Expanded data from the phase I C-800 study showed the immunotherapy combination of botensilimab and balstili­mab appeared to be active in patients with microsatellite-stable (MSS) metastatic colorectal cancer. The findings were reported at the European Society for Medical Oncology (ESMO) World Congress on Gastrointestinal Cancers 2022 by Anthony B. El-Khoueiry, MD, Phase I Program Director at the USC Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles.¹

The combination elicited responses (all partial) in 24% of the 41 evaluable patients at a median follow-up of 5.8 months. Additionally, 49% of patients achieved stable disease with the regimen, for a disease control rate of 73%. Responses were less frequent in patients without active liver metastases, Dr. El-Khoueiry reported.

Anthony B. El-Khoueiry, MD

Botensilimab and balstilimab demonstrated “promising activity for immunotherapy” in heavily pretreated patients with metastatic microsatellite-stable colorectal cancer and “compelling efficacy in patients without liver metastases,” along with a manageable safety profile, he said. “Roughly 95% of colorectal cancers are classified as MSS and historically unresponsive to immunotherapy. Patients with treatment-resistant MSS colorectal cancer lack effective options in the third line and beyond. The combination of robust response rate, durability, and tolerability demonstrated by the combination of botensilimab and balstilimab supports its further development in MSS colorectal cancer, as well as more broadly, in other cold and treatment-resistant tumors,” Dr. El-Khoueiry said.

About the C-800 Study

The open-label, multicenter, first-in-human phase I C-800 trial evaluated the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of botensilimab as a single agent and of the combination of botensilimab and balstilimab. Botensilimab is a novel fragment crystallizable–engineered immunoglobulin G1 anti–cytotoxic T-lymphocyte antigen 4 (anti–CTLA-4) human monoclonal antibody, and balstilimab is an anti–PD-1 antibody. Botensilimab has an enhanced Fc region that increases binding to Fc gamma receptors on antigen presenting cells and natural killer cells, thereby tightening the “immune synapse” with T cells and resulting in several unique properties relative to first-generation CTLA-4 antibodies. The presentation reported early results from the microsatellite-stable colorectal cohort, which continues to enroll. To be considered evaluable, patients had to have at least one restaging scan at 6 weeks. Patients received botensilimab at 1 mg/kg (n = 7) or 2 mg/kg every 6 weeks in combination with balstilimab at 3 mg/kg (n = 34) every 2 weeks.

Study results revealed that 80% of objective responses were ongoing at the time of data cutoff, and 30% of objective responses exceeded 1 year. Based on an exploratory retrospective analysis, the response rate was 42%, and the disease control rate was 96% in patients without active liver metastases (this group included patients with no history of liver metastases and patients whose liver metastases were ablated or resected without recurrence). 

Responses were noted independent of RAS mutation status; one responder was reported to have PD-L1–positive disease, and all responders had a low tumor mutational burden of up to 10; two responders were refractory to prior immunotherapy including a PD-1/tyrosine kinase inhibitor combination. Dr. El- Khoueiry noted that other trials of PD-1 and first-generation CTLA-4 combinations in the microsatellite-stable population have reported a response rate of up to 5%.

Safety Profile

Treatment-related adverse events of any grade were experienced by 76% of patients, mostly grade 1 or 2 (51%) or grade 3 (24%). There were no grade 4 or 5 toxicities. The most common treatment-related grade 3 toxicities included diarrhea or colitis (10%), fatigue (2%), pyrexia (2%), increased aspartate aminotransferase levels (2%), and arthralgia (2%). No hypophysitis was reported, and pneumonitis was rare. Immune-related adverse events of any grade were observed in 46% of patients, 17% of which were grade 3. A total of 10% of patients discontinued botensilimab because of a treatment-related adverse event, and an additional 10% discontinued both drugs. 

DISCLOSURE: Dr. El-Khoueiry reported financial relationships with Roche Genentech, Gilead, AstraZeneca, Merck, Agenus, BMS, ABL Bio, QED, Servier, and Senti Biosciences.

REFERENCE

1. Bullock AJ, Grossman JE, Fakih MG, et al:  ESMO World Congress on Gastrointestinal Cancer 2022. Abstract LBA-09. Presented June 29, 2022.