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November 26, 2018, with PAP

On November 26, 2018, the Food and Drug Administration granted accelerated approval to larotrectinib (VITRAKVI, Loxo Oncology Inc. and Bayer) for adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (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.

This is the second tissue-agnostic FDA approval for the treatment of cancer.

Approval was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431). Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) or fluorescence in situ hybridization (FISH). 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 (ORR) and response duration, as determined by a blinded independent review committee according to RECIST 1.1.

Efficacy was evaluated in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across the three trials. All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity for locally advanced disease. Twelve patients were less than 18 years of age. A total of 12 cancer types were represented, with the most common being salivary gland tumors (22%), soft tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%).

ORR was 75% (95% CI: 61%, 85%), including 22% complete responses and 53% partial responses. At the time of database lock, median duration of response had not been reached. Response duration was 6 months or longer for 73%, 9 months or longer for 63%, and 12 months or longer for 39% of patients.

The safety of larotrectinib was evaluated in 176 patients enrolled across the three clinical trials, including 44 pediatric patients. The most common adverse reactions (≥20%) with larotrectinib were fatigue, nausea, dizziness, vomiting, increased AST, cough, increased ALT, constipation, and diarrhea.

The recommended larotrectinib doses are 100 mg orally twice daily for adults and 100 mg/m2 orally twice daily (maximum of 100 mg per dose) for pediatric patients.

View full prescribing Information for Vitrakvi.

This indication is approved under accelerated approval and continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. FDA granted this application priority review, breakthrough therapy designation and orphan product designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

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, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

Pharmacist’s Applications to Practice

Larotrectinib for Adult and Pediatric Patients with Solid Tumors That Have a Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion

Author: Andrea Clarke, PharmD
PGY2 Hematology/Oncology Pharmacy Resident
University of Minnesota Health
Minneapolis, MN

What is the potential role for larotrectinib in the treatment of solid tumors with NTRK gene fusion?1-6

  • On November 26, 2018, the U.S. Food and Drug Administration (FDA) granted larotrectinib accelerated approval for the treatment of adult and pediatric patients with metastatic or unresectable solid tumors that have an NTRK gene fusion without a known acquired-resistance mutation and have no satisfactory alternative treatments or whose disease has progressed following treatment.
  • Larotrectinib is the FDA’s second tissue-agnostic drug approved for cancer treatment.
  • Larotrectinib works by inhibiting the tropomyosin receptor kinases (TRKs) TRKA, TRKB, and TRKC, which are encoded by NTRK1, NTRK2, and NTRK3. Gene fusions of these NTRK genes can result in constitutively activated chimeric TRK fusion proteins that can act as oncogenic drivers, promoting tumor cell proliferation and survival. NTRK gene fusion rates vary by cancer type but are generally <5%. Some cancers (e.g., salivary gland and thyroid cancers and pediatric high-grade gliomas) may be associated with higher rates.
  • Approval was based on data from the multicenter open-label single-arm trials LOXO-TRK-14001, SCOUT, and NAVIGATE, in which all patients had unresectable or metastatic solid tumors with NTRK gene fusion and had disease progression following systemic therapy or would have required surgery with significant morbidity.
    • Efficacy was evaluated in the first 55 patients enrolled across the three trials, with the most common cancers being salivary gland tumors (22%), soft-tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%).
    • The overall response rate was 75%, including a 22% complete response rate and a 53% partial response rate.
    • At the time of database lock, the median duration of response was not yet reached. The response lasted at least 6 months in 73% of responders and at least 12 months in 39% of responders.
  • The most common adverse reactions (occurring in at least 20% of patients) of any grade experienced in clinical trials included anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), neutropenia (23%), diarrhea (22%), and increased aspartate aminotransferase (AST) or alanine aminotransferase (ALT) (45%). Neurologic adverse reactions of any grade occurred in 53% of patients. Grade 3 or 4 adverse reactions occurred in 51% of patients, most commonly anemia (10%), neutropenia (7%), neurologic reactions (6.6%), and AST/ALT elevation (6.6%).
  • The National Comprehensive Cancer Network (NCCN) has incorporated larotrectinib into a number of solid tumor treatment guidelines as a Category 2A treatment option in the unresectable or metastatic setting, including colorectal cancer, head and neck cancer, cutaneous melanoma, non-small-cell lung cancer (NSCLC), pancreatic adenocarcinoma, soft-tissue sarcoma, and thyroid carcinoma. In most guidelines, larotrectinib is recommended only as a subsequent treatment option, but in the NSCLC guidelines, the NCCN includes a recommendation for its use as a first-line treatment option as well.

What role can the pharmacist play in the management of patients on larotrectinib?2,4

  • Ensure that appropriate dosing is used for larotrectinib.
    • Patients with body surface area (BSA) ≥1.0 m2: 100 mg by mouth twice a day
    • Patients with BSA <1.0 m2: 100 mg/m2/dose by mouth twice a day
    • Treatment should continue until the disease progresses or an unacceptable level of toxicity is reached.
    • Dosing recommendations with known drug interactions:
      • Concomitant use of strong CYP3A4 inhibitors should be avoided, but if coadministration is necessary, reduce the larotrectinib dose by 50%.
      • Concomitant use of strong CYP3A4 inducers should be avoided, but if coadministration is necessary, double the larotrectinib dose.
    • For baseline moderate to severe hepatic impairment (Child-Pugh Class B or C liver function), reduce the larotrectinib dose by 50%.
  • Pharmacists can promote appropriate monitoring prior to and during therapy, including     
    • assessment of NTRK gene fusion status prior to initiation
    • pregnancy test in applicable females prior to initiation
    • liver function tests every 2 weeks during the first month of treatment and then monthly
    • assessment for signs and symptoms of neurotoxicity.
  • For Grade 3 or 4 adverse reactions, larotrectinib should be withheld until the event improves to Grade 1 or baseline and then resumed at the next dosage modification as outlined below. If the adverse reaction does not resolve within 4 weeks, larotrectinib should be permanently discontinued.
    • First reduction level: 75 mg twice daily (75 mg/m2 twice daily if BSA < 1.0 m2)
    • Second reduction level: 50 mg twice daily (50 mg/m2 twice daily if BSA < 1.0 m2)
    • Third reduction level: 100 mg once daily (25 mg/m2 twice daily if BSA < 1.0 m2)
    • Discontinue larotrectinib permanently if the patient is unable to tolerate it after three dose reductions.
  • Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during therapy and for at least 1 week after the final dose.
  • Larotrectinib should be administered without regard to food, and capsules should be swallowed whole without chewing or crushing. If vomiting occurs after a dose, the next dose should be taken at the scheduled time. Missed doses may be taken unless within 6 hours of the next scheduled dose. Oral solution should be measured with the provided oral syringe.

Clinical Pearls2,7,8

  • Larotrectinib is available as 25-mg capsules, 100-mg capsules, and a 20-mg/mL solution (100 mL). The solution should be kept refrigerated. Capsules and solution may be used interchangeably.
  • The TRAK Assist patient assistance program is available to facilitate patients’ access to larotrectinib, providing copay assistance and free drugs to patients whose coverage is delayed or who experience a temporary lapse in coverage. The program also provides refunds to eligible patients and payers when clinical benefit is not seen in 90 days.7
  • An FDA-approved test for the NTRK gene fusion is not currently available. Next-generation sequencing (NGS) can be used to identify NTRK gene fusions, and the larotrectinib website lists NGS laboratories that can detect all 3 NTRK gene fusions.8
  • Immunohistochemistry identification of TRK can be used as a screening diagnostic, but confirmation of NTRK fusion is needed prior to initiation of larotrectinib.


  1. U.S. Food and Drug Administration. FDA approves larotrectinib for solid tumors with NTRK gene fusions. Available at Accessed May 21, 2019.
  2. VITRAKVI [package insert]. Stamford, CT: Loxo Oncology, Inc.; November 2018.
  3. Vaishnavi A, Le AT, Doebele RC. TRKing down an old oncogene in a new era of targeted therapy. Cancer Discov. 2015;5(1):25-34.
  4. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739.
  5. Lassen UN, Albert CM, Kummar S, et al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach [abstract 409O]. Ann. Oncol. 2018;29(suppl_8):mdy279.397. Available at
  6. National Comprehensive Cancer Network. NCCN Guidelines for Treatment of Cancer by Site. Available at Accessed May 23, 2019.
  7. TRAK Assist patient assistance program. Available at Accessed May 23, 2019.
  8. Vitrakvi testing. Available at Accessed May 23, 2019.