On May 15, 2020, the U.S. Food and Drug Administration (FDA) approved ripretinib (Qinlock™) for adult patients with advanced gastrointestinal stromal tumors (GISTs) who received prior treatment with three or more kinase inhibitors, including imatinib.
Efficacy was evaluated in an international, multicenter, randomized, double-blind, placebo-controlled trial (INVICTUS; NCT03353753) of 129 patients with GIST who were previously treated with imatinib, sunitinib, and regorafenib.
Patients were randomized 2:1 to receive either 150 mg of ripretinib or placebo orally once daily until disease progression or unacceptable toxicity. Crossover was permitted at disease progression for patients randomized to receive placebo.
The major efficacy outcome measure was progression-free survival (PFS) based on assessment by blinded independent central review (BICR) using modified response evaluation criteria in solid tumors 1.1 in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a pre-existing tumor mass must meet specific criteria to be considered unequivocal evidence of progression. Additional efficacy outcome measures were overall response rate (ORR) by BICR and overall survival (OS).
The trial demonstrated a statistically significant improvement in PFS for patients in the ripretinib arm compared to those in the placebo arm (HR = 0.15; 95% CI = 0.09, 0.25; p < 0.0001). Median PFS was 6.3 months (95% CI = 4.6, 6.9) for ripretinib compared to 1.0 month (95% CI = 0.9, 1.7) for placebo. ORR was 9% (95% CI = 4.2, 18) in the ripretinib arm compared to 0% (95% CI = 0, 8) in the placebo arm, although the difference was not statistically significant. Median OS in the ripretinib arm was 15.1 months (95% CI = 12.3, 15.1) compared to 6.6 months (95% CI = 4.1, 11.6) in the placebo arm (HR = 0.36; 95% CI = 0.21, 0.62), although OS was not evaluated for statistical significance because of the sequential testing procedure for the secondary endpoints (PFS, ORR, and OS).
The most common adverse reactions (≥ 20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Other important risks included new primary cutaneous malignancies, hypertension, and cardiac dysfunction.
The recommended ripretinib dose is 150 mg orally once daily with or without food.
FDA collaborated with the Australian Therapeutic Goods Administration (TGA) and Health Canada on the application review as part of Project Orbis. FDA approved ripretinib three months ahead of schedule. The review is ongoing for the Australian TGA and Health Canada.
It also 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 FDA’s assessment.
FDA granted the application priority review, fast track, and breakthrough therapy designation. Ripretinib also received orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions—Drugs and Biologics.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 800-FDA-1088.