The European Commission has granted conditional marketing authorisation for Rozlytrek ( Entrectinib ) for the treatment of adult and paediatric patients 12 years of age and older with solid tumours expressing a neurotrophic tyrosine receptor kinase ( NTRK ) gene fusion, who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and who have not received a prior NTRK inhibitor, who have no satisfactory treatment options.
The European Commission has also approved Rozlytrek for the treatment of adults with ROS1-positive, advanced non-small cell lung cancer ( NSCLC ) not previously treated with ROS1 inhibitors.
The approval is based on results from the integrated analysis of the pivotal phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials, and data from the phase I/II STARTRK-NG study.
These studies have demonstrated that Rozlytrek has durable responses across several NTRK gene fusion-positive solid tumours, including sarcoma, non-small cell lung, salivary MASC, secretory and non-secretory breast, thyroid, colorectal, neuroendocrine, pancreatic, ovarian, endometrial carcinoma, cholangiocarcinoma, gastrointestinal cancers and neuroblastoma, as well as ROS1-positive NSCLC.
Entrectinib shrank tumours in more than half of people with NTRK fusion-positive, locally advanced or metastatic solid tumours ( overall response rate [ ORR ]=63.5%; N=74 ), and objective responses were observed across 13 tumour types ( median duration of response [ DoR ]=12.9 months [ 9.3 months – not reached ], N=21 out of 47 patients defined by ORR ).
In ROS1-positive, advanced NSCLC, Entrectinib shrank tumours in 73.4% of people with the disease ( ORR; N=94 with a minimum of 12 months follow up ), with a median DoR of 16.5 months ( 14.6 – 28.6 months ). In a group of 161 patients with a minimum of 6 months follow up, including 29% of patients with central nervous system ( CNS ) metastases at baseline, ORR was observed to be 67.1%.
Objective responses to Entrectinib were seen in people with CNS metastases at baseline, with an intracranial ORR of 62.5% and 79.2% in both NTRK and ROS1 populations, respectively.
In paediatric patients, Entrectinib shrank tumours ( ORR ) in all children and adolescents who had NTRK gene fusions ( N=5 ), with two achieving a complete response ( CR ). Two patients with primary high-grade tumours in the CNS had objective responses, including one patient with a CR. Entrectinib was well tolerated.
The most common adverse reactions ( 20% or more ) with Entrectinib were fatigue, constipation, altered sense of taste ( dysgeusia ), oedema, dizziness, diarrhoea, nausea, nervous system disorders ( dysaesthesia ), dyspnoea, anaemia, increased weight, increased blood creatinine, pain, cognitive disorders, vomiting, cough, and pyrexia.
Rozlytrek has been granted Priority Medicines ( PRIME ) designation by the EMA for the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumours in adult and paediatric patients who have either progressed following prior therapies or who have no acceptable standard therapies.
NTRK gene fusions have been identified in a range of solid tumour types, and are present in up to 90% of some rare cancer types and less than 1% of other more common tumours, including lung and colorectal.
ROS1 gene fusions account for 1-2% of NSCLC, the most common type of lung cancer that accounts for up to 85% of all diagnoses.
The approval in Europe is based on an integrated analysis including data from 86 people with locally advanced or metastatic NTRK fusion-positive solid tumours ( 13 tumour types ) and 161 people with ROS1-positive NSCLC from the phase II STARTRK-2, phase I STARTRK-1 and phase I ALKA-372-001 trials. It is also based on data from the phase I/II STARTRK-NG study in paediatric patients.
The studies enrolled people across 15 countries and more than 150 clinical trial sites.
Safety was assessed from an integrated analysis of 504 people across these four trials. ( Xagena )
Source: Roche, 2020