Bintrafusp Alfa, an Anti-PD-L1:TGFβ Trap Fusion Protein, in Patients with ctDNA-positive, Liver-limited Metastatic Colorectal Cancer

Author:

Morris Van K.1ORCID,Overman Michael J.1ORCID,Lam Michael2,Parseghian Christine M.1ORCID,Johnson Benny1ORCID,Dasari Arvind1,Raghav Kanwal1,Kee Bryan K.1,Huey Ryan1ORCID,Wolff Robert A.1,Shen John Paul1ORCID,Li June3,Zorrilla Isabel1,Tzeng Ching-Wei D.4ORCID,Tran Cao Hop S.4ORCID,Chun Yun Shin4,Newhook Timothy E.4,Vauthey Nicolas4ORCID,Duose Dzifa5,Luthra Raja5,Haymaker Cara3ORCID,Kopetz Scott1ORCID

Affiliation:

1. 1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

2. 2Department of Medical Oncology and Cancer Services, The University of Melbourne, Melbourne, Australia.

3. 3Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

4. 4Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

5. 5Department of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Abstract

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) colorectal cancer, increased TGFβ signaling results in exclusion of antitumor cytotoxic T cells from the tumor microenvironment. Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the TGFβRII receptor (“TGFβ trap”) and anti-PD-L1 antibody. 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 1,200 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. Only 4 of 15 planned patients received BA before the study was stopped early for loss of equipoise. There was no grade ≥3 adverse event. 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 with a historical cohort, patients administered BA developed more metastases (15 vs. 2, P = 0.005) and greater tumor volumes (9 cm vs. 2 cm, P = 0.05). 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 TGFβ and PD-L1 inhibition. Significance: Use of ctDNA to identify patients with micrometastatic disease for therapeutic intervention is feasible. Treatment with BA in patients with liver-limited mCRC and with detectable ctDNA after resection generated rapid progression. Approaches targeting TGFβ signaling must consider its pathway complexity in future immunotherapy combination strategies.

Funder

HHS | NIH | National Cancer Institute

Cancer Prevention and Research Institute of Texas

Publisher

American Association for Cancer Research (AACR)

Reference45 articles.

1. Cancer statistics, 2021;Siegel;CA Cancer J Clin,2021

2. [Epidemiology of colorectal cancer liver metastases];Faivre;Bull Acad Natl Med,2003

3. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy;Kopetz;J Clin Oncol,2009

4. Resection of colorectal liver metastases;Scheele;World J Surg,1995

5. Trends in long-term survival following liver resection for hepatic colorectal metastases;Choti;Ann Surg,2002

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