Botensilimab/Balstilimab Combo Produces Deep Responses in Microsatellite Stable CRC

The combination of botensilimab (AGEN1181) and balstilimab (AGEN2034) elicited deep objective responses with evidence of durability and encouraging tolerability in heavily pretreated patients with microsatellite stable (MSS), metastatic colorectal cancer (mCRC), according to expanded data from the phase 1b C-800 study (NCT03860272).¹

Findings were shared as part of a late-breaking oral presentation at the 2022 ESMO World Congress on Gastrointestinal Cancers. At a median follow-up of 5.8 months (range, 1.6-24.4), the doublet elicited an objective response rate (ORR) of 24% (95% CI, 14%-39%) among 42 evaluable patients; this included a 24% partial response rate. 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 roughly 95% classified as MSS and historically unresponsive to immunotherapy. Treatment-resistant MSS CRC patients 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 El-Khoueiry, MD, Phase I Program director at the USC Norris Comprehensive Cancer Center, Keck Medicine of USC, 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 treatment-resistant tumors.”

To be eligible to enroll to the first-in-human trial, patients were required to have advanced solid tumors that were refractory to standard treatment. These patients were permitted to have previously received immunotherapy. To be included in the CRC cohort, patients needed to have metastatic disease and MSS status per local assessment.

Those in this cohort (n = 41) received the Fc-enhanced CTLA-4 inhibitor botensilimab at 1 mg/kg or 2 mg/kg every 6 weeks in combination with the PD-1 inhibitor balstilimab at 3 mg/kg every 2 weeks.

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

Among the 41 patients included in the MSS CRC cohort, the median age was 57 years (range, 36-82), 59% were female, 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 response were ongoing at the time of data cutoff, and 30% of objective 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%).

Any-grade treatment-related adverse effects (TRAEs) were experienced by 76% of patients; these effects 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 alanine aminotransferase (grade 1/2, 12%) and increased aspartate aminotransferase (grade 1/2, 7%; grade 3, 2%). Musculoskeletal effects include arthralgia (grade 1/2, 10%; grade 3, 2%) and myalgia (grade 1/2, 12%). Skin toxicities include 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 due to 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. 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