Repotrectinib in ROS1 Fusion-Positive Non-Small-Cell Lung Cancer
Alexander Drilon1, D Ross Camidge1, Jessica J Lin1
1From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College (A.D.) and the NYU Perlmutter Cancer Center (V.V.) - all in New York; the University of Colorado, Anschutz Medical Campus, Aurora (D.R.C.); Massachusetts General Hospital, Harvard Medical School, Boston (J.J.L.); Asan Medical Center (S.-W.K.) and Yonsei Cancer Center, Yonsei University College of Medicine (B.C.C.), Seoul, and Chungbuk National University Hospital, Cheongju-si (K.H.L.) - all in South Korea; the Peter MacCallum Cancer Center, Melbourne, VIC (B.J.S.), and the Chris O'Brien Lifehouse, Camperdown, NSW (S.K.) - both in Australia; the Department of Oncology and Radiotherapy and Early Clinical Trials Center, Medical University of Gdansk, Gdansk, Poland (R.D.); Paris-Saclay University, Gustave Roussy Cancer Center, Villejuif (B.B.), and Centre Hospitalier Universitaire de Grenoble-Alpes, La Tronche (D.M.-S.) - both in France; National Cancer Center Hospital East, Kashiwa, Japan (K.G.); the Netherlands Cancer Institute, Amsterdam (A.J.L.); the Center for Integrated Oncology, University Hospital of Cologne, Cologne (J.W.), and the Department of Medical Oncology, Heidelberg University Hospital, National Center for Tumor Diseases, Heidelberg (C.S.) - both in Germany; the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London (S.P.), and the University of Manchester and the Christie NHS Foundation Trust, Manchester (M.G.K.) - all in the United Kingdom; the University of California, Irvine, School of Medicine, Orange (M.N.), and Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb, San Diego (S.S., M.M., D.T., A.G., G.S.) - both in California; Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, Barcelona (E.F.); Hunan Cancer Hospital, Hunan (N.Y.), the Department of Oncology, Shanghai Chest Hospital, Shanghai (S.L.), Sichuan Cancer Hospital and Institute, Chengdu (W.Y.), and Henan Cancer Hospital, Zhengzhou (X.H.) - all in China; the Respiratory Oncology Unit, University Hospitals Leuven, Leuven, Belgium (C.D.); UT Southwestern Medical Center, Dallas (M.S.B.); William Osler Health System, University of Toronto, Toronto (P.C.); and Bristol Myers Squibb, Princeton, NJ (Y.Y.).
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.).
Insights
Repotrectinib shows durable clinical activity in ROS1 fusion-positive non-small-cell lung cancer (NSCLC), even with resistance mutations. This next-generation tyrosine kinase inhibitor (TKI) offers a promising treatment option for patients with advanced NSCLC.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Early-generation ROS1 tyrosine kinase inhibitors (TKIs) for ROS1 fusion-positive non-small-cell lung cancer (NSCLC) exhibit antitumor activity but face challenges with resistance and suboptimal intracranial efficacy.
- Repotrectinib, a next-generation ROS1 TKI, demonstrates preclinical efficacy against ROS1-positive cancers, including those with resistance mutations like ROS1 G2032R.
Purpose of the Study:
- To assess the efficacy and safety of repotrectinib in patients with advanced solid tumors, with a focus on ROS1 fusion-positive NSCLC.
- To evaluate repotrectinib's performance in patients with and without prior ROS1 TKI treatment, including those with specific resistance mutations.
Main Methods:
- A registrational phase 1-2 clinical trial involving patients with advanced solid tumors, including ROS1 fusion-positive NSCLC.
- Primary efficacy endpoint: confirmed objective response. Secondary endpoints: duration of response, progression-free survival, and safety.
- Efficacy analyses included data from both phase 1 and phase 2 of the trial.
Main Results:
- In treatment-naïve ROS1-positive NSCLC patients, repotrectinib achieved a 79% objective response rate with a median duration of response of 34.1 months and median progression-free survival of 35.7 months.
- In patients previously treated with one ROS1 TKI (and no chemotherapy), the objective response rate was 38%, with a median duration of response of 14.8 months and median progression-free survival of 9.0 months.
- Among patients with the ROS1 G2032R mutation, 59% showed a response. Common adverse events included dizziness, dysgeusia, and paresthesia, with a low discontinuation rate due to treatment-related adverse events.
Conclusions:
- Repotrectinib demonstrates durable clinical activity in patients with ROS1 fusion-positive NSCLC, irrespective of prior ROS1 TKI treatment history.
- The adverse event profile of repotrectinib is generally low-grade and manageable, supporting its potential for long-term administration.
- The study, TRIDENT-1 (NCT03093116), was funded by Turning Point Therapeutics.
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