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Larotrectinib for Solid Tumors With NTRK Gene Fusions


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In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

On November 26, 2018, larotrectinib (Vitrakvi) was granted accelerated approval 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. These patients have metastatic disease or surgical resection is likely to result in severe morbidity, there is no satisfactory alternative treatments, or their cancer has progressed after treatment.1,2 The approval is the second tissue-agnostic approval for the treatment of cancer.

Supporting Efficacy Data

Approval was based on data on objective response rates and response durations from three single-arm clinical trials—LOXO-TRK-14001 (ClinicalTrials.gov identifier NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431)—in pediatric and adult patients with unresectable or metastatic solid tumors with an NTRK gene fusion.2,3 All patients were required to have disease progression after systemic therapy, if available, or would have required surgery with significant morbidity for locally advanced disease. Identification of positive NTRK gene fusion status was prospectively determined using next-generation sequencing or fluorescence in situ hybridization. Adult patients received 100 mg orally twice daily, and pediatric patients (≤ 18 years) received 100 mg/m2, up to a maximum dose of 100 mg orally twice daily.

OF NOTE

Larotrectinib has warnings/precautions for neurotoxicity, hepatotoxicity, and embryofetal toxicity.

Efficacy was evaluated in the first 55 patients with unresectable or metastatic solid tumors harboring an NTRK gene fusion enrolled across the 3 trials. Twelve patents were younger than age 18. Patients had a total of 12 cancer types, with the most common being salivary gland tumors (22%), soft-tissue sarcoma (20%), infantile fibrosarcoma (13%), and thyroid cancer (9%).

The overall response rate was 75%, including complete response in 22% and partial response in 53%. At the time of database lock, the median duration of response had not been reached, with durations ranging from 1.6+ to 33.2+ months. The response duration was at least 6 months in 73%, at least 9 months in 63%, and at least 12 months in 39% of responders.

How It Works

Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRKs) TRKA, TRKB, and TRKC. TRKA, TRKB, and TRKC are encoded by the genes NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively activated chimeric TRK fusion proteins, which can act as oncogenic drivers in promoting cell proliferation and survival in tumor cell lines.

In in vitro and in vivo tumor models, larotrectinib demonstrated antitumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.

How It Is Used

Patients should be selected for treatment with larotrectinib based on the presence of an NTRK gene fusion in tumor specimens. No U.S. Food and Drug Administration–approved test for the detection of NTRK gene fusion is currently available.

The recommended larotrectinib doses are 100 mg orally twice daily for adult and pediatric patients with a body surface area ≥ 1.0 m2 and 100 mg/m2 orally twice daily (maximum of 100 mg per dose) for pediatric patients with a body surface area < 1.0 m2. Treatment should continue until disease progression or unacceptable toxicity. The starting dose should be reduced by 50% in patients with moderate or severe hepatic impairment.

Larotrectinib in Solid Tumors

  • Larotrectinib (Vitrakvi) was granted accelerated approval 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.
  • The recommended larotrectinib doses are 100 mg orally twice daily for adult and pediatric patients with a body surface area ≥ 1.0 m2 and 100 mg/m2 orally twice daily (maximum of 100 mg per dose) for pediatric patients with a body surface area < 1.0 m2.

Product labeling provides information on stepwise dose reductions for adverse events in adult and pediatric patients for up to three reductions; treatment should be discontinued in patients unable to tolerate larotrectinib after three dose reductions. For grade 3 or 4 adverse reactions (see below), treatment should be withheld until resolution or improvement to baseline or grade 1; treatment can be resumed at the next lower dosage if resolution occurs within 4 weeks. Treatment should be permanently discontinued if an adverse reaction does not resolve within 4 weeks.

Concomitant use of larotrectinib with strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, indinavir), strong CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin), and sensitive CYP3A4 substrates should be avoided. Product labeling provides instructions on dose modification in the concomitant use of strong CYP3A4 inhibitors (50% dose reduction of larotrectinib) and strong CYP3A4 inducers (doubling of larotrectinib dose) if concomitant use cannot be avoided.

Safety Profile

The safety of larotrectinib was evaluated in 176 patients enrolled in the 3 single-arm clinical trials, including 44 pediatric patients. The most common adverse events of any grade (≥ 20% of patients) were fatigue, nausea, dizziness, vomiting, cough, constipation, and diarrhea. Grade 3 or 4 adverse events occurred in 51% of patients, and neurologic adverse events of any grade occurred in 53% of patients. Grade 3 neurologic adverse events included delirium, dysarthria, dizziness, gait disturbance, and paresthesia.

Increased aspartate transaminase (AST), increased alanine transaminase (ALT), and anemia of any grade occurred in 45%, 45%, and 42% of patients, respectively. The most common grade 3 or 4 laboratory abnormalities were anemia and neutropenia.

The most common serious adverse reactions (≥ 2%) were pyrexia, diarrhea, sepsis, abdominal pain, dehydration, cellulitis, and vomiting. Adverse events led to dose interruption or reduction in 37% and permanent treatment discontinuation in 13%.

Larotrectinib has warnings/precautions for neurotoxicity, hepatotoxicity, and embryofetal toxicity. Patients and caretakers should be advised of the risk of neurologic adverse reactions as well as advised not to drive or operate hazardous machinery if experiencing neurotoxicity. Liver function tests including ALT and AST should be monitored every 2 weeks during the first month of treatment, monthly thereafter, and as clinically indicated. Patients should be advised not to breastfeed while receiving larotrectinib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves larotrectinib for solid tumors with NTRK gene fusions. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626720.htm. Accessed December 11, 2018.

2. Vitrakvi (larotrectinib) capsules and oral solution prescribing information, Loxo Oncology Inc and Bayer, November 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/211710s000lbl.pdf. Accessed December 11, 2018.

3. Drilon A, Laetsch TW, Kummar S, et al: Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med 378:731-739, 2018.


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