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.
Bibliographical noteFunding Information:
A. Drilon is a consultant/advisory board member for Ignyta, Genentech, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Roche, Loxo Oncology, TP Therapeutics, AstraZeneca, Pfizer, Blueprint, Takeda/Ariad, and Helsinn Therapeutics and has received Pocket Oncology royalties from Wolters Kluwer. M. Fakih reports receiving commercial research grants from AstraZeneca, Novartis, and Amgen, has received honoraria from the speakers bureaus of Amgen, Taiho,
Genentech, and SIRTEX, and is a consultant/advisory board member for Array, Genentech, Seattle Genetics, and Bayer. D. Morgensztern is a consultant/advisory board member for AbbVie, Bristol-Myers Squibb, Takeda, and PharmaMar. S.V. Liu reports receiving commercial research grants from Genentech, AstraZeneca, Molecular Partners, OncoMed, Pfizer, Threshold, Bayer, Blueprint, Clovis, Corvus, Esanex, Lilly, Lycera, and Merck and is a consultant/advisory board member for AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, Heron, Lilly, Pfizer, Regeneron, Taiho, and Takeda. L. Bazhenova is a consultant/advisory board member for Genentech. C.P. Rodriguez reports receiving commercial research grants from Bristol-Myers Squibb, AstraZeneca, Ignyta, Merck, Acerta, Genentech, Pharma-cyclics, Portola, and Seattle Genetics and is a consultant/advisory board member for AstraZeneca and Merck. R.C. Doebele reports receiving a commercial research grant from Ignyta, has received honoraria from the speakers bureau of Guardant Health, has ownership interest (including stock, patents, etc.) in Rain Therapeutics, is a consultant/advisory board member for Rain Therapeutics, Ignyta, Loxo, Pfizer, Torvagene, Ariad, AstraZeneca, Takeda, Spectrum Pharmaceuticals, and Bayer, and has received other remuneration from Abbott Molecular. A. Wozniak reports receiving commercial research support from Boehringer Ingelheim and is a consultant/ advisory board member for AstraZeneca, Boehringer Ingelheim, and Takeda. K.L. Reckamp reports receiving commercial research grants from Eisai and Loxo and is a consultant/advisory board member for Boehringer Ingelheim, Euclises, Exelixis, Guardant, Genentech, Loxo, Seattle Genetics, Takeda, and Tesaro. P. Nikolinakos has received honoraria from the speakers bureau of Boehringer Ingel-heim and is a consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Genentech, and Tesaro. Z. Hu is a Scientist II at Ignyta. P.S. Multani is chief medical officer at Ignyta, Inc. M.-J. Ahn has received honoraria from the speakers bureaus of Takeda and AstraZeneca and is a consultant/advisory board member for Takeda, AstraZeneca, Merck, Alpha Pharmaceutical, Bristol-Myers Squibb, and Boehringer Ingelheim. No potential conflicts of interest were disclosed by the other authors.
A. Drilon is supported by the NIH award P30 CA008748. This study was sponsored by Ignyta.
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