Entrectinib and Tyrosine Receptor Kinase (NTRK) Gene Fusion

The U.S. Food and Drug Administration (FDA) gave accelerated approval to entrectinib, an oncology therapy for both adults and children with tumors that have neurotrophic tyrosine receptor kinase (NTRK) gene fusion and have exhausted all other treatment options.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” FDA Acting Commissioner Ned Sharpless, MD commented. “Using the FDA’s expedited review pathways, including breakthrough therapy designation and accelerated approval process, we’re supporting this innovation in precision oncology drug development and the evolution of more targeted and effective treatments for cancer patients. We remain committed to encouraging the advancement of more targeted innovations in oncology treatment and across disease types based on our growing understanding of the underlying biology of diseases.”

This approval marks the third of its kind, with the FDA approving a cancer treatment based on a biomarker that might appear in different tumor types, rather than based on the location of the primary tumor. This helps reaffirm an important precedent in the development and approval of drugs that are tissue agnostic, something that has only been officially endorsed by the FDA since 2018. The two agnostic indication drugs approved by the FDA previously were pembrolizumab, indicated for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib for NTRK gene fusion tumors in 2018.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumors by relying on efficacy information obtained primarily in adults. The FDA continues to encourage the inclusion of adolescents in clinical trials. Traditionally, clinical development of new cancer drugs in pediatric populations is not started until development is well underway in adults, and often not until after approval of an adult indication,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

Entrectinib’s ability to shrink tumors was analyzed in four clinical trials that looked at 54 adults with NTRK fusion+ tumors. Some 57% of patients had significant tumor shrinkage (overall response rate), while 7.4% had complete remission. Among the 31 patients whose tumors were shrinking, 61% had tumors that continued to shrink for nine months or more. The most common locations for the cancer were breast, lung, colon/rectum, salivary gland, and thyroid. 

Entrectinib was also approved to treat adults with non-small cell lung cancer whose tumors are ROS1-positive (mutation of the ROS1 gene) and has metastasized. Clinical studies looked at 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients experiencing complete remission of their tumors. Of the 40 patients whose tumors shrank, 55% had continual shrinkage for 12 months or longer.

Entrectinib’s common side effects are fatigue, dizziness, constipation, diarrhea, nausea, dysgeusia (distorted sense of taste), edema (swelling), dysesthesia (distorted sense of touch), dyspnea (shortness of breath), myalgia (painful or aching muscles), cognitive impairment (confusion, problems with memory or attention, difficulty speaking, or hallucinations), vomiting, weight gain, fever, arthralgia, cough, and vision disorders (blurred vision, sensitivity to light, double vision, worsening of vision, cataracts, or floaters). The most serious side effects are congestive heart failure (weakening or damage to the heart muscle), central nervous system effects (cognitive impairment, anxiety, depression, including suicidal thinking, dizziness or loss of balance, and change in sleep pattern, including insomnia and excessive sleepiness), skeletal fractures, hepatotoxicity (damage to the liver), hyperuricemia (elevated uric acid), QT prolongation (abnormal heart rhythm) and vision disorders. Clinicians are advised to tell female patients of reproductive age and males with a female partner of reproductive age to use effective contraception during treatment with entrectinib. Women who are pregnant or breastfeeding should not take entrectinib because it may harm a developing fetus or newborn baby.

Entrectinib was granted accelerated approval, which means that the sponsor must provide additional data to the FDA. Entrectinib received priority review, breakthrough therapy, and orphan drug status, and is licensed to Genentech, Inc.