CHMP Backs Bristol Myers Squibb's Repotrectinib for Advanced ROS1-Positive Lung Cancer and NTRK-Positive Tumors

Bristol Myers Squibb has announced that 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). This recommendation is for the treatment of adult patients with ROS1-positive advanced non-small cell lung cancer (NSCLC) and for both adult and pediatric patients aged 12 and older with advanced solid tumors expressing an NTRK gene fusion. These patients must have either received a prior NTRK inhibitor, not received a prior NTRK inhibitor and have limited treatment options, or exhausted other treatment methods.

The European Commission (EC) will now review CHMP's recommendation, with a final decision expected by January 2025. Joseph Fiore, vice president and global program lead for repotrectinib at Bristol Myers Squibb, expressed optimism about the potential approval, emphasizing the significant unmet need for effective therapies for patients with ROS1-positive NSCLC and NTRK-positive solid tumors.

The positive CHMP opinion is based on data from the TRIDENT-1 and CARE clinical trials, which showed that repotrectinib achieved significant response rates in patients with ROS1-positive NSCLC and NTRK-positive solid tumors. These responses were observed both as an initial targeted treatment and after progression on a prior targeted treatment. The trials also highlighted the durability of the response and noted intracranial responses in patients, including those with common resistance mutations. Repotrectinib's safety profile was well-documented and generally manageable with standard care treatments. The ongoing study continues to evaluate long-term outcomes and other endpoints for these patient populations.

In the United States, repotrectinib, marketed as Augtyro, has already received approval from the Food and Drug Administration (FDA) for treating adult patients with locally advanced or metastatic ROS1-positive NSCLC (November 2023) and for patients with NTRK-positive locally advanced or metastatic solid tumors (June 2024).

The TRIDENT-1 trial is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical trial assessing the safety, tolerability, pharmacokinetics, and anti-tumor activity of repotrectinib in patients with advanced solid tumors, including NSCLC. This trial includes patients with locally advanced or metastatic solid tumors harboring ROS1 and NTRK fusions. The primary endpoint for Phase 2 is the overall response rate (ORR), with secondary endpoints including duration of response (DOR), progression-free survival (PFS), and intracranial response.

Similarly, the CARE trial is a Phase 1/2 open-label study evaluating repotrectinib in pediatric and young adult patients with locally advanced or metastatic solid tumors harboring ALK, ROS1, or NTRK1-3 gene alterations. The study's primary endpoints for Phase 1 include dose-limiting toxicities and recommended Phase 2 dose (RP2D), with secondary endpoints like ORR, clinical benefit rate (CBR), and others. Phase 2 seeks to demonstrate the efficacy and anti-tumor activity of the drug in these populations.

Lung cancer remains a leading cause of cancer deaths, with non-small cell lung cancer (NSCLC) accounting for a significant majority of diagnoses. About 1-2% of NSCLC patients have ROS1 fusions, which tend to be aggressive and often spread to the brain. The current standard of care for ROS1-positive tumors includes tyrosine kinase inhibitor therapy. Similarly, NTRK-positive solid tumors are rare but identifiable through gene fusion testing, with TRK inhibitor therapy offering potential benefits.

Repotrectinib is a next-generation TKI designed to improve response durability and enhance brain penetration, addressing significant unmet medical needs for patients with ROS1- or NTRK-positive advanced solid tumors. In addition to its current FDA approvals, repotrectinib has received multiple Breakthrough Therapy and Fast Track designations, highlighting its clinical significance and potential to address critical gaps in cancer treatment.