FDA Grants Accelerated Approval to Repotrectinib for NTRK+ Solid Tumors

FDA

The FDA granted accelerated approval to repotrectinib (Augtyro) for adult and pediatric patients aged 12 years and older with solid tumors harboring an NTRK gene fusion, that are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity, and that have progressed after treatment or have no satisfactory alternative therapy.¹

The regulatory decision was supported by findings from the phase 1/2 TRIDENT-1 study (NCT03093116) in which repotrectinib elicited a confirmed overall response rate (cORR) of 58% (95% CI, 41%-73%) by blinded independent central review (BICR) and RECIST 1.1 criteria in patients who were TKI naive (n = 40), with a median duration of response (DOR) that was not estimable (NE; 95% CI, NE-NE). In those who received a prior TKI inhibitor (n = 48), the confirmed ORR was 50% (95% CI, 35%-65%) with the agent, with a median DOR of 9.9 months (95% CI, 7.4-13.0).

TRIDENT-1: Eligibility, Treatment, and Objectives

The multicenter, single-arm, open-label, multi-cohort trial enrolled patients with locally advanced or metastatic solid tumors harboring ROS1 or NTRK1-3 gene fusions irrespective of prior receipt of a TRK TKI. At baseline, all participants were evaluated for central nervous system lesions. Patients with symptomatic brain metastases were excluded.

Those in the phase 1 dose-escalation cohorts were given repotrectinib at the recommended phase 2 dose of 160 mg daily for 14 days and then 160 mg twice daily. Those with NTRK-positive locally advanced or metastatic solid tumors received treatment in phase 2 dose expansion cohorts and were divided into those who were TKI naive (n = 40) and pretreated (n = 48).

In the NTRK-positive population, the primary end point was cORR by BICR, and key secondary end points included DOR, clinical benefit rate, time to response; cORR in TKI-pretreated patients harboring NTRK1-3 resistance mutations; progression-free survival and overall survival; intracranial ORR by modified RECIST 1.1 criteria in those with measurable brain metastases; safety and patient-reported outcomes.

Patient Characteristics

The median patient age across the TKI-naive and -pretreated cohorts was 59 years (range, 20-84). Patients received treatment in the United States (27.5%), Asia (32.5%), or other (40%). Females accounted for 60% of the TKI-naive group and 48% of the TKI-pretreated group. More than half of patients in both cohorts had an ECOG performance status of 1 (55% vs 60%). Brain metastases were present in 22% and 25% of patients, respectively.

With regard to resistance mutations in the TKI-naive group, 78% were negative and 22% had unknown status. In the TKI-pretreated group, 52% had a solvent front resistance mutation, 2% had a gatekeeper mutation, 42% were negative, and 4% had unknown status. Moreover, in the TKI-naive group, 48% of patients received 1 prior line of chemotherapy with or without immunotherapy; in the TKI-pretreated group, this rate was 46%. Fifteen percent and 23% of patients, respectively received 2 or more prior lines. In the TKI-pretreated group, 50% previously received entrectinib (Rozlytrek), 48% had prior exposure to larotrectinib (Vitrakvi), and 14% were exposed to another TKI.

Safety

Regarding safety, the most common adverse effects occurring in more than 20% of patients included dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.¹

References

1. FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. FDA. June 13, 2024. Accessed June 13, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-repotrectinib-adult-and-pediatric-patients-ntrk-gene-fusion-positive
2. Solomon BJ, Drilon 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