Repotrectinib Earns FDA Priority Review in NTRK+ Advanced Solid Tumors

Supporting data for the sNDA came from the phase 1/2 TRIDENT-1 trial (NCT03093116) assessing repotrectinib in patients with locally advanced or metastatic solid tumors harboring ROS1 or NTRK fusions.

The FDA has granted priority review to a supplemental new drug application (sNDA) for repotrectinib (Augtyro) as a treatment for patients 12 years and older with locally advanced or metastatic solid tumors that are unsuitable for surgical resection and harbor an NTRK gene fusion, according to a press release from Bristol Myers Squibb, the developer of the agent.¹

The regulatory agency set a Prescription Drug User Fee Act date of June 15, 2024 for its decision on the approval for repotrectinib in this indication.

“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 [TKIs] are critical to helping patients with these aggressive tumors,” Joseph Fiore, vice president and global program lead of repotrectinib at Bristol Myers Squibb, said in the press release. “We look forward to working closely with the FDA on the review of our application for [repotrectinib] for this tumor-agnostic indication and potentially offering patients with NTRK-positive disease a new, durable treatment option.”

Supporting data for the sNDA came from the phase 1/2 TRIDENT-1 trial (NCT03093116) assessing repotrectinib in patients with locally advanced or metastatic solid tumors harboring ROS1 or NTRK fusions. Findings from the phase 1/2 CARE study (NCT04094610) evaluating the agent in pediatric and young adult patients with locally advanced or metastatic solid tumors with ALK, ROS1, or NTRK alterations also supported the TRIDENT-1 trial.

TRIDENT-1 Trial

According to findings published in Annals of Oncology, the confirmed objective response rate (ORR) with repotrectinib in patients with NTRK-positive non–small cell lung cancer (NSCLC) who received no prior treatment with TKIs was 62% (95% CI, 38%-82%).² Additionally, responses were ongoing in 92% (95% CI, 76%-100%) at 12 months in this cohort, and the estimated 12-month progression-free survival (PFS) rate was 64% (95% CI, 43%-86%).

Among those with TKI-pretreated NSCLC harboring NTRK fusions, the confirmed ORR was 43% (95% CI, 18%-71%), and 44% (95% CI, 1%-88%) were estimated to have sustained responses at 12 months. Investigators also highlighted an estimated 12-month PFS rate of 23% (95% CI, 0%-49%).

In TRIDENT-1, patients received repotrectinib at 160 mg once daily for 14 days followed by 160 mg twice daily. The primary end point in the phase 2 portion was confirmed ORR as assessed by blinded independent central review. Secondary end points included DOR, clinical benefit, and safety.

The most common treatment-emergent adverse effect (TEAE) was dizziness (62% any-grade; 3% grade 3 or higher). Additionally, 7% of patients discontinued treatment due to TEAEs, and 3% discontinued due to treatment-related AEs.

CARE Study

The open-label phase 1/2 CARE study was designed to evaluate the safety, tolerability, pharmacokinetics, and clinical activity of repotrectinib in pediatric and young adult patients with advanced or metastatic solid tumors harboring ALK, ROS1, or NTRK1-3 alterations.

The primary end points in phase 1 include dose-limiting toxicities and the pediatric recommended phase 2 dose. Secondary end points in this phase include ORR, clinical benefit rate (CBR), time to response (TTR), duration of response (DOR), and intracranial ORR.

The study’s primary end point in phase 2 is ORR. Secondary end points in this phase will include CBR, TTR, DOR, intracranial ORR, progression-free survival, and overall survival.

The FDA granted approval to repotrectinib in locally advanced or metastatic ROS1-posititve NSCLC in November 2023.³ Supporting data for the approval came from the TRIDENT-1 trial.

References

1. U.S. Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for Augtyro™ (repotrectinib) for the treatment of patients with NTRK-positive locally advanced or metastatic solid tumors. News release. Bristol Myers Squibb. February 14, 2024. Accessed February 14, 2024. http://tinyurl.com/3x8398sh
2. Solomon BJ, Drillon A, Lin JJ, et al. Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: update from the phase I/II TRIDENT-1 trial. Ann Oncol. 2023;34(suppl 2):S787-S788. doi:10.1016/j.annonc.2023.09.2405
3. U.S. Food and Drug Administration approves Augtyro™ (repotrectinib), a next-generation tyrosine kinase inhibitor (TKI), for the treatment of locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). News release. Bristol Myers Squibb. November 15, 2023. Accessed February 14, 2024. https://shorturl.at/AKLP4