Phase I Study of Bms-986299, an NLRP3 Agonist, As Monotherapy and in Combination With Nivolumab and Ipilimumab in Patients With Advanced Solid Tumors

Authors

Blessie E Nelson
Shaun O'Brien
Rahul A Sheth
David S Hong
Aung Naing
Xiaoping Zhang
Amy Xu
Lora Hamuro
Rasika Suryawanshi
Derrick McKinley
Ruslan D Novosiadly
Sarina A Piha-Paul

Publication Date

1-16-2025

Journal

Journal of Immunotherapy of Cancer

Abstract

Purpose: BMS-986299 is a first-in-class, NOD-, LRR-, and pyrin-domain containing-3 (NLRP3) inflammasome agonist enhancing adaptive immune and T-cell memory responses.

Materials and methods: This was a phase-I (NCT03444753) study that assessed the safety and tolerability of intra-tumoral BMS-986299 monotherapy (part 1A) and in combination (part 1B) with nivolumab, and ipilimumab in advanced solid tumors. Reported here are single-center results.

Results: 36 patients were enrolled, with breast (31%), colorectal (17%), and head and neck (14%) being the more commonly enrolled cancers. Most patients (58%) had received prior immunotherapy. Therapy was well-tolerated, with G1-G2 fever (70%), neutrophilia (36%), and leukocytosis (33%) being the most common treatment-related adverse events with one case of G4 interstitial nephritis and one case of G3 hepatotoxicity and G3 colitis. Intratumoral BMS-986299 monotherapy resulted in dose-dependent increases in systemic exposure with increase in tumor CTLs (67%), CD4+ TILs (63%), along with notable above twofold increases in serum IL-1B, G-CSF and IL-6 at doses above 2000 µg. Systemic BMS-986299 exposure was positively associated with systemic cytokine elevation for G-CSF and IL-6. No antitumor activity was noted in BMS-986299 monotherapy cohort. However, in the combination therapy cohort (BMS-986299+nivolumab+ipilimumab), overall objective response rate was 10%, with confirmed PRs observed in TNBC, hormone receptor-positive, human epidermal growth factor receptor 2 negative breast cancer, and cutaneous squamous cell carcinoma.

Conclusion: BMS-986299 in combination with immune checkpoint inhibitors demonstrated manageable toxicities, good tolerability, and promising antitumor activity in certain cancer types.

Trial registration number: NCT03444753.

Keywords

Humans, Female, Middle Aged, Male, Aged, Neoplasms, Ipilimumab, Nivolumab, Antineoplastic Combined Chemotherapy Protocols, Adult, NLR Family, Pyrin Domain-Containing 3 Protein, Aged, 80 and over, Intratumoral, Combination therapy, Immune Checkpoint Inhibitor, Solid tumor, Tumor microenvironment - TME

Comments

This article has been corrected. See J Immunother Cancer. 2025 May 2;13(5):e010013corr1.

DOI

10.1136/jitc-2024-010013

PMID

39824531

PMCID

PMC11749293

PubMedCentral® Posted Date

1-16-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes