FDA Advises Against Accelerated Approval Pathway for Botensilimab/Balstilimab in R/R MSS CRC

Although data from a phase 2 trial (NCT05608044) demonstrated that botensilimab plus balstilimab was active in patients with relapsed/refractory microsatellite stable (MSS) metastatic colorectal cancer (mCRC) without liver metastases, the FDA advised against filing for accelerated approval of the combination since the objective response rates (ORRs) may not translate to a survival benefit, according to an announcement from Agenus following an end-of-phase 2 meeting.¹

During the meeting, the FDA and Agenus reached an agreement on the recommended dose for a phase 3 study of 75 mg of botensilimab once every 6 weeks for up to 4 doses plus 240 mg of balstilimab once every 2 weeks for up to 2 years. Notably, the FDA also recommended the inclusion of a botensilimab monotherapy arm in the phase 3 study at the discretion of Agenus.

Interim topline data from the phase 2 study showed that patients treated with the 75-mg dose of botensilimab plus balstilimab (n = 62) experienced an ORR of 19.4% (95% CI, 10.4%-31.4%). In this arm, the 6-month overall survival (OS) rate was 90%.

In patients given the 150-mg dose of botensilimab plus balstilimab (n = 61), the ORR was 8.2% (95% CI, 2.7%-18.1%). Notably, botensilimab monotherapy given at 75 mg once every 6 weeks (n = 38) and at 150 mg once every 6 weeks (n = 40) elicited ORRs of 0% (95% CI, 0%-9.3%) and 7.5% (95% CI, 1.6%-20.4%), respectively. In the standard-of-care (SOC) arm (n = 33), the ORR was 0% (95% CI, 0%-10.6%).

“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,” Steven O’Day, MD, chief medical officer of Agenus, stated in a news release. “This includes exploring opportunities to partner in the United States to accomplish a successful phase 3 trial.”

The phase 2 data build on previously reported data from a phase 1 trial (NCT03860272), which showed that patients with refractory MSS mCRC who did not have active liver metastases (n = 77) achieved an ORR of 23% at a median follow-up of 13.6 months Furthermore, the median OS was 21.2 months, and the respective 6-, 12-, and 18-month OS rates were 86%, 71%, and 62%.

In the phase 2, open-label, multicenter trial, investigators enrolled patients at least 18 years of age with unresectable and metastatic CRC adenocarcinoma whose tumors needed to be assessed for microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) status. At least 1 prior chemotherapy regimen in the recurrent or metastatic setting was required. Other key inclusion criteria consisted of measurable disease per RECIST 1.1 criteria, a life expectancy of at least 12 weeks, an ECOG performance status of 0 or 1, and adequate organ function.²

Patients with MSI-H or dMMR disease were excluded. Other key exclusion criteria included prior treatment with anti–PD-1, –PD-L1, or –CTLA-4 agents; prior treatment with regorafenib (Stivarga) or trifluridine/tipiracil (TAS-102; Lonsurf); partial or complete bowel obstruction within 3 months of enrollment, symptoms of obstruction or radiological evidence of impending obstruction; refractory ascites; and liver metastases.

Enrolled patients were randomly assigned to receive botensilimab plus balstilimab at 1 of 2 dose levels; botensilimab monotherapy at 1 of 2 dose levels; or SOC, which consisted of regorafenib or TAS-102.

ORR served as the trial’s primary end point. Secondary end points included duration of response, progression-free survival, OS, safety, and pharmacokinetics.

The combination’s safety profile was manageable, and no new safety signals were reported. Full topline data from the phase 2 study will be presented at an upcoming medical meeting.¹

“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,” Michael Sapienza, chief executive officer of Colorectal Cancer Alliance, added in a news release. “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.”

References

1. Agenus announces end-of-phase-2 meeting outcomes and topline interim phase 2 data for BOT/BAL in MSS colorectal cancer. News release. Agenus. July 18, 2024. Accessed July 18, 2024. https://investor.agenusbio.com/news/news-details/2024/Agenus-Announces-End-of-Phase-2-Meeting-Outcomes-and-Topline-Interim-Phase-2-Data-for-BOTBAL-in-MSS-Colorectal-Cancer/default.aspx
2. A study of botensilimab and balstilimab for the treatment of colorectal cancer. ClinicalTrials.gov. Updated June 4, 2024. Accessed July 18, 2024. https://clinicaltrials.gov/study/NCT05608044