Initial Results From Phase 1/2 Study of the RETSelective Inhibitor Vepafestinib in Patients With RETAberrant Solid Tumors

Document Type

Conference Proceeding

Publication Date

10-1-2025

Publication Title

J Thorac Oncol

Keywords

biological marker, vepafestinib, adult, aged, antineoplastic activity, backache, cancer inhibition, Caucasian, clinical article, conference abstract, drug dose escalation, drug therapy, female, headache, human, malaise, male, maximum tolerated dose, multicenter study, nausea, non small cell lung cancer, pharmacokinetics, phase 1 clinical trial, side effect, solid tumor, special situation for pharmacovigilance, thyroid cancer, treatment response time

Abstract

Introduction: Cancers with RET alterations have limited next-gener- ation targeted therapeutic options. Vepafestinib (TAS0953/HM06), a RET-selective inhibitor, is being evaluated in patients with locally advanced or metastatic solid tumors harboring RET alterations in MARGARET (NCT04683250), an open-label, single-arm, phase 1/2, first-in-human study. Here, we present the preliminary phase 1 safety and antitumor-activity results (data cutoff date: November 15, 2024). Methods: Phase 1 consists of dose escalation (DE; for patients with solid tumors harboring RET alterations) and dose expansion (EX; for patients with locally advanced or metastatic RET-fusion-positive nonsmall- cell lung cancer [NSCLC]). In EX, patients naive to RET-selective inhibitors and systemic anticancer treatment were enrolled in cohort 1 (C1), and patients pretreated with RET-selective inhibitors were enrolled in cohort 2 (C2). The initial dose in DE was 20 mg BID, and accelerated titration was performed. The primary endpoints were the maximum tolerated dose (MTD) for DE and the recommended phase 2 dose in EX. The secondary endpoints included safety, tolerability, antitumor activity, pharmacokinetics, and predictive biomarkers. Results: As of November 15, 2024, 32 patients were enrolled for DE (Asian: 41%, White: 50%, other: 9%), and 14 patients (C1: 4, C2: 10 patients) for EX (Asian: 100%). The DE tumor types were lung (n=23), thyroid (n=8), and pancreatic (n=1) cancer. The vepafestinib dose was escalated to 650 mg BID. Dose-limiting toxicities (DLTs) occurred in two of the three patients at 650 mg BID, and 500 mg BID was deemed the MTD. The DLTs were grade 3 headache (n=1) and grade 3 back pain (n=1). The most common treatment-emergent adverse events (TEAEs) in DE (any grade, grade >3) were headache (25%, 6%), nausea (25%, 0%), and malaise (19%, 3%). Confirmed/unconfirmed partial responses (PRs) in DE were reported in four of 32 patients: a patient with RET-fusion-positive NSCLC who was pretreated with an RET-selective inhibitor, a patient with RET-fusionpositive thyroid cancer who was pretreated with an RET-selective inhibitor, and two patients who were naive to RET-selective inhibitors and had fusion-positive NSCLC. In EX, 500 mg vepafestinib was administered BID. The most common TEAEs (any grade, grade >3) in EX were headache (79%, 7%), nausea (29%, 0%), and malaise (21%, 0%). In C1, PRs were observed in two of four patients; the disease control rate (DCR) and median time to response (mTTR) were 50% and 1.3 months, respectively. On C2, PRs were observed in three of 10 patients, and the DCR and mTTR were 80% and 1.4 months, respec- tively. Conclusions: Vepafestinib was well tolerated and displayed preliminary antitumor activity in patients with solid tumors harboring RET alterations, both in treatment-naive and RET-selective inhibitorpretreated cancers, indicating encouraging therapeutic potential. Enrollment in this trial continues.

Volume

20

Issue

10

First Page

S493

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