As reported in The Lancet by Javier Cortes, MD, of the International Breast Cancer Center, Quiron Group, Madrid and Barcelona, and colleagues, the second interim analysis of 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) ≥ 10.¹

Javier Cortes, MD

The trial supported the November 2020 accelerated approval of pembrolizumab combined with chemotherapy for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer with tumors expressing PD-L1 with a CPS ≥ 10.

Study Details

In the double-blind trial, 847 patients (intention-to-treat population) from sites in 29 countries were randomly assigned 2:1 between January 2017 and June 2018 to receive pembrolizumab at 200 mg every 3 weeks plus chemotherapy consisting of the 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 was continued for up to 35 administrations, with chemotherapy continued at the investigator’s discretion, or until disease progression or unacceptable toxicity. Crossover between treatment groups was not permitted.

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 hierarchic 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 a CPS ≥ 10 and 425 vs 211 had a CPS ≥ 1. Nab-paclitaxel, paclitaxel, and gemcitabine/carboplatin were received by 29% vs 35%, 15% vs 11%, and 56% vs 54% in the CPS ≥ 10 population; 31% vs 35%, 15% vs 10%, and 55% vs 55% in the CPS ≥ 1 population; and 31% vs 34%, 14% vs 11%, and 55% vs 55% in the intention-to-treat population. Among all patients, disease status was de novo metastatic in 30% vs 30%, 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, the 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 a 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 rates at 6 and 12 months were 65.0% vs 46.9% and 39.1% vs 23.0%, respectively. 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.² Hazard ratios were 0.68 (95% CI = 0.46–1.00) among patients with < 3 and 0.52 (95% CI = 0.34–0.78) among patients with at least three metastatic sites.

Median progression-free survival was 7.6 vs 5.6 months (not significant) among patients with a CPS ≥ 1, with 6- and 12-month rates of 56.4% vs 46.6%, 31.7% vs 19.4%, and 7.5 vs 5.6 months among the intention-to-treat population, with 6- and 12-month rates of 55.4% vs 47.8% and 29.8% vs 20.9%.

Overall, the benefit of pembrolizumab increased with increasing PD-L1 CPS. Median progression-free survival was 6.3 vs 6.2 months among 211 patients with a CPS < 1 and 9.5 vs 5.4 months among 204 patients with a CPS ≥ 20.

Adverse Events

The most common treatment-related adverse events of any grade in the pembrolizumab group were anemia (49% vs 46% in control group), neutropenia (41% vs 38%), and nausea (39% vs 41%). Grade ≥ 3 treatment-related adverse event rates occurred in 68% of 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 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%).

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 a 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.”

DISCLOSURE: The study was supported by Merck Sharp & Dohme, a subsidiary of Merck & Co. Dr. Cortes has served as a consultant or advisor for Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, and Kyowa Kirin; has received honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, and Daiichi Sankyo; has received research funding from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth Health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, and Queen Mary University of London; holds stock, patents and intellectual property with MedSIR; and has received travel expenses from Roche, Novartis, Eisai, Pfizer, and Daiichi Sankyo.

REFERENCES

1. Cortes J, Cescon DW, Rugo HS, et al: Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355). Lancet 396:1817-1828, 2020.

2. Rugo H, Schmid P, Cescon D, et al: Additional efficacy endpoints from the phase lll KEYNOTE-355 study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy as first-line therapy for locally recurrent inoperable or metastatic triple-negative breast cancer. 2020 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 10, 2020.