LCCC 1525: Combination immunotherapy with cyclophosphamide plus pembrolizumab in patients with advanced triple negative breast cancer (TNBC).

Abstract

TPS1125 Background: Immunotherapy is a promising strategy to treat advanced TNBC, an aggressive subtype of BC lacking expression of estrogen and progesterone receptors and HER2. TNBC response to antibodies targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1) are modest (< 20%); high expression of PD-L1 is associated with enhanced response. The presence of intratumoral regulatory T cells (Tregs), potent suppressors of the immune response, dampens response to checkpoint inhibitors. The capacity of cyclophosphamide (Cy), a cytotoxic with known activity in BC, to deplete Tregs is well-established. Preclinical mouse models of TNBC illustrate Treg depletion with improved outcome when Cy is administered prior to PD-1 inhibition. We are testing the hypothesis that a single dose of Cy given prior to pembrolizumab (pembro) will improve progression free survival (PFS) beyond historical control in advanced TNBC. Methods: This phase II, single-arm, multicenter study will evaluate pembro 200 mg IV every 3 weeks following a single priming dose of Cy 300 mg/m2 IV in patients (pts) with advanced TNBC who have received ≥1 prior therapy in the metastatic setting. The primary objective is to estimate PFS for Cy + pembro in advanced TNBC pts. A co-primary objective is to describe reduction in circulating Tregs. Secondary objectives include overall response rate (ORR, RECIST 1.1), duration of response (DOR), disease control rate (DCR) and overall survival (OS). Determination of ORR based on immune response criteria (irRECIST) and association of immunogenomic features with PFS are exploratory. Statistical considerations: A sample size of 36 pts has an 80% power to detect change in median PFS from 1.9 (null) to 2.9 (alternative hypothesis) months at a 0.05 significance level. Assuming 10% dropout rate, we will enroll 40 pts. We will also be able to detect a 67% reduction in Tregs with 80% power and one-sided alpha = 0.05. Correlative studies: Archival primary and/or metastatic tissues are required of all pts to evaluate molecular subtype, gene signature expression, T and B cell receptor repertoires, and PD-1 and PD-L1 expression; correlations with outcome will be performed. Clinical trial information: NCT02768701.