The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for
the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor
activity, but resistance develops in tumors, and intracranial activity is suboptimal.
Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1
fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R.In
this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib
in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The
primary efficacy end point in the phase 2 trial was confirmed objective response;
efficacy analyses included patients from phase 1 and phase 2. Duration of response,
progression-free survival, and safety were secondary end points in phase 2.On the
basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib
was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in
56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive
NSCLC who had not previously received a ROS1 TKI; the median duration of response
was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free
survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred
in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who
had previously received one ROS1 TKI and had never received chemotherapy; the median
duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and
median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the
17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response.
A total of 426 patients received the phase 2 dose; the most common treatment-related
adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia
(in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events.Repotrectinib
had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless
of whether they had previously received a ROS1 TKI. Adverse events were mainly of
low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics,
a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number,
NCT03093116.).
