Purpose:
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 (MSS) colorectal cancer.
Patients and Methods:
HIS BALB/c-Rag2nullIl2rγnullSirpαNOD mice with PDXs were treated with triple therapy or its components. Patients with refractory MSS colorectal cancer 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. historic control).
Results:
In HIS-PDX mice, triple therapy decreased the growth of MSS colorectal cancer tumors and increased tumor-infiltrating CD8+ T cells. Sixteen patients were treated on the clinical trial across two evorpacept dose levels: N = 12 in stage 1 and N = 4 in stage 2. Trial enrollment was terminated early because of 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 objective response rate 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:
Whereas triple therapy demonstrated evidence of efficacy in refractory MSS colorectal cancer, safety concerns halted enrollment. Further investigation is necessary to determine the optimal use of CD47-targeted therapies in MSS colorectal cancer.
Citation: Robert W. LentzJulie LangTodd M. PittsPatrick BlatchfordJunxiao HuKimberly R. JordanAdrie Van BokhovenStacey M. BagbyAdrian T.A. DominguezCameron A. BinnsHannah R. RobinsonNicole BalmacedaEmily BaiyeeAlexis D. LealSunnie S. KimS. Lindsey DavisChristopher H. LieuRaymond C. WadlowKristen SpencerAaron J. ScottPatrick M. BolandHoward S. HochsterWells A. Messersmith; Phase II Clinical Trial and Preclinical Evaluation of a Novel CD47 Blockade Combination in Refractory Microsatellite-Stable Metastatic Colorectal Cancer. Cancer Research Communications 1 November 2025; 5 (11): 2039–2052.