KEYNOTE-355: Pembrolizumab Plus Chemotherapy Improves Progression-Free Survival in PD-L1–Enriched Advanced Triple-Negative Breast Cancer

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Pembrolizumab plus chemotherapy improved progression-free survival vs chemotherapy alone as first-line treatment of advanced or metastatic triple-negative breast cancer, according to the results of KEYNOTE-355.1 Progression-free survival was significantly improved with pembrolizumab plus chemotherapy in PD-L1–positive triple-negative breast cancer (ie, Combined Positive Score [CPS] ≥ 10) regardless of the chemotherapy regimen used in the trial.

“Pembrolizumab plus chemotherapy achieved a statistically significant and clinically meaningful improvement in progression-free survival vs chemotherapy alone for the first-line treatment of PD-L1–positive metastatic triple-negative breast cancer. A trend toward improved progression-free survival was observed with PD-L1 enrichment,” said lead author Hope S. Rugo, MD, Professor and Medical Director of Breast Oncology, University of California, San Francisco. “A subgroup analysis showed that pembrolizumab plus chemotherapy improved progression-free survival regardless of the chemotherapy partner.” Dr. Rugo presented additional endpoints from KEYNOTE-355 at the 2020 San Antonio Breast Cancer Symposium.

Hope S. Rugo, MD

Hope S. Rugo, MD

“These findings provide further support for the addition of pembrolizumab to standard chemotherapy for first-line metastatic triple-negative breast cancer. Based on the progression-free survival results from KEYNOTE-355, the combination of pembrolizumab and chemotherapy was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with locally recurrent, unresectable, or metastatic triple-negative breast cancer whose tumors express PD-L1 [CPS ≥ 10],” she stated.

Study Details

Numerous trials in the neoadjuvant and adjuvant settings have shown the benefits of pembrolizumab as monotherapy and in combination with chemotherapy in PD-L1–positive triple-negative breast cancer. The combination of pembrolizumab plus chemotherapy was granted Breakthrough Therapy designation by the FDA for the neoadjuvant treatment of patients with high-risk, early-stage triple-negative breast cancer. The KEYNOTE-355 results extend the benefits to the advanced breast cancer setting.

KEYNOTE-355 enrolled adult women with previously untreated locally recurrent or inoperable or metastatic triple-negative breast cancer who completed curative treatment more than 6 months before first disease recurrence. Criteria for study entry stipulated no active central nervous system disease, no systemic steroid use, and no active autoimmune disease.

Participants (n = 847) were randomly assigned 2:1 to receive pembrolizumab (35 infusions in every-3-week cycles) plus investigator’s choice of chemotherapy (taxane or anthracycline-based) vs chemotherapy alone. Treatment was continued until progressive disease or cessation of study therapy. No crossover to the other treatment arm was allowed during the trial.

Results were stratified according to the type of chemotherapy (taxane vs gemcitabine/carboplatin); PD-L1 tumor expression (CPS ≥ 1 or CPS < 1); and prior treatment with the same class of chemotherapy in the neoadjuvant or adjuvant setting.

Dual primary endpoints were progression-free survival and overall survival. Secondary endpoints included overall response rate, disease control rate, and duration of response. An exploratory endpoint was the consistency of treatment effect in all patients (intent-to-treat population) and in those with PD-L1–positive tumors CPS ≥ 10 and CPS ≥ 1.

The randomized, placebo-controlled phase III study was conducted at 209 sites in 24 countries around the world; 566 women were randomly assigned to receive pembrolizumab plus chemotherapy and 281 were assigned to receive chemotherapy.

Median follow-up was about 26 months. At baseline, disease and demographic characteristics were well balanced between both arms. About 75% had a PD-L1 CPS ≥ 1 and 38% hadPD-L1 CPS ≥ 10.

About one-third of patients received nab-paclitaxel, 13% received paclitaxel, and about 55% received gemcitabine/carboplatin. About 22% received the same treatment as adjuvant or neoadjuvant treatment. Regarding the disease-free interval prior to study entry, about 30% had de novo metastasis, around 20% had less than 12 months, and approximately 50% had more than 12 months.

Progression-Free Survival Outcomes

The primary analysis of progression-free survival was previously presented at the 2020 ASCO Virtual Scientific Program.2 Pembrolizumab plus chemotherapy significantly improved progression-free survival in patients with a PD-L1 CPS ≥ 10 (P = .0012).

Dr. Rugo presented an analysis of progression-free survival according to each chemotherapy partner as well as secondary endpoints. In patients with a CPS ≥ 10, 61.8% of patients treated with pembrolizumab plus chemotherapy vs 76.7% of those who received chemotherapy were free of disease progression or death at 6 months. Median progression-free survival was 9.7 months and 5.6 months for the two arms, respectively, for a significant 35% reduction in risk favoring the pembrolizumab arm (P = .0012).

“The separation of progression-free survival curves began at 4 months,” Dr. Rugo noted.

Among patients with a PD-L1 CPS ≥ 1, at 6 months, 56.4% of patients receiving pembrolizumab plus chemotherapy and 47.8% of those receiving chemotherapy alone were free of disease progression or death. Median progression-free survival was 7.6 months and 5.6 months, respectively, for a 26% reduction in risk favoring the pembrolizumab-containing arm (P = .0014).


  • KEYNOTE-355 further supports the utility of first-line pembrolizumab plus chemotherapy combinations in advanced PD-L1–positive triple-negative breast cancer.
  • Regardless of the chemotherapy regimen used, the addition of pembrolizumab significantly improved progression-free survival over chemotherapy alone.
  • Improvement was correlated with PD-L1 enrichment.

In the intent-to-treat population at 6 months, 55.4% % and 47% had experienced disease progression or death. Median progression-free survival was 7.5 and 5.6 months, respectively, for an 18% reduction in risk.

“The statistical significance was not tested in the intent-to-treat analysis because of the small numbers,” Dr. Rugo noted.

Subgroup analysis of progression-free survival according to the type of chemotherapy used favored the combination of pembrolizumab over chemotherapy in the PD-L1 CPS ≥ 10, CPS ≥ 1, and intent-to-treat analyses.

Response Rates

Objective response rates with pembrolizumab plus chemotherapy improved with higher CPS. In those with a CPS > 10, objective response rate was 53.2% for the pembrolizumab combination vs 39.8% with chemotherapy. In those with a CPS ≥ 1, overall response rates were 45.2% and 37.9%, respectively. In the intent-to-treat population, objective response rates were 41% and 35.9%.

“Regardless of the chemotherapy partner, overall response rates were higher with pembrolizumab plus chemotherapy,” she stated.

Disease control rates and duration of response rates followed a similar pattern, with pembrolizumab plus chemotherapy superior to chemotherapy alone and increasing percentages seen corresponding with PD-L1 enrichment.

Overall survival results will be reported in the future. 

DISCLOSURE: Funding for the KEYNOTE-355 study was provided by Merck Sharp & Dohme Corp. Dr. Rugo has served as a consultant or advisor to Celltrion, Puma Biotechnology, and Samsung; has received institutional research funding from Daiichi Sankyo, Eisai, Genentech, Immunomedics, Lilly, MacroGenics, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, and Seattle Genetics; and has been reimbursed for travel, accommodations, or other expenses by AstraZeneca Spain, Daiichi Sankyo, MacroGenics, Mylan, Novartis, and Pfizer.


1. Rugo HS, Schmid P, Cescon DW, et al: 2020 San Antonio Breast Cancer Symposium. Abstract GS3-01. Presented December 10, 2020.

2. Cortes J, Cescon DW, Rugo HS, et al: 2020 ASCO Virtual Scientific Program. Abstract 1000.

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