The FDA ( U.S. Food and Drug Administration ) has approved Larotrectinib ( Vitrakvi ), the first oral TRK inhibitor.
The approval is for the treatment of adult and pediatric patients with solid tumors with a neurotrophic receptor tyrosine kinase ( NTRK ) gene fusion without a known acquired resistance mutation that are either metastatic or where surgical resection will likely result in severe morbidity, and have no satisfactory alternative treatments or have progressed following treatment.
This indication is approved under accelerated approval based on overall response rate ( ORR ) and duration of response ( DOR ).
Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Larotrectinib is the first treatment to receive a tumor-agnostic indication at the time of initial FDA approval.
In clinical trials of patients with TRK fusion cancer, Larotrectinib demonstrated an ORR of 75 percent ( n=55 ) ( 95% CI: 61, 85% ), including a 22% complete response ( CR ) rate.
NTRK gene fusions are genomic alterations that result in constitutively-activated chimeric TRK fusion proteins, which act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines.
Larotrectinib is a CNS active TRK inhibitor designed to inhibit these proteins.
TRK fusions can be found in many types of solid tumors and affect both children and adults.
In the clinical trials that were the basis for this approval, Larotrectinib showed clinical benefit across numerous unique tumor types, including lung, thyroid, melanoma, GIST, colon, soft tissue sarcoma, salivary gland and infantile fibrosarcoma.
TRK fusion cancer is diagnosed through the identification of NTRK gene fusions using specific tests, including those that employ next-generation sequencing ( NGS ) and fluorescence in situ hybridization ( FISH ).
Patients eligible for treatment with Larotrectinib should be selected based on the presence of an NTRK gene fusion in their tumor.
The FDA reviewed Larotrectinib under Priority Review, which is reserved for medicines that could provide significant improvements in the safety or effectiveness of the treatment for serious conditions.
The FDA previously granted Larotrectinib Breakthrough Therapy Designation, Rare Pediatric Disease Designation and Orphan Drug Designation.
The FDA approval of Larotrectinib is based on pooled data across the phase I adult trial, phase II NAVIGATE trial and phase I/II pediatric SCOUT trial ( n=55 ).
In pooled study results, Larotrectinib has demonstrated an overall response rate ( ORR ) of 75% ( 95% CI, 61%, 85% ) by blinded independent review committee ( with 22% of patients achieving a complete response and 53% of patients achieving a partial response ) across various tumor types, including soft tissue sarcoma, salivary gland, infantile fibrosarcoma, thyroid, lung, melanoma, colon, GIST, cholangiocarcinoma, appendix, breast and pancreas.
Seventy-three percent of responding patients ( n=41 ) had a duration of response ( DOR ) lasting 6 months or greater at the time of data cut-off. Median DOR ( range 1.6+, 33.2+ ) and progression-free survival ( PFS ) had not been reached at the time of analysis.
Median time to response was 1.84 months.
In the safety database ( n=176 ), which included patients with and without an NTRK gene fusion, the majority of adverse events reported in greater than or equal to 10% of patients were grade 1 or 2.
Adverse events of any grade observed in more than 20% of patients included increased ALT ( 45% ), increased AST ( 45% ), anemia ( 42% ), fatigue ( 37% ), nausea ( 29% ), dizziness ( 28% ), cough ( 26% ), vomiting ( 26% ), constipation ( 23% ), and diarrhea ( 22% ). ( Xagena )
Source: Bayer, 2018