Larotrectinib, First TRK Inhibitor Approved by the FDA for Solid Tumors

by Scarlett Zou Best Blog on Biochemical

LAROTRECTINIB APPROVED FOR SOLID TUMORS WITH NTRK MUTATION

On November 26, 2018, the US Food and Drug Administration (FDA) approved larotrectinib (Vitrakvi; Loxo Oncology), the first drug approved for the treatment of adults and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed after treatment. Larotrectinib received accelerated approval based on overall response rate and duration of response data. Further clinical trials are required to confirm the clinical benefit of larotrectinib.

Commenting on this approval, FDA Commissioner Scott Gottlieb, MD, said, “Today’s approval marks another step in an important shift toward treating cancers based on their tumor genetics rather than their site of origin in the body.”

MECHANISM OF ACTION

Larotrectinib is an inhibitor of TRK, including TRKA, TRKB, and TRKC. These kinases are encoded by the genes NTRK1, NTRK2, and NTRK3. Using in vitro and in vivo tumor models, larotrectinib demonstrated antitumor activity in cells with constitutive activation of TRK proteins that resulted from gene fusions or the deletion of a protein regulatory domain, and in cells with TRK protein overexpression. Point mutations in the TRKC kinase domain (ie, G623R, G696A, and F617L) result in resistance to larotrectinib.

DOSING AND ADMINISTRATION

Patients should be selected for the consideration of larotrectinib treatment based on the presence of NTRK gene fusion in the tumor specimens. Currently no FDA-approved test is available for the detection of NTRK gene fusion.In clinical trials, the identification of positive NTRK gene fusion status was determined prospectively in local laboratories using NGS or fluorescence in situ hybridization testing.

The recommended starting dose of larotrectinib in adults and young patients with a body surface area of ≥1 m2 is 100 mg orally twice daily, with or without food, until disease progression or unacceptable toxicity. For pediatric patients whose body surface area is <1 m2, the recommended starting dose of larotrectinib is <100 mg/m2 orally twice daily.

Larotrectinib is available in a capsule form and as an oral solution (20 mg/mL). These dosage forms can be used interchangeably. Larotrectinib capsules should be swallowed whole and should not be chewed or crushed.

CONCLUSION

Larotrectinib, a novel oral inhibitor of TRK, is the first therapy approved for the treatment of adults and pediatric patients with solid tumors associated with an identified NTRK gene fusion. It is approved for patients with solid tumors and this biomarker who have progressive metastatic disease that has no satisfactory alternative treatment. Because this tissue-agnostic drug has demonstrated durable responses and safety in this patient population, larotrectinib represents an innovative milestone in precision medicine and in oncology drug development.

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