BOS172738, a selective RET inhibitor, for the treatment of patients with RET-altered tumors including RET-fusion-positive non-small-cell lung cancer and RET-mutant medullary thyroid cancer: a phase I dose-escalation/ expansion multicenter study

Korte inhoud:BACKGROUND: This phase I dose-escalation (part A)/dose-expansion (part B) study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of BOS172738 [a selective rearranged during transfection (RET) inhibitor] in patients with RET-altered tumors including RET-fusion-positive non-small-cell lung cancer (NSCLC) and RET-mutant medullary thyroid cancer (MTC). PATIENTS AND METHODS: Adult patients with advanced solid tumors with RET gene alteration received BOS172738 10-150 mg orally once daily in part A, and the recommended phase II dose (RP2D) in part B. Primary endpoints included safety (Common Terminology Criteria for Adverse Event v.4.03) and tolerability, and in part A, determining the maximum tolerated dose (MTD) and RP2D. Secondary endpoints included objective response rate (ORR; RECIST v.1.1), disease control rate (DCR), progression-free survival, duration of response (DoR), and pharmacokinetic assessments. Exploratory endpoints involved pharmacodynamic biomarkers. RESULTS: A total of 117 patients were enrolled (67 part A, 50 part B). Patients had advanced disease, were heavily pretreated, and 21% had brain metastases. In part A, three patients had dose-limiting toxicities, but MTD was not reached, with 75 mg recommended for part B. At final cut-off (November 2023), 85% had BOS172738-related treatment-emergent adverse events [54% grade ≥3, most common: blood creatine phosphokinase increased (25%), neutrophil count decreased (10%), and anemia (9%)]. In RET-fusion-positive NSCLC, 28% had an objective response and 59% disease control, with a median DoR (mDoR) of 10.17 months. In RET-mutant MTC, 30% had an objective response, and DCR was 74%, with a mDoR of 19.15 months. CONCLUSIONS: BOS172738 showed preliminary efficacy and a manageable safety profile in RET-altered tumors, including those resistant to prior therapies and in patients with brain metastases.

Jaar van publicatie:2025

Toegankelijkheid:Open

Reviewstatus:Peerreview