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The FDA has approved ripretinib (QinlockTM, Deciphera Pharmaceuticals, LLC) for adults with metastatic gastrointestinal stromal tumor (GIST) previously treated with at least three kinase inhibitors, including imatinib.
Gastrointestinal stromal tumor is a rare tumor type with a yearly incidence of around 4,000 to 6,000 in the United States.
"Despite the progress that has been made over the past 20 years in developing treatments for GIST, including four FDA-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," commented Richard Pazdur, MD, 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. "Today's approval provides a new treatment option for patients who have exhausted all FDA-approved therapies for GIST."
The approval of ripretinib, a kinase inhibitor, was based on data from the international, double-blind INVICTUS trial (NCT03353753), in which 129 patients with advanced GIST previously treated with at least imatinib, sunitinib, and regorafenib were randomized in a 2:1 ratio to receive daily ripretinib 150 mg or placebo. Dosing was escalated for patients experiencing progressive disease on ripretinib 150 mg, and patients receiving placebo crossed over to the ripretinib arm upon disease progression. The study's primary end point was progression-free survival, with secondary end points including objective response rate, considered a key end point, and overall survival.
During the double-blind period of the trial, ripretinib substantially increased progression-free survival compared with placebo (6.3 vs 1.0 months). Six-month progression-free survival rates were 51% and 3.2%, respectively, with subgroup analyses also favoring ripretinib for progression-free survival. Ripretinib produced an objective response rate of 9.4%, compared with 0% for placebo, although this difference did not quite reach statistical significance (P=0.0504). Median overall survival was higher with ripretinib (15.1 vs 6.6 months), with 12-month overall survival rates of 65.4% and 25.9%, respectively, but overall survival was not evaluated for statistical significance as a result of the sequential testing procedure for the secondary end points.
Treatment was well tolerated for the most part; 7 patients taking ripretinib (8.2%) received dose reductions, compared with 1 patient taking placebo (2.3%). Treatment interruptions occurred in 18 patients (21.2%) for ripretinib, compared with 8 patients (18.6%) for placebo. Adverse reactions occurring in at least 20% of patients taking ripretinib included alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Grade 3/4 treatment-emergent adverse events occurring in at least 5% of patients included anemia (9.4%), abdominal pain (7.1%), and hypertension (7.1%). Additional important treatment-related risks include new primary cutaneous malignancies and cardiac dysfunction.
"Ripretinib improved progression-free survival over placebo in advanced GIST patients after progression on standard treatments [and] was associated with a favorable tolerability profile," concluded the INVICTUS investigators, led by first author Margaret von Mehren, MD, Chief of Sarcoma Medical Oncology and Associate Director of Clinical Research at Fox Chase Cancer Center, in their presentation abstract from the European Society of Medical Oncology (ESMO) 2019 Congress in September. "Ripretinib is a novel therapy in a population with no other approved therapy and may represent a new standard of care."
The recommended dose of ripretinib is 150 mg taken orally once per day, with or without food.
For More Information
von Mehren M, Serrano C, Bauer S, et al (2019). INVICTUS: a phase 3, interventional, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as _4th-line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753). Ann Oncol (ESMO Congress Abstracts), 30(suppl_5):v851-v934. Abstract 4794. DOI:10.1093/annonc/mdz394
US Food and Drug Administration (2020). FDA approves ripretinib for advanced gastrointestinal stromal tumor. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-ripretinib-advanced-gastrointestinal-stromal-tumor
Image credit: KGH.