As reported in The Lancet Oncology by Jean-Yves Blay, MD, and colleagues, the phase III INVICTUS trial has shown that the oral KIT and PDGFRα tyrosine kinase inhibitor ripretinib prolonged progression-free survival vs placebo in patients with advanced gastrointestinal stromal tumors (GIST) whose disease progressed on or who are intolerant of imatinib, sunitinib, and regorafenib.

Jean-Yves Blay, MD

The trial supported the May 2020 U.S. Food and Drug Administration approval of ripretinib in patients with advanced GIST who have received prior treatment with three or more kinase inhibitors, including imatinib.

Study Details

In the double-blind trial, 129 patients from 29 specialized hospitals in 12 countries were randomly assigned 2:1 between February 2018 and November 2018. Patients either received 150 mg of ripretinib (n = 85) or placebo (n = 44) once daily, both with best supportive care, in 28-day cycles until disease progression or unacceptable toxicity. Treatment allocation was masked until progressive disease was confirmed on blinded independent central review; patients in the placebo group were permitted to cross over to receive open-label ripretinib at 150 mg/d at disease progression. The primary endpoint was progression-free survival on blinded independent central review assessment in the intention-to-treat population.

For the ripretinib vs placebo groups, median age was 59 vs 65 years (33% vs 50% ≥ 65 years); 55% vs 59% were male; 75% vs 75% were white; 47% vs 46% were from the United States; number of previous therapies was three in 64% vs 61% and four or more in 36% vs 39%; Eastern Cooperative Oncology Group performance status was 0 in 44% vs 39% and 1 or 2 in the remainder; the most common primary tumor sites were gastric (40% vs 41%) and jejunum or ileum (24% vs 18%); and the most common primary mutation was KIT exon 11 mutation (55% vs 64%).

Progression-Free Survival

During the double-blind period, with a median follow-up of 6.3 months in the ripretinib group and 1.6 months in the placebo group, median progression-free survival was 6.3 months (95% confidence interval [CI] = 4.6–6.9 months) in the ripretinib group vs 1.0 months (95% CI = 0.9–1.7 months) in the placebo group (hazard ratio [HR] = 0.15, 95% CI = 0.09–0.25, P < .0001). Estimated progression-free survival at 6 months was 51% vs 3%. The benefit of ripretinib was consistent across subgroups examined, including three (HR = 0.15, 95% CI = 0.08–0.29) and four or more (HR = 0.24, 95% CI = 0.12–0.51) prior therapies; age 65 to 74 years (HR = 0.18, 95% CI = 0.06–0.56) and ≥ 75 years (HR = 0.03, 95% CI = 0.00–0.56); and U.S. (HR = 0.15, 95% CI = 0.07–0.31) and non-U.S. residence (HR = 0.23, 95% CI = 0.12–0.43).

Objective response was observed in eight patients in the ripretinib group (9.4%; all partial responses) vs no patients in the placebo group (P = .0504). As of data cutoff, median duration of response had not yet been reached, with disease progression having occurred in one of eight responders.

A total of 29 patients randomly assigned to placebo crossed over to open-label ripretinib. Due to protocol-specified hierarchical testing and the lack of significant difference in objective response rate, no formal statistical testing of overall survival was performed. With follow-up including both the double-blind and open-label periods, median overall survival was 15.1 months (95% CI = 12.3–15.1 months) in the ripretinib group vs 6.6 months (95% CI = 4.1–11.6 months) in the placebo group (HR = 0.36, 95% CI = 0.21–0.62). Estimated 6- and 12-month overall survival was 84.3% vs 55.9% and 65.4% vs 25.9%.

Adverse Events

The most common grade 3 or 4 treatment-related adverse events in the ripretinib group included increased lipase (in 5% of patients), hypertension (4%), fatigue (2%), and hypophosphatemia (2%) and the most common in the placebo group included anemia (7%), fatigue (2%), diarrhea (2%), decreased appetite (2%), dehydration (2%), hyperkalemia (2%), acute kidney injury (2%), and pulmonary edema (2%).

Treatment-related adverse events led to discontinuation of treatment in 5% of patients in the ripretinib group (due to cardiac failure, death of unknown cause, general physical health deterioration, and palmar-plantar erythrodysesthesia in one patient each) and 2% of the placebo group (fatigue in one patient).

Treatment-related serious adverse events were reported in 9% of the ripretinib group (one case each of anemia, cardiac failure, death of unknown cause, dyspnea, fecaloma, gastroesophageal reflux disease, hyperkalemia, hypophosphatemia, nausea, and upper gastrointestinal hemorrhage) and in 7% of the placebo group (one case each of hyperkalemia, dehydration, pulmonary edema, and septic shock). Death considered related to treatment occurred in one patient in the ripretinib group (cause unknown) and one patient in the placebo group (due to septic shock and pulmonary edema).

The investigators concluded: “Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumors who were resistant to approved treatments.”

Dr. Blay, of the Department of Medical Oncology, Centre Léon Bérard, Lyon, is the corresponding author for The Lancet Oncology article

Disclosure: The study was funded by Deciphera Pharmaceuticals. For full disclosures of the study authors, visit thelancet.com.