In the INTRIGUE trial, the tyrosine kinase inhibitor ripretinib was not superior to sunitinib in the second-line treatment of patients with advanced gastrointestinal stromal tumors (GIST); however, the agent was better tolerated. These findings were presented by Michael C. Heinrich, MD, FACP, and colleagues during the January 2022 session of the ASCO Plenary Series (Abstract 359881).

Investigators had hypothesized that ripretinib, which is approved in the fourth line, would be more effective in the second line than sunitinib, the current standard of care. Ripritinib is a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor.

Michael C. Heinrich, MD, FACP

“Ripretinib did not meet the primary endpoint of superiority in progression-free survival over sunitinib,” said Dr. Heinrich, Professor of Medicine at Oregon Health & Science University and Head of the Knight Cancer Institute GIST Translational and Clinical Research Programs. While it will not replace sunitinib as a second-line agent, he said, “ripretinib has remarkable activity as a fourth-line or later agent and remains the only [U.S. Food and Drug Administration]-approved agent in this setting.”  

Progression-free survival was comparable between the arms—about 8 months—but the objective response rate was higher for patients with KIT exon 11 treated with ripretinib, and tolerability was improved. Patients treated with ripretinib had fewer treatment-emergent events, were less likely to need dose modification, and reported less impact on quality of life than patients receiving sunitinib.

George D. Demetri, MD, FASCO, Professor of Medicine at Harvard Medical School and Director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute, commented that INTRIGUE is an “intriguing failure,” since it showed comparable efficacy but better tolerability for ripretinib. While less toxicity is a good thing for patients, he said, this was not the study’s primary endpoint.  

George Demetri, MD

Though “technically this was a failed study,” INTRIGUE adds significantly to the evidence base for both these drugs and will allow him to have “thoughtful discussions” of the findings with his patients, Dr. Demetri said. “This was not a failure to move our field forward.”   

INTRIGUE Details

INTRIGUE was an international trial that compared the efficacy and safety of ripretinib vs sunitinib in 453 patients with advanced GIST who had disease progression on or were intolerant to imatinib, 72% of whom had KIT exon 11 mutations. Dosing was with ripretinib at 150 mg once daily (n = 226) and sunitinib at 50 mg once daily on a schedule of 4 weeks on/2 weeks off (n = 227).

Of note, clinicians today prefer continuous dosing of sunitinib at 37.5 mg, which is better tolerated. Dosing in INTRIGUE followed the schedule initially approved for this drug, as is dictated by regulatory authorities for trial design.

The primary endpoint was progression-free survival by independent radiologic review.

Comparable Outcomes

Overall, median progression-free survival was 8.0 months with ripretinib compared to 8.3 months with sunitinib (hazard ratio [HR] = 1.05, P = .72); in patients with a KIT exon 11 primary mutation, it was 8.3 months and 7.0 months, respectively (HR = 0.88, P = .360). 

By stratification subgroup, the progression-free survival benefit for patients with primary KIT exon 9 mutations favored treatment with sunitinib (HR = 2.85). For all other subgroups, outcomes were very comparable, Dr. Heinrich reported.

The overall response rate in the all-patient intent-to-treat population was similar between the arms: 21.7% with ripretinib vs 17.6% with sunitinib (nominal P = .27). For the KIT exon 11–mutated population, it was higher with ripretinib: 23.9% and 14.6%, respectively (nominal P = .03). Duration of response in both analyses was 20.1 months with ripretinib and 15.7 months with sunitinib.    

Better Tolerability With Ripretinib

“Fewer patients who received ripretinib underwent any dose modification (38.1%) compared with those who received sunitinib (63.3%),” Dr. Heinrich added. While modification to the current dosing schedule of sunitinib was allowed, only 15% of patients made this switch (investigators have not “drilled down” to look for differences in efficacy and tolerability in this small subset). Treatment was discontinued due to the drug in 3.6% of patients in the ripretinib arm vs 7.7% in the sunitinib arm.

Grade 3 or 4 adverse events were less common with ripretinib (41.3% vs 65.6%, nominal P < .0001); this included three times less grade 3 hypertension, seven times less grade 3 hand-foot syndrome, and less grade 3 or 4 diarrhea and stomatitis. The most common toxicity with ripretinib was alopecia (all grades, 64.1%), while for sunitinib, it was hand-foot syndrome (all grades, 51.1%).

Using the Dermatology Life Quality Index, investigators found that fewer patients receiving ripretinib experienced a moderate to extremely large impact on their lives. Patients also reported less deterioration in their ability to engage in either work or leisure activities during treatment.

Disclosure: For full disclosures of the study authors, visit coi.asco.org.