On April 13, 2022 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a clinical-stage precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported positive topline results from the registrational TRIDENT-1 study across all four ROS1-positive advanced non-small cell lung cancer (NSCLC) cohorts, as reported by Blinded Independent Central Review (BICR) (Press release, Turning Point Therapeutics, APR 13, 2022, View Source [SID1234612158]).

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"We are very encouraged by the topline results from the pooled Phase 1 and Phase 2 portions of TRIDENT-1 by BICR shared today and continue to believe repotrectinib is a potentially best-in-class drug candidate for patients with ROS1-positive advanced NSCLC," said Athena Countouriotis, M.D., President and Chief Executive Officer. "The confirmed ORR data and 95% confidence intervals across all four cohorts remain strong, and the initial estimated Kaplan-Meier landmark analyses based on limited median follow-up of approximately 10 months for both duration of response and progression free survival in the TKI-naïve population are trending in the direction we had hoped for given this is the highest area of unmet medical need. We believe a differentiated profile is built upon a strong ORR and durability of response that could improve upon the current standard of care."

The primary objective of the TRIDENT-1 study is to determine the cORR based on BICR as assessed by RECIST 1.1, and the key secondary objectives include duration of response (DOR), progression free survival (PFS) and intracranial activity. The dataset utilizes a February 11, 2022 data cutoff date. The safety analysis included 380 treated patients from the pooled Phase 1 and Phase 2 portions of TRIDENT-1 across all cohorts, of which 287 patients were treated at the Phase 2 dose. The efficacy analyses included pooled patients from Phase 1 across all dose levels with an identified ROS1 fusion by next generation sequencing at baseline and Phase 2 patients. All patients received at least one dose of repotrectinib with at least four months of follow-up, and the majority of responders had at least six months of DOR follow-up.

Pooled Phase 1 and Phase 2 Topline Efficacy Analyses by BICR
ROS1-positive TKI-Naïve NSCLC (EXP-1; n=71 (8 from Phase 1 and 63 from Phase 2)):

In the ROS1-positive TKI-naïve advanced NSCLC population (EXP-1: n=71), the cORR was 79% (n=56/71; 95% CI: 68, 88), with 4 patients (6%) achieving a complete response (CR) and 52 patients (73%) achieving a partial response (PR). The cORR does not include one patient in an unconfirmed partial response (uPR) with tumor regression of -38% on the last scan, who remained on treatment awaiting the next scan as of the data cutoff date.

DOR ranged from 1.4+ to 35.1+ months with probability of patients in a response at 6, 9, 12 and 18 months reflected in Table 1 utilizing a Kaplan-Meier analysis, with a median duration of follow-up of 10.2 months.

Patients at Risk: Patients who have reached the specified timepoint without censoring or an event (progression or death).

PFS ranged from 0+ to 40.4+ months with probability of patients remaining progression free at 6, 9, 12 and 18 months reflected in Table 2 utilizing a Kaplan-Meier analysis, with a median duration of follow-up of 10.8 months.
Patients at Risk: Patients who have reached the specified timepoint without censoring or an event (progression or death).

ROS1-positive TKI-Pretreated NSCLC (EXP-2, EXP-3, and EXP-4; n=100):

In the ROS1-positive advanced NSCLC population pretreated with one prior TKI and prior platinum-based chemotherapy (EXP-2: n=26 (3 from Phase 1 and 23 from Phase 2)), the cORR was 42% (n=11/26; 95% CI: 23, 63), with 1 patient (4%) achieving a CR and 10 patients (38%) achieving a PR. Duration of response ranged from 3.6 to 18.3+ months.

In the ROS1-positive advanced NSCLC population pretreated with two prior TKIs without prior chemotherapy (EXP-3: n=18 (1 from Phase 1 and 17 from Phase 2)), the cORR was 28% (n=5/18; 95% CI: 10, 54), with 1 patient (6%) achieving a CR and 4 patients (22%) achieving a PR. Duration of response ranged from 1.9+ to 20.3+ months.

In the ROS1-positive advanced NSCLC population pretreated with one prior TKI without prior chemotherapy (EXP-4: n=56 (3 from Phase 1 and 53 from Phase 2)), the cORR was 36% (n=20/56; 95% CI: 23, 50), with 4 patients (7%) achieving a CR and 16 patients (30%) achieving a PR. The cORR does not include two patients with an uPR who both had tumor regressions of -47% on their last scans, both of whom remained on treatment awaiting their next scans as of the data cutoff date. Duration of response ranged from 1.9+ to 17.8 months.

Across the ROS1-positive TKI-pretreated advanced NSCLC population (EXP-2, EXP-3 and EXP-4), 17 patients had an identified ROS1 G2032R solvent front mutation detected, of which the cORR was 59% (n=10/17; 95% CI: 33, 82), with 1 patient (6%) achieving a CR and 9 patients (53%) achieving a PR. Duration of response ranged from 1.9+ to 20.3+ months.
TRIDENT-1 Topline Safety Analyses
Repotrectinib was generally well tolerated in a total of 380 patients with a safety and tolerability profile that was consistent with previously reported findings. The most commonly reported treatment emergent adverse event remained dizziness (61% all grade), of which 76% of patients who reported dizziness had a maximum severity of grade 1. The safety profile was comparable among the 287 patients who were treated at the Phase 2 dose.

As previously guided, the company anticipates discussing the topline BICR data with the U.S. Food and Drug Administration (FDA) at a pre-NDA meeting this quarter. The company plans to present detailed study results, including intracranial activity, from the ROS1-positive advanced NSCLC cohorts of the TRIDENT-1 study, at a medical conference in the second half of 2022.

Webcast/Conference Call Information
Turning Point will host a webcast and conference call on April 13, 2022 at 8 a.m. ET / 5 a.m. PT to discuss these results. Athena Countouriotis, M.D., President and Chief Executive Officer of Turning Point Therapeutics, will host the virtual event for investors and will be joined by Mohammad Hirmand, M.D., Chief Medical Officer. In addition, Alexander Drilon, M.D., Chief, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, will also be available on the call.

The event will be accessible through the "Investors" section of www.tptherapeutics.com or by dialing (877) 388-2118 (in the United States) or (470) 495-9489 (outside the U.S.) using conference ID 3197444. A replay will be available shortly after the live event through the "Investors" section of www.tptherapeutics.com.