Bintrafusp Alfa, an Anti-PD-L1:TGF-β Trap Fusion Protein, in Patients With ctDNA-Positive, Liver-Limited Metastatic Colorectal Cancer

Authors

Van K Morris
Michael J Overman
Michael Lam
Christine M Parseghian
Benny Johnson
Arvind Dasari
Kanwal Raghav
Bryan K Kee
Ryan Huey
Robert A Wolff
John Paul Shen
June Li
Isabel Zorrilla
Ching-Wei D Tzeng
Hop S Tran Cao
Yun Shin Chun
Timothy E Newhook
Nicolas Vauthey
Dzifa Duose
Raja Luthra
Cara Haymaker
Scott Kopetz

Publication Date

9-1-2022

Journal

Cancer Research Communications

DOI

10.1158/2767-9764.crc-22-0194

PMID

36382087

PMCID

PMC9648419

PubMedCentral® Posted Date

9-14-2022

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Identification of circulating tumor DNA (ctDNA) following curative intent therapies is a surrogate for microscopic residual disease for patients with metastatic colorectal cancer (mCRC). Preclinically, in micrometastatic microsatellite stable (MSS) CRC, increased TGF-β signaling results in exclusion of anti-tumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGF-βRII receptor ("TGF-β trap") and anti-PD-L1 antibody.

Methods: Patients with liver-limited, MSS mCRC and with detected ctDNA after complete resection of all known tumors and standard-of-care therapy were treated with 1200 mg of BA intravenously every 14 days for six doses. The primary endpoint was ctDNA clearance. Radiographic characteristics at recurrence were compared using independent t-tests to historical data from a similar cohort of patients with liver-limited mCRC who underwent observation.

Results: Only 4 of 15 planned patients received BA before the study was stopped early for loss of equipoise. There was no grade ≥3 AE. None of the patients cleared ctDNA. All patients developed radiographic recurrence by the first planned restaging. Although not detectable at prior to treatment, TGFβ3 was found in circulation in all patients at cycle 2 day 1. Compared to a historical cohort, patients administered BA developed more metastases (15 versus 2, p=0.005) and greater tumor volumes (9 cm vs 2 cm, p=0.05).

Conclusions: Treatment with BA in patients with ctDNA-detected, liver-limited mCRC did not clear ctDNA and was associated with large-volume recurrence, highlighting the potential context-specific complexity of dual TGF-β and PD-L1 inhibition.

Keywords

Humans, Colonic Neoplasms, Colorectal Neoplasms, Liver Neoplasms, Rectal Neoplasms, Immunologic Factors, Tumor Microenvironment

Published Open-Access

yes

Recommended Citation

Morris, Van K; Overman, Michael J; Lam, Michael; et al., "Bintrafusp Alfa, an Anti-PD-L1:TGF-β Trap Fusion Protein, in Patients With ctDNA-Positive, Liver-Limited Metastatic Colorectal Cancer" (2022). Faculty, Staff and Student Publications. 4935.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4935