What is larotrectinib and how does it work?
Larotrectinib is an oral small molecule inhibitor, which has anti-tumor activity for adult and pediatric patients with solid tumors that express neurotrophic receptor tyrosine kinase (NTRK) gene fusion.
Larotrectinib is a potent and selective inhibitor of TRK proteins. NTRK genes encode for TRK proteins. Chromosomal rearrangements involving fusions of NTRK genes may result in activated chimeric TRK fusion proteins, acting as an oncogenic driver to promote cell proliferation and survival in tumor cell lines.
What is this approved for?
Larotrectinib received accelerated approval for adult and pediatric patients with solid tumors that have NTRK gene fusion without a known acquired resistance mutation. Patients must have no satisfactory alternative treatments, or cancer that has progressed following treatment who are either metastatic or unresectable disease. This is the second tissue-agnostic FDA approval for the treatment of cancer.
What is the basis for this approval?
Larotrectinib was approved on data from three separate multicenter, open-label, single-arm clinical trials. LOXO-TRK-14001, SCOUT, and NAVIGATE enrolled pediatric and adult patients with positive NTRK gene fusion who had progressed following systemic therapy for their disease or would have required surgery with significant morbidity for locally advanced disease. Adult patients received larotrectinib 100 mg twice daily and pediatric patients (18 years or younger) received larotrectinib 100 mg/m2 up to a maximum dose of 100 mg twice daily until disease progression or unacceptable toxicity. Overall response rate (ORR) and duration of response (DOR) were the major efficacy endpoints.
Efficacy was evaluated in the first 55 patients enrolled across the three trials. Twelve 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 percent (95% CI: 61-85). At 1 year, 71 percent of the responses were ongoing and 55 percent remained progression free. Overall, 22 percent had a complete response and 53 percent obtained a partial response. Median DOR had not yet been reached. At a median follow-up of 9.4 months, 86 percent of patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative (N Engl J Med 2018;378(8):731-739).
How do you administer this drug?
Larotrectinib is given as a 100 mg oral capsule by mouth twice daily for adults. Pediatric patients should receive a dose of 100 mg/m2 (max of 100 mg dose) taken twice daily. An oral solution is available as a 20 mg/mL concentration. Therapy can be given with or without food.
Are there any premedications needed for larotrectinib?
There are no required premedications for larotrectinib.
What are the common side effects associated with larotrectinib (> or =10%)?
* Hematologic: anemia, neutropenia
* Cardiovascular: edema, hypertension
* CNS: dizziness, neurotoxicity, headache, myasthenia
* GI: diarrhea, nausea, vomiting
* General: fatigue, fever
* Endocrine & Metabolic: weight gain
* Neuromuscular & Skeletal: myalgia, arthralgia, back pain, limb pain
* Hepatic: increased AST/ALT/Alk Phos
* Respiratory: Cough, dyspnea
What are the uncommon side effects associated with larotrectinib (less than 10%)?
Additional side effects include falling (10%), delirium (2%), abnormal gait (1%), dysarthria (1%), and paresthesia (1%).
Are there any important drug interactions I should be aware of?
Larotrectinib is a major substrate of CYP3A4 and P-glycoprotein. Avoid use with strong CYP3A4 inhibitors and inducers. Larotrectinib is also a weak inhibitor of CYP3A4. It is recommended to avoid coadminsitration with sensitive CYP3A4 substrates.
How do I adjust the dose in the setting of renal or hepatic insufficiency?
There are no renal dose adjustments for larotrectinib. An initial dose reduction by 50 percent is recommended for patients with baseline moderate to severe liver impairment (Child-Pugh classes B and C).
Practical tips
* Hepatotoxicity has occurred during treatment. For grade 3 or 4 hepatic adverse reactions, withhold therapy until resolution to Grade 1. If resolution occurs within 4 weeks, resume at a 25 percent dose reduction. No more than 3 dose reductions should be considered. If recovery takes greater than 4 weeks, discontinue therapy permanently.
* Larotrectinib can cause fetal harm. Patients should be advised to use effective methods of contraception during treatment and for 1 week after the final dose of therapy.
What should my patients know about larotrectinib?
Patients using the oral solution should use the provided oral syringe and discard the syringe after 7 days of use. The oral solution requires refrigeration and should be discarded after 90 days of first opening the bottle.
What else should I know about larotrectinib?
* Monitor liver function tests (ALT and AST) every 2 weeks during the first month of treatment, then monthly thereafter and as clinically indicated.
* Monitor for neurotoxicity regularly. Withhold and modify dosage, or permanent discontinuation may be warranted based on severity of symptoms.
What useful links are available?
* FDA Approval Announcement: https://bit.ly/2YMWbAT
* Highlights of Prescribing Information: https://bit.ly/2FRqH8u
Any ongoing clinical trials related to larotrectinib?
Clinical trials with larotrectinib continue to expand into TRK fusion-positive hematologic malignancies, as well as continued access in the pediatric and adult solid tumor arena. More information is available about the clinical trials at https://clinicaltrials.gov.
JANELLE E. MANN, PHARMD, BCOP, is the Manager of Clinical Pharmacy Services and practices as an Ambulatory Clinical Oncology Pharmacist, Washington University School of Medicine, Alvin J. Siteman Cancer Center, St. Louis, Mo., She serves as the Pharmacy Forum column editor. RAMASWAMY GOVINDAN, MD, Professor of Medicine; Anheuser Busch Chair in Medical Oncology; Director, Section of Medical Oncology, Division of Oncology, Washington University School of Medicine, serves as the Pharmacy Forum column physician advisor.