FDA Grants FTD to Botensilimab/Balstilimab in non–MSI-H/dMMR Metastatic CRC

The FDA has granted fast track designation to botensilimab (AGEN1181) and balstilimab (AGEN2034) for the treatment of patients with non-microsatellite instability high (MSI-H)/mismatch repair deficient metastatic colorectal cancer (CRC) with no active liver involvement, according to a press release from Agenus, Inc.¹

In a phase 1a/1b study, botensilimab plus balstilimab yielded an ORR of 23% in patients with non–MSI-H/dMMR metastatic CRC.

At the 2023 Gastrointestinal Cancers Symposium, investigators presented clinical data from ongoing clinical trials evaluating botensilimab/balstilimab in those with non-MSI-H CRC. Data from a phase 1a/1b study (NCT03860272) highlighted an objective response rate (ORR) of 23% (95% CI, 14%-34%) with the combination regimen, and a disease control rate (DCR) of 76% (95% CI, 64%-85%). Moreover, the median progression-free survival (PFS) of 4.1 months (95% CI, 2.8-5.5).² The 12-month overall survival (OS) rate was 63% (95% CI, 46%-76%), and the median OS was not reached (NR; 95% CI, 10.3-NR).

Investigators will also evaluate botensilimab plus balstilimab in those with non-MSI-H CRC as part of a global phase 3 trial (NCT05608044) planned 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, said in the press release.

Manufacturers designed the investigational CTLA-4 antibody botensilimab to extend clinical benefits to “cold” tumors that have not responded to standard-of-care therapies. The agent binds to the CTLA-4 receptor, and its FC-enhanced structure induces a memory immune response, downregulates regulatory T cells, and delivers enhanced priming and activation of T cells to amplify immune responses.

In the phase 1a/1b trial, patients received 1 or 2 mg/kg of botensilimab every 6 weeks plus 3 mg/kg of balstilimab every 2 weeks. Investigators allowed crossover from monotherapy to combination therapy as well as a fixed-dosing schedule of 150 mg of botensilimab every 6 weeks plus 450 mg of balstilimab every 3 weeks.

The primary end points of the trial included the incidence of treatment-emergent adverse effects (TEAEs) and the dose-limiting toxicities and recommended phase 2 dose of botensilimab. Secondary end points included ORR, DCR, duration of response, PFS, and OS.

Patients 18 years and older who had refractory metastatic CRC and microsatellite stable disease by local assessment were eligible for enrollment in the CRC cohort of the trial. Patients were also eligible if they had received prior immunotherapy.

Among 70 patients in the CRC cohort, the median patient age was 57 years (range, 25-83). Additionally, most patients were female (57%), had an ECOG performance status of 1 at baseline (60%), and had a median of 4 prior lines of therapy (range, 1-10). A total of 31% of patients received prior immunotherapy and 59% had a RAS mutation.

Of 16 patients who had a response following treatment with botensilimab plus balstilimab, 11 had ongoing responses. Moreover, response was observed in 1 patient with a tumor mutational burden of more than 10 mut/Mb, 1 with PD-L1–positive disease, and 11 who had RAS mutations.

Overall, 91% of patients receiving botensilimab plus balstilimab had any-grade treatment-related AEs (TRAEs), the most common of which included immune-mediated diarrhea or colitis (43%), fatigue (34%), and decreased appetite (27%). Additionally, 40% of patients had grade 3 TRAEs, which included immune-mediated diarrhea or colitis (20%), pyrexia (4%), and fatigue (4%). There was 1 grade 4 AE (colitis).

Investigators concluded that the regimen had a manageable safety profile.

References

1. Agenus receives fast track designation for botensilimab and balstilimab in colorectal cancer. News release. Agenus, Inc. April 17, 2023. Accessed April 18, 2023. yhoo.it/3mG5Mvd
2. 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; abstr LBA8). doi:10.1200/JCO.2023.41.4_suppl.LBA8