In updated findings from the phase III KEYNOTE-756 trial, the addition of pembrolizumab to chemotherapy in the neoadjuvant setting improved the rates of pathologic complete response for patients with high-risk estrogen receptor–positive, HER2-negative breast cancer, regardless of their age or menopausal status, researchers reported at the 2024 European Breast Cancer Conference.1 The latest analysis was presented by Heather McArthur, MD, Associate Professor in the Department of Internal Medicine and Clinical Director of the Breast Cancer Program, Harold C. Simmons Comprehensive Cancer Center at The University of Texas Southwestern Medical Center, Dallas.
Heather McArthur, MD
The international KEYNOTE-756 trial, which has been yielding important data for 8 years, randomly assigned 1,278 patients to receive pembrolizumab or placebo in addition to neoadjuvant chemotherapy, followed by adjuvant pembrolizumab for 6 months or placebo in combination with endocrine therapy. The dual primary endpoints are pathologic complete response and event-free survival.
The investigators previously reported a statistically significant increase in pathologic complete response rates in the pembrolizumab arm—24.3% vs 15.6% in the control arm—an absolute 8.7% improvement that was maintained regardless of how pathologic complete response was defined.2 The benefit of the checkpoint inhibitor was seen regardless of geography, disease stage, lymph node status, level of PD-L1 expression (by combined positive score [CPS]), and estrogen receptor positivity level, though the greatest benefit was observed in node-positive tumors, in estrogen receptor–low tumors (< 10%), and in tumors with high PD-L1 expression.
Findings From the Latest Analysis
The latest analysis showed this benefit regardless of the patients’ age or menopausal status, with pembrolizumab resulting in about 7% to 10% more pathologic complete responses. Rates of pathologic complete response for the pembrolizumab arm vs control arm follow:
- Patients aged < 50 years: 23.8% vs 16.9%
- Patients aged ≥ 50 years: 24.7% vs 14.2%
- Premenopausal patients: 23.4% vs 16.1%
- Postmenopausal patients: 24.8% vs 14.6%.
“The benefit of pembrolizumab was maintained in subgroups defined by baseline characteristics including age (< 50 or ≥ 50 years old) and menopausal status,” Dr. McArthur said.
The addition of pembrolizumab did not delay the time to surgery (which averaged about 1 month in each arm), nor the time to initiation of adjuvant therapy (1.2 months per arm). Rates of breast-conserving surgery and mastectomy were similar, as was the distribution of treatment. Among patients undergoing breast-conserving surgery, 41.3% received pembrolizumab, and 43.7% received chemotherapy alone; these rates for patients who underwent mastectomy were 55.3% and 54.4%, respectively.
Residual Cancer Burden: Less With Pembrolizumab
Tissue collected at the time of surgery was analyzed for residual cancer burden (RCB), with categories (0, 1, 2, 3) denoting increasing burden of residual disease after definitive surgery. “The addition of pembrolizumab to neoadjuvant chemotherapy shifted more patients to the lower RCB categories, and this phenomenon was consistently seen at all PD-L1 thresholds,” Dr. McArthur said.
For the pembrolizumab vs chemotherapy-alone arms, the residual cancer burden rates were:
- RCB-0/RCB-1 (none or minor): 35.0% vs 23.6%
- RCB-2 (moderate): 40.8% vs 45.3%
- RCB-3 (extensive): 20.5% vs 28.9%.
With increasing PD-L1 expression (CPS < 1 to CPS ≥ 20), RCB-0/RCB-1 rates climbed from 15.7% to 60.8%, with absolute changes of 5.5% to 15.2% in the pembrolizumab arm over the chemotherapy-alone arm. Increasing PD-L1 expression was also associated with steadily increasing rates of pathologic complete response, from 7.2% with CPS < 1 to 53.6% with CPS ≥ 20, reflecting improvements of 4.5% to 17.4%, she said.
Examination of RCB according to estrogen receptor expression level revealed more RCB-0 and RCB-1 patients among the lower-expression groups. For PD-L1 expression < 10%, RCB-0 or RCB-1 was achieved by 64.7% with pembrolizumab vs 37.2% with chemotherapy, a 27.5% improvement. With PD-L1 expression ≥ 10%, this level was 33.3% vs 22.7%, an increase of 10.6%.
“[KEYNOTE-756] is the only trial that is powered to analyze the impact of immunotherapy in long-term outcomes for this subtype of breast cancer.”— Fatima Cardoso, MD
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Treatment-related adverse events were unchanged from previous reports from the trial and were consistent with what is known already about each regimen.
The coprimary endpoint of event-free survival is immature. KEYNOTE-756 principal investigator Fatima Cardoso, MD, Director of the Breast Unit of the Champalimaud Clinical Centre, Lisbon, noted that this study is “the only trial powered to analyze the impact of immunotherapy in long-term outcomes for this subtype of breast cancer.”
DISCLOSURE: Dr. McArthurhas served as a consultant for Amgen, AstraZeneca, Bristol Myers Squibb, Calithera, Celgene, Crown Bioscience, Daiichi Sankyo, Eli Lilly, Genentech/Roche, Gilead Sciences, Immunomedics, Merck, OBI Pharma, Peregrine, Pfizer, Puma Biotechnology, Seattle Genetics, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, and TapImmune; and has received research support from Bristol Myers Squibb, BTG, Medimmune/AstraZeneca, and Merck. Dr. Cardoso has received honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, Gilead Sciences, GlaxoSmithKline, IQVIA, MacroGenics, Medscape, Merck, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre-Fabre, Prime Oncology, Roche, Sanofi, Samsung, Bioepis, Seagen, Teva, and TouchIME; and support for attending meetings and/or travel from Pfizer, AstraZeneca, Roche, Gilead Sciences, and Seagen.
REFERENCES
1. Cardoso F, O’Shaughnessy J, McArthur H, et al: Neoadjuvant pembrolizumab or placebo + chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2− breast cancer: Results from the phase 3 KEYNOTE-756 study. 2024 European Breast Cancer Conference. Abstract 4. Presented March 20, 2024.
2. Cardoso F, O’Shaughnessy J, McArthur H, et al: Phase 3 study of neoadjuvant pembrolizumab or placebo plus chemotherapy, followed by adjuvant pembrolizumab or placebo plus endocrine therapy for early-stage high-risk ER+/HER2– breast cancer: KEYNOTE-756. 2023 San Antonio Breast Cancer Symposium. Abstract GS01-02. Presented December 6, 2023.
EXPERT POINT OF VIEW
The invited discussant of the phase III KEYNOTE-756 trial was Marleen Kok, MD, PhD, a medical oncologist and group leader of the Netherlands Cancer Institute, Amsterdam. Dr. Kok pointed out that, in general, estrogen receptor–positive breast cancer is considered a “cold tumor,” but KEYNOTE-756 achieved an 8.5% increase in the rate of pathologic complete response with the addition of pembrolizumab to neoadjuvant chemotherapy.
Marleen Kok, MD, PhD
“Are we now facing a potential indication for a cold tumor immunotherapy in the neoadjuvant setting?” she asked. “That would be extremely interesting, though still there are only data on pathologic complete response. We need to wait to see an event-free survival benefit and ideally an overall survival benefit.” The encouraging findings, she said, lead to further questions: Is 1 year of adjuvant pembrolizumab necessary, or is neoadjuvant treatment alone sufficient? Which patients with estrogen receptor–positive, HER2-negative disease will benefit?
Dr. Kok highlighted several points made in the presentation. In contrast to the design of KEYNOTE-522 (demonstrating the benefit of neoadjuvant pembrolizumab in triple-negative breast cancer),1 physicians in KEYNOTE-756 could choose between dose-dense or every-3-week anthracycline therapy. “At least in the estrogen receptor–positive setting, in patients who have been treated with [every-2-week] schedules, the benefit of pembrolizumab has been lower,” she noted. “But is this making pembrolizumab less efficacious? I don’t think so. I think you have a better control arm, and that’s why the pembrolizumab benefit seems less.”
Lowest Estrogen Receptor Expression Levels
She further noted that the most benefit occurred among patients with very low estrogen receptor expression (< 10%), “which in some countries is considered triple-negative.” CheckMate 7FL, whose results were presented at the 2023 San Antonio Breast Cancer Symposium,2 “provided a sneak preview” about estrogen receptor levels and outcomes of immunotherapy, with greater changes in pathologic complete response among patients with expression < 50%. More breakdown by estrogen receptor expression level will be important from KEYNOTE-756, she said. Meanwhile, the “huge benefit” in patients with < 10% expression, she added, supports the concept of treating this subset as if they are triple-negative.
As the “revolution” in triple-negative breast cancer now moves into estrogen receptor–positive breast cancer, it is likely that “history will repeat itself” with regard to the need for biomarkers, the determination of optimal duration, and the question of neoadjuvant vs adjuvant therapy. Lessons learned from triple-negative disease could guide treatment in the estrogen receptor–positive setting, Dr. Kok said.
DISCLOSURE: Dr. Kok reported financial relationships with Natera, Alderaan, AstraZeneca, Bristol Myers Squibb, Domain Therapeutics, MSD, Roche, and Gilead Sciences.
REFERENCES
1. Schmid P, Cortes J, Dent R, et al: Event-free survival with pembrolizumab in early triple-negative breast cancer. N Engl J Med 386:556-567, 2022.
2. Loi S, Curigliano G, Salgado R, et al: Biomarker results in high-risk estrogen receptor‑positive, human epidermal growth factor receptor 2‑negative primary breast cancer following neoadjuvant chemotherapy ± nivolumab: An exploratory analysis of CheckMate 7FL. 2023 San Antonio Breast Cancer Symposium. Abstract GS01-01. Presented December 6, 2023.
