On February 14, 2024 Bristol Myers Squibb (NYSE: BMY) reported that the U.S. Food and Drug Administration (FDA) has accepted the supplemental New Drug Application (sNDA) for Augtyro (repotrectinib) for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, and are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity (Press release, Bristol-Myers Squibb, FEB 14, 2024, View Source [SID1234640083]). The filing acceptance is based on results from the registrational Phase 1/2 TRIDENT-1 trial (adult patients with NTRK-positivesolid tumors) and CARE study (pediatric patients with NTRK-positivesolid tumors). The FDA granted the application Priority Review status and assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 15, 2024.

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"While great advancements have been made over the last decade, patients with NTRK-positive locally advanced or metastatic solid tumors still experience significant unmet needs. New and effective treatment options that may improve durability of response and address resistance to existing tyrosine kinase inhibitors are critical to helping patients with these aggressive tumors," said Joseph Fiore, vice president, global program lead, Augtyro, Bristol Myers Squibb. "We look forward to working closely with the FDA on the review of our application for Augtyro for this tumor-agnostic indication and potentially offering patients with NTRK-positive disease a new, durable treatment option."

The filing was based on the results from the TRIDENT-1 and CARE trials. In the TRIDENT-1 study, Augtyro demonstrated clinically meaningful response rates in patients with NTRK-positive locally advanced or metastatic solid tumors. Durability of response was robust, including among patients whose tumors harbor common resistance mutations, and intracranial responses were observed. Augtyro showed a safety profile that was well tolerated and generally manageable. The study remains ongoing to assess long-term outcomes and additional endpoints. Results from TRIDENT-1 were supported by data from the CARE study, which evaluates Augtyro in pediatric and young adult patients with locally advanced or metastatic solid tumors harboring ALK, ROS1 or NTRK1-3 gene alterations. Additionally, in November 2023 the U.S. Food and Drug Administration approved Augtyro for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer NSCLC.

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

Turning Point Therapeutics is a wholly owned subsidiary of the Bristol-Myers Squibb Company. As of August 2022, Bristol Myers Squibb acquired the company, including its asset repotrectinib.

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 Augtyro 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 or 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 Augtyro 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). Phase 2 of the study will seek to demonstrate the efficacy and anti-tumor activity of Augtyro 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 NTRK-Positive Solid Tumors

Neurotrophic tropomyosin kinase receptors (NTRK) are a family of receptors involved in neural development. NTRK gene fusions can play a role in the development of cancer. They are rare in patients with solid tumors with less than 1% of patients testing positive, though may be more frequent in patients with secretory breast cancer, infantile fibrosarcoma, thyroid cancer, gastrointestinal stromal tumors, spitzoid tumors and infantile fibrosarcoma, among other cancers. Per international treatment guidelines, targeted agents are part of the treatment armamentarium for patients with a tumor harboring this gene alteration.