As reported in The Lancet Oncology by Alexander Drilon, MD, and colleagues, an integrated analysis of three phase I/II trials has shown high activity of the TRK and ROS1 inhibitor entrectinib in ROS1 fusion-positive non–small cell lung cancer (NSCLC). This analysis supported the August 2019 U.S. Food and Drug Administration approval of entrectinib in this setting.

Alexander Drilon, MD

Study Details

The integrated efficacy analysis included 53 efficacy-evaluable adult patients with advanced or metastatic ROS1 fusion–positive NSCLC enrolled in the single-arm ALKA-372-001, STARTRK-1, and STARTRK-2 studies. Patients received entrectinib at a dose of at least 600 mg once per day and had ≥ 12 months of follow-up. Patients could have received prior anticancer therapy, except for prior ROS1 inhibitor treatment. Overall, 68% of patients had received one or more prior systemic therapies.

Responses

Median follow-up was 15.5 months. Objective response on blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1, was observed in 41 patients (77%, 95% confidence interval [CI] = 64%–88%), including complete response in 3 (6%). Stable disease was observed in one additional patient (2%).

Median duration of response was 24.6 months (95% CI = 11.4–34.8 months). Median progression-free survival was 19.0 months (95% CI = 12.2–36.6 months). Among 20 patients with central nervous system metastases on blinded independent central review, 11 (55%, 95% CI = 32%–77%) had intracranial response, including complete response in 4.

Adverse Events

Among 134 patients with NSCLC who received at least one dose of entrectinib in the studies (including patients with < 12 months of follow up, those who had received prior ROS1 inhibitor treatment, and others not eligible for efficacy evaluation), 79 (59%) had grade 1 or 2 and 46 (34%) had grade 3 or 4 treatment-related adverse events. The most common grade 3 or 4 adverse events were weight increase (8%) and neutropenia (4%). Serious treatment-related adverse events occurred in 15 patients (11%), with the most common being nervous system disorders (in 4 patients) and cardiac disorders (in 3 patients). No treatment-related deaths were observed.

The investigators concluded, “Entrectinib is active with durable disease control in patients with ROS1 fusion–positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion–positive NSCLC.”

Robert C. Doebele, MD, of the University of Colorado School of Medicine, Aurora, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Ignyta/F. Hoffmann-La Roche. For full disclosures of the study authors, visit thelancet.com.