Written By: Elizabeth Ledbetter, PharmD
Description: The purpose of this PQI is to help provide awareness of larotrectinib and educate on management techniques.
Background: Larotrectinib is indicated 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
- Are metastatic or where surgical resection is likely to result in severe morbidity
- Have no satisfactory alternative treatments or that have progressed following treatment
This indication is approved under accelerated approval based on overall response rate and duration of response.1 It is important to note that larotrectinib is approved in patients with a NTRK fusion not just an NTRK mutation. NTRK genes, which encode for TRK proteins, can become fused to other genes abnormally, resulting in growth signals that support tumor growth.
The efficacy of larotrectinib was studied in three clinical trials that included 55 pediatric and adult patients with solid tumors. Larotrectinib demonstrated a 75% overall response rate across different types of solid tumors, with 73% of responses lasting at least six months, and 39% lasting a year or more at data cutoff. Presented at ESMO 2020, with a data cut-off of July 2019 included 120 additional patients where ORR was 78% and a median PFS of 36.8 months.8 Tumor types with an NTRK fusion that responded to larotrectinib include: soft tissue sarcoma, salivary gland cancer, infantile fibrosarcoma, thyroid cancer, lung cancer, primary CNS and cancers with CNS metastasis.9 In a study determining expected life-years and quality-adjusted life-years (QALYs) a larotrectinib base case found a mean pre-progression QALYs of 5.0 and mean total QALYs of 5.8.7 Evidence also suggests patients treated with larotrectinib see some degree of benefit with different lines of therapy and performance statuses.10
- Confirm that NTRK fusion was identified on pathology report
- See Larotrectinib (Vitrakvi®) Genomic Testing Management PQI for more information
- Confirm correct dosing
- Adults and pediatric patients with BSA ≥ 1 m2: 100 mg orally twice daily with or without food
- Pediatric patients with BSA < 1 m2: 100 mg/m2 orally twice daily with or without food
- Larotrectinib comes as a capsule (25 mg & 100 mg) and as an oral solution (20 mg/mL)
- The capsule and oral solution are interchangeable
- Dosing considerations
- No renal dose adjustments
- Hepatic impairment prior to initiation:
- Child-Pugh class A: No dose adjustment necessary
- Child-Pugh class B and C: Reduce initial dose by 50%
- Coadministration with strong CYP3A4 inhibitors/inducers:
- If coadministration cannot be avoided,
- Reduce larotrectinib dose by 50% with inhibitors
- Double the dose with inducers
- Upon discontinuation, resume larotrectinib at the original dose after 3-5 elimination half-lives of the CYP3A4 inhibitor/inducer
- Half-life is 2.9 hours following oral administration in a conventional situation/healthy patient
- Monitor LFTs every 2 weeks during the first month of treatment and monthly thereafter
- Monitor for signs/symptoms of neurotoxicity
- Dose reductions for Grade 3 or Grade 4 toxicity; hold until resolution, then as follows:
- If coadministration cannot be avoided,
|Dose Modification||Patients with BSA ≥ 1 m2||Patients with BSA < 1 m2|
|1st Dose Modification||75 mg orally twice daily||75 mg/m2 orally twice daily|
|2nd Dose Modification||50 mg orally twice daily||50 mg/m2 orally twice daily|
|3rd Dose Modification||100 mg orally once daily||25 mg/m2 orally twice daily|
- Permanently discontinue for any Grade 3 or 4 Adverse Event that does not resolve within 4 weeks, or any patients unable to tolerate after 3 dose modifications
- The most common adverse reactions (≥20%) were: any neurological event (53%), Increased ALT (45%), Increased AST (45%), anemia (42%), fatigue (37%), nausea (29%), dizziness (28%), cough (26%), vomiting (26%), constipation (23%), and diarrhea (22%)
- Withdrawal pain – Case reports with holding/discontinuation. Consider tapering at discontinuation11
Patient Centered Activities:
- Provide Oral Chemotherapy Education (OCE) Sheet
- Counsel patients on:
- Do not make up a missed dose within 6 hours of the next scheduled dose
- If vomiting occurs after taking dose, take the next dose at the scheduled time
- Store the glass bottle of oral solution in the refrigerator. Discard after 90 days of first opening the bottle if any medication is remaining
- Patients should not eat grapefruit or drink grapefruit juice while taking this medication
- Pregnancy: Females of reproductive potential should use effective contraception during therapy and for at least 1 week after the final larotrectinib dose. Males with female partners of reproductive potential should also use effective contraception during therapy
- Breastfeeding: Do not breast feed during treatment and for 1 week after last dose
- Ensure patients are aware of side effects to monitor at home
- Nervous system problems: Patients should reach out to their provider if they develop symptoms such as confusion, difficulty speaking, dizziness, coordination problems, tingling, numbness, or burning sensation in hands and feet
- Liver problems: Patients should reach out to their provider if they develop symptoms such as loss of appetite, nausea or vomiting, pain in the upper right side of the stomach area
- Oral solution counseling points:
- Drawing up the dose
- Always use the bottle adaptor and oral syringes provided with larotrectinib to ensure the dose is measured correctly * Do not use a household teaspoon to measure the dose*
- Both 1mL and 5mL syringes are provided for accurate measurement
- Each syringe may be used over a 7-day period and replaced thereafter
- Administering the dose
- Place the tip of the oral syringe into the child’s mouth against the side of the check and slowly squirt as they swallow
- Child should be in the upright position for a few minutes following dose administration
- If the child spits up the dose, do not give another. Wait until the next scheduled dose
- After a dose is administered, always place the child-resistant cap back on the bottle *Do NOT remove the bottle adaptor*
- Clean the oral syringes by removing the plunger from the barrel and rinse with warm water
- Drawing up the dose
Patient Financial Assistance:
- TRAK Assist – Online or call 1-844-634-8725
- $0 co-pay program for eligible patients with commercial or private insurance
- Vitrakvi Bridge Program is available for commercially insured patients whose coverage is delayed/lapsed
- Bayer US Patient Assistance Foundation is available for qualified uninsured/underinsured
- Vitrakvi® Commitment ProgramTM will refund the cost of up to 60 days supply in certain situations
- VITRAKVI® [package insert]. Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ.
- Kummar S, Lassen UN. TRK Inhibition: A New Tumor-Agnostic Treatment Strategy. Target Oncol. 2018;13(5):545-556.
- 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.
- Dubois SG, Laetsch TW, Federman N, et al. The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer. 2018;124(21):4241-4247.
- Chen Y, Chi P. Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers. J Hematol Oncol. 2018;11(1):78.
- Support for Taking Vitrakvi®. vitrakvi-us.com/patient-support.
- Roth JA, Carlson JJ, Xia F, et al. The Potential Long-Term Comparative Effectiveness of Larotrectinib and Entrectinib for Second-Line Treatment of TRK Fusion-Positive Metastatic Lung Cancer. J Managed Care & Specialty Pharmacy 2020 26:8, 981-986.
- McDermott R, van Tillburg CM, Farago AF, et al. Survival benefits of larotrectinib in an integrated dataset of patients with TRK fusion cancer. Presented at ESMO Virtual Congress 2020, Annals of Oncology (2020) 31 (suppl_4): S1034-S1051.
- Drilon AE, DuBois SG, Farago AF, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. J of Clin Onc 37, no. 15_suppl.
- Drilon AE, van Tilburg CM, Farago AF, et al. Larotrectinib in TRK fusion cancer patients: Outcomes by prior therapy and performance status [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT199.
- Liu, D. (2020, May 15). Characterization of on-target adverse events caused by TRK inhibitor therapy. Annals of Oncology.