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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Tolaney reported receiving grants from Merck & Co and Eisai during the conduct of the study; receiving grants from Bristol-Myers Squibb, Exelixis, Eli Lilly, Pfizer, Novartis, AstraZeneca, Nektar, Odonate, and Sanofi outside the submitted work; and serving on advisory boards for Genentech, Eli Lilly, Novartis, Pfizer, Nektar, Immunomedics, Nanostring, Daiichi Sankyo, Bristol-Myers Squibb, Sanofi, Athenex, AstraZeneca, Eisai, Puma, and Merck & Co. Dr Barroso-Sousa reported receiving personal fees and travel, accommodations, or expenses from Roche and personal fees from Pfizer, Libbs, Eli Lilly, Bristol-Myers Squibb, and Novartis outside the submitted work. Dr Vaz-Luis reported personal fees from Amgen, AstraZeneca, and Kephren outside the submitted work. Dr Wulf reported receiving grants from Merck & Co, Stand Up to Cancer/American Association of Cancer Research (SU2C-AACR-DT0209), Mary Kay Ash Foundation, Ovarian Cancer Research Foundation, Breast Cancer Alliance, Breast Cancer Research Foundation, and the National Institutes of Health (RO1 1R01CA226776-01) during the conduct of the study, and receiving nonfinancial support from Arctic Pharma outside the submitted work; in addition, Dr Wulf had a patent Application 14/348810, Compositions and Methods for the Treatment of Proliferative Diseases, pending, and a patent to US 20090258352 A1, Pin1 as a Marker for Abnormal Cell Growth, licensed to Cell Signaling; R&D Systems issued, licensed, and with royalties paid. Dr Spring reported receiving personal fees from Novartis, Puma, and Lumicell and institutional research support from Tesaro and Merck & Co outside the submitted work. Dr Dillon reported receiving personal fees from Novartis outside the submitted work and serving on the Advisory Board for Oncology Analytics. Dr Lin reported receiving grants from Genentech, Merck & Co, Array Biopharma, Pfizer, and Novartis; grants and personal fees from Seattle Genetics; and personal fees from Puma and Daiichi Sankyo outside the submitted work. Dr Overmoyer reported receiving institutional research support from Genentech, Eisai, and Incyte during the conduct of the study. Dr Van Allen reported receiving grants from Novartis and Bristol-Myers Squibb and personal fees from Tango Therapeutics, Genome Medical, Ervaxx, Manifold Bio, Invitae, and Janssen outside the submitted work; and institutional patents filed on ERCC2 mutations and chemotherapy response, chromatin mutations and immunotherapy response, and methods for clinical interpretation. Dr Mittendorf reported receiving study drug and financial support from Merck & Co and study drug from Eisai during the conduct of the study; receiving personal fees for serving on advisory boards from Merck & Co, Genomic Health, and Sellas Lifesciences; serving (uncompensated) on steering committees for Roche, Bristol-Myers Squibb, and Eli Lilly and Company; and receiving laboratory funding from GlaxoSmithKline outside the submitted work. Dr Winer reported receiving institutional research support from Genentech and honoraria from Verastem, Genentech, Tesaro, Eli Lilly and Company, Carrick Therapeutics, GlaxoSmithKline, Jounce Therapeutics, Genomic Health, Seattle Genetics, Merck & Co, and Leap Therapeutics. Dr Krop reported receiving grants from Pfizer; grants and personal fees from Genentech/Roche; and personal fees from Merck & Co, Novartis, Daiichi Sankyo, AstraZeneca, Bristol-Myers Squibb, Macrogenics, Seattle Genetics, Celltrion, Taiho Oncology, and Context Therapeutics outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

PD-L1 indicates programmed cell death ligand 1.

Figure 2.. Kaplan-Meier Analysis of Progression-Free Survival (PFS) and Overall Survival (OS)

The dashed lines indicate the median PFS for each arm. PD-L1 indicates programmed cell death ligand 1.