Second-line Ripretinib Provides Clinical Benefit in GIST Harboring Mutations in KIT Exon 11 and 17/18

Ripretinib (Qinlock) improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) over sunitinib (Sutent) when given as second-line treatment to patients with gastrointestinal stromal tumor (GIST) harboring mutations in KIT exon 11 and 17/18 only and who received prior imatinib (Gleevec), according to data from a circulating tumor (ct) DNA analysis of the phase 3 INTRIGUE trial (NCT03673501).¹

The median PFS with ripretinib (n = 27) was 14.2 months vs 1.5 months with sunitinib (n = 25) in this patient subset (HR, 0.22; 95% CI, 0.11-0.44; nominal P < .0001). Moreover, ripretinib elicited an ORR of 44.4% vs 0% with sunitinib, translating to a response difference of 44.4% (95% CI, 23.0%-62.7%; nominal P = .0001). The median OS was not estimable in the ripretinib arm vs 17.5 months in the sunitinib arm (HR, 0.34; 95% CI, 0.15-0.76; nominal P = .0061).

“We are extremely pleased by the exploratory analysis showing that [ripretinib], already the standard of care for fourth-line GIST patients, provided substantial clinical benefit to this subgroup of second-line patients compared to sunitinib,” Matthew L. Sherman, MD, chief medical officer of Deciphera, stated in a press release.

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

A total of 453 patients with a confirmed diagnosis of GIST who had progressed on or had documented intolerance to imatinib and were 18 years of age were enrolled to the open-label, multicenter, phase 3 INTRIGUE trial.

They were randomly assigned 1:1 to ripretinib given at a once-daily dose of 150 mg continuously or sunitinib at a once-daily dose of 50 mg for a 4-weeks-on and 2-weeks-off schedule. Stratification factors comprised mutational status (KIT exon 11 vs KIT exon 9 vs KIT/PDGFRA wild-type vs other KIT/PDGFRA) and imatinib intolerance (yes vs no).

PFS by RECIST v1.1 criteria in the subset of patients with KIT exon 11 mutations and in the overall patient population served as the primary end point of the trial. Important secondary end points comprised ORR by independent radiologic review and OS in both populations. Time to response, disease control rate, safety, and quality of life were also examined.

Data from the trial reported at the 2022 ASCO Annual Meeting showed that ripretinib missed the primary end point of the trial.⁴ The statistical analysis plan included a hierarchical testing sequence that comprised testing those with a KIT exon 11 primary mutation and then in the intention-to-treat (ITT) population.

In the subgroup of patients with KIT exon 11 mutations, the median PFS in the investigative (n = 163) and control (n = 164) arms was 8.3 months (95% CI, 6.8-13.3) and 7.0 months (95% CI, 5.6-10.9), respectively (HR, 0.88; 95% CI, 0.66-1.16; P = .36). In this subset, the ORRs with ripretinib vs sunitinib were 23.9% (95% CI, 17.6%-31.2%) and 14.6% (95% CI, 9.6%-21.0%), respectively, translating to a 9.3% difference (95% CI, 0.7%-17.8%; nominal P = .03).

Although not formally tested because of the rules of hierarchical testing sequence, the median PFS with ripretinib (n = 226) was 8.0 months (95% CI, 6.5-10.8) vs 8.3 months (95% CI, 6.3-11.0) with sunitinib (HR, 1.05; 95% CI, 0.82-1.33; P = .72). The ORR achieved with ripretinib in this population was 21.7% (95% CI, 16.5%-27.6%) vs 17.6% (95% CI, 12.9%-23.2%), translating to a 4.2% difference (95% CI, -3.2% to 11.5%; nominal P = .27).

One of the exploratory objectives of the trial was to examine the antitumor activity achieved with ripretinib in patients who received prior imatinib according to baseline KIT primary and secondary mutation status. To do this, investigators utilized the liquid biopsy assay, Guardant360. Of the 453 patients who comprised the overall population, 362 patients had baseline ctDNA in the peripheral blood examined and were deemed to be evaluable.

Of these patients, 157 patients had KIT exon 11 mutations and 36 patients had KIT exon 9 mutations. In 89 patients, resistance mutations in KIT were detected in exons 17/18. In 81 patients, these mutations were detected in exons 13/14. Moreover, 52 of the patients with a KIT exon 11 primary mutation had mutations in exon 17/18 only; 41 patients had them in exon 13/14 only, and 22 had mutations in exon 13/14 and 17/18.

The data cutoff date for median PFS and ORR reported in the ctDNA analysis was September 1, 2021, and the cutoff date for OS was September 1, 2022. Efficacy data in those with detectable ctDNA in the KIT exon 11 and ITT populations were noted to be in line with what was reported in the primary analysis of the trial; safety data in the subgroups were also consistent.

Based on the data from the analysis, and discussions with regulators, Deciphera Pharmaceuticals, Inc. shared plans to launch the phase 3 INSIGHT trial, which will further explore the safety and efficacy of second-line ripretinib vs sunitinib in this specific population.

The trial is expected to enroll about 54 patients who will be randomly assigned 2:1 to receive 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. PFS by IRR and RECIST v1.1 criteria will serve as the primary end point of the research.

The trial is expected to be initiated in the second half of 2023.

References

1. Deciphera Pharmaceuticals announces results from ctDNA analysis from INTRIGUE phase 3 clinical study demonstrating substantial clinical benefit of QINLOCK in second-line GIST patients with mutations in KIT exon 11 and 17/18 only. News release. Deciphera Pharmaceuticals, Inc. January 3, 2023. Accessed January 4, 2023. https://bit.ly/3ihxeNG
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 January 4, 2023. 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. 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