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Repotrectinib, an Investigational TKI, Induces Response in ROS1-Fusion–Positive NSCLC

TOP - August 2019, Vol 12, No 3
Chicago, IL—Expanded data from an early phase 1/2 clinical trial showed that treatment with repotrectinib, an investigational tyrosine kinase inhibitor (TKI) with potent selectivity against tumors with ROS1 rearrangement, induced a response in 9 of 11 patients with TKI-naïve, ROS1-fusion–positive non–small-cell lung cancer (NSCLC).

In the study known as TRIDENT-1, patients with TKI-refractory NSCLC had similarly positive outcomes when treated with repotrectinib, reported Byoung Chul Cho, MD, PhD, Associate Professor, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, at the 2019 American Society of Clinical Oncology Annual Meeting.

TRIDENT-1 supports repotrectinib “as a potential best-in-class ROS1 agent in advanced NSCLC. Across 7 dose cohorts, we confirmed an objective response rate [ORR] of 82% in TKI-naïve and 39% in TKI-pretreated patients. Notably, we observed an ORR of 57% in crizotinib-pretreated patients at 160 mg daily and above. Central nervous system [CNS] activity was observed both in TKI-naïve and TKI-pretreated patients,” said Dr Cho.

The full cohort of patients included 83 individuals with ROS1- and TRK/ALK-positive solid tumors who were enrolled across 9 dose-escalation cohorts (40 mg daily to 200 mg twice daily). Of these patients, 85% received previous chemotherapy and 67% had received previous ROS1 TKIs, with 12 having received crizotinib. More than half had CNS metastases at baseline.

The preliminary efficacy analysis was conducted in 33 patients with ROS1-positive NSCLC. With a median follow-up of 16.4 months, median duration of response was not yet reached, with 5 of the 9 patients remaining in response from 10.9 months to longer than 17.7 months.

“Intracranial response rate was 100%, and the clinical benefit rate was 100%. This is exciting because this is the most promising data presented so far on a ROS1 TKI in a TKI-naïve population,” Dr Cho said.

Among the 22 patients with TKI-­refractory NSCLC, 3 of 4 patients treated with ≥1 previous TKIs experienced tumor regression from baseline, and 7 patients treated with ≥1 previous TKIs had “dramatic” tumor regression from baseline.

Among 18 patients pretreated with 1 previous TKI, the confirmed ORR was 39%, and the ORR for doses ≥160 mg daily was 55%. The ORR after crizotinib as the only previous TKI was 57%.

“This is important because there is no available therapy option after crizotinib progression in this disease,” Dr Cho said. The intracranial response rate was 75%, and the clinical benefit rate was 78%. Five patients who received previous crizotinib also had a G2032R mutation—and all 5 experienced tumor regression with repotrectinib.

“Time to response was rapid, usually within 2 months following repotrectinib treatment,” Dr Cho said. At data cutoff, 15 of the 33 (45%) patients remained on treatment, with 12 of the 15 (80%) remaining on treatment for >12 months. The longest duration of treatment exceeded >20 months for both cohorts, “suggesting excellent tolerability,” he said.

All 83 patients with solid tumors enrolled were assessed for safety. Most adverse events were manageable and were grade 1 or 2 in severity. The most frequent treatment-emergent adverse events were dizziness (57%), dysgeusia (51%), dyspnea (30%), fatigue (30%), constipation (29%), paresthesia (29%), and anemia (28%). Grade 3 treatment-related adverse events were anemia (N = 3); dizziness (N = 2); and dyspnea, hypophosphatemia, hypoxia, pleural effusion, and weight increase (all N = 1). There were 4 dose-limiting toxicities (grade 3 dyspnea/hypoxia and grade 2 or 3 dizziness), and 12 treatment-related adverse events were observed that required dose modifications. The maximum tolerated dose is still unknown.

“Dizziness is an on-target adverse event associated with TRK inhibition, and manageable,” Dr Cho said.

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