Larotrectinib Displays Favorable Safety and Efficacy in Patients with NTRK Fusion–Positive Lung Cancers

Alexander Drilon, MD

Patients with advanced lung cancers whose tumors harbor NTRK gene fusions experienced durable responses, survival benefit, and a favorable safety profile with larotrectinib (Vitrakvi) treatment. The supporting data were taken from phase 2 and phase 1 trials analyzing the effects larotrectinib would have on both adult and young adult patients with NTRK gene fusions.

The objective response rate (ORR) among 15 evaluable patients was 73% (95% CI, 45%-92%). One patient (7%) had a complete response, 10 patients (67%) patients had partial responses, 3 patients (20%) had stable disease, and 1 patient (7%) had progressive disease as a best response.

Both studies administered 100 mg of larotrectinib twice daily in continuous 28-day cycles. Treatment beyond progression was permitted if the patient continued to benefit. The data cutoff was July 20, 2020. The primary end point was ORR, and the secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Patients were included in the phase 2 NAVIGATE trial (NCT02576431)2 if they had a locally advanced or metastatic solid tumor, had an ECOG performance status of 0 to 3, had adequate major organ function, and had received prior standard therapy appropriate for their tumor type. Patients enrolled in this trial were 12 years or older.

Patients were eligible for inclusion in the phase 1 study (NCT02122913)3 if they had a locally advanced or metastatic solid tumor that progressed or was nonresponsive to available therapies, were considered unfit for standard chemotherapy or had a tumor for which no available curative therapy exists, and had an ECOG performance status of 0 to 2. Patients enrolled in this trial were 18 years or older.

The median DOR was 33.9 months (95% CI, 5.6-33.9) at a median follow up of 17.4 months. PFS was 35.4 months (95% CI, 5.3-35.4) with a median follow up of 16.6 months. OS was 40.7 months (95% CI, 17.2-not estimable) at a median follow up of 16.2 months. Eight patients with central nervous system metastases had an ORR of 63% (95% CI, 25%-91%).

A total of 20 patients were included from the 2 trials who had lung cancer with NTRK fusion. The median age was 48.5 years (range, 25.0-76.0). Ninety percent of patients (n = 18) had an ECOG performance score of 0 or 1. Half of the patient population was female. Patient histology was mostly adenocarcinoma in 19 patients (95%), and 1 patient (5%) had neuroendocrine carcinoma. Most patients (n = 16) had NTRK1 gene fusion, and the remaining 4 had NTRK3 gene fusion. Patients were pretreated for a median of 3 prior lines of therapy (range, 0-6).

In terms of safety, treatment-related adverse events (TRAEs) were reported in 16 patients (80%) among the whole patient population. AEs were mostly grade 1 or 2, and the most common AEs were myalgia (50%), constipation (40%), cough (40%), and dizziness (40%). Eight patients experienced grade 3 TRAEs. One patient felt a grade 5 AE, cardiac arrest, but investigators determined this was not related to larotrectinib treatment.

These findings support routine testing for NTRK fusions in patients with lung cancer.

_REFERENCE

_{1. Drilon A, Tan DSW, Lassen UN, et al. Efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase fusion-positive lung cancers. JCO Precis Oncol. 2022;6:e2100418. doi:10.1200/PO.21.00418}

_{2. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448}

_{3. Hong DS, Bauer TM, Lee JJ, et al. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019;30(2):325-331. doi:10.1093/annonc/mdy539}