The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA–C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROS1, or NTRK1–3 rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALKG1202R, ROS1G2032R or ROS1D2033N, TRKAG595R, and TRKCG623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA–C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent-front substitutions in vitro and in vivo. As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusion– positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance. SIGNIFICANCE: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1–3, and ALK. Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRK1–3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs.
Bibliographical noteFunding Information:
Funding for this study was provided by TP Therapeutics, Inc.
A. Drilon has received honoraria from the speakers bureaus of TP Therapeutics, Ignyta, Loxo Oncology, and Ono. S.-H.I. Ou has received honoraria from the speakers bureaus of Roche/Genentech, AstraZeneca, and Takeda/ARIAD, has ownership interest (including stock, patents, etc.) in TP Therapeutics, is a member of the Scientific Advisory Board of TP Therapeutics, and served as a consultant for Pfizer, Roche Genen-tech, AstraZeneca, and Foundation Medicine. V.W. Zhu has received honoraria from the speakers bureaus of Roche-Foundation Medicine, Roche/Genentech, and Takeda, has ownership interest (including stock, patents, etc.) in TP Therapeutics, and is a consultant/advisory board member for TP Therapeutics. D.R. Camidge is a consultant/advisory board member for Takeda and Roche. D.M. Hyman reports receiving commercial research grants from Loxo Oncology, PUMA Biotechnology, and AstraZeneca and is a consultant/advisory board member for Pfizer, Genentech, Chugai, Atara, Boehringer Ingelheim, and CytomX. R.C. Doebele reports receiving a commercial research grant from Ignyta, has ownership interest (including stock, patents, etc.) in Rain Therapeutics, is a consultant/advisory board member for Takeda, AstraZeneca, and Ignyta, and has received other remuneration from Ignyta and Abbott Molecular. J.J. Cui has ownership interest (including stock, patents, etc.) in TP Therapeutics, Inc. A.T. Shaw is a consultant/advisory board member for member for TP Therapeutics, Pfizer, Blueprint Medicines, KSQ Therapeutics, Novartis, Roche/Genentech, LOXO, Ignyta, Takeda/Ariad, Foundation Medicine, Guardant, and Natera. No potential conflicts of interest were disclosed by the other authors.
©2018 American Association for Cancer Research.
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