Botensilimab Plus Balstilimab Shows Remarkable Activity in MSS CRC

Expanded data from the phase 1b C-800 study (NCT03860272) of botensilimab (AGEN1181) plus balstilimab (AGEN2034) in patients with microsatellite stable (MSS) colorectal cancer (CRC) demonstrate the combination to offer strong durability and superior efficacy compared with previously reported data, according to Agenus.¹

The combination elicited an objective response rate (ORR) of 24% (95% CI, 14%-39%) among 42 evaluable patients at a median follow-up of 5.8 months (range, 1.6-24.4), including a 24% partial response rate. Additionally, 49% of patients achieved stable disease with the regimen and 27% experienced disease progression.²

At the time these findings were shared by Anthony El-Khoueiry, MD, at the 2022 ESMO World Congress on Gastrointestinal Cancers as part of a late-breaking oral presentation, the median duration of response (DOR) had not yet been reached with the doublet. However, the disease control rate (DCR) reported was 73% (95% CI, 58%-84%).

“These data reinforce the strong therapeutic potential of botensilimab, when used in combination with balstilimab, in cold tumors such as MSS CRC,” stated Steven O’Day, MD, chief medical officer at Agenus, in the press release. “Thus far, botensilimab has demonstrated activity in 9 cold and treatment-resistant cancers, and we plan to initiate a robust, global phase 2 program, including in MSS CRC, later this year.”

The open-label, multicenter, phase 1, looked to evaluate the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of a novel fragment crystallizable (Fc)-engineered immunoglobulin G1 anti-cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) human monoclonal antibody, botensilimab, in combination with an anti-programmed cell death protein-1 (PD-1) antibody, balstilimab.³ Maximum tolerated dose was assessed in patients with advanced solid tumors, and the study aimed to find the recommended phase 2 dose of the doublet.

Eligibility in the first-in-human trial was open to adult patients with a histologically or cytologically confirmed diagnosis of metastatic or locally advanced solid tumor refractory to standard treatment. Patients must have had a measurable disease on imaging based on RECIST 1.1, a life expectancy of 3 months or greater, an ECOG performance status of 0 or 1, adequate organ, bone marrow reserve function, hematological, liver, and renal function, and no history of prior or concomitant malignancy that requires other active treatment. Inclusion in the CRC cohort was open to patients with metastatic disease and MSS status per local assessment.

The study enrolled a total of 41 evaluable patients with metastatic MSS CRC who 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.

Patients were heavily pre-treated, with a median of 4 prior lines of therapy (range 2-10), with 12% of patients receiving 2 prior lines, 32% who received 3 prior lines, 22% who received 4 prior lines and 35% who received 5 or more prior lines. Among those 41 patients, 34% had received prior immunotherapy. The median age of patients enrolled in the MSS CRC cohort was 57 years (range, 36-82). A total of 59% were female, 59% had an ECOG performance status of 1, and 34% received prior immunotherapy. Further, 51% of patients had tumors harboring a RAS mutation, and 5% of patients had tumors which harbored BRAF mutations.

Findings revealed that 80% of objective responses were ongoing at the time of the data cut-off and 30% objective responses exceeded 1 year.

In the patient sub-populations, an objective response was seen in 5 patients with RAS mutations for a 24% overall response rate and 81% disease control rate in this population. Other trials examining PD-1 combinations have reported only rare responses in this population (≤1% response rate). Additionally, in patients with metastases historically resistant to immunotherapy, including patients with malignant pleural effusions, soft tissue, peritoneal, retroperitoneal, and bone metastases, responses were observed.

Additionally, data showed that those without active liver metastases (n = 24) experienced positive responses with the combination with the combination achieving an ORR of 42% (95% CI, 25%-61%), and a DCR of 96% (95% CI, 80%-99%).

In regard to safety, any-grade treatment-related adverse effects (TRAEs) were experienced by 76% of patients, all of which were grade 1 or 2 in (51%) or grade 3 (24%). Botensilimab was shown to be well tolerated with no grade 4 or 5 TRAES demonstrated. The rates of gastrointestinal and skin toxicities ended up being comparable to those reported with first-generation CTLA-4 inhibitors.

Of the gastrointestinal toxicities reported with the combination, the most common consisted of diarrhea or colitis (grade 1/2, 29%; grade 3, 10%), nausea (grade 1/2, 17%), and vomiting (grade 1/2, 10%). Constitutional toxicities seen in patients 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%). Additionally, hepatic toxicities included increased alanine aminotransferase (grade 1/2, 12%) and increased aspartate aminotransferase (grade 1/2, 7%; grade 3, 2%).

Musculoskeletal effects observed in patients included arthralgia (grade 1/2, 10%; grade 3, 2%) and myalgia (grade 1/2, 12%), while skin toxicities included pruritus (grade 1/2, 10%) and rash (grade 1/2, 10%). No hypophysitis was reported in patients given the combination, and it was noted that pneumonitis as a result of the combination was rare.

In 46% of patients, investigator-assessed irAEs of any grade occurred, and 17% experienced grade 3 irAEs. A total of 10% of patients ended up discontinuing treatment with botensilimab due to a TRAE, while 10% discontinued both agents.

Overall, the doublet demonstrated deep objective responses and showed evidence of durability in this patient population. The combination was well tolerated and had a differentiated safety profile along with showing enriched responses in patients who did not have active liver metastases.

A global phase 2 dose-randomized trial examining patients with MSS CRC is expected to be launched within the year.

“Colorectal cancer is the second leading cause of cancer-related death worldwide, with roughly 95% classified as microsatellite stable and historically unresponsive to immunotherapy. Treatment-resistant MSS CRC patients lack effective options, with standard of care offering only a 1-2% response rate and a median expected survival ranging from 6 to 7 months,” said Anthony El-Khoueiry, MD, phase 1 program director at the USC Norris Comprehensive Cancer Center, Keck Medicine of USC, in the press release. “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.”

References

1. 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 30, 2022. https://bit.ly/3OOvt56

2. 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/3NM4rdT

3. Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. ClinicalTrials.gov. Accessed June 30, 2022. https://clinicaltrials.gov/ct2/show/NCT03860272