Rationale for Requested Change: This data is being submitted in response to a standing request from the NCCN® for new data. We request the panel to review the data of repotrectinib that were presented at the European Society for Medical Oncology Congress 2023 (Solomon B, et al. ESMO 2023) and the recent approval of repotrectinib for patients with NTRK-positive (NTRK+) locally advanced or metastatic solid tumors.
Study design:
TRIDENT-1 (NCT03093116) is a global, single-arm, multi-cohort, ongoing, registrational phase 1/2 trial that evaluated the efficacy and safety of repotrectinib, a ROS1 and TRK tyrosine kinase inhibitor (TKI), in patients with locally advanced or metastatic solid tumors harboring ROS1 or NTRK1/2/3-fusions. Patients with asymptomatic central nervous system metastases were eligible to enroll. This submission focuses on the TRIDENT-1 data in patients with NTRK+ solid tumors. The phase 1 portion evaluated various doses and schedules with an objective of determining the recommended phase 2 dose (RP2D). The RP2D was determined to be repotrectinib 160 mg once daily for 14 days, then increase to 160 mg twice daily. The phase 2 portion evaluated repotrectinib in patients with NTRK+ advanced or metastatic solid tumors.
Patients with NTRK+ tumors were placed into one of two cohorts by treatment history: NTRK TKI-naïve or NTRK TKI-pretreated. The primary endpoint of phase 2 was confirmed objective response rate (ORR) by BICR using RECIST v1.1. Key secondary endpoints included duration of response (DOR) and safety. The safety analysis included all patients from TRIDENT-1 who were treated with repotrectinib at the RP2D regardless of tumor type or molecular characteristics.
NTRK TKI-naive cohort: repotrectinib as a first NTRK TKI treatment for NTRK+ metastatic solid tumors
The NTRK TKI-naïve cohort included 40 patients with the following tumor types: non-small cell lung cancer (n = 21), thyroid cancer (n = 5), salivary gland cancer (n = 3), soft tissue sarcoma (n = 3), breast cancer (n = 2), colorectal cancer (n = 1), glioblastoma (n = 1), esophageal cancer (n = 1), cholangiocarcinoma (n = 1), head and neck cancer (n = 1), and peripheral nerve sheath tumor (n = 1). The median age in this cohort was 61 years (range: 25 - 84). Majority of the patients were female (60%) and had an ECOG PS of 1 (55%); 23% of the patients had brain metastasis at baseline. (AUGTYRO™ Prescribing Information and Solomon B, et al. ESMO 2023)
In the NTRK TKI-naïve cohort, repotrectinib showed a confirmed ORR of 58% (95% CI, 41 - 73) when used as the first NTRK TKI to treat NTRK+ advanced solid tumors. The median DOR was not reached. At 12-months, the DOR rate was 83%. Among the 2 patients who had measurable baseline brain metastases, repotrectinib led to an intracranial ORR of 100%.
NTRK TKI-pretreated cohort: repotrectinib as a subsequent treatment for NTRK+ metastatic solid tumor
This cohort evaluated repotrectinib as a subsequent NTRK TKI to treat NTRK+ advanced or metastatic solid tumors following progression on prior NTRK TKI such as entrectinib or larotrectinib. The NTRK TKI-pretreated cohort included 48 patients with the following tumor types: non-small cell lung cancer (29%, n = 14), salivary gland cancer (n = 8), soft tissue sarcoma (n = 6), thyroid cancer (n = 4), glioblastoma (n = 3), pancreatic cancer (n = 2), cholangiocarcinoma (n = 2), colorectal cancer (n = 2), neuroendocrine tumor (n = 2), peripheral nerve sheath tumor (n = 2), breast cancer (n = 1), gallbladder cancer (n = 1), and unknown primary cancer (n = 1). The median age in this cohort was 58 years (range: 20 to 81). Majority of the patients were male (52%) and had an ECOG PS of 1 (60%); 25% of the patients had brain metastasis at baseline.
In the NTRK TKI-pretreated cohort, repotrectinib showed a confirmed ORR of 50% (95% CI, 35 - 65). The median DOR was 9.9 months (95% CI, 7.4 - 13), with a 12-month DOR rate of 42%. In the 3 patients who had measurable baseline brain metastases, repotrectinib led to an intracranial ORR of 100%. In patients with solvent front mutation (n = 25), the ORR was 60% (95% CI, 39 - 79).
Safety results:
The safety analysis included all patients from TRIDENT-1 who were treated with repotrectinib at RP2D regardless of tumor type or molecular characteristics (n = 426). Of the patients in the safety analysis, 35% of patients experienced a serious adverse reaction with the most common being pneumonia (6.3%), dyspnea (3.1%), pleural effusion (2.8%), and hypoxia (2.6%). A total of 3.5% of patients who received repotrectinib experienced a fatal adverse reaction. Adverse events leading to dose reductions, drug interruption, and permanent treatment discontinuation occurred in 38%, 50%, and 7% of patients who received repotrectinib, respectively. The most common adverse event reported for repotrectinib was dizziness (65%), dysgeusia (54%), peripheral neuropathy (49%), constipation (38%), dyspnea (30%), fatigue (30%), ataxia (28%), cognitive impairment (25%), muscular weakness (20%) and nausea (20%). Grade 3 or 4 dizziness occurred in only 2.8% of patients.
Thank you for your consideration of this request.