daratumumab with regard to overall response rate and maximum trough concentration (Ctrough).

The safety profiles of the two formulations were similar, although patients who received SC daratumumab had a lower rate of infusion-related reactions. SC daratumumab also had a lower treatment burden.

“The COLUMBA study shows that [SC daratumumab] can be used in every myeloma patient [as a] single agent or, maybe in the future, in combination with the different backbones,” said Maria-Victoria Mateos, MD, PhD, of University Hospital of Salamanca (Spain).

Dr. Mateos presented results from the COLUMBA trial at the annual meeting of the American Society of Clinical Oncology.

Dr. Mateos cited a previous phase 1b study that had suggested that SC daratumumab might produce similar results as IV daratumumab (Blood. 2017;130:838) while providing a more convenient delivery method. She pointed out that infusions of IV daratumumab can last hours, while the SC formulation can be delivered in minutes.

The aim of the phase 3 COLUMBA study was to compare the IV and SC formulations head-to-head. The trial enrolled 522 patients with relapsed/refractory multiple myeloma. They were randomized to receive daratumumab SC (n = 263) or IV (n = 259).

The median patient age was 68 years (range, 33-92 years) in the IV arm and 65 years (range, 42-84 years) in the SC arm. Patients had received a median of four prior lines of therapy (range, 1-15 in the IV arm and 2-12 in the SC arm). Most patients were refractory to their last line of therapy – 85% in the IV arm and 80% in the SC arm – and most patients had standard-risk cytogenetics – 83% and 74%, respectively.

Treatment

Patients received SC daratumumab at 1,800 mg and IV daratumumab at 16 mg/kg. Both were given weekly for cycles 1-2, every 2 weeks for cycles 3-6, and every 4 weeks thereafter until disease progression.

The median duration of the first infusion was 421 minutes in the IV arm and 5 minutes in the SC arm. The median duration of the second infusion was 255 minutes and 5 minutes, respectively, and the median duration of subsequent infusions was 205 minutes and 5 minutes, respectively.

At a median follow-up of 7.46 months, 57% of patients in each arm had discontinued the study treatment. The most common reasons for discontinuation were progression – 44% of the IV arm and 43% of the SC arm – and adverse events (AEs) – 8% and 7%, respectively.

Safety

Dr. Mateos said the safety profiles of IV and SC daratumumab were comparable. However, infusion-related reactions were significantly less likely in the SC arm, occurring in 12.7% of those patients and 34.5% of patients in the IV arm (P less than .0001).

Grade 3 or higher treatment-emergent AEs occurred in 49% of patients in the IV arm and 46% of those in the SC arm. Rates of grade 5 AEs were 7% and 5%, respectively. The most common grade 3/4 AEs (in the IV and SC arms, respectively) were anemia (14% and 13%), thrombocytopenia (14% for both), neutropenia (8% and 13%), lymphopenia (6% and 5%), and hypertension (6% and 3%).

Efficacy

One of the study’s primary endpoints was overall response rate, which was 37.1% in the IV arm and 41.1% in the SC arm (relative risk, 1.11; 95% CI, 0.89-1.37; P less than .0001). This met the criteria for noninferiority, and overall response rates were comparable across all patient subgroups, Dr. Mateos noted.

The rates of complete response or stringent complete response were also comparable at 2.7% in the IV arm and 1.9% in the SC arm. Rates of very good partial response were 17.0% and 19.0%, respectively.

The study’s other primary endpoint was maximum Ctrough predose on day 1 of cycle 3. The ratio of maximum Ctrough for daratumumab SC over IV was 107.93% (90% CI, 95.74%-121.67%), which met the noninferiority criterion.

Survival outcomes were also similar between the IV and SC arms. The median progression-free survival was 6.1 months and 5.6 months, respectively (P = .9258). The rate of overall survival at 6 months was 83.0% and 87.5%, respectively (P = .6032).

Considering these results together, Dr. Mateos and colleagues concluded that SC daratumumab is noninferior to IV daratumumab.

“[SC daratumumab] has a reduced treatment burden due to a considerably shorter administration duration, and patients treated with [SC daratumumab] reported higher satisfaction with therapy,” Dr. Mateos said.

The results support the use of flat-dose 1,800-mg SC daratumumab, which is comparable with the IV formulation, she said.

The COLUMBA trial was sponsored by Janssen Research & Development. Dr. Mateos reported relationships with Amgen, Celgene, Janssen-Cilag, and Takeda.

jensmith@mdedge.com

SOURCE: Mateos MV et al. ASCO 2019, Abstract 8005.

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – A bispecific anti-CD19, anti-CD20 chimeric antigen receptor (CAR) T cell approach is safe and produced complete responses in the majority of patients with relapsed or refractory non-Hodgkin lymphoma in a phase 1 study, an investigator reported.

Eleven of 17 assessable patients had a response to treatment with the bispecific lentiviral CAR T cell (LV20.19CAR) at day 28, and of those 11 patients, 9 had complete responses, all of which are ongoing, said Nirav Niranjan Shah, MD, of the Medical College of Wisconsin in Milwaukee.

“To date, there’s no dose-limiting toxicity, no ICU-level care, no deaths attributed to treatment, no grade 3 to 4 cytokine release syndrome, and only two patients had reversible grade 3 neurotoxicity,” Dr. Shah said at the annual meeting of the American Society of Clinical Oncology.

Patients who did relapse or progress on treatment maintained CD19 or CD20 positivity, with no observed downregulation of target receptors, he reported in an oral abstract session.

Of note, the CAR T cells were produced locally at the point of care, with a 100% success rate and a set 14-day manufacturing time, he added.

Bispecific targeting of CD19 and CD20 is a new approach being investigated at a time when there are already two CD19-specific CAR T cell therapies approved for aggressive B-cell non-Hodgkin lymphomas, Dr. Shah told attendees.

“Despite the great promise of CD19 CAR T cell therapies, very quickly after the development of these therapies, we discovered mechanisms of resistance—specifically, the development of a CD19 negative relapse,” he said.

The hypothesis that targeting more than one B-cell antigen could potentially mitigate that effect stemmed from preclinical studies showing that targeting both CD19 and CD20 decreased downregulation of CD19 but not other B-cell antigens, he added.

In the present phase 1 study of the first-in-human, bispecific tandem CAR T cell against CD19 and CD20, patients have been treated at several dose levels, some with a split infusion over 2 days to evaluate safety, and some with a single infusion, Dr. Shah said.

A total of 17 patients have been treated with a lymphodepletion regimen followed by LV20.19CAR: 8 patients with diffuse large B-cell lymphoma, 6 with mantle cell lymphoma, 2 with chronic lymphocytic leukemia, and 1 with follicular lymphoma, according to the investigator. The median age of patients is 59 years, and patients had received at least 3 and up to 11 prior lines of therapy.

There have been no dose-limiting toxicities to date with dosing up to the target of 2.5 x 106 cells/kg, Dr. Shah reported, adding that there has been no grade 3-4 cytokine release syndrome and no grade 4 neurotoxicity. Grade 1-2 cytokine release syndrome has been seen in 11 patients, while grade 3 neurotoxicity occurred in 2 patients.

Fourteen of 17 patients had a response, including 11 complete responses and 3 partial responses. Eleven patients were treated at the target dose of 2.5 x 106 cells/kg, and of those, 9 had a complete response and 1 had a partial response (overall response rate, Dr. Shah said.

To date, all patients in complete response have remained in a complete response, with durations of response of 1 to 18 months.

Next, investigators plan to conduct phase 2 studies in more specific cohorts, including patients with mantle cell lymphoma, and patients who have relapsed after CD19 CAR T cell therapy, Dr. Shah said.

Dr. Shah reported disclosures related to Cidara Therapeutics, Exelixis, Geron, Oncosec, Incyte, Jazz Pharmaceuticals, Juno Therapeutics, Kite Pharma, and Miltenyi Biotec.

SOURCE: Shah NN et al. ASCO 2019. Abstract 2510.

This article was updated on 7/8/2019

CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.

APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.

TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.

Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).

As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.

“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.

The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.

The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.

As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).

HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).

A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.

However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.

“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.

“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.

Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.

SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .

CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.

APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.

TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.

Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).

As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.

“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.

The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.

The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.

As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).

HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).

A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.

However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.

“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.

“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.

Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.

SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .

CHICAGO – Higher levels of several immune markers confer better response and outcomes in patients with HER2-positive breast cancer treated with trastuzumab and pertuzumab, according to a comprehensive biomarker analysis of data from the randomized, phase 3 APHINITY trial.

APHINITY randomized 4,805 patients with HER2-positive breast cancer to adjuvant chemotherapy with trastuzumab plus either pertuzumab or placebo and demonstrated a small improvement of just 1.7% in invasive disease–free survival at 4 years with the addition of adjuvant pertuzumab. The current analysis involved a nested case-control assessment of 1,023 patient samples from the trial to identify “biomarkers beyond clinical parameters” that could identify subgroups of patients who might benefit more from the addition of pertuzumab, Ian E. Krop, MD, PhD, reported at the annual meeting of the American Society of Clinical Oncology.

The genomic and immune marker-based analysis included DNA, whole transcriptome, tumor-infiltrating lymphocytes (TILs), and HER2 analyses, and after adjustment for treatment, hormone receptor status, nodal status, age, and chemotherapy type. Topoisomerase II-alpha amplification and higher messenger RNA expression of an immune signature consisting of interferon-gamma (IFNG), programmed death-ligand 1 (PD-L1), and chemokine (C-X-C motif) ligand 9 (CXCL9) were associated with better prognosis (hazard ratios, 0.68 and 0.91, respectively), said Dr. Krop, associate chief of the division of breast oncology at the Susan F. Smith Center for Women’s Cancers and clinical research director of the breast oncology center at Dana-Farber Cancer Institute, both in Boston.

TILs also suggested better outcomes (HR, 0.91), and HER2 copy number of six or greater versus lower levels of HER2 copy number was also associated with better prognosis (HR, 0.68), he noted.

Conversely, PI3K/PTEN/AKT gene alterations and MYC and ZNF703 amplification each were associated with worse outcomes (HRs, 1.35, 1.61, and 1.62, respectively).

As for predictive value, no significant association was seen between any of the amplification events and benefit of pertuzumab, nor was an interaction seen between the three-gene signature and pertuzumab benefit, Dr. Krop said.

“But if you look at the individual genes and ... the highest quartiles of expression of these genes – particularly interferon gamma and CXCL9 – it did appear that there was a statistically significant improvement in the benefit of pertuzumab if you had the highest levels of these genes, compared to lower levels of these genes,” he added.

The hazard ratios for CXCL9 of 0%-75% and greater than 75%, for example, were 0.95 and 0.49, respectively.

The interaction P values for IFNG and CXCL9 were statistically significant, but a trend toward benefit with PD-L1 did not reach statistical significance, Dr. Krop noted.

As with IFNG and CXCL9, the highest quartiles of TILs also predicted greater pertuzumab benefit (HRs for TILs at 0-75% and greater than 75%, 0.95 and 0.35, respectively), and the association was highly significant (P = .003).

HER2 copy number of six or greater was also associated with significantly greater benefit with pertuzumab (HRs for copy number of six or greater vs. less than six, 0.75 and 1.41, respectively).

A trend was seen toward decreased benefit of pertuzumab in patients with P13K/PTEN/AKT alteration, but this was not statistically significant, he noted.

However, the trend, coupled with the poor prognosis found to be associated with P13K-altered cancers, “would suggest that we need to identify new therapies – alternative approaches – to maximize treatment benefit in this cancer subtype,” he said.

“This biomarker analysis is possibly the largest and most comprehensive to date in HER2-positive breast cancer,” Dr. Krop said, noting that the findings provide support for an immune-mediated mechanism of action for pertuzumab, and suggest a need for alternative therapies for patients with low levels of TILs or immune gene markers in order to maximize their outcomes.

“We hope these data will be useful to refine future trials of early-stage HER2-positive breast cancer,” he said.

Dr. Krop reported relationships – including employment, leadership, and stock ownership – with AMAG, as well as honoraria from Genentech/Roche; consulting or advisory roles with Context Therapeutics, Daiichi Sankyo, Genentech/Roche, MacroGenics, Seattle Genetics, and Taiho Pharmaceutical; and research funding from Genentech and Pfizer to his institution.

SOURCE: Krop IE et al. ASCO 2019, Abstract 1012 .

CHICAGO – Tumor protein 53 (TP53) mutation, fibroblast growth factor receptor 1 (FGFR1) amplification, and tumor purity in plasma each predict early progression on palbociclib and/or fulvestrant in patients with advanced estrogen receptor–positive (ER+) breast cancer, according to genomic analyses of PALOMA-3 trial data.

Sharon Worcester/MDedge News

Overall, the presence of one or more of these genomic changes identified 131 out of 310 patients from the phase 3 trial who had baseline samples available, Ben O’Leary, MBBS, said at the annual meeting of the American Society of Clinical Oncology.

“So, a significant minority of patients – 42.3% – potentially who fall into a more poor-prognosis group,” said Dr. O’Leary of the Institute of Cancer Research at the Royal Marsden Hospital in London.

The findings suggest that a “liquid biopsy” at the start of treatment could identify patients at risk for progression.

The PALOMA-3 trial randomized 521 patients with ER+, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had previously progressed on endocrine therapy 2:1 to CDK4/CDK6 inhibition with palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F), and it showed that adding palbociclib significantly improved progression-free survival (PFS) (N Engl J Med. Jul 16 2015;373:209-19).

For the current analysis, the investigators assessed circulating tumor DNA (ctDNA) in baseline plasma samples from 459 study participants in an effort to identify genomic biomarkers for progression, to examine the association between baseline tumor fraction and clinical outcome, and to explore differences in predictive markers by treatment arm. A custom amplicon-sequencing analysis was performed to look for mutations in 17 different relevant genes, and another was used to estimate tumor fraction by looking at about 800 common germline single-nucleotide polymorphisms and to assess copy-number gain in the amplification status in 11 different genes, Dr. O’Leary said.


Results for mutations and circulating nucleic acids were available in 203 and 107 patients from the P+F and F groups, respectively, and on multivariable analysis of all 310 patients (including palbociclib as a variable in the model and with ctDNA fraction as a continuous variable), higher baseline tumor purity in plasma was associated with highly significantly worse PFS (HR 1.2 per 10% increase in purity), and baseline TP53 mutation and FGFR1 amplification each were associated with significantly shorter PFS (HRs, 1.8 and 2.9, respectively).

“[It is] very important to note ... that we did look specifically for interaction between our genomic changes and treatment, and we didn’t find any evidence of a significant interaction, so these genomic markers [are] prognostic rather than predictive in terms of the two treatment arms of the trial,” he said.

A survival analysis showed a median PFS of 3.7 vs. 12.7 months in patients with vs. without TP53 mutation in the P+F arm, and 1.8 vs. 5.4 months, respectively, in the F arm, with similar HRs of 2.0 and 2.3 in the arms, respectively.

“Even in the [P+F] arm, you see almost half of the patients with a TP53 mutation ... have relapsed by 2 months, the earliest clinical assessment in the trial,” he noted.

For FGFR1, the PFS was 3.9 vs. 12 months with vs. without amplification in the P+F arms, and 1.8 vs. 5.8 months, respectively in th F arm, with HRs of 3.4 and 3.6, respectively.

These findings are notable because markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited – despite the key role of these combinations in treating ER+ advanced breast cancer, Dr. O’Leary explained.

“Although many patients derive a great deal of benefit from these combinations, there are a subset of patients who will relapse relatively early, and ... we don’t have an established means of identifying those patients at the present,” he said. “From the technical perspective, liquid biopsies have emerged in recent years as a promising means of genotyping patients’ cancers from circulating tumor DNA, and in addition, the overall level of circulating tumor DNA – the fractional purity – has been associated with poor prognosis, specifically in the triple-negative breast cancer setting.”

The results, which require independent validation, could potentially inform future clinical trials of CDK4/6 inhibitor combinations in advanced ER+ breast cancer to identify a high-risk group of patients who require escalation of therapy, he concluded.

Dr. O’Leary reported receiving research funding from Pfizer to his institution.

SOURCE: O’Leary B et al. ASCO 2019, Abstract 1010.

CHICAGO – Tumor protein 53 (TP53) mutation, fibroblast growth factor receptor 1 (FGFR1) amplification, and tumor purity in plasma each predict early progression on palbociclib and/or fulvestrant in patients with advanced estrogen receptor–positive (ER+) breast cancer, according to genomic analyses of PALOMA-3 trial data.

Sharon Worcester/MDedge News

Overall, the presence of one or more of these genomic changes identified 131 out of 310 patients from the phase 3 trial who had baseline samples available, Ben O’Leary, MBBS, said at the annual meeting of the American Society of Clinical Oncology.

“So, a significant minority of patients – 42.3% – potentially who fall into a more poor-prognosis group,” said Dr. O’Leary of the Institute of Cancer Research at the Royal Marsden Hospital in London.

The findings suggest that a “liquid biopsy” at the start of treatment could identify patients at risk for progression.

The PALOMA-3 trial randomized 521 patients with ER+, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had previously progressed on endocrine therapy 2:1 to CDK4/CDK6 inhibition with palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F), and it showed that adding palbociclib significantly improved progression-free survival (PFS) (N Engl J Med. Jul 16 2015;373:209-19).

For the current analysis, the investigators assessed circulating tumor DNA (ctDNA) in baseline plasma samples from 459 study participants in an effort to identify genomic biomarkers for progression, to examine the association between baseline tumor fraction and clinical outcome, and to explore differences in predictive markers by treatment arm. A custom amplicon-sequencing analysis was performed to look for mutations in 17 different relevant genes, and another was used to estimate tumor fraction by looking at about 800 common germline single-nucleotide polymorphisms and to assess copy-number gain in the amplification status in 11 different genes, Dr. O’Leary said.


Results for mutations and circulating nucleic acids were available in 203 and 107 patients from the P+F and F groups, respectively, and on multivariable analysis of all 310 patients (including palbociclib as a variable in the model and with ctDNA fraction as a continuous variable), higher baseline tumor purity in plasma was associated with highly significantly worse PFS (HR 1.2 per 10% increase in purity), and baseline TP53 mutation and FGFR1 amplification each were associated with significantly shorter PFS (HRs, 1.8 and 2.9, respectively).

“[It is] very important to note ... that we did look specifically for interaction between our genomic changes and treatment, and we didn’t find any evidence of a significant interaction, so these genomic markers [are] prognostic rather than predictive in terms of the two treatment arms of the trial,” he said.

A survival analysis showed a median PFS of 3.7 vs. 12.7 months in patients with vs. without TP53 mutation in the P+F arm, and 1.8 vs. 5.4 months, respectively, in the F arm, with similar HRs of 2.0 and 2.3 in the arms, respectively.

“Even in the [P+F] arm, you see almost half of the patients with a TP53 mutation ... have relapsed by 2 months, the earliest clinical assessment in the trial,” he noted.

For FGFR1, the PFS was 3.9 vs. 12 months with vs. without amplification in the P+F arms, and 1.8 vs. 5.8 months, respectively in th F arm, with HRs of 3.4 and 3.6, respectively.

These findings are notable because markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited – despite the key role of these combinations in treating ER+ advanced breast cancer, Dr. O’Leary explained.

“Although many patients derive a great deal of benefit from these combinations, there are a subset of patients who will relapse relatively early, and ... we don’t have an established means of identifying those patients at the present,” he said. “From the technical perspective, liquid biopsies have emerged in recent years as a promising means of genotyping patients’ cancers from circulating tumor DNA, and in addition, the overall level of circulating tumor DNA – the fractional purity – has been associated with poor prognosis, specifically in the triple-negative breast cancer setting.”

The results, which require independent validation, could potentially inform future clinical trials of CDK4/6 inhibitor combinations in advanced ER+ breast cancer to identify a high-risk group of patients who require escalation of therapy, he concluded.

Dr. O’Leary reported receiving research funding from Pfizer to his institution.

SOURCE: O’Leary B et al. ASCO 2019, Abstract 1010.

CHICAGO – Tumor protein 53 (TP53) mutation, fibroblast growth factor receptor 1 (FGFR1) amplification, and tumor purity in plasma each predict early progression on palbociclib and/or fulvestrant in patients with advanced estrogen receptor–positive (ER+) breast cancer, according to genomic analyses of PALOMA-3 trial data.

Sharon Worcester/MDedge News

Overall, the presence of one or more of these genomic changes identified 131 out of 310 patients from the phase 3 trial who had baseline samples available, Ben O’Leary, MBBS, said at the annual meeting of the American Society of Clinical Oncology.

“So, a significant minority of patients – 42.3% – potentially who fall into a more poor-prognosis group,” said Dr. O’Leary of the Institute of Cancer Research at the Royal Marsden Hospital in London.

The findings suggest that a “liquid biopsy” at the start of treatment could identify patients at risk for progression.

The PALOMA-3 trial randomized 521 patients with ER+, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer who had previously progressed on endocrine therapy 2:1 to CDK4/CDK6 inhibition with palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F), and it showed that adding palbociclib significantly improved progression-free survival (PFS) (N Engl J Med. Jul 16 2015;373:209-19).

For the current analysis, the investigators assessed circulating tumor DNA (ctDNA) in baseline plasma samples from 459 study participants in an effort to identify genomic biomarkers for progression, to examine the association between baseline tumor fraction and clinical outcome, and to explore differences in predictive markers by treatment arm. A custom amplicon-sequencing analysis was performed to look for mutations in 17 different relevant genes, and another was used to estimate tumor fraction by looking at about 800 common germline single-nucleotide polymorphisms and to assess copy-number gain in the amplification status in 11 different genes, Dr. O’Leary said.


Results for mutations and circulating nucleic acids were available in 203 and 107 patients from the P+F and F groups, respectively, and on multivariable analysis of all 310 patients (including palbociclib as a variable in the model and with ctDNA fraction as a continuous variable), higher baseline tumor purity in plasma was associated with highly significantly worse PFS (HR 1.2 per 10% increase in purity), and baseline TP53 mutation and FGFR1 amplification each were associated with significantly shorter PFS (HRs, 1.8 and 2.9, respectively).

“[It is] very important to note ... that we did look specifically for interaction between our genomic changes and treatment, and we didn’t find any evidence of a significant interaction, so these genomic markers [are] prognostic rather than predictive in terms of the two treatment arms of the trial,” he said.

A survival analysis showed a median PFS of 3.7 vs. 12.7 months in patients with vs. without TP53 mutation in the P+F arm, and 1.8 vs. 5.4 months, respectively, in the F arm, with similar HRs of 2.0 and 2.3 in the arms, respectively.

“Even in the [P+F] arm, you see almost half of the patients with a TP53 mutation ... have relapsed by 2 months, the earliest clinical assessment in the trial,” he noted.

For FGFR1, the PFS was 3.9 vs. 12 months with vs. without amplification in the P+F arms, and 1.8 vs. 5.8 months, respectively in th F arm, with HRs of 3.4 and 3.6, respectively.

These findings are notable because markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited – despite the key role of these combinations in treating ER+ advanced breast cancer, Dr. O’Leary explained.

“Although many patients derive a great deal of benefit from these combinations, there are a subset of patients who will relapse relatively early, and ... we don’t have an established means of identifying those patients at the present,” he said. “From the technical perspective, liquid biopsies have emerged in recent years as a promising means of genotyping patients’ cancers from circulating tumor DNA, and in addition, the overall level of circulating tumor DNA – the fractional purity – has been associated with poor prognosis, specifically in the triple-negative breast cancer setting.”

The results, which require independent validation, could potentially inform future clinical trials of CDK4/6 inhibitor combinations in advanced ER+ breast cancer to identify a high-risk group of patients who require escalation of therapy, he concluded.

Dr. O’Leary reported receiving research funding from Pfizer to his institution.

SOURCE: O’Leary B et al. ASCO 2019, Abstract 1010.

CHICAGO – A six-drug combination produced complete responses in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL) patients in a phase 2 trial.

Jennifer Smith/ MDedge News

Induction with durvalumab and R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) produced complete response rates of 54% in the entire cohort and 41% in patients with double- or triple-hit lymphoma. Immune-related adverse events (AEs) were common with this regimen, but no unexpected AEs occurred, according to researchers.

Grzegorz S. Nowakowski, MD, of the Mayo Clinic in Rochester, Minn., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

Treatment

The phase 2 trial (NCT03003520) was designed to assess durvalumab plus R-CHOP as well as durvalumab plus R-CHOP and lenalidomide (R2-CHOP) in patients with previously untreated, high-risk DLBCL. However, the R2-CHOP arm was closed early.

In cycle one, all patients received durvalumab plus R-CHOP. For subsequent cycles, patients with activated B-cell (ABC) DLBCL were assigned to durvalumab plus R2-CHOP, while patients with non-ABC DLBCL continued on durvalumab plus R-CHOP.

The R2-CHOP arm was closed early due to safety issues observed in trials combining checkpoint inhibitors with immunomodulatory agents. A partial clinical hold was placed on the R2-CHOP arm, but patients could continue on the regimen if they experienced a clinical benefit. Any patients with ABC DLBCL who were enrolled after the partial hold received treatment with durvalumab plus R-CHOP.

Induction was given for up to eight cycles and was followed by consolidation with durvalumab alone for up to 12 months from the start of induction.

Patient characteristics

The researchers presented data on 43 patients in the durvalumab plus R-CHOP arm. The patients’ median age was 62 years, and 61% were men.

“I think it’s worth noting that 46% of patients in the durvalumab plus R-CHOP group had very high-risk features, including double-hit or triple-hit genetic features,” said Justin Kline, MD, of the University of Chicago Medicine who reviewed this study in a poster discussion session.

Specifically, 30% of patients had double-hit lymphoma, and 16% had triple-hit lymphoma. Most patients had a high-intermediate-risk (49%) or high-risk (21%) International Prognostic Index score, and 79% of patients had Ann Arbor stage IV disease.

Efficacy

As of Aug. 2, 2018, 70% of patients had completed induction, 2% had completed consolidation, 44% remained on treatment, and 54% had discontinued therapy. The most common reasons for stopping treatment were progression (16%), AEs (14%), and consent withdrawal (12%).

“The combination of durvalumab plus R-CHOP demonstrated encouraging response rates … in subjects with high-risk DLBCL, including double- and triple-hit lymphomas,” Dr. Kline said.

The complete response rate was 54% (20/37) at the end of induction and 68% (n = 25) at the end of consolidation. The partial response rate at the end of consolidation was 30% (n = 11).

In patients with double- or triple-hit lymphoma, the complete response rate at the end of induction was 41% (7/17). The overall response rate in this group was 88% (n = 15).

Safety

“The safety profile was as expected for the components of the combination, and no new safety signals were observed,” Dr. Kline said.

He noted that AEs of special interest, or immune-related AEs, occurred in 61% of patients, but most of these events were grade 1 or 2.

AEs of special interest included diarrhea (28%), rash (23%), infusion-related reactions (16%), dermatitis (12%), hypothyroidism (5%), myocarditis (5%), adrenal insufficiency (2%), and hepatitis (2%).

Grade 3 or 4 AEs of special interest included infusion-related reactions (5%), rash (2%), diarrhea (2%), and hepatitis (2%).

The safety and efficacy results support further evaluation of durvalumab plus R-CHOP, although it will be important to identify DLBCL patients who are more likely to derive a clinical benefit from PD-1 or PD-L1 blockade, Dr. Kline said.

“This early study showed that the combination is feasible,” Dr. Nowakowski added. “I think, down the road, we’ll need to identify patients who can actually benefit from this combination. We definitely have clinical evidence of exceptional responses to PD-1 blockade.”

The trial was sponsored by Celgene. Dr. Nowakowski reported relationships with Celgene, Genentech, MorphoSys, and NanoString Technologies. Dr. Kline reported relationships with Cardinal Health, Merck, Seattle Genetics, Kite/Gilead, ITeos Therapeutics, and Bristol-Myers Squibb.

jensmith@mdedge.com

SOURCE: Nowakowski GS et al. ASCO 2019, Abstract 7520.

CHICAGO – A six-drug combination produced complete responses in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL) patients in a phase 2 trial.

Jennifer Smith/ MDedge News

Induction with durvalumab and R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) produced complete response rates of 54% in the entire cohort and 41% in patients with double- or triple-hit lymphoma. Immune-related adverse events (AEs) were common with this regimen, but no unexpected AEs occurred, according to researchers.

Grzegorz S. Nowakowski, MD, of the Mayo Clinic in Rochester, Minn., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

Treatment

The phase 2 trial (NCT03003520) was designed to assess durvalumab plus R-CHOP as well as durvalumab plus R-CHOP and lenalidomide (R2-CHOP) in patients with previously untreated, high-risk DLBCL. However, the R2-CHOP arm was closed early.

In cycle one, all patients received durvalumab plus R-CHOP. For subsequent cycles, patients with activated B-cell (ABC) DLBCL were assigned to durvalumab plus R2-CHOP, while patients with non-ABC DLBCL continued on durvalumab plus R-CHOP.

The R2-CHOP arm was closed early due to safety issues observed in trials combining checkpoint inhibitors with immunomodulatory agents. A partial clinical hold was placed on the R2-CHOP arm, but patients could continue on the regimen if they experienced a clinical benefit. Any patients with ABC DLBCL who were enrolled after the partial hold received treatment with durvalumab plus R-CHOP.

Induction was given for up to eight cycles and was followed by consolidation with durvalumab alone for up to 12 months from the start of induction.

Patient characteristics

The researchers presented data on 43 patients in the durvalumab plus R-CHOP arm. The patients’ median age was 62 years, and 61% were men.

“I think it’s worth noting that 46% of patients in the durvalumab plus R-CHOP group had very high-risk features, including double-hit or triple-hit genetic features,” said Justin Kline, MD, of the University of Chicago Medicine who reviewed this study in a poster discussion session.

Specifically, 30% of patients had double-hit lymphoma, and 16% had triple-hit lymphoma. Most patients had a high-intermediate-risk (49%) or high-risk (21%) International Prognostic Index score, and 79% of patients had Ann Arbor stage IV disease.

Efficacy

As of Aug. 2, 2018, 70% of patients had completed induction, 2% had completed consolidation, 44% remained on treatment, and 54% had discontinued therapy. The most common reasons for stopping treatment were progression (16%), AEs (14%), and consent withdrawal (12%).

“The combination of durvalumab plus R-CHOP demonstrated encouraging response rates … in subjects with high-risk DLBCL, including double- and triple-hit lymphomas,” Dr. Kline said.

The complete response rate was 54% (20/37) at the end of induction and 68% (n = 25) at the end of consolidation. The partial response rate at the end of consolidation was 30% (n = 11).

In patients with double- or triple-hit lymphoma, the complete response rate at the end of induction was 41% (7/17). The overall response rate in this group was 88% (n = 15).

Safety

“The safety profile was as expected for the components of the combination, and no new safety signals were observed,” Dr. Kline said.

He noted that AEs of special interest, or immune-related AEs, occurred in 61% of patients, but most of these events were grade 1 or 2.

AEs of special interest included diarrhea (28%), rash (23%), infusion-related reactions (16%), dermatitis (12%), hypothyroidism (5%), myocarditis (5%), adrenal insufficiency (2%), and hepatitis (2%).

Grade 3 or 4 AEs of special interest included infusion-related reactions (5%), rash (2%), diarrhea (2%), and hepatitis (2%).

The safety and efficacy results support further evaluation of durvalumab plus R-CHOP, although it will be important to identify DLBCL patients who are more likely to derive a clinical benefit from PD-1 or PD-L1 blockade, Dr. Kline said.

“This early study showed that the combination is feasible,” Dr. Nowakowski added. “I think, down the road, we’ll need to identify patients who can actually benefit from this combination. We definitely have clinical evidence of exceptional responses to PD-1 blockade.”

The trial was sponsored by Celgene. Dr. Nowakowski reported relationships with Celgene, Genentech, MorphoSys, and NanoString Technologies. Dr. Kline reported relationships with Cardinal Health, Merck, Seattle Genetics, Kite/Gilead, ITeos Therapeutics, and Bristol-Myers Squibb.

jensmith@mdedge.com

SOURCE: Nowakowski GS et al. ASCO 2019, Abstract 7520.

CHICAGO – A six-drug combination produced complete responses in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL) patients in a phase 2 trial.

Jennifer Smith/ MDedge News

Induction with durvalumab and R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) produced complete response rates of 54% in the entire cohort and 41% in patients with double- or triple-hit lymphoma. Immune-related adverse events (AEs) were common with this regimen, but no unexpected AEs occurred, according to researchers.

Grzegorz S. Nowakowski, MD, of the Mayo Clinic in Rochester, Minn., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

Treatment

The phase 2 trial (NCT03003520) was designed to assess durvalumab plus R-CHOP as well as durvalumab plus R-CHOP and lenalidomide (R2-CHOP) in patients with previously untreated, high-risk DLBCL. However, the R2-CHOP arm was closed early.

In cycle one, all patients received durvalumab plus R-CHOP. For subsequent cycles, patients with activated B-cell (ABC) DLBCL were assigned to durvalumab plus R2-CHOP, while patients with non-ABC DLBCL continued on durvalumab plus R-CHOP.

The R2-CHOP arm was closed early due to safety issues observed in trials combining checkpoint inhibitors with immunomodulatory agents. A partial clinical hold was placed on the R2-CHOP arm, but patients could continue on the regimen if they experienced a clinical benefit. Any patients with ABC DLBCL who were enrolled after the partial hold received treatment with durvalumab plus R-CHOP.

Induction was given for up to eight cycles and was followed by consolidation with durvalumab alone for up to 12 months from the start of induction.

Patient characteristics

The researchers presented data on 43 patients in the durvalumab plus R-CHOP arm. The patients’ median age was 62 years, and 61% were men.

“I think it’s worth noting that 46% of patients in the durvalumab plus R-CHOP group had very high-risk features, including double-hit or triple-hit genetic features,” said Justin Kline, MD, of the University of Chicago Medicine who reviewed this study in a poster discussion session.

Specifically, 30% of patients had double-hit lymphoma, and 16% had triple-hit lymphoma. Most patients had a high-intermediate-risk (49%) or high-risk (21%) International Prognostic Index score, and 79% of patients had Ann Arbor stage IV disease.

Efficacy

As of Aug. 2, 2018, 70% of patients had completed induction, 2% had completed consolidation, 44% remained on treatment, and 54% had discontinued therapy. The most common reasons for stopping treatment were progression (16%), AEs (14%), and consent withdrawal (12%).

“The combination of durvalumab plus R-CHOP demonstrated encouraging response rates … in subjects with high-risk DLBCL, including double- and triple-hit lymphomas,” Dr. Kline said.

The complete response rate was 54% (20/37) at the end of induction and 68% (n = 25) at the end of consolidation. The partial response rate at the end of consolidation was 30% (n = 11).

In patients with double- or triple-hit lymphoma, the complete response rate at the end of induction was 41% (7/17). The overall response rate in this group was 88% (n = 15).

Safety

“The safety profile was as expected for the components of the combination, and no new safety signals were observed,” Dr. Kline said.

He noted that AEs of special interest, or immune-related AEs, occurred in 61% of patients, but most of these events were grade 1 or 2.

AEs of special interest included diarrhea (28%), rash (23%), infusion-related reactions (16%), dermatitis (12%), hypothyroidism (5%), myocarditis (5%), adrenal insufficiency (2%), and hepatitis (2%).

Grade 3 or 4 AEs of special interest included infusion-related reactions (5%), rash (2%), diarrhea (2%), and hepatitis (2%).

The safety and efficacy results support further evaluation of durvalumab plus R-CHOP, although it will be important to identify DLBCL patients who are more likely to derive a clinical benefit from PD-1 or PD-L1 blockade, Dr. Kline said.

“This early study showed that the combination is feasible,” Dr. Nowakowski added. “I think, down the road, we’ll need to identify patients who can actually benefit from this combination. We definitely have clinical evidence of exceptional responses to PD-1 blockade.”

The trial was sponsored by Celgene. Dr. Nowakowski reported relationships with Celgene, Genentech, MorphoSys, and NanoString Technologies. Dr. Kline reported relationships with Cardinal Health, Merck, Seattle Genetics, Kite/Gilead, ITeos Therapeutics, and Bristol-Myers Squibb.

jensmith@mdedge.com

SOURCE: Nowakowski GS et al. ASCO 2019, Abstract 7520.

CHICAGO – Lenalidomide plus rituximab (R²) demonstrated activity against relapsed or refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase 3b MAGNIFY trial.

Jennifer Smith/MDedge News

R² produced responses in FL and MZL patients, including those who had previously experienced early relapse and patients who were refractory to rituximab or both lenalidomide and rituximab at baseline.

David Jacob Andorsky, MD, of Rocky Mountain Cancer Centers in Boulder, Colo., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

The ongoing MAGNIFY trial has enrolled 370 patients with relapsed/refractory FL (grade 1-3a) or MZL.

For induction, patients receive lenalidomide (20 mg per day on days 1-21 for 12 cycles) and rituximab (375 mg/m² per week in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11). Patients who achieve stable disease or better on R² induction are randomized to maintenance with R² or rituximab alone.

Dr. Andorsky and colleagues presented results of R² induction in 310 evaluable patients – 247 with FL and 63 with MZL.

The patients had a median age of 66 years (range, 35-91 years) at baseline, and they had received a median of two prior therapies (range, one to eight). Some patients had experienced early relapse (37%, n = 115), were refractory to rituximab (36%, n = 113), or were refractory to both rituximab and lenalidomide (20%, n = 63) at baseline.

Results

At a median follow-up of 16.7 months, the overall response rate was 73%, and the complete response rate was 45%. The overall response rate was 74% in FL patients, 65% in MZL patients, 63% in rituximab-refractory patients, 51% in double-refractory patients, and 68% in patients with an early relapse.

The median duration of response was 36.8 months in all patients, 35.8 months in MZL patients, and not reached in FL patients. The median duration of response was 35.8 months in patients who were rituximab refractory and was not reached in patients who were not refractory to rituximab.

The median progression-free survival was 36 months overall, 30 months in FL patients, 38 months in MZL patients, 23 months in patients with early relapse, and 15.5 months in double-refractory patients.

“While these [subgroup analyses of efficacy] were exploratory endpoints, I think this suggests that [R²] is a promising regimen for patients that are in the high-risk subgroup,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.

The most common adverse events in this trial were fatigue (48%), neutropenia (40%), diarrhea (35%), nausea (30%), and constipation (29%). The most common grade 3/4 adverse event was neutropenia (34%).

The MAGNIFY trial is sponsored by Celgene. Dr. Andorsky reported financial relationships with Celgene, CTI BioPharma, and Gilead Sciences. Dr. Casulo reported financial relationships with Gilead Sciences, Celgene, and Roche.

jensmith@mdedge.com

SOURCE: Andorsky DJ et al. ASCO 2019, Abstract 7513.

CHICAGO – Lenalidomide plus rituximab (R²) demonstrated activity against relapsed or refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase 3b MAGNIFY trial.

Jennifer Smith/MDedge News

R² produced responses in FL and MZL patients, including those who had previously experienced early relapse and patients who were refractory to rituximab or both lenalidomide and rituximab at baseline.

David Jacob Andorsky, MD, of Rocky Mountain Cancer Centers in Boulder, Colo., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

The ongoing MAGNIFY trial has enrolled 370 patients with relapsed/refractory FL (grade 1-3a) or MZL.

For induction, patients receive lenalidomide (20 mg per day on days 1-21 for 12 cycles) and rituximab (375 mg/m² per week in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11). Patients who achieve stable disease or better on R² induction are randomized to maintenance with R² or rituximab alone.

Dr. Andorsky and colleagues presented results of R² induction in 310 evaluable patients – 247 with FL and 63 with MZL.

The patients had a median age of 66 years (range, 35-91 years) at baseline, and they had received a median of two prior therapies (range, one to eight). Some patients had experienced early relapse (37%, n = 115), were refractory to rituximab (36%, n = 113), or were refractory to both rituximab and lenalidomide (20%, n = 63) at baseline.

Results

At a median follow-up of 16.7 months, the overall response rate was 73%, and the complete response rate was 45%. The overall response rate was 74% in FL patients, 65% in MZL patients, 63% in rituximab-refractory patients, 51% in double-refractory patients, and 68% in patients with an early relapse.

The median duration of response was 36.8 months in all patients, 35.8 months in MZL patients, and not reached in FL patients. The median duration of response was 35.8 months in patients who were rituximab refractory and was not reached in patients who were not refractory to rituximab.

The median progression-free survival was 36 months overall, 30 months in FL patients, 38 months in MZL patients, 23 months in patients with early relapse, and 15.5 months in double-refractory patients.

“While these [subgroup analyses of efficacy] were exploratory endpoints, I think this suggests that [R²] is a promising regimen for patients that are in the high-risk subgroup,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.

The most common adverse events in this trial were fatigue (48%), neutropenia (40%), diarrhea (35%), nausea (30%), and constipation (29%). The most common grade 3/4 adverse event was neutropenia (34%).

The MAGNIFY trial is sponsored by Celgene. Dr. Andorsky reported financial relationships with Celgene, CTI BioPharma, and Gilead Sciences. Dr. Casulo reported financial relationships with Gilead Sciences, Celgene, and Roche.

jensmith@mdedge.com

SOURCE: Andorsky DJ et al. ASCO 2019, Abstract 7513.

CHICAGO – Lenalidomide plus rituximab (R²) demonstrated activity against relapsed or refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL) in the phase 3b MAGNIFY trial.

Jennifer Smith/MDedge News

R² produced responses in FL and MZL patients, including those who had previously experienced early relapse and patients who were refractory to rituximab or both lenalidomide and rituximab at baseline.

David Jacob Andorsky, MD, of Rocky Mountain Cancer Centers in Boulder, Colo., and colleagues presented these results in a poster at the annual meeting of the American Society of Clinical Oncology.

The ongoing MAGNIFY trial has enrolled 370 patients with relapsed/refractory FL (grade 1-3a) or MZL.

For induction, patients receive lenalidomide (20 mg per day on days 1-21 for 12 cycles) and rituximab (375 mg/m² per week in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11). Patients who achieve stable disease or better on R² induction are randomized to maintenance with R² or rituximab alone.

Dr. Andorsky and colleagues presented results of R² induction in 310 evaluable patients – 247 with FL and 63 with MZL.

The patients had a median age of 66 years (range, 35-91 years) at baseline, and they had received a median of two prior therapies (range, one to eight). Some patients had experienced early relapse (37%, n = 115), were refractory to rituximab (36%, n = 113), or were refractory to both rituximab and lenalidomide (20%, n = 63) at baseline.

Results

At a median follow-up of 16.7 months, the overall response rate was 73%, and the complete response rate was 45%. The overall response rate was 74% in FL patients, 65% in MZL patients, 63% in rituximab-refractory patients, 51% in double-refractory patients, and 68% in patients with an early relapse.

The median duration of response was 36.8 months in all patients, 35.8 months in MZL patients, and not reached in FL patients. The median duration of response was 35.8 months in patients who were rituximab refractory and was not reached in patients who were not refractory to rituximab.

The median progression-free survival was 36 months overall, 30 months in FL patients, 38 months in MZL patients, 23 months in patients with early relapse, and 15.5 months in double-refractory patients.

“While these [subgroup analyses of efficacy] were exploratory endpoints, I think this suggests that [R²] is a promising regimen for patients that are in the high-risk subgroup,” said Carla Casulo, MD, of the University of Rochester (N.Y.), who reviewed this study in a poster discussion session.

The most common adverse events in this trial were fatigue (48%), neutropenia (40%), diarrhea (35%), nausea (30%), and constipation (29%). The most common grade 3/4 adverse event was neutropenia (34%).

The MAGNIFY trial is sponsored by Celgene. Dr. Andorsky reported financial relationships with Celgene, CTI BioPharma, and Gilead Sciences. Dr. Casulo reported financial relationships with Gilead Sciences, Celgene, and Roche.

jensmith@mdedge.com

SOURCE: Andorsky DJ et al. ASCO 2019, Abstract 7513.

CHICAGO – Clinical risk stratification adds prognostic value to the 21-gene recurrence score for guiding treatment selection in patients with early breast cancer, according to a secondary analysis of data from the practice-changing TAILORx study.

Sharon Worcester/MDedge News

Specifically, tumor size and histology-based risk stratification improves the prediction of disease-free survival and distant recurrence, and – for some patient groups – chemotherapy benefit, Joseph A. Sparano, MD, reported at the annual meeting of the American Society of Clinical Oncology.

Combining these tools could help determine whether endocrine therapy (ET) alone or ET with adjuvant chemotherapy is the best treatment approach for a given patient, said Dr. Sparano, professor of medicine and obstetrics, gynecology, and women’s health at Albert Einstein College of Medicine, New York.

The phase 3 TAILORx study established that ET alone is noninferior to adjuvant chemotherapy (CT) plus ET in patients with early breast cancer and RS of 11-25, and that ET alone has some benefit over ET+CT in women aged 50 years and younger with RS of 16-25, he explained.

Those findings were presented at the 2018 ASCO annual meeting and subsequently published in the New England Journal of Medicine.

The current analysis focused on the integration of clinical and genomic features for prognosis, and the results were published online June 3 in a corresponding article in the New England Journal of Medicine.

“The totality of the data, including TAILORx and the prior prospective validation studies, indicate that assessment of genomic risk with the 21-gene recurrence score provides complementary prognostic information to pathologic features, and is also predictive of a large chemotherapy benefit if the recurrence score is greater than 25, or lack thereof if 25 or lower,” he said.

However, there is a three-way interaction between age, RS, and CT use, which results in an absolute CT benefit in women aged 50 or younger of about 2% for RS of 16-20, and about 7% for RS of 21-25, he added.

“Assessment of clinical risk using pathological features also provides prognostic information that doesn’t correlate well with the recurrence score, therefore it stands to reason that integration of clinical and genomic risk offers the potential for greater precision in prognosis and, ultimately, guiding the use of adjuvant therapy,” he said.

Clinical risk for this analysis was assessed using a binary clinical risk categorization employed in the MINDACT trial and calibrated to greater than 92% 10-year breast cancer-specific survival for ET alone based on Adjuvant! version 8.0. Low-grade tumors up to 3 cm, intermediate-grade tumors up to 2 cm, and high-grade tumors up to 1 cm were categorized as low clinical risk (LCR), and all others not meeting these criteria were categorized as high clinical risk (HCR), he explained.

Of 9,427 patients included in the analysis, 70% had LCR and 30% had HCR.

“For distant recurrence, high clinical risk was associated with a 2.5- to 3-fold higher recurrence rate for those with a recurrence score of 11 or higher, and in a multivariate model for distant recurrence in the [group with a] recurrence score of 11-25, high clinical risk was independently associated with a 2.4-fold higher recurrence risk,” he said. “Continuous recurrence score also provided significant prognostic information, with each 1-unit increase associated with an 8% higher distant recurrence risk.”

For the overall population, clinical risk added significant prognostic information to the RS for both distant recurrence and disease-free survival, and stratification by age showed that among women over age 50 years, the hazard ratios for distant recurrence ranged from 2.20 to 2.36, and did not substantially vary by age or RS, he said.

However, for the overall population, adding clinical risk to the RS did not improve prediction of chemotherapy benefit.

“This was also true for the two-thirds of women who were over 50 years of age. For the remaining women 50 or younger, there was a trend favoring chemo, irrespective of clinical risk, though not significant – a finding consistent with the treatment interaction previously described,” he said.

Finally, the absolute differences in 9-year distant recurrence rates by clinical risk stratified by age, RS, and CT use showed an absolute 4%-6% higher distant recurrence risk for HCR vs. LCR among those over age 50 with RS of 0-25 irrespective of CT use, and a 13% difference for those with RS of 26-100 who were treated with CT.

“For those 50 or younger, clinical risk had no impact on recurrence if the RS was 0-10. For RS of 11-25, the difference was about 9% with endocrine therapy alone, and 2% with chemo plus ET, reflecting absolute chemo benefit in younger women who had high clinical risk,” he said, adding that for those with RS of 26-100, there was a 9% higher absolute recurrence rate in the HCR vs. LCR population.

“We therefore further evaluated absolute differences in distance recurrence rates associated with chemotherapy use in women 50 and younger with RS of 16-25, further stratified by RS and clinical risk,” he said, noting that when not stratified by clinical risk, as reported in the primary analysis, the absolute CT benefit was 1.6% for RS of 16-20, and 6.5% for RS of 21-25.

When stratified by clinical risk, the absolute CT benefit ranged from 6% to 9% in those with RS of 21-25, irrespective of clinical risk, and in those with RS of 16-20 and HCR.

“This accounted for 51% of patients with RS of 16-25,” he said. “However, there was no demonstrable chemo benefit for those with LCR and RS of 16-20, who accounted for the remaining 49%.”

Additional analysis looking at age at diagnosis and CT benefit showed a benefit in premenopausal women aged 46-50 years (but not postmenopausal women), a trend toward benefit in those aged 41-45 years, and no benefit in those aged 40 years and younger, who are less likely to develop premature menopause as a consequence of cytotoxic CT.

“In addition, we saw no consistent effect favoring chemotherapy in older women. Taken together, these findings suggest the chemo benefit observed for the RS 16-25 group may, in fact, be due to a castration effect associated with cytotoxic therapy rather than an effect in eradicating micrometastatic disease,” Dr. Sparano said.

Applying this framework to the TAILORx study population categorized 68% of those aged 50 years and younger into a low integrated risk group with less than 5% risk of distant recurrence. This included all patients with RS of 0-10 irrespective of clinical risk (14% of the patient population; distant recurrence rate 1.8% or less), and all with RS of 11-25 and LCR (54% of the patient population, 4.7% distant recurrence rate).

In contrast, 25% fell into the high integrated risk group (greater than 10% distant recurrence risk), including those with RS of 11-25 and HCR (17% of the patient population; distant recurrence rate 12.3%), and RS of 26-100 and HCR (8% of the patient population; distant recurrence rate 15.2%).

“This framework encompasses 93% of all TAILORx subjects, with the remaining 7% having a distant recurrence risk of between 5% and 10%,” he said.


Overall, the primary results of TAILORx remain unchanged based on this secondary analysis as the addition of clinical risk did not predict CT benefit in the RS 11-25 group, he noted.

“However, for women 50 and under and RS 16-25, integrated risk distinguished 50% who derived no chemo benefit from the 50% who derived an absolute benefit of approximately 6%-9% – a level that is higher than an unselected population,” he said, reiterating that the absolute CT benefit was greater in premenopausal women aged 45-50 with RS 16-25, suggesting that the absolute CR benefit seen in younger women in TAILORx may be due to an endocrine effect.

“Integrated risk clearly provides greater prognostic precision and may have clinical utility; the prognostic precision afforded by the integrated risk model is superior to that by the use of clinical or genomic features alone, and in addition, the genomic assay also provides predictive information for chemo benefit that is not captured by clinical features alone,” he concluded.

As an example of the potential clinical utility of this integrated approach for guiding treatment in women aged 50 years or younger, he presented “a highly stratified integrated risk assessment model” separating TAILORx patients into low integrated risk (58% of the study population) and high integrated risk (31% of the study population).

In the low integrated risk patients with RS of 0-10 and any clinical risk level, or with RS of 11-25 and LCR, tamoxifen alone appears adequate, he said.

In those with high integrated risk and RS of 16-25 with HCR, ovarian function suppression plus an aromatase inhibitor (OFS/AI) could be considered as an alternative to chemo, and in those with high integrated risk, RS of 26-100, and HCR who have not developed chemotherapy-induced menopause, ovarian function suppression and an AI could be added to chemotherapy.

“Indeed, data from the SOFT and TEXT trials indicate that patients with a high RS risk experienced an absolute improvement of up to 10%-15% in 5-year breast cancer–free interval with an OFS/AI, compared with tamoxifen, whereas improvement was minimal in those at lowest risk, supporting the strategy of using integrated clinical and genomic risk to select for ovarian function suppression plus an AI,” he said.

During a discussion of the findings and how they might impact practice, Vered Stearns, MD, an oncology professor and codirector of the Breast Cancer Program at Johns Hopkins University, Baltimore, noted that in her practice she will “carefully select women for whom genomic assay [use] is appropriate.

“I will also assess clinical risk and RS to inform recommendations for chemotherapy use, and possibly appropriate endocrine agents in select populations,” she said.

Sharon Worcester/MDedge News

Dr. Stearns further noted that the interaction between RS and age as reported by Dr. Sparano is exploratory and should be interpreted with caution as the majority of those aged 50 and younger received tamoxifen alone and the question remains as to whether they would have received similar benefits from ovarian suppression and tamoxifen/AI instead of chemo-endocrine therapy.

“Indeed, indirect hypotheses from other studies suggest that may be the case,” she said, adding that these women may be offered ovarian suppression and tamoxifen or AI based on the SOFT and TEXT results.

“TAILORx remains a rich resource for new explorations, new biomarkers, new models, and new machine learning opportunities,” she said.

TAILORx was funded by the National Institutes of Health. Dr. Sparano reported stock ownership, a consulting role, and research funding from several pharmaceutical companies. Dr. Stearns reported consulting or advisory roles with Iridium Therapeutics; research funding from Abbvie, Biocept, MedImmune, Novartis, Pfizer, and Puma Biotechnology; and an “other relationship” with Immunomedics.

SOURCE: Sparano JA et al. ASCO 2019. Abstract 503.

CHICAGO – Clinical risk stratification adds prognostic value to the 21-gene recurrence score for guiding treatment selection in patients with early breast cancer, according to a secondary analysis of data from the practice-changing TAILORx study.

Sharon Worcester/MDedge News

Specifically, tumor size and histology-based risk stratification improves the prediction of disease-free survival and distant recurrence, and – for some patient groups – chemotherapy benefit, Joseph A. Sparano, MD, reported at the annual meeting of the American Society of Clinical Oncology.

Combining these tools could help determine whether endocrine therapy (ET) alone or ET with adjuvant chemotherapy is the best treatment approach for a given patient, said Dr. Sparano, professor of medicine and obstetrics, gynecology, and women’s health at Albert Einstein College of Medicine, New York.

The phase 3 TAILORx study established that ET alone is noninferior to adjuvant chemotherapy (CT) plus ET in patients with early breast cancer and RS of 11-25, and that ET alone has some benefit over ET+CT in women aged 50 years and younger with RS of 16-25, he explained.

Those findings were presented at the 2018 ASCO annual meeting and subsequently published in the New England Journal of Medicine.

The current analysis focused on the integration of clinical and genomic features for prognosis, and the results were published online June 3 in a corresponding article in the New England Journal of Medicine.

“The totality of the data, including TAILORx and the prior prospective validation studies, indicate that assessment of genomic risk with the 21-gene recurrence score provides complementary prognostic information to pathologic features, and is also predictive of a large chemotherapy benefit if the recurrence score is greater than 25, or lack thereof if 25 or lower,” he said.

However, there is a three-way interaction between age, RS, and CT use, which results in an absolute CT benefit in women aged 50 or younger of about 2% for RS of 16-20, and about 7% for RS of 21-25, he added.

“Assessment of clinical risk using pathological features also provides prognostic information that doesn’t correlate well with the recurrence score, therefore it stands to reason that integration of clinical and genomic risk offers the potential for greater precision in prognosis and, ultimately, guiding the use of adjuvant therapy,” he said.

Clinical risk for this analysis was assessed using a binary clinical risk categorization employed in the MINDACT trial and calibrated to greater than 92% 10-year breast cancer-specific survival for ET alone based on Adjuvant! version 8.0. Low-grade tumors up to 3 cm, intermediate-grade tumors up to 2 cm, and high-grade tumors up to 1 cm were categorized as low clinical risk (LCR), and all others not meeting these criteria were categorized as high clinical risk (HCR), he explained.

Of 9,427 patients included in the analysis, 70% had LCR and 30% had HCR.

“For distant recurrence, high clinical risk was associated with a 2.5- to 3-fold higher recurrence rate for those with a recurrence score of 11 or higher, and in a multivariate model for distant recurrence in the [group with a] recurrence score of 11-25, high clinical risk was independently associated with a 2.4-fold higher recurrence risk,” he said. “Continuous recurrence score also provided significant prognostic information, with each 1-unit increase associated with an 8% higher distant recurrence risk.”

For the overall population, clinical risk added significant prognostic information to the RS for both distant recurrence and disease-free survival, and stratification by age showed that among women over age 50 years, the hazard ratios for distant recurrence ranged from 2.20 to 2.36, and did not substantially vary by age or RS, he said.

However, for the overall population, adding clinical risk to the RS did not improve prediction of chemotherapy benefit.

“This was also true for the two-thirds of women who were over 50 years of age. For the remaining women 50 or younger, there was a trend favoring chemo, irrespective of clinical risk, though not significant – a finding consistent with the treatment interaction previously described,” he said.

Finally, the absolute differences in 9-year distant recurrence rates by clinical risk stratified by age, RS, and CT use showed an absolute 4%-6% higher distant recurrence risk for HCR vs. LCR among those over age 50 with RS of 0-25 irrespective of CT use, and a 13% difference for those with RS of 26-100 who were treated with CT.

“For those 50 or younger, clinical risk had no impact on recurrence if the RS was 0-10. For RS of 11-25, the difference was about 9% with endocrine therapy alone, and 2% with chemo plus ET, reflecting absolute chemo benefit in younger women who had high clinical risk,” he said, adding that for those with RS of 26-100, there was a 9% higher absolute recurrence rate in the HCR vs. LCR population.

“We therefore further evaluated absolute differences in distance recurrence rates associated with chemotherapy use in women 50 and younger with RS of 16-25, further stratified by RS and clinical risk,” he said, noting that when not stratified by clinical risk, as reported in the primary analysis, the absolute CT benefit was 1.6% for RS of 16-20, and 6.5% for RS of 21-25.

When stratified by clinical risk, the absolute CT benefit ranged from 6% to 9% in those with RS of 21-25, irrespective of clinical risk, and in those with RS of 16-20 and HCR.

“This accounted for 51% of patients with RS of 16-25,” he said. “However, there was no demonstrable chemo benefit for those with LCR and RS of 16-20, who accounted for the remaining 49%.”

Additional analysis looking at age at diagnosis and CT benefit showed a benefit in premenopausal women aged 46-50 years (but not postmenopausal women), a trend toward benefit in those aged 41-45 years, and no benefit in those aged 40 years and younger, who are less likely to develop premature menopause as a consequence of cytotoxic CT.

“In addition, we saw no consistent effect favoring chemotherapy in older women. Taken together, these findings suggest the chemo benefit observed for the RS 16-25 group may, in fact, be due to a castration effect associated with cytotoxic therapy rather than an effect in eradicating micrometastatic disease,” Dr. Sparano said.

Applying this framework to the TAILORx study population categorized 68% of those aged 50 years and younger into a low integrated risk group with less than 5% risk of distant recurrence. This included all patients with RS of 0-10 irrespective of clinical risk (14% of the patient population; distant recurrence rate 1.8% or less), and all with RS of 11-25 and LCR (54% of the patient population, 4.7% distant recurrence rate).

In contrast, 25% fell into the high integrated risk group (greater than 10% distant recurrence risk), including those with RS of 11-25 and HCR (17% of the patient population; distant recurrence rate 12.3%), and RS of 26-100 and HCR (8% of the patient population; distant recurrence rate 15.2%).

“This framework encompasses 93% of all TAILORx subjects, with the remaining 7% having a distant recurrence risk of between 5% and 10%,” he said.


Overall, the primary results of TAILORx remain unchanged based on this secondary analysis as the addition of clinical risk did not predict CT benefit in the RS 11-25 group, he noted.

“However, for women 50 and under and RS 16-25, integrated risk distinguished 50% who derived no chemo benefit from the 50% who derived an absolute benefit of approximately 6%-9% – a level that is higher than an unselected population,” he said, reiterating that the absolute CT benefit was greater in premenopausal women aged 45-50 with RS 16-25, suggesting that the absolute CR benefit seen in younger women in TAILORx may be due to an endocrine effect.

“Integrated risk clearly provides greater prognostic precision and may have clinical utility; the prognostic precision afforded by the integrated risk model is superior to that by the use of clinical or genomic features alone, and in addition, the genomic assay also provides predictive information for chemo benefit that is not captured by clinical features alone,” he concluded.

As an example of the potential clinical utility of this integrated approach for guiding treatment in women aged 50 years or younger, he presented “a highly stratified integrated risk assessment model” separating TAILORx patients into low integrated risk (58% of the study population) and high integrated risk (31% of the study population).

In the low integrated risk patients with RS of 0-10 and any clinical risk level, or with RS of 11-25 and LCR, tamoxifen alone appears adequate, he said.

In those with high integrated risk and RS of 16-25 with HCR, ovarian function suppression plus an aromatase inhibitor (OFS/AI) could be considered as an alternative to chemo, and in those with high integrated risk, RS of 26-100, and HCR who have not developed chemotherapy-induced menopause, ovarian function suppression and an AI could be added to chemotherapy.

“Indeed, data from the SOFT and TEXT trials indicate that patients with a high RS risk experienced an absolute improvement of up to 10%-15% in 5-year breast cancer–free interval with an OFS/AI, compared with tamoxifen, whereas improvement was minimal in those at lowest risk, supporting the strategy of using integrated clinical and genomic risk to select for ovarian function suppression plus an AI,” he said.

During a discussion of the findings and how they might impact practice, Vered Stearns, MD, an oncology professor and codirector of the Breast Cancer Program at Johns Hopkins University, Baltimore, noted that in her practice she will “carefully select women for whom genomic assay [use] is appropriate.

“I will also assess clinical risk and RS to inform recommendations for chemotherapy use, and possibly appropriate endocrine agents in select populations,” she said.

Sharon Worcester/MDedge News

Dr. Stearns further noted that the interaction between RS and age as reported by Dr. Sparano is exploratory and should be interpreted with caution as the majority of those aged 50 and younger received tamoxifen alone and the question remains as to whether they would have received similar benefits from ovarian suppression and tamoxifen/AI instead of chemo-endocrine therapy.

“Indeed, indirect hypotheses from other studies suggest that may be the case,” she said, adding that these women may be offered ovarian suppression and tamoxifen or AI based on the SOFT and TEXT results.

“TAILORx remains a rich resource for new explorations, new biomarkers, new models, and new machine learning opportunities,” she said.

TAILORx was funded by the National Institutes of Health. Dr. Sparano reported stock ownership, a consulting role, and research funding from several pharmaceutical companies. Dr. Stearns reported consulting or advisory roles with Iridium Therapeutics; research funding from Abbvie, Biocept, MedImmune, Novartis, Pfizer, and Puma Biotechnology; and an “other relationship” with Immunomedics.

SOURCE: Sparano JA et al. ASCO 2019. Abstract 503.

CHICAGO – Clinical risk stratification adds prognostic value to the 21-gene recurrence score for guiding treatment selection in patients with early breast cancer, according to a secondary analysis of data from the practice-changing TAILORx study.

Sharon Worcester/MDedge News

Specifically, tumor size and histology-based risk stratification improves the prediction of disease-free survival and distant recurrence, and – for some patient groups – chemotherapy benefit, Joseph A. Sparano, MD, reported at the annual meeting of the American Society of Clinical Oncology.

Combining these tools could help determine whether endocrine therapy (ET) alone or ET with adjuvant chemotherapy is the best treatment approach for a given patient, said Dr. Sparano, professor of medicine and obstetrics, gynecology, and women’s health at Albert Einstein College of Medicine, New York.

The phase 3 TAILORx study established that ET alone is noninferior to adjuvant chemotherapy (CT) plus ET in patients with early breast cancer and RS of 11-25, and that ET alone has some benefit over ET+CT in women aged 50 years and younger with RS of 16-25, he explained.

Those findings were presented at the 2018 ASCO annual meeting and subsequently published in the New England Journal of Medicine.

The current analysis focused on the integration of clinical and genomic features for prognosis, and the results were published online June 3 in a corresponding article in the New England Journal of Medicine.

“The totality of the data, including TAILORx and the prior prospective validation studies, indicate that assessment of genomic risk with the 21-gene recurrence score provides complementary prognostic information to pathologic features, and is also predictive of a large chemotherapy benefit if the recurrence score is greater than 25, or lack thereof if 25 or lower,” he said.

However, there is a three-way interaction between age, RS, and CT use, which results in an absolute CT benefit in women aged 50 or younger of about 2% for RS of 16-20, and about 7% for RS of 21-25, he added.

“Assessment of clinical risk using pathological features also provides prognostic information that doesn’t correlate well with the recurrence score, therefore it stands to reason that integration of clinical and genomic risk offers the potential for greater precision in prognosis and, ultimately, guiding the use of adjuvant therapy,” he said.

Clinical risk for this analysis was assessed using a binary clinical risk categorization employed in the MINDACT trial and calibrated to greater than 92% 10-year breast cancer-specific survival for ET alone based on Adjuvant! version 8.0. Low-grade tumors up to 3 cm, intermediate-grade tumors up to 2 cm, and high-grade tumors up to 1 cm were categorized as low clinical risk (LCR), and all others not meeting these criteria were categorized as high clinical risk (HCR), he explained.

Of 9,427 patients included in the analysis, 70% had LCR and 30% had HCR.

“For distant recurrence, high clinical risk was associated with a 2.5- to 3-fold higher recurrence rate for those with a recurrence score of 11 or higher, and in a multivariate model for distant recurrence in the [group with a] recurrence score of 11-25, high clinical risk was independently associated with a 2.4-fold higher recurrence risk,” he said. “Continuous recurrence score also provided significant prognostic information, with each 1-unit increase associated with an 8% higher distant recurrence risk.”

For the overall population, clinical risk added significant prognostic information to the RS for both distant recurrence and disease-free survival, and stratification by age showed that among women over age 50 years, the hazard ratios for distant recurrence ranged from 2.20 to 2.36, and did not substantially vary by age or RS, he said.

However, for the overall population, adding clinical risk to the RS did not improve prediction of chemotherapy benefit.

“This was also true for the two-thirds of women who were over 50 years of age. For the remaining women 50 or younger, there was a trend favoring chemo, irrespective of clinical risk, though not significant – a finding consistent with the treatment interaction previously described,” he said.

Finally, the absolute differences in 9-year distant recurrence rates by clinical risk stratified by age, RS, and CT use showed an absolute 4%-6% higher distant recurrence risk for HCR vs. LCR among those over age 50 with RS of 0-25 irrespective of CT use, and a 13% difference for those with RS of 26-100 who were treated with CT.

“For those 50 or younger, clinical risk had no impact on recurrence if the RS was 0-10. For RS of 11-25, the difference was about 9% with endocrine therapy alone, and 2% with chemo plus ET, reflecting absolute chemo benefit in younger women who had high clinical risk,” he said, adding that for those with RS of 26-100, there was a 9% higher absolute recurrence rate in the HCR vs. LCR population.

“We therefore further evaluated absolute differences in distance recurrence rates associated with chemotherapy use in women 50 and younger with RS of 16-25, further stratified by RS and clinical risk,” he said, noting that when not stratified by clinical risk, as reported in the primary analysis, the absolute CT benefit was 1.6% for RS of 16-20, and 6.5% for RS of 21-25.

When stratified by clinical risk, the absolute CT benefit ranged from 6% to 9% in those with RS of 21-25, irrespective of clinical risk, and in those with RS of 16-20 and HCR.

“This accounted for 51% of patients with RS of 16-25,” he said. “However, there was no demonstrable chemo benefit for those with LCR and RS of 16-20, who accounted for the remaining 49%.”

Additional analysis looking at age at diagnosis and CT benefit showed a benefit in premenopausal women aged 46-50 years (but not postmenopausal women), a trend toward benefit in those aged 41-45 years, and no benefit in those aged 40 years and younger, who are less likely to develop premature menopause as a consequence of cytotoxic CT.

“In addition, we saw no consistent effect favoring chemotherapy in older women. Taken together, these findings suggest the chemo benefit observed for the RS 16-25 group may, in fact, be due to a castration effect associated with cytotoxic therapy rather than an effect in eradicating micrometastatic disease,” Dr. Sparano said.

Applying this framework to the TAILORx study population categorized 68% of those aged 50 years and younger into a low integrated risk group with less than 5% risk of distant recurrence. This included all patients with RS of 0-10 irrespective of clinical risk (14% of the patient population; distant recurrence rate 1.8% or less), and all with RS of 11-25 and LCR (54% of the patient population, 4.7% distant recurrence rate).

In contrast, 25% fell into the high integrated risk group (greater than 10% distant recurrence risk), including those with RS of 11-25 and HCR (17% of the patient population; distant recurrence rate 12.3%), and RS of 26-100 and HCR (8% of the patient population; distant recurrence rate 15.2%).

“This framework encompasses 93% of all TAILORx subjects, with the remaining 7% having a distant recurrence risk of between 5% and 10%,” he said.


Overall, the primary results of TAILORx remain unchanged based on this secondary analysis as the addition of clinical risk did not predict CT benefit in the RS 11-25 group, he noted.

“However, for women 50 and under and RS 16-25, integrated risk distinguished 50% who derived no chemo benefit from the 50% who derived an absolute benefit of approximately 6%-9% – a level that is higher than an unselected population,” he said, reiterating that the absolute CT benefit was greater in premenopausal women aged 45-50 with RS 16-25, suggesting that the absolute CR benefit seen in younger women in TAILORx may be due to an endocrine effect.

“Integrated risk clearly provides greater prognostic precision and may have clinical utility; the prognostic precision afforded by the integrated risk model is superior to that by the use of clinical or genomic features alone, and in addition, the genomic assay also provides predictive information for chemo benefit that is not captured by clinical features alone,” he concluded.

As an example of the potential clinical utility of this integrated approach for guiding treatment in women aged 50 years or younger, he presented “a highly stratified integrated risk assessment model” separating TAILORx patients into low integrated risk (58% of the study population) and high integrated risk (31% of the study population).

In the low integrated risk patients with RS of 0-10 and any clinical risk level, or with RS of 11-25 and LCR, tamoxifen alone appears adequate, he said.

In those with high integrated risk and RS of 16-25 with HCR, ovarian function suppression plus an aromatase inhibitor (OFS/AI) could be considered as an alternative to chemo, and in those with high integrated risk, RS of 26-100, and HCR who have not developed chemotherapy-induced menopause, ovarian function suppression and an AI could be added to chemotherapy.

“Indeed, data from the SOFT and TEXT trials indicate that patients with a high RS risk experienced an absolute improvement of up to 10%-15% in 5-year breast cancer–free interval with an OFS/AI, compared with tamoxifen, whereas improvement was minimal in those at lowest risk, supporting the strategy of using integrated clinical and genomic risk to select for ovarian function suppression plus an AI,” he said.

During a discussion of the findings and how they might impact practice, Vered Stearns, MD, an oncology professor and codirector of the Breast Cancer Program at Johns Hopkins University, Baltimore, noted that in her practice she will “carefully select women for whom genomic assay [use] is appropriate.

“I will also assess clinical risk and RS to inform recommendations for chemotherapy use, and possibly appropriate endocrine agents in select populations,” she said.

Sharon Worcester/MDedge News

Dr. Stearns further noted that the interaction between RS and age as reported by Dr. Sparano is exploratory and should be interpreted with caution as the majority of those aged 50 and younger received tamoxifen alone and the question remains as to whether they would have received similar benefits from ovarian suppression and tamoxifen/AI instead of chemo-endocrine therapy.

“Indeed, indirect hypotheses from other studies suggest that may be the case,” she said, adding that these women may be offered ovarian suppression and tamoxifen or AI based on the SOFT and TEXT results.

“TAILORx remains a rich resource for new explorations, new biomarkers, new models, and new machine learning opportunities,” she said.

TAILORx was funded by the National Institutes of Health. Dr. Sparano reported stock ownership, a consulting role, and research funding from several pharmaceutical companies. Dr. Stearns reported consulting or advisory roles with Iridium Therapeutics; research funding from Abbvie, Biocept, MedImmune, Novartis, Pfizer, and Puma Biotechnology; and an “other relationship” with Immunomedics.

SOURCE: Sparano JA et al. ASCO 2019. Abstract 503.

CHICAGO – Adding isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, a phase 3 trial suggests.

The median PFS was 11.53 months among patients who received isatuximab (isa) plus pomalidomide and dexamethasone (Pd), compared with 6.47 months in patients who received Pd alone (P = .001).

“[W]e now have the first randomized, phase 3 study demonstrating a significant prolonged PFS benefit of CD38 targeting combined with pomalidomide and dexamethasone in relapsed/refractory myeloma,” said Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston.

“The PFS was the longest observed in this population to date ..., and ... this PFS benefit was consistent among subgroups.”

Dr. Richardson presented these results from the ICARIA-MM trial at the annual meeting of the American Society of Clinical Oncology.

Researchers enrolled 307 patients with relapsed/refractory multiple myeloma. The patients had a median age of 67 years (range, 36-86 years) and a median time from diagnosis of 4.23 years (range, 0.5-20.5 years).

The patients had received a median of three prior therapies (range, 2-11 for the isa-Pd arm and 2-10 for the Pd arm). All patients had previously received a proteasome inhibitor and an immunomodulatory agent.

The patients received isatuximab at 10 mg/kg on days 1, 8, 15, and 22 in cycle 1, then on days 1 and 15 for subsequent cycles. Pomalidomide and dexamethasone were given at standard doses in both treatment arms.

At a median follow-up of 11.6 months, 42.2% of patients were still receiving isa-Pd, and 22.9% of patients were still on Pd alone. The most common reason for stopping either treatment was disease progression (42.9% in the isa-Pd arm and 57.5% in the Pd arm).

Efficacy

The overall response rate was 60.4% in the isa-Pd arm and 35.3% in the Pd arm (P less than .0001). The rates of complete response/stringent complete response were 4.5% and 2.0%, respectively. The rates of minimal residual disease negativity were 5.2% and 0%, respectively.

The median time to next treatment was 9.1 months in the Pd arm and was not reached in the isa-Pd arm (hazard ratio, 0.538).

The median PFS was 11.53 months in the isa-Pd arm and 6.47 months in the Pd arm (HR, 0.596; P = .001). There was a PFS benefit with isa-Pd across subgroups, including in patients with renal dysfunction, those with high-risk cytogenetics, and patients who were refractory to lenalidomide.

The median overall survival was not reached in either treatment arm. The overall survival rate was 72% in the isa-Pd arm and 63% in the Pd arm (HR, 0.687).

Safety

There were more grade 3 or higher treatment-emergent adverse events (TEAEs) with isa-Pd. However, as Dr. Richardson noted, adding isa to Pd did not increase the rates of TEAEs leading to treatment discontinuation or death.

The incidence of grade 3 or higher TEAEs was 86.8% in the isa-Pd arm and 70.5% in the Pd arm. The rate of serious TEAEs was 61.8% and 53.7%, respectively.

TEAEs leading to treatment discontinuation occurred in 7.2% of patients in the isa-Pd arm and 12.8% in the Pd arm. TEAEs leading to death occurred in 7.9% and 9.4%, respectively.

Grade 3 TEAEs (in the isa-Pd and Pd arms, respectively) included upper respiratory tract infection (3.3% and 0.7%), diarrhea (2.0% and 0.7%), bronchitis (3.3% and 0.7%), pneumonia (15.1% and 13.4%), fatigue (3.9% and 0%), back pain (2.0% and 1.3%), asthenia (3.3% and 2.7%), and dyspnea (3.9% and 1.3%).

The only grade 4 TEAE was pneumonia (1.3% in both arms).

Based on the safety and efficacy results, Dr. Richardson concluded that isa-Pd “is an important new treatment option for our patients with relapsed/refractory myeloma.”

This study was funded by Sanofi. Dr. Richardson reported financial relationships with Celgene, Janssen, and Takeda. His coinvestigators reported relationships with a range of companies.

jensmith@mdedge.com

SOURCE: Richardson P et al. ASCO 2019, Abstract 8004.

CHICAGO – Adding isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, a phase 3 trial suggests.

The median PFS was 11.53 months among patients who received isatuximab (isa) plus pomalidomide and dexamethasone (Pd), compared with 6.47 months in patients who received Pd alone (P = .001).

“[W]e now have the first randomized, phase 3 study demonstrating a significant prolonged PFS benefit of CD38 targeting combined with pomalidomide and dexamethasone in relapsed/refractory myeloma,” said Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston.

“The PFS was the longest observed in this population to date ..., and ... this PFS benefit was consistent among subgroups.”

Dr. Richardson presented these results from the ICARIA-MM trial at the annual meeting of the American Society of Clinical Oncology.

Researchers enrolled 307 patients with relapsed/refractory multiple myeloma. The patients had a median age of 67 years (range, 36-86 years) and a median time from diagnosis of 4.23 years (range, 0.5-20.5 years).

The patients had received a median of three prior therapies (range, 2-11 for the isa-Pd arm and 2-10 for the Pd arm). All patients had previously received a proteasome inhibitor and an immunomodulatory agent.

The patients received isatuximab at 10 mg/kg on days 1, 8, 15, and 22 in cycle 1, then on days 1 and 15 for subsequent cycles. Pomalidomide and dexamethasone were given at standard doses in both treatment arms.

At a median follow-up of 11.6 months, 42.2% of patients were still receiving isa-Pd, and 22.9% of patients were still on Pd alone. The most common reason for stopping either treatment was disease progression (42.9% in the isa-Pd arm and 57.5% in the Pd arm).

Efficacy

The overall response rate was 60.4% in the isa-Pd arm and 35.3% in the Pd arm (P less than .0001). The rates of complete response/stringent complete response were 4.5% and 2.0%, respectively. The rates of minimal residual disease negativity were 5.2% and 0%, respectively.

The median time to next treatment was 9.1 months in the Pd arm and was not reached in the isa-Pd arm (hazard ratio, 0.538).

The median PFS was 11.53 months in the isa-Pd arm and 6.47 months in the Pd arm (HR, 0.596; P = .001). There was a PFS benefit with isa-Pd across subgroups, including in patients with renal dysfunction, those with high-risk cytogenetics, and patients who were refractory to lenalidomide.

The median overall survival was not reached in either treatment arm. The overall survival rate was 72% in the isa-Pd arm and 63% in the Pd arm (HR, 0.687).

Safety

There were more grade 3 or higher treatment-emergent adverse events (TEAEs) with isa-Pd. However, as Dr. Richardson noted, adding isa to Pd did not increase the rates of TEAEs leading to treatment discontinuation or death.

The incidence of grade 3 or higher TEAEs was 86.8% in the isa-Pd arm and 70.5% in the Pd arm. The rate of serious TEAEs was 61.8% and 53.7%, respectively.

TEAEs leading to treatment discontinuation occurred in 7.2% of patients in the isa-Pd arm and 12.8% in the Pd arm. TEAEs leading to death occurred in 7.9% and 9.4%, respectively.

Grade 3 TEAEs (in the isa-Pd and Pd arms, respectively) included upper respiratory tract infection (3.3% and 0.7%), diarrhea (2.0% and 0.7%), bronchitis (3.3% and 0.7%), pneumonia (15.1% and 13.4%), fatigue (3.9% and 0%), back pain (2.0% and 1.3%), asthenia (3.3% and 2.7%), and dyspnea (3.9% and 1.3%).

The only grade 4 TEAE was pneumonia (1.3% in both arms).

Based on the safety and efficacy results, Dr. Richardson concluded that isa-Pd “is an important new treatment option for our patients with relapsed/refractory myeloma.”

This study was funded by Sanofi. Dr. Richardson reported financial relationships with Celgene, Janssen, and Takeda. His coinvestigators reported relationships with a range of companies.

jensmith@mdedge.com

SOURCE: Richardson P et al. ASCO 2019, Abstract 8004.

CHICAGO – Adding isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, a phase 3 trial suggests.

The median PFS was 11.53 months among patients who received isatuximab (isa) plus pomalidomide and dexamethasone (Pd), compared with 6.47 months in patients who received Pd alone (P = .001).

“[W]e now have the first randomized, phase 3 study demonstrating a significant prolonged PFS benefit of CD38 targeting combined with pomalidomide and dexamethasone in relapsed/refractory myeloma,” said Paul Richardson, MD, of the Dana-Farber Cancer Institute in Boston.

“The PFS was the longest observed in this population to date ..., and ... this PFS benefit was consistent among subgroups.”

Dr. Richardson presented these results from the ICARIA-MM trial at the annual meeting of the American Society of Clinical Oncology.

Researchers enrolled 307 patients with relapsed/refractory multiple myeloma. The patients had a median age of 67 years (range, 36-86 years) and a median time from diagnosis of 4.23 years (range, 0.5-20.5 years).

The patients had received a median of three prior therapies (range, 2-11 for the isa-Pd arm and 2-10 for the Pd arm). All patients had previously received a proteasome inhibitor and an immunomodulatory agent.

The patients received isatuximab at 10 mg/kg on days 1, 8, 15, and 22 in cycle 1, then on days 1 and 15 for subsequent cycles. Pomalidomide and dexamethasone were given at standard doses in both treatment arms.

At a median follow-up of 11.6 months, 42.2% of patients were still receiving isa-Pd, and 22.9% of patients were still on Pd alone. The most common reason for stopping either treatment was disease progression (42.9% in the isa-Pd arm and 57.5% in the Pd arm).

Efficacy

The overall response rate was 60.4% in the isa-Pd arm and 35.3% in the Pd arm (P less than .0001). The rates of complete response/stringent complete response were 4.5% and 2.0%, respectively. The rates of minimal residual disease negativity were 5.2% and 0%, respectively.

The median time to next treatment was 9.1 months in the Pd arm and was not reached in the isa-Pd arm (hazard ratio, 0.538).

The median PFS was 11.53 months in the isa-Pd arm and 6.47 months in the Pd arm (HR, 0.596; P = .001). There was a PFS benefit with isa-Pd across subgroups, including in patients with renal dysfunction, those with high-risk cytogenetics, and patients who were refractory to lenalidomide.

The median overall survival was not reached in either treatment arm. The overall survival rate was 72% in the isa-Pd arm and 63% in the Pd arm (HR, 0.687).

Safety

There were more grade 3 or higher treatment-emergent adverse events (TEAEs) with isa-Pd. However, as Dr. Richardson noted, adding isa to Pd did not increase the rates of TEAEs leading to treatment discontinuation or death.

The incidence of grade 3 or higher TEAEs was 86.8% in the isa-Pd arm and 70.5% in the Pd arm. The rate of serious TEAEs was 61.8% and 53.7%, respectively.

TEAEs leading to treatment discontinuation occurred in 7.2% of patients in the isa-Pd arm and 12.8% in the Pd arm. TEAEs leading to death occurred in 7.9% and 9.4%, respectively.

Grade 3 TEAEs (in the isa-Pd and Pd arms, respectively) included upper respiratory tract infection (3.3% and 0.7%), diarrhea (2.0% and 0.7%), bronchitis (3.3% and 0.7%), pneumonia (15.1% and 13.4%), fatigue (3.9% and 0%), back pain (2.0% and 1.3%), asthenia (3.3% and 2.7%), and dyspnea (3.9% and 1.3%).

The only grade 4 TEAE was pneumonia (1.3% in both arms).

Based on the safety and efficacy results, Dr. Richardson concluded that isa-Pd “is an important new treatment option for our patients with relapsed/refractory myeloma.”

This study was funded by Sanofi. Dr. Richardson reported financial relationships with Celgene, Janssen, and Takeda. His coinvestigators reported relationships with a range of companies.

jensmith@mdedge.com

SOURCE: Richardson P et al. ASCO 2019, Abstract 8004.