The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the approval of repotrectinib, a next-generation tyrosine kinase inhibitor (TKI), for specific advanced cancers. Bristol Myers Squibb's repotrectinib is recommended for adult patients with ROS1-positive advanced non-small cell lung cancer (NSCLC) and for patients 12 years and older with advanced solid tumors expressing an NTRK gene fusion. This includes those who have received a prior NTRK inhibitor, or those without prior NTRK inhibitor treatment where other options provide limited benefit. The European Commission (EC) is expected to make its final decision in January 2025.
Clinical Trial Data and Efficacy
The positive opinion is based on results from the TRIDENT-1 and CARE trials. These trials demonstrated clinically meaningful response rates in patients with ROS1-positive NSCLC and NTRK-positive solid tumors, both as an initial targeted treatment and after progression on a prior targeted treatment. The trials also showed robust durability of response and intracranial responses in both settings, including in patients whose tumors harbor common resistance mutations. The safety profile of repotrectinib was well-characterized and generally manageable with routine standard-of-care treatments.
TRIDENT-1 Trial Details
TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort phase 1/2 clinical trial. It evaluates the safety, tolerability, pharmacokinetics, and anti-tumor activity of repotrectinib in patients with advanced solid tumors, including NSCLC. The trial includes patients with locally advanced or metastatic solid tumors harboring ROS1 and NTRK fusions. Asymptomatic central nervous system (CNS) metastases were allowed. Phase 2 of the trial has a primary endpoint of overall response rate (ORR). Key secondary endpoints include duration of response (DOR), progression-free survival (PFS), and intracranial response.
CARE Trial Details
CARE is a phase 1/2 open-label clinical trial evaluating repotrectinib in pediatric and young adult patients with locally advanced or metastatic solid tumors harboring ALK, ROS1, or NTRK1-3 gene alterations. Phase 2 of the study seeks to demonstrate the efficacy and anti-tumor activity of repotrectinib in pediatric and young adult patients. The primary endpoint of phase 2 is ORR, and secondary endpoints include CBR, TTR, DOR, IC-ORR, progression-free survival (PFS), central nervous system PFS (CNS-PFS) and overall survival (OS).
Addressing Unmet Needs
Joseph Fiore, vice president, global program lead, repotrectinib, Bristol Myers Squibb, stated that patients in the EU with ROS1-positive NSCLC and NTRK-positive solid tumors face a great unmet need for new therapies. These therapies may improve outcomes and address or delay the issue of treatment resistance.
Background on ROS1 and NTRK Fusions
ROS1 fusions occur in about 1-2% of patients with NSCLC. Patients with ROS1-positive tumors tend to be younger, more often female, and may have little to no smoking history. ROS1-positive lung cancer tends to be aggressive and can often spread to the brain. NTRK gene fusions are alterations that lead to abnormal proteins, which may cause cancer cells to grow. Testing for NTRK gene fusions allows for the identification of patients who may benefit from TRK inhibitor therapy.
Repotrectinib: A Next-Generation TKI
Repotrectinib (TPX-0005, BMS-986472) is a next-generation tyrosine kinase inhibitor (TKI) targeting ROS1- or NTRK-positive advanced solid tumors, including non-small cell lung cancer (NSCLC). It was designed to improve durability of response and with favorable properties for human brain penetration to enhance intracranial activity.
