Abstract P3-11-04: A phase II study of pembrolizumab, letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer

Background: The combination of CDK4/6 inhibitor and aromatase inhibitor is the current standard of care therapy for patients with estrogen receptor positive (ER+) metastatic breast cancer (MBC). Single agent immune check point inhibitor (ICI) pembrolizumab has a response rate of 12% in selected patients (PD-L1+), and preclinical studies demonstrated immune-modulatory effect of CDK4/6 inhibitors. The combination of CDK 4/6 inhibitors and ICI might turn “immune-cold” breast cancer tumors into “immune-hot” tumors. This study was designed to evaluate the safety and efficacy of adding pembrolizumab to letrozole and palbociclib in patients with ER+ MBC. Methods: This is an open-label single arm study enrolling patients with biopsy proven ER+ MBC with measurable disease by RECIST1.1, ECOG performance status 0-1. Patient received letrozole (2.5mg po daily), palbociclib (125mg po daily 3 weeks on, 1 week off), and pembrolizumab (200mg iv q3wks). Two cohorts were included: cohort 1 for patients who were previously on letrozole and palbociclib for > 6 months and had pembrolizumab added on C1D1, and cohort 2 for patients who had all 3 drugs started on C1D1. Premenopausal patients received ovarian suppression prior to C1D1. The primary objective was to determine the safety and tolerability of the combination. The secondary objectives were RR, PFS, and OS. For both cohorts, a three-at-risk design (modified rolling design) was used for safety-lead to ensure the triplet was well-tolerated. This design permitted only 3 patients to be a risk for DLT at any one time during the “safety lead-in” and permitted continuing accrual if ≤1 DLT occurred in the first 6 patients. Secondary consideration was response (cohort 2 only), with an a priori requirement of at least 9 responses to warrant further evaluation. Baseline tumor specimen, peripheral blood plasma, and PBMCs were collected for immune correlative analysis. Results: A total of 20 patients were accrued to this trial (4 in cohort 1, 16 in cohort 2), with 19 eligible for response assessment because one patient was determined to be TNBC upon repeat of biopsy. Median age was 49 years, with 40% Hispanic, and 60% non-Hispanic. There were 2 DLTs (1 biopsy site infection and delay in treatment that was possibly related to treatment in cohort 1, and 1 pneumonitis in cohort 2). 9/20 patients (45%) had dose delay and 9/20 patients (45%) had dose reduction, with the most common cause being neutropenia. Gr 4 AEs included neutropenia (n=4), WBC (n=3), LFT (n=1), and bowel perforation (n=1). Grade 3 AEs included neutropenia (n=11), WBC (n=9), LFT (n=3), PLT (n=2), and pneumonitis, pruritus, anemia, biopsy site infection (n=1 each). Other immune-related toxicities of Grade 2 included: hypothyroidism, colitis, LFTs, and dermatitis (n≤2 each). Responses were CR 1/19 (5.3%), PR 8/19 (42.1%), SD 6/19 (31.6%) and PD 4/19 (21.1%). Median follow up was 13.7 (95% CI 6.4-16.9) months and median PFS was not reached. No association of baseline tumor PD-L1 (22C3) and clinical response were observed (data available on 13 patients). PBMC flow from the first 9 patients (5 PR, 4 SD) showed lower percentage of naive CD8+ T cells (CD8+CD45RA+ CD27+), and higher level of non-naive KLRG1+CD8+ T cell (CD8+CD45RA− CD27− KLRG1+) were associated with clinical response (p Conclusion: The combination of letrozole, palbociclib, and pembrolizumab is well tolerated in patients with ER+ MBC. Citation Format: Yuan Yuan, Susan E Yost, Jin Sun Lee, Colt Egelston, Paul H Frankel, Christopher Ruel, Simran Padam, Aileen Tang, Norma Martinez, Jana Portnow, Christina Yeon, Cary Presant, Swapnil Rajurkar, Mina Sedrak, Niki Patel, Peter Lee, Joanne Mortimer. A phase II study of pembrolizumab, letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-04.