Authors

  1. Fuerst, Mark L.

Article Content

Ripretinib demonstrates comparable efficacy with fewer side effects than sunitinib in patients with gastrointestinal stromal tumors (GIST) who were previously treated with imatinib, according to a large, Phase III trial.

  
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"Even though the INTRIGUE study did not meet its primary endpoint of improved progression-free survival (PFS), ripretinib and sunitinib efficacy appeared comparable. Although ripretinib was not superior to sunitinib as a second-line treatment for GIST, ripretinib has remarkable activity as a fourth-line or later agent and remains the only FDA-approved agent in this setting," said lead author Michael C. Heinrich, MD, FACP, Professor of Medicine at the Portland VA Health Care System and Oregon Health & Science University.

 

About 80 percent of patients with GIST have primary mutations in KIT. Imatinib is effective against KIT-mutated GIST, but over time most imatinib-treated patients experience tumor progression due to the development of secondary kinase domain mutations, said Heinrich during the January session of the American Society of Clinical Oncology Plenary Series.

 

The multitargeted tyrosine kinase inhibitor (TKI) sunitinib is approved for advanced GIST after imatinib failure. Ripretinib, a broad-spectrum KIT and PDGFRA switch-control TKI, has superior in vitro activity to sunitinib against imatinib-resistant secondary KIT mutations. Ripretinib is indicated for the treatment of adult patients with advanced GIST who have received prior treatment with three or more TKIs, including imatinib.

 

Study Details

Heinrich and colleagues conducted an international, multicenter study in 122 active sites across 22 countries of 453 adult patients with advanced GIST who had progressed or had documented intolerance to imatinib. They were randomized to ripretinib (226 patients) 150 mg daily given continuously or sunitinib (227 patients) 50 mg once daily given 4 weeks on, 2 weeks off.

 

At the time of the data lock in September 1, 2021, 65 patients remained on treatment with ripretinib and 52 patients remained on treatment with sunitinib. Demographics and clinical characteristics were well-balanced between the arms, researchers noted. Approximately 72 percent of patients in both arms had KIT exon 11 mutant GIST.

 

The results show an overall median PFS of 8 months for ripretinib as compared to 8.3 months for sunitinib. In patients with a KIT exon 11 primary mutation, median PFS for ripretinib was 8.3 months compared to 7 months for sunitinib arm. These are not statistically significant differences.

 

The overall objective response rate (ORR) for ripretinib was 21.7 percent (49 patients) compared to 17.6 percent (40 patients) for sunitinib. In patients with a KIT exon 11 primary mutation, the ORR for ripretinib was 23.9 percent (39 patients) compared to 14.6 percent (24 patients) for sunitinib. Heinrich noted that "both arms yielded higher ORRs than had previously been reported in studies of second-line treatment, including second-line sunitinib treatment."

 

The median duration of response was 16.7 months for patients randomized to ripretinib and 20.1 months for patients randomized to sunitinib. "We analyzed dose modification for the two treatments. The median duration of treatment was 7.9 months for ripretinib and 6.5 months for sunitinib. In terms of dose modification, 38 percent of ripretinib patients had any dose modification compared with 63 percent for sunitinib," said Heinrich.

 

Dose reductions of ripretinib occurred in approximately 20 percent of patients compared with 50 percent for patients treated with sunitinib. Slightly more than 21 percent of the sunitinib-treatment patients had a change in dose regimen from cycle 1, usually to continuous dosing.

 

Ripretinib was generally well-tolerated. Fewer patients in the ripretinib arm experienced Grade 3-4 adverse events (41.3%) compared to sunitinib (65.6%). Patients receiving sunitinib were 3 times more likely to develop Grade 3 hypertension compared with patients receiving ripretinib (26.7% vs. 8.5%) and 7 times more likely to develop Grade 3 hand-foot syndrome as compared to patients receiving ripretinib (10% vs. 1.3%).

 

Fewer patients receiving ripretinib experienced a moderate to extremely large impact on their lives as measured by the Dermatology Life Quality Index. Patients receiving ripretinib also experienced less deterioration in their ability to engage in either work or leisure activities during treatment.

 

"Ripretinib did not meet the primary endpoint of superiority in PFS over sunitinib. However, the median PFS observed with ripretinib was comparable to the median PFS observed with sunitinib. The ORR was higher for patients receiving ripretinib in the KIT exon 11 ITT population compared with sunitinib," Heinrich noted.

 

"Ripretinib had a more favorable safety profile compared with sunitinib. Patients receiving ripretinib were less likely to experience Grade 3/4 treatment-emergent adverse events, including hypertension, palmar-plantar erythrodysesthesia syndrome, diarrhea, and stomatitis, compared with patients receiving sunitinib. Patients receiving ripretinib were less likely to need dose modification compared with patients receiving sunitinib. Patients receiving ripretinib reported better tolerability than patients receiving sunitinib. Ripretinib may provide meaningful clinical benefit to patients with advanced GIST previously treated with imatinib."

 

George Demetri, MD, Director of the Sarcoma Center and Senior Vice President for Experimental Therapeutics at Dana-Farber Cancer Institute, commented: "INTRIGUE is an aspirational, very well-designed, and expertly conducted clinical trial. It's difficult to show superiority over an existing approved therapy with any targeted therapies. Essentially, what we see in INTRIGUE is the same control of disease of GIST with very similar PFS with either drug, ripretinib or sunitinib. But there were fewer problems noted with toxicities using ripretinib than with sunitinib.

 

"Ripretinib is still a very good drug with excellent tolerability and reasonably good activity against advanced GIST, regardless of KIT mutational status. And for that reason, this drug will stay on the market as a late-line GIST drug approved by the FDA. And we've learned from this INTRIGUE study that sunitinib is also still a very good drug with very good activity against advanced GIST."

 

Mark L. Fuerst is a contributing writer.