Repotrectinib Elicits Encouraging Response Rates in ROS1- and NTRK-Driven Tumors

Athena Countouriotis, MD

Treatment with repotrectinib (TPX-0005) resulted in favorable responses in patients with ROS1- or NTRK-driven tumors, regardless of prior treatment with TKIs, according to interim data from the phase 2 TRIDENT-1 trial.¹

“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 of Turning Point Therapeutics, Inc, stated in the press release.

The first 39 patients who received treatment with the agent were included in the early dataset; the data cutoff was July 10, 2020. Patients had to have had at least 1 post-baseline scan to be included in the analysis. Responses to treatment were confirmed via a subsequent scan at least 28 days later in accordance with RECIST v1.1 criteria and physician assessment. The median follow-up was 3.6 months and the median duration of treatment was 3.7 months.

In a total of 7 patients with ROS1-positive non–small cell lung cancer (NSCLC) who had not previously received treatment with TKI, 6 achieved a confirmed response (CR). The objective response rate reported in this population was 86% and the duration of response (DOR) ranged from 0.9+ months to 2.0+ months.

Notably, all patients who had responded to treatment were still responding at the time of the data cutoff. Moreover, since the cutoff, the seventh patient in this group was reported to have had an unconfirmed partial response; this patient remains on repotrectinib and will undergo a confirmatory scan.

In a total of 5 patients with ROS1-positive NSCLC who received prior treatment with 1 TKI without chemotherapy, 4 patients had a CR to repotrectinib. The ORR in this patient population was 67% and the DOR ranged from 1.0+ months to 5.7+ months. All patients who achieved a CR remained in response at the time of the data cutoff.

In a total of 10 heavily pretreated patients with ROS1-positive NSCLC who had received prior treatment with 2 TKIs and chemotherapy, no objective responses were observed with the investigational agent. However, half of these patients (n = 5) achieved stable disease.

Turning Point Therapeutics, Inc recommended that expansion cohort 3 be revised to remove the requirement for previous chemotherapy based on limited activity observed with repotrectinib in this fourth-line cohort. The company intends to only support patients in this cohort who are receiving third-line treatment going forward. The study’s data monitoring committee agreed to proceed with the recommended change to the cohort.

Of the 5 patients with ROS1-positive NSCLC who received previous treatment with 2 TKIs without chemotherapy, 2 experienced a CR to repotrectinib. The ORR reported in this cohort was 40%. Both patients who achieved CRs continued to respond to treatment for a duration of 1.9+ months at the time of the data cutoff.

Lastly, of 6 patients with NTRK-positive solid tumors had received prior treatment with TKIs, half (n = 3) achieved a CR with repotrectinib; the ORR in this population was 50% with the agent, and the DOR ranged from 1.7+ months to 3.6+ months. All 3 patients continued to respond at the time of data cutoff.

In phase 1 of the TRIDENT-1 trial, investigators sought to determine the maximum-tolerated dose and/or recommended phase 2 dose of single-agent repotrectinib for both TKI-naïve and -refractory patients with advanced ALK/ROS1/NTRK-positive solid tumors. Secondary end points included safety, pharmacokinetics, and preliminary antitumor efficacy.²

In the trial, patients with several solid tumors received treatment; the majority of patients, or 83%, had NSCLC. The median age of the participants was 52 years and the median number of previous systemic treatments received was 2. Sixty-seven percent of patients received prior ROS1 TKIs, while 90% had previously received chemotherapy.

Previous results reported during the 19th World Conference on Lung Cancer showed an ORR of 80% in those who were TKI naïve and 18% in those who were TKI refractory. As of the data cutoff of July 13, 2018, a total of 72 patients had been treated with repotrectinib across several dose levels, including: 40 mg once daily (n = 13), 80 mg once daily (n = 12), 160 mg once daily (n = 23), 240 mg once daily (n = 10), 160 mg twice daily (n = 12), and 200 mg twice daily (n = 2).

Updated data from the phase 1 portion of the study, with a data cutoff of July 22, 2019, showed ORRs of 91% in the ROS1-positive cohort who were TKI-naïve, 36% in the ROS1-positive cohort who received prior treatment with 1 TKI and chemotherapy, 50% in the ROS1-positive cohort who received prior TKI treatment without chemotherapy, 0% in the ROS1-positive cohort who received 2 prior TKIs without chemotherapy, and 33% in the NTRK-positive cohort that was pretreated with TKIs.

A total of 39 patients with ROS1- and NTRK-positive disease were included in the preliminary safety analysis. Patients started on a dose of 160 mg daily; 90% of patients were then escalated after 14 days to receive repotrectinib at 160 mg twice daily per the dose titration approach defined in the study protocol.

The agent was found to be well tolerated, with the majority of the treatment-emergent adverse effects (TEAEs) reported being just grade 1 or 2 in severity. Toxicities reported in 25% or more participants included dizziness (62%), fatigue (39%), constipation (33%), dysgeusia (33%), and dyspnea (28%). No grade 3 cases of dizziness were reported and no patients who experienced dizziness ended up discontinuing treatment. No grade 4 or 5 TEAEs were reported.

“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,” added Countouriotis. “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.”

References

1. Turning Point Therapeutics reports early interim data from registrational phase 2 Trident-1 study of repotrectinib, provides regulatory update. News release. Turning Point Therapeutics, Inc. August 19, 2020. Accessed August 19, 2020.
2. Lin J, Kim D, Drilon A, et al. Safety and Preliminary Clinical Activity of Repotrectinib (TPX-0005), a ROS1/TRK/ALK Inhibitor, in Advanced ROS1 Fusion-Positive NSCLC. Presented at: the IASLC 19th World Conference on Lung Cancer; September 23-26; Toronto, Canada. Abstract OA02.02.