Ripretinib Does Not Provide Superior PFS Benefit Over Sunitinib in Second-line GIST, But Shows Better Tolerability

Ripretinib (Qinlock) did not result in a significant improvement in progression-free survival (PFS) over sunitinib (Sutent) in patients with gastrointestinal stromal tumor (GIST) who were previously treated with imatinib (Gleevec), missing the primary end point of the phase 3 INTRIGUE trial (NCT03673501) presented during the 2022 ASCO Annual Meeting.¹

Although the PFS benefit provided by ripretinib (n = 226) was not determined to be superior to that achieved with sunitinib (n = 227), the benefit derived with the agents was noted to be comparable in the overall patient population, at 8.0 months (95% CI, 6.5-10.8) vs 8.3 months (95% CI, 6.3-11.0), respectively (HR, 1.05; 95% CI, 0.82-1.33; P = .72).

Moreover, in a subset of patients with KIT exon 11 mutations, the median PFS with ripretinib (n = 163) was 8.3 months (95% CI, 6.8-13.3) vs 7.0 months (95% CI, 5.6-10.9) with sunitinib (n = 164; HR, 0.88; 95% CI, 0.66-1.16; P = .36).

In a presentation on the data, Michael C. Heinrich, MD, lead study author, professor of medicine in the School of Medicine, at the Oregon Health & Science University, said that ripretinib has meaningful clinical activity and a more favorable safety profile compared with sunitinib, with fewer grade 3/4 treatment-emergent adverse effects (TEAEs).

“For each stratification subgroup examined, there was no clear advantage of 1 treatment over the other, with exception of patients with KIT exon 9 GIST, in which the hazard ratio strongly favored sunitinib treatment,” Heinrich said. In this subgroup, the median PFS was 13.8 months in the sunitinib arm vs 5.5 months in the ripretinib arm (HR, 2.85; 95% CI, 1.48-5.48).

Ripretinib is a broad-spectrum KIT and PDGFRA switch-control TKI that is indicated for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more TKIs, including imatinib; the agent received FDA approval in May 2020 for use as a fourth-line treatment in this population.² The regulatory decision was based on data from the phase 3 INVICTUS trial (NCT03353753), in which the agent resulted in an 85% reduction in the risk of disease progression or death vs placebo in heavily pretreated patients with advanced GIST (HR, 0.15; 95% CI, 0.09-0.25; P < .0001).³

Previously, ripretinib was found to have superior in vitro activity to sunitinib in imatinib-resistant secondary KIT mutations.⁴ The agent was also found to exhibit an encouraging PFS of 10.7 months (95% CI, 5.5-13.8) when used as a second-line therapy in a phase 1 study (NCT02571036) done in patients with advanced GIST.⁵ These data supported the hypothesis that ripretinib may be superior to sunitinib in the second-line treatment setting; investigators set out to test this by launching the INTRIGUE trial.

The multicenter, open-label, phase 3 INTRIGUE study enrolled patients who were aged 18 years and older who had a confirmed diagnosis of GIST and who had progressed on or who had documented intolerance to imatinib.

A total of 453 participants were randomized 1:1 to receive 150 mg of ripretinib once daily continuously or sunitinib at 50 mg once daily for a 4-weeks-on and 2-weeks-off schedule. Crossover was not permitted. Patients were stratified by mutational status (KIT exon 11 vs KIT exon 9 vs KIT/PDGFRA wild-type vs other KIT/PDGFRA), and intolerance to imatinib (yes vs no).

The primary end point of the trial was PFS by RECIST v. 1.1 criteria in the KIT exon 11 and overall patient populations. Key secondary end points included objective response rate (ORR) by independent radiologic review (IRR) and overall survival in both populations. Other secondary end points included time to response, quality of life, disease control rate, and safety.

“A hierarchical testing sequence was performed for primary and key secondary end points,” Heinrich said. “Statistical testing of patients with a KIT exon 11 primary mutation preceded the all-patient population. The estimated 426-patient sample size was based on the assumption that the median PFS would be 9 months for ripretinib and 6 months for sunitinib according to previous studies.”

Subgroup analyses of PFS, which were based on stratification factors, showed that the PFS benefit for patients with primary KIT exon 9 mutations favored treatment with sunitinib vs ripretinib.

Additional data from these analyses indicated that the median PFS with ripretinib in those with KIT/PDGFRA wild-type disease was 7.0 months vs 4.1 months with sunitinib (HR, 0.90; 95% CI, 0.36-2.23); in those with other KIT/PDGFRA mutations, the median PFS in the investigative and control arms was 6.8 months vs 8.4 months, respectively (HR, 0.90; 95% CI, 0.35-2.28).

Moreover, in those who were intolerant to imatinib, the median PFS with ripretinib was 13.7 months vs 10.9 months with sunitinib (HR, 1.01; 95% CI, 0.44-2.33); in those who were not intolerant, the median PFS was 7.1 months and 8.1 months, respectively (HR, 1.02; 95% CI, 0.80-1.31).

In the population of patients with a KIT exon 11 mutation, the ORR was 23.9% (95% CI, 17.6%-31.2%) in the ripretinib arm vs 14.6% (95% CI, 9.6%-21.0%) in the sunitinib arm, translating to a difference of 9.3% (95% CI, 0.7-17.8; nominal P = .03). In this subgroup, 2 patients who received sunitinib achieved a complete response (CR) and 22 experienced a partial response (PR) vs 39 PRs in those who were given ripretinib.

In the overall population, the ORR was 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 arm, translating to a difference of 4.2% (95% CI, -3.2 to 11.5; nominal P = .27). Three CRs were reported in the sunitinib arm vs 1 in the ripretinib arm; PRs were achieved by 37 and 48 patients, respectively.

Ripretinib was generally well tolerated. Grade 3 hypertension was noted to be 3 times more likely to occur with sunitinib; these patients were also 7 times more likely to develop grade 3/4 palmar-plantar erythrodysesthesia, according to Heinrich.

Grade 3 /4 TEAEs were less common 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 3/4 TEAEs included hypertension (26.7%), palmar-plantar erythrodysesthesia (10.0%), and abdominal pain (2.7%).

In an assessment of the impact of skin toxicity on tolerability, measured by DLQI, “fewer patients [who received] ripretinib experienced a moderate to extremely large impact on their lives due to the skin toxicity compared with sunitinib,” Heinrich said.

Patients receiving ripretinib also experienced less deterioration on the ERTC QLQC-30 role functioning instrument, which measures the ability to engage in work or leisure activities, compared with sunitinib.

Tumor biopsy and circulating tumor DNA analyses are ongoing.

References

1. Heinrich MC, Jones RL, 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. J Clin Oncol. 2022;40(suppl 17):359881. doi:10.1200/JCO.2022.40.36_suppl.359881
2. FDA grants full approval of Deciphera Pharmaceuticals’ Qinlock (ripretinib) for the treatment of fourth-line gastrointestinal stromal tumor. News release. Deciphera Pharmaceuticals, Inc. May 15, 2020. Accessed June 14, 2022. https://bwnews.pr/3xpyYYC
3. van Mehren M, Serrano C, Bauer S, et al. INVICTUS: a phase 3, international, double-blind, placebo-controlled study to assess the safety and efficacy of ripretinib as >4th line therapy in patients with advanced gastrointestinal stromal tumors (GIST) who have received treatment with prior anticancer therapies (NCT03353753). Ann Oncol. 2019;30(suppl 5):LBA87. doi:10.1093/annonc/mdz394.087
4. Smith BD, Kaufman MD, Lu W-P, et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell. 2019;35(5):738-751. doi:10.1016/j.ccell.2019.04.006
5. 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