FDA Grants Fast Track Designation to Botensilimab Plus Balstilimab in Non–MSI-H/dMMR mCRC

FDA

The FDA has granted a fast track designation to the combination of botensilimab (AGEN1181) plus balstilimab (AGEN2034) for the treatment of patients with non–microsatellite instability–high (MSI-H)/mismatch repair–deficient (dMMR) metastatic colorectal cancer (mCRC) with no active liver involvement.¹

The designation is intended for heavily pretreated patients who are resistant or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan, and who have also received a VEGF inhibitor, an EGFR inhibitor, and/or a BRAF inhibitor, if indicated.

An ongoing phase 2 trial (NCT05608044) is evaluating botensilimab monotherapy and in combination balstilimab vs standard-of-care therapy in patients with unresectable mCRC who have received prior chemotherapy for metastatic or recurrent disease.

A global phase 3 trial evaluating the combination in patients with non–MSI-H CRC is expected to launch in 2023.

“We are pleased that the FDA has granted fast track designation for the combination of botensilimab with balstilimab in patients with non–MSI-H CRC, recognizing the high unmet medical need in this population,” Steven O’Day, MD, chief medical officer of Agenus, stated in a news release. “The fast track designation offers important benefits, including the potential eligibility for a priority review, and we will be working with the FDA and all key stakeholders to rapidly advance the botensilimab/balstilimab combination in CRC as well as other solid tumor indications.”

Findings from a phase 1a/b trial (NCT03860272) presented at the 2023 Gastrointestinal Cancers Symposium showed that at a median follow-up of 7 months (range, 2-31), the combination of botensilimab and balstilimab elicited an overall response rate (ORR) of 23% (95% CI, 14%-34%) in patients with microsatellite stable (MSS), refractory mCRC (n = 70).² One patient (1%) had a complete response, 21% had a partial response, and 53% had stable disease. The disease control rate (DCR) was 76% (95% CI, 64%-85%).

The first-in-human study included patients with advanced cancer. Patients with CRC were required to have refractory mCRC that was MSS. Prior immunotherapy was permitted. Patients needed to have a total bilirubin level of no more than 1.5 times the institutional upper limit of normal (ULN), and aspartate aminotransferase/alanine transaminase levels no more than 2.5 times the ULN.

Patients were treated with 1 or 2 mg/kg of botensilimab once every 6 weeks plus 3 mg/kg of balstilimab once every 2 weeks. The incidence of treatment-emergent adverse effects (AEs), identifying dose-limiting toxicities for botensilimab, and establishing the recommended phase 2 dose of botensilimab served as the primary end points of the phase 1a/b study. Secondary outcomes included ORR, duration of response, DCR, progression-free survival (PFS), and overall survival (OS).³

Additional data showed that among the 16 responders, 11 had an ongoing response at data cutoff, 3 received prior immunotherapy, and 11 had RAS-mutant disease. One of 13 evaluable responders had a tumor mutational burden of more than 10 mut/Mb, and 1 of 8 evaluable responders were PD-L1 positive.

The median OS was not yet reached (NR; 95% CI, 10.3 months-NR) for the overall population, and the 12-month OS rate was 63% (95% CI, 46%-76%). Among patients without active liver metastases, the median OS was NR (95% CI, NR-NR), and the 12-month OS rate was 81% (95% CI, 66%-90%). Those with active liver metastases had a median OS of 9.4 months (95% CI, 6.1-NR) and a 12-month OS rate of 40% (95% CI, 17%-62%).

The median PFS in the overall population was 4.1 months (95% CI, 2.8-5.5).

Regarding safety, any-grade treatment-related AEs (TRAEs) occurred in 64% of patients, including 40% who had grade 3 TRAEs and 3% who experienced grade 4 TRAEs. The most common any-grade TRAEs included immune-mediated diarrhea (43%), nausea (23%), fatigue (34%), decreased appetite (27%), chills (21%), pyrexia (23%), rash (27%), pruritus (17%), and hypo/hyperthyroidism (16%).

Botensilimab is also being investigated in phase 2 trials in patients with advanced melanoma (NCT05529316) and metastatic pancreatic cancer (NCT05630183).

References

1. Agenus receives fast track designation for botensilimab and balstilimab in colorectal cancer. News release. Agenus. April 17, 2023. Accessed April 19, 2023. https://investor.agenusbio.com/news-releases/
2. El-Khoueiry AB, Fakih MG, Gordon MS, et al. Results from a phase 1a/1b study of botensilimab (BOT), a novel innate/adaptive immune activator, plus balstilimab (BAL; anti-PD-1 antibody) in metastatic heavily pretreated microsatellite stable colorectal cancer (MSS CRC). J Clin Oncol. 2023;41(suppl 4):LBA8. doi:10.1200/JCO.2023.41.4_suppl.LBA8
3. Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. ClinicalTrials.gov. Updated September 16, 2022. Accessed April 19, 2023. https://clinicaltrials.gov/ct2/show/NCT03860272