N Engl J Med. 2024 Jan 11;390(2):118-131.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.)
--------------------------------------------------
・ROS1-TKI既治療の患者のうち、ROS1 G2032R耐性変異陽性の患者17人ではmedian PFSが9.2か月だったのに対し、ROS1 G2032R耐性が陰性、あるいは未検出の患者83人ではmedian PFSは5.5か月にとどまっていた。
・ROS1-TKI治療歴なしとありのコホートについて、無増悪生存曲線を並べてみると、ほぼダブルスコアであることが分かります。
・ROS1-TKI治療歴なしでrepotrectinibを使用した際の無増悪生存期間中央値は約36ヶ月。クリゾチニブやエヌトレクチニブの無増悪生存期間中央値が約16ヶ月。そこからreporectinibを使用して上乗せされる無増悪生存期間中央値が9ヶ月ですから、併せて約25ヶ月。ほぼ1年間の開きがありますので、最初からrepotrectinibを使用した方が良さそうです。
・脳転移
