Results from an expanded phase 1 trial of botensilimab, a multifunctional anti-CTLA-4, plus balstilimab (anti-PD-1) for metastatic heavily pretreated microsatellite stable colorectal cancer

Document Type

Abstract

Publication Date

6-1-2023

Keywords

oregon; chiles

Abstract

Background Botensilimab (BOT), a multifunctional Fc-enhanced anti-CTLA-4 antibody has previously shown durable objective responses in 9 immunotherapy-resistant / ‘cold’ tumors. BOT is designed to enhance T cell priming, activation, and memory formation; to deplete intratumoral T regulatory cells and activate antigen presenting cells; and to improve safety by reducing complement fixation. Here we present updated efficacy and safety data from an ongoing expanded phase Ib study investigating BOT ± balstilimab (BAL; anti-PD-1) in patients with refractory metastatic microsatellite stable colorectal cancer (MSS or non-microsatellite instability-high CRC). Methods Patients received BOT 1 or 2 mg/kg every 6 weeks (Q6W) + BAL 3 mg/kg Q2W. RECIST 1.1 imaging assessments were performed at least once every 6 weeks. Primary and secondary endpoints included adverse events, objective response rate (ORR), disease control rate (DCR; best response of complete response [CR], partial response [PR], or stable disease [SD]), progression-free survival (PFS), and overall survival (OS). Results As of May 26, 2023, a total of 101 MSS CRC patients were enrolled and received at least one dose of combination treatment (intent-to-treat population; ITT). Eighty-seven were evaluable for efficacy (at least one post-baseline 6-week scan): 69 with no active liver metastases and 18 with active liver metastases. In the ITT population (N=101), median age was 54 years (range, 25–82); median number of prior therapies was 4 (range, 1–10); 25% received prior immunotherapy; 58/100 (58%) had RAS mutations, 3/71 (4%) BRAF mutations, and only 3/76 (4%) had a tumor mutational burden (TMB) of >10 mutations/Mb (none > 13). In the evaluable population without active liver metastases (n=69), RECIST 1.1 confirmed ORR was 23% (95% CI, 14–35) including 1 CR, 15 PRs, and 39 SDs; DCR was 80% (95% CI, 68–88) with 11/16 (69%) responses ongoing. The 12-month OS was 74% (95% CI, 59–84), and median OS was 20.9 months (95% CI, 20.9–NR) with a median follow-up of 9.8 months (range, 1.4–36.5). Of the 16 responders, 11/16 (69%) had RAS mutations (8 KRAS, 3 NRAS) and 1/14 (7%) had BRAF mutations. In all efficacy evaluable patients (n=87), median OS was 20.9 months (95% CI, 10.6–NR), with a median follow-up of 9.3 months (range, 1.4–36.5). The safety profile remains favorable and consistent with previously reported data across tumor types. Treatment-related adverse events (TRAEs) of any grade occurred in 88% of patients, 37% grade 3, 2% grade 4, and no treatment-related deaths. Most common all-grade TRAEs included immune-mediated diarrhea/colitis (40%; 16% grade 3; 1% grade 4), fatigue (32%), and decreased appetite (27%). Conclusions In patients with heavily pretreated metastatic MSS CRC and longer follow-up, the combination of BOT + BAL continues to show durable responses and prolonged overall survival across all subgroups, and a favorable safety profile with no new signals. This study is ongoing, and a randomized global phase 2 trial in MSS CRC patients is actively enrolling (NCT05608044). Clinical trial identification NCT03860272.

Clinical Institute

Cancer

Clinical Institute

Digestive Health

Department

Oncology

Department

Gastroenterology

Comments

Bullock AJ, Fakih MG, Gordon MS, Tsimberidou AM, El-Khoueiry AB, Wilky BA, Pimentel A, Margolin KA, Mahadevan D, Balmanoukian AS, Sanborn RE, Schwartz GK, Abou-Alfa GK, Bockorny B, Moser JC, Sharma S, Grossman JE, Rosenthal K, O’Day SJ, Lenz H-J, Schlechter BL. ESMO 25th Annual World Congress on Gastrointestinal Cancer; June 28-July 1; Barcelona, Spain. 2023: LBA-4.

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