FDA approves ripretinib for GI stromal tumors resistant to other kinase inhibitors

The U.S. Food and Drug Administration has approved Qinlock (ripretinib) tablets as the first new drug specifically approved as a fourth-line treatment for advanced gastrointestinal stromal tumor (GIST). Qinlock is indicated for adult patients who have received prior treatment with three or more kinase inhibitor therapies, including imatinib. The other FDA approved kinase inhibitors include imatinib , sunitinib, regorafenib and avapritinib.

Food and Drug Administration collaborated with the Australian Therapeutic Goods Administration (TGA) and Health Canada on the review of this application as part of Project Orbis. Food and Drug Administration approved Qinlock three months ahead of schedule

Qinlock is a kinase inhibitor, meaning it works by blocking a type of enzyme called a kinase, which helps keep the cancer cells from growing.

Gastrointestinal stromal tumors arise when abnormal cells form in the tissues of the gastrointestinal tract. GISTs most commonly occur in the stomach, small intestine, and large intestine but can start anywhere along the gastrointestinal tract.

"Despite the progress that has been made over the past 20 years in developing treatments for GIST, including four Food and Drug Administration -approved targeted therapies – imatinib in 2002, sunitinib in 2006, regorafenib in 2013 and avapritinib earlier this year – some patients don't respond to treatment and their tumors continues to progress. Today's approval provides a new treatment option for patients who have exhausted all FDA-approved therapies for GIST," said Richard Pazdur, M.D., director of the FDA's Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research.

Qinlock's approval was based on the results of an international, multi-center, randomized, double-blind, placebo-controlled clinical trial that enrolled 129 patients with advanced GIST who had received prior treatment with other FDA-approved targeted therapies, imatinib, sunitinib and regorafenib. The trial compared patients who were randomized to receive Qinlock to patients who were randomized to receive placebo, to determine whether progression free survival (PFS) – the time from initial treatment in the clinical trial to growth of the cancer or death – was longer in the Qinlock group compared to the placebo group. During treatment in the trial, patients received Qinlock or placebo once a day in 28-day cycles, repeated until tumor growth disease progression was observed or the patient experienced intolerable side effects. After disease progression, patients who were randomized to placebo were given the option of switching to Qinlock.

On average, the PFS rate in patients in the Qinlock group was 6.3 months, compared to one month for patients in the placebo group.

The most common side effects with Qinlock were alopecia , fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome (a skin reaction in the palms and soles) and vomiting.

Qinlock can also cause serious side effects including skin cancer, hypertension (high blood pressure) and cardiac dysfunction manifested as ejection fraction decrease (when the muscle of the left ventricle of the heart is not pumping as well as normal). Health care providers should routinely check for symptoms and signs of these and other risks of Qinlock.

Qinlock may cause harm to a developing fetus or a newborn baby. Health care professionals should advise pregnant women of this risk and should advise both females of reproductive potential and male patients with female partners of reproductive potential, to use effective contraception during treatment and for one week after the last dose. Patients should be advised not to breastfeed while taking Qinlock.

The Food and Drug Administration granted this application Priority Review and Fast Track designation, as well as Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. Qinlock also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. This review used the Real-Time Oncology Review, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA's assessment.

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