On October 23, 2020, the U.S. Food and Drug Administration (FDA) approved the next-generation sequencing–based FoundationOne CDx test as a companion diagnostic to identify fusions in the neurotrophic receptor tyrosine kinase (NTRK) genes NTRK1, NTRK2, and NTRK3 in DNA isolated from tumor tissue specimens from patients with solid tumors eligible for treatment with larotrectinib (Vitrakvi). The FoundationOne CDx test is a next-generation sequencing–based in vitro diagnostic device that is capable of detecting several mutations in addition to NTRK gene fusions.
Larotrectinib was granted accelerated approval on November 26, 2018, for adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or whose cancer has progressed following treatment.
Approval of larotrectinib was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001, SCOUT, and NAVIGATE. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next-generation sequencing, fluorescence in situ hybridization (FISH), and reverse transcriptase–polymerase chain reaction methods. NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The major efficacy outcome measures were overall response rate and response duration, as determined by a blinded independent review committee according to Response Evaluation Criteria in Solid Tumors version 1.1.
The FoundationOne CDx assay approval as a companion diagnostic for larotrectinib was based on the retrospective testing with FoundationOne CDx of available tumor tissue samples from patients enrolled in the three clinical trials that supported the accelerated approval of larotrectinib. Efficacy for larotrectinib was shown to be maintained in patients with confirmed NTRK fusion–positive results by FoundationOne CDx.