FDA Grants Breakthrough Therapy Designation to Repotrectinib for NTRK+ TKI-Pretreated Advanced Solid Tumors

The FDA has granted a breakthrough therapy designation to repotrectinib as a potential therapeutic option for patients with advanced solid tumors that harbor an NTRK gene fusion who have progressed after treatment with 1 or 2 prior TRK TKIs, with or without prior chemotherapy, and who have no satisfactory alternative options.¹

Turning Point Therapeutics Inc. announced plans to discuss next steps toward potential registration of the agent for use in this population at a Type B meeting with the regulatory agency, which is anticipated to occur in the first half of 2022.

Repotrectinib is a small, macrocyclic TKI of ROS1, TRK, and ALK.² The agent was developed to effectively bind with the active kinase conformation and avoid steric interference from several clinically-resistant mutations. The compact and rigid structure of the agent is hypothesized to allow for deeper binding in the ATP binding pocket of the kinase and potential circumvention of the steric inference that is known to result in resistance to bulkier kinase inhibitors.

Previously, repotrectinib was granted a breakthrough therapy designation for use in patients with ROS1-positive metastatic non–small cell lung cancer (NSCLC) who were TKI-naïve.³ Data from the phase 1/2 TRIDENT-1 trial (NCT03093116) showed that the agent elicited encouraging objective responses with acceptable tolerability in this patient population.^4,5

A total of 15 patients were enrolled to the phase 2 portion of the trial, and data from a preliminary efficacy analysis demonstrated that repotrectinib elicited a confirmed objective response rate per physician assessment of 93% (95% CI, 68%-100%). In a total of 22 patients pooled from the phase 1 and phase 2 portions of the trial, the agent resulted in a confirmed ORR of 91% (95% CI, 71%-99%).

At a data cutoff date of December 31, 2020, the preliminary interim efficacy update for the trial included 22 patients with ROS1-positive, TKI-naïve NSCLC who were pooled from the phase 1 portion of the research and were dosed at or above the recommended phase 2 dose, as well as those from the phase 2 portion who had completed at least 2 post-baseline scans. For the phase 2 portion of the trial, responses were identified via physician assessment.

Of the 15 patients who received treatment in the phase 2 portion of the research, the 1 non-responder continued to receive repotrectinib and experienced stable disease; this patient also experienced a tumor reduction of 13%. Additionally, 1 of the 14 patients who achieved a partial response (PR) to treatment at the time of the data cutoff date converted to a confirmed complete response.

The duration of responses to repotrectinib ranged from 1.3+ months to 7.4+ months, and the duration of treatment ranged from 3.7+ months to 10.9+ months. Fourteen of the 15 patients continued to receive the agent. As of the data cutoff date, 1 additional patient (not included in the confirmed ORR) had an unconfirmed PR, continued to receive repotrectinib, and was awaiting a confirmatory scan.

Prior phase 2 data, which had a July 10, 2020 cutoff date, demonstrated that in 7 total patients, the confirmed ORR with repotrectinib was 86% (95% CI, 42%-100%).

The safety of the agent was evaluated in a total of 185 patients from both phases of the trial and the update utilized a cutoff date of October 30, 2020. Repotrectinib was noted to be generally well tolerated in both portions of the research, with treatment-emergent adverse effects (TEAEs) that included dizziness (58%), dysgeusia (43%), constipation (32%), dyspnea (31%), fatigue (27%), paresthesia (25%), anemia (22%), nausea (20%), and muscular weakness (16%).

Four cases of grade 3 dizziness (2%) were reported with repotrectinib, although none of these cases resulted in discontinuation of the agent. Dose modifications due to toxicities were infrequent. Eighteen percent of patients experienced TEAEs that led to dose reductions and 9% experienced toxicities that resulted in discontinuation.

Notably, the majority of the treatment-related AEs (TRAEs) experienced with repotrectinib were either grade 1 or 2 in severity. No grade 4 or 5 TRAEs were observed.

Repotrectinib has been granted 4 fast track designations in the following patients:

• Those with ROS1-positive advanced NSCLC who are ROS1 TKI naïve
• Those with ROS1-positive advanced NSCLC who have received 1 prior line of platinum-based chemotherapy and 1 prior ROS1 TKI
• Those with ROS1-positive advanced NSCLC who were pretreated with 1 prior ROS1 TKI without prior platinum-based chemotherapy
• Those with NTRK-positive advanced solid tumors who experienced disease progression after at least 1 prior line of chemotherapy and 1 or 2 prior TRK TKIs who have no satisfactory alternative options

The agent also received an orphan drug designation in 2017.

References

1. Zai Lab Partner Turning Point Therapeutics granted breakthrough therapy designation for repotrectinib treatment in patients with NTRK-positive, TKI-pretreated advanced solid tumors. News release. Zai Lab Limited, Turning Point Therapeutics, Inc. October 4, 2021. Accessed October 5, 2021. https://bit.ly/3Fk0NEJ
2. Repotrectinib. Turning Point Therapeutics, Inc. Accessed October 5, 2021. https://bit.ly/3Ahxkro
3. Turning Point Therapeutics granted FDA breakthrough therapy designation for repotrectinib treatment in patients with ROS1-positive metastatic non-small cell lung cancer who have not been treated with a ROS1 Tyrosine Kinase Inhibitor. News release. Turning Point Therapeutics, Inc. December 8, 2020. Accessed October 5, 2021. https://bit.ly/3oE67gm
4. Cho BC, Doebele RC, Lin JJ, et al. Phase 1/2 TRIDENT-1 study of repotrectinib in patients with ROS1+ or NTRK+ advanced solid tumors. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract MA11.07
5. Turning Point Therapeutics reports updated interim data from registrational phase 1 Trident-1 study of repotrectinib in patients with ROS1-positive TKI-naïve non-small cell lung cancer. News release. January 29, 2021. Accessed October 5, 2021. https://bit.ly/3izqibC