Background: NTRK genes encode tropomyosin receptor kinases (TRKA/B/C) involved in development and function of the nervous system. While NTRK amplifications and mutations occur, they are not strong drivers of cancer development associated with NTRK fusions. Fusions form when a portion of the NTRK gene (3’ end) fuses with a portion of another gene (5’ end), resulting in continual activation of various signal transduction pathways leading to cancer cell proliferation, transformation and invasiveness. NTRK fusions have been identified in less than 1% of patients with NSCLC and tend to be mutually exclusive of other mutational drivers in treatment-naive patients.
Most Common Alterations:
NTRK Fusion Genes (NTRK1/2/3): Majority fusions identified in NSCLC are NTRK1 and NTRK3.
NTRK Secondary Acquired Resistance Mutations: Develop after first-generation TKI therapy for NTRK fusion. Multiple mechanisms of resistance have been identified, with gene rearrangements being the most common, often resulting in substitution of a larger amino acid for a smaller amino acid in the ATP binding site of the TKI drug — ie, TRKA G595R and G667C and TRKC G623R and G696A. This substitution interferes with the ability of the TKI to bind and interrupt the oncogenic pathway. Next-generation drugs were developed, including selitrectinib (selective TRK inhibitor, Bayer) and repotrectinib (TRK/ROS1 inhibitor, Turning Point Therapeutics) that are smaller than first-generation TKIs and are able to shut down oncogenic signaling again.
FDA-Approved Targeted Therapies:
- Larotrectinib (Vitrakvi, Bayer):
- First-generation highly selective inhibitor of all three TRK kinases was granted approval by the FDA in 2018 for adult and pediatric patients with solid tumors withNTRK gene fusions without known acquired resistance mutation, metastatic or no other viable effective treatments. Larotrectinib has been shown to cross the blood-brain barrier. Approval was based on the results of three multicenter clinical trials (LOXO-TRK-14001, SCOUT and NAVIGATE). Combined results at time of approval showed an ORR of 75%, including 22% patients with complete responses and 53% patients with partial responses; 63% of patients experienced a duration of response of 9 months or longer at time of data lock. A separate analysis of patients with NTRK fusion-positive lung cancer found an ORR of 73%, median duration of response (DoR) of 33.9 months, PFS of 35.4 months and OS of 40.7 months.
- Most Common Adverse Events: fatigue, nausea, dizziness, vomiting, cough, elevated liver enzymes (AST), constipation, diarrhea
- Entrectinib (Rozlytrek, Genentech):
- First-generation TRK inhibitor against all three TRKs, ROS1 and ALK was granted approval by the FDA in 2019 for patients 12 years of age and older withNTRK fusion-positive solid tumors with no known acquired resistance mutations, metastatic and no available effective treatment options. Entrectinib is able to cross the blood-brain barrier but is not effective against NTRK secondary mutations. Approval was based on data from multiple clinical trials of NTRK fusion-positive patients (ALKA, STARTRK-1, STARTRK-2, STARTRK-NG). A combined ORR of 57% was found with 68% of patients exhibiting response for 6 months or longer at time of approval. An analysis of NTRK fusion-positive NSCLC patients found an ORR of 67% with a median PFS and OS of 14.9 months.
- Most Common Adverse Events: fatigue, constipation, altered taste, swelling, dizziness, diarrhea, nausea, trouble breathing, impairment of sensitivity often to touch, muscle and joint pain, cognitive impairment, increased weight, cough, vomiting, vision disorders, fever
- Second-generation multi-kinase inhibitor against all three TRKs, ROS1 and ALK was granted breakthrough therapy designation by the FDA in fall of 2021 for patients with advanced solid tumors with NTRK gene fusion who progressed on prior TRK inhibitors with or without chemotherapy and no alternative options available. Repotrectinib is able to cross the blood-brain barrier. The approval was based on preliminary data from the phase 1/2 TRIDENT-1 study of patients with NTRK fusion-positive NSCLC. An ORR of 50% in six patients with TKI-pretreated advanced NTRK-positive solid tumors.
- Most Common Adverse Events: dizziness, fatigue, constipation, trouble breathing, altered taste
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