Consensus molecular subtype (CMS) as a novel integral biomarker in colorectal cancer: A phase II trial of bintrafusp alfa in CMS4 metastatic CRC

4084 Background: Consensus Molecular Subtype 4 (CMS4) colorectal cancer (CRC) features increased TGFβ signaling, which may account for de novo resistance to immunotherapy for patients (pts) with microsatellite stable mCRC. To date, no prior trial has incorporated CMS status as an integral biomarker. Bintrafusp alfa (M7824) is a dual PD-L1 antibody/TGFβ trap with acceptable safety. Methods: Primary tumors from pts with metastatic CRC underwent CMS testing in a CLIA setting. In this Simon two-stage phase II trial (Ho: p < .05; Ha: p≥.25) for CMS4 mCRC, pts received bintrafusp alfa 1200mg IV every 14 days. RT (8Gy/day x 3 days) to a single metastatic lesion with abscopal intent was administered between doses 2 and 3. The primary objective was to estimate response rate (RR) per iRECIST. Correlative studies including RNA sequencing were performed on pre- and on-treatment biopsies. Results: 53 of 137 tested pts (39%) between June 2018-December 2019 had CMS4 mCRC. 13 of 15 treated pts received the agent with RT. All pts were evaluable for toxicity, and 13 for response. Median number of doses was 3 (IQR, 2-4). There was one grade 3 immune-related adverse event (colitis) requiring study discontinuation. There were 2 pts with stable disease and 11 with progressive disease as best response (RR 0%, 95% CI 0-22%). Enrollment was stopped after first stage for futility. Median PFS and OS were 1.6 months and 5.0 months, respectively. In paired samples, treatment with bintrafusp alfa resulted in an increase in the expression of IFNγ signature in nonirradiated metastatic lesions ( p< .001, q< .001). Updated results will be presented. Conclusions: This is the first reported clinical trial to utilize CMS status as an integral biomarker for pts with metastatic CRC and capitalizes on treating CRC subpopulations with targeted agents based upon validated RNA-based signatures. Although the efficacy for bintrafusp alfa and RT is low, changes in IFNγ signature provides a potential signal for refining therapeutic strategies based upon TGFβ enrichment in pts with mCRC. Clinical trial information: NCT03436563 .