The FDA has advised against filing for accelerated approval of the immunotherapy combination botensilimab plus balstilimab for treating relapsed/refractory microsatellite stable (MSS) metastatic colorectal cancer without liver metastases, despite promising phase 2 trial results. During an end-of-phase 2 meeting with Agenus, regulators expressed concern that the objective response rates observed may not translate to a meaningful survival benefit.
However, the regulatory setback has not derailed development plans. The FDA and Agenus reached agreement on the recommended dosing regimen for a phase 3 study: botensilimab 75 mg administered once every 6 weeks for up to 4 doses, combined with balstilimab 240 mg once every 2 weeks for up to 2 years. The FDA also recommended including a botensilimab monotherapy arm at Agenus' discretion.
Phase 2 Trial Results Show Promise
Interim topline data from the phase 2 study (NCT05608044) demonstrated meaningful clinical activity for the combination therapy. Patients receiving botensilimab 75 mg plus balstilimab (n = 62) achieved an objective response rate (ORR) of 19.4% (95% CI, 10.4%-31.4%), with investigators pending confirmation of 2 additional responses. The 6-month overall survival rate in this group reached 90%.
In comparison, patients treated with the higher 150 mg dose of botensilimab plus balstilimab (n = 61) had an ORR of 8.2% (95% CI, 2.7%-18.1%). Botensilimab monotherapy showed limited activity, with ORRs of 0% at the 75 mg dose (n = 38) and 7.5% at the 150 mg dose (n = 40). Notably, patients receiving standard of care treatment (n = 33) had an ORR of 0% (95% CI, 0%-10.6%).
The safety profile of the combination was described as manageable with no new safety signals reported during the phase 2 study.
Building on Phase 1 Success
These phase 2 results build upon encouraging data from an earlier phase 1 trial (NCT03860272) in patients with refractory MSS metastatic colorectal cancer without active liver metastases. Among 77 patients in that study, the combination achieved an ORR of 23% at a median follow-up of 13.6 months. The median overall survival reached 21.2 months, with survival rates of 86%, 71%, and 62% at 6, 12, and 18 months, respectively.
Addressing Unmet Medical Need
MSS colorectal cancer represents approximately 95% of all colorectal cancer cases and remains a challenging disease setting with substantial unmet medical need. The condition is considered one of the most difficult cancer types to treat due to its high incidence and mortality rates.
"MSS CRC, representing approximately 95% of CRC cases, remains a disease setting with substantial unmet need and is considered to be one of the most challenging types of cancer due to its high incidence and mortality rates," said Michael Sapienza, chief executive officer of Colorectal Cancer Alliance. "The rapidly growing number of diagnoses in younger individuals is particularly alarming. There is an urgent need for new treatment options that can transform the trajectory of MSS CRC and provide lasting benefits for patients."
Company Commitment Despite Setback
Despite the FDA's position on accelerated approval, Agenus remains committed to advancing the combination therapy. "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/balstilimab available to patients is unwavering," said Steven O'Day, MD, chief medical officer of Agenus. "This includes exploring opportunities to partner in the United States to accomplish a successful phase 3 trial."
Trial Design and Patient Population
The open-label, multicenter phase 2 trial enrolled patients aged 18 years or older with unresectable and metastatic colorectal adenocarcinoma. Eligible patients had tumors assessed for microsatellite instability-high or mismatch repair-deficient status and had received at least one prior chemotherapy regimen in the recurrent or metastatic setting. Key inclusion criteria included measurable disease per RECIST 1.1 criteria, life expectancy of at least 12 weeks, ECOG performance status of 0 or 1, and adequate organ function.
Patients were randomized to receive botensilimab plus balstilimab at one of two dose levels, botensilimab monotherapy at one of two dose levels, or standard of care consisting of regorafenib or trifluridine/tipiracil.
Full topline data from the phase 2 study are expected to be presented at an upcoming medical meeting.
