Merck's Keytruda (pembrolizumab) in combination with chemotherapy has demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) for patients with high-risk early-stage triple-negative breast cancer (TNBC). The findings, from the Phase III KEYNOTE-522 trial, were presented at the European Society for Medical Oncology (ESMO) Congress and published in the New England Journal of Medicine. The study marks the first time an immunotherapy-based treatment has shown such a survival benefit in this patient population compared to chemotherapy alone.
The KEYNOTE-522 trial (NCT03036488) evaluated Keytruda in combination with chemotherapy as a neoadjuvant treatment before surgery, followed by Keytruda as a single-agent adjuvant treatment after surgery. A total of 1,174 patients were randomized, with 784 receiving Keytruda plus chemotherapy and 390 receiving placebo plus chemotherapy. The primary endpoints were pathological complete response (pCR) rate and event-free survival (EFS), with OS as a key secondary endpoint.
Survival and Efficacy Outcomes
After a median follow-up of 75.1 months (range, 65.9-84.0), the Keytruda regimen reduced the risk of death by 34% (HR=0.66; 95% CI, 0.50-0.87; p=0.0015) compared to chemotherapy alone. The estimated five-year OS rate was 86.6% (95% CI, 84.0 to 88.8) in the Keytruda-chemotherapy group, compared to 81.7% (95% CI, 77.5 to 85.2) in the placebo-chemotherapy group. Median OS was not reached in either group.
Event-free survival was also significantly improved in the Keytruda arm, with a 35% reduction in the risk of EFS events (HR=0.65; 95% CI, 0.51-0.83). The five-year EFS rate was 81.2% (95% CI, 78.3-83.8) in the Keytruda combination cohort compared to 72.2% (95% CI, 67.4-76.4) in the chemotherapy-placebo cohort.
"These impactful overall survival results add to the previously reported pathological complete response and event-free survival (EFS) data from the KEYNOTE-522 trial," said Peter Schmid, MD, PhD, FRCP, lead, Centre for Experimental Cancer Medicine, Barts Cancer Institute, London, England.
Safety Profile and Adverse Events
Treatment-related adverse events (TRAEs) were reported in 98.9% of patients in the Keytruda combination cohort and 99.7% in the chemotherapy-placebo cohort. Immune-mediated adverse events and infusion reactions of any grade occurred in 33.5% of patients in the Keytruda arm and 11.3% in the chemotherapy-placebo arm. While the increase in AEs in the Keytruda group could raise concerns, the demonstrated OS benefits suggest that commercial adoption is likely to be strong, with careful patient management strategies around side effects being crucial.
Implications for TNBC Treatment
TNBC accounts for 10-15% of all breast cancer cases and is associated with a shorter OS compared to other subtypes, even with standard chemotherapy. The five-year EFS rate is approximately 71%, and the OS rate is roughly 77% in patients with stage II or III TNBC, highlighting a significant unmet need. Keytruda's approval for early-stage TNBC in 2021 was based on EFS data, and the new OS data further solidifies its role in perioperative therapy.
"After a median follow-up of 75.1 months, the 5-year overall survival was 4.9 percentage points higher with the addition of [Keytruda]," the study authors wrote. "These results provide further support for [Keytruda] plus neoadjuvant chemotherapy followed by adjuvant [Keytruda] as treatment for high-risk, early-stage triple-negative breast cancer."
Keytruda works by enhancing the immune system's ability to detect and fight tumor cells by blocking the interaction between PD-1 and its ligands, PD-L1 and PD-L2, leading to the activation of T lymphocytes. With over 1,600 trials evaluating Keytruda across various cancer types, its impact on cancer treatment continues to expand.
