Impressive Activity of Larotrectinib in TRK Fusion–Positive Cancers

Fusions of the NTRK genes, which encode tropomyosin receptor kinase (TRK) proteins, occur in up to 1% of cancers and are found in more than 20 tumor types. These fusions result in constitutively active downstream singling and oncogene addiction regardless of tissue of origin. Larotrectinib (LOXO-101) is an oral, highly selective, potent inhibitor of TRK that is currently being evaluated in clinical trials in patients with solid tumors with TRK fusions as part of an age and tumor agnostic development program.

In a pooled safety and efficacy analysis from three phase I and II trials of the first 55 patients with TRK fusion–positive cancers enrolled across the studies (age 4 months to 76 years), larotrectinib was associated with an overall response rate (ORR) of 75%, including complete response (CR) in 13% and partial response (PR) in 62% of patients. Responses were observed regardless of tumor type, age of the patient, or TRK fusion characteristics. After 1 year of treatment, 71% of responding patients maintained their response. At a median 9.9 months follow-up, the median progression-free survival (PFS) has not been reached. Estimated 1-year PFS is 55%. There was no difference in response across the tumor types enrolled in this study. In these studies, TRK fusions were identified by next generation sequencing or by fluorescence in situ hybridization (FISH).

Larotrectinib was associated with a mild toxicity profile, comprising mostly grade 1 adverse events (AE). The most common grade 3/4 AEs were anemia (11%), increased alanine or aspartate aminotransferase (7%), and neutropenia (7%). No patient discontinued treatment due to treatment-related AEs, though 15% required dose reduction due to grade 2 or 3 AEs. Of note, in patients whose doses were reduced, best response was maintained at the lower dose. No patients discontinued treatment due to AEs.

By sequencing tumor and plasma samples obtained at progression, investigators also identified that mutations altering the kinase domain of TRK represent the key mechanism of acquired resistance to larotrectinib and could potentially be targeted with the next generation TRK inhibitor, LOXO-195.

The investigators concluded that larotrectinib demonstrates safety and clinically meaningful activity in patients with TRK fusions regardless of age or tumor type. They pointed out that screening strategies will need to include assays with the ability to identify TRK fusions to identify patients who may benefit from this targeted therapy.  In an accompanying commentary, Fabrice André, MD, PhD (Gustave Roussy, Villejuif, France), commented on the difficulty of enrolling clinical trials for rare genomic alterations and praised the basket design of the trials in overcoming this hurdle. Dr Andre highlighted the need for developing molecular assays to identify patients who have disease that will be refractory to conventional therapies early in their disease course. As alterations such as TRK fusions are rare, he called for a global effort, including harmonization among regulatory agencies and expansion of global trials.

N Engl J Med. 2018;378(8):731-739.

 N Engl J Med. 2018;378(8):763-765.