Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	9	3	2019 03	384-395	Cancer Discov

URL

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