Ripretinib Shows Comparable Survival to Sunitinib in Advanced GIST with Improved Safety Profile
Key Insights
Final analysis of the phase 3 INTRIGUE trial demonstrates similar overall survival between ripretinib and sunitinib in patients with advanced gastrointestinal stromal tumor (search) previously treated with imatinib.
Ripretinib showed significantly fewer grade 3/4 treatment-emergent adverse events (43% vs 67%) and drug-related adverse events (27% vs 58%) compared to sunitinib.
Median overall survival was 35.5 months for ripretinib versus 31.5 months for sunitinib, with comparable second progression-free survival outcomes.
The final analysis of the phase 3 INTRIGUE trial has revealed that ripretinib (Qinlock) demonstrates comparable survival outcomes to sunitinib malate (Sutent) while offering a more favorable safety profile in patients with metastatic gastrointestinal stromal tumor (search) (GIST (search)) who had previously received imatinib (Gleevec) treatment. The results, published in the Journal of Clinical Oncology, provide important insights for second-line therapy selection in advanced GIST management.
Survival Outcomes Show Non-Inferiority
In the overall intention-to-treat population of 453 patients, investigators reported 211 overall survival events with a median follow-up of 34.5 months. The median overall survival was 35.5 months for patients treated with ripretinib compared with 31.5 months for patients treated with sunitinib (HR, 0.86; 95% CI, 0.65–1.13).
In the subset of patients with KIT (search) exon 11 mutations, which comprised 72.2% of the study population, 151 overall survival events were recorded. The median overall survival for ripretinib was 35.5 months versus 32.8 months for sunitinib (HR, 0.98; 95% CI, 0.71–1.34).
Safety Profile Favors Ripretinib
The safety analysis revealed significant differences between the two treatments. As reported by Michael C. Heinrich, MD, and colleagues, "Fewer patients experienced grade 3/4 treatment-emergent adverse events (TEAEs; 43% v 67%) and grade 3/4 drug-related TEAEs (27% v 58%) with ripretinib versus sunitinib, respectively."
The most common all-grade treatment-emergent adverse event in patients treated with ripretinib was alopecia (65%), while in patients treated with sunitinib, hypertension and diarrhea were both reported at 48%. In the total population, palmar-plantar erythrodysesthesia and fatigue were each reported in 40% of patients.
Third-Line Therapy Outcomes Remain Unaffected
An important finding from the study was that median second progression-free survival, defined as the time from randomization to the second instance of disease progression or death, was comparable between treatment arms. The median second PFS was 7.7 months with ripretinib versus 7.4 months with sunitinib (HR, 1.03; 95% CI, 0.78–1.35).
After discontinuation of study treatment, most patients followed the standard treatment algorithm. In the ripretinib arm, 60% of patients received sunitinib as third-line therapy with a median second PFS of 8.5 months. In the sunitinib arm, 43% received regorafenib as third-line therapy with a median second PFS of 6.3 months.
Study Design and Patient Population
The INTRIGUE trial was an open-label, randomized phase 3 study that enrolled patients with advanced GIST (search) who had disease progression on or intolerance to imatinib. Patients were randomly assigned 1:1 to receive either 150 mg of ripretinib once daily continuously (n = 226) or 50 mg of sunitinib once daily on a 4-weeks-on/2-weeks-off schedule (n = 227). Crossover between treatment arms was not permitted.
Baseline characteristics were well-balanced between treatment arms, with an overall median age of 60 years (range, 18-88). The majority of patients were male (62.0%) and White (66.2%), with 72.2% harboring KIT (search) exon 11 mutations.
Clinical Implications and Future Directions
At the data cutoff of March 15, 2023, 44% of patients assigned to ripretinib and 40% to sunitinib remained on study, with 13% and 5% remaining on ripretinib and sunitinib treatment, respectively. The higher proportion of patients remaining on ripretinib treatment reflects its improved tolerability profile.
The National Comprehensive Cancer Network (search) Clinical Practice Guidelines in Oncology now include ripretinib as an option for patients with advanced GIST (search) who are intolerant of second-line sunitinib, based on these results.
The investigators concluded that "These results confirm the efficacy and safety of ripretinib and demonstrate the potential benefit of ripretinib as an earlier treatment option for patients who do not tolerate treatment with sunitinib."
The findings suggest that second-line ripretinib does not adversely affect the efficacy of third-line therapy, providing clinicians with additional flexibility in treatment sequencing for patients with advanced GIST (search). Future studies, including the ongoing INSIGHT phase III trial in patients with specific KIT (search) mutations, may further refine personalized treatment approaches in this patient population.