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Ref Type Journal Article
PMID (40992271)
Authors Schöffski P, Gazzah A, Trigo J, Italiano A, Gougis P, Subbiah V, Shih JY, Loong HH, Doger B, Keegan M, Jeglinski B, Andreas K, Cho BC
Title 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.
Journal Vol Issue Date Pages Journal Short Title
ESMO open 10 10 2025 Sep 23 105543 ESMO Open
URL
Abstract Text 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).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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET mutant medullary thyroid carcinoma sensitive Zeteletinib Phase I Actionable In a Phase I trial, Zeteletinib (DS-5010) treatment led to an objective response rate (ORR) of 28% (28/101), disease control rate (DCR) of 58% (59/101), median progression-free survival (mPFS) of 7.16 mo, and median duration of response (mDOR) of 11.10 mo in patients with RET-altered advanced solid tumors, with an ORR of 30% (8/27, all PR), DCR of 74% (20/27), mPFS of 12.75 mo, and mDOR of 19.15 mo in medullary thyroid cancer patients harboring a RET mutation including M918T (PMID: 40992271; NCT03780517). 40992271
RET fusion lung non-small cell carcinoma sensitive Zeteletinib Phase I Actionable In a Phase I trial, Zeteletinib (DS-5010) treatment led to an objective response rate (ORR) of 28% (28/101), disease control rate (DCR) of 58% (59/101), median progression-free survival (mPFS) of 7.16 mo, and median duration of response (mDOR) of 11.10 mo in patients with RET-altered advanced solid tumors, with an ORR of 28% (17/61), DCR of 59% (36/61), mPFS of 6.18 mo, and mDOR of 10.17 mo in patients with non-small cell lung cancer harboring a RET fusion (PMID: 40992271; NCT03780517). 40992271