FDA Grants Priority Review to Entrectinib for Two Treatment Indications

The Food and Drug Administration (FDA) granted a priority review to entrectinib for two treatment indications, according to Genentech, the investigational agent’s manufacturer.

The agency’s decision includes the treatment of adult and pediatric patients with neurotrophic tropomyosin receptor kinase (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).

“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, M.D., 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 2, 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, as well as duration of response, time to response, clinical benefit rate, intracranial tumor response, progression-free survival, central nervous system progression-free survival and overall survival.
• STARTRK-1, a phase 1, 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 2 dose.
• ALKA-372-001, a phase 1, 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 1/1b 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 1/1b 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 demonstrated that entrectinib shrank tumors in more than half of people with NTRK fusion-positive solid tumors, with a median duration of response of 10.4 months. In addition, the agent shrank tumors that had spread to the brain in more than half of patients, with more than a quarter of them having a complete response.

For those with locally advanced or metastatic ROS1-positive NSCLC, entrectinib shrank tumors in 77.4 percent of patients, also demonstrating a demonstrated a durable response of more than two years. Moreover, the agent shrank intracranial tumors in more than half of these patients with central nervous system metastases at baseline.

The safety profile of entrectinib was consistent with that seen in previous analyses. The most commonly reported side effects included fatigue, constipation, altered sense of taste, swelling, dizziness, diarrhea, nausea, nervous system disorders, shortness of breath, pain, anemia, cognitive disorders, weight increased, vomiting, cough, blood creatinine increase, joint pain, fever and muscle pain.

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