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Carefully Designing De-escalation Trials in Breast Cancer
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
Over the past few years, several new, highly effective treatment strategies have improved survival outcomes in patients with early breast cancer.
“We’ve been very fortunate” to see these advances, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, told attendees at the European Society of Medical Oncology (ESMO) Breast Cancer annual congress.
However, Dr. Tolaney noted, these new treatment approaches can come with big limitations — namely, potential overtreatment of some patients as well as short- and long-term toxicities, some of which can be life-threatening.
These caveats have prompted trials exploring strategies to de-escalate therapy, which essentially means providing the right amount of treatment to the right patient at the right time, said Dr. Tolaney. The goal is to “right-size” or “optimize therapy” to maintain strong outcomes while mitigating side effects.
she explained.
But, she added, de-escalation trials are “not a very attractive strategy to pharmaceutical companies” and can be challenging for researchers to conduct. These trials may, for instance, lack adequate sample sizes and sufficient statistical power, which can interfere with achieving clinically meaningful findings that may affect practice.
That is why carefully designing de-escalation trials is crucial, Dr. Tolaney said.
In her talk at ESMO Breast, Dr. Tolaney highlighted several strategies for designing these trials.
One strategy is to shorten the duration of therapy, said Dr. Tolaney.
This approach was explored in the PHARE and PERSEPHONE trials, which looked at 6 vs 12 months of trastuzumab in nonmetastatic breast cancer. Other trials, such as GeparNuevo and KEYNOTE-522, explored whether adjuvant checkpoint inhibitor therapy was needed, or could be skipped, following neoadjuvant therapy. This approach requires establishing noninferiority, or similar efficacy, between the standard of care and the shorter duration of therapy.
A second strategy is to remove part of the chemotherapy regimen, typically the most toxic agent, Dr. Tolaney continued.
Conducting a prospective, randomized trial exploring this approach in human epidermal growth factor receptor 2–positive (HER2+) early breast cancer, for example, would be difficult for a range of reasons, such as the need to enroll thousands of patients.
Dr. Tolaney and colleagues, however, designed a nonrandomized prospective study — the APT trial — with just over 400 patients to assess adjuvant paclitaxel plus trastuzumab in patients with node-negative HER2+ disease. The open-label, single-arm, phase 2 APT trial found that adjuvant paclitaxel and trastuzumab led to a 10-year recurrence-free interval of 96.3%, 10-year overall survival of 94.3%, and 10-year breast cancer–specific survival of 98.8%.
Outcomes with this adjuvant regimen were comparable to previous findings in historical controls who received doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab or docetaxel, carboplatin, and trastuzumab.
Dr. Tolaney concluded that given few events, “it’s unlikely we need to escalate therapy to do better for most patients,” and the APT regimen “can be considered a reasonable and appealing approach for the majority of patients” with node-negative HER2+ breast cancer.
“A single-arm design for a de-escalation study can be practice-changing but only if there are very few recurrences,” Dr. Tolaney said.
Substituting chemotherapy with a targeted, potentially less-toxic agent is a third de-escalation approach. The ATEMPT trial compared patients receiving trastuzumab emtansine (T-DM1) with those receiving paclitaxel plus trastuzumab followed by maintenance trastuzumab.
Investigators found that de-escalation with T-DM1 was associated with very few recurrences but similar rates of certain adverse events, including grade 2 or higher neurotoxicity, febrile neutropenia, and grade 4 or higher hematologic toxicity.
However, there are questions about how to define “less toxic,” Dr. Tolaney said. The trial found, for instance, that T-DM1 did have some advantages — patients reported better quality of life and experienced less alopecia and neurotoxicity, as well as a less severe impact on fertility.
Understanding the right endpoint to demonstrate less toxicity is critical, “as we start to think about how to replace standard chemotherapies with better targeted drugs,” she added.
The ATEMPT 2.0 trial, which is currently enrolling, will aim to answer some of these questions about defining and demonstrating less toxicity, she said.
Finally, some researchers are attempting to omit chemotherapy altogether with the help of biomarkers. The TAILORx trial, for instance, aimed to stratify patients with early-stage breast cancer by clinical risk factors combined with a 21-gene expression assay and found that adjuvant chemotherapy was not necessary in a large proportion of these women.
On the biomarker front, oncologists might be able to use ctDNA to guide decision-making and personalize therapy, Tolaney said. The presence of ctDNA is associated with an almost 100% likelihood of having a recurrence, whereas its absence suggests better outcomes, she explained.
Oncologists could use the presence or absence of ctDNA to guide next steps — assign patients to follow-up assessments when ctDNA is not present or to standard or experimental treatment when it is present. It may also be possible to leverage the presence of minimal residual disease to help direct treatment choices.
But ctDNA is currently not as perfect a predictor of outcome as it could be, she cautioned. “We need more sensitive assays [so] I’m not sure we’re quite ready to use lack of ctDNA to de-escalate treatment,” she said.
Dr. Tolaney declared relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, and other companies.
A version of this article appeared on Medscape.com .
FROM ESMO BREAST CANCER 2024
ADCs for Breast Cancer: Clear Benefits, Manageable Risks
These medications, which are designed to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens such as human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (TROP2), can be highly effective but can also come with significant toxicities.
The latest data on several ADCs — their clinical benefit and safety — were the focus of three presentations here at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
TROPION-Breast01
In her presentation, Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported additional safety analyses from the phase 3 TROPION-Breast01 trial looking at datopotamab deruxtecan (Dato-DXd) in patients with metastatic hormone receptor–positive (HR+)/HER2− breast cancer resistant to endocrine therapy.
Dato-DXd is an investigational ADC composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.
As previously reported by this news organization, median progression-free survival was 6.9 months with Dato-DXd compared with 4.9 months for investigator’s choice of chemotherapy (eribulin mesylate, vinorelbine, gemcitabine, or capecitabine), which translated into a 37% (hazard ratio [HR], 0.63; P < .0001) reduction in risk for disease progression.
In addition, the rate of grade 3 or higher treatment-related adverse events with Dato-DXd was less than half that with standard chemotherapy and led to fewer dose interruptions or reductions, indicating that Dato-DXd is better tolerated.
Dr. Jhaveri focused on three treatment-related adverse events of special interest: Stomatitis/oral mucositis, ocular surface events, and adjudicated drug-related interstitial lung disease.
The rate of any grade oral mucositis with Dato-DXd was 56%, she reported. Most were grade 1 (25%) or grade 2 (23%), with only 7% grade 3. About 13% of patients had a dose reduction for oral mucositis, and only one (0.3%) patient discontinued treatment.
The median time to onset was 22 days, and median time to resolution (for events recovered/resolved at data cutoff) was 36 days.
“The study did provide toxicity management guidelines for patients who experienced stomatitis,” Dr. Jhaveri told attendees. The guidelines highly recommended daily use of a steroid-containing mouthwash as prophylaxis or, if that wasn’t available, an inert, bland mouth rinse.
“Prophylactic cryotherapy — ice chips or ice water held in the mouth throughout the infusion — was also suggested,” she said.
The overall rate of ocular surface events with Dato-DXd was 40%, with most grade 1 (32%) or grade 2 (7%), with only 0.8% grade 3. Rates of dose reduction/interruption (3.3%) and discontinuation (0.3%) were low. Most ocular events were either dry eye (22%) or keratitis (14%).
The incidence of ocular events in the chemotherapy group was 12%, higher than typically seen. The study mandated regular ocular assessments, and Jhaveri noted that it was possible that this contributed to the high rate of low-grade ocular events found in both arms.
Median time to onset of ocular events was 65 days, and median time to resolution was 67 days.
Toxicity management guidelines were also incorporated for ocular events, suggesting daily use of artificial tears and avoidance of contact lenses, Dr. Jhaveri said.
In the Dato-DXd group, there were 12 adjudicated cases (3.3%) of drug-related interstitial lung disease; most were grade 1 (1.4%) and grade 2 (1.1%).
“There was one patient who had a grade 5 event, which was characterized by the investigator as grade 3 pneumonitis, with death attributed to disease progression,” Dr. Jhaveri said. This was subsequently adjudicated to be a grade 5 drug-related death.
The median time to onset of interstitial lung disease was 84.5 days, and median time to resolution was 28 days.
Among other treatment-related adverse events of clinical interest, any grade nausea was the most common event with Dato-DXd, reported by 51% of patients, with only 1.4% grade 3 or higher.
“Prophylactic antiemetic agents are highly recommended prior to infusion of Dato-DXd and on subsequent days as needed,” Dr. Jhaveri said.
Any grade diarrhea was reported in 7.5%, with no grade 3+ diarrhea. Alopecia was reported in 36.4%, of which grade 1 was 21% and grade 2 was 15%.
Summing up, the researcher said the new safety data suggest that Dato-DXd offers “better tolerability” than standard chemotherapy. Coupled with the efficacy data, this further supports “Dato-DXd as a potential new therapeutic option for patients with previously treated, inoperable, or metastatic HR+/HER2− breast cancer.”
DESTINY-Breast02
New data from the phase 3 DESTINY-Breast02 study confirm a long-term survival benefit, as well as a favorable benefit/risk profile of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), reported Sung-Bae Kim, MD, PhD, with University of Ulsan College of Medicine, Seoul, Republic of Korea.
In the phase 3 randomized, multicenter, open-label clinical trial, study participants received either trastuzumab deruxtecan or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine. The primary results of the trial were published last year in The Lancet.
As previously reported by this news organization, after median follow-up of 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of choice group, median progression-free survival was 17.8 months for trastuzumab deruxtecan vs 6.9 months for the physician’s choice group (HR, 0.36; P < .000001).
The latest data show that after a median follow-up of 30.2 months in the trastuzumab deruxtecan group and 20.5 months in the treatment of choice group, median progression-free survival was 16.7 months with trastuzumab deruxtecan vs 5.5 months with the treatment of choice — a 70% reduction in risk for progression (HR, 0.30), Dr. Kim said.
From time of randomization to progression to next line of therapy or death, median progression-free survival was 33.0 months with trastuzumab deruxtecan vs 15.0 with treatment of choice (HR, 0.42).
Median overall survival was 35.7 months with trastuzumab deruxtecan vs 25.0 months with the treatment of choice, with the risk for death reduced by 31% with trastuzumab deruxtecan (HR, 0.69).
The safety profile of trastuzumab deruxtecan continues to be “manageable, with no long-term toxicity observed with longer follow-up,” Dr. Kim told attendees. The most common treatment-emergent adverse events were nausea (73%), fatigue (62%), and vomiting (38%).
There were a total of 46 (11.4%) adjudicated drug-related interstitial lung disease/pneumonitis cases with trastuzumab deruxtecan. Most were grade 1 or 2. This risk did not increase with longer treatment duration; most events occurred within 12 months of starting treatment, Dr. Kim noted.
With longer follow-up, results of DESTINY-Breast02 “reinforce the substantial benefit” of trastuzumab deruxtecan over the treatment of physician’s choice in patients with HER2+ metastatic breast cancer previously treated with T-DM1, he concluded.
Pooled Data from TROPiCS-02 and EVER-132-002
Hope S. Rugo, MD, of the University of California San Francisco, and colleagues reported a meta-analysis of data from the phase 3 TROPiCS-02 and EVER-132-002 trials of the TROP2-directed ADC sacituzumab govitecan vs the treatment of physician’s choice in HR+/HER2− metastatic breast cancer.
In the pooled analysis, median overall survival was significantly longer with sacituzumab govitecan than with the treatment of physician’s choice in the overall population (16.2 vs 12.7 months) and in patients who received prior CDK4/6 inhibitor treatment (15.4 vs 11.5 months). Progression-free survival also favored sacituzumab govitecan.
These results are consistent with trial-level results from TROPICS-02 and EVER-132-002, reinforcing the efficacy benefits of sacituzumab govitecan over the treatment of physician’s choice, the study team said.
Evolving Landscape of ADCs in Breast Cancer
Giuseppe Curigliano, MD, PhD, with the University of Milan, Italy, who served as discussant for the TROPION-Breast01 safety analysis, noted that the clinical landscape of ADCs has “evolved over time.”
He added that despite having a similar target and similar payload, the anti-TROP2 ADCs in development for HR+/HER2− metastatic breast cancer — Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan — appear to have different spectrums of toxicity.
Looking ahead, he said it will be important to determine whether toxicity of these agents can be predicted with a pharmacogenomic analysis and whether toxicity is related to the payload or to the linker antibody complex.
“The science and chemistry of ADCs has shown significant promise in terms of clinical activity, but we also need to better understand safety,” Dr. Curigliano told attendees.
“We need to pay attention to signals in the early phase trials of ADCs and be willing to adjust accordingly to maximize therapeutic benefit and minimize toxicity. Team science will be important in the future developmental ADCs,” he added.
TROPION-Breast01 was sponsored by AstraZeneca. DESTINY-Breast-02 was sponsored by Daiichi Sankyo. TROPiCS-02 and EVER-132-002 were supported by Gilead Sciences. Several trial investigators have disclosed various relationships with these and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
These medications, which are designed to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens such as human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (TROP2), can be highly effective but can also come with significant toxicities.
The latest data on several ADCs — their clinical benefit and safety — were the focus of three presentations here at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
TROPION-Breast01
In her presentation, Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported additional safety analyses from the phase 3 TROPION-Breast01 trial looking at datopotamab deruxtecan (Dato-DXd) in patients with metastatic hormone receptor–positive (HR+)/HER2− breast cancer resistant to endocrine therapy.
Dato-DXd is an investigational ADC composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.
As previously reported by this news organization, median progression-free survival was 6.9 months with Dato-DXd compared with 4.9 months for investigator’s choice of chemotherapy (eribulin mesylate, vinorelbine, gemcitabine, or capecitabine), which translated into a 37% (hazard ratio [HR], 0.63; P < .0001) reduction in risk for disease progression.
In addition, the rate of grade 3 or higher treatment-related adverse events with Dato-DXd was less than half that with standard chemotherapy and led to fewer dose interruptions or reductions, indicating that Dato-DXd is better tolerated.
Dr. Jhaveri focused on three treatment-related adverse events of special interest: Stomatitis/oral mucositis, ocular surface events, and adjudicated drug-related interstitial lung disease.
The rate of any grade oral mucositis with Dato-DXd was 56%, she reported. Most were grade 1 (25%) or grade 2 (23%), with only 7% grade 3. About 13% of patients had a dose reduction for oral mucositis, and only one (0.3%) patient discontinued treatment.
The median time to onset was 22 days, and median time to resolution (for events recovered/resolved at data cutoff) was 36 days.
“The study did provide toxicity management guidelines for patients who experienced stomatitis,” Dr. Jhaveri told attendees. The guidelines highly recommended daily use of a steroid-containing mouthwash as prophylaxis or, if that wasn’t available, an inert, bland mouth rinse.
“Prophylactic cryotherapy — ice chips or ice water held in the mouth throughout the infusion — was also suggested,” she said.
The overall rate of ocular surface events with Dato-DXd was 40%, with most grade 1 (32%) or grade 2 (7%), with only 0.8% grade 3. Rates of dose reduction/interruption (3.3%) and discontinuation (0.3%) were low. Most ocular events were either dry eye (22%) or keratitis (14%).
The incidence of ocular events in the chemotherapy group was 12%, higher than typically seen. The study mandated regular ocular assessments, and Jhaveri noted that it was possible that this contributed to the high rate of low-grade ocular events found in both arms.
Median time to onset of ocular events was 65 days, and median time to resolution was 67 days.
Toxicity management guidelines were also incorporated for ocular events, suggesting daily use of artificial tears and avoidance of contact lenses, Dr. Jhaveri said.
In the Dato-DXd group, there were 12 adjudicated cases (3.3%) of drug-related interstitial lung disease; most were grade 1 (1.4%) and grade 2 (1.1%).
“There was one patient who had a grade 5 event, which was characterized by the investigator as grade 3 pneumonitis, with death attributed to disease progression,” Dr. Jhaveri said. This was subsequently adjudicated to be a grade 5 drug-related death.
The median time to onset of interstitial lung disease was 84.5 days, and median time to resolution was 28 days.
Among other treatment-related adverse events of clinical interest, any grade nausea was the most common event with Dato-DXd, reported by 51% of patients, with only 1.4% grade 3 or higher.
“Prophylactic antiemetic agents are highly recommended prior to infusion of Dato-DXd and on subsequent days as needed,” Dr. Jhaveri said.
Any grade diarrhea was reported in 7.5%, with no grade 3+ diarrhea. Alopecia was reported in 36.4%, of which grade 1 was 21% and grade 2 was 15%.
Summing up, the researcher said the new safety data suggest that Dato-DXd offers “better tolerability” than standard chemotherapy. Coupled with the efficacy data, this further supports “Dato-DXd as a potential new therapeutic option for patients with previously treated, inoperable, or metastatic HR+/HER2− breast cancer.”
DESTINY-Breast02
New data from the phase 3 DESTINY-Breast02 study confirm a long-term survival benefit, as well as a favorable benefit/risk profile of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), reported Sung-Bae Kim, MD, PhD, with University of Ulsan College of Medicine, Seoul, Republic of Korea.
In the phase 3 randomized, multicenter, open-label clinical trial, study participants received either trastuzumab deruxtecan or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine. The primary results of the trial were published last year in The Lancet.
As previously reported by this news organization, after median follow-up of 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of choice group, median progression-free survival was 17.8 months for trastuzumab deruxtecan vs 6.9 months for the physician’s choice group (HR, 0.36; P < .000001).
The latest data show that after a median follow-up of 30.2 months in the trastuzumab deruxtecan group and 20.5 months in the treatment of choice group, median progression-free survival was 16.7 months with trastuzumab deruxtecan vs 5.5 months with the treatment of choice — a 70% reduction in risk for progression (HR, 0.30), Dr. Kim said.
From time of randomization to progression to next line of therapy or death, median progression-free survival was 33.0 months with trastuzumab deruxtecan vs 15.0 with treatment of choice (HR, 0.42).
Median overall survival was 35.7 months with trastuzumab deruxtecan vs 25.0 months with the treatment of choice, with the risk for death reduced by 31% with trastuzumab deruxtecan (HR, 0.69).
The safety profile of trastuzumab deruxtecan continues to be “manageable, with no long-term toxicity observed with longer follow-up,” Dr. Kim told attendees. The most common treatment-emergent adverse events were nausea (73%), fatigue (62%), and vomiting (38%).
There were a total of 46 (11.4%) adjudicated drug-related interstitial lung disease/pneumonitis cases with trastuzumab deruxtecan. Most were grade 1 or 2. This risk did not increase with longer treatment duration; most events occurred within 12 months of starting treatment, Dr. Kim noted.
With longer follow-up, results of DESTINY-Breast02 “reinforce the substantial benefit” of trastuzumab deruxtecan over the treatment of physician’s choice in patients with HER2+ metastatic breast cancer previously treated with T-DM1, he concluded.
Pooled Data from TROPiCS-02 and EVER-132-002
Hope S. Rugo, MD, of the University of California San Francisco, and colleagues reported a meta-analysis of data from the phase 3 TROPiCS-02 and EVER-132-002 trials of the TROP2-directed ADC sacituzumab govitecan vs the treatment of physician’s choice in HR+/HER2− metastatic breast cancer.
In the pooled analysis, median overall survival was significantly longer with sacituzumab govitecan than with the treatment of physician’s choice in the overall population (16.2 vs 12.7 months) and in patients who received prior CDK4/6 inhibitor treatment (15.4 vs 11.5 months). Progression-free survival also favored sacituzumab govitecan.
These results are consistent with trial-level results from TROPICS-02 and EVER-132-002, reinforcing the efficacy benefits of sacituzumab govitecan over the treatment of physician’s choice, the study team said.
Evolving Landscape of ADCs in Breast Cancer
Giuseppe Curigliano, MD, PhD, with the University of Milan, Italy, who served as discussant for the TROPION-Breast01 safety analysis, noted that the clinical landscape of ADCs has “evolved over time.”
He added that despite having a similar target and similar payload, the anti-TROP2 ADCs in development for HR+/HER2− metastatic breast cancer — Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan — appear to have different spectrums of toxicity.
Looking ahead, he said it will be important to determine whether toxicity of these agents can be predicted with a pharmacogenomic analysis and whether toxicity is related to the payload or to the linker antibody complex.
“The science and chemistry of ADCs has shown significant promise in terms of clinical activity, but we also need to better understand safety,” Dr. Curigliano told attendees.
“We need to pay attention to signals in the early phase trials of ADCs and be willing to adjust accordingly to maximize therapeutic benefit and minimize toxicity. Team science will be important in the future developmental ADCs,” he added.
TROPION-Breast01 was sponsored by AstraZeneca. DESTINY-Breast-02 was sponsored by Daiichi Sankyo. TROPiCS-02 and EVER-132-002 were supported by Gilead Sciences. Several trial investigators have disclosed various relationships with these and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
These medications, which are designed to selectively deliver potent cytotoxic drugs to cancer cells expressing specific surface antigens such as human epidermal growth factor receptor 2 (HER2) and trophoblast cell surface antigen 2 (TROP2), can be highly effective but can also come with significant toxicities.
The latest data on several ADCs — their clinical benefit and safety — were the focus of three presentations here at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
TROPION-Breast01
In her presentation, Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York City, reported additional safety analyses from the phase 3 TROPION-Breast01 trial looking at datopotamab deruxtecan (Dato-DXd) in patients with metastatic hormone receptor–positive (HR+)/HER2− breast cancer resistant to endocrine therapy.
Dato-DXd is an investigational ADC composed of a monoclonal antibody targeting TROP2, a transmembrane glycoprotein overexpressed in cancer cells, linked to the topoisomerase 1 inhibitor deruxtecan as the toxic payload.
As previously reported by this news organization, median progression-free survival was 6.9 months with Dato-DXd compared with 4.9 months for investigator’s choice of chemotherapy (eribulin mesylate, vinorelbine, gemcitabine, or capecitabine), which translated into a 37% (hazard ratio [HR], 0.63; P < .0001) reduction in risk for disease progression.
In addition, the rate of grade 3 or higher treatment-related adverse events with Dato-DXd was less than half that with standard chemotherapy and led to fewer dose interruptions or reductions, indicating that Dato-DXd is better tolerated.
Dr. Jhaveri focused on three treatment-related adverse events of special interest: Stomatitis/oral mucositis, ocular surface events, and adjudicated drug-related interstitial lung disease.
The rate of any grade oral mucositis with Dato-DXd was 56%, she reported. Most were grade 1 (25%) or grade 2 (23%), with only 7% grade 3. About 13% of patients had a dose reduction for oral mucositis, and only one (0.3%) patient discontinued treatment.
The median time to onset was 22 days, and median time to resolution (for events recovered/resolved at data cutoff) was 36 days.
“The study did provide toxicity management guidelines for patients who experienced stomatitis,” Dr. Jhaveri told attendees. The guidelines highly recommended daily use of a steroid-containing mouthwash as prophylaxis or, if that wasn’t available, an inert, bland mouth rinse.
“Prophylactic cryotherapy — ice chips or ice water held in the mouth throughout the infusion — was also suggested,” she said.
The overall rate of ocular surface events with Dato-DXd was 40%, with most grade 1 (32%) or grade 2 (7%), with only 0.8% grade 3. Rates of dose reduction/interruption (3.3%) and discontinuation (0.3%) were low. Most ocular events were either dry eye (22%) or keratitis (14%).
The incidence of ocular events in the chemotherapy group was 12%, higher than typically seen. The study mandated regular ocular assessments, and Jhaveri noted that it was possible that this contributed to the high rate of low-grade ocular events found in both arms.
Median time to onset of ocular events was 65 days, and median time to resolution was 67 days.
Toxicity management guidelines were also incorporated for ocular events, suggesting daily use of artificial tears and avoidance of contact lenses, Dr. Jhaveri said.
In the Dato-DXd group, there were 12 adjudicated cases (3.3%) of drug-related interstitial lung disease; most were grade 1 (1.4%) and grade 2 (1.1%).
“There was one patient who had a grade 5 event, which was characterized by the investigator as grade 3 pneumonitis, with death attributed to disease progression,” Dr. Jhaveri said. This was subsequently adjudicated to be a grade 5 drug-related death.
The median time to onset of interstitial lung disease was 84.5 days, and median time to resolution was 28 days.
Among other treatment-related adverse events of clinical interest, any grade nausea was the most common event with Dato-DXd, reported by 51% of patients, with only 1.4% grade 3 or higher.
“Prophylactic antiemetic agents are highly recommended prior to infusion of Dato-DXd and on subsequent days as needed,” Dr. Jhaveri said.
Any grade diarrhea was reported in 7.5%, with no grade 3+ diarrhea. Alopecia was reported in 36.4%, of which grade 1 was 21% and grade 2 was 15%.
Summing up, the researcher said the new safety data suggest that Dato-DXd offers “better tolerability” than standard chemotherapy. Coupled with the efficacy data, this further supports “Dato-DXd as a potential new therapeutic option for patients with previously treated, inoperable, or metastatic HR+/HER2− breast cancer.”
DESTINY-Breast02
New data from the phase 3 DESTINY-Breast02 study confirm a long-term survival benefit, as well as a favorable benefit/risk profile of trastuzumab deruxtecan in patients with HER2+ metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1), reported Sung-Bae Kim, MD, PhD, with University of Ulsan College of Medicine, Seoul, Republic of Korea.
In the phase 3 randomized, multicenter, open-label clinical trial, study participants received either trastuzumab deruxtecan or physician’s choice of trastuzumab plus capecitabine or lapatinib or capecitabine. The primary results of the trial were published last year in The Lancet.
As previously reported by this news organization, after median follow-up of 21.5 months in the trastuzumab deruxtecan group and 18.6 months in the treatment of choice group, median progression-free survival was 17.8 months for trastuzumab deruxtecan vs 6.9 months for the physician’s choice group (HR, 0.36; P < .000001).
The latest data show that after a median follow-up of 30.2 months in the trastuzumab deruxtecan group and 20.5 months in the treatment of choice group, median progression-free survival was 16.7 months with trastuzumab deruxtecan vs 5.5 months with the treatment of choice — a 70% reduction in risk for progression (HR, 0.30), Dr. Kim said.
From time of randomization to progression to next line of therapy or death, median progression-free survival was 33.0 months with trastuzumab deruxtecan vs 15.0 with treatment of choice (HR, 0.42).
Median overall survival was 35.7 months with trastuzumab deruxtecan vs 25.0 months with the treatment of choice, with the risk for death reduced by 31% with trastuzumab deruxtecan (HR, 0.69).
The safety profile of trastuzumab deruxtecan continues to be “manageable, with no long-term toxicity observed with longer follow-up,” Dr. Kim told attendees. The most common treatment-emergent adverse events were nausea (73%), fatigue (62%), and vomiting (38%).
There were a total of 46 (11.4%) adjudicated drug-related interstitial lung disease/pneumonitis cases with trastuzumab deruxtecan. Most were grade 1 or 2. This risk did not increase with longer treatment duration; most events occurred within 12 months of starting treatment, Dr. Kim noted.
With longer follow-up, results of DESTINY-Breast02 “reinforce the substantial benefit” of trastuzumab deruxtecan over the treatment of physician’s choice in patients with HER2+ metastatic breast cancer previously treated with T-DM1, he concluded.
Pooled Data from TROPiCS-02 and EVER-132-002
Hope S. Rugo, MD, of the University of California San Francisco, and colleagues reported a meta-analysis of data from the phase 3 TROPiCS-02 and EVER-132-002 trials of the TROP2-directed ADC sacituzumab govitecan vs the treatment of physician’s choice in HR+/HER2− metastatic breast cancer.
In the pooled analysis, median overall survival was significantly longer with sacituzumab govitecan than with the treatment of physician’s choice in the overall population (16.2 vs 12.7 months) and in patients who received prior CDK4/6 inhibitor treatment (15.4 vs 11.5 months). Progression-free survival also favored sacituzumab govitecan.
These results are consistent with trial-level results from TROPICS-02 and EVER-132-002, reinforcing the efficacy benefits of sacituzumab govitecan over the treatment of physician’s choice, the study team said.
Evolving Landscape of ADCs in Breast Cancer
Giuseppe Curigliano, MD, PhD, with the University of Milan, Italy, who served as discussant for the TROPION-Breast01 safety analysis, noted that the clinical landscape of ADCs has “evolved over time.”
He added that despite having a similar target and similar payload, the anti-TROP2 ADCs in development for HR+/HER2− metastatic breast cancer — Dato-DXd, sacituzumab govitecan, and sacituzumab tirumotecan — appear to have different spectrums of toxicity.
Looking ahead, he said it will be important to determine whether toxicity of these agents can be predicted with a pharmacogenomic analysis and whether toxicity is related to the payload or to the linker antibody complex.
“The science and chemistry of ADCs has shown significant promise in terms of clinical activity, but we also need to better understand safety,” Dr. Curigliano told attendees.
“We need to pay attention to signals in the early phase trials of ADCs and be willing to adjust accordingly to maximize therapeutic benefit and minimize toxicity. Team science will be important in the future developmental ADCs,” he added.
TROPION-Breast01 was sponsored by AstraZeneca. DESTINY-Breast-02 was sponsored by Daiichi Sankyo. TROPiCS-02 and EVER-132-002 were supported by Gilead Sciences. Several trial investigators have disclosed various relationships with these and other pharmaceutical companies.
A version of this article appeared on Medscape.com.
FROM ESMO BREAST CANCER 2024
Research Highlights From ESMO Breast Cancer
Among the topics the speakers addressed were breast cancer prevention, early breast cancer, advanced breast cancer, and supportive care.
In recent years, the way clinicians look at carcinogenesis in breast cancer has changed, and many new targets for potential early detection and prevention have emerged, said Suzette Delaloge, MD, of Gustave Roussy, Paris, France, in her presentation at the meeting.
Instant risk assessment at different time points could potentially intercept cancer among high-risk individuals, she said.
A study by Mikael Eriksson, PhD, and colleagues focused on external validation of the Profound AI tool to identify breast cancer risk in the general population. The researchers showed an area under the curve of 0.72 in their AI risk model, which has the potential to be clinically meaningful, although it must be prospectively validated, Dr. Delaloge said in her presentation.
She also reviewed two studies on the use of genes to further refine breast cancer risk among carriers. One of these, a prospective study presented in a session by Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Center, Melbourne, Australia, used the CANRISK online risk assessment tool and validated increased breast cancer risk in BRCA1 and BRCA2 carriers, with AUCs of 0.79 and 0.78, respectively. The other study, which was by Maria Rezqallah Aron, MD, and colleagues examined polygenic scores as a way to refine breast cancer risk stratification among carriers of the ALM and PALB2 genes as well. These genes might be useful in identifying individuals who could benefit from early intervention, including surgery, Dr. Delaloge said.
Translational Research
“Preparing my talk, I felt like a kid in a candy store,” because of the amount of new translational research presented, including several studies of endocrine treatment–based approaches to therapy, said Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam.
In her presentation, Dr. Kok highlighted findings from an analysis of patients in the monarchE study (a trial of high-risk patients) showing a consistent improvement in invasive disease-free survival for the subset of patients with germline BRCA1 and BRCA2 mutations who received abemaciclib plus endocrine therapy.
The value of tumor-infiltrating lymphocytes (TILs) on patients who are not receiving chemotherapy is important because of the focus on prognosis, and prospective trials are underway, she said.
A poster on the impact of chemotherapy and stromal tumor-infiltrating lymphocytes (sTILs) in stage I triple-negative breast cancer showed no association between chemotherapy and better outcomes regardless of sTILs in patients who did and did not receive chemotherapy, which has implications for potential treatment sparing in this population, Dr. Kok noted.
Artificial Intelligence (AI) was the subject of several posters at the meeting, and Dr. Kok identified a multisite European study of an automated HER2 scoring system as notable for its size and accuracy. In the study, the accuracy among pathologists was much higher with the assistance of AI, she said. Using AI for more complex analysis has shown success, she said.
Dr. Kok ended her talk with a poster that surveyed breast cancer patients about their understanding of their disease. The results showed that less than half (44%) of patients reported that their healthcare providers had given them enough information to learn about their breast cancer type, and less than one third could recall terminology about biomarkers; the study is important because it shows that clinicians need to do better in explaining these terms to patients, Dr. Kok said.
Early Breast Cancer
Right-sizing therapy, meaning identifying the right treatment for every patient, is a key element of new research in early breast cancer, said Erika Hamilton, MD, of the Sarah Cannon Research Institute, Nashville, Tenn.
She highlighted safety and treatment duration updates from the NATALEE study, which compared adjuvant ribociclib plus nonsteroidal aromatase inhibitor (NSAI) to NSAI alone for ER+/HER2- breast cancer. The current analysis presented at the meeting showed significant benefits with the addition of ribociclib and no evidence of new safety signals or adverse event exacerbations at 3 years, she said. Dose modifications had no significant impact on efficacy, she added.
The findings of no impact of dose reduction on efficacy in both the NATALEE and monarchE studies provide important information on whether dosage can be reduced in patients, which will increase the odds that patients will tolerate extended therapy with good outcomes and stay on their prescribed therapies, Dr. Hamilton emphasized.
The CARABELA study, a phase 2 trial of neoadjuvant letrozole plus abemaciclib vs adriamycin and cyclophosphamide (AC), showed clinically similar response rates but did not meet its endpoint for residual cancer burden (RCB) scores. These data add to results from other studies and show that it is too soon to universally replace neoadjuvant chemotherapy as first-line treatment for highly proliferative ER+ breast cancer, Dr. Hamilton said in her presentation.
Advanced Breast Cancer
Take-home messages about advanced breast cancer include growing evidence for the potential benefits of antibody drug conjugates (ADCs), said Eva Ciruelos, MD, of University Hospital, Madrid, Spain. The TROPION-BREAST01 study, a phase 3 randomized trial, showed significant and clinically meaningful improvement in progression-free survival in patients with previously treated, inoperable, or metastatic HR+/HER2- breast cancer who received datopotamab deruxtecan (Dato-DXd) compared with those who received chemotherapy.
Data from an additional safety analysis were presented at the meeting; although Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate, was well-tolerated, it is important to remain aware of toxicities, notably oral mucositis, which occurred in 55.6% of the patients in the study across all grades, and ocular surface toxicity, which occurred in 40% of patients across all grades, Dr. Ciruelos emphasized.
Key research in the area of advanced triple-negative breast cancer included data from the IMPASSION 132 study. This study is “specifically centered on early relapsers,” a population often excluded from other trials, Dr. Ciruelos said. In this study, patients with advanced triple-negative breast cancer were randomized to chemotherapy with or without atezolizumab, and the study showed no benefits with atezolizumab for overall survival, progression-free survival, or overall response rate, she said. “This is something to work with, because this is a very refractory population,” Dr. Ciruelos noted.
New immunotherapy combinations are needed to improve survival in advanced breast cancer patients, Dr. Ciruelos said. At the meeting, researchers presented interim data from a subset of patients in the MORPHEUS-pan breast cancer trial, a phase 1B/2 study involving multiple treatment combinations in locally advanced/metastatic breast cancer patients.
The interim analysis included 18-week data from triple-negative breast cancer patients and compared outcomes for patients randomized to atezolizumab with or without sacituzumab govitecan (SG).
The study was small, with only 31 patients in the combination arm and 11 controls, but the results were promising, with an overall response rate of 76.7% in the combination arm vs 66.7% in the control arm, Dr. Ciruelos said.
Supportive Care
Key supportive care takeaways included data on pregnancy in young breast cancer survivors and the safety of vaginal estrogen therapy in breast cancer patients with genitourinary symptoms, said Anne May, MD, of the University Medical Center Utrecht, Utrecht, Netherlands.
A study previously published in JAMA including nearly 5000 BRCA carriers who were diagnosed with invasive breast cancer at age 40 years or younger showed no association between pregnancy after breast cancer and adverse maternal or fetal outcomes, and pregnancy had no significant impact on overall survival. The authors presented new data on the safety of assisted reproductive techniques (ART) based on the 543 pregnancies in the original study, at the meeting. Of these, 436 conceived naturally, and 107 used ART. After a median of 9.1 years, ART had no effect on disease-free survival compared to natural conception (hazard ratio [HR], 0.64). Based on these findings, fertility preservation should be offered to all women who receive a breast cancer diagnosis and are interested in future fertility, Dr. May said.
Conceiving after breast cancer treatment and follow-up should not be contraindicated for young BRCA carriers, she added.No trial data are available for the effects of vaginal estrogen therapy (VET) on disease-free survival in breast cancer survivors with genitourinary symptoms caused by declining estrogen levels, Dr. May said. However, researchers in France and Switzerland conducted an emulation of a hypothetical target trial using data from the French National social security system for more than 130,000 individuals. Although VET therapy had no impact on disease-free survival in most breast cancer survivors overall, it did have a negative impact in a subset of patients with HR-positive and HR-negative tumors who were treated with aromatase inhibitors. The study was hypothetical, but important because the results suggest that clinicians can safely propose VTE to patients who report genitourinary symptoms after treatment for early-stage breast cancer with tamoxifen, but VTE should be avoided in patients treated with aromatase inhibitors, Dr. May said.
Dr. Delaloge disclosed research support to her institution from AstraZeneca, MSD, Bristol Myers Squibb, Sanofi, Taiho, Novartis, European Commission, INCa, Banque des Territoires, and Fondation Philanthropia. She also disclosed honoraria to her institution from AstraZeneca, Gilead, Novartis, Elsan, Besins, Sanofi, Exact Sciences, and Lilly, as well as travel support from Novartis.
Dr. Kok disclosed research funding from AstraZeneca, Bristol Myers Squibb, Daichi, and Roche, and advisory board membership/speaker’s fees from Alderaan Biotechnology, BIONTECH, Domain Therapeutics, AstraZeneca, Daichi, Bristol Myers Squibb, Gilead, Medscape, MSD, and Roche.
Dr. Hamilton disclosed a consulting advisory role (to her institution) for Accutar Biotechology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos, Forsum Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Roche/Genentech, Stemline Therapeutics, ands others. She also disclosed contracted research/grant support to her institution only from Abbvie, Acerta Pharma, Accutar Biotechnology , ADC Therapeutics, AKESOBIO Australia , Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond and others.
Dr. Ciruelos disclosed serving as an external advisor for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, and Lilly, as well as serving as a speaker for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, Lilly, and Pierre Fabre. She also disclosed travel grants from Roche, Pfizer, and AstraZeneca, and research grants from Seagen and Roche.
Dr. May had no financial conflicts to disclose.
Among the topics the speakers addressed were breast cancer prevention, early breast cancer, advanced breast cancer, and supportive care.
In recent years, the way clinicians look at carcinogenesis in breast cancer has changed, and many new targets for potential early detection and prevention have emerged, said Suzette Delaloge, MD, of Gustave Roussy, Paris, France, in her presentation at the meeting.
Instant risk assessment at different time points could potentially intercept cancer among high-risk individuals, she said.
A study by Mikael Eriksson, PhD, and colleagues focused on external validation of the Profound AI tool to identify breast cancer risk in the general population. The researchers showed an area under the curve of 0.72 in their AI risk model, which has the potential to be clinically meaningful, although it must be prospectively validated, Dr. Delaloge said in her presentation.
She also reviewed two studies on the use of genes to further refine breast cancer risk among carriers. One of these, a prospective study presented in a session by Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Center, Melbourne, Australia, used the CANRISK online risk assessment tool and validated increased breast cancer risk in BRCA1 and BRCA2 carriers, with AUCs of 0.79 and 0.78, respectively. The other study, which was by Maria Rezqallah Aron, MD, and colleagues examined polygenic scores as a way to refine breast cancer risk stratification among carriers of the ALM and PALB2 genes as well. These genes might be useful in identifying individuals who could benefit from early intervention, including surgery, Dr. Delaloge said.
Translational Research
“Preparing my talk, I felt like a kid in a candy store,” because of the amount of new translational research presented, including several studies of endocrine treatment–based approaches to therapy, said Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam.
In her presentation, Dr. Kok highlighted findings from an analysis of patients in the monarchE study (a trial of high-risk patients) showing a consistent improvement in invasive disease-free survival for the subset of patients with germline BRCA1 and BRCA2 mutations who received abemaciclib plus endocrine therapy.
The value of tumor-infiltrating lymphocytes (TILs) on patients who are not receiving chemotherapy is important because of the focus on prognosis, and prospective trials are underway, she said.
A poster on the impact of chemotherapy and stromal tumor-infiltrating lymphocytes (sTILs) in stage I triple-negative breast cancer showed no association between chemotherapy and better outcomes regardless of sTILs in patients who did and did not receive chemotherapy, which has implications for potential treatment sparing in this population, Dr. Kok noted.
Artificial Intelligence (AI) was the subject of several posters at the meeting, and Dr. Kok identified a multisite European study of an automated HER2 scoring system as notable for its size and accuracy. In the study, the accuracy among pathologists was much higher with the assistance of AI, she said. Using AI for more complex analysis has shown success, she said.
Dr. Kok ended her talk with a poster that surveyed breast cancer patients about their understanding of their disease. The results showed that less than half (44%) of patients reported that their healthcare providers had given them enough information to learn about their breast cancer type, and less than one third could recall terminology about biomarkers; the study is important because it shows that clinicians need to do better in explaining these terms to patients, Dr. Kok said.
Early Breast Cancer
Right-sizing therapy, meaning identifying the right treatment for every patient, is a key element of new research in early breast cancer, said Erika Hamilton, MD, of the Sarah Cannon Research Institute, Nashville, Tenn.
She highlighted safety and treatment duration updates from the NATALEE study, which compared adjuvant ribociclib plus nonsteroidal aromatase inhibitor (NSAI) to NSAI alone for ER+/HER2- breast cancer. The current analysis presented at the meeting showed significant benefits with the addition of ribociclib and no evidence of new safety signals or adverse event exacerbations at 3 years, she said. Dose modifications had no significant impact on efficacy, she added.
The findings of no impact of dose reduction on efficacy in both the NATALEE and monarchE studies provide important information on whether dosage can be reduced in patients, which will increase the odds that patients will tolerate extended therapy with good outcomes and stay on their prescribed therapies, Dr. Hamilton emphasized.
The CARABELA study, a phase 2 trial of neoadjuvant letrozole plus abemaciclib vs adriamycin and cyclophosphamide (AC), showed clinically similar response rates but did not meet its endpoint for residual cancer burden (RCB) scores. These data add to results from other studies and show that it is too soon to universally replace neoadjuvant chemotherapy as first-line treatment for highly proliferative ER+ breast cancer, Dr. Hamilton said in her presentation.
Advanced Breast Cancer
Take-home messages about advanced breast cancer include growing evidence for the potential benefits of antibody drug conjugates (ADCs), said Eva Ciruelos, MD, of University Hospital, Madrid, Spain. The TROPION-BREAST01 study, a phase 3 randomized trial, showed significant and clinically meaningful improvement in progression-free survival in patients with previously treated, inoperable, or metastatic HR+/HER2- breast cancer who received datopotamab deruxtecan (Dato-DXd) compared with those who received chemotherapy.
Data from an additional safety analysis were presented at the meeting; although Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate, was well-tolerated, it is important to remain aware of toxicities, notably oral mucositis, which occurred in 55.6% of the patients in the study across all grades, and ocular surface toxicity, which occurred in 40% of patients across all grades, Dr. Ciruelos emphasized.
Key research in the area of advanced triple-negative breast cancer included data from the IMPASSION 132 study. This study is “specifically centered on early relapsers,” a population often excluded from other trials, Dr. Ciruelos said. In this study, patients with advanced triple-negative breast cancer were randomized to chemotherapy with or without atezolizumab, and the study showed no benefits with atezolizumab for overall survival, progression-free survival, or overall response rate, she said. “This is something to work with, because this is a very refractory population,” Dr. Ciruelos noted.
New immunotherapy combinations are needed to improve survival in advanced breast cancer patients, Dr. Ciruelos said. At the meeting, researchers presented interim data from a subset of patients in the MORPHEUS-pan breast cancer trial, a phase 1B/2 study involving multiple treatment combinations in locally advanced/metastatic breast cancer patients.
The interim analysis included 18-week data from triple-negative breast cancer patients and compared outcomes for patients randomized to atezolizumab with or without sacituzumab govitecan (SG).
The study was small, with only 31 patients in the combination arm and 11 controls, but the results were promising, with an overall response rate of 76.7% in the combination arm vs 66.7% in the control arm, Dr. Ciruelos said.
Supportive Care
Key supportive care takeaways included data on pregnancy in young breast cancer survivors and the safety of vaginal estrogen therapy in breast cancer patients with genitourinary symptoms, said Anne May, MD, of the University Medical Center Utrecht, Utrecht, Netherlands.
A study previously published in JAMA including nearly 5000 BRCA carriers who were diagnosed with invasive breast cancer at age 40 years or younger showed no association between pregnancy after breast cancer and adverse maternal or fetal outcomes, and pregnancy had no significant impact on overall survival. The authors presented new data on the safety of assisted reproductive techniques (ART) based on the 543 pregnancies in the original study, at the meeting. Of these, 436 conceived naturally, and 107 used ART. After a median of 9.1 years, ART had no effect on disease-free survival compared to natural conception (hazard ratio [HR], 0.64). Based on these findings, fertility preservation should be offered to all women who receive a breast cancer diagnosis and are interested in future fertility, Dr. May said.
Conceiving after breast cancer treatment and follow-up should not be contraindicated for young BRCA carriers, she added.No trial data are available for the effects of vaginal estrogen therapy (VET) on disease-free survival in breast cancer survivors with genitourinary symptoms caused by declining estrogen levels, Dr. May said. However, researchers in France and Switzerland conducted an emulation of a hypothetical target trial using data from the French National social security system for more than 130,000 individuals. Although VET therapy had no impact on disease-free survival in most breast cancer survivors overall, it did have a negative impact in a subset of patients with HR-positive and HR-negative tumors who were treated with aromatase inhibitors. The study was hypothetical, but important because the results suggest that clinicians can safely propose VTE to patients who report genitourinary symptoms after treatment for early-stage breast cancer with tamoxifen, but VTE should be avoided in patients treated with aromatase inhibitors, Dr. May said.
Dr. Delaloge disclosed research support to her institution from AstraZeneca, MSD, Bristol Myers Squibb, Sanofi, Taiho, Novartis, European Commission, INCa, Banque des Territoires, and Fondation Philanthropia. She also disclosed honoraria to her institution from AstraZeneca, Gilead, Novartis, Elsan, Besins, Sanofi, Exact Sciences, and Lilly, as well as travel support from Novartis.
Dr. Kok disclosed research funding from AstraZeneca, Bristol Myers Squibb, Daichi, and Roche, and advisory board membership/speaker’s fees from Alderaan Biotechnology, BIONTECH, Domain Therapeutics, AstraZeneca, Daichi, Bristol Myers Squibb, Gilead, Medscape, MSD, and Roche.
Dr. Hamilton disclosed a consulting advisory role (to her institution) for Accutar Biotechology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos, Forsum Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Roche/Genentech, Stemline Therapeutics, ands others. She also disclosed contracted research/grant support to her institution only from Abbvie, Acerta Pharma, Accutar Biotechnology , ADC Therapeutics, AKESOBIO Australia , Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond and others.
Dr. Ciruelos disclosed serving as an external advisor for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, and Lilly, as well as serving as a speaker for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, Lilly, and Pierre Fabre. She also disclosed travel grants from Roche, Pfizer, and AstraZeneca, and research grants from Seagen and Roche.
Dr. May had no financial conflicts to disclose.
Among the topics the speakers addressed were breast cancer prevention, early breast cancer, advanced breast cancer, and supportive care.
In recent years, the way clinicians look at carcinogenesis in breast cancer has changed, and many new targets for potential early detection and prevention have emerged, said Suzette Delaloge, MD, of Gustave Roussy, Paris, France, in her presentation at the meeting.
Instant risk assessment at different time points could potentially intercept cancer among high-risk individuals, she said.
A study by Mikael Eriksson, PhD, and colleagues focused on external validation of the Profound AI tool to identify breast cancer risk in the general population. The researchers showed an area under the curve of 0.72 in their AI risk model, which has the potential to be clinically meaningful, although it must be prospectively validated, Dr. Delaloge said in her presentation.
She also reviewed two studies on the use of genes to further refine breast cancer risk among carriers. One of these, a prospective study presented in a session by Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Center, Melbourne, Australia, used the CANRISK online risk assessment tool and validated increased breast cancer risk in BRCA1 and BRCA2 carriers, with AUCs of 0.79 and 0.78, respectively. The other study, which was by Maria Rezqallah Aron, MD, and colleagues examined polygenic scores as a way to refine breast cancer risk stratification among carriers of the ALM and PALB2 genes as well. These genes might be useful in identifying individuals who could benefit from early intervention, including surgery, Dr. Delaloge said.
Translational Research
“Preparing my talk, I felt like a kid in a candy store,” because of the amount of new translational research presented, including several studies of endocrine treatment–based approaches to therapy, said Marleen Kok, MD, of the Netherlands Cancer Institute, Amsterdam.
In her presentation, Dr. Kok highlighted findings from an analysis of patients in the monarchE study (a trial of high-risk patients) showing a consistent improvement in invasive disease-free survival for the subset of patients with germline BRCA1 and BRCA2 mutations who received abemaciclib plus endocrine therapy.
The value of tumor-infiltrating lymphocytes (TILs) on patients who are not receiving chemotherapy is important because of the focus on prognosis, and prospective trials are underway, she said.
A poster on the impact of chemotherapy and stromal tumor-infiltrating lymphocytes (sTILs) in stage I triple-negative breast cancer showed no association between chemotherapy and better outcomes regardless of sTILs in patients who did and did not receive chemotherapy, which has implications for potential treatment sparing in this population, Dr. Kok noted.
Artificial Intelligence (AI) was the subject of several posters at the meeting, and Dr. Kok identified a multisite European study of an automated HER2 scoring system as notable for its size and accuracy. In the study, the accuracy among pathologists was much higher with the assistance of AI, she said. Using AI for more complex analysis has shown success, she said.
Dr. Kok ended her talk with a poster that surveyed breast cancer patients about their understanding of their disease. The results showed that less than half (44%) of patients reported that their healthcare providers had given them enough information to learn about their breast cancer type, and less than one third could recall terminology about biomarkers; the study is important because it shows that clinicians need to do better in explaining these terms to patients, Dr. Kok said.
Early Breast Cancer
Right-sizing therapy, meaning identifying the right treatment for every patient, is a key element of new research in early breast cancer, said Erika Hamilton, MD, of the Sarah Cannon Research Institute, Nashville, Tenn.
She highlighted safety and treatment duration updates from the NATALEE study, which compared adjuvant ribociclib plus nonsteroidal aromatase inhibitor (NSAI) to NSAI alone for ER+/HER2- breast cancer. The current analysis presented at the meeting showed significant benefits with the addition of ribociclib and no evidence of new safety signals or adverse event exacerbations at 3 years, she said. Dose modifications had no significant impact on efficacy, she added.
The findings of no impact of dose reduction on efficacy in both the NATALEE and monarchE studies provide important information on whether dosage can be reduced in patients, which will increase the odds that patients will tolerate extended therapy with good outcomes and stay on their prescribed therapies, Dr. Hamilton emphasized.
The CARABELA study, a phase 2 trial of neoadjuvant letrozole plus abemaciclib vs adriamycin and cyclophosphamide (AC), showed clinically similar response rates but did not meet its endpoint for residual cancer burden (RCB) scores. These data add to results from other studies and show that it is too soon to universally replace neoadjuvant chemotherapy as first-line treatment for highly proliferative ER+ breast cancer, Dr. Hamilton said in her presentation.
Advanced Breast Cancer
Take-home messages about advanced breast cancer include growing evidence for the potential benefits of antibody drug conjugates (ADCs), said Eva Ciruelos, MD, of University Hospital, Madrid, Spain. The TROPION-BREAST01 study, a phase 3 randomized trial, showed significant and clinically meaningful improvement in progression-free survival in patients with previously treated, inoperable, or metastatic HR+/HER2- breast cancer who received datopotamab deruxtecan (Dato-DXd) compared with those who received chemotherapy.
Data from an additional safety analysis were presented at the meeting; although Dato-DXd, a trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate, was well-tolerated, it is important to remain aware of toxicities, notably oral mucositis, which occurred in 55.6% of the patients in the study across all grades, and ocular surface toxicity, which occurred in 40% of patients across all grades, Dr. Ciruelos emphasized.
Key research in the area of advanced triple-negative breast cancer included data from the IMPASSION 132 study. This study is “specifically centered on early relapsers,” a population often excluded from other trials, Dr. Ciruelos said. In this study, patients with advanced triple-negative breast cancer were randomized to chemotherapy with or without atezolizumab, and the study showed no benefits with atezolizumab for overall survival, progression-free survival, or overall response rate, she said. “This is something to work with, because this is a very refractory population,” Dr. Ciruelos noted.
New immunotherapy combinations are needed to improve survival in advanced breast cancer patients, Dr. Ciruelos said. At the meeting, researchers presented interim data from a subset of patients in the MORPHEUS-pan breast cancer trial, a phase 1B/2 study involving multiple treatment combinations in locally advanced/metastatic breast cancer patients.
The interim analysis included 18-week data from triple-negative breast cancer patients and compared outcomes for patients randomized to atezolizumab with or without sacituzumab govitecan (SG).
The study was small, with only 31 patients in the combination arm and 11 controls, but the results were promising, with an overall response rate of 76.7% in the combination arm vs 66.7% in the control arm, Dr. Ciruelos said.
Supportive Care
Key supportive care takeaways included data on pregnancy in young breast cancer survivors and the safety of vaginal estrogen therapy in breast cancer patients with genitourinary symptoms, said Anne May, MD, of the University Medical Center Utrecht, Utrecht, Netherlands.
A study previously published in JAMA including nearly 5000 BRCA carriers who were diagnosed with invasive breast cancer at age 40 years or younger showed no association between pregnancy after breast cancer and adverse maternal or fetal outcomes, and pregnancy had no significant impact on overall survival. The authors presented new data on the safety of assisted reproductive techniques (ART) based on the 543 pregnancies in the original study, at the meeting. Of these, 436 conceived naturally, and 107 used ART. After a median of 9.1 years, ART had no effect on disease-free survival compared to natural conception (hazard ratio [HR], 0.64). Based on these findings, fertility preservation should be offered to all women who receive a breast cancer diagnosis and are interested in future fertility, Dr. May said.
Conceiving after breast cancer treatment and follow-up should not be contraindicated for young BRCA carriers, she added.No trial data are available for the effects of vaginal estrogen therapy (VET) on disease-free survival in breast cancer survivors with genitourinary symptoms caused by declining estrogen levels, Dr. May said. However, researchers in France and Switzerland conducted an emulation of a hypothetical target trial using data from the French National social security system for more than 130,000 individuals. Although VET therapy had no impact on disease-free survival in most breast cancer survivors overall, it did have a negative impact in a subset of patients with HR-positive and HR-negative tumors who were treated with aromatase inhibitors. The study was hypothetical, but important because the results suggest that clinicians can safely propose VTE to patients who report genitourinary symptoms after treatment for early-stage breast cancer with tamoxifen, but VTE should be avoided in patients treated with aromatase inhibitors, Dr. May said.
Dr. Delaloge disclosed research support to her institution from AstraZeneca, MSD, Bristol Myers Squibb, Sanofi, Taiho, Novartis, European Commission, INCa, Banque des Territoires, and Fondation Philanthropia. She also disclosed honoraria to her institution from AstraZeneca, Gilead, Novartis, Elsan, Besins, Sanofi, Exact Sciences, and Lilly, as well as travel support from Novartis.
Dr. Kok disclosed research funding from AstraZeneca, Bristol Myers Squibb, Daichi, and Roche, and advisory board membership/speaker’s fees from Alderaan Biotechnology, BIONTECH, Domain Therapeutics, AstraZeneca, Daichi, Bristol Myers Squibb, Gilead, Medscape, MSD, and Roche.
Dr. Hamilton disclosed a consulting advisory role (to her institution) for Accutar Biotechology, AstraZeneca, Daiichi Sankyo, Ellipses Pharma, Entos, Forsum Pharma, Gilead Sciences, Greenwich LifeSciences, Jazz Pharmaceuticals, Lilly, Medical Pharma Services, Mersana, Novartis, Olema Pharmaceuticals, Orum Therapeutics, Roche/Genentech, Stemline Therapeutics, ands others. She also disclosed contracted research/grant support to her institution only from Abbvie, Acerta Pharma, Accutar Biotechnology , ADC Therapeutics, AKESOBIO Australia , Amgen, Aravive, ArQule, Artios, Arvinas, AstraZeneca, AtlasMedx, BeiGene, Black Diamond and others.
Dr. Ciruelos disclosed serving as an external advisor for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, and Lilly, as well as serving as a speaker for Roche, MSD, Gilead, AstraZeneca, Daichii Sankyo, Reveal Genomics, Pfizer, Novartis, Lilly, and Pierre Fabre. She also disclosed travel grants from Roche, Pfizer, and AstraZeneca, and research grants from Seagen and Roche.
Dr. May had no financial conflicts to disclose.
FROM ESMO BREAST CANCER 2024
Statin Use May Extend Life for Early Breast Cancer Patients
Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
What Is Known About Statins and Breast Cancer?
Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.
Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.
The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
How Was the Current Study Designed?
To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.
As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.
The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.
The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
What Did the Results Show?
The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).
The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).
The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.
“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.
The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
What Is the Takeaway Message for Clinical Practice?
“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.
What Are the Next Steps for Research?
The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.
However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.
Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
What Do Clinicians Think of the Study?
The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.
Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.
“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.
Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.
“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.
The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.
The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.
The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.
Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
What Is Known About Statins and Breast Cancer?
Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.
Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.
The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
How Was the Current Study Designed?
To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.
As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.
The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.
The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
What Did the Results Show?
The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).
The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).
The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.
“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.
The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
What Is the Takeaway Message for Clinical Practice?
“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.
What Are the Next Steps for Research?
The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.
However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.
Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
What Do Clinicians Think of the Study?
The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.
Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.
“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.
Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.
“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.
The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.
The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.
The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.
Previous research examining the association between cholesterol and breast cancer metabolism suggests that cholesterol-lowering medications such as statins may improve outcomes in breast cancer patients, Sixten Harborg, a medical student and PhD student at Aarhus University, Denmark, said in a presentation at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
In addition, cardiovascular-related death is the second most common cause of death for breast cancer survivors, and given the survival rates in early breast cancer, there is a demand for cardioprotective initiatives and maintenance of cardioprotective drugs after diagnosis, he said in an interview.
What Is Known About Statins and Breast Cancer?
Statins are the most common drugs used to lower cholesterol and may deprive tumor cells of the cholesterol needed for cell membrane synthesis, Mr. Harborg said in his presentation.
Data from a randomized trial published in the Journal of Clinical Oncology in 2017 showed significantly improved disease-free survival, breast cancer–free interval, and distant recurrence–free interval in early stage breast cancer patients randomized to cholesterol-lowering medication vs. those who did not receive cholesterol-lowering medication.
The 2017 study prompted the creation of the MASTER study, a randomized, multicenter, double-blind, placebo-controlled trial comparing standard adjuvant therapy plus placebo to standard adjuvant therapy plus atorvastatin in patients with early breast cancer (NCT04601116), Mr. Harborg said. The MASTER trial is currently recruiting patients in Denmark.
How Was the Current Study Designed?
To provide preliminary analysis, Mr. Harborg and colleagues used an emulation trial design based on electronic health care data from 110,160 females with a diagnosis of stage I, II, or III breast cancer who were part of the Danish Breast Cancer Group, a national clinical registry in Denmark, between 2000 and 2020.
As defined in the European Journal of Epidemiology in 2017, target trial emulation involves application of randomized trial designs to observational data with the goal of improving the quality of observational epidemiology when a comparator trial is not yet available.
The researchers created a cohort of patients based on electronic health care data to simulate a target trial of the use of atorvastatin after breast cancer diagnosis. Patients were randomized to one of two treatment strategies: starting to use statins within 36 months of diagnosis, or not using statins. The primary outcome was death from breast cancer. The follow-up for the MASTER study starts with inclusion and ends with death, emigration from Denmark, end of clinical follow-up, or 10 years of follow-up (whichever comes first); the follow-up was the same in the current study.
The researchers calculated hazard ratios (HR) of breast cancer mortality in statin users vs. non–statin users and used a technique known as inverse-probability of censoring-weighting (IPCW) to estimate the effects of statin use based on prognostic factors.
What Did the Results Show?
The results favored statin use for improved survival in early breast cancer patients, Mr. Harborg said. Overall, the hazard ratio for breast cancer mortality was 0.96 in statin users compared with non–statin users, and was similar in both a Cox regression analysis (HR 0.81), and in a 10-year landmark analysis (HR 0.86).
The difference in mortality between statin and non–statin users was even stronger in patients who were receiving adjuvant chemotherapy (HR 0.94, 0.64, and 0.76 on the IPCW, Cox, and landmark analyses, respectively).
The results were in line with previous reports of statins’ effect on breast cancer survival, Mr. Harborg said in an interview.
“We believe the results encourage the continuous effort of the currently enrolling MASTER trial,” he said.
The results also suggest that deprescribing statins at the time of breast cancer diagnosis is not recommended, and that statin treatment can safely be prescribed to breast cancer patients with increased cardiovascular disease risk and/or dyslipidemia, Mr. Harborg said in the interview.
What Is the Takeaway Message for Clinical Practice?
“The clinical takeaway from our study is that statin use is associated with reduced risk of dying from breast cancer, but that it is not possible to determine the true effect of statins on breast cancer survival without a randomized, placebo-controlled trial,” Mr. Harborg told this publication. “Statins are inexpensive and well-tolerated drugs and may have a beneficial effect in terms of survival for breast cancer patients. However, with the current level of evidence [because the MASTER study is ongoing], we still cannot recommend that oncologists prescribe statins to prevent mortality from breast cancer,” he said.
What Are the Next Steps for Research?
The findings were limited by the study design, and real-world data are needed, Dr. Harborg said. Other limitations include the presence of residual bias, and the use of data based on prescription codes, but these were not considered to have an effect on the main conclusion of the study, Mr. Harborg said in the interview.
However, the results suggest that the addition of statins may improve outcomes for early breast cancer patients, especially when used with chemotherapy, and support the value of the ongoing MASTER study, he concluded.
Ultimately, the MASTER study will provide a more definitive answer to the question of whether statins should be added to the adjuvant treatment regimen of breast cancer to improve breast cancer outcomes, he said.
What Do Clinicians Think of the Study?
The current study is timely and highlights the need for phase 3 trials to examine the potential of statin use for breast cancer outcomes, Malinda T. West, MD, a medical oncologist and breast oncologist at the University of Wisconsin Carbone Cancer Center, Madison, said in an interview.
Questions for future research include whether statins can be used in combination with adjuvant abemaciclib if indicated, or how to best sequence these agents, said Dr. West, who was not involved in the study. Other questions raised by the current study include whether other cholesterol-lowering agents have a potential adjuvant benefit in reducing breast cancer recurrent and/or mortality, and whether the addition of statins would benefit subgroups such as HER2+ and triple negative breast cancer, she said.
“I was not surprised to see another study reporting benefit with statins and reduced risk of breast cancer recurrence and/or mortality, but I think the larger question is defining the subgroups who benefit the most, and identifying predictors for benefit or resistance,” Dr. West said in an interview.
Previous studies have shown that cholesterol elevation, specifically LDL levels, can be linked to increased tumor growth in breast cancer, so the lower mortality risk associated with lipid-lowering therapies in the current study was consistent, Peyton L. Reves, MD, a hematology/oncology fellow, also at the University of Wisconsin, said in an interview. In practice, data from the current study and previous research could be especially useful for patients with elevated LDL levels, said Dr. Reves, who was not involved in the study.
“These results could impact clinical practice in many ways, including leading to routine cholesterol monitoring in breast cancer patients on adjuvant therapy as well as the addition of lipid-lowering therapy with statins in these patients,” Dr. Reves said.
The findings showing particular benefit for patients on adjuvant chemotherapy highlight the need for more research on this specific population and the effect of statins on overall breast cancer mortality, to explore the extent to which the results of the current study were driven by the benefit seen in patients receiving adjuvant chemotherapy, Dr. Reves said.
The study was supported by Director Michael Hermann Nielsen’s Memorial Grant, Manufacturer Einar Willumsen’s Memorial Grant, Astrid Thaysen’s Grant for Medical Basic Research, Eva and Henry Fraenkel’s Memorial Fund, and the Novo Nordisk Foundation.
The researchers had no financial conflicts to disclose. Dr. West and Dr. Reves had no financial conflicts to disclose.
FROM ESMO BREAST CANCER 2024
New Immunotherapy Combo Shows Promise for Triple-Negative Breast Cancer
MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.
The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Rationale for Combining Antibody-Drug Conjugates with Immunotherapy
Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.
TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.
Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.
“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
Study Design
The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.
“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.
During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.
“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.
Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
Promising Anti-tumor Activity
The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.
“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.
The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.
Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”
She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
Encouraging survival trends
Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.
During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”
These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
Relationship between biomarker expression and response
The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).
“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.
Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
Safety of combination treatment
The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.
All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).
The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.
“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.
Looking Ahead
Dr. Tolaney highlighted that the cohort size of this study was small and the follow-up time was insufficient to draw conclusions about survival outcomes. Larger studies with long-term follow-up are needed to confirm the efficacy of first-line atezolizumab plus sacituzumab govitecan, she said.
“While this was a small study, the response data is very intriguing, with 17% of patients experiencing complete responses. The PFS data are also impressive, and there seems to be an interesting trend towards better response in patients with high Trop-2 expression and those with high levels of stromal TILs,” she added.
Dr. Tolaney also noted that the response rates and PFS data presented are similar to those of one of the treatment arms in the BEGONIA trial (NCT03742102), which investigated different combinations of immunotherapy in patients with metastatic TNBC. Like MORPHEUS-pan BC (NCT03424005), this study evaluated the efficacy of a different antibody-drug conjugate with chemotherapy. Patients in the study arm of the BEGONIA trial she was referring to received durvalumab (an anti-PD-L1 agent) and datopotamab deruxtecan (an antibody-drug conjugate).
Dr. Schmid said that biomarker analyses are ongoing to assess whether there is a correlation between Trop-2 expression levels and the benefits of sacituzumab govitecan. Studies are also needed to determine whether this combination can improve pathologic complete response rates in early-stage TNBC.
Dr. Tolaney echoed the importance of evaluating the efficacy of antibody-drug conjugates plus immune checkpoint inhibitors in different settings, including patients with PD-L1–negative or immunologically cold tumors and those with early-stage disease. “Ultimately, we want this combination treatment to move forward to early-stage TNBC to see if we could cure more patients,” she said, during the discussion.
Dr. Schmid reported financial relationships with Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (consulting or advisory roles); Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (honoraria); and AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas, and Medivation (research funding). Dr. Tolaney reported financial relationships with Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., Beyond Spring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, and Jazz Pharmaceuticals (consulting or advisory roles); Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Nanostring, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, Cyclacel, Sanofi, and Seattle Genetics (research funding).
MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.
The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Rationale for Combining Antibody-Drug Conjugates with Immunotherapy
Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.
TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.
Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.
“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
Study Design
The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.
“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.
During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.
“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.
Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
Promising Anti-tumor Activity
The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.
“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.
The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.
Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”
She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
Encouraging survival trends
Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.
During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”
These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
Relationship between biomarker expression and response
The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).
“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.
Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
Safety of combination treatment
The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.
All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).
The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.
“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.
Looking Ahead
Dr. Tolaney highlighted that the cohort size of this study was small and the follow-up time was insufficient to draw conclusions about survival outcomes. Larger studies with long-term follow-up are needed to confirm the efficacy of first-line atezolizumab plus sacituzumab govitecan, she said.
“While this was a small study, the response data is very intriguing, with 17% of patients experiencing complete responses. The PFS data are also impressive, and there seems to be an interesting trend towards better response in patients with high Trop-2 expression and those with high levels of stromal TILs,” she added.
Dr. Tolaney also noted that the response rates and PFS data presented are similar to those of one of the treatment arms in the BEGONIA trial (NCT03742102), which investigated different combinations of immunotherapy in patients with metastatic TNBC. Like MORPHEUS-pan BC (NCT03424005), this study evaluated the efficacy of a different antibody-drug conjugate with chemotherapy. Patients in the study arm of the BEGONIA trial she was referring to received durvalumab (an anti-PD-L1 agent) and datopotamab deruxtecan (an antibody-drug conjugate).
Dr. Schmid said that biomarker analyses are ongoing to assess whether there is a correlation between Trop-2 expression levels and the benefits of sacituzumab govitecan. Studies are also needed to determine whether this combination can improve pathologic complete response rates in early-stage TNBC.
Dr. Tolaney echoed the importance of evaluating the efficacy of antibody-drug conjugates plus immune checkpoint inhibitors in different settings, including patients with PD-L1–negative or immunologically cold tumors and those with early-stage disease. “Ultimately, we want this combination treatment to move forward to early-stage TNBC to see if we could cure more patients,” she said, during the discussion.
Dr. Schmid reported financial relationships with Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (consulting or advisory roles); Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (honoraria); and AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas, and Medivation (research funding). Dr. Tolaney reported financial relationships with Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., Beyond Spring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, and Jazz Pharmaceuticals (consulting or advisory roles); Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Nanostring, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, Cyclacel, Sanofi, and Seattle Genetics (research funding).
MORPHEUS-pan BC (NCT03424005) is evaluating multiple treatment combinations in patients with locally advanced or metastatic TNBC.
The trial’s interim clinical data was presented at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
Rationale for Combining Antibody-Drug Conjugates with Immunotherapy
Peter Schmid, MD, PhD, professor at the Centre for Experimental Cancer Medicine in London, England, presented interim findings from one study arm of MORPHEUS-pan BC at the meeting. The arm consisted of patients with TNBC who were treated with a combination of atezolizumab, a PD-L1 inhibitor, and sacituzumab govitecan, an antibody-drug conjugate targeting the Trop-2 protein commonly expressed in TNBC.
TNBC is one of the most challenging subtypes of breast cancer to treat because of its aggressive characteristics and innate resistance to hormonal therapy and HER2-targeted treatments. However, the recent approval of immunotherapy for TNBC has provided renewed hope for patients, according to Dr. Schmid.
Atezolizumab, in combination with nab-paclitaxel, has already been approved as a first-line treatment for PD-L1–positive, unresectable locally advanced or metastatic TNBC; however, not all patients respond to this combination treatment. Sacituzumab govitecan is approved for second-line and subsequent-line treatment of metastatic TNBC.
“Cancer immunotherapy in combination with chemotherapy has transformed the TNBC treatment landscape, but new combinations are needed to further improve survival outcomes,” Dr. Schmid said during his presentation. “We hoped that combining immunotherapy with an antibody-drug conjugate would not only improve safety but also increase efficacy through enhanced immune activation.”
Study Design
The MORPHEUS-pan BC trial enrolled patients with previously untreated, PD-L1–positive, inoperable, locally advanced or metastatic TNBC. Patients were randomized to receive experimental treatment consisting of atezolizumab plus the antibody-drug conjugate sacituzumab govitecan. Patients in the second arm received a control regimen of atezolizumab plus nab-paclitaxel chemotherapy.
“The control regimen is part of the current standard of care for patients with PD-L1–positive TNBC,” Dr. Schmid explained in his presentation. As of the data cut-off, 11 patients were enrolled in the control arm and 31 in the atezolizumab plus sacituzumab govitecan arm.
During the discussion session after his talk, Dr. Schmid commented on the use of PD-L1 expression to select patients for enrollment, acknowledging that PD-L1 is not the best biomarker.
“Its expression is very dynamic and can change rapidly,” he said. He added, however, that it is currently the most suitable biomarker for patient selection for treatment with anti–PD-1/PD-L1 agents.
Sara M. Tolaney, MD, MPH, added that, because patients were selected based on PD-L1 expression, it is unclear whether this combination therapy would show anti-tumor activity in patients with PD-L1–negative tumors. Dr. Tolaney, a medical oncologist at the Dana-Farber Cancer Institute who was not involved in the study, served as a discussant, providing her expert opinion on the findings presented by Dr. Schmid.
Promising Anti-tumor Activity
The combination of atezolizumab and sacituzumab govitecan demonstrated promising anti-tumor activity as initial treatment for this patient population. The interim analysis at 18 weeks showed an objective response rate of 76.7% (95% CI, 57.7-90.1; n = 23, including five complete responses) in the atezolizumab plus sacituzumab govitecan arm, versus 66.7% (95% CI, 29.9-92.5; n = 6, all of which were partial responses) in the control arm.
“The 66% response rate in the control arm aligns with what we see in historical data from patients treated with immunotherapy plus chemotherapy,” noted Dr. Schmid during his talk.
The clinical benefit rate, which includes complete and partial responses as well as stable disease, was also encouraging at 83.3% (95% CI, 65.3-94.4) with the dual immunotherapy regimen versus 66.7% (95% CI, 29.9-92.5) with standard therapy.
Commenting on the potential mechanisms of the synergistic effect of this combination therapy, Dr. Tolaney said, “In addition to delivering chemotherapy payloads to cancer cells, antibody-drug conjugates can lead to dendritic cell activation, T-cell activation, and immune cell infiltration.”
She added that antibody-drug conjugates can cause Fc activation in NK cells, thereby enhancing antibody-dependent cytotoxicity.
Encouraging survival trends
Interim survival data showed trends favoring atezolizumab plus sacituzumab govitecan over the control arm of atezolizumab plus nab-paclitaxel chemotherapy. The median progression-free survival (PFS) was 12.2 months (95% CI, 7.4-not estimable) in the immunotherapy combination group versus 5.9 months (95% CI, 4.1-8.7) in the control group, yielding a hazard ratio of 0.29 (95% CI, 0.11-0.70). The overall survival data are still immature.
During the discussion session, Dr. Schmid cautioned that, although the benefit of this combination therapy in terms of PFS seems promising, the validity of the hazard ratio is limited because of the small cohort size. He added, “The survival data is still immature, and longer follow-up is needed.”
These encouraging response and PFS rates need to be confirmed in larger studies of this immunotherapy combination as a potential new first-line standard for PD-L1–positive TNBC, according to Dr. Schmid.
Relationship between biomarker expression and response
The MORPHEUS-pan BC trial enrolled only patients with PD-L1–positive tumors at baseline, defined as PD-L1 expression in at least 1% of immune cells infiltrating the tumor. Tumors at baseline were also tested for Trop-2 expression, CD8 immune phenotype, and stromal tumor-infiltrating lymphocytes (TILs).
“We wanted to get an idea of whether these biomarkers are associated with treatment response,” Dr. Schmid explained during his talk.
Although the benefit of sacituzumab govitecan treatment was observed across all Trop-2 expression levels, preliminary analyses suggest that high Trop-2 expression, CD8 immune phenotype, and stromal TILs may be associated with response to atezolizumab plus sacituzumab govitecan. However, Dr. Schmid noted that validation of these associations in larger cohorts is required.
Safety of combination treatment
The side effect profile of atezolizumab plus sacituzumab govitecan appeared consistent with that expected from the two individual drugs, with no new toxicity signals.
All patients in both treatment arms experienced at least one adverse event; however, there were no fatal adverse events. Grade 3-4 adverse events were more common in the experimental arm (70.0%) than in the control arm (44.4%), while serious adverse events were more common in the control group (44.4% versus 23.3%). Immune-related adverse events were considerably more common in the atezolizumab plus sacituzumab govitecan group than in the control group (80.0% versus 55.6%).
The most common adverse events in patients treated with atezolizumab plus sacituzumab govitecan were nausea, alopecia, diarrhea, and neutropenia. Dr. Schmid emphasized in his presentation that this toxicity profile was dominated by adverse events that are common in patients treated with chemotherapy.
“These safety data are significant as they suggest that the combination therapy does not introduce additional risks beyond those already associated with each drug,” he added.
Looking Ahead
Dr. Tolaney highlighted that the cohort size of this study was small and the follow-up time was insufficient to draw conclusions about survival outcomes. Larger studies with long-term follow-up are needed to confirm the efficacy of first-line atezolizumab plus sacituzumab govitecan, she said.
“While this was a small study, the response data is very intriguing, with 17% of patients experiencing complete responses. The PFS data are also impressive, and there seems to be an interesting trend towards better response in patients with high Trop-2 expression and those with high levels of stromal TILs,” she added.
Dr. Tolaney also noted that the response rates and PFS data presented are similar to those of one of the treatment arms in the BEGONIA trial (NCT03742102), which investigated different combinations of immunotherapy in patients with metastatic TNBC. Like MORPHEUS-pan BC (NCT03424005), this study evaluated the efficacy of a different antibody-drug conjugate with chemotherapy. Patients in the study arm of the BEGONIA trial she was referring to received durvalumab (an anti-PD-L1 agent) and datopotamab deruxtecan (an antibody-drug conjugate).
Dr. Schmid said that biomarker analyses are ongoing to assess whether there is a correlation between Trop-2 expression levels and the benefits of sacituzumab govitecan. Studies are also needed to determine whether this combination can improve pathologic complete response rates in early-stage TNBC.
Dr. Tolaney echoed the importance of evaluating the efficacy of antibody-drug conjugates plus immune checkpoint inhibitors in different settings, including patients with PD-L1–negative or immunologically cold tumors and those with early-stage disease. “Ultimately, we want this combination treatment to move forward to early-stage TNBC to see if we could cure more patients,” she said, during the discussion.
Dr. Schmid reported financial relationships with Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (consulting or advisory roles); Pfizer, AstraZeneca, Novartis, Gilead, Roche, Merck, MSD, BI, Seagen, Amgen, Bayer, Eisai, Celgene, Lilly, and Puma (honoraria); and AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas, and Medivation (research funding). Dr. Tolaney reported financial relationships with Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., Beyond Spring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, and Jazz Pharmaceuticals (consulting or advisory roles); Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Nanostring, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, Cyclacel, Sanofi, and Seattle Genetics (research funding).
FROM ESMO BREAST CANCER 2024
ART Safe for Breast Cancer Survivors with BRCA1/2 Mutations
For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However,
“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
Unmet Fertility Needs for Women With Breast Cancer
With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.
According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.
“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
Study Design and Patient Population
The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.
Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.
Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
No Increased Risks for Pregnancy and Fetal Outcomes
Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.
Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.
“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
No Adverse Effects on Breast Cancer Prognosis
At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).
“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.
Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.
“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
Clinical Implications and Future Work
According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.
“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”
During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.
“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.
She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”
Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”
Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).
For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However,
“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
Unmet Fertility Needs for Women With Breast Cancer
With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.
According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.
“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
Study Design and Patient Population
The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.
Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.
Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
No Increased Risks for Pregnancy and Fetal Outcomes
Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.
Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.
“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
No Adverse Effects on Breast Cancer Prognosis
At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).
“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.
Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.
“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
Clinical Implications and Future Work
According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.
“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”
During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.
“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.
She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”
Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”
Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).
For breast cancer survivors harboring BRCA1/2 gene mutations, the prospect of future pregnancy often raises concerns because of limited data on the safety of assisted reproductive techniques (ART) in this population. However,
“Our primary aim was to evaluate the safety profile of ART in this high-risk population by comparing maternal and fetal outcomes between those who conceived spontaneously versus those using ART,” explained Matteo Lambertini, MD, PhD, during his talk at the conference. “We found no statistically significant differences in pregnancy complications or fetal abnormalities.” Dr. Lambertini is an associate professor and medical oncologist at the University of Genova and IRCCS Policlinico San Martino Hospital, Genova, Italy.
Unmet Fertility Needs for Women With Breast Cancer
With the rising rates of early-onset breast cancer and improved survival outcomes with new therapies, the number of long-term breast cancer survivors is increasing. Fertility preservation and future reproductive choices are important considerations for young patients with breast cancer, especially for high-risk patients carrying pathogenic BRCA1/2 mutations. During his talk, Dr. Lambertini explained that defects in DNA damage repair due to BRCA1/2 mutations, in addition to chemotherapy after breast cancer diagnosis, can lead to premature menopause.
According to Dr. Lambertini, physicians face challenges in counseling these patients regarding the potential risks and benefits of pursuing pregnancy after cancer treatment because of the limited evidence available on the safety of ART in BRCA1/2 mutation carriers.
“Clinicians have to counsel BRCA carriers based on very limited data about the safety of pursuing pregnancy with ART after a breast cancer diagnosis,” he said during his presentation.
Study Design and Patient Population
The retrospective cohort study pooled data from 78 centers worldwide to explore ART outcomes in BRCA1/2 mutation carriers. The analysis included 4732 women diagnosed with stage I-III breast cancer at age 40 years or younger, all harboring a pathogenic BRCA1 or BRCA2 variant.
Among these high-risk patients, 543 became pregnant after completing cancer treatment; of these, 436 conceived naturally and 107 used ART. In the ART group, 45.5% underwent oocyte or embryo cryopreservation at breast cancer diagnosis, 33.3% underwent ovarian stimulation for in vitro fertilization after cancer treatment, and 21.2% underwent embryo transfer following oocyte donation.
Dr. Janice Tsang, MD, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, highlighted that this is the largest study focusing on ART safety in young patients with BRCA1/2 mutations. “With over 500 BRCA1/2 mutation carriers studied across nearly 80 sites, the cohort analysis had sufficient statistical power and global representation to detect potential safety signals with ART utilization, unlike prior smaller studies,” she said. Dr. Tsang, a clinical oncology specialist and assistant professor at the University of Hong Kong who was not involved in this study, served as a discussant, providing her expert opinion on the findings presented by Dr. Lambertini.
No Increased Risks for Pregnancy and Fetal Outcomes
Although women using ART had slightly higher miscarriage rates (11.3% versus 8.8%) and lower rates of induced abortion (0.9% versus 8.3%) than women with spontaneous conceptions, the analysis revealed no statistically significant differences in the frequency of pregnancy complications, delivery complications, or congenital abnormalities between those who received ART and those who conceived naturally.
Dr. Lambertini explained that variations in baseline characteristics, such as age, may have contributed to differences in miscarriage rates.
“Patients in the ART group tended to be older at the time of conception, with a median age of 37.1 years, compared with 34.3 years in the spontaneous pregnancy group,” he said, during his presentation. Women in the ART group also more frequently had hormone receptor–positive breast cancer (43.4% versus 30.8%) and longer median time from diagnosis to conception (4.2 versus 3.3 years).
No Adverse Effects on Breast Cancer Prognosis
At a median follow-up of 5.2 years from conception, there was no detrimental effect of ART on disease-free survival for carriers of pathogenic BRCA1/2 variants who were treated for breast cancer. The ART group showed 13 (13.1%) recurrence events, compared with 118 (27.1%) recurrences in the spontaneous pregnancy group (adjusted hazard ratio, 0.72; 95% CI, 0.38-1.33; P = .147).
“The risk of cancer recurrence was comparable between those using and not using ART to become pregnant after their breast cancer diagnosis and treatment, and the small number of recurrence events in the ART group mostly involved locoregional recurrences,” Dr. Lambertini noted during his talk.
Moreover, breast cancer–specific survival and overall survival appeared to be similar between the two groups, although the small number of deaths precluded the conduction of formal analysis.
“These survival data suggest that utilizing ART does not appear to negatively impact the prognosis or course of the underlying breast cancer,” Dr. Lambertini said during the discussion.
Clinical Implications and Future Work
According to Dr. Lambertini, these results are incredibly valuable for clinicians counseling young breast cancer survivors with pathogenic BRCA1/2 mutations who wish to have biological children.
“Given the interest of patients in having their own family and for some of them in avoiding the transmission of the BRCA1/2 pathogenic variants, our results are critical in improving the oncofertility counseling of young women with breast cancer,” said Dr. Lambertini during his presentation. “We can reassure patients that pursuing ART does not appear to worsen their cancer prognosis or compromise pregnancy outcomes compared to spontaneous conceptions.”
During her discussion session, Dr. Tsang echoed the clinical implications of these findings, emphasizing that, by incorporating this evidence into clinical practice, healthcare providers can better support patients in making informed choices regarding fertility preservation and family planning after cancer treatment.
“Though this study is [retrospective] with a relatively small number, these real-world findings make a major contribution to our limited evidence base on ART safety for cancer survivors carrying BRCA1/2 mutations,” she said.
She cautioned, however, that there remain several unanswered questions and uncertainties. “We need prospective data with a larger sample size to confirm the safety of ART in this population, as well as studies to assess whether different types of ART have different safety profiles.”
Dr. Lambertini concluded his talk by saying, “While waiting for prospective studies to confirm our results, fertility preservation at diagnosis of early breast cancer should be offered to all women interested in future fertility, including BRCA carriers.”
Dr. Lambertini reported financial relationships with Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead, Pierre Fabre, and Menarini (consulting or advisory roles); Takeda, Roche, Lilly, Novartis, Pfizer, AstraZeneca, Sandoz, Ipsen, Libbs, Knight, Dalichi Sankyo, Gilead, Menarini (honoraria); Gilead, Daiichi Sankyo, and Roche (travel support); and Gilead (research funding to the institution). Dr. Tsang reported financial relationships with AstraZeneca, Amgen, Daichi Sankyo, Eisai, Gilead, Lilly, Lucence, Novartis, Pfizer, and Veracyte (honoraria); De Novo (consulting or advisory roles); and Pfizer (grant panel reviewer).
FROM ESMO BREAST CANCER 2024
No Improvement in OS With Atezolizumab in Early Relapsing TNBC
Our results “highlight the importance of recognizing TNBC heterogeneity, especially in the first-line setting” said Rebecca A. Dent, MD, MSc, National Cancer Center Singapore and Duke-NUS Medical School, Singapore, who presented the study at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
“These patients have a dismal prognosis and represent a high unmet need,” she added.
The current findings follow those from the IMpassion130 trial, which showed that the combination of atezolizumab with nab-paclitaxel chemotherapy offered no survival benefit in previously untreated locally advanced or metastatic TNBC despite a progression-free survival benefit on interim analysis.
Rapidly relapsing TNBC “represents one of most challenging clinical situations” because it is aggressive and “intrinsically resistant to standard therapies,” said Dr. Dent. It is also more common in younger patients with large primary tumors and no BRCA alterations.
“Most importantly, however, is that most trials actually exclude these patients,” she noted, “posing a real challenge for us in clinical practice.”
IMpassion132 enrolled 594 patients with unresectable locally advanced or metastatic TNBC who had experienced disease progression more than 12 months after their last treatment for early TNBC with curative intent.
Patients had received prior anthracycline and taxane therapy for but no prior chemotherapy for advanced disease.
Study participants were randomly assigned to chemotherapy with carboplatin-gemcitabine or capecitabine plus atezolizumab or placebo, with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival.
Initially, all patients with TNBC who met the study criteria were enrolled in the randomized, phase 3, double-blinded trial; however, the trial was then amended to include only PD-L1–positive patients after the results of IMpassion130 “clearly showed us that the benefits of immune checkpoint inhibition were largely driven by those patients,” Dr. Dent explained.
The 354 patients with PD-L1–positive disease were “young,” she added, with a median age of 48 years. The youngest was 23 years old.
The majority (66%-69%) had a disease-free interval of less than 6 months after treatment with curative intent. Lung and/or liver metastases were present in 60%-62% of patients, and 18% had previously received platinum-based chemotherapy.
After a median follow-up of 9.8 months, overall survival was a median of 12.1 months in the atezolizumab group vs 11.2 months with placebo, at a hazard ratio of 0.93 (P = .59).
A similar result was seen when looking at the modified intention-to-treat population, and when stratifying the patients by prespecified subgroup.
Dr. Dent pointed out that in the placebo group, patients treated with capecitabine had a median overall survival of 12.6 months vs 9.9 months in those given carboplatin-gemcitabine , which she described as “hypothesis generating” because “prior therapy may trigger a variety of resistance mechanisms.”
The disease-free interval also seemed to play a role in the placebo group. Patients who had a disease-free interval of 6 or more months prior to study enrollment had a median overall survival of 12.8 months vs 9.4 months in those with an interval of less than 6 months.
There were no significant differences in progression-free survival or duration of overall response between the atezolizumab and placebo groups.
“In terms of the safety data, clearly we’re getting better at identifying immune checkpoint inhibition toxicities and initiating therapies for these toxicities earlier,” Dr. Dent said, because there were “no new safety signals.”
The rate of treatment-related grade 3 or 4 adverse events was similar between patients given atezolizumab and those assigned to placebo, at 65% vs 62%. Rates of grade 5 events were identical, at 1%.
Commenting on the study, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, questioned the role for immunotherapy in patients with TNBC who experience early relapse.
This is not the first trial to fail to show a benefit in this space, she said. Collectively, these results make “me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition.”
The patients that do relapse, “have highly treatment refractory disease,” and “we need to think about other novel therapeutic strategies for this population,” she told this news organization.
IMpassion132 nevertheless represents a “unique opportunity to better understand the biology of these rapidly relapsing tumors, and hopefully use this information to develop more novel treatment approaches for this population,” she said.
“That being said, I do think that this is going to become an even more challenging area,” Dr. Tolaney said. “In the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many then go on to receive additional systemic treatment in the adjuvant setting.”
The study was sponsored by Hoffmann-La Roche.
Dr. Dent declares relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer. Dr. Tolaney declares relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, Jazz Pharmaceuticals, Exelixis, Novartis, Nanonstring, and Cyclacel.
A version of this article appeared on Medscape.com .
Our results “highlight the importance of recognizing TNBC heterogeneity, especially in the first-line setting” said Rebecca A. Dent, MD, MSc, National Cancer Center Singapore and Duke-NUS Medical School, Singapore, who presented the study at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
“These patients have a dismal prognosis and represent a high unmet need,” she added.
The current findings follow those from the IMpassion130 trial, which showed that the combination of atezolizumab with nab-paclitaxel chemotherapy offered no survival benefit in previously untreated locally advanced or metastatic TNBC despite a progression-free survival benefit on interim analysis.
Rapidly relapsing TNBC “represents one of most challenging clinical situations” because it is aggressive and “intrinsically resistant to standard therapies,” said Dr. Dent. It is also more common in younger patients with large primary tumors and no BRCA alterations.
“Most importantly, however, is that most trials actually exclude these patients,” she noted, “posing a real challenge for us in clinical practice.”
IMpassion132 enrolled 594 patients with unresectable locally advanced or metastatic TNBC who had experienced disease progression more than 12 months after their last treatment for early TNBC with curative intent.
Patients had received prior anthracycline and taxane therapy for but no prior chemotherapy for advanced disease.
Study participants were randomly assigned to chemotherapy with carboplatin-gemcitabine or capecitabine plus atezolizumab or placebo, with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival.
Initially, all patients with TNBC who met the study criteria were enrolled in the randomized, phase 3, double-blinded trial; however, the trial was then amended to include only PD-L1–positive patients after the results of IMpassion130 “clearly showed us that the benefits of immune checkpoint inhibition were largely driven by those patients,” Dr. Dent explained.
The 354 patients with PD-L1–positive disease were “young,” she added, with a median age of 48 years. The youngest was 23 years old.
The majority (66%-69%) had a disease-free interval of less than 6 months after treatment with curative intent. Lung and/or liver metastases were present in 60%-62% of patients, and 18% had previously received platinum-based chemotherapy.
After a median follow-up of 9.8 months, overall survival was a median of 12.1 months in the atezolizumab group vs 11.2 months with placebo, at a hazard ratio of 0.93 (P = .59).
A similar result was seen when looking at the modified intention-to-treat population, and when stratifying the patients by prespecified subgroup.
Dr. Dent pointed out that in the placebo group, patients treated with capecitabine had a median overall survival of 12.6 months vs 9.9 months in those given carboplatin-gemcitabine , which she described as “hypothesis generating” because “prior therapy may trigger a variety of resistance mechanisms.”
The disease-free interval also seemed to play a role in the placebo group. Patients who had a disease-free interval of 6 or more months prior to study enrollment had a median overall survival of 12.8 months vs 9.4 months in those with an interval of less than 6 months.
There were no significant differences in progression-free survival or duration of overall response between the atezolizumab and placebo groups.
“In terms of the safety data, clearly we’re getting better at identifying immune checkpoint inhibition toxicities and initiating therapies for these toxicities earlier,” Dr. Dent said, because there were “no new safety signals.”
The rate of treatment-related grade 3 or 4 adverse events was similar between patients given atezolizumab and those assigned to placebo, at 65% vs 62%. Rates of grade 5 events were identical, at 1%.
Commenting on the study, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, questioned the role for immunotherapy in patients with TNBC who experience early relapse.
This is not the first trial to fail to show a benefit in this space, she said. Collectively, these results make “me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition.”
The patients that do relapse, “have highly treatment refractory disease,” and “we need to think about other novel therapeutic strategies for this population,” she told this news organization.
IMpassion132 nevertheless represents a “unique opportunity to better understand the biology of these rapidly relapsing tumors, and hopefully use this information to develop more novel treatment approaches for this population,” she said.
“That being said, I do think that this is going to become an even more challenging area,” Dr. Tolaney said. “In the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many then go on to receive additional systemic treatment in the adjuvant setting.”
The study was sponsored by Hoffmann-La Roche.
Dr. Dent declares relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer. Dr. Tolaney declares relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, Jazz Pharmaceuticals, Exelixis, Novartis, Nanonstring, and Cyclacel.
A version of this article appeared on Medscape.com .
Our results “highlight the importance of recognizing TNBC heterogeneity, especially in the first-line setting” said Rebecca A. Dent, MD, MSc, National Cancer Center Singapore and Duke-NUS Medical School, Singapore, who presented the study at the European Society for Medical Oncology (ESMO) Breast Cancer annual congress.
“These patients have a dismal prognosis and represent a high unmet need,” she added.
The current findings follow those from the IMpassion130 trial, which showed that the combination of atezolizumab with nab-paclitaxel chemotherapy offered no survival benefit in previously untreated locally advanced or metastatic TNBC despite a progression-free survival benefit on interim analysis.
Rapidly relapsing TNBC “represents one of most challenging clinical situations” because it is aggressive and “intrinsically resistant to standard therapies,” said Dr. Dent. It is also more common in younger patients with large primary tumors and no BRCA alterations.
“Most importantly, however, is that most trials actually exclude these patients,” she noted, “posing a real challenge for us in clinical practice.”
IMpassion132 enrolled 594 patients with unresectable locally advanced or metastatic TNBC who had experienced disease progression more than 12 months after their last treatment for early TNBC with curative intent.
Patients had received prior anthracycline and taxane therapy for but no prior chemotherapy for advanced disease.
Study participants were randomly assigned to chemotherapy with carboplatin-gemcitabine or capecitabine plus atezolizumab or placebo, with treatment continued until disease progression or unacceptable toxicity. The primary endpoint was overall survival.
Initially, all patients with TNBC who met the study criteria were enrolled in the randomized, phase 3, double-blinded trial; however, the trial was then amended to include only PD-L1–positive patients after the results of IMpassion130 “clearly showed us that the benefits of immune checkpoint inhibition were largely driven by those patients,” Dr. Dent explained.
The 354 patients with PD-L1–positive disease were “young,” she added, with a median age of 48 years. The youngest was 23 years old.
The majority (66%-69%) had a disease-free interval of less than 6 months after treatment with curative intent. Lung and/or liver metastases were present in 60%-62% of patients, and 18% had previously received platinum-based chemotherapy.
After a median follow-up of 9.8 months, overall survival was a median of 12.1 months in the atezolizumab group vs 11.2 months with placebo, at a hazard ratio of 0.93 (P = .59).
A similar result was seen when looking at the modified intention-to-treat population, and when stratifying the patients by prespecified subgroup.
Dr. Dent pointed out that in the placebo group, patients treated with capecitabine had a median overall survival of 12.6 months vs 9.9 months in those given carboplatin-gemcitabine , which she described as “hypothesis generating” because “prior therapy may trigger a variety of resistance mechanisms.”
The disease-free interval also seemed to play a role in the placebo group. Patients who had a disease-free interval of 6 or more months prior to study enrollment had a median overall survival of 12.8 months vs 9.4 months in those with an interval of less than 6 months.
There were no significant differences in progression-free survival or duration of overall response between the atezolizumab and placebo groups.
“In terms of the safety data, clearly we’re getting better at identifying immune checkpoint inhibition toxicities and initiating therapies for these toxicities earlier,” Dr. Dent said, because there were “no new safety signals.”
The rate of treatment-related grade 3 or 4 adverse events was similar between patients given atezolizumab and those assigned to placebo, at 65% vs 62%. Rates of grade 5 events were identical, at 1%.
Commenting on the study, Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, questioned the role for immunotherapy in patients with TNBC who experience early relapse.
This is not the first trial to fail to show a benefit in this space, she said. Collectively, these results make “me think that these tumors are pretty immunologically cold, making them less likely to benefit from checkpoint inhibition.”
The patients that do relapse, “have highly treatment refractory disease,” and “we need to think about other novel therapeutic strategies for this population,” she told this news organization.
IMpassion132 nevertheless represents a “unique opportunity to better understand the biology of these rapidly relapsing tumors, and hopefully use this information to develop more novel treatment approaches for this population,” she said.
“That being said, I do think that this is going to become an even more challenging area,” Dr. Tolaney said. “In the modern era, these patients are receiving multi-agent chemotherapy with preoperative checkpoint inhibition, and many then go on to receive additional systemic treatment in the adjuvant setting.”
The study was sponsored by Hoffmann-La Roche.
Dr. Dent declares relationships with AstraZeneca, Roche, Eisai, Lilly, MSD, Novartis, and Pfizer. Dr. Tolaney declares relationships with Novartis, Pfizer, Merck, Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squib, Seattle Genetics, CytomX Therapeutics, Daiichi Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc, BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Myovant, Zetagen, Umoja Biopharma, Menarini/Stemline, Aadi Biopharma, Bayer, Jazz Pharmaceuticals, Exelixis, Novartis, Nanonstring, and Cyclacel.
A version of this article appeared on Medscape.com .
FROM ESMO BREAST CANCER 2024