TRIDENT-1 Trial for Repotrectinib Shows Encouraging Data in Subgroup of Patients with NSCLC

August 20, 2020

Early interim data from the registrational phase 2 TRIDENT-1 study of repotrectinib was reported by Turning Point Therapeutics, as well as regulatory feedback from the FDA regarding the TRIDENT-1 trial design.

Turning Point Therapeutics reported early interim data from the registrational phase 2 TRIDENT-1 study of repotrectinib in patients with ROS1- or NTRK-driven tumors, including those who are TKI-naïve and TKI-pretreated.

With a data cutoff of July 10, 2020, the interim data includes the first 39 patients treated who have had at least 1 post-baseline scan. Patients were treated at a starting dose of 160 mg daily, with 90% of patients escalating after 14 days to 160 mg twice daily per the study defined dose titration approach.

Responses were confirmed with a subsequent scan at least 28 days later per RECIST 1.1 and were determined by physician assessment. Across all cohorts, the median follow-up was 3.6 months (range, 0.4-7.4+) and median duration of treatment was 3.7 months (range, 0.7-8.2+).

In patients with ROS1-positive TKI-naïve non-small cell lung cancer (NSCLC; n = 7), 6 patients achieved a confirmed response (CR) for an objective response rate (ORR) of 86%. The duration of response ranged from 0.9+ to 2.0+ months and all patients who achieved a response remained in a response at the time of the data cutoff. Notably, since the data cutoff, the seventh patient in this cohort has achieved an unconfirmed partial response (PR) and remains on treatment awaiting a confirmatory scan.

Of patients with ROS1-positive NSCLC pretreated with 1 prior TKI with prior chemotherapy (n = 5), 2 patients achieved a CR for an ORR of 40%. The durations of response were 4.5 and 5.6+ months at the time of the data cutoff.

Moreover, in patients with ROS1-positive NSCLC pretreated with 2 prior TKIs with prior chemotherapy (n = 10), no objective responses were observed; however, 5 patients did achieve stable disease. Importantly, Turning Point Therapeutics recently recommended to the study’s data monitoring committee (DMC) that this cohort be modified to remove the requirement for prior chemotherapy based on limited activity to date. The DMC recommended the study proceed and agreed with the recommended change to this cohort.

Of patients with ROS1-positive NSCLC pretreated with 2 prior TKIs without prior chemotherapy (n = 5), 2 patients achieved a CR for an ORR of 40%. Both patients remained in a response with a duration of 1.9+ months at the time of the data cutoff.

Lastly, in patients with NTRK-positive TKI-pretreated solid tumor (n = 6), 3 patients achieved a CR for an ORR of 50%. For this population, the duration of response ranged from 1.7+ to 3.6+ months with all three patients remaining in a response at the time of the data cutoff.

With regard to safety, repotrectinib was generally well tolerated. The majority of treatment emergent adverse events (TEAEs) were grade 1 or 2. The TEAEs of any grade found in more than 25% of patients were dizziness (62%), fatigue (39%), constipation (33%), dysgeusia (33%), and dyspnea (28%). There were no grade 3 cases of dizziness and no cases of dizziness leading to treatment discontinuation. In addition, there no grade 4 or grade 5 TRAEs.

“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,” Athena Countouriotis, MD, president and chief executive officer at Turning Point Therapeutics, said in a press release.

“Additionally, 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,” Countouriotis added. “Hence, we are modifying the TRIDENT-1 study sample sizes and adding new interim analyses that may support approval into 2 of our ROS1-positive TKI-pretreated patient cohorts. We now anticipate providing an update in early 2021 on the overall study timelines.”

Modifications made by the company per FDA feedback include:

  • Phase 2 cohort sample sizes to support potential approval may include phase 1 patients treated at the recommended phase 2 dose. Even further, the pooling of phase 1 and phase 2 data may aid in shortening timelines to potential regulatory submission based on fewer patients from the phase 2 portion of the study.
  • The company plans to decrease the sample size of patients with ROS1-positive NSCLC pretreated with 1 prior TKI with prior chemotherapy from the current target of 100 patients to 60 total patients with 1 formal interim analysis after approximately 30 patients. The FDA provided guidance that 6 months of follow up may be sufficient to support approval.
  • The company plans to increase the sample size of patients with ROS1-positive NSCLCpretreated with 2 prior TKIs with prior chemotherapy to a target of 60 patients with 1 formal interim analysis after approximately 30 patients; previously, this patient population was an exploratory cohort. The FDA also provided guidance that 6 months of follow up may be sufficient to support approval for this cohort.
  • For both patients with ROS1-positive NSCLC pretreated with two prior TKIs without prior chemotherapy and those with NTRK-positive TKI-pretreated solid tumor, the FDA provided guidance that 9 months and 6 months of follow up, respectively, from the last response may be sufficient to support approval. Previous guidance was 12 months for both patient cohorts.

According to Turning Point Therapeutics, the company is now reviewing its timelines for when it expects the top-line interim analysis data sets will be achieved and anticipates sharing those timelines as it gets closer to achieving full site activation in early 2021.

Reference:

Turning Point Therapeutics Reports Early Interim Data From Registrational Phase 2 Trident-1 Study of Repotrectinib, Provides Regulatory Update [news release]. San Diego. Published August 19, 2020. Accessed August 19, 2020. https://ir.tptherapeutics.com/news-releases/news-release-details/turning-point-therapeutics-reports-early-interim-data