Entrectinib treatment in patients with ROS1+ NSCLC

Brain metastases are often seen in treatment-naïve patients with stage 4 ROS1+ NSCLC, and the CNS is a common first site of progression [7]. Crizotinib is the only agent approved for treatment of patients with stage 4 ROS1+ NSCLC. However, preclinical data indicate that entrectinib is a more potent ROS1 inhibitor than crizotinib [8]. Entrectinib is a selective oral ROS1/NTRK/ALK TKI with activity in the CNS [8]. Designed to cross the blood-brain barrier and remain in the CNS, it is clinically active in primary brain tumours and secondary CNS metastases.

Doebele et al. conducted an integrated analysis of three phase 1/2 studies—STARTRK-2 [9]; STARTRK-1 [10], and ALKA-372-001 [10]. Enrolled patients had locally advanced or metastatic solid tumours. The safety-evaluable population included patients who had received ≥1 dose of entrectinib. The efficacy analysis included those with ROS1+ NSCLC and identified ROS1 fusions. Tumours were assessed at the end of cycle 1 and every 8 weeks thereafter. Primary endpoints were ORR and DoR (blinded independent central review [BIRC]; RECIST v1.1). Secondary endpoints were PFS and OS; intracranial ORR and DoR in patients with or without measurable CNS lesions at baseline; and safety and tolerability.

The efficacy analyses included 53 patients with treatment-naïve ROS1+ NSCLC. BIRC-determined ORR was 77.4%, with clinical response in 3 patients (5.7%). Median BIRC DoR was 24.6 months. Per baseline CNS status, median BIRC PFS was 26.3 months for patients without CNS disease (n=30) and 13.6 months for those with CNS metastases (n=23). Intracranial ORR was 55.0% and the median intracranial DoR was 12.9 months in patients with baseline CNS disease. The median for entrectinib had not been reached. Most treatment-related AEs in the overall safety cohort (n=355) were grade 1-2. Entrectinib was tolerable, with a manageable safety profile. Data show a robust systemic response in patients with ROS1+ NSCLC treated with entrectinib compared with crizotinib [7]. Outcomes suggest that those with ROS1 tumours may benefit from first-line use of a CNS-penetrant ROS1 inhibitor.