New Paper Alert! Promising Results for MSS Colorectal Cancer Treated with Balstilimab and Botensilimab

Promising Results for MSS Colorectal Cancer Treated with Balstilimab and Botensilimab

Authors: Andrea J. Bullock, Benjamin L. Schlechter, Marwan G. Fakih, Apostolia M. Tsimberidou, Joseph E. Grossman, Michael S. Gordon, Breelyn A. Wilky, Agustin Pimentel, Daruka Mahadevan, Ani S. Balmanoukian, Rachel E. Sanborn, Gary K. Schwartz, Ghassan K. Abou-Alfa, Neil H. Segal, Bruno Bockorny, Justin C. Moser, Sunil Sharma, Jaymin M. Patel, Wei Wu, Dhan Chand, Katherine Rosenthal, Gabriel Mednick, Chloe Delepine, Tyler J. Curiel, Justin Stebbing, Heinz-Josef Lenz, Steven J. O’Day and Anthony B. El-Khoueiry

Published in Nature Medicine on June 13, 2024

Introduction:

Metastatic colorectal cancer (mCRC) remains a formidable clinical challenge, with limited treatment options and poor outcomes, particularly for patients with microsatellite stable (MSS) tumors. Immune checkpoint blockade (ICB) has been largely ineffective in this population, as MSS mCRC is considered a “cold” tumor with an immunosuppressive tumor microenvironment (TME).

BOT, an Fc-enhanced anti-CTLA-4 antibody, was specifically designed to overcome resistance mechanisms to Immune checkpoint blockade and was investigated in combination with BAL to assess its potential to elicit durable responses in this challenging patient population.

Design and Methods:

This open-label, phase 1, multicenter trial (NCT03860272) evaluated the safety, tolerability, and efficacy of an innovative combination – botensilimab (BOT), a novel multifunctional Fc-enhanced anti-CTLA-4 antibody, and balstilimab (BAL), an anti-PD-1 antibody.

The study comprised a dose-escalation portion (3+3 design) and disease-specific expansion cohorts, including heavily pre-treated patients with microsatellite stable metastatic colorectal cancer (MSS mCRC).

The primary endpoint assessed the occurrence of dose-limiting toxicities (DLTs), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and progression-free survival (PFS).

Study Population:

A total of 148 heavily pre-treated patients with MSS mCRC were enrolled, including 10 from the dose-escalation cohort and 142 from the expansion cohort. These patients had received a median of 3 prior lines of therapy (range 1-10), with 16% having prior exposure to PD-(L)1 inhibitors.

The study population had a significant metastatic burden, with 68% having more than one metastatic site and 42% with peritoneal disease.

Notably, 17% had active liver metastases at enrollment. In a preplanned analysis, 101 patients with at least 6 months of follow-up were evaluated for efficacy as the response-evaluable population, with ORR assessed by RECIST 1.1 criteria. Safety was evaluated in all 148 treated patients..

What We Learned:

In the response-evaluable population (n=101), confirmed objective responses were observed in 17 patients (17%; 95% CI 10-26%), including 1 complete response. Additionally, 45 patients achieved stable disease, resulting in a disease control rate of 61% (95% CI 51-71%).

The median duration of response was not reached (95% CI 5.7 months – not reached), and the median progression-free survival was 3.5 months (95% CI 2.7-4.1 months). Notably, the median overall survival was 20.9 months (95% CI 10.6 months – not reached) at a median follow-up of 10.3 months.

In an exploratory analysis stratified by liver metastasis status, patients without liver metastases (n=77) demonstrated superior outcomes, with an ORR of 22%, a DCR of 73%, and a median PFS of 4.1 months. In contrast, patients with active liver metastases (n=24) had a 0% ORR, a 25% DCR, and a median PFS of 1.4 months.

Regarding safety, treatment-related adverse events occurred in 89% of patients, most commonly fatigue (35%), diarrhea (32%), and pyrexia (24%). Notably, 12% of patients discontinued both drugs due to adverse events. Importantly, no new safety signals were observed with this combination.

Summary By Amalya Sargsyan, MD

Promising Results for MSS Colorectal Cancer Treated with Balstilimab and Botensilimab