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, advanced non–small-cell lung cancer (NSCLC) and ROS1 fusion.
In the TRIDENT-1 study, patients with TKI-refractory NSCLC had similar positive outcomes when they received repotrectinib, reported Byoung Chul Cho, MD, PhD, Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, at ASCO 2019.
Repotrectinib a Best-in-Class Drug?
TRIDENT-1 supports repotrectinib “as a potential best-in-class ROS1 agent in advanced NSCLC,” said Dr Cho. “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 activity was observed both in TKI-naïve and TKI-pretreated patients.”
The full cohort of patients included 83 patients with ROS1- and TRK/ALK-positive solid tumors who were enrolled across 9 dose-escalation cohorts (from 40 mg daily to 200 mg twice daily). Overall, 85% of patients had received chemotherapy and 67% had received ROS1 TKIs, with 12 patients having received crizotinib. More than 50% of the patients had central nervous system 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, the median duration of response was not yet reached, and 5 of the 9 remaining patients were still responding at 10.9 months to more than 17.7 months.
“The intracranial response rate was 100%, and the clinical benefit rate was 100%,” Dr Cho noted. “This is exciting, because this is the most promising data presented so far on a ROS1 TKI in a TKI-naïve population.”
Among the 22 patients with TKI-refractory NSCLC, 3 of 4 patients who received ≥1 previous TKIs had tumor regression from baseline. A total of 7 patients who received ≥1 previous TKIs had “dramatic” tumor regression from baseline, said Dr Cho.
Among 18 patients who received pretreatment with 1 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 therapy was 57%.
“This is important, because there is no available therapy option after crizotinib progression in this disease,” Dr Cho pointed out. The intracranial response rate was 75%, and the clinical benefit rate was 78%. Five patients who received previous crizotinib therapy also had a G2032R mutation, and all 5 patients had tumor regression with repotrectinib.
“The time to response was rapid, usually within 2 months following repotrectinib treatment,” Dr Cho said. At data cutoff, 15 (45%) of the 33 patients continued to receive treatment, with 12 (80%) of the 15 patients continuing treatment for >12 months. The longest duration of treatment exceeded 20 months for both cohorts, “suggesting excellent tolerability,” he noted.
All 83 patients with solid tumors in the study were assessed for safety. Most adverse events were grade 1 or 2 and were manageable. The most common 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 included 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 or hypoxia and grade 2 or 3 dizziness), and 12 treatment-related adverse events required dose modifications. The maximum tolerated dose is still unknown.
“Dizziness is an on-target adverse event associated with TRK inhibition, and is manageable,” Dr Cho said.