FDA Discourages Accelerated Approval of Botensilimab/Balstilimab Combo in R/R MSS CRC

The recommendation was made following mid-stage, end-of-phase 2 data for the botensilimab/balstilimab combination, which yielded lower responses in patients.

The FDA has discouraged the drug developer Agenus from applying for accelerated approval for its botensilimab and balstilimab combination regimen for the treatment of patients with relapsed or refractory microsatellite stable (MSS) colorectal cancer (CRC) with no active liver metastases, according to a news release by Agenus.¹

The recommendation was made following interim mid-stage data (NCT05608044) presented during an end-of-phase 2 meeting. A 75-mg dose of botensilimab dose combined with 240-mg balstilimab yielded an overall response rate (ORR) of 19.4% at a median follow-up of 9.5 months; however, when botensilimab dosage was increased to 150 mg, the ORR was 8.2%. Additionally, standard treatment led to a 0% ORR.

Additionally, no dose-limiting toxicities (DLTs) were observed in either dose-escalation cohort and the maximum-tolerated dose was not reached.

“Based on the high level of enthusiasm from significant numbers of global clinical experts and the promising clinical activity we have seen in the phase 1 and 2 studies, our commitment to seek all possible pathways to make [botensilimab and balstilimab] available to patients is unwavering,” said Steven O’Day, chief medical officer of Agenus, in a news release on the outcomes for the end-of-phase 2 meeting.²

Agenus noted that it is now seeking potential alternative options to make the combination available for patients. As for a phase 3 trial, the FDA suggested adding a botensilimab monotherapy arm to the study design.

Dose-escalation within the C-800-01 study occurred from April 1, 2019 to August 31, 2023 with a data cutoff of November 29, 2023.³ Of patients enrolled with advanced solid tumors (n = 83), 10 had metastatic MSS CRC. Botensilimab monotherapy was administered intravenously every 3 or 6 weeks starting at 0.1 mg/kg^-1 up to 3 mg/kg^-1 for up to 2 years to 48 patients. Alternatively, combination therapy was administered intravenously 3 mg/kg^-1 every 2 weeks for up to 2 years.

The primary end point was DLTs. Secondary end points include severity and causality of treatment-emergent adverse events (TEAEs), overall survival (OS), ORR, disease control rate (DCR), and progression-free survival (PFS), pharmacokinetics, and immunogenicity.

According to phase 1 trial data, 8 of 83 (10%; 95% CI, 4%-18%) dose-escalation patients had objective responses, including 2 (4%) in the monotherapy arm and 6 (17%) of the combination arm. Within those with observed responses (n = 83), 1 had a complete response (monotherapy arm, n = 1; combination therapy arm, n = 0), 7 had a partial response (n = 1; 6), 28 patients had stable disease (n = 17; 11), and the DCR was 43% (95% CI, 33%-55%) as of the data cutoff date.

The median follow-up was 6.3 months (range, 0.7-42.6 months), with the median DOR not reached (95% CI, 4.2 months-not estimable) in the combination arm and 7 months (95% CI) in the monotherapy arm; there were 2 ongoing responses in the combination arm Median PFS was 1.4 months (95% CI, 1.3-2.7), with a 6-month PFS rate of 17% (95% CI, 9%-27%). The median OS among both cohorts was 11.0 months (95% CI, 6.3-17.9), with a 12-month OS rate at 48% (95% CI, 36%-59%).

Between the monotherapy and combination arms, median OS was 9.6 months (95% CI, 4.8-17.9) vs 12.0 months (95% CI, 5.3-20.9), with a 12-month OS rate of 47% (95% CI, 31%-61%) vs 49% (95% CI, 29%-66%). Additionally, median PFS was 1.4 months (95% CI, 1.3-2.7) vs 2.7 months (95% CI, 1.3-4.4), with a 6-month PFS rate of 11% (95% CI, 4%-23%) vs 25% (95%, 11%-42%).

Agenus has engaged with European regulatory authorities to discuss a regulatory path for the approval of the botensilimab/balstilimab combination in Europe.

References

1. Future of Agenus’ immunotherapy combo uncertain as FDA discourages accelerated approval in CRC. News release. BioSpace. Published July 18, 2024. Accessed July 18, 2024. https://tinyurl.com/ycxbmytm
2. Agenus announces end-of-phase-2 meeting outcomes and topline interim phase 2 data for BOT/BAL in MSS colorectal cancer. News release. Agenus. Published July 18, 2024. Accessed July 18, 2024. https://tinyurl.com/bdhs8za9
3. Bullock AJ, Schlechter BL, Fakih MG, et al. Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial. Nat Med. Published June 13, 2024. doi:10.1038/s41591-024-03083-7