On October 8, 2021 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported the presentation of early clinical data from the NTRK-positive TKI-naïve and TKI-pretreated advanced solid tumor cohorts (EXP-5 and EXP-6) of the ongoing TRIDENT-1 Phase 1/2 study of its lead drug candidate repotrectinib (Press release, Turning Point Therapeutics, OCT 8, 2021, View Source [SID1234591020]).
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These data are being presented today at a plenary session at the Virtual AACR-NCI-EORTC (Free AACR-NCI-EORTC Whitepaper) International Conference on Molecular Targets and Cancer Therapeutics (EORTC-NCI-AACR) (Free ASGCT Whitepaper) (Free EORTC-NCI-AACR Whitepaper) hosted by the American Association for Cancer Research (AACR) (Free AACR Whitepaper), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC) being held October 7-10.
"These data in patients with NTRK-positive advanced solid tumors are encouraging and support further investigation of repotrectinib in this patient population, especially in the TKI-pretreated setting where there are no currently approved targeted therapies," said Mohammad Hirmand, M.D., chief medical officer. "Based on these findings and repotrectinib having recently been granted Breakthrough Therapy designation for NTRK-positive TKI-pretreated advanced solid tumors, we look forward to discussing next steps toward potential registration of repotrectinib in this patient population at a Type B meeting with the FDA anticipated in the first half of 2022."
Repotrectinib Early Data from Phase 1/2 TRIDENT-1 Study from NTRK-Positive Advanced Solid Tumor Cohorts (EXP-5, EXP-6)
The early Phase 2 TRIDENT-1 dataset utilizes an August 26, 2021 data cutoff. The safety analysis includes 301 treated patients from the pooled Phase 1 and Phase 2 portions of TRIDENT-1 across all cohorts, and the preliminary efficacy analysis includes 40 evaluable patients from the pooled Phase 1 and Phase 2 portions of TRIDENT-1 in the NTRK-positive advanced solid tumor cohorts (EXP-5, EXP-6). Of the 40 patients, 17 were TKI-naïve and 23 were TKI-pretreated. Phase 2 patients included in the efficacy analysis had baseline measurable disease and at least one post-baseline evaluable scan or were off treatment prior to first post-baseline scan. Responses were confirmed with a subsequent scan at least 28 days later per RECIST 1.1 and were determined by physician assessment for Phase 2 patients. Phase 1 patients included in the efficacy analysis were treated at or above the Phase 2 dose, with responses assessed by blinded independent central review (BICR). The Phase 1 data cutoff date was July 22, 2019 for responses and August 26, 2021 for duration of treatment.
The findings were reported in a pre-recorded oral plenary presentation by Benjamin Besse, M.D., Ph.D., professor of Medical Oncology at Paris-Saclay University and full-time cancer specialist at Gustave Roussy Cancer Center available on October 8 at 10:05 a.m. ET on the meeting website.
Pooled Phase 1 and Phase 2 Preliminary Efficacy Analysis (n=40)
In the NTRK-positive TKI-naïve advanced solid tumor population (EXP-5: n=17), the confirmed Objective Response Rate (cORR) was 41% (95% CI: 18-67). At the time of the data cutoff, three patients with limited time on treatment achieved stable disease with tumor regression of -21%, -23%, and -27% on their first post-baseline scans, and were awaiting their next scans. Duration of response ranged from 1.9+ to 7.4+ months, and the duration of treatment in the 17 patients ranged from 0.9 to 30.7+ months.
In the NTRK-positive TKI-pretreated advanced solid tumor population (EXP-6: n=23), the cORR was 48% (95% CI: 27-69). As of the cutoff date, three patients had unconfirmed partial responses (uPRs). Two uPRs have been confirmed since the cutoff date and are included in the cORR; the third patient with a uPR was on treatment awaiting a confirmatory scan and is not considered a responder in the cORR. The 48% cORR is an update since the pre-recorded presentation. Duration of response ranged from 0.9+ to 15.1 months, and the duration of treatment in the 23 patients ranged from 0.6 to 20.8 months.
Of the 23 NTRK-positive TKI-pretreated advanced solid tumor patients, 13 (57%) had NTRK solvent front mutations. In these 13 patients, the cORR was 62% (95% CI: 32-86) including one patient who had a complete response. As of the cutoff date, three patients had unconfirmed partial responses (uPRs). Two uPRs have been confirmed since the cutoff date and are included in the cORR; the third patient with a uPR was on treatment awaiting a confirmatory scan and is not considered a responder in the cORR. The 62% cORR is an update since the pre-recorded presentation. Duration of response ranged from 0.9+ to 13.7 months.
Preliminary Safety Analysis (n=301)
Repotrectinib was generally well tolerated.
The most frequently reported treatment-emergent adverse event (TEAE) was low-grade dizziness (60%) of which 76% of reported cases were grade 1. Eleven patients (4%) reported ataxia in the absence of dizziness. No events of dizziness or ataxia led to treatment discontinuation.
Dose modifications due to TEAEs included 27% of patients who had dose reduction and 11% who had drug discontinuation.
Turning Point also announced the publication of preclinical data of repotrectinib in the American Association of Cancer Research’s peer reviewed journal, Molecular Cancer Therapeutics. Preclinical studies described in the publication titled "Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations" show that repotrectinib potently inhibited TRK fusion proteins and resistance mutations. Repotrectinib was the most potent inhibitor of wild-type TRKA/B/C fusions and was more potent than selitrectinib against all tested resistance mutations.
Repotrectinib was recently granted Breakthrough Therapy designation for the treatment of patients with advanced solid tumors that have an NTRK gene fusion who have progressed following treatment with one or two prior TRK tyrosine kinase inhibitors, with or without prior chemotherapy, and have no satisfactory alternative treatments. The company is planning to discuss next steps towards potential registration of repotrectinib in this patient population at a Type B meeting with the U.S. Food and Drug Administration (FDA) anticipated in the first half of 2022.