Repotrectinib Shows Promising Interim Results in ROS1+ and NTRK+ Tumors, FDA Responds to Data

Objective response rates (ORRs) for repotrectinib in patients with ROS1-positive non–small cell lung cancer (NSCLC) and NTRK fusion-positive advanced solid tumors are encouraging, according to interim data from the phase 2 TRIDENT-1 clinical trial, announced by developer Turning Point Therapeutics, in a press release.

“We are very encouraged by the early interim data from the phase 2 TRIDENT-1 study as they reaffirm our belief that repotrectinib has the potential to be the best-in-class treatment for patients with ROS1- or NTRK-driven tumors, including patients who are TKI-naïve and TKI-pretreated,” said Athena Countouriotis, MD, president and chief executive officer, Turning Point Therapeutics, in a statement.

As of the July 10, 2020 data cutoff date, 39 patients were evaluated for interim efficacy and safety. These patients included those who were naïve to treatment with a tyrosine kinase inhibitor (TKI) as well as those who were previously treated with a TKI. Repotrectinib was administered at a starting dose of 160 mg daily (QD), with 90% of patients escalating after 14 days to 160 mg twice daily.

In the cohort of 7 patients with ROS1-positive TKI-naïve NSCLC, the ORR was 86% (95% CI, 42%-100%), which included confirmed responses in 6 patients. The duration of response (DOR) in this group ranged from 0.9+ to 2.0+ months, and each patient who responded to treatment was able to maintain response at the time of data cutoff. An unconfirmed partial response in the remaining patient in this cohort was reported after the data cutoff date.

The ROS1-positive NSCLC cohort of 5 patients who were pretreated with 1 prior TKI and platinum-based chemotherapy had an ORR of 40% (95% CI, 5%-85%). In this group, the DOR ranged from 4.5+ months to 5.6+ months. In the other cohort of 6 patients with ROS1-positive NSCLC who were pretreated with 1 prior TKI but did not receive prior chemotherapy, the ORR was 67% (95% CI, 22%-96%).

The study had a similar cohort of 10 patients who had ROS1-positive disease pretreated with 2 prior TKIs and had not received prior chemotherapy. No patients in this cohort had an objective response as of the data cutoff date, but stable disease was observed in 5 patients.

Recommendations from the developer to the Data Monitoring Committee (DMC) were made to adjust the protocol for this cohort to remove the prior chemotherapy requirement. The DMC agreed. However, the 5 patients enrolled under the study’s original protocol achieved an ORR of 40% (95% CI, 5%-85%), and the DOR was 1.9+ months.

The cohort of 6 patients with NTRK-positive NSCLC who were pretreated with a TKI achieved an ORR of 50% (95% CI, 12%-88%). The DOR in this group had a range from 1.7+ months to 3.6+ months. Notably, 3 patients were still responding at the time of data cutoff.

The responses observed in the phase 2 portion of the study were similar to those observed in the phase 1 portion.

In terms of safety, all 39 patients were evaluable and the agent was well-tolerated overall, with most treatment-emergent adverse events (TEAEs) being grade 1 or 2. Occurring in more than 25% of the study population, the most common TEAEs of any grade were dizziness (62%), fatigue (39%), constipation (33%), dysgeusia (33%), and dyspnea (28%). No grade 3 dizziness or dizziness leading to treatment discontinuation was observed in the study.

Based on these efficacy and safety data, Turning Point Therapeutics received positive feedback from the FDA on the timeline of a potent FDA approval of repotrectinib as treatment of these 2 patient populations.

“…We recently received FDA feedback that may provide a faster path to potential approval, including pooling of patients from the Phase 1 portion of the study treated at the recommended dose of repotrectinib with patients treated in the Phase 2 portion, and cohort sample size modifications. Hence, we are modifying the TRIDENT-1 study sample sizes and adding new interim analyses that may support approval into two of our ROS1-positive TKI-pretreated patient cohorts. We now anticipate providing an update in early 2021 on the overall study timelines, said Countouriotis, in a statement.

The company plans to review timelines on their topline interim analysis data sets based on the FDA’s feedback on the TRIDENT-1 phase 2 portion.

_References:

_{Turning Point Therapeutics reports early interim data from registrational phase 2 trident-1 study of repotrectinib, provides regulatory update. News release. Turning Point Therapeutics. August 19, 2002. Accessed August 19, 2020. https://bit.ly/3iV1w3h}