Larotrectinib Treats NTRK Gene Fusion-Positive Cancers Successfully With Low Rates of Adverse Effects

Larotrectinib was the first drug to receive accelerated FDA approval for patients of all ages based on a common molecular marker, independent of tissue origin for targeted therapy.

Larotrectinib (Vitrakvi) is a tyrosine kinase receptor (TRK) inhibitor indicated for the treatment of metastatic or unresectable neurotrophic receptor tyrosine kinase (NTRK) gene fusion-positive solid tumors in adults and children.1 NTRK gene fusion is an actionable oncogenic driver, a gene variation that promotes initiation and continuation of tumor growth.

Patients are eligible for treatment based on history of unsatisfactory prior treatment and presence of NTRK (1, 2, or 3) gene fusion in tumor samplings.1,2

Dosage

Larotrectinib is available as a 25 mg capsule, 100 mg capsule, and a 20 mg/ml oral solution. Adults and children with body surface area (BSA) ≥1m2 should take 100 mg twice daily until disease progression or adverse effect (AE) intolerability. Pediatric patients with BSA ≤1m2 should take 100 mg/m2 twice daily.1

FDA approval

Larotrectinib is the first drug to receive accelerated FDA approval (November 26, 2018) for patients of all ages based on a common molecular marker, independent of tissue origin for targeted therapy.1,3,4

The approval of larotrectinib was based on data from 3 trials, 2 of which were cohorts conducted in 2018 (N=55 in primary group and N=67 in secondary).4

The total response rate was 81% (63% partial response, 17% complete response) over 24 different types of NTRK fusion-positive tumors. Most patients (75%) in the primary group stayed disease-free for 1 year after treatment.3,4

AEs and Drug Interactions

The 2018 New England Journal of Medicine (NEJM) studies mentioned above found larotrectinib to be safe and tolerable, with only 1 of the 122 patients discontinuing treatment due to AEs.2 The most common AEs noted were fatigue, anemia, elevated liver enzymes, weight gain, and neutropenia. Only 8 (15%) of the 55 patients in the initial group had their doses reduced due to elevated liver enzymes.2,3,4

Clinicians should monitor liver tests (ALT and AST) every 2 weeks during the first month of treatment then monthly thereafter. Patients with existing moderate to severe hepatotoxicity should begin therapy at half of the typical starting dose.1

Patients should avoid strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice) while taking larotrectinib or a clinician must reduce the dose by 50% to prevent toxicity. CYP3A4 inducers (e.g., carbamazepine, St. John’s Wort) can reduce the efficacy of larotrectinib. Clinicians should increase the larotrectinib dose by 50% if these drugs cannot be avoided.1

Pregnancy/Lactation

Larotrectinib can cause fetal harm and should not be taken during pregnancy. Females of reproductive age should use effective contraception during treatment and for 1 week after last dose. Clinicians should advise women not to breastfeed during therapy and for 1 week after last larotrectinib dose.1

Conclusion

Larotrectinib is a highly tolerable and effective NTRK-gene fusion positive targeting agent that treats a vast variety of solid tumors among adults and children.

About the Author

Sara L. Tolliday, PharmD, RPh, is a full-time clinical pharmacist in the Outpatient Pharmacy at Wentworth-Douglass Hospital in Dover, NH.

References

1. VITRAKVI (larotrectinib) – Official Healthcare Provider Site. Last updated May 2021. Accessed October 17, 2021. https://hcp.vitrakvi-us.com/safety.

2. Drilon, A. TRK inhibitors in TRK fusion-positive cancers. Ann Oncol. 2019;30(8):viii24-viii30. doi:10.1093/annonc/mdz282.

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. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448.

4. Larotrectinib OK'd for Cancers with TRK Fusions. Cancer Discov. 2019;9(1):8-9. doi:10.1158/2159-8290.CD-NB2018-163.