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

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).

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).

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%).

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).

NCT03860272.

Agenus Inc.

Agenus Inc.

M. Fakih: Honoraria (self): Guardant Health, Incyte; Advisory / Consultancy: Incyte, Seattle Genetic, GSK; Research grant / Funding (institution): Verastem, Amgen, BMS. A. Tsimberidou: Advisory / Consultancy: Diaccurate, VinceRx; Research grant / Funding (institution): Agenus, Boston Biomedical, IMMATICS, Karus Therapeutics, Novocure, OBI Pharma, Parker Institute for Cancer Immunotherapy, Tempus, Tvardi. A. El-Khoueiry: Honoraria (self): Roche genentech, Gilead, Astrazeneca, Merck, Agenus, BMS, ABL Bio, QED, Servier, Senti Biosciences; Advisory / Consultancy: Roche genentech, Gilead, Astrazeneca, Merck, Agenus, BMS, ABL Bio, QED, Servier, Senti Biosciences; Research grant / Funding (institution): Astrazeneca, Astex, Fulgent. B. Wilky: Advisory / Consultancy: Immune Design, Janssen Oncology, Eli Lilly, Novartis; Research grant / Funding (self): Agenus, ArQule, Daiichi Sankyo, Merck Sharp & Dohmn, Novartis; Travel / Accommodation / Expenses: Advenchen Laboratories, Agenus, Eli Lilly, Novartis. A. Pimentel: Advisory / Consultancy: Bristol-Myers Squibb, Foundation Medicine, Taiho Pharmaceutical; Research grant / Funding (institution): Array BioPharma; BeiGene; Bristol-Myers Squibb; Halozyme; Hoosier Cancer Research Network (Inst); Isofol Medical; Ludwig Institute for Cancer Research (Inst); Turnstone Bio. D. Mahadevan: Advisory / Consultancy: Janssen (Steering Committee); Speaker Bureau / Expert testimony: Caris, Guardant Health. A. Balmanoukian: Speaker Bureau / Expert testimony: AstraZeneca, Bristol-Myers Squibb, Genentech, Regeneron, Mirati, Merck; Research grant / Funding (institution): AbbVie, Arcus Biosciences, Genentech/Roche, Incyte, Merck Seattle Genetics, Nexcture, BioAtla, Agenus, Incyte. R. Sanborn: Honoraria (self): Amgen, AstraZeneca; Advisory / Consultancy: AstraZeneca, Blueprint Medicines, Daichi Sankyo/Eli Lilly, EMD Serono, GlaxoSmithKline, Janssen Oncology, Macrogenics, Mirati Therapeutics, Regeneron, Roche/Genentech, Sanofi/Aventis; Research grant / Funding (self): AstraZeneca, Merck; Travel / Accommodation / Expenses: AstraZeneca. G. Abou-Alfa: Advisory / Consultancy: Astellas, Astra Zeneca, Autem, Berry Genomics, BioNtech, Boehringer Ingelheim, BMS, Eisai, Exelixis, Fibriogen, Genentech/Roche, Helio, Incyte, Ipsen, Merck, Merus, Neogene, Newbridge, Novartis, QED, Servier, Tempus, Thetis, Vector, Yiviva; Research grant / Funding (self): Agenus, Arcus, Astra Zeneca, BioNtech, BMS, Elicio, Genentech/Roche, Helsinn, Parker Institute, Pertzye, Puma, QED, Yiviva. J. Moser: Advisory / Consultancy: Adagene, Amunix, Bristol-Myers Squibb, Thirona Bio, Imaging Endpoints, Boxer Capital, IQVIA, Genome Insight; Speaker Bureau / Expert testimony: Caris Life Sciences, Immunocore; Research grant / Funding (institution): NovoCure (Inst), Genentech (Inst), Alpine Immune Sciences (Inst), Amgen (Inst), Trishula Therapeutics (Inst), BioEclipse Therapeutics (Inst), FujiFilm (Inst), ImmuneSensor (Inst), Simcha (Inst), Repertoire Immune Sciences (Inst), Nektar Therapuetics (Inst), Synthorx Inc (Inst), Istari Oncology (Inst), Ideaya Biosciences (Inst), Rubius (Inst), University of Arizona (Inst), Senwha (Inst), Storm Therapeutics (Inst), Werewolf Therapeutics (Inst), Fate Therapeutics (Inst), Y-Mab (Inst). J. Grossman: Leadership role: Agenus Inc.; Shareholder / Stockholder / Stock options: Agenus Inc.; Full / Part-time employment: Agenus Inc.; Officer / Board of Directors: Agenus Inc.. K. Rosenthal: Shareholder / Stockholder / Stock options: Agenus; Full / Part-time employment: Agenus. H. Lenz: Honoraria (self): BMS, Bayer, Roche ; Advisory / Consultancy: Bayer, Merck, Roche; Travel / Accommodation / Expenses: BMS, Bayer, Merck KG; Shareholder / Stockholder / Stock options: Fulgent . All other authors have declared no conflicts of interest.