An Fc-enhanced anti-CTLA4 (botensilimab) designed to engage activating FcγRs of NK cells and APCs was combined with anti-PD-1 (balstilimab) in 148 patients with treatment-refractory MSS mCRC. Serious (grade 3+) TRAEs occurred in 35% of patients; the most common immune-related TRAEs (diarrhea and colitis) were well managed with infliximab (anti-TNF). The ORR was 17%, 45% of patients experienced SD, and the mPFS was 3.5 months. Active liver metastasis (LM) was a significant predictor of non-response. While the ORR was 0% and the mPFS was 1.4 months in patients with LM , the ORR in patients without LM was 22%, with an mPFS of 4.1 months.
Contributed by Morgan Janes
ABSTRACT: Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6_months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n_=_101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7_months-NR), and median PFS was 3.5_months (95% CI, 2.7-4.1_months), at a median follow-up of 10.3_months (range, 0.5-42.6_months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .
Author Info: (1) Beth Israel Deaconess Medical Center, Boston, MA, USA. (2) Dana-Farber Cancer Institute, Boston, MA, USA. (3) City of Hope Comprehensive Cancer Center, Duarte, CA, USA. (4) The
Author Info: (1) Beth Israel Deaconess Medical Center, Boston, MA, USA. (2) Dana-Farber Cancer Institute, Boston, MA, USA. (3) City of Hope Comprehensive Cancer Center, Duarte, CA, USA. (4) The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Agenus, Inc., Lexington, MA, USA. (6) HonorHealth Research Institute, Scottsdale, AZ, USA. (7) University of Colorado Cancer Center, Aurora, CO, USA. (8) Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA. (9) The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. (10) The Angeles Clinic and Research Institute, Los Angeles, CA, USA. (11) Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, OR, USA. (12) Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA. (13) Memorial Sloan Kettering Cancer Center, New York, NY, USA. Weill Medical College at Cornell University, New York, NY, USA. Trinity College Dublin, Dublin, Ireland. (14) Memorial Sloan Kettering Cancer Center, New York, NY, USA. Weill Medical College at Cornell University, New York, NY, USA. (15) Beth Israel Deaconess Medical Center, Boston, MA, USA. (16) HonorHealth Research Institute, Scottsdale, AZ, USA. (17) HonorHealth Research Institute, Scottsdale, AZ, USA. (18) Agenus, Inc., Lexington, MA, USA. (19) Agenus, Inc., Lexington, MA, USA. (20) Agenus, Inc., Lexington, MA, USA. (21) Agenus, Inc., Lexington, MA, USA. (22) Agenus, Inc., Lexington, MA, USA. (23) Agenus, Inc., Lexington, MA, USA. (24) Dartmouth Cancer Center, Lebanon, NH, USA. (25) Anglia Ruskin University, Cambridge, UK. justin.stebbing@aru.ac.uk. (26) University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA. (27) Agenus, Inc., Lexington, MA, USA. Providence Saint John's Cancer Institute, Santa Monica, CA, USA. (28) University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA. elkhouei@med.usc.edu.
