Abstract OT2-01-17: A Phase II randomized trial of pembrolizumab with carboplatin and gemcitabine for treatment of patients with metastatic triple-negative breast cancer (mTNBC)
Authors: Obeid E , Miller KD , Sparano JA , Blackwell K , Goldstein LJ 
Published: March 2017

Abstract
Background: Treatment for mTNBC is limited, and significant challenges persist in treating this disease, as outcomes remain largely dependent on chemotherapy without any effective targeted treatment. Pembrolizumab (MK-3475) is a highly selective, humanized monoclonal antibody against PD-1, blocking the negative immune regulatory signaling of the PD-1 receptor that is usually expressed by T-cells. Recent data showed that some patients with mTNBC may benefit from immune-based therapies (PD-1 or PD-L1 antibodies). Cumulative evidence suggest that stromal tumor infiltrating lymphocytes (sTILs) have a prognostic and predictive role in response to treatment in subsets of TNBC, particularly in response to carboplatin use. Preclinical data revealed that blocking PD-1/PD-L1 pathway in combination with platinum containing cytotoxic therapy improved response rates and survival. High levels of sTILs and an increased PD-L1 expression make mTNBC a candidate for PD-1–targeted therapy. As studies showed that the subset of TNBC with better response rates to carboplatin are heavily infiltrated with sTILs, pembrolizumab, becomes a very attractive drug to be tested in combination with carboplatin, with the goal of improving outcomes in mTNBC. A Phase II multicenter, randomized, trial has been initiated to evaluate the efficacy and safety of combining pembrolizumab with carboplatin and gemcitabine in patients with mTNBC.
Methods: A safety run-in will assess the safety and tolerability of combining pembrolizumab with carboplatin and gemcitabine in patients with mTNBC. Following the completion of the safety run-in, patients will be randomized 2:1 to receive pembrolizumab (200 mg IV) on day 1 along with carboplatin (AUC 2, day 1 and day 8, IV) plus gemcitabine (800 mg/m2, day 1 and day 8, IV) of a 21-day cycle, or carboplatin plus gemcitabine (same aforementioned dose) alone. Patients will have histologically documented unresectable mTNBC. Prior systemic therapy for mTNBC, for up to 2 lines is allowed, and patients will have ECOG PS 0–2 and measurable disease (RECIST v1.1). Prior carboplatin/gemcitabine or cisplatin therapy is allowed in the adjuvant or neoadjuvant setting, as long as it occurred more than 12 months from the beginning of their enrollment. Subjects whose tumors progressed while on treatment with carboplatin or cisplatin are excluded. Known CNS disease (except asymptomatic treated metastases), autoimmune disease or prior immune checkpoint blockade therapy is an exclusion to enrollment on this trial. Primary endpoint is assessing the objective response rate according to RECIST v1.1 . Other endpoints include clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Tumor biopsies will be obtained at baseline and just prior to initiation of cycle 3 to assess biomarkers of response and immune escape. PD-L1 expression will be evaluated in exploratory analysis with a planned assessment of response based on PD-L1 status. This trial will enroll 6-12 patients in the safety run-in portion, and 75 patients in the randomized part, at 7 sites in the United States. Clinical trial information: NCT02755272 www.clinicaltrials.gov.
Citation Format: Obeid E, Miller KD, Sparano JA, Blackwell K, Goldstein LJ. A Phase II randomized trial of pembrolizumab with carboplatin and gemcitabine for treatment of patients with metastatic triple-negative breast cancer (mTNBC) [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 OT2-01-17.