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Original Investigation
September 3, 2020

Effect of Eribulin With or Without Pembrolizumab on Progression-Free Survival for Patients With Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer: A Randomized Clinical Trial

Author Affiliations
  • 1Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 2Oncology Center, Hospital Sírio-Libanês, Brasília, Brazil
  • 3Broad Institute of MIT and Harvard, Boston, Massachusetts
  • 4Division of Biostatistics, Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
  • 5Unit Inserm 981, Gustave Roussy, Villejuif, France
  • 6Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 7Medical Oncology, Massachusetts General Hospital, Boston
  • 8Pathology, Brigham and Women’s Hospital, Boston, Massachusetts
  • 9Division of Breast Surgery, Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts
  • 10Breast Oncology Program, Dana-Farber/Brigham and Women’s Cancer Center, Boston, Massachusetts
JAMA Oncol. Published online September 3, 2020. doi:10.1001/jamaoncol.2020.3524
Visual Abstract. Effect of Eribulin With or Without Pembrolizumab on Progression-Free Survival in Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer
Effect of Eribulin With or Without Pembrolizumab on Progression-Free Survival in Hormone Receptor–Positive, ERBB2-Negative Metastatic Breast Cancer
Key Points

Question  Does the addition of pembrolizumab to eribulin improve efficacy compared with eribulin alone in patients with hormone receptor–positive/ERBB2-negative metastatic breast cancer?

Findings  In this phase 2 randomized clinical trial that included 88 patients, the median progression-free survival was 4.1 months for patients receiving pembrolizumab and eribulin vs 4.2 months for patients receiving eribulin alone.

Meaning  The results do not support the use of pembrolizumab in combination with eribulin for patients with hormone receptor–positive/ERBB2-negative metastatic breast cancer, independent of programmed cell death ligand 1 status.

Abstract

Importance  Prior studies have shown that only a small proportion of patients with hormone receptor (HR)–positive metastatic breast cancer (MBC) experience benefit from programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors given as monotherapy. There are data suggesting that activity may be greater with combination strategies.

Objective  To compare the efficacy of eribulin plus pembrolizumab vs eribulin alone in patients with HR-positive, ERBB2 (formerly HER2)–negative MBC.

Design, Setting, and Participants  Multicenter phase 2 randomized clinical trial of patients with HR-positive, ERBB2-negative MBC who had received 2 or more lines of hormonal therapy and 0 to 2 lines of chemotherapy.

Interventions  Patients were randomized 1:1 to eribulin, 1.4 mg/m2 intravenously, on days 1 and 8 plus pembrolizumab, 200 mg/m2 intravenously, on day 1 of a 21-day cycle or eribulin alone. At time of progression, patients in the eribulin monotherapy arm could cross over and receive pembrolizumab monotherapy.

Main Outcomes and Measures  The primary end point was progression-free survival (PFS). Secondary end points were objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and genomic alterations.

Results  Eighty-eight patients started protocol therapy; the median (range) age was 57 (30-76) years, median (range) number of prior lines of chemotherapy was 1 (0-2), and median (range) number of prior lines of hormonal therapy was 2 (0-5). Median follow-up was 10.5 (95% CI, 0.4-22.8) months. Median PFS and ORR were not different between the 2 groups (PFS, 4.1 vs 4.2 months; hazard ratio, 0.80; 95% CI, 0.50-1.26; P = .33; ORR, 27% vs 34%, respectively; P = .49). Fourteen patients started crossover treatment with pembrolizumab; 1 patient experienced stable disease. All-cause adverse events occurred in all patients (grade ≥3, 65%) including 2 treatment-related deaths in the combination group, both from immune-related colitis in the setting of sepsis, attributed to both drugs. The PD-L1 22C3 assay was performed on archival tumor samples in 65 patients: 24 (37%) had PD-L1–positive tumors. Analysis indicated that PD-L1 status, TILs, TMB, and genomic alterations were not associated with PFS.

Conclusions and Relevance  In this randomized clinical trial of patients with HR-positive, ERBB2-negative MBC, the addition of pembrolizumab to eribulin did not improve PFS, ORR, or OS compared with eribulin alone in either the intention-to-treat or PD-L1–positive populations. Further efforts to explore the benefits of adding checkpoint inhibition to chemotherapy among less heavily pretreated patients are needed.

Trial Registration  ClinicalTrials.gov Identifier: NCT03051659

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