A phase 2/3 randomized study of BMS-986504 with nab-paclitaxel (nab-P) and gemcitabine (GEM) in first-line (1L) metastatic pancreatic ductal adenocarcinoma (PDAC) with homozygous <i>MTAP</i> deletion ( <i>MTAP</i> -del): MountainTAP-30.

Abstract

TPS796 Background: MTAP -del is a genetic alteration found in 10–15% of all cancers and 20–25% of patients (pts) with PDAC, making this alteration a promising therapeutic target particularly for pts with PDAC. Pts with homozygous MTAP -del cancers have a worse prognosis compared to those with MTAP –wild type (WT) cancers. BMS-986504 is a first-in-class MTA-cooperative PRMT5 inhibitor that selectively binds to and inhibits the PRMT5-MTA complex, a synthetic lethal target in MTAP -del cancer cells, while sparing MTAP –WT cells. In the first-in-human phase 1 CA240-0007 study in advanced, unresectable or metastatic solid tumors with homozygous MTAP -del, BMS-986504 was well tolerated and demonstrated clinical activity in heavily pretreated pts across multiple tumor types including PDAC. Among clinical activity-evaluable pts with PDAC (n = 35; data cutoff, 7 Feb 2025), the objective response rate (ORR) and disease control rate were 17% and 69%, respectively; median duration of response (DOR) was not reached (95% CI, 4.8–not reached). Among patients with PDAC treated with BMS-986504 400 mg and 600 mg QD, the ORR was 25%. MountainTAP-30 (NCT07076121) is a global, randomized phase 2/3 study designed to evaluate the efficacy and safety of BMS-986504 + nab-P/GEM vs placebo + nab-P/GEM in pts with 1L metastatic PDAC with MTAP -del. Methods: Adults with previously untreated metastatic PDAC with confirmed homozygous MTAP -del or MTAP loss, ≥ 1 measurable lesion per RECIST v1.1, and ECOG PS ≤ 1 are eligible for enrollment. Pts with current or history of malignancy within 2 years of screening, active brain metastases, select cardiac abnormalities, or prior PRMT5 or MAT2A inhibitor treatment will be excluded. If clinically indicated per investigator discretion, pts may receive 1 cycle of nab-P/GEM in the metastatic setting prior to randomization and must have not progressed or discontinued due to toxicity. In phase 2, pts will be randomized 2:2:1:1 to receive BMS-986504 (1 of 2 doses) QD + nab-P/GEM or placebo equivalents of BMS-986504 QD + nab-P/GEM. In phase 3, pts will be randomized 1:1 to receive the optimal phase 2 dose of BMS-986504 + nab-P/GEM or placebo + nab-P/GEM. The primary endpoint for phase 2 is progression-free survival (PFS) by RECIST v1.1 per investigator assessment. Dual primary endpoints for phase 3 are PFS by RECIST v1.1 per blinded independent central review and overall survival. Secondary endpoints include ORR, DCR, duration of response, and time to response by RECIST v1.1. MountainTAP-30 is currently recruiting. Clinical trial information: NCT07076121 .