FDA to Hold End-of-Phase 2 Meeting for Botensilimab Plus Balstilimab in R/R mCRC

The FDA will hold a Type B end-of-phase 2 meeting with Agenus to discuss studies investigating the combination of botensilimab (AGEN1181) and balstilimab (AGEN2034) for the treatment of patients with relapsed/refractory metastatic colorectal cancer (mCRC) that is not microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR). The regulatory agency and Agenus will also discuss the elements necessary to support the future submission of a biologics license application seeking approval for the combination.¹

In a news release, Agenus announced that data from a phase 2 trial (NCT05608044) evaluating botensilimab monotherapy and in combination with balstilimab in patients with refractory, microsatellite stable (MSS) mCRC will be submitted for presentation at a major medical conference later in 2024.

“Our upcoming end-of-phase 2 meeting with the FDA represents a significant milestone in the ongoing development of botensilimab/balstilimab for patients diagnosed with MSS CRC who do not have active liver metastases,” Steven O’Day, MD, chief medical officer of Agenus, stated in a news release. “The results from our phase 1 [NCT03860272] and phase 2 studies contribute valuable insights into the potential of this therapy for managing a specific and challenging subgroup of CRC. We remain dedicated to further exploring innovative immunotherapeutic strategies.”

Phase 1 Data

Previously reported data from the phase 1 study investigating botensilimab plus balstilimab showed that patients with refractory MSS/mismatch repair–proficient mCRC without active liver metastases (n = 77) achieved a median overall survival of 21.2 months, along with 12- and 18-month OS rates of 71% and 62%, respectively.²

Furthermore, at a median follow-up of 13.6 months, these patients experienced an overall response rate (ORR) of 23%, and the median duration of response (DOR) had not been reached as of the March 1, 2024, data cutoff.

The open-label, multicenter trial investigated botensilimab alone and in combination with balstilimab for the treatment of patients at least 18 years of age with histologically or cytologically confirmed metastatic or locally advanced solid tumors who had no standard therapy available. Key inclusion criteria included measurable disease per RECIST v1.1 criteria, except for patients with prostate cancer; a life expectancy of at least 3 months; an ECOG performance status of 0 or 1; and adequate organ and bone marrow reserve function.³

Patients received either botensilimab monotherapy once every 3 weeks at doses ranging from 0.1 mg/kg to 4 mg/kg for up to 2 years; botensilimab monotherapy once every 6 weeks at doses ranging from 1 mg/kg to 4 mg/kg for up to 2 years; or botensilimab once every 6 weeks at doses ranging from 0.1 mg/kg to 4 mg/kg in combination with balstilimab once every 2 weeks at 3 mg/kg.

Safety, the incidence of dose-limiting toxicities, and establishing the recommended phase 2 dose of botensilimab served as the trial’s primary end points. Secondary end points included ORR, DOR, disease control rate, progression-free survival (PFS), and OS.

Phase 2 Trial

The open-label, multicenter phase 2 study, which has completed enrollment,² included patients at least 18 years of age with histologically confirmed unresectable or metastatic CRC who received at least 1 prior chemotherapy regimen for metastatic or recurrent CRC.⁴

Patients were also required to have measurable disease per RECIST v1.1 criteria; a life expectancy of at least 12 weeks; ECOG performance status of 0 or 1; and adequate organ function.

Key exclusion criteria included MSI-H or dMMR tumors per local testing; prior treatment with anti–PD-1, anti–PD-L1, or anti–CTLA-4 therapies; prior treatment with regorafenib (Stivarga) or trifluridine/tipiracil (TAS-102; Lonsurf); partial or complete bowel obstruction within 3 months prior to enrollment; refractory ascites; liver metastases; and clinically significant cardiovascular disease.

Enrolled patients were randomly assigned to receive botensilimab at dose level 1 plus balstilimab; botensilimab at dose level 2 plus balstilimab; botensilimab monotherapy at dose level 1; botensilimab monotherapy at dose level 2; or regorafenib or TAS-102.

ORR was the trial’s primary end point. Secondary end points consisted of DOR, PFS, OS, and safety.

References

1. FDA grants Agenus Type B end-of-phase 2 meeting to discuss BOT/BAL therapy for relapsed or refractory metastatic colorectal cancer. News release. Agenus. May 16, 2024. Accessed May 16, 2024. https://investor.agenusbio.com/news/news-details/2024/FDA-Grants-Agenus-Type-B-End-of-Phase-2-Meeting-to-Discuss-BOTBAL-Therapy-for-Relapsed-or-Refractory-Metastatic-Colorectal-Cancer/default.aspx
2. Agenus announces updated phase 1 data and progress on BOT/BAL development in metastatic MSS colorectal cancer. News release. Agenus. April 12, 2024. Accessed May 16, 2024. https://investor.agenusbio.com/news/news-details/2024/Agenus-Announces-Updated-Phase-1-Data-and-Progress-on-BOTBAL-Development-in-Metastatic-MSS-Colorectal-Cancer/default.aspx
3. Fc-engineered anti-CTLA-4 monoclonal antibody in advanced cancer. ClinicalTrials.gov. Updated November 13, 2023. Accessed May 16, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03860272
4. A study of botensilimab and balstilimab for the treatment of colorectal cancer. ClinicalTrials.gov. Updated March 25, 2024. Accessed May 16, 2024. https://clinicaltrials.gov/study/NCT05608044