Botensilimab Plus Balstilimab in Heavily Pretreated MSS CRC: Phase 1A/1B Results

Botensilimab (BOT) enhances the priming, activation, and formation of memory in T cells by reinforcing the co-engagement of antigen-presenting cells and T cells. BOT, an Fc-enhanced next-generation anti-CTLA-4 antibody, also facilitates the depletion of regulatory T cells within the tumor and minimizes complement fixation. The outcomes of individuals diagnosed with microsatellite stable colorectal cancer who underwent treatment with bowel obstruction therapy and bile acid malabsorption were showcased in an extended phase 1a/1b clinical trial registered under NCT03860272. Metastatic patients diagnosed with microsatellite stable colorectal cancer (MSS CRC) were administered BOT at 1 or 2 mg/kg every 6 weeks (Q6W) and Balstilimab (BAL) at 3 mg/kg every 2 weeks. Transitioning from monotherapy to combination therapy was authorized as a rescue measure, and utilizing a fixed-dosing regimen consisting of 150 milligrams administered bi-weekly on alternate weeks and 450 milligrams administered every three weeks.

Fifty-nine patients who received combination therapy were assessed for efficacy and safety. These patients underwent at least one imaging assessment every six weeks as of May 19th, 2022. The group included one patient who required rescue therapy and one who received a fixed dose. The median age of the patients was 57 years (range 25-83), with 58% being female. Moreover, 76% of the patients had received at least three prior lines of therapy, including prior immunotherapy in 34% of the cases. The median duration of follow-up was 6.4 months, with a range of 1.6 to 29.5 months. The objective response rate (ORR) was 22% (95% CI, 12-35) in all patients. The disease control rate (DCR) was 73% (95% CI, 60-84). The median duration of response (DOR) was not reached (NR), with 9 out of 13 ongoing responses. The 12-month overall survival rate was 61% (95% CI, 42-75), and the median overall survival was not reached. Of the 13 respondents, 9 exhibited mutations in RAS (7 KRAS and 2 NRAS), while none had mutations in BRAF. Moreover, none of the 10 respondents had a TMB of ≥10 mutations/Mb, and only 1 out of 7 had a positive PD-L1 status (≥1% combined positive score). A dose-dependent subgroup analysis was performed on the administration of BOT.

Among the 8 patients who received a dosage of 1 milligram per kilogram, the overall response rate (ORR) was 38%, with a 95% confidence interval (CI) ranging from 9% to 76%. The disease control rate (DCR) was 100% among all eight patients, with a 95% CI ranging from 63% to 100%. In the 50 patients who received 2 milligrams per kilogram, the ORR was 20%, with a 95% CI ranging from 10% to 34%. The DCR was 70% among 35 out of 50 patients, with a 95% CI ranging from 55% to 82%. The incidence of treatment-related adverse events (TRAEs) of all grades was observed in 88% of patients, with grade 3 events occurring in 32% and grade 4 events in 2% of patients. The sole grade 3/4 treatment-related adverse event (TRAE) that manifested in over three patients was diarrhea/colitis, with 15% of patients experiencing grade 3 and 2% experiencing grade 4. The prevailing grade 3 treatment-related adverse events (TRAEs) apart from diarrhea/colitis encompassed fatigue (5%) and pyrexia (5%). No grade 5 treatment-related adverse events (TRAEs) were documented. Fifteen percent of patients experienced a treatment-related adverse event (TRAE) that resulted in the discontinuation of botulinum toxin (BOT) alone. At the same time, 12% had a TRAE that led to the discontinuation of both BOT and baclofen (BAL). In patients with heavily treated metastatic microsatellite stable colorectal cancer, the combination of bowel obstruction treatment and bowel adhesion lysis exhibited encouraging clinical efficacy with long-lasting responses. Furthermore, the treatment was well-tolerated and did not result in any novel immune-mediated safety concerns. A comprehensive presentation, including a larger patient cohort, subgroup analyses, and supplementary translational data, will be delivered during the meeting. A randomized phase 2 clinical trial currently enrolls patients with microsatellite stable colorectal cancer (MSS CRC) (NCT05608044).

Source: https://meetings.asco.org/abstracts-presentations/215759

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03860272

Anthony B. El-Khoueiry, Marwan Fakih, Michael S. Gordon, Apostolia Maria Tsimberidou, Andrea J. Bullock, Breelyn A. Wilky, Jonathan C. Trent, Kim Allyson Margolin, Daruka Mahadevan, Ani Sarkis Balmanoukian, Rachel E. Sanborn, Gary K. Schwartz, Bruno Bockorny, Justin C Moser, Joseph Elan Grossman, Waldo Ignacio Ortuzar Feliu, Katherine Rosenthal, Steven O’Day, Heinz-Josef Lenz, Benjamin L. Schlechter/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 41, 2023 (suppl 4; abstr LBA8) DOI10.1200/JCO.2023.41.4_suppl.LBA8