Phase I/II trial of palbociclib, pembrolizumab and letrozole in patients with hormone receptor-positive metastatic breast cancer

Abstract

Background: CDK4/6 inhibitors modulate immune response in breast cancer. This phase I/II trial was designed to test the safety and efficacy of palbociclib, pembrolizumab and letrozole in women with hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC).

Patients and methods: Women with stage IV HR+ HER2- MBC were enrolled and treated with palbociclib, pembrolizumab and letrozole. Primary end-points were safety, tolerability and efficacy.

Results: Between November 2016 and July 2020, 23 patients were enrolled with 20 evaluable for response, including 4 patients in cohort 1 and 16 patients in cohort 2. Cohort 1 median age was 48 years (33-70) and cohort 2 median age was 55 (37-75). Cohort 1 closed early due to limited accrual. Grade III-IV adverse events were neutropenia (83%), leucopaenia (65%), thrombocytopenia (17%) and elevated liver enzymes (17%). In cohort 1, 50% achieved a partial response (PR) and 50% had stable disease (SD). In cohort 2, 31% achieved complete response (CR), 25% had PR and 31% had SD by Response Evaluation Criteria in Solid Tumours version 1.1. Median progression-free survival was 25.2 months (95% confidence interval [CI] 5.3, not reached) and median overall survival was 36.9 months (95% CI 36.9, not reached) in cohort 2 with a median follow-up of 24.8 months (95% CI 17.1, not reached). A correlative immune biomarker analysis was published separately.

Conclusion: The combination of palbociclib, pembrolizumab and letrozole is well tolerated, and a complete response rate of 31% was identified in HR+ MBC patients who received this combination as front-line therapy. Confirmatory trials are required to better understand the immune-priming effects of CDK4/6 inhibitors.

Trial registration: ClinicalTrials.gov NCT02778685.

Keywords: CDK 4/6 inhibitor; Hormone receptor positive; Immune checkpoint inhibitor; Metastatic breast cancer.

Conflict of interest statement

Conflict of interest statement Dr. Yuan has contracted research sponsored by Merck, Eisai, Novartis, Puma, Genentech, Celgene, and Pfizer; is a consultant for Puma, Pfizer, and Immunomedics; and is on the Speakers Bureau for Eisai, Genentech, AstraZeneca, Daiichi Sankyo, Pfizer, Merck, and Immunomedics. The other authors declare they have no competing interests.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1.. Response to therapy.

A) Cohort 1 bar plot (N=4) showing patient response to study drug over time starting with palbociclib and letrozole treatment on cycle 1 day 1 (C1D1) and the black triangle representing protocol therapy with the addition of pembrolizumab; each bar represents one patient; B) Cohort 1 spider plot (N=4) showing relative change in tumor size from baseline over time starting at time of protocol therapy with pembrolizumab; C) Cohort 2 bar plot (N=16); and D) Cohort 2 spider plot (N=16). CR (blue), complete response; PR (green), partial response; SD (orange), stable disease; PD (red), progression of disease; X, off trial for progression; Y, off pembrolizumab for toxicity; Z, off pembrolizumab per patient decision; +, off treatment per physician decision.

Figure 2.. Kaplan Meier survival analysis for cohort 2 (N=16).

A) Median PFS was 25.2 months (95% CI 5.3, NR) from start of treatment; B) Median OS was 36.9 months (95% CI 36.9, NR). PFS, progression free survival; OS, overall survival; NR, not reached.

Figure 3.. Pre-treatment tumor stromal TILs, PD-L1, and TMB.

A) % Stromal TILs vs. response (N=19); B) % PD-L1 vs. response (N=19); and C) TMB (m/MB) vs. response (N=14). Tumor mutation burden (TMB), progression of disease (PD), stable disease (SD), partial response (PR), complete response (CR).