Ripretinib Stills Holds a Place in the Advanced GIST Landscape After INTRIGUE Study

Michael C. Heinrich, MD

Based on the median progression-free survival (PFS) observed with ripretinib (Qinlock) in the phase 3 INTRIGUE trial, the agent may provide clinical benefit to patients with advanced gastrointestinal stromal tumor (GIST), even though the PFS was not superior to sunitinib (Sutent), missing the primary end point of the study.¹

Results presented during the 2022 January ASCO Plenary Series showed that ripretinib did perform better than sunitinib in terms of the objective response rate (ORR), and the safety profile of the drug was favorable compared with sunitinib.

Sunitinib is an FDA-approved, second-line treatment of patients with imatinib (Gleevec)-refractory or -intolerant GIST. But research around sunitinib has demonstrated a median PFS of only 5.6 months.

“Ripretinib is indicated for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more tyrosine kinase inhibitors, including imatinib. In a phase 1 study, the median PFS for ripretinib as the second-line therapy was 10.7 months,” explained Michael H. Heinrich, professor of medicine, School of Medicine Cell and Developmental Biology Graduate Program, Cancer Biology Graduate Program, and Program in Molecular and Cellular Biosciences, at the School of Medicine at Oregon Health & Science University in Portland, Oregon, during the ASCO plenary.

Therefore, Heinrich et al aimed to determine if ripretinib would be superior to sunitinib for the treatment of patients with advanced GIST who are previously treated with imatinib in the interventional, randomized, multicenter, open-label, phase 3 INTRIGUE trial.

Patients with confirmed advanced GIST who were at least 18 years of age and progressed on or were intolerant to imatinib were enrolled. A total of 453 patients were randomized 1:1 to receive either ripretinib 150 mg once daily (n = 226) or sunitinib 50 mg once daily (n = 227). Patients were stratified by mutational status (KIT exon 11, KIT exon, KIT/PDGFRA wild type, or other PDGFRA mutations), intolerance to imatinib.

The investigators primarily assessed for PFS by independent radiographic review in the overall KIT exon 11 intent-to-treat (ITT) population versus the all-patients (AP) ITT population.

The secondary end points evaluated in the study were ORR by independent review, and overall survival in the KIT exon 11 ITT population compared with the AP ITT population.

Of the 453 patients randomized, 223 from the ripretinib arm and 221 from the sunitinib arm received at least 1 dose of treatment. At the time of data cutoff, treatment was ongoing for 65 patients in the ripretinib arm and 52 in the sunitinib arm.

The population had a median age of 60 years (range, 18-88). In the cohort, 62% of patients were male and 66.2% were White. The majority of the patients were from Europe (46.8%), followed by North America (36.0%), Asia-Pacific (13.2%), and SouthAmerica (4.0%).

Disease characteristics screened at baseline showed that 57.2% of patients had an ECOG performance score of 0, and 41.9% had an ECOG performance score of 1. The remaining patients had a score of 2. KIT exon 11 mutations were the most common among the patients (72.2%), followed by KIT exon 9 (13.2%). More than 9% of patients in the study had intolerance to imatinib. The sum of the longest diameters of target lesions among the patients was 90.5 mm (range, 11-456).

According to the Kaplan-Meir analysis for survival, in the KIT exon 11 ITT group, the median PFS was 8.3 months (95% CI, 6.8-13.3) with ripretinib compared with 7.0 months (95% CI, 5.6-10.9) with sunitinib (HR, 0.88; 95% CI, 0.66-1.6; P =.36).

In the AP ITT population, the median PFS observed with ripretinib was 8.0 months (95% CI, 6.5-10.8) versus 8.3 months (95% CI, 6.3-11.0) with sunitinib (HR, 1.05; 95% CI, 0.82-1.33; nominal P =.72).

PFS was also evaluated across the prespecified mutational subgroups. “For the overall population the hazard ratio was 1.05. The confidence intervals for all of the stratification subgroups showed no clear difference between the treatment arms, with the exception of patients with KIT exon 9-mutant GIST, in which sunitinib treatment appeared to provide a PFS benefit compared with repetitive treatment,” Heinrich explained.

The ORR shown with ripretinib in the KIT exon 11 population was 23.9% (95% CI, 17.6%-31.2%) compared with 14.6% (95% CI, 9.6%-21.0%) in the sunitinib-treated patients. Notably, all responses to ripretinib were partial responses and there were 2 complete responses to sunitinib. The overall difference in ORR was 9.3% (95% CI, 0.7%-17.8%; P = .03).

In the AP ITT population, the ORR also favored the ripretinib arm at 21.7% (95% CI, 16.5%-27.6%) versus 17.6% (95% CI, 12.9%-23.2%) with sunitinib. Again, responses to ripretinib were largely partial with 1 complete response (CR), and there were 3 CRs in the sunitinib group. The overall difference in ORR was 4.2% (95% CI, -3.2 to 11.5; P = .27).

Any-grade treatment-emergent adverse events (TEAEs) were observed in 99.1% of the ripretinib arm compared with 99.1% of the sunitinib arm. Grade 3 and 4 TEAEs were seen in 41.3% of the ripretinib arm versus 65.6% of the sunitinib arm, and serious TEAEs occurred in 7.0% versus 9.9%, respectively. More dose reductions, dose interruptions, treatment discontinuations, and TEAEs leading to death occurred in the sunitinib arm versus the ripretinib arm.

In the ripretinib arm, the most common any-grade TEAEs observed were alopecia (64.1%), fatigue (37.7%), myalgia (36.3%), and constipation (35.0%). The most common any-grade events in the sunitinib arm included palmar-plantar erythrodysesthesia (51.1%), diarrhea (48.0%), hypertension (47.1%), fatigue (41.2%), and stomatitis (36.2%).

Treatment tolerability in INTRIGUE was based on patient-reported measures. Heinrich stated: “fewer patients receiving ripretinib experienced a moderate to an extremely large impact on their lives due to skin toxicity across the treatment cycles compared with sunitinib. In addition, we measured more than 50 function symptom and health status questions, and these measures provided evidence [supporting] greater tolerability of ripretinib versus sunitinib on almost all dimensions.”

Despite missing its primary end point, the research shows that the ORR benefit and tolerability of ripretinib make it a solid candidate for the treatment of advanced GIST in patients who failed or who developed intolerance to imatinib, Heinrich said.

During a post-presentation discussion about the INTRIGUE data, George D. Demetri, MD, FASCO, FACP, director, Sarcoma Center, senior vice president for Experimental Therapeutics, institute physician, Quick Family Chair in Medical Oncology, Dana-Farber Cancer Institute, and, professor of medicine, Harvard Medical School, said² “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 shift drug approved by the FDA in the United States. We also know and we've learned more from this INTRIGUE study that sunitinib is also still a very good drug with very good activity against advanced GIST, but with some annoying, yet manageable toxicities.”

_References:

_{1. Heinrich MC. 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. Presented at: 2022 January ASCO Plenary Series. January 25, 2022.}

_{2. Demetri GD. Discussion of Abstract 359881: 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. Presented at: 2022 January ASCO Plenary Series. January 25, 2022.}