As reported in the Journal of Clinical Oncology by Bauer et al, the phase III INTRIGUE trial showed no significant progression-free survival benefit with second-line ripretinib vs sunitinib in imatinib-pretreated patients with gastrointestinal stromal tumor (GIST), including among patients with KIT exon 11 mutations.

Study Details

In the open-label trial, 453 patients (intent-to-treat [ITT] population) from sites in 22 countries who had disease progression on or were intolerant to (10% of population) first-line imatinib were randomly assigned to receive ripretinib at 150 mg once daily (n = 226) or sunitinib at 50 mg once daily for 4 weeks on/2 weeks off (n = 227). A total of 163 patients in the ripretinib group and 164 in the sunitinib group had KIT exon 11 mutations and constituted the KIT exon 11 ITT population. 

The primary endpoint was progression-free survival on independent radiologic review. If comparison in the KIT exon 11 ITT population was not significant, P values for all other comparisons of endpoints were considered nominal.

Progression-Free Survival

At data cutoff (September 1, 2021), median progression-free survival in the KIT exon 11 ITT population was 8.3 months (95% confidence interval [CI] = 6.8–13.3 months) in the ripretinib group vs 7.0 months (95% CI = 5.6–10.9 months) in the sunitinib group (hazard ratio [HR] = 0.88, 95% CI = 0.66–1.16, P = .36). In the total ITT population, median progression-free survival was 8.0 months (95% CI = 6.5–10.8 months) in the ripretinib group vs 8.3 months (95% CI = 6.3–11.0 months) in the sunitinib group (HR = 1.05, 95% CI = 0.82–1.33, nominal P = .72). Overall survival data were not mature.   

In the KIT exon 11 ITT population, objective response was observed in 39 patients (23.9%, 95% CI = 17.6%–31.2%) in the ripretinib group vs 24 (14.6%, 95% CI = 9.6%–21.0%) in the sunitinib group (nominal P = .03), with complete response in 2 patients in the sunitinib group. In the total ITT population, objective response was observed in 49 (21.7%, 95% CI = 16.5%–27.6%) vs 40 (17.6%, 95% CI = 12.9%–23.2%; nominal P = .27), with complete response in 1 and 3 patients, respectively. Median durations of response were 16.7 months (95% CI = 12.5 months–not estimable) vs 20.1 months (95% CI = 11.0 months–not estimable) in the KIT exon 11 ITT population and 16.7 months (95% CI = 12.5 months–not estimable) vs 20.1 months (95% CI = 12.3 months–not estimable) in the total ITT population.

Adverse Events

The most common adverse events of any grade were alopecia (64.1%), fatigue (37.7%), and myalgia (36.3%) in the ripretinib group, and palmar-plantar erythrodysesthesia syndrome (51.1%), diarrhea (48.0%), and hypertension (47.1%) in the sunitinib group. Grade 3 or 4 adverse events occurred in 41.3% of patients in the ripretinib group vs 65.6% in the sunitinib group (nominal P < .0001). Those more common in the sunitinib group included hypertension (8.5% vs 26.7%), neutropenia/decreased neutrophil count (0% vs 13.1%), and palmar-plantar erythrodysesthesia syndrome (1.3% vs 10%).

Serious adverse events occurred in 25.6% vs 25.8% of patients. Dose modification occurred in 38.1% vs 63.3% of patients, with dose reduction and treatment discontinuation occurring in 20.2% vs 48.0% and 3.6% vs 7.7%, respectively. One treatment-related death occurred, due to intracranial hemorrhage in a patient in the sunitinib group.

The investigators concluded; “Ripretinib was not superior to sunitinib in terms of progression-free survival. However, meaningful clinical activity, fewer grade 3 [or] 4 treatment-emergent adverse events, and improved tolerability were observed with ripretinib.”

Sebastian Bauer, MD, of the West German Cancer Center, Internal Medicine Clinic (Tumor Research), Essen, Germany, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Deciphera Pharmaceuticals, LLC. For full disclosures of the study authors, visit ascopubs.org.