Abstract OT2-01-03: Phase II Trial of the addition of pembrolizumab to letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer who have stable disease on letrozole and palbociclib
Authors: Yuan Y , Frankel P , Synold T , Yost S , Lee P , Waisman J , Somlo G , Hurria A , Mortimer J 
Published: March 2017

Abstract
Background: The combination of palbociclib and letrozole has become the standard of care for patients with newly diagnosed estrogen receptor positive (ER+) metastatic breast cancer (MBC), with promising prolongation of progression free survival (PFS). However, nearly half of all patients achieved stable disease only after the first 6 months of therapy. Check-point inhibitor pembrolizumab was effective in ER+ MBC with a response rate of 13-17%, this study will evaluate the efficacy of adding pembrolizumab for patients with ER+ MBC who have achieved stable disease (SD) on letrozole and palbociclib.
Trial Design:This is an open-label single institutional study. Patient will receive letrozole (2.5 mg) once a day and palbociclib (125 mg, 100 mg, or 75 mg as established tolerated dose) once a day for 3 weeks on and 1 week off. Pembrolizumab will be given at 200 mg IV every 3 weeks.
Eligibility Criteria: Eligible patients must be postmenopausal women with ER+ MBC with measurable disease by RECIST1.1, ECOG performance status 0-1; must have received letrozole and palbociclib for at least 6 months, and have documented SD per RECIST 1.1. Up to3 lines of previous systemic therapy including endocrine therapy and/or chemotherapy are allowed. Patients are excluded if they had prior treatment with anti--PD1 or anti-PD-L1therapy, immunodeficiency; currently using systemic steroids active tuberculosis infection; major surgery within 28 days; active or untreated CNS metastases; history of interstitial lung disease; active infection requiring systemic therapy; or active cardiac disease.
Specific Aims: The primary objective is to evaluate the objective response rate(ORR). The secondary objective is to determine the safety and tolerability of pembrolizumab plus the letrozole/palbociclib combination. We will use clinical benefit rate (CBR), duration of response (DOR), PFS, and OS to test the efficacy of this novel drug combination.
Statistical Design: We will employ a three-at-risk design (modified rolling design) for the initial cohort of this Phase II study to insure the triplet is well-tolerated. This design permits only 3 patients to be a risk for DLT at any one time during the “safety lead-in” .When the first 6 patients have completed the observation period and treatment with ≤1 DLT, the safety lead-in for the triplet will be considered successful, and accrual will proceed to a total of 18 patients. Response (CR or PR by RECIST version 1.1) in patients who have demonstrated only SD on letrozole and palbociclib can be reasonably attributed to the addition of pembrolizumab. As a result, we set the probability of a response occurring without the addition of pembrolizumab as 3% or less. With 18 patients, a true response rate of 20% would result in at least 2 responders with 90% power and a type I error of 10%. With 18 patients, the response can be estimated with a 95% CI half-width of 23%.
Target Accrual: 18.
Citation Format: Yuan Y, Frankel P, Synold T, Yost S, Lee P, Waisman J, Somlo G, Hurria A, Mortimer J. Phase II Trial of the addition of pembrolizumab to letrozole and palbociclib in patients with metastatic estrogen receptor positive breast cancer who have stable disease on letrozole and palbociclib [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-01-03.