Botensilimab and Balstilimab Stimulate Deep Responses in Population with MSS CRC

Anthony B. El-Khoueiry, MD

A combination of novel PD-1 and CTLA-4 checkpoint inhibitors led to durable responses and encouraging tolerability in heavily pretreated patients with microsatellite stable (MSS) metastatic colorectal cancer (CRC), according to expanded data from the phase 1b C-800-01 study (NCT03860272). These findings were presented at the 2022 European Society for Medical Oncology World Congress on Gastrointestinal Cancer.¹

Those in MSS CRC cohort (n = 41) received Fcenhanced CTLA-4 inhibitor botensilimab at 1 mg/kg or 2 mg/kg every 6 weeks in combination with PD-1 inhibitor balstilimab at 3 mg/kg every 2 weeks. At a median follow-up of 5.8 months (range, 1.6-24.4), the botensilimab (AGEN1181) and balstilimab (AGEN2034) doublet elicited an objective response rate (ORR) of 24% (95% CI, 14%-39%) among 41 evaluable patients, which included a partial response rate of 24%. Forty-nine percent of patients achieved stable disease with the regimen and 27% experienced disease progression. Moreover, the median duration of response (DOR) was not yet reached with the combination. The disease control rate (DCR) reported with the doublet was 73% (95% CI, 58%-84%).

“CRC is the second-leading cause of cancer-related death worldwide, with [approximately] 95% classified as MSS and historically unresponsive to immunotherapy. Treatment-resistant patients [with MSS CRC]lack effective options, with standard of care offering only a 1% to 2% response rate and a median expected survival ranging from 6 to 7 months,” Anthony B. El-Khoueiry, MD, director of the Phase 1 Drug Development Clinical Program at the University of Southern California (USC) Norris Comprehensive Cancer Center, Keck School of Medicine of USC in Los Angeles, stated in a press release.² “The combination of robust response rate, durability, and tolerability demonstrated by botensilimab and balstilimab supports further development of the combination in MSS CRC, as well as more broadly in other cold and treatmentresistant tumors.”

To be eligible to enroll in the first-inhuman trial, patients were required to have advanced solid tumors that were refractory to standard treatment. These patients were permitted to have previously received immunotherapy. In the CRC cohort, patients had to have metastatic disease and MSS status.

The efficacy end points of the trial include ORR, DCR, progression-free survival, DOR, and overall survival. Key safety end points include adverse events (AEs), treatment-related AEs (TRAEs), and immune-related AEs (irAEs).

Among the 41 patients included in the MSS CRC cohort, the median age was 57 years (range, 36-82), 59% were women, 59% had an ECOG performance status of 1, and 34% received prior immunotherapy. The median number of prior lines of therapy received was 4 (range, 2-10); 12% of patients received 2 prior lines, 32% received 3 prior lines, 22% received 4 prior lines, and 34% received 5 or more prior lines. Fifty-one percent of patients had tumors that harbored a RAS mutation, and 5% harbored BRAF mutations.

Moreover, 17% of patients (n = 7) received botensilimab at 1 mg/kg every 6 weeks and 83% (n = 34) received botensilimab at 2 mg/kg every 6 weeks. Additional data showed that 80% of objective responses were ongoing at the time of data cutoff, and 30% of responses exceeded 1 year.

Data from an exploratory analysis showed that those without active liver metastases (n = 24) experienced enriched responses with the combination. In these patients, the ORR achieved with the combination was 42% (95% CI, 25%-61%), and the DCR was 96% (95% CI, 80%-99%) (TABLE¹).

Any-grade TRAEs were experienced by 76% of patients; these events were grade 1 or 2 in 51% of patients and grade 3 in 24% of patients. The most common gastrointestinal toxicities reported with the doublet included diarrhea or colitis (grade 1/2, 29%; grade 3, 10%), nausea (grade 1/2, 17%), and vomiting (grade 1/2, 10%). Constitutional toxicities included fatigue (grade 1/2, 20%; grade 3, 2%), decreased appetite (grade 1/2, 22%), chills (grade 1/2, 17%), and pyrexia (grade 1/2, 12%; grade 3, 2%).

Hepatic toxicities included increased levels of alanine aminotransferase (grade 1/2, 12%) and aspartate aminotransferase (grade 1/2, 7%; grade 3, 2%). Musculoskeletal effects included arthralgia (grade 1/2, 10%; grade 3, 2%) and myalgia (grade 1/2, 12%). Skin toxicities included pruritus (grade 1/2, 10%) and rash (grade 1/2, 10%).

No hypophysitis has been reported with the combination, and pneumonitis with the combination was noted to be rare. Notably, grade 4 or 5 TRAEs were reported with the regimen. Investigator-assessed irAEs of any grade occurred in 46% of patients, and 17% experienced grade 3 irAEs.

Ten percent of patients discontinued botensilimab only because of a TRAE, and 10% discontinued both agents. A global, dose-randomized, phase 2 trial examining the combination is anticipated to launch later in 2022.

_REFERENCES:

_{1. Bullock AJ, Grossman JE, Fakih MG, et al. Botensilimab, a novel innate/ adaptive immune activator, plus balstilimab (anti-PD-1) for metastatic heavily pretreated microsatellite stable colorectal cancer. Presented at: 2022 ESMO World Congress on Gastrointestinal Cancers; June 29-July 2, 2022; Barcelona, Spain. Abstract LBA-09. Accessed July 2, 2022. https://bit.ly/3ywvZzw}

_{2. Agenus shows unprecedented activity for botensilimab/balstilimab combination in microsatellite stable colorectal cancer at ESMO World GI Congress. News release. Agenus; June 29, 2022. Accessed June 29, 2022. https://bit.ly/3bCNoNE}