Consensus molecular subtype (CMS) status in patients with metastatic colorectal cancer (CRC) provides a potential signal for refining therapeutic strategies based upon TGFβ enrichment in this patient population, according to study results presented at the virtual 2020 ASCO Annual Meeting.

“[CMS4 CRC] features increased TGFβ signaling, which may account for de novo resistance to immunotherapy for patients… with microsatellite stable [metastatic] CRC,” explained Amir Mehrvarz Sarshekeh, MD, University of Texas MD Anderson Cancer Center, Houston, and colleagues noting that to date, no prior trial has incorporated CMS status as an integral biomarker in CRC.

The Simon 2-stage phase 2 trial screened 137 patients for CMS4 metastatic CRC between June 2018 and December 2019. CMS testing was conducted on primary tumors in a CLIA setting. Eligible patients received bintrafusp alfa, , a dual PD-L1 antibody/TGFβ trap, IV at 1200mg every 14 days as well as radiotherapy (RT) 3Gy per day for 3 days administered to a single metastatic lesion between doses 2 and 3.

The primary end point was to estimate response rate per iRECIST. Secondary endpoints included estimated progression-free survival (PFS), overall survival (OS), and toxicity.

Overall 53 (39%) of the 137 patients screened had treatment refractory CMS4 metastatic CRC and 15 patients were initially enrolled in the first stage for treatment with bintrafusp alfa. Overall 13 of the initial 15 patients received bintrafusp alfa in combination with RT. All patients were evaluable for toxicity, and 13 for response.

The median number of doses received was 3. Stable disease was achieved in 2 patients and 11 patients had progressive disease as the best response. Median PFS was 1.6 months and median OS was 5.0 months. Dr Sarshekeh and colleagues noted that bintrafusp alfa did not meet its primary end point and was discontinued for futility.

The most common adverse events were rash, puritis, fatigue and. One grade-3 immune-related adverse event was reported. Overall, treatment with bintrafusp alfa was well-tolerated.

Additionally, Dr Sarshekeh and coinvestigators highlighted that in paired samples, treatment with bintrafusp alfa resulted in an increase in the expression of IFNγ signature in nonirradiated metastatic lesions.

“This is the first reported trial ever that we’re aware of for metastatic colorectal cancer to use CMS as an integral biomarker for patients,” stated Dr Sarshekeh at the virtual ASCO 2020 Annual meeting.

“Although the efficacy for bintrafusp alfa and radiotherapy is low, changes in IFNγ signature provides a potential signal for refining therapeutic strategies based upon TGFβ enrichment in pts with [metastatic] CRC,” researchers concluded.—Kaitlyn Manasterski

Sarshekeh A M, Lam M, Zorrilla I R, et al. Consensus molecular subtype (CMS) as a novel integral biomarker in colorectal cancer: A phase II trial of bintrafusp alfa in CMS4 metastatic CRC. Presented at: the 2020 ASCO Annual Meeting; May 29-31, 2020. Abstract 4084.