Regulatory Decision Summary for Rozlytrek

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 Rozlytrek (entrectinib) targets the Tyrosine Receptor Kinase family of proteins inclusive of the tropomyosin receptor kinases TRKA, TRKB, and TRKC, in addition to several other tyrosine kinases.

Three ongoing, open-label, single-arm clinical studies in adult patients with advanced cancers contributed 54 patients to a pre-specified integrated efficacy analysis evaluating Rozlytrek for the treatment of extracranial NTRK-fusion positive solid tumours. The most frequently represented tumour types were sarcoma, non-small cell lung cancer, mammary analogue secretory carcinoma (salivary gland tumours), and breast cancer (mainly secretory breast cancers). The NTRK gene fusions involved NTRK1 (in 41% of patients), NTRK2 (in one patient), or NTRK3 (in 57%). The overall response rate (ORR) (primary endpoint) was 57% (95% confidence interval [CI]: 43%, 71%). The median duration of response (DOR) was 10.4 months. In the seven patients who had measurable central nervous system (CNS) metastases at baseline, the intracranial objective response rate was 57% (95% CI: 18%, 90%). In the 6 adult patients with primary brain tumours in these three studies (not included in the pre-specified analysis), one partial response was observed that was not durable (2.8 months).

Four single-arm studies contributed 355 adult and pediatric patients with heterogeneous advanced cancers both with and without the NTRK gene fusion to the safety analysis set. The most common treatment-emergent adverse events (TEAEs) (≥20%), in order of decreasing frequency, were constipation, dysgeusia, fatigue, dizziness, diarrhea, nausea, dyspnea, edema peripheral, and anemia. The primary serious risks that have been identified are neurologic toxicity, congestive heart failure, QT interval prolongation, eye disorders, skeletal fractures, hyperuricemia, elevated liver laboratory tests, and anemia and neutropenia. The safety profile of entrectinib was generally comparable between subgroups with the exception of skeletal fractures for which a higher incidence was reported in children as compared to adults (23% in pediatric patients versus 5% in adults).

The pooling of efficacy data to support a tissue agnostic indication for Rozlytrek recognizes the rarity of TRK fusion cancer and the tumour heterogeneity represented therein. The tissue agnostic indication is supported by the strength of the scientific rationale supporting the hypothesis that the inhibition of TRK would cause shrinkage of tumours with NTRK gene fusions; the strength of supportive non-clinical data; the clinically meaningful and durable responses observed in a variety of tumour types harbouring a diverse array of NTRK fusions; and the recent authorization of larotrectinib, another TRK inhibitor, for a tumour agnostic indication. However, given the current small sample size of the integrated efficacy analysis set and the limited duration of follow-up, not all tumour types and not all NTRK gene fusion partners have been adequately characterized, and the durability of responses has not been fully characterized. In addition, efficacy in patients with primary brain tumours and safety in pediatric patients have not been established. Overall, Health Canada considers that within a tumour agnostic indication in adults, an extrapolation of efficacy findings to other extracranial tumour types and NTRK gene fusion partners 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.

The safety profile of entrectinib is considered acceptable in the setting of a life-threatening disease with no satisfactory treatment options. However, given that entrectinib is not a selective inhibitor of the TRK proteins, its safety profile is a result of a number of off-target effects, in addition to those known to be related to inhibition of the TRK proteins, and thus is broader than that of larotrectinib, a selective inhibitor of the TRK proteins.

A Risk Management Plan (RMP) for Rozlytrek was submitted by Hoffmann-La Roche Limited 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.

Health Canada recommended issuance of a marketing authorization with conditions for Rozlytrek for the treatment of adult patients with extracranial NTRK fusion-positive advanced cancers (including patients with brain metastases) and no other satisfactory treatment options, pending the results of new information to verify its clinical benefit. Hoffmann-La Roche Ltd. has committed to provide two final reports from confirmatory trials to verify and expand upon the entrectinib efficacy data (including results for additional tumour types), and results from additional safety analyses to further characterize the cardiac and fracture risks and their sequelae in patients exposed to entrectinib.