Updated Phase 1 Data Support Further Research of Botensilimab/Balstilimab in Refractory MSS CRC

Steven O’Day, MD

Updated findings from a phase 1 trial (NCT03860272) evaluating botensilimab (AGEN1181) plus balstilimab (AGEN2034) for the treatment of patients with refractory microsatellite-stable (MSS)/mismatch repair–proficient (pMMR) metastatic colorectal cancer (mCRC) show that the combination elicited 12- and 18-month overall survival (OS) rates of 71% and 62%, respectively.¹

Among 77 patients in the phase 1 trial with refractory MSS mCRC who did not have active liver metastases, at a median follow-up of 13.6 months and a data cutoff of March 1, 2024, the overall response rate (ORR) was 23%. In the 18 responders, the median duration of response (DOR) was not yet reached. Furthermore, the median OS was 21.2 months among the overall population.

“These results underscore the potential of botensilimab/balstilimab in mCRC, the second leading cause of cancer mortality in the United States,” Steven O’Day, MD, chief medical officer at Agenus, stated in a press release. “We continue to work expeditiously to bring this promising combination to patients in need.”

Botensilimab is a novel, Fc-enhanced, next-generation anti–CTLA-4 antibody and innate/adaptive immune activator that promotes optimized T-cell priming, activation, and memory formation by strengthening co-engagement between antigen-presenting cells and T cells.² The agent also reduces complement fixation and promotes intratumoral T-regulatory cell (Treg) depletion. In the phase 1a/1b trial, botensilimab was combined with balstilimab, a PD-1 inhibitor, in patients with MSS mCRC.

An ongoing phase 2 trial (NCT05608044) of botensilimab monotherapy vs botensilimab plus balstilimab vs botensilimab plus investigator’s choice of standard-of-care therapy (either regorafenib [Stivarga] or trifluridine/tipiracil [Lonsurf]) in patients with refractory mCRC has completed enrollment. ORR serves as the primary end point of this trial, and key secondary end points include DOR, progression-free survival, OS, and adverse effects (AEs).³

Agenus is planning discussions with the FDA about interim data from the phase 2 trial and plans to submit phase 2 efficacy data, including response durability, and updated survival data from the phase 1 trial, to a major medical conference in the second half of 2024.¹ Pending meetings between Agenus and the FDA, Agenus also plans to submit a biologics license application for botensilimab plus balstilimab for patients with MSS CRC later in 2024.

Previously, the investigator-initiated, phase 2 NEST-1 trial (NCT05571293) evaluated botensilimab plus balstilimab as neoadjuvant therapy in patients with resectable MSS CRC with MRR-deficient (dMMR)/pMMR status.⁴ In this trial, patients receive botensilimab at 75 mg and balstilimab at 240 mg on day 0, followed by balstilimab at 240 mg at week 2, followed by surgery.

Topline results from NEST-1 showed that among the 9 patients with MSS CRC, 6 achieved pathological complete response (CR), defined as a 50% or greater reduction in tumor size, and 2 achieved CR. Furthermore, in 3 patients with microsatellite instability–high (MSI-H) CRC, 3 achieved major pathologic response, defined as a 98% or greater reduction in tumor size, and 2 achieved a CR. No patients needed to delay surgery because of treatment-related AEs.

Among the 7 patients with ctDNA at screening, 100% cleared circulating tumor DNA (ctDNA). Additionally, 100% of the 11 patients tested after surgery remained minimal residual disease/ctDNA negative for more than 30 cumulative draws.

Immunohistochemistry/immunofluorescence testing conducted post-treatment showed that the combination produced robust Treg depletion, T-cell infiltration, and repolarization of dendritic and myeloid cells. NEST-1 investigators concluded that the deep pathological responses and clinical downstaging observed in this trial support the reduction of reliance on surgery and/or adjuvant chemotherapy in future CRC research, and that neoadjuvant botensilimab plus balstilimab is a safe and active combination in patients with pMMR/MSS and dMMR/MSI-H CRC.

References

1. Agenus announces updated phase 1 data and progress on BOT/BAL development in metastatic MSS colorectal cancer. News Release. Agenus, Inc. April 12, 2024. Accessed April 12, 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
2. El-Khoueiry AB, 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). doi:10.1200/JCO.2023.41.4_suppl.LBA8
3. A study of botensilimab and balstilimab for the treatment of colorectal cancer. ClinicalTrials.gov. Updated March 25, 2024. Accessed April 12, 2024. https://clinicaltrials.gov/study/NCT05608044?term=NCT05608044&rank=1
4. Kasi PM, Jafari MD, Yeo H, et al. Neoadjuvant botensilimab plus balstilimab in resectable mismatch repair proficient and deficient colorectal cancer: NEST-1 clinical trial. J Clin Oncol. 2024;42(suppl 3):117. doi:10.1200/JCO.2024.42.3_suppl.117