In heavily pretreated patients with metastatic colorectal cancer who have microsatellite-stable tumors, the novel combination of the monoclonal antibodies botensilimab and balstilimab showed clinical activity, producing durable responses and an estimated 63% overall survival rate at 12 months, according to a phase Ia/IIb study reported at the 2023 ASCO GI Cancers Symposium.¹ These findings were presented by Anthony B. El-Khoueiry, MD, Associate Director for Clinical Research at the University of Southern California Norris Comprehensive Cancer Center, Los Angeles.

Anthony B. El-Khoueiry, MD

Botensilimab is a CTLA-4 antibody with enhanced binding to activating Fc receptors, which enables innate and adaptive immune activation. Balstilimab is a PD-1 inhibitor whose safety and efficacy profiles are analogous to those of the currently approved anti–PD-1 antibodies. Dr. El-Khoueiry reported the results of a first-in-human, expanded phase Ia/Ib C-800 trial of this combination in patients with microsatellite-stable, treatment-refractory metastatic colorectal cancer.

“Botensilimab is designed to extend the benefits of immunotherapy to ‘cold’ and immunotherapy-refractory tumors. So, in addition to blocking CTLA-4, the enhanced Fc region of the compound increases binding to Fc-γ receptors on antigen-presenting cells and natural killer cells, which results in several unique properties relative to first-generation CTLA-4 antibodies. They include a boost in T-cell priming, expansion, and memory T-cell formation; increased frequency of activated antigen presenting cells; enhanced T-regulation depletion; and a decrease in complement-mediated toxicity,” Dr. El-Khoueiry explained.

Conventionally, immunotherapy is effective against tumors with high microsatellite instability or mismatch-repair deficiency. In this population, the tumors were stable but were still amenable to this treatment. “It’s about these particular drugs,” he told The ASCO Post.

Study Details

The 70 patients in the C-800 study had received a median of four prior lines of therapy, which for 31% of patients included immunotherapy. Participants received botensilimab at 1 or 2 mg/kg every 6 weeks plus balstilimab at 3 mg/kg every 2 weeks.

The objective response rate to the combination (all but one confirmed) was 23%, with one complete response, and the disease control rate was 76%. Of 16 responses, 11 are ongoing, and 3 of these patients had received prior immunotherapy. One responder had a high tumor mutational burden (> 10 mut/Mb), and one was PD-L1–positive; 11 responders had RAS mutations.

“All the objective responses were in patients without active liver metastases, but even in patients with active liver metastases, we still saw a decrease in target lesions and some prolonged stability,” he noted, explaining that patients without active liver metastases included those whose liver metastases had been resected or ablated.

At a median follow-up of 7 months, median overall survival was not reached, yielding an overall survival rate of 63% at 12 months; median progression-free survival was 4.1 months. According to the presence or absence of active liver metastases, the 12-month survival was 40% for those with liver metastases and 81% for those without; median overall survival was 9.4 months and not reached, respectively, according to Dr. El-Khoueiry.

Treatment-related adverse events grade ≥ 3 occurred in 43% of patients, primarily immune-mediated diarrhea or colitis in 21%. Less common grade ≥ 3 toxicities included fatigue and pyrexia.

A global randomized phase II trial in microsatellite-stable metastatic colorectal cancer is enrolling (ClinicalTrials.gov identifier NCT05608044), and a global phase III trial is planned for later in 2023. 

DISCLOSURE: Dr. El-Khoueiry reported financial relationships with ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck, QED Therapeutics, Qurient, Roche/Genentech, Senti Biosciences, Servier, Pieris Pharmaceuticals, and Tallac Therapeutics.

REFERENCE

1. El-Khoueiry AB, Fakih MG, Gordon MS, et al: Results from a phase 1a/1b study of botensilimab, a novel innate/adaptive immune activator, plus balstilimab (anti–PD-1 antibody) in metastatic heavily pretreated microsatellite stable colorectal cancer. 2023 ASCO GI Cancers Symposium. Abstract LBA8. Presented January 21, 2023.