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Rozlytrek
Sponsor
ARTGs
Device/Product name
Rozlytrek
Active Ingredient
Entrectinib
Date of decision
Published
ATC codes
L01XE56
Decision
Approved
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 Rozlytrek 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 |
|---|---|
| Submission dossier accepted and first round evaluation commenced | 1 July 2019 |
| First round evaluation completed | 17 March 2020 |
| Sponsor provides responses on questions raised in first round evaluation | 17 April 2020 |
| Second round evaluation completed | 14 May 2020 |
| Delegate's overall benefit-risk assessment and request for Advisory Committee advice | 13 May 2020 |
| Sponsor's pre-Advisory Committee response | Not applicable |
| Advisory Committee meeting | Not applicable |
| Registration decision (Outcome) | 14 May 2020 |
| Completion of administrative activities and registration on ARTG | 15 May 2020 |
| Number of working days from submission dossier acceptance to registration decision* | 196 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Original publication date
Black triangle scheme
Yes. This product will remain in the scheme for 5 years, starting on the date the product is first supplied in Australia.
Dose forms
Hard capsule
Strength
100 mg, 200 mg
Other ingredients
Capsule content: Lactose, Microcrystalline cellulose, Tartaric acid, Hypromellose, Crospovidone, Magnesium stearate, Colloidal anhydrous silica
Capsule shell: Hypromellose, Titanium dioxide, Iron oxide yellow (100 mg capsule only), Sunset yellow FCF (200 mg capsule only)
Printing ink: Shellac, Propylene glycol, Strong ammonia solution, Indigo carmine aluminium lake
Containers
Bottle
Pack sizes
100 mg hard capsules: 30 capsules per bottle200 mg hard capsules: 90 capsules per bottle
Routes of administration
Oral
Dosage
A validated assay is required for the selection of patients with c ros oncogene 1 (ROS1)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC). ROS1-positive status should be established prior to initiation of Rozlytrek therapy.
The recommended dose of Rozlytrek for adults is 600 mg given orally, once daily.
For further information on dosage, refer to the Product Information.
Pregnancy category
DDrugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. 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
Rozlytrek (entrectinib) was approved for the following therapeutic use:
Non-small cell lung cancer (NSCLC)
Rozlytrek is indicated for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) whose tumours are ROS1-positive.
What is this medicine and how does it work
Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2 and NTRK3, respectively), receptor tyrosine kinase c-ros oncogene 1 (ROS1; encoded by the gene ROS1), and anaplastic lymphoma kinase (ALK; encoded by the gene ALK) with half-maximal inhibitory concentration (IC50) values of 0.1 to 2 nM. Entrectinib also inhibits Janus kinase 2 (JAK2) and tyrosine kinase non receptor 2 (TNK2) with IC50 values > 5 nM. The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1 and ALK.Fusion proteins that include TRK, ROS1 or ALK kinase domains can drive tumourigenic potential through hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation. Entrectinib inhibits the TRK kinases, ROS1 and ALK, leading to inhibition of downstream signalling pathways, cell proliferation and induction of tumour cell apoptosis. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumour types harbouring NTRK, ROS1 and ALK fusion genes.Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4 to 2.2 in multiple animal species (mice, rats and dogs) and demonstrated in vivo anti-tumour activity in mice with intracranial implantation of TRKA- and ALK-driven tumour cell lines.
What post-market commitments will the sponsor undertake
- Rozlytrek (entrectinib) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicines Information (CMI) for Rozlytrek 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 entire period of provisional registration*, whichever is longer.
- The sponsor must submit to TGA all of the same reports that are submitted to the Food and Drug Administration (FDA) in fulfilling their post market requirements and commitments relevant to the FDA registration of entrectinib for c-ros oncogene 1 (ROS1)-positive non-small cell lung cancer (NSCLC). The reports are expected to include:
- A study of off-target activation or inhibition by entrectinib including receptors involved in suicidal ideation (submission expected September 2020).
- A final report characterising response rates and duration of responses in a group of at least 92 patients with ROS1-positive NSCLC enrolled across the ALKA, STARTRK-1 and STARTRK-2 trials, including the 51 patients whose data supported initial registration of the ROS1-positive NSCLC indication, once all responders have been followed for at least 18 months from the date of initial response (submission expected June 2021).
- A study of the effect of moderate and severe hepatic impairment on the pharmacokinetics and safety of entrectinib (submission expected December 2021).
- A study of cardiac risks and sequelae (submission expected June 2022).
- A study of fracture risks and sequelae (submission expected March 2025).
- The Rozlytrek European Union-Risk Management Plan (EU-RMP) (version 1.2, dated 6 November2019, data lock point 31 October 2018), with Australian specific Annex (version 2.0, dated December 2019), included with submission PM-2019-01808-1-4 to be revised to the satisfaction of 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).
Unless agreed separately between the supplier who is the recipient of the approval and the TGA, the first report must be submitted to TGA no later than nine calendar months after the date of the approval letter. The subsequent reports must be submitted no less frequently than every six months from the date of the first submitted report until the period covered by such reports is not less than three years from the date of the approval letter, or the entire 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. Each report must have been prepared within ninety calendar days of the data lock point for that report.
*Provisional registration of this product for the treatment of adult and paediatric patients 12 years of age and older with NTRK fusion-positive solid tumours was approved on 15 May 2020.