The U.S. Food and Drug Administration (FDA) today granted accelerated approval to entrectinib, a treatment for adult and adolescent patients whose cancers have the specific genetic defect, NTRK (neurotrophic tyrosine receptor kinase) gene fusion and for whom there are no effective treatments.

“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,” said FDA Acting Commissioner Ned Sharpless, M.D.

“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,” added Shapless.

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumours rather than the location in the body where the tumour originated.

The approval marks a new paradigm in the development of cancer drugs that are “tissue agnostic.”

It follows the policies that the FDA developed in a guidance document released in 2018.

The previous tissue agnostic indications approved by the FDA were pembrolizumab for tumours with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumours in 2017 and larotrectinib for NTRK gene fusion tumours in 2018.

“Today’s approval includes an indication for paediatric patients, 12 years of age and older, who have NTRK-fusion-positive tumours 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 paediatric 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 paediatric patients.”

The ability of entrectinib to shrink tumours was evaluated in four clinical trials studying 54 adults with NTRK fusion-positive tumours.

The proportion of patients with substantial tumour shrinkage (overall response rate) was 57 percent, with 7.4 percent of patients having complete disappearance of the tumour.

Among the 31 patients with tumour shrinkage, 61 percent had tumour shrinkage persist for nine months or longer.

The most common cancer locations were the lung, salivary gland, breast, thyroid and colon/rectum.

Entrectinib was also approved today for the treatment of adults with non-small cell lung cancer whose tumours are ROS1-positive (mutation of the ROS1 gene) and has spread to other parts of the body (metastatic).

Clinical studies evaluated 51 adults with ROS1-positive lung cancer.

The overall response rate was 78 percent, with 5.9 percent of patients having complete disappearance of their cancer.

Among the 40 patients with tumour shrinkage, 55 percent had tumour shrinkage persist for 12 months or longer.

Entrectinib’s common side effects are fatigue, constipation, dysgeusia (distorted sense of taste), edema (swelling), dizziness, diarrhea, nausea, 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), weight gain, cough, vomiting, fever, arthralgia and vision disorders (blurred vision, sensitivity to light, double vision, worsening of vision, cataracts, or floaters).

The most serious side effects of entrectinib 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.

Health care professionals should inform females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with entrectinib.

Women who are pregnant or breastfeeding should not take entrectinib because it may cause harm to a developing foetus or newborn baby.

Source: The Food and Drug Administration (FDA)