Efficacy & Safety of Larotrectinib for TRK Fusion Lung Cancer

NTRK gene fusions are oncogenic drivers in a range of cancers, including lung cancer. Larotrectinib, a first-in-class, highly selective, CNS-active TRK inhibitor, has been approved for the tumor-agnostic treatment of TRK fusion cancers due to its robust and durable efficacy across various tumor types.

Jessica Lin and the team aimed to assess the updated efficacy, safety, and biomarker profile of larotrectinib in patients with TRK fusion lung cancer.

They performed an inclusive analysis of patients with TRK fusion lung cancer who were treated with larotrectinib in 2 clinical trials (NCT02122913 and NCT02576431). Larotrectinib was given at 100 mg twice daily. Independent review committee (IRC) evaluated the responses using Response Evaluation Criteria in Solid Tumors version 1.1. The data cutoff for this analysis was July 20, 2023.

A total of 32 patients with TRK fusion lung cancer, with a median age of 55.5 years (range 25-81), were enrolled by the data cutoff, including 12 with CNS metastases at baseline. All patients had their NTRK gene fusions identified locally using next-generation sequencing (NGS), with fusions involving NTRK1 (n=24; 75%) and NTRK3 (n=8; 25%). The patients had a median of 2 prior lines of systemic therapies, with 1 patient being treatment-naïve.

The overall response rate per IRC was 66% (95% confidence interval [CI] 47-81), comprising 4 complete responses (CR), 17 partial responses, 7 stable disease, 2 progressive disease, and 2 not evaluable. The median time to first response was 1.8 months (range 1.5-7.3). The median duration of response was 34 months (95% CI 10-not estimable [NE]), with a median follow-up of 26 months. The median progression-free survival (PFS) was 22 months (95% CI 10-NE), with a median follow-up of 28 months.

The median overall survival was 39 months (95% CI 17-NE), with a median follow-up of 33 months. Treatment duration varied from 2 to over 75 months. By the data cutoff, 11 patients had experienced progression and 6 of these continued treatment for ≥4 weeks post-progression due to ongoing clinical benefit. Treatment-related adverse events (TRAEs) were mostly Grade 1/2, with Grade 3/4 TRAEs reported in 9 patients.

Of these 1 patient discontinued treatment due to TRAEs (elevated alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase). Baseline genomic data, derived from circulating tumor DNA (ctDNA; n=15 patients) or tissue DNA (n=13 patients), were available for 16 patients. Baseline ctDNA analysis detected NTRK gene fusions in 6 of 15 patients.

Additional baseline NTRK and known or likely oncogenic co-occurring mutations were found in 6 of the 16 patients. Post-baseline, potential oncogenic mutations were identified in 7 of 13 patients with available DNA samples. About 5 patients had acquired potential resistance mutations, 2 had on-target mutations, 2 had off-target mutations, and 1 had both.

The study concluded that larotrectinib continues to show rapid and durable responses, prolonged survival benefits, and a favorable safety profile in patients with advanced TRK fusion lung cancer. These findings reinforce the value of using NGS panels, including ctDNA, to detect NTRK gene fusions in patients with lung cancer to identify those who might benefit from targeted therapy.

The trial is sponsored by Bayer.

Source: https://cattendee.abstractsonline.com/meeting/20598/presentation/2579

Clinical Trials: https://clinicaltrials.gov/study/NCT02122913
https://clinicaltrials.gov/study/NCT02576431

Lin J.J, Tan D.S.W, Kummar S, et al. (2024). “Updated Efficacy, Safety, and Biomarker Analysis in Patients with TRK Fusion Lung Cancer Treated with Larotrectinib.” Presented at IASLC-WCLC 2024, September 8, 2024; Singapore.