Regulatory Decision Summary for Rozlytrek

This New Drug Submission was filed to support the indication of Rozlytrek (entrectinib) in the treatment of patients with ROS1-positive non-small cell lung cancer (NSCLC) - a rare molecularly defined subset of NSCLC with a high propensity for brain metastases. Lung cancer is the most common cancer and the main cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for most lung cancer cases (>80%), among which the ROS1 oncogenic rearrangements are observed in 1% to 2% of patients.

The integrated efficacy population comprised of a pooled subgroup of 94 patients from three global ongoing adult studies (ALKA, STARTRK-1 and STARTRK-2). To be included in this subgroup, patients were required to have histologically confirmed, recurrent or metastatic, ROS1-positive NSCLC, ECOG performance status ≤ 2, measurable disease per RECIST v 1.1, and no prior therapy with a ROS1 inhibitor.

The primary efficacy outcome measures were objective response rate (ORR) and duration of response (DOR), per RECIST v 1.1 as evaluated by Blinded Independent Central Review (BICR). The secondary efficacy outcome measures included progression-free survival (PFS), overall survival (OS), and in patients presenting with central nervous system (CNS) metastases at baseline - intracranial (IC) ORR, and IC-DOR (evaluated by BICR using RECIST v1.1).

Rozlytrek demonstrated a clinically meaningful objective response rate (ORR) which was durable in patients with and without CNS metastases at baseline. An ORR of 73%, together with the median duration of response (DOR) of 15.3 months and progression-free survival (PFS) of 15.7 months provided evidence of benefits with Rozlytrek treatment. Rozlytrek also showed intracranial activity in patients with ROS1-positive NSCLC with measurable brain lesions at baseline as determined by blinded independent clinical review (BICR). The intracranial response rate was 50% with a median intracranial DOR of 12.9 months.

In adult patients with metastatic ROS1-positive NSCLC, the most common (≥25%) adverse reactions and laboratory test abnormalities included constipation, dysgeusia, dizziness, diarrhea, fatigue, dyspnea, oedema peripheral, weight increased, and blood creatinine increased. The majority of adverse events (AEs) were mild in severity. Serious and severe AEs were managed with dose reductions and interruptions in 34% and 45% of patients, respectively. Rozlytrek demonstrated an acceptable risk profile with only 9% of patients who permanently discontinued treatment as a result of AEs.

There was insufficient evidence of clinical benefit of Rozlytrek for patients previously treated with a ROS1-inhibitor (crizotinib). Therefore, the indication was restricted to patients who had not received prior treatment with crizotinib. The clinically meaningful benefit, together with the predictable and manageable Rozlytrek safety profile observed across all clinical studies, indicate that the benefits of Rozlytrek outweigh the risks for the approved indication.