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320237, 320238, 320239
320237, 320238, 320239
320237, 320238, 320239
Device/Product name
Active Ingredient
Larotrectinib (as sulfate)
Date of decision
Submission type
New chemical entity
ATC codes
Approved for provisional registration
What was the decision based on
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology), clinical (pharmacology, safety and efficacy) and risk management plan information submitted by the sponsor. The benefit-risk profile of Vitrakvi was considered favourable for the therapeutic use approved.
What steps were involved in the decision process

Registration timeline

The following table summarises the key steps and dates for this application.

Description Date
Designation (Provisional) 20 June 2019
Submission dossier accepted and first round evaluation commenced 30 August 2019
First round evaluation completed 30 March 2020
Sponsor provides responses on questions raised in first round evaluation 2 June 2020
Second round evaluation completed 21 July 2020
Delegate's overall benefit-risk assessment 7 July 2020
Sponsor's pre-Advisory Committee response Not applicable
Advisory Committee meeting Not applicable
Registration decision (Outcome) 27 August 2020
Completion of administrative activities and registration on ARTG 7 September 2020
Number of working days from submission dossier acceptance to registration decision* 210

*Statutory timeframe for standard applications is 255 working days

Date of entry onto ARTG
Original publication date
Black triangle scheme
As a provisionally registered product, this medicine will remain in the Black Triangle Scheme for five years, or for the period of provisional registration, whichever is longer.
Dose forms
Hard capsule and oral solution
25 mg, 100 mg, 20 mg/mL
Other ingredients

Hard capsule: gelatin, titanium dioxide and printing ink

Oral solution: Purified water, hydroxypropyl betadex, sodium citrate, Ora-Sweet, Ingredient 123042, 123043, 125173, 126186

Hard capsule bottle and bottle
Pack sizes
56 capsules for 25 mg or 100 mg1 x 100 mL bottle for 20 mg/mL solution
Routes of administration

Treatment with Vitrakvi should be initiated by physicians experienced in the administration of anticancer therapies.

The presence of a neurotrophic tyrosine receptor kinase (NTRK) gene fusion in a tumour specimen should be confirmed by a validated test prior to initiation of treatment with Vitrakvi.

The recommended dose of Vitrakvi in adults is 100 mg taken orally, twice daily until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Dosing in paediatric patients is based on body surface area (BSA). The recommended dose of Vitrakvi in paediatric patients (1 month to 18 years) is 100 mg/m2 taken orally, twice daily with a maximum of 100 mg per dose until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

For further information refer to the Product Information.

Pregnancy category
CDrugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
What was approved

Vitrakvi (larotrectinib (as sulfate)) was approved for the following therapeutic use:

Vitrakvi (larotrectinib) has provisional approval in Australia for the treatment of adult and paediatric patients with locally advanced or metastatic solid tumours that:

  • have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation,
  • are metastatic or where surgical resection is likely to result in severe morbidity, and
  • have either progressed following treatment or who have no satisfactory alternative therapy.

The decision to approve this indication has been made on the basis of objective response rate (ORR) and duration of response from single arm clinical studies. The sponsor is required to submit further clinical data to confirm the clinical benefit of the medicine.

What is this medicine and how does it work
Larotrectinib is an orally-bioavailable, adenosine triphosphate (ATP)-competitive, potent and highly selective tyrosine receptor kinase (TRK) inhibitor that was rationally designed to avoid activity with off-target kinases. The target for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by neurotrophic tyrosine receptor kinase 1 (NTRK1), NTRK2 and NTRK3 genes, respectively.In-frame gene fusion events resulting from chromosomal rearrangements of the human genes NTRK1, NTRK2, and NTRK3 lead to the formation of oncogenic TRK fusion proteins. These resultant novel chimeric oncogenic proteins are aberrantly expressed driving constitutive kinase activity subsequently activating downstream cell signalling pathways involved in cell proliferation and survival leading to TRK fusion cancer.Larotrectinib demonstrated potent inhibition of TRK proteins and inhibition of proliferation of tumour cells in a concentration-dependent manner. In TRK fusion-driven mouse xenograft models larotrectinib treatment induced a significant reduction of tumour growth.Acquired resistance mutations after progression on TRK inhibitors have been observed. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutation in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.
What post-market commitments will the sponsor undertake
  • Vitrakvi (larotrectinib) is to be included in the Black Triangle Scheme. The PI and CMI for Vitrakvi must include the black triangle symbol and mandatory accompanying text for five years, which starts from the date that the sponsor notifies the TGA of supply of the product, or for the period of provisional registration, whichever is longer.
  • The larotrectinib European Union (EU)-Risk Management Plan (RMP) (version 1.0, dated 30 September 2019, data lock point 12 August 2019), with Australian Specific Annex (version 1.1, dated 26 March 2020), included with submission PM-2019-03170-1-4, and any subsequent revisions, as agreed with the TGA will be implemented in Australia.

    An obligatory component of risk management plans is routine pharmacovigilance. Routine pharmacovigilance includes the submission of periodic safety update reports (PSURs).Reports are to be provided in line with the current published list of EU reference dates and frequency of submission of PSURs until the period covered by such reports is not less than three years from the date of the approval letter, or for the period of provisional registration, whichever is longer.

    The reports are to at least meet the requirements for PSURs as described in the European Medicines Agency's Guideline on good pharmacovigilance practices (GVP) Module VII-periodic safety update report (Rev 1), Part VII.B Structures and processes. Note that submission of a PSUR does not constitute an application to vary the registration.

  • Confirmatory trial data (as identified in the sponsor's plan to submit comprehensive clinical data on the safety and efficacy of the medicine before the end of the 6 years that would start on the day that registration would commence) must be provided.
  • Specifically, the sponsor must conduct studies as described in the clinical study plan in version 1.1 (dated 26 March 2020) of the Australia-Specific Annex. The following study reports should be submitted to TGA:
    • Study 20289 (also known as LOXO-TRK-15002 and NAVIGATE), 'A Phase 2 Basket Study of the Oral TRK Inhibitor larotrectinib in Subjects with NTRK Fusion-Positive Tumors', final study report due second quarter 2024
    • Study 20290 (also known as LOXO-TRK-15003 and SCOUT), 'A Phase 1/2 Study of the Oral TRK Inhibitor LOXO-101 in Pediatric Patients with Advanced Solid or Primary Central Nervous System Tumors', final study report due first quarter 2027
    • Study 20288 (also known as LOXO-TRK-14001), 'A Phase 1 Study of the Oral TRK Inhibitor Larotrectinib in Adult Patients with Solid Tumors', final study report due second quarter2022

Further guidance for sponsors is available on the TGA website.

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