Ripretinib Does Not Meet Primary End Point vs Sunitinib for Pretreated GIST in Phase 3 INTRIGUE Study

The phase 3 INTRIGUE study (NCT03673501) of ripretinib (Qinlock) for patients with gastrointestinal stromal tumors (GIST) who were previously treated with imatinib (Gleevec) did not meet the primary end point of progression-free survival (PFS) superiority when compared with sunitinib (Sutent), according to data presented as part of the American Society of Clinical Oncology (ASCO) Plenary Series Session.¹

Despite these findings, the investigative team determined that the multitargeted tyrosine kinase inhibitor was still a viable option for this patient population given its comparable efficacy with sunitinib and manageable safety profile.

Those who had KIT exon 11 mutations in the ripretinib arm had a median PFS of 8.3 months compared with 7.0 months in the sunitinib arm (HR, 0.88; 95% CI, 0.66-1.16; P = .36). When looking at the entire population, ripretinib yielded a median PFS of 8.0 months compared with 8.3 months in the sunitinib arm (HR, 1.05;95% CI, 0.82-1.33; nominal P value = .72).

“Patients with GIST in the post-imatinib setting are in need of additional treatment options for their disease, and the results from INTRIGUE demonstrate that ripretinib is an active and well-tolerated agent. Although the INTRIGUE study did not meet its primary end point of superiority in progression-free survival versus sunitinib, the efficacy of ripretinib appears comparable to sunitinib in second-line [disease],” Michael Heinrich, MD, FACP, professor of medicine at Oregon Health & Science University, said in a press release.² “In addition, ripretinib had a more favorable safety profile than sunitinib with fewer grade 3/4 adverse events and patients reported less deterioration in role functioning and several other key patient-reported outcome measures of tolerability.”

Previous data from a phase 1 study showed that ripretinib use in the second line after imatinib resulted in a median PFS of 10.7 months, leading the investigators to hypothesize that it may have superior efficacy compared with other later-line agents.³

A total of 453 patients were enrolled in INTRIGUE, of whom 226 were in the ripretinib group and 227 in the sunitinib group. Of those, 163 and 164, respectively, harbored KIT exon 11 mutations. Patients received 150 mg of ripretinib once daily continuously vs sunitinib at 50 mg once daily for 4 weeks on and 2 weeks off. The primary end point was PFS by RECIST version 1.1 in the KIT exon 11 and intention-to-treat (ITT) populations. The secondary end points were objective response rate (ORR), overall survival, time to response, quality of life, disease control rate (DCR), and safety.

At the data cut-off of September 1, 2021, 65 patients in the ripretinib group and 52 on sunitinib were in ongoing treatment. Top reasons for treatment discontinuation were progressive disease, clinical progression, withdrawal of consent, and adverse effects (AEs).

Patient characteristics were well balanced in the treatment arms, with a median overall age of 60 years (range, 18-88) and a majority male (62.0%) and White (66.2%) population. Most patients had an ECOG performance score of 0 (57.2%) and a KIT exon 11 mutation (72.2%); the second most common mutation was KIT exon 9 in 13.2% of patients. Additionally, 9.9% of patients had imatinib intolerance.

Patient disposition from the phase 3 INTRIGUE study

Patients with KIT exon 9 mutations had inferior PFS with ripretinib at 5.5 months vs the sunitinib group at 13.8 months (HR, 2.85; 95% CI, 1.48-5.48). Those with wild-type KIT/PDGFRA (HR, 0.90; 95% CI, 0.36-2.23), other KIT/PDGFRA mutations (HR, 0.90; 95% CI, 0.35-2.28), or imatinib intolerance (HR, 1.01; 95% CI, 0.44-2.33) had similar outcomes with both agents.

An ORR of 23.9% (95% CI, 17.6%-31.3%) was observed in the ripretinib arm for patients with a KIT exon 11 mutation compared with 14.6% (95% CI, 9.6%-21.0%) in the sunitinib arm (nominal P = .03). Two patients had a complete response (CR) and 22 had a partial response (PR) in the sunitinib arm vs 39 with PRs in the ripretinib arm. The ORR difference in the those with KIT exon 11 mutations was 9.3% (95% CI, 0.7%-17.8%).

The overall population exhibited an ORR of 21.7% (95% CI, 16.5%-27.6%) in the ripretinib arm compared with 17.6% (95% CI, 12.9%-23.2%) in the sunitinib group (nominal P = .27). CRs occurred in 3 patients treated with sunitinib vs 1 with ripretinib, with PRs in 48 vs 37, respectively. The ORR difference in the ITT population was 4.2% (95% CI, –3.2% to 11.5%).

The median DOR in the KIT exon 11 population was 16.7 months in the ripretinib group vs 20.1 months in the sunitinib arm. In the ITT population, the DOR mirrored results in the KIT exon 11–positive group.

Median treatment duration was 7.9 months (95% CI, 0.20-26.45) for ripretinib vs 6.5 months (95% CI, 0.20-26.32) with sunitinib. Any dose modification occurred in 38.1% of patients in ripretinib arm vs 63.3% in the sunitinib arm.

Grade 3 or 4 treatment-emergent adverse effects (TEAEs) were observed less frequently in the ripretinib arm (41.3%) compared with the sunitinib arm (65.6%). In the ripretinib arm, the most common grade 3/4 TEAEs were hypertension (8.5%), fatigue (3.1%), and abdominal pain (2.7%). In the sunitinib arm, the most common grade 3 TEAEs were hypertension (26.7%), palmar-plantar erythrodysesthesia (10.0%), and abdominal pain (2.7%).

“[Although] ripretinib did not meet the primary end point of superiority in PFS over sunitinib, it had a more favorable safety profile, and may provide meaningful clinical benefit to patients with advanced GIST previously treated with imatinib,” Heinrich concluded.

References

1. Heinrich M, Jones R, Gelderblom H, et al. INTRIGUE: A phase III, randomized, open-label study to evaluate the efficacy and safety or ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib. Presented at: ASCO Plenary Series; January 25, 2022. https://bit.ly/3rSL8X4

2. Deciphera Pharmaceuticals presents results from the INTRIGUE phase 3 clinical study at the American Society of Clinical Oncology Plenary series session. News Release. Deciphera Pharmaceuticals. January 24, 2022. Accessed January 25, 2022. https://bit.ly/3AwD4zi

3. Janku F, Abdul Razak AR, Chi P, et al. Switch Control Inhibition of KIT and PDGFRA in Patients With Advanced Gastrointestinal Stromal Tumor: A Phase I Study of Ripretinib. J Clin Oncol. 2020;38(28):3294-3303. doi:10.1200/JCO.20.00522