Results of the phase III randomized KEYNOTE-355 trial showed that the addition of the PD-1 inhibitor pembrolizumab to investigator’s choice of first-line chemotherapy improved progression-free and overall survival in women with metastatic triple-negative breast cancer compared with placebo and chemotherapy whose tumors expressed PD-L1 (combined positive score [CPS] ≥ 10).

The study met its dual primary endpoint, showing a statistically significant and clinically meaningful improvement in progression-free survival and overall survival for pembrolizumab plus chemotherapy vs chemotherapy alone for the first-line treatment of PD-L1 CPS ≥ 10 metastatic triple-negative breast cancer. No new safety concerns emerged during the trial.

“A CPS ≥ 10 is a reasonable cutoff to define the population of women with metastatic triple-negative breast cancer expected to derive treatment benefit from pembrolizumab plus chemotherapy,” stated lead author Javier Cortés, MD, PhD, of the International Breast Cancer Center, Quiron Group, Madrid, and Barcelona and Vall d’Hebron Institute of Oncology, Barcelona, at the 2021 San Antonio Breast Cancer Symposium (SABCS).

The benefit of pembrolizumab and chemotherapy was pretty much the same for a CPS between 10 and 19 and a CPS ≥ 20.

— Javier Cortés, MD, PhD

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Pembrolizumab is currently approved by the U.S. Food and Drug Administration (FDA) in combination with chemotherapy for patients with locally recurrent unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (CPS ≥ 10), as determined by an FDA-approved test.

“In my opinion, the results of KEYNOTE-355 lend further support to pembrolizumab plus chemotherapy as a standard-of-care treatment regimen for this group of patients,” Dr. Cortés told listeners.

Previously, results of KEYNOTE-355 showed improved progression-free survival with the combined regimen of pembrolizumab plus chemotherapy as first-line therapy for metastatic triple-negative breast cancer. At SABCS 2021, Dr. Cortés presented overall survival and the analysis stratified by levels of PD-L1 expression as assessed by CPS score.¹

Study Details

KEYNOTE-355 was an international randomized, placebo-controlled phase III trial conducted at 209 sites in 29 countries. The study evaluated pembrolizumab plus investigator’s choice of one of three chemotherapies (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin) compared with placebo plus one of the chemotherapies for the first-line treatment of metastatic triple-negative breast cancer. Study endpoints were progression-free survival and overall survival in patients whose tumors expressed PD-L1 (CPS > 1 and CPS > 10) and in all participants in an intent-to-treat analysis.

KEYNOTE-355 randomly assigned 847 patients 2:1 to receive pembrolizumab at 200 mg every 3 weeks plus chemotherapy (n = 566) or placebo plus chemotherapy (n = 281). In both arms of the study, about 75% of patients had tumors expressing PD-L1 (CPS ≥ 1), and about 38% had tumors expressing PD-L1 at a CPS ≥ 10. Patients were stratified for PD-L1 expression, type of chemotherapy on study, and type of prior chemotherapy for neoadjuvant or adjuvant therapy. Median follow-up was 44 months in both treatment arms.

PD-L1 expression according to CPS was well balanced between the two treatment arms. A CPS between 10 and 19 was identified in 14.1% of the pembrolizumab-plus-chemotherapy arm vs 13.9% in the placebo-plus-chemotherapy arm; a CPS between 10 and 20 was observed in about 24% of both arms.

“Baseline characteristics were as expected,” Dr. Cortés said. Median patient age was about 53; 45% were on taxanes; 55% were on gemcitabine/carboplatin; 30% had de novo metastatic disease; about 20% had a disease-free interval of less than 12 months; and about 50% had a disease-free interval or 12 months or longer.

Survival Analyses

For the primary analysis of overall survival, a statistically significant difference favoring pembrolizumab plus chemotherapy was observed in patients with a CPS ≥ 10, who had a 37% improvement in overall survival (P = .0061). Among patients with a CPS ≥ 1, a 12% nonsignificant trend in improved overall survival was observed favoring the checkpoint inhibitor/chemotherapy combination.

“We did not formally test the intent-to-treat population. Overall survival was similar in the pembrolizumab and placebo subgroups with a CPS < 1 and a CPS between 1 and 9. The benefit of pembrolizumab and chemotherapy was pretty much the same for a CPS between 10 and 19 and a CPS ≥ 20,” Dr. Cortés said. “These data suggest that a CPS of 10 could be a reasonable cutoff.”

In additional subgroups, the overall survival curves overlapped for a CPS < 1 and a CPS between 1 and 9. Median overall survival was similar in both treatment arms. As for a CPS between 10 and 19 and a CPS > 20 separately, in both subgroups the survival curves separated and were sustained at 10 months; survival was improved by about 28%.

“For the final analysis of progression-free survival, a trend was observed for improvement with PD-L1 enrichment of a CPS ≥ 10,” he stated. “The general trend for ­progression-free survival was consistent with that observed for overall survival. The progression-free survival curves overall for a CPS of 1 and  a CPS between 1 and 9 overlap at earlier timepoints and separate slightly at 10 months.”

For the subgroups with a CPS between 10 and 19 and a CPS ≥ 20, there is a sustained separation of progression-free survival curves at 4 months.

Toxicity Profile

Treatment-related adverse events of any grade were reported in 96.3% of the experimental arm and 95% of the placebo-plus-chemotherapy arm. The rate of grades 3 to 5 treatment-related adverse events was 68.1% and 66.9%, respectively. Serious adverse events were reported in 17.8% and 12.2%, respectively. The rates of treatment-related adverse events leading to treatment discontinuation were 18.3% and 11%, respectively. “The majority of treatment discontinuations in the study were for progressive disease,” Dr. Cortés noted.

The most common treatment-related adverse events were anemia, neutropenia, nausea, alopecia, and fatigue. The rates were comparable in the two arms of the study.

Immune-mediated adverse events were reported in 26.5% of the pembrolizumab-plus-chemotherapy group and in 6.4% of the placebo-plus-chemotherapy group. The rate of grades 3 to 5 adverse events was 5.3% and 0%, respectively. “The great majority of immune-mediated adverse events were hypothyroidism,” he noted.

DISCLOSURE: KEYNOTE-355 was funded by Merck Sharp & Dohme. Dr. Cortés has had a consulting or advisory role with Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, and Zymeworks; 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; owns stock, patents and intellectual property with MedSIR; and has received travel, accommodation, and expenses from Roche, Novartis, Eisai, Pfizer, and Daiichi Sankyo.

REFERENCE

1. Cortés J, Cescon DW, Rugo HS, et al: Final results of KEYNOTE-355: Randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 7, 2021.