On November 15, 2024 Bristol Myers Squibb (NYSE: BMY) reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval for repotrectinib, a next-generation tyrosine kinase inhibitor (TKI), as a treatment for adult patients with ROS1 -positive advanced non-small cell lung cancer (NSCLC) and for the treatment of adult and pediatric patients 12 years of age and older with advanced solid tumors expressing a NTRK gene fusion, and who have received a prior NTRK inhibitor, or have not received a prior NTRK inhibitor and treatment options not targeting NTRK provide limited clinical benefit, or have been exhausted (Press release, Bristol-Myers Squibb, NOV 15, 2024, View Source [SID1234648438]). The European Commission (EC), which has the authority to approve medicines for the European Union (EU), will now review the CHMP recommendation. The final EC decision is expected in January 2025.

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"Patients in the EU with ROS1 -positive non-small cell lung cancer and NTRK -positive solid tumors face a great unmet need for new therapies that may improve their outcomes and address or delay the difficult issue of treatment resistance," said Joseph Fiore, vice president, global program lead, repotrectinib, Bristol Myers Squibb. "We look forward to the EC’s upcoming decision and to potentially bringing this next-generation treatment to patients with tumors harboring ROS1 or NTRK fusions in the EU."

The positive opinion is based on results from the TRIDENT-1 and CARE trials, in which repotrectinib demonstrated clinically meaningful response rates in patients across ROS1 -positive NSCLC and NTRK -positive solid tumor cohorts, both as an initial targeted treatment or after progression on a prior targeted treatment. Durability of response was robust and intracranial responses were observed in both settings, as well as 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. The study remains ongoing to assess long-term outcomes and additional endpoints across patient populations with ROS1 -positive advanced NSCLC and NTRK -positive advanced solid tumors.

In November 2023 the U.S. Food and Drug Administration approved Augtyro (repotrectinib) for the treatment of adult patients with locally advanced or metastatic ROS1 -positive NSCLC. In June 2024 the U.S. Food and Drug Administration approved Augtyro for the treatment of patients with NTRK-positive locally advanced or metastatic solid tumors.

Bristol Myers Squibb thanks the patients and investigators involved in the TRIDENT-1 and CARE clinical trials.

About TRIDENT-1

TRIDENT-1 is a global, multicenter, single-arm, open-label, multi-cohort Phase 1/2 clinical trial evaluating the safety, tolerability, pharmacokinetics and anti-tumor activity of repotrectinib in patients with advanced solid tumors, including non-small cell lung cancer (NSCLC). Phase 1/2 includes patients with locally advanced or metastatic solid tumors harboring ROS1 and NTRK fusions. Additional analyses of the trial are still being conducted; asymptomatic central nervous system (CNS) metastases are allowed. The trial excludes patients with symptomatic brain metastases, among other exclusion criteria. Phase 1 of the trial included the dose escalation that determined the recommended Phase 2 dose.

Phase 2 of the trial has a primary endpoint of overall response rate (ORR). Key secondary endpoints include duration of response (DOR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by Blinded Independent Central Review (BICR), progression-free survival (PFS), and intracranial response in six distinct expansion cohorts, including tyrosine kinase inhibitor (TKI)-naïve and TKI-pretreated patients with ROS1 -positive locally advanced or metastatic NSCLC and NTRK -positive locally advanced or metastatic solid tumors.

About CARE

CARE is a Phase 1/2 open-label, safety, tolerability, pharmacokinetics and anti-tumor activity 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 1 of the study aims to evaluate the safety and tolerability at different dose levels. Phase 1 of the trial has primary endpoints of dose limiting toxicities (DLTs) and pediatric recommended Phase 2 dose (RP2D). Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DOR) and intracranial ORR (IC-ORR). Patients less than 12 years of age will initially be enrolled in Phase 1 to determine the RP2D for this age group.

Once the pediatric RP2D is determined, patients less than 12 years of age may be enrolled into Phase 2 of the study. Patients ages 12 to 25 years will be directly enrolled into Phase 2 concurrent with Phase 1 enrollment. Phase 2 of the study will seek 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).

About ROS1 -Positive Lung Cancer

Lung cancer is the leading cause of cancer deaths in the United States. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) represents up to 85% of diagnoses. Survival rates vary depending on the stage and type of the cancer when diagnosed. ROS1 fusions are rare and occur in about 1-2% of patients with NSCLC. With a median age of 50, patients with tumors that are ROS1-positive tend to be younger than the average lung cancer patient, more often female than male and may have little to no smoking history. ROS1 -positive lung cancer tends to be aggressive and can often spread to the brain. ROS1 tyrosine kinase inhibitor (TKI) therapy is the current standard of care for patients with a tumor harboring this gene alteration.

About NTRK -Positive Solid Tumors

Neurotrophic tropomyosin receptor kinase (NTRK) are a family of receptors involved in neural development. An NTRK gene fusion is an alteration that occurs when a piece of the chromosome containing the NTRK gene breaks off and joins with a gene on another chromosome. These fusions lead to abnormal proteins, which may cause cancer cells to grow. While NTRK gene fusions are rare in patients with solid tumors, testing for NTRK gene fusions allows for the identification of patients who may benefit from TRK inhibitor therapy.