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Ref Type Journal Article
PMID (30487236)
Authors Drilon A, Fu S, Patel MR, Fakih M, Wang D, Olszanski AJ, Morgensztern D, Liu SV, Cho BC, Bazhenova L, Rodriguez CP, Doebele RC, Wozniak A, Reckamp KL, Seery T, Nikolinakos P, Hu Z, Oliver JW, Trone D, McArthur K, Patel R, Multani PS, Ahn MJ
Title A Phase I/Ib Trial of the VEGFR-Sparing Multikinase RET Inhibitor RXDX-105.
Abstract Text RET fusions are oncogenic drivers of various tumors, including non-small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor-naïve patients with RET fusion-positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%-38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%-17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion-positive NSCLC), and 67% (95% CI, 30%-93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion-positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non-KIF5B-RET-containing cancers. Novel approaches to targeting KIF5B-RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.This article is highlighted in the In This Issue feature, p. 305.


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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
EML4 RET EML4 - RET fusion gain of function - predicted EML4-RET results from the fusion of EML4 and RET (PMID: 33082208), which results in increased Erk phosphorylation in cultured cells (PMID: 33848463), and therefore, is predicted to lead to a gain of protein function. EML4-RET has been identified in lung cancer (PMID: 33082208, PMID: 31485557, PMID: 30487236).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET rearrange lung non-small cell carcinoma predicted - sensitive RXDX-105 Phase I Actionable In a Phase Ib trial, treatment with RXDX-105 (CEP-32496) resulted in an overall response rate of 19% (6/31) and stable disease in 39% (12/31) of patients with treatment-naive non-small cell lung cancer harboring a RET fusion (PMID: 30487236; NCT01877811) 30487236