For women with early-stage triple-negative breast cancer, KEYNOTE-522 changed the treatment paradigm several years ago. Support for neoadjuvant use of the PD-1 inhibitor pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab, was bolstered by the positive overall survival analysis presented during Presidential Symposium II at the European Society for Medical Oncology (ESMO) Congress 2024.1
Peter Schmid, MD, PhD
“It is my pleasure to announce that the trial has hit [statistical] significance for overall survival, with a hazard ratio of 0.66 (P = .00150). There’s a significantly and clinically meaningful benefit. At 5 years, the absolute delta is 5%, based on 86.6% of patients alive when treated with pembrolizumab and chemotherapy compared with 81.7% treated with chemotherapy alone,” said Peter Schmid, MD, PhD, of Barts Cancer Institute at Queen Mary University, London.
The phase III KEYNOTE-522 trial enrolled 574 women with previously untreated, nonmetastatic triple-negative breast cancer. They were randomly assigned to receive neoadjuvant treatment with pembrolizumab or placebo plus paclitaxel and carboplatin for 12 weeks, then pembrolizumab or placebo for an additional four cycles plus doxorubicin or epirubicin and cyclophosphamide for 12 weeks. In the adjuvant setting, patients received pembrolizumab or placebo for up to nine cycles, with radiotherapy permitted.
Dr. Schmid presented the 5-year overall survival data and updated event-free survival, after a median follow-up of 75 months. The results were simultaneously published in The New England Journal of Medicine.2
Building on Benefits Previously Reported
Previously, KEYNOTE-522 met its two primary endpoints—pathologic complete response rate and event-free survival—and also reduced deaths by 34%. In the first interim analysis, at a median follow-up of 15.5 months, pathologic complete response rates were 64.8% with pembrolizumab and 51.2% with placebo, a difference of 13.6% (P < .001).3 The fourth interim analysis showed the 36-month event-free survival rate to be 84.5% with pembrolizumab and 76.8% with placebo (hazard ratio [HR] = 0.63; P < .001).4
In July 2021, the U.S. Food and Drug Administration approved pembrolizumab in combination with chemotherapy as neoadjuvant treatment, then continued as a single agent as adjuvant treatment after surgery, for patients with high-risk, early-stage triple-negative breast cancer based on these prior data.
Overall survival data in patient subgroups showed nearly a universal benefit with pembrolizumab, including those defined by PD-L1 expression, nodal status, tumor size, and tumor stage—and regardless of pathologic complete response outcome. Pembrolizumab’s benefit was also maintained for event-free survival in the overall population, with a 5-year rate of 81.2% for the pembrolizumab arm vs 72.2% for the placebo arm (HR = 0.65; 95% confidence interval [CI] = 0.51–0.83).
Patients who achieved a pathologic complete response with treatment experienced an overall survival benefit, irrespective of the treatment arm. For responders treated with pembrolizumab, the 5-year overall survival rate was 95.1%; for placebo recipients, it was 94.4% (HR = 0.69; 95% CI = 0.38–1.26). In nonresponders, the 5-year overall survival rates were 71.8% and 65.7%, respectively (HR = 0.76; 95% CI = 0.56–1.05).
EXPERT POINT OF VIEW
Marleen Kok, MD, PhD
The invited discussant of KEYNOTE-522 was Marleen Kok, MD, PhD, a medical oncologist and research group leader at the Netherlands Cancer Institute in Amsterdam. “Neoadjuvant pembrolizumab added to chemotherapy significantly improves overall survival in triple-negative breast cancer and is the new standard of care for patients with stage II/III disease,” she stated.
“When you add pembrolizumab, you reduce the number of patients without a pathologic complete response,” she explained, noting that patients lacking a pathologic complete response had an overall survival rate of just 65.7% without pembrolizumab, in the study. “This high-risk group with a nonpathologic complete response is the one that seems to benefit,” she said, noting the survival rate rose to 71.8% with pembrolizumab plus chemotherapy. “We’ve now seen that pembrolizumab contributes to the cure of patients with high-risk triple-negative breast cancer.”
Remaining Questions and Next Steps
The oncology community should now build upon these pivotal findings, according to Dr. Kok. Several important questions need to be addressed: Who are the patients who can be cured with neoadjuvant pembrolizumab? Do all patients need a full year of intensified treatment? To this end, biomarker discovery is critical. Biomarker research from registration trials is in general very limited, and this is problematic. There is a shared responsibility of pharmaceutical companies, clinicians, guideline committees, and regulatory bodies to make biomarker data available to tailor decisions for our patients, Dr. Kok added. Furthermore, she called for research that would differentiate the -“contributions of the components” of perioperative use of pembrolizumab. As to which patients need adjuvant pembrolizumab, a second randomization in KEYNOTE-522 could have provided information.
“And what about giving adjuvant capecitabine or olaparib, which are both approved in this setting?” Novel postneoadjuvant strategies are urgently needed for patients with residual cancer burden 3 who still have a dismal outcome, she emphasized. Finally, Dr. Kok is concerned that classic patient-reported outcome instruments may not capture the full picture of immune-related toxicities, especially in “those rare patients” who develop long-term side effects. “Long-term immune-related toxicity as well as fertility needs more attention,” she urged, “now that we are curing 5% of young breast cancer patients with immunotherapy.”
DISCLOSURE: KEYNOTE-522 was funded by Merck Sharp & Dohme. Dr. Schmid reported personal financial relationships with AstraZeneca, Novartis, Pfizer, Roche, Gilead Sciences, Eisai, Merck Sharp & Dohme, Seagen, and Lilly and institutional financial relationships with AstraZeneca, Genentech, and Roche. Dr. Kok reported her institution has received research grants from AstraZeneca/Daiichi Sankyo, BMS, and Roche; speakers fees from AstraZeneca/Daiichi Sankyo, and Gilead Sciences; compensation for advisory work from Alderaan Biotechnology, AstraZeneca/Daiichi Sankyo, BioNTech, BMS, Domain Therapeutics, Gilead Sciences, MSD, Novartis, and Roche; and nonfinancial support from Natera.
REFERENCES
1. Schmid P, Cortés J, Dent RA, et al: Neoadjuvant pembrolizumab or placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo for high-risk early-stage TNBC: Overall survival results from the phase III KEYNOTE-522 study. ESMO Congress 2024. Abstract LBA4. Presented September 15, 2024.
2. Schmid P, Cortes J, Dent R, et al: Overall survival with pembrolizumab in early-stage triple-negative breast cancer. N Engl J Med. September 15, 2024 (early release online).
3. Schmid P, Cortes J, Pusztai L, et al: Pembrolizumab for early triple-negative breast cancer. N Engl J Med 382:810-821, 2020.
4. 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.
