Japan Becomes the First Country to Approve Entrectinib

Tumour-agnostic medicine is approved in Japan for adult and paediatric patients with NTRK fusion-positive advanced recurrent solid tumours

Roche announced on 18 June 2019 that Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved entrectinib (Rozlytrek®) for the treatment of adult and paediatric patients with neurotrophic tyrosine receptor kinase (NTRK) fusion-positive, advanced recurrent solid tumours. Entrectinib is the first tumour-agnostic medicine to be approved in Japan that targets NTRK gene fusions, which have been identified in a range of solid tumour types, including pancreatic, thyroid, salivary gland, breast, colorectal, and lung. It has been granted Sakigake designation and orphan drug designation by the MHLW.

Entrectinib is also undergoing regulatory review in Japan for the treatment of patients with ROS1 fusion-positive locally advanced or metastatic non-small cell lung cancer (NSCLC).

The data package for this first approval of entrectinib includes the pivotal phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials, as well as data from the phase I/II STARTRK-NG study in paediatric patients. The studies enrolled patients across 15 countries and more than 150 clinical trial sites. Tumour types evaluated in the studies included breast, cholangiocarcinoma, colorectal, gynaecological, neuroendocrine, NSCLC, salivary gland, pancreatic, sarcoma and thyroid cancers.

STARTRK-2 is a phase II, global, multicentre, open-label basket study in patients with solid tumours that harbour an NTRK1/2/3, ROS1 or ALK-positive gene fusion. The primary endpoint is objective response rate (ORR), and duration of response (DoR) is a secondary endpoint. Other secondary outcome measures include time to response, clinical benefit rate, intracranial tumour response, progression-free survival (PFS), central nervous system (CNS) PFS and overall survival (OS). In this pivotal study, entrectinib induced ORR in 56.9% of patients with NTRK fusion-positive solid tumours. Objective responses to entrectinib were seen across 10 different solid tumour types, including patients with and without CNS metastases at baseline. Median DoR was 10.4 months. Importantly, entrectinib induced intracranial response in 50.0% of patients.

STARTRK-1 is a phase I, multicentre, open-label dose escalation study of a daily continuous dosing schedule in patients with solid tumours with NTRK1/2/3, ROS1 or ALK gene fusions in the US and South Korea. The trial assessed the safety and tolerability of entrectinib via a standard dose escalation scheme and determined the recommended phase II dose.

ALKA-372-001 is phase I, multicentre, open-label dose escalation study of an intermittent and continuous entrectinib dosing schedule in patients with advanced or metastatic solid tumours with TRKA/B/C, ROS1 or ALK gene fusions in Italy.

Initial results from an integrated analysis of the phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials, evaluating the efficacy of entrectinib in adults with solid tumours and CNS metastases, were presented at 2019 ASCO Annual Meeting, as well as results from a Real World Data study, evaluating time-to-treatment discontinuation and PFS as endpoints for comparative efficacy analysis of clinical trials of entrectinib and crizotinib for the treatment of patients with ROS1-positive NSCLC.

STARTRK-NG is a phase I/II open-label dose-escalation and expansion study evaluating the safety and efficacy of entrectinib in children and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumours or primary CNS tumours, with or without TRK, ROS1 or ALK fusions. Earlier this month, the study results were presented at 2019 ASCO Annual Meeting. The study enrolled 29 children and adolescents aged 4.9 months through to 20 years. Of the 28 patients evaluated, 11 children were identified to have tumours with NTRK, ROS1 or ALK fusions and one with ALK F1174L-mutated neuroblastoma. Complete responses were observed in 2 patients with tumours harbouring NTRK and ALK fusions: 1 with an NTRK fusion-positive primary CNS tumour and 1 with an ALK fusion-positive inflammatory myofibroblastic tumour. Another complete response was observed in 1 neuroblastoma patient with an ALK F1174L mutation. Partial responses were observed in 9 patients, 3 unconfirmed at the time of the clinical cut-off date, across NTRK, ROS1 and ALK fusion-positive primary CNS (n=4) and extracranial (n=5) solid tumours. Median duration of therapy for confirmed fusion-positive responders was 10.51 months, and median time to response was 1.89 months. The safety profile of entrectinib was consistent with that seen in previous analyses.

The most commonly reported adverse reactions of entrectinib treatment include constipation, dysgeusia, diarrhoea, dizziness, fatigue, oedema, weight increase, anaemia, blood creatinine increase, dyspnoea, and nausea.

Biomarker testing for NTRK gene fusions is the only way to identify patients who may be eligible for treatment with entrectinib. Roche is leveraging its expertise in developing precision cancer medicines and advanced diagnostics, in conjunction with Foundation Medicine, to help identify patients with NTRK gene fusions using a companion diagnostic that is undergoing review.

The US Food and Drug Administration (FDA) recently granted Priority Review for entrectinib for both the treatment of paediatric and adult patients with NTRK fusion-positive, locally advanced or metastatic solid tumours who have either progressed following prior therapies or as an initial therapy when there are no acceptable standard therapies, and for the treatment of patients with metastatic ROS1-positive NSCLC. These new drug applications are based on results from the integrated analysis of the phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials, and data from the STARTRK-NG study. The FDA is expected to make a decision on approval by 18 August 2019.

Entrectinib has also been granted Priority Medicines (PRIME) designation by the European Medicines Agency.