SUMMARY: The FDA on November 15, 2023, approved AUGTYRO® (Repotrectinib) for locally advanced or metastatic ROS1-positive Non-Small Cell Lung Cancer (NSCLC). This is the first FDA approval that includes patients with ROS1-positive NSCLC who have previously received a ROS1 Tyrosine Kinase Inhibitor (TKI), in addition to patients who are TKI naïve.
Approximately 1-2% of lung adenocarcinomas harbor ROS1 gene rearrangements. ROS1 gene is located on chromosome 6q22 (long arm of chromosome 6) and plays an important role in cell growth and development. ROS1 gene fusion with another gene results in a mutated DNA sequence which then produces an abnormal protein responsible for unregulated cell growth and cancer. ROS1 gene rearrangement has been identified as a driver mutation in Non Small Cell Lung Cancer with adenocarcinoma histology. This is more common in nonsmokers or in light smokers (<10 pack years) who are relatively young (average age of 50 years), and thus share similar characteristics with ALK-positive patients. ROS1 mutations have been also been associated with Cholangiocarcinoma (Bile duct cancer) and Glioblastoma multiforme. ROS1 rearrangements are mutually exclusive with other oncogenic mutations found in NSCLC such as EGFR mutations, KRAS mutations and ALK rearrangement. The presence of a ROS1 rearrangement can be detected by Fluorescence In Situ Hybridization (FISH), ImmunoHistoChemistry (IHC), Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and Next Generation-Sequencing. There are currently two FDA-approved treatment options for ROS1-positive metastatic NSCLC- Crizotinib and Entrectinib.
Repotrectinib is a next-generation TKI targeting ROS1 or NTRK-positive locally advanced or metastatic solid tumors, including NSCLC. Repotrectinib was designed to improve durability of response and with favorable properties to enhance intracranial activity.
The FDA approval was based on the results of the TRIDENT-1 global, multicenter, single-arm, Phase I/II, open-label, multi-cohort clinical trial, designed to evaluate the safety, tolerability, pharmacokinetics, and anti-tumor activity of Repotrectinib, in patients with advanced solid tumors, including locally advanced or metastatic NSCLC. Phase I component of the trial evaluated the safety and pharmacokinetics, whereas in the Phase II component of the study included six distinct expansion cohorts, including TKI-naïve and TKI-pretreated patients with ROS1-positive locally advanced or metastatic NSCLC and NTRK-positive advanced solid tumors. Eligibility requirements included locally advanced or metastatic solid tumors harboring ROS1 or NTRK1-3 gene fusions. Patients with asymptomatic CNS metastases were allowed. Patients received Repotrectinib 160 mg once daily, orally for 14 days, followed by 160 mg twice daily until disease progression or unacceptable toxicities. The Primary endpoint was Overall Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR), and Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and Clinical Benefit Rate (CBR). The efficacy was evaluated in ROS1 TKI-naïve patients (N=71) who received up to one prior line of platinum-based chemotherapy and/or immunotherapy, and in patients who received one prior ROS1 TKI with no prior platinum-based chemotherapy or immunotherapy (N=56).
In TKI-naïve patients with median follow-up of 24.0 months, the confirmed Objective Response Rate by BICR was 79%, median Duration of Response was 34.1 months and PFS was 35.7 months. In patients with measurable brain metastases at baseline (N=9), intracranial ORR per BICR was 89% and these responses were prolonged.
In patients who received one prior ROS1 TKI with no prior chemotherapy or immunotherapy, at a median follow-up of 21.5 months, the confirmed Objective Response Rate by BICR was 38%, median Duration of Response was 14.8 months and PFS was 9.0 months. In this subset of patients with measurable brain metastases at baseline (N=13), intracranial ORR per BICR was 38%.
The most common adverse reactions were fatigue, dizziness, dyspnea, dysgeusia, peripheral neuropathy, constipation, ataxia, cognitive disorders, and muscular weakness.
It was concluded that the TRIDENT-1 trial demonstrated the efficacy of Repotrectinib in both, TKI-naïve and previously treated patients, showcasing high response rates and durable outcomes. These data will provide physicians with valuable insights into the clinical benefits with Repotrectinib , paving the way for its potential adoption as a new standard of care, in the treatment of ROS1-positive NSCLC. TRIDENT-1 trial is ongoing to assess long term outcomes and additional endpoints across patient populations with ROS1-positive locally advanced or metastatic NSCLC, and NTRK-positive advanced solid tumors.
Repotrectinib in patients with ROS1 fusion-positive (ROS1+) NSCLC: Update from the pivotal phase 1/2 TRIDENT-1 trial. Cho BC, Camidge DR, Lin JJ, et al. Presented at the IASLC 2023 World Conference on Lung Cancer; September 10-12, 2023; Singapore. Abstract OA03.06.
