Ripretinib did not significantly improve progression-free survival over sunitinib in patients with gastrointestinal stromal tumor who previously received imatinib, missing the primary end point of the phase 3 INTRIGUE trial.
Ripretinib (Qinlock) did not significantly improve progression-free survival (PFS) over sunitinib (Sutent) in patients with gastrointestinal stromal tumor (GIST) who previously received imatinib (Gleevec), missing the primary end point of the phase 3 INTRIGUE trial (NCT03673501).1
The statistical analysis plan for the trial included a hierarchical testing sequence that included testing patients whose tumors harbored a KIT exon 11 primary mutation, and then in the all-patient (AP), intent-to-treat (ITT) population.
Topline data showed that in the 327 patients whose tumors harbored a KIT exon 11 primary mutation, ripretinib resulted in a median PFS of 8.3 months per independent radiologic review (IRR) and RECIST criteria vs 7.0 months with sunitinib (HR, 0.88; P = .360). Although this was not formally tested in the AP population because of the testing sequence, the median PFS in the investigative arm was 8.0 months vs 8.3 months in the control arm (HR, 1.05; nominal P = .715).
“While we are disappointed with these results, which we learned yesterday, we believe this was a robust, well-designed, and well-executed study. The full results from the INTRIGUE phase 3 clinical study are expected to be presented at an upcoming medical meeting,” Steve Hoerter, president and chief executive officer of Deciphera Pharmaceuticals, Inc., stated in a press release. “…[Ripretinib] remains the standard of care and only approved therapy in patients with fourth-line GIST, and we are committed to ensuring that patients around the world in the fourth-line GIST treatment setting have access to [the agent].”
The global, multicenter, open-label, phase 3 INTRIGUE trial enrolled patients who were at least 18 years of age who had a histologic diagnosis of GIST and who had a tumor tissue sample available.2 Patients must have progressed on, or were intolerant to, imatinib; had an ECOG performance status of 0 to 2 at screening; at least 1 measurable lesion per modified RECIST v1.1 criteria; acceptable organ function and bone marrow reserve; and resolution of all adverse effects (AEs) from prior therapies to grade 1 or less within 1 week prior to the first study dose.
If patients had treatment with any other line of therapy in addition to imatinib for advanced GIST, a previous or concurrent malignancy whose natural history or treatment potentially could interfere with the safety and efficacy assessments of the trial, known active central nervous system metastases, left ventricular ejection fraction of less than 50% at screening, arterial thrombotic or embolic events like cerebrovascular accident, or venous thrombotic or pulmonary arterial events, they were excluded.
Other exclusion criteria included having undergone major surgeries, use of known substrate or inhibitors of BCRP transporters within 14 days, gastrointestinal abnormalities, and active bleeding except for hemorrhoidal or gum bleeding.
A total of 453 participants were randomized 1:1 to receive either ripretinib at a once-daily dose of 150 mg or sunitinib at a once-daily dose of 50 mg for 4 weeks followed by 2 weeks without sunitinib.
The primary end point of the trial was PFS per IRR using modified RECIST criteria in the prespecified subsets of patients with a KIT exon 11 mutation and then in the AP ITT population. Key secondary end points comprised objective response rate (ORR) as determined by IRR using modified RECIST criteria and overall survival in both groups.
In May 2020, ripretinib was approved by the FDA for use as a fourth-line treatment of adult patients with advanced GIST who had previously received 3 or more kinase inhibitor therapies like imatinib.3 The decision was supported by earlier findings from the phase 3 INVICTUS trial (NCT03353753).
When ripretinib was given at a once-daily dose of 150 mg in this population (n = 85), it resulted in a significant improvement in median PFS compared with placebo (n = 44). The median PFS in the investigative arm was 6.3 months (95% CI, 4.6-8.1) vs 1.0 months (95% CI, 0.9-1.7) with placebo (HR, 0.16; 95% CI, 0.10-0.27).
Moreover, ripretinib elicited an ORR of 11.8% (95% CI, 5.8%-20.6%) vs 0% (95% CI, 0.0%-8.0%) with placebo. The median duration of response in the investigative arm was 14.5 months (95% CI, 3.7–not evaluable [NE]) vs NE (95% CI, NE–NE) with placebo.
With 19 months of additional follow-up following the primary analysis of the trial, the median OS with ripretinib was 18.2 months (95% CI, 13.1-30.7) vs 6.3 months (95% CI, 4.1-10.0) with placebo (HR, 0.41; 95% CI, 0.26-0.65). The median OS was 10 months in the patients who originally received placebo and crossed over to receive ripretinib.
At 12 months, the estimated OS rate in those randomized to receive ripretinib was 65.1% (95% CI, 53.6%-74.5%) vs 29.7% (95% CI, 16.8%-43.7%) with placebo. The estimated OS rates at 18 months in the investigative and control arms were 50.1% (95% CI, 38.5%-60.7%) and 29.7% (95% CI, 16.8%-43.7%), respectively; the estimated rates at 24 months were 42.8% (95% CI, 31.5%-53.7%) and 19.8% (95% CI, 9.4%-33.0%), respectively.
Most treatment-emergent AEs were grade 1 or 2 in severity. The most common toxicities experienced with ripretinib included alopecia (any grade, 52%), fatigue (any grade, 47%; grade 3/4, 4%), nausea (any grade, 41%; grade 3/4, 4%), abdominal pain (any grade, 40%; grade 3/4, 7%), constipation (any grade, 38%; grade 3/4, 1%), myalgia (any grade, 37%; grade 3/4, 1%), diarrhea (any grade, 33%; grade 3/4, 1%), decreased appetite (any grade, 29%, grade 3/4, 1%), and Palmar-plantar erythrodysesthesia (any grade, 22%; grade 3/4, 0%), among others.