LBA O-9 Botensilimab, a novel innate/adaptive immune activator, plus balstilimab (anti-PD-1) for metastatic heavily pretreated microsatellite stable colorectal cancer

Abstract

Botensilimab (BOT) promotes optimized T cell priming, activation and memory formation by strengthening antigen presenting cell/T cell co-engagement. As a fragment crystallizable (Fc)-enhanced next-generation anti–cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody, BOT also promotes intratumoral regulatory T cell depletion via enhanced Fc gamma receptor signaling and activation on natural killer cells and macrophages. Further, BOT is specifically engineered to avoid complement binding and complement-mediated toxicities including hypophysitis. This analysis presents results from patients with microsatellite stable colorectal cancer (MSS CRC) treated with BOT + balstilimab (BAL; an anti-programmed cell death 1 [PD-1] antibody), in an expanded phase IA/B study; NCT03860272. Patients with metastatic MSS CRC received BOT at 1 or 2 mg/kg every 6 weeks (Q6W) + BAL 3 mg/kg every 2 weeks and were evaluable with ≥1 Q6W tumor imaging assessment. Primary and secondary endpoints include incidence of adverse events (AE), objective response rate (ORR), disease control rate (DCR; patients with a best overall response of either stable disease [SD] or a complete [CR] or partial response [PR]), duration of response (DOR), progression free survival (PFS), and overall survival (OS). Enrollment is ongoing. Forty-one evaluable patients are included in this analysis. Patients were heavily pretreated and the median number of prior lines of therapy was 4 (range, 2-10) including 34% with prior immunotherapy. ORR measured 24% (10/41), DCR was 73% (30/41), and DOR ranged from 0.0+-17.0+ months. Median follow-up is 5.8 months (range, 1.6-24.4). In patients with no history of liver metastases or status post resection or ablation of liver metastases without recurrence (n=24), ORR was 42% (10/24) and DCR was 96% (23/24), with eight of ten responses ongoing. Additionally, a patient with SD by RECIST 1.1 developed an ongoing metabolic CR by PET with CEA normalization. In responders, metastatic sites included soft tissue, peritoneum, retroperitoneum, pleural effusions, bone, lungs, and lymph nodes. Of the ten responders, five had RAS mutations (4 KRAS, 1 NRAS), none had BRAF mutations, one had a TMB of ≥10 mutations/Mb (TMB=10), one was reported PD-L1 positive (50% combined positive score by IHC 22C3 pharmDx, Agilent) and none had POLE mutations. The safety profile in all 41 patients is favorable with no cases of hypophysitis. Most AEs were grade 1 or 2; grade 3 treatment-related AEs (TRAEs) occurred in 24% of patients, with no grade 4 or 5 TRAEs reported. Diarrhea/colitis was the only grade 3 TRAE occurring in more than one patient (10%). Eight patients (20%) discontinued BOT and four patients (10%) discontinued BOT + BAL due to a TRAE. Immune and genomic analyses are ongoing. BOT + BAL demonstrates unprecedented activity for immunotherapy in heavily pretreated patients with metastatic MSS CRC and manageable safety, consistent with its design. The ORR and DOR, including compelling efficacy in patients without liver metastases, are informing phase 2/3 study designs.