FDA Grants Priority Review to Entrectinib for NTRK+ Solid Tumors, ROS1+ NSCLC

The FDA granted a priority review to entrectinib for the treatment of adult and pediatric patients with NTRK fusion-positive, locally advanced or metastatic solid tumors who have either progressed following prior therapies or as initial therapy when there are no acceptable standard therapies, and for the treatment of patients with metastatic, ROS1-positive non-small cell lung cancer (NSCLC), according to Genentech, the investigational agent’s manufacturer.

“Entrectinib represents a unique approach to cancer treatment that can potentially target a range of hard-to-treat and rare NTRK fusion-positive tumors regardless of their site of origin, as well as treat ROS1-positive non-small cell lung cancer,” Sandra Horning, MD, chief medical officer and head of global product development at Genentech, said in a press release.

“By combining comprehensive genomic profiling with actionable targeted therapies, like entrectinib, we are advancing our personalized health care goal to find the right treatment for each patient,” she added.

Integrated Analysis

The new drug applications were based on data from the following studies:

• STARTRK-2, a phase II, global, multicenter, open-label basket study in people with solid tumors that harbor an NTRK1/2/3-, ROS1- or ALK-positive gene fusion — designed to evaluate objective response rate (ORR), as well as duration of response (DOR), time to response, clinical benefit rate, intracranial tumor response, progression-free survival (PFS), central nervous system (CNS) PFS and overall survival (OS).
• STARTRK-1, a phase I, multicenter, open-label dose escalation study of a daily continuous dosing schedule in people with solid tumors with NTRK1/2/3, ROS1 or ALK gene fusions in the U.S. and South Korea — designed to assess the safety and tolerability of entrectinib using a standard dose escalation scheme to determine the recommended phase II dose.
• ALKA-372-001, a phase I, multicenter, open-label dose escalation study of an intermittent and continuous entrectinib dosing schedule in people with advanced or metastatic solid tumors with TRKA/B/C, ROS1 or ALK gene fusions in Italy.
• STARTRK-NG, a phase I/Ib dose escalation and expansion study evaluating the safety and efficacy of entrectinib in children and adolescent patients with no curative first-line treatment option, recurrent or refractory extracranial solid tumors or primary central nervous system tumors, with or without TRK, ROS1 or ALK fusions.

The integrated analysis included data from 53 people with ROS1-activating gene fusions and 54 people with locally advanced or metastatic NTRK fusion-positive solid tumors, and data from the pediatric patients in the phase I/Ib study were also included in the application. Tumor types evaluated in the studies included breast, cholangiocarcinoma, colorectal, gynecological, neuroendocrine, non-small cell lung, salivary gland, pancreatic, sarcoma and thyroid cancers.

Results from the integrated analysis demonstrated that entrectinib shrank tumors (ORR) in 57.4% of patients with NTRK fusion-positive solid tumors. ORR to entrectinib were seen across 10 different solid tumor types (median DOR, 10.4 months), including patients with and without CNS metastases at baseline. The agent shrank tumors that had spread to the brain in 54.5%, with more than a quarter of these people having a complete response.

In addition, entrectinib shrank tumors in 77.4% of those with locally advanced or metastatic ROS1-positive NSCLC, demonstrating a median DOR of 24.6 months. Importantly, it also shrank intracranial tumors in 55% of patients with CNS metastases at baseline.

The safety profile of entrectinib was consistent with that seen in previous analyses. The most commonly reported adverse events included fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, pain, anemia, cognitive disorders, weight increased, vomiting, cough, blood creatinine increase, arthralgia, pyrexia, and myalgia.

The FDA is expected to make its decision by Aug. 18, 2019.