FDA Approval Summary: Ripretinib for advanced gastrointestinal stromal tumor.

On May 15, 2020, the Food and Drug Administration (FDA) approved ripretinib for adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib. The approval was based on results from INVICTUS (NCT03353753), an international, multi-center, double-blind, placebo-controlled trial. Patients were randomly allocated (2:1) to receive either ripretinib 150 mg once daily (n=85) or matching placebo (n=44). The trial demonstrated a statistically significant improvement in progression-free survival (PFS) as assessed by modified RECIST v1.1 by blinded independent central review for patients randomized to ripretinib, with a median PFS of 6.3 months (95% confidence interval [CI]: 4.6, 6.9) compared with 1.0 month (95% CI: 0.9, 1.7) for placebo (hazard ratio [HR]: 0.15 (95% CI: 0.09, 0.25); p<0.0001, stratified log rank test). There was no statistically significant difference in objective response rate (ORR) in the ripretinib arm 9% (95% CI: 4.2, 18) compared to placebo 0% [(95% CI: 0, 8); p= 0.0504, Fisher's Exact Test]. The median overall survival (OS) in the ripretinib arm was 15.1 months (95% CI: 12.3, 15.1) compared with 6.6 months (95% CI: 4.1, 11.6) in the placebo arm. A formal statistical comparison of OS was not made due to the prespecified hierarchical analysis plan. The most common (≥20%) adverse events with ripretinib, in order of decreasing frequency, were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Other important risks of ripretinib include new primary cutaneous malignancies, hypertension, and cardiac dysfunction.