Phase II clinical trial and preclinical evaluation of a novel CD47 blockade combination in refractory microsatellite stable metastatic colorectal cancer

Abstract

Introduction In this preclinical human immune system patient-derived xenograft (HIS PDX) model and phase II clinical trial, we assessed evorpacept (anti-CD47 engineered fusion protein with inactive Fc), cetuximab, and pembrolizumab (triple therapy) in microsatellite stable colorectal cancer (MSS CRC). Materials, Patients, and Methods HIS BRGS mice with PDXs were treated with triple therapy or its components. Patients with refractory MSS CRC were treated with triple therapy in a safety run-in (Stage 1) followed by expansion (Stage 2, planned N=42). The co-primary objectives were to determine the recommended dose of evorpacept and objective response rate (vs historical control). Results In HIS-PDX mice, triple therapy decreased the growth of MSS CRC tumors and increased tumor-infiltrating CD8+ T cells. Sixteen patients were treated on the clinical trial across two evorpacept dose levels, including N=12 in Stage 1 and N=4 in Stage 2. Trial enrollment was terminated early due to safety concerns (one treatment-related grade 5 event each of hemophagocytic lymphohistiocytosis and cytokine release syndrome). Otherwise, the adverse event profile was as expected. Among all patients, the ORR was 6.3%; formal hypothesis testing was not performed. The disease control rate was 12.5%, the median progression-free survival was 2.3 months, and the median overall survival was 10.9 months. Blood- and tumor-based clinical trial correlative analyses identified innate and adaptive immune system activation. Conclusions While triple therapy demonstrated evidence of efficacy in refractory MSS CRC, safety concerns halted enrollment. Further investigation is necessary to determine the optimal use of CD47-targeted therapies in MSS CRC.