In an interim analysis of this phase 3 trial, the addition of pembrolizumab to chemotherapy resulted in longer progression-free survival than chemotherapy alone among patients with advanced triple-negative breast cancer whose tumors expressed programmed death ligand 1 (PD-L1) with a combined positive score (CPS; the number of PD-L1–staining tumor cells, lymphocytes, and macrophages, divided by the total number of viable tumor cells, multiplied by 100) of 10 or more. The results of the final analysis of overall survival have not been reported.
We randomly assigned patients with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer in a 2:1 ratio to receive pembrolizumab (200 mg) every 3 weeks plus the investigator’s choice of chemotherapy (nanoparticle albumin-bound paclitaxel, paclitaxel, or gemcitabine–carboplatin) or placebo plus chemotherapy. The primary end points were progression-free survival (reported previously) and overall survival among patients whose tumors expressed PD-L1 with a CPS of 10 or more (the CPS-10 subgroup), among patients whose tumors expressed PD-L1 with a CPS of 1 or more (the CPS-1 subgroup), and in the intention-to-treat population. Safety was also assessed.
A total of 847 patients underwent randomization: 566 were assigned to the pembrolizumab–chemotherapy group, and 281 to the placebo–chemotherapy group. The median follow-up was 44.1 months. In the CPS-10 subgroup, the median overall survival was 23.0 months in the pembrolizumab–chemotherapy group and 16.1 months in the placebo–chemotherapy group (hazard ratio for death, 0.73; 95% confidence interval [CI], 0.55 to 0.95; two-sided P=0.0185 [criterion for significance met]); in the CPS-1 subgroup, the median overall survival was 17.6 and 16.0 months in the two groups, respectively (hazard ratio, 0.86; 95% CI, 0.72 to 1.04; two-sided P=0.1125 [not significant]); and in the intention-to-treat population, the median overall survival was 17.2 and 15.5 months, respectively (hazard ratio, 0.89; 95% CI, 0.76 to 1.05 [significance not tested]). Adverse events of grade 3, 4, or 5 that were related to the trial regimen occurred in 68.1% of the patients in the pembrolizumab–chemotherapy group and in 66.9% in the placebo–chemotherapy group, including death in 0.4% of the patients in the pembrolizumab–chemotherapy group and in no patients in the placebo–chemotherapy group.
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. (Funded by Merck Sharp and Dohme; KEYNOTE-355 ClinicalTrials.gov number, NCT02819518.)
Funding and Disclosures
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. Rugo and Schmid contributed equally to this article.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the patients and their families and caregivers for participating in this trial, all the investigators and site personnel, and the following current or former employees or contractors of Merck Sharp and Dohme: Gursel Aktan for trial oversight; Jing Zhao for supervision of statistical analyses; Aline Galvao, Krystal Bourdon, Laura Domrzalski, Karla Gonzalez, Deborah Card, Eleanor Readinger, Shana Hamm, Donna Letizia, Jennifer Kimmel, Roger Maxwell, and Craig Pritch for collection of data, supervision of research, provision of trial materials or patients, and administrative or logistic support; Melissa Lewis and Mercedes Bustamante for data management; Madhusudhan Reddy Papasani, Karuna Dhananjay Samudralwar, and Xuan Peng for statistical expertise; and Christine McCrary Sisk and Michele McColgan for medical writing and editorial assistance with an earlier version of the manuscript.
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