As reported in The New England Journal of Medicine by Javier Cortés, MD, PhD, and colleagues, the phase III KEYNOTE-355 trial has shown improved overall survival with the addition of pembrolizumab to chemotherapy in previously untreated patients with advanced triple-negative breast cancer with a PD-L1 combined positive score (CPS) of 10 or more.
An interim analysis in the trial supported the November 2020 accelerated approval of pembrolizumab plus chemotherapy in this setting on the basis of improved progression-free survival.
Javier Cortés, MD, PhD
Study Details
The double-blind trial included 847 patients with locally recurrent inoperable or metastatic disease from sites in 29 countries. Patients were randomly assigned 2:1 between January 2017 and June 2018 to receive pembrolizumab at 200 mg (n = 566) or placebo (n = 281) every 3 weeks for up to 35 doses, plus investigator’s choice of chemotherapy with nab-paclitaxel (100 mg/m2 on days 1, 8, and 15 of 28-day cycles), paclitaxel (90 mg/m2 on days 1, 8, and 15 of 28-day cycles), or gemcitabine (1,000 mg/m2) plus carboplatin (AUC 2; on days 1 and 8 of 21-day cycles).
The primary endpoints were progression-free survival (previously reported) and overall survival among patients with CPS ≥ 10, those with CPS ≥ 1, and in the intention-to-treat (ITT) population.
Overall Survival
Median follow-up was 44.1 months (range = 36.1–53.2 months).
Among 220 vs 103 patients in the CPS ≥ 10 population, median overall survival was 23.0 months (95% confidence interval [CI] = 19.0–26.3 months) in the pembrolizumab group vs 16.1 months (95% CI = 12.6–18.8 months) in the control group (hazard ratio [HR] = 0.73, 95% CI = 0.55–0.95, P = .0185). Estimated 18-month rates were 58.3% (95% CI = 51.4%–64.5%) vs 44.7% (95% CI = 34.9%–53.9%).
Among 425 vs 211 patients in the CPS ≥ 1 population, median overall survival was 17.6 months (95% CI = 15.5–19.5 months) in the pembrolizumab group vs 16.0 months (95% CI = 12.8–17.4 months) in the control group (HR = 0.86, 95% CI = 0.72–1.04, P = .1125). Estimated 18-month rates were 48.4% (95% CI = 43.5%–53.0%) vs 41.4% (95% CI = 34.7%–48.0%).
In the ITT population (566 vs 281 patients), median overall survival was 17.2 months (95% CI = 15.3–19.0 months) in the pembrolizumab group vs 15.5 months (95% CI = 13.9–17.2 months) in the control group (HR = 0.89, 95% CI = 0.76–1.05; significance not tested due to hierarchical testing). Estimated 18-month rates were 47.8% (95% CI = 43.6%–51.9%) vs 41.8% (95% CI = 36.0%–47.5%).
Among 141 vs 70 patients with CPS < 1, median overall survival was 16.2 vs 14.7 months (HR = 0.97, 95% CI = 0.72–1.32).
KEY POINTS
- The addition of pembrolizumab to chemotherapy significantly improved overall survival among patients with CPS ≥ 10.
- Median overall survival was 23.0 vs 16.1 months, with 18-month rates of 58.3% vs 44.7%.
Adverse Events
Treatment-related grade ≥ 3 adverse events occurred in 68.1% of patients in the pembrolizumab group vs 66.9% of the control group. The most common in the pembrolizumab group were neutropenia (29.7% vs 29.9% in control group), decreased neutrophils (17.4% vs 20.3%), and anemia (16.5% vs 14.6%). Immune-mediated adverse events occurred in 26.5% of patients in the pembrolizumab group (grade 3 or 4 in 5.3%), most commonly hypothyroidism (15.8%) and hyperthyroidism (4.3%). Treatment-related death occurred in two patients (0.4%) in the pembrolizumab group (due to acute kidney injury and pneumonia) and in no patients in the control group.
The investigators concluded, “Among patients with advanced triple-negative breast cancer whose tumors expressed PD-L1 with a CPS of 10 or more, the addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival than chemotherapy alone.”
Dr. Cortés, of the International Breast Cancer Center, Barcelona, is the corresponding author for The New England Journal of Medicine article.
Disclosure: The study was funded by Merck Sharp and Dohme. For full disclosures of the study authors, visit nejm.org.
