FDA Approves VITRAKVI (Larotrectinib) for Certain Solid Tumors with NTRK Gene Fusions


On November 26, 2018, the U.S. Food and Drug Administration (FDA) approved VITRAKVI (larotrectinib) for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (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 following treatment. Select patients for treatment with VITRAKVI based on the presence of a NTRK gene fusion in tumor specimens. An FDA-approved test for the detection of NTRK gene fusion is not currently available. VITRAKVI 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.

The approved recommended dosages of VITRAKVI capsules and oral solution are as follows:

  • 100 mg orally twice daily in adult and pediatric patients with body surface area (BSA) of at least 1.0 m2
  • 100 mg/m2 orally twice daily in pediatric patients with BSA less than 1.0 m2

Administer VITRAKVI capsules or oral solution with or without food, until disease progression or until unacceptable toxicity.

Advise patients of risk of neurologic adverse reactions with VITRAKVI and not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Monitor for hepatotoxicity with liver tests including ALT and AST, every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated. Withhold and modify dosage, or permanently discontinue VITRAKVI based on severity of neurologic or hepatic adverse reactions. Additional information regarding recommended dosage modifications, warnings, and precautions can be found in the full prescribing information linked below.

VITRAKVI can cause fetal harm when administered to a pregnant woman. Advise women of the potential risk to a fetus. Advise women of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of VITRAKVI.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

  • MOA: Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC, which are encoded by the genes NTRK1, NTRK2, and NTRK3.
  • General PK: Larotrectinib systemic exposure (Cmax and AUC) was dose proportional over the dose range of 100 mg to 400 mg (1 to 4 times the recommended adult dose) and slightly greater than proportional at doses of 600 mg to 900 mg (6 to 9 times the recommended adult dose) in healthy adults receiving a single dose of VITRAKVI capsules. In adult patients with locally advanced or metastatic solid tumors who received VITRAKVI capsules 100 mg twice daily, Cmax of larotrectinib was achieved at approximately 1 hour after dosing and steady-state was reached within 3 days.
  • Absorption: The mean absolute bioavailability of VITRAKVI capsules was 34% (range: 32% to 37%). In healthy subjects, the AUC of VITRAKVI oral solution was similar to that of the capsules and the Cmax was 36% higher with the oral solution. The AUC of larotrectinib was similar and the Cmax was reduced by 35% after oral administration of a single 100 mg capsule of VITRAKVI to healthy subjects taken with a high-fat meal compared to the Cmax and AUC in the fasted state.
  • Distribution: The mean (CV%) volume of distribution at steady-state (Vss) of larotrectinib is 48 (38%) L following intravenous administration of larotrectinib in healthy subjects. Larotrectinib is 70% bound to human plasma proteins in vitro and binding is independent of drug concentrations.
  • Elimination: The mean (CV%) clearance (CL/F) of larotrectinib is 98 (44%) L/h and the half-life is 2.9 hours following oral administration of VITRAKVI in healthy subjects.
  • Metabolism: Larotrectinib is metabolized predominantly by CYP3A4.
  • Excretion: Following oral administration of a single 100 mg dose of [14C]-larotrectinib to healthy subjects, 58% (5% unchanged) of the administered radioactivity was recovered in feces and 39% (20% unchanged) was recovered in urine.

Drug Interactions

Avoid coadministration of strong CYP3A4 inhibitors, strong CYP3A4 inducers, or sensitive CYP3A4 substrates with VIKRAKVI. If coadministration cannot be avoided, additional information regarding recommended dosage modifications and monitoring can be found in the full prescribing information linked below.

Use in Specific Populations

No dose adjustment is recommended for age (28 days to 82 years), sex, body weight (range: 3.8 kg to 179 kg), any severity of renal impairment or mild hepatic impairment (Child-Pugh A). Reduce VITRAKVI dose as recommended in patients with moderate (Child‑Pugh B) to severe (Child‑Pugh C) hepatic impairment.

Efficacy and Safety

Efficacy of VITRAKVI was demonstrated in 55 pediatric and adult patients with unresectable or metastatic solid tumors with a NTRK gene fusion enrolled in one of three multicenter, open-label, single-arm clinical trials. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) or fluorescence in situ hybridization (FISH). The major efficacy outcome measures were ORR and DOR. Additional information regarding efficacy trial(s) can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 20%) with VITRAKVI were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea. The most common adverse reactions (≥ 3%) resulting in dose modification (interruption or reduction) were increased ALT (6%), increased AST (6%), and dizziness (3%). Most (82%) adverse reactions leading to dose modification occurred during the first three months of exposure.

Full prescribing information is available at https://go.usa.gov/xP6df.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at http://go.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to [email protected].

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.