Long-Term Efficacy and Safety of Entrectinib in ROS1 Fusion-Positive NSCLC

Abstract

Introduction: Entrectinib is an approved tyrosine kinase inhibitor (TKI) for ROS1 fusion-positive NSCLC. An updated integrated analysis of entrectinib from the ALKA-372-001, STARTRK-1, and STARTRK-2 trials is presented, with substantially longer follow-up, more patients, and the first description of the median overall survival (OS). An exploratory analysis of entrectinib in ROS1 fusion-positive NSCLC with the central nervous system (CNS)-only progression post-crizotinib is reported.

Methods: Adults with ROS1 fusion-positive, locally advanced or metastatic NSCLC who received at least one dose of entrectinib and had 12 months or longer of follow-up were included in the analysis. Co-primary end points were confirmed objective response rate (ORR) and duration of response (DoR) by blinded independent central review. The data cutoff was on August 31, 2020.

Results: The efficacy-assessable population comprised 168 ROS1 TKI-naïve patients. The median survival follow-up was 29.1 months (interquartile range, 21.8-35.9). The ORR was 68% (95% confidence interval [CI]: 60.2-74.8); the median DoR was 20.5 months. The median progression-free survival (PFS) was 15.7 months and the median OS was 47.8 months. In the 25 patients with measurable baseline CNS metastases, the intracranial ORR was 80% (95% CI: 59.3-93.2), median intracranial DoR was 12.9 months, and median intracranial PFS was 8.8 months. Among 18 patients with CNS-only progression on previous crizotinib treatment, two achieved a partial response (11%) and four had stable disease (22%). In seven patients with measurable CNS disease from this cohort, the intracranial ORR was 14% (1 partial response).

Conclusions: Entrectinib is active and achieves prolonged survival in ROS1 TKI-naïve patients with ROS1 fusion-positive NSCLC. Modest activity is seen in patients with CNS-only progression post-crizotinib.

Keywords: Entrectinib; Intracranial efficacy; NSCLC; ROS1 fusions; Treatment post-crizotinib.

Figure 1

Efficacy in patients with ROS1 fusion–positive NSCLC who were ROS1 TKI–naïve (efficacy-assessable population). (A) Best overall response with entrectinib. (B) Time-to-event analysis for progression-free survival. (C) Time-to-event analysis for overall survival. (D) Best intracranial responses with entrectinib in patients with BICR-assessed measurable CNS metastases at baseline. (E) Time to CNS progression (deaths censored) in all patients, patients with baseline investigator-assessed CNS metastases, and patients without baseline investigator-assessed CNS metastases. Best response (panels A and D) was measured as the maximum percentage improvement in the SLD of identified target lesions compared with baseline. Patients with missing SLD change were excluded from the waterfall plots. Patients with new CNS lesions or unequivocal progression of nontarget lesions had an overall response classified as PD, even if the SLD of all lesions was reduced. As brain scans were not required per the protocol, CNS progression in patients without CNS metastases at baseline was detected through scans triggered by symptoms or performed routinely at the investigator’s discretion. BICR, blinded independent central review; CNS, central nervous system; CR, complete response; ND, not determined; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease; SLD, sum of longest diameters; TKI, tyrosine kinase inhibitor.

Figure 2

Efficacy in patients with ROS1 fusion–positive NSCLC and CNS-only progression on previous crizotinib therapy. (A) Best overall response with entrectinib. (B) Time-to-event analysis for progression-free survival. (C) Time-to-event analysis for overall survival. (D) Time to CNS progression in all patients (deaths censored). Best response (panel A) was measured as the maximum percentage improvement in the SLD of identified target lesions compared with baseline. Patients with missing SLD change were excluded from the waterfall plots. Patients with new CNS lesions or unequivocal progression of nontarget lesions had an overall response classified as PD, even if the SLD of all lesions was reduced. BICR, blinded independent central review; CNS, central nervous system; CR, complete response; ND, not determined; NE, not estimable; PD, progressive disease; PR, partial response; SD, stable disease; SLD, sum of longest diameters.