In the INTRIGUE trial, reported during the January 2022 session of the virtual ASCO Plenary Series, the tyrosine kinase inhibitor ripretinib was not superior to sunitinib in the second-line treatment of patients with advanced gastrointestinal stromal tumors (GIST) but was better tolerated.¹ Investigators had hypothesized that ripretinib would be superior to sunitinib, which is the standard of care in patients with disease progression on imatinib.

“Ripretinib did not meet the primary endpoint of superiority in progression-free survival over sunitinib,” said Michael C. Heinrich, MD, Professor of Medicine at Oregon Health and Science University in Portland and Head of the Knight Cancer Institute GIST Translational and Clinical Research Programs. While progression-free survival was comparable between the arms, the objective response rate was higher for patients with KIT exon 11 treated with ripretinib, and tolerability was improved.

“Ripretinib did not meet the primary endpoint of superiority in progression-free survival over sunitinib.”

— Michael C. Heinrich, MD

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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. “Grade 3 or 4 treatment-related adverse events with an absolute difference of at least 1% were nearly all [less frequent] with ripretinib than with sunitinib,” he said. “Ripretinib may provide meaningful clinical benefit to patients with advanced GIST previously treated with imatinib.”

To GIST expert George D. Demetri, MD, FASCO, Professor of Medicine at Harvard Medical School, INTRIGUE’s findings show that ripretinib is “still a very good drug with excellent tolerability and reasonably good activity against advanced GIST, regardless of KIT mutational status, and that sunitinib is “also a very good drug with very good activity” but with some “annoying yet manageable” toxicities.

Approximately 80% of patients with GIST have primary mutations in KIT. Imatinib is effective against KIT-mutated GIST, but most patients ultimately develop resistance. The multitargeted tyrosine kinase inhibitor sunitinib has become the standard second-line treatment, whereas ripretinib, a broad-spectrum KIT and PDGFRA switch-control tyrosine kinase inhibitor, is indicated after treatment with at least three prior tyrosine kinase inhibitors.

INTRIGUE Details

The international randomized INTRIGUE trial compared the two agents as second-line therapies in 453 patients with advanced GIST who had disease progression on or were intolerant to imatinib. By primary mutation status, 72% had KIT exon 11 mutations and 13% had exon 9 mutations.

Patients received 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 currently 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 dictated by regulatory authorities. The primary endpoint was progression-free survival by independent radiologic review.

Comparable Outcomes

Overall, median progression free survival was 8.0 months with ripretinib and 8.3 months with sunitinib (hazard ratio [HR] = 1.05; P = .72). In patients with a KIT exon 11 primary mutation, progression-free survival 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 comparable, Dr. Henrich reported.

The overall response rate in the 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 population it was higher with ripretinib: 23.9% and 14.6%, respectively (nominal P = .03). The 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 dose modifications (38.1%) compared with those who received sunitinib (63.3%). Although modification to the current dosing schedule of sunitinib was allowed, only 15% of patients made this switch; investigators have not yet examined differences in efficacy and tolerability in this small subset. Treatment was discontinued due to the drug in only 3.6% of the ripretinib arm vs 7.7% of the sunitinib arm.

Fewer patients on ripretinib experienced grade 3 or 4 adverse events (41.3% vs 65.6%; nominal P < .0001). This included three times less grade 3 hypertension (8.5% vs 26.7%) and seven times less grade 3 hand-foot syndrome (1.3% vs 10.0%). Ripretinib recipients also reported less grade 3 or 4 diarrhea and stomatitis. The most common toxicity with ripretinib was alopecia (all grades, 64.1%); for sunitinib, it was hand-foot syndrome (all grades, 51.1%).

Considering the incidence of skin toxicity with sunitinib, investigators queried patients using the Dermatology Life Quality Index and found that fewer patients receiving ripretinib reported 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.

Can Clinicians Act on These Data?

A listener questioned whether clinicians could choose ripretinib in the second line, given its comparable efficacy and better tolerability. Dr. Heinrich said the answer is dependent on regulators and third-party payers, not clinicians.“I don’t think we live in that world,” he said.

With sunitinib now available in generic form, the price differential is considerable, he further noted. “In the trial, we chose a pretty aggressive 50% improvement in progression-free survival as the goal because we thought clinically that would be a game-changer and would move the regulators, but we didn’t achieve that.”

Nevertheless, Dr. Henrich emphasized, “Although ripretinib was not superior to sunitinib as a second-line treatment for GIST, it 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.” 

DISCLOSURE: Dr. Heinrich has consulted or advised for and/or received honoraria from Novartis, Blueprint Medicines, Deciphera, Novartis, and Theseus Pharmaceuticals.

REFERENCE

1. Heinrich MC, Jones RL, Gelderblom H, et al: INTRIGUE: A phase III, randomized, open-label study to evaluate the efficacy and safety of ripretinib versus sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib. ASCO Plenary Series. Abstract 359881. Presented January 25, 2022.