FDA Grants Fast Track Designation to Botensilimab/Balstilimab for MSS/dMMR mCRC Treatment

The combination of botensilimab and balstilimab is moving down the FDA pipeline and may become an approved treatment for non-microsatellite instability-high and deficient mismatch repair metastatic colorectal cancer in the future.

The FDA has granted a fast track designation to the combination of botensilimab (AGEN1181) and balstilimab (AGEN2034) for the treatment of patients with non-microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) metastatic colorectal cancer (CRC) who have no active liver involvement.1

“This is a modified or second-generation combination of a CTLA-4 inhibitor and a PD-1 inhibitor, so checkpoint inhibitors, for refractory colorectal cancer. In the past, conventional checkpoint inhibitors have been universally ineffective in microsatellite stable colorectal cancer. This is an agent, the CTLA-4 antibody, which is modified to decrease complement fixation and increase NK cell activation, which hopefully can improve the safety profile and improve the activity of the drug,” Benjamin Schlechter, MD, FACS, senior physician at Dana-Farber Cancer Institute, told Targeted Oncology™, in an interview.

The combination of botensilimab and balstilimab is being investigated against either trifluridine (FTD) plus tipiracil (TPI; Lonsurf) or regorafenib (Stivarga) in an open-label, phase 2 multicenter study (NCT05608044). The study is assessing the efficacy and safety of the combination with the primary end point of objective response rate (ORR). The secondary end points of the study include duration of response (DOR), progression-free survival (PFS), overall survival (OS), and the number of patients who experience treatment-emergent adverse events (TEAEs).2

In a prior phase 1 study (NCT03860272), treatment with botensilimab plus balstilimab achieved an ORR of 22% (95% CI, 12%-35%) in patients with microsatellite stable (MSS) CRC. At 12 months, the survival rate in the study was 61% (95% CI, 42%-75%). In comparison, standard-of-care therapy produces an ORR of only 1%-2% and a 12-month survival rate of about 25%. Moreover, responses to botensilimab plus balstilimab in the study were durable with 69% of patients having had an ongoing response at the time of data cutoff. The median DOR was not reached.3

[3d rendered illustration of bowel cancer 3D illustration]  Image Credit © [appledesign] - [Adobe Stock]

Image Credit: © appledesign [stock.adobe.com]

Up to 230 patients with mCRC will be enrolled in the phase 2 study. Patients are required to have a histologically confirmed diagnosis of mCRC, be MSS and dMMR, and have received at least 1 prior chemotherapy regimen for mCRC. Patients are also required to have measurable disease per RECIST 1.1, a life expectancy of at least 12 weeks, and an ECOG performance status of 0 or 1, as well as adequate organ function.2

According to Agenus Inc, a future approval of botensilimab plus balstilimab for the non-MSI-H or MSS and dMMR mCRC population would offer a new option to patients who are heavily pretreated, and resistant or intolerant to fluoropyrimidine, oxaliplatin, and irinotecan. In addition, patients who have received a VEGF inhibitor, an EGFR inhibitor and/or a BRAF inhibitor may benefit from further development of botensilimab plus balstlimab.1

"We are pleased that the FDA has granted fast track designation for the combination of botensilimab with balstilimab in patients with non-MSI-H colorectal cancer, recognizing the high unmet medical need in this population," said Steven O’Day, MD, chief medical officer of Agenus, in a press release. "The fast track designation offers important benefits, including the potential eligibility for a priority review, and we will be working with the FDA and all key stakeholders to rapidly advance the botensilimab/ balstilimab combination in colorectal cancer as well as other solid tumor indications."


1. Agenus receives fast track designation for botensilimab and balstilimab in colorectal cancer. News release. Agenus Inc. April 17, 2023. Accessed April 18, 2023. https://bit.ly/3L7xZo4

2. A study of botensilimab and balstilimab for the treatment of colorectal cancer. ClinicalTrials.gov. Updated April 17, 2023. Accessed April 18, 2023. https://clinicaltrials.gov/ct2/show/NCT05608044?term=botensilimab&draw=2&rank=4

3. El-Khoueiry A, Fakih M, Gordon MS, et al. 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):LBA8. doi:10.1200/JCO.2023.41.4_suppl.LBA8

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