Repotrectinib is a next-generation ROS1/TRK/ALK TKI with >90-fold potency versus crizotinib against ROS1 and >100-fold potency versus larotrectinib against TRK in engineered Ba/F3 cell proliferation assays. Preclinical studies demonstrate robust activity against all known ROS1/TRK resistance mutations, including the most common solvent-front mutations (SFM) ROS1 G2032R, TRKA G595R, and TRKC G623R/E.
In the ongoing phase 1 study (NCT03093116), TKI-naïve and TKI-pretreated (≥1 TKI) pts with advanced ROS1, TRK, or ALK fusion+ solid tumors received repotrectinib. Endpoints include safety, PK, and confirmed overall response (cORR).
As of 4-March-2019, 83 pts were treated with repotrectinib (dose levels from 40 mg QD to 200 mg BID under fasted/fed conditions). Most AEs were manageable and grade (gr) 1-2. The most common treatment-emergent AEs (found in > 30% of pts) were dizziness (57%), dysgeusia (51%), dyspnea (30%), and fatigue (30%). Four DLTs occurred and were manageable with dose modifications: gr3 dyspnea/hypoxia (n = 1); gr2 (n = 1) and gr3 (n = 1) dizziness at 160 mg BID, and gr3 dizziness (n = 1) at 240 mg QD. In ROS1+ NSCLC, the median number of prior TKIs was 1 (0-3); all TKI-naïve and 77% of TKI-pretreated pts received prior chemotherapy. In 11 evaluable TKI-naïve ROS1+ NSCLC pts, cORR by Blinded Central Review (BCR) was 82% (95% CI 48 - 98); median duration of response was not reached ((range 5.6 - 17.7+ months (mos)). In 18 ROS1+ NSCLC pts pretreated with 1 prior TKI, cORR by BCR was 39% (95% CI 17 – 64), and in 11 pts with 1 prior TKI at doses of 160 mg QD or above cORR was 55% (95% CI 23 - 83). All pts with ROS1 G2032R had tumor regression [cORR of 40% (n = 2/5)]. In 1 TKI-pretreated pt with ETV6-NTRK3+ and an acquired TRKC G623E-mutant salivary gland tumor, a cPR of 9.8 mos was achieved; the patient was treated for 17.9 mos. Enrollment continues. Updated data in ∼10 additional ROS1+ NSCLC and TRK+ solid tumor pts will be presented.
Repotrectinib was well tolerated and demonstrated encouraging overall clinical activity in pts with ROS1 fusion-positive NSCLC and TRK fusion-positive solid tumors.
NCT03093116.
Turning Point Therapeutics Inc, San Diego, CA, USA.
Turning Point Therapeutics Inc, San Diego, CA, USA.
A. Drilon: Honoraria (self), Advisory / Consultancy: Ignyta/Genentech/Roche; Honoraria (self), Advisory / Consultancy: Loxo Oncology/Bayer/Lilly; Honoraria (self), Advisory / Consultancy: TP Therapeutics Inc; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Blueprint Medicines; Honoraria (institution), Advisory / Consultancy: Takeda/Ariad/Milenium; Honoraria (self), Advisory / Consultancy: Helsinn; Honoraria (institution), Advisory / Consultancy: Beigene; Honoraria (self), Advisory / Consultancy: BergenBio; Honoraria (self), Advisory / Consultancy: Hengrui Therapeutics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Exelixis; Honoraria (self), Advisory / Consultancy: Tyra Biosciences; Research grant / Funding (institution): Foundation Medicine; Licensing / Royalties: Wolters Kluwer; Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: MORE Health; Honoraria (self), Advisory / Consultancy: Verastem; Travel / Accommodation / Expenses: Puma; Research grant / Funding (institution): Teva; Research grant / Funding (institution): GlaxoSmithKlein. B.C. Cho: Shareholder / Stockholder / Stock options: heraCanVac Inc; Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Research grant / Funding (institution): AtraZeneca; Honoraria (self), Research grant / Funding (institution): MOGAM Institute; Honoraria (self): Dong-A ST; Licensing / Royalties: Champions Oncology. J.J. Lin: Speaker Bureau / Expert testimony: TP Therapeutics Inc; Honoraria (institution): Chugai; Honoraria (institution): Boehringer-Ingelheim. V. Zhu: Shareholder / Stockholder / Stock options: TP Therapeutics Inc; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Astra Zeneka; Honoraria (institution), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Takeda; Honoraria (self): Biocept; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche/Genentech. R.D. Camidge: Research grant / Funding (self): Takeda. S. Stopatschinskaja: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: TP Therapeutics Inc. J..J. Cui: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: TP Therapeutics Inc. D.M. Hyman: Advisory / Consultancy, Travel / Accommodation / Expenses: Chugai; Advisory / Consultancy: CytomX Therapeutics; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Research grant / Funding (self): Puma Biotechnology; Research grant / Funding (self): Loxo. S. Ou: Advisory / Consultancy, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: TP Therapeutics Inc; Shareholder / Stockholder / Stock options: Ignyta; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Ariad; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech/Roche; Honoraria (self), Research grant / Funding (institution): Ignyta; Honoraria (self): Novartis; Research grant / Funding (institution): Blueprint Medicine. A.T. Shaw: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Honoraria (self): Foundation Medicine; Honoraria (self): Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Ariad; Advisory / Consultancy, Research grant / Funding (institution): Ignyta; Advisory / Consultancy: Blueprint Medicine; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: EDM Serono; Advisory / Consultancy: Taiho Pharmaceutical; Advisory / Consultancy: KSQ Therapeutics; Advisory / Consultancy: Natera; Advisory / Consultancy: Loxo; Advisory / Consultancy: Takeda; Advisory / Consultancy: Bayer; Advisory / Consultancy: Chugai Pharm; Research grant / Funding (institution): TP Therapeutics. R.C. Doebele: Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Licensing / Royalties: Ignyta; Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Genentech; Shareholder / Stockholder / Stock options: Roche; Research grant / Funding (institution), Licensing / Royalties: Rain Therapeutics; Licensing / Royalties: Abbott Molecular. All other authors have declared no conflicts of interest.