Regulatory Decision Summary for Vitrakvi

Tropomyosin receptor kinase (TRK) fusion cancer is a genetically defined cancer occurring in a histologically diverse group of tumours harbouring an oncogenic neurotrophic tyrosine kinase receptor (NTRK) gene fusion [that is (i.e.), NTRK1, NTRK2 or NTRK3 gene fusion] that leads to the overexpression and constitutive activation of a TRK protein (i.e. TRKA, TRKB and TRKC protein, respectively). It is estimated that NTRK gene fusions are present in up to 1% of all solid tumour malignancies; however, their prevalence varies considerably across tumour types, with low frequency expression in some common adult cancers and either common or up to 100% expression in some very rare cancers in which the NTRK gene fusion is considered the defining genetic feature.

The antineoplastic agent Vitrakvi (larotrectinib) targets the Tyrosine Receptor Kinase family of proteins inclusive of the tropomyosin receptor kinases TRKA, TRKB, and TRKC.

Three ongoing, open-label, single-arm clinical studies in patients with advanced cancers contributed 73 patients to a pooled efficacy analysis set evaluating Vitrakvi for the treatment of adult and pediatric patients with unresectable or metastatic solid tumours with an NTRK gene fusion. All patients were required to have progressed following systemic therapy for their disease, if available, or would have required surgery with significant morbidity. The most common of the fourteen tumour types represented in the pooled analysis set were soft tissue sarcoma, salivary gland tumour, and infantile fibrosarcoma, all of which are rare cancers. The TRK fusions involved NTRK1 (in 44% of patients), NTRK2 (in 3%), or NTRK3 (in 48%) and 16 unique upstream fusion partners. The overall response rate (ORR) (primary endpoint) was 75% [95% confidence interval (CI): 64, 85]. The median duration of response (DOR) was not yet estimable. Responses were typically seen by the time of the first protocol specified disease assessment at the end of Cycle 2. Overall, responses were deep with the maximal reduction in tumour size well exceeding 30% in many individual subjects. Vitrakvi was generally well tolerated in the 176 patients with heterogeneous advanced cancers comprising the overall safety analysis set. The most common treatment-emergent adverse events (TEAEs) (≥20%), in order of decreasing frequency, were fatigue, nausea, dizziness, vomiting, anemia, alanine transaminase (ALT) increased, aspartate transaminase (AST) increased, cough, constipation, and diarrhea. The primary serious risks have been identified as transaminase elevations and neurologic/psychiatric TEAEs.

The pooling of efficacy data to support a tissue agnostic indication for Vitrakvi recognizes the rarity of TRK fusion cancer and the tumour heterogeneity represented therein. The strength of the scientific rationale supporting the hypothesis that the inhibition of TRK would cause shrinkage of tumours with NTRK fusions; the strength of supportive non-clinical data; and the clinically significant and durable responses observed in a variety of tumour types harbouring a diverse array of NTRK fusions support a tissue agnostic indication. However, given the current small sample size of the pooled analysis set, not all tumour types and not all NTRK gene fusion partners have been adequately characterized. Most patients had rare cancers; and in some cancers, including some common cancers, with limited representation, a response was not achieved. Overall, Health Canada considers that an extrapolation of efficacy findings to some tumour types and NTRK gene fusion partners within a tissue agnostic indication is acceptable in the context of providing access to a promising new drug for patients with advanced TRK fusion cancer in whom there are no satisfactory treatment options.

A Risk Management Plan (RMP) for Vitrakvi was submitted by Bayer Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product. Per the RMP, Vitrakvi will be provided only to specialized oncology pharmacies to address the potential risk of medication errors due to brand name confusion.

Health Canada issued a marketing authorization with conditions for Vitrakvi, pending the results of trials to verify its clinical benefit. Bayer Inc. has committed to provide two final reports from confirmatory trials to verify and expand upon efficacy data (including results for additional tumour types) and results from an additional study including a sufficient number of pediatric patients with NTRK-fusion solid tumours to evaluate the potential risk of adverse long-term effects of Vitrakvi on growth and development.