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Ref Type abstract
PMID
Authors Patrick Schoffski, Byoung Chul Cho, Antoine Italiano, Herbert H. F. Loong, Christophe Massard, Laura Medina Rodriguez, Jin-Yuan Shih, Vivek Subbiah, Loic Verlingue, Karen Andreas, Craig T. Basson, Alicia Clawson, Peter T.C. Ho, Shelley Knight, Anita Scheuber, Mitchell Keegan
Title BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: Phase 1 study results
Journal Vol Issue Date Pages Journal Short Title
Journal of Clinical Oncology 39 15_Suppl May 28, 2021
URL https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.3008
Abstract Text Background: RET (REarranged during Transfection) gene alterations (mutations and fusions) leading to constitutive kinase activity are identified as drivers of disease progression in multiple tumor types, including non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). BOS172738 is an investigational, potent, selective oral RET kinase inhibitor. This next-generation inhibitor was designed with nanomolar potency against RET and >300-fold selectivity against vascular endothelial growth factor receptor 2, to maximize the potential therapeutic window. Methods: NCT03780517 is a phase 1 study consisting of a dose-escalation and dose-expansion phase. During the escalation, 67 patients with RET-altered advanced solid tumors received once-daily oral doses of BOS172738 (10-150 mg). Intra-patient dose escalation was allowed as was over-accrual to dose levels deemed to be safe. Study endpoints were safety (CTCAE v. 4.03), tolerability and confirmed overall response rate (ORR; RECIST 1.1). The data cutoff was Dec. 11, 2020. Results: BOS172738 exhibited a favorable safety profile (n=67) for long-term administration with most treatment-emergent adverse events (TEAEs) classified as grade ≤2 and deemed unrelated to drug. The most common TEAEs were creatinine phosphokinase (CPK) increase (54%), dyspnea (34%), facial edema, aspartate aminotransferase elevation, anemia (25% each), neutropenia, diarrhea (22% each), fatigue (21%), and constipation (20%). BOS172738 was not associated with hypertension or significant hepatoxicity. BOS172738 demonstrated broad anti-tumor activity with an investigator-assessed ORR of 33% (n=18/54), a NSCLC ORR of 33% (n=10/30), MTC ORR of 44% (n=7/16, including 1 complete response) and one patient with RET fusion+ pancreatic cancer reported a partial response. Responders included patients with brain metastases with one patient whose brain lesion decreased by 43%. The median duration of response has not been reached. Many patients remain on study, including the longest of 659 days, at data cutoff. BOS172738 exhibited dose-dependent exposure (AUC, Cmax), rapid absorption (median Tmax 1 to 4.5 h), and an extended half-life (approximately 65 hours) maximizing target coverage. Conclusions: BOS172738 is a highly potent and selective RET inhibitor with a differentiated safety profile and clinical activity against RET-altered tumors, including patients with brain metastases. BOS172738 continues to be evaluated in patients with NSCLC, MTC, and in patients previously treated with other selective RET inhibitors. Clinical trial information: NCT03780517.

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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 fusion pancreatic cancer predicted - sensitive Zeteletinib Case Reports/Case Series Actionable In a Phase I trial, Zeteletinib (DS-5010) treatment resulted in an objective response rate (ORR) of 33% (18/54) in patients with RET-altered advanced solid tumors including an ORR of 33% (10/30) in non-small cell lung cancer patients harboring a RET fusion, an ORR of 44% (7/16) in patients with medullary thyroid cancer harboring RET mutations, and a partial response in a pancreatic cancer patient (J Clin Oncol 2021 39: 15_suppl, 3008; NCT03780517). detail...