As reported in The Lancet by Javier Cortes, MD, and colleagues, the phase III KEYNOTE-355 trial has shown that the addition of pembrolizumab to chemotherapy improved progression-free survival among previously untreated patients with locally recurrent inoperable or metastatic triple-negative breast cancer with a PD-L1 expression combined positive score (CPS) of ≥ 10.

The trial supported the November 2020 U.S. Food and Drug Administration accelerated approval of pembrolizumab for use in combination with chemotherapy for treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer and tumors expressing PD-L1 with a CPS ≥ 10.

Javier Cortes, MD

KEYNOTE-355 Details

The double-blind trial included 847 patients (intention-to-treat population) from sites in 29 countries. They were randomly assigned 2:1 between January 2017 and June 2018 to receive pembrolizumab at 200 mg every 3 weeks plus chemotherapy consisting of physician’s choice of nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin (n = 566) or placebo plus chemotherapy (n = 281). Chemotherapy consisted of nab-paclitaxel at 100 mg/m² on days 1, 8, and 15 every 28 days; paclitaxel at 90 mg/m² on days 1, 8, and 15 every 28 days; or gemcitabine at 1,000 mg/m² plus carboplatin area under the curve = 2 on days 1 and 8 every 21 days. Chemotherapy administration was open label. Pembrolizumab or placebo were continued for up to 35 administrations, with chemotherapy continued at investigator’s discretion or until disease progression or unacceptable toxicity.

The dual primary endpoints were progression-free survival and overall survival assessed in the PD-L1 CPS ≥ 10, CPS ≥ 1, and intention-to-treat populations. The definitive assessment of progression-free survival was done at the current interim analysis; follow-up to assess overall survival is ongoing. A hierarchical testing strategy was used for progression-free survival, with testing done first in the CPS ≥ 10 population (prespecified statistical criterion of α = .00411), then in the CPS ≥ 1 population (α = .00111), and then in the intention-to-treat population (α = .00111).

In the pembrolizumab vs control groups, 220 vs 103 patients had CPS ≥ 10 and 425 vs 211 had CPS ≥ 1. Among all patients, disease status was de novo metastatic in 30% in the pembrolizumab/chemotherapy group vs 30% in the placebo/chemotherapy group, recurrent metastatic in 68% vs 66%, and locally recurrent inoperable in 2% vs 4%.

Progression-Free Survival

At the second interim analysis data cutoff in December 2019, median follow-up was 25.9 months (interquartile range [IQR] = 22.8–29.9 months) in the pembrolizumab group and 26.3 months (IQR = 22.7–29.7 months) in the control group.   

Among patients with CPS ≥ 10, median progression-free survival was 9.7 months in the pembrolizumab group vs 5.6 months in the control group (hazard ratio [HR] = 0.65, 95% confidence interval [CI] = 0.49–0.86, P = .0012; primary objective met). Progression-free survival at 6 and 12 months was 65.0% vs 46.9% and 39.1% vs 23.0%. According to chemotherapy regimen, hazard ratios were 0.57 (95% CI = 0.34–0.95) for nab-paclitaxel, 0.33 (95% CI = 0.14–0.76) for paclitaxel, and 0.77 (95% CI = 0.53–1.11) for gemcitabine/carboplatin. Median progression-free survival among 524 patients with CPS < 10 was 5.8 vs 5.7 months (HR = 0.94, 95% CI = 0.76–1.16).

Median progression-free survival was 7.6 vs 5.6 months (HR = 0.74, 95% CI =  0.61–0.90, P = .0014; not significant) among patients with CPS ≥ 1, with 6- and 12-month rates of 56.4% vs 46.6% and 31.7% vs 19.4%, and 7.5 vs 5.6 months (HR = 0.82, 95% CI =  0.69-0.97; not tested due to hierarchical testing) among the intention-to-treat population, with 6- and 12-month rates of 55.4% vs 47.8% and 29.8% vs 20.9%.

Median progression-free survival was 6.3 vs 6.2 months (HR = 1.08, 95% CI = 0.77–1.53) among 211 patients with CPS < 1 and 9.5 vs 5.4 months (HR = 0.61, 95% CI = 0.43–0.87) among 204 patients with CPS ≥ 20.

Adverse Events

Grade ≥ 3 treatment-related adverse event rates occurred in 68% of patients in the pembrolizumab group vs 67% of the control group, with the most common in the pembrolizumab group including neutropenia (30% vs 30%), decreased neutrophil count (17% vs 20%), anemia (16% vs 15%), and increased alanine aminotransferase (6% vs 5%). Treatment-related adverse events led to death in two patients (< 1%) in the pembrolizumab group—with causes consisting of acute kidney injury in one and pneumonia in one—and in no patients in the control group.

Immune-mediated adverse events of any grade occurred in 26% vs 6% of patients, with the most common in the pembrolizumab group being hypothyroidism (15%) and hyperthyroidism (5%). Grade ≥ 3 events occurred in 5% vs 0%, with the most common in the pembrolizumab group being severe skin reaction (2%). No patients died due to immune-mediated adverse events.

The investigators concluded, “Pembrolizumab/chemotherapy showed a significant and clinically meaningful improvement in progression-free survival vs placebo/chemotherapy among patients with metastatic triple-negative breast cancer with CPS of 10 or more. These findings suggest a role for the addition of pembrolizumab to standard chemotherapy for the first-line treatment of metastatic triple-negative breast cancer.”

Dr. Cortes, of the International Breast Cancer Center, Quiron Group, Madrid and Barcelona, is the corresponding author for The Lancet article.

Disclosure: The study was supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc. For full disclosures of the study authors, visit thelancet.com.