Ripretinib Under Investigation for Second-Line GIST in Phase 3 INTRIGUE Trial

Pipeline Report | <b>Pipeline Report: December 2020</b>

January 5th, 2021 - Ripretinib is under investigation as a second-line treatment in patients with gastrointestinal stromal tumor versus sunitinib in the phase 3 INTRIGUE trial, which recently completed its target enrollment.

Ripretinib (Qinlock) is under investigation as a second-line treatment in patients with gastrointestinal stromal tumor (GIST) versus sunitinib (Sutent) in the phase 3 INTRIGUE (NCT03673501), which recently completed its target enrollment.1

“We are pleased to announce the completion of target enrollment for our phase 3 INTRIGUE study in patients with second-line GIST,” Matthew L. Sherman, MD, executive vice president and chief medical officer of Deciphera Pharmaceuticals, stated in a press release. “This marks an important step forward to potentially bringing [ripretinib] to an early-stage GIST population and establishing [ripretinib] as the best-in-class treatment for this disease.”

The switch-control TKI was developed to broadly hinder KIT- and PDGFRA-mutated kinases through a dual mechanism of action that controls the kinase switch pocket and activation loop. Specifically, the agent inhibits both primary and secondary KIT mutations in exons 9, 11, 13, 14, 17, and 18 that are involved in GIST; the drug also inhibits the primary exon 17 D816V. Ripretinib also impedes primary PDGFRA mutations in exons 12, 14, and 18.

In the global, multicenter, open-label phase 3 INTRIGUE trial, investigators set out to examine the safety and efficacy of ripretinib versus sunitinib in patients with GIST who experienced disease progression or proved to be intolerant to first-line treatment with imatinib (Gleevec).

To be eligible for participation, patients had to be at least 18 years of age, a histologic diagnosis of GIST, an ECOG performance status of 0-2 at the time of screening, at least 1 measurable lesion according to modified RECIST v1.1 criteria, and acceptable organ function and bone marrow reserve, among other criteria.2

If they received therapy with any other line of therapy in addition to imatinib for advanced disease, they were excluded. Moreover, patients with a previous or concurrent malignancy whose natural history or treatment that possesses the potential to interfere with the safety and efficacy of this trial are not eligible for inclusion. Patients with known active central nervous system metastases, left ventricular ejection fraction of less than 50% at the time of screening, those with clinically significant comorbidities, certain gastrointestinal abnormalities, or any active bleeding with the exception of hemorrhoidal or gum bleeding, could not participate.

About 426 patients were randomized in a 1:1 fashion to receive either ripretinib at a once-daily dose of 150 mg or sunitinib at a once-daily dose of 50 mg, which was delivered for 4 weeks and was followed by 2 weeks without sunitinib.

The primary end point of the trial is median progression-free survival (PFS) per independent radiologic review (IRR) in accordance with modified RECIST (mRECIST) criteria. Key secondary end points comprised objective response rate (ORR) and overall survival (OS), also by IRR per mRECIST criteria.

Topline data are anticipated to read out in the second half of 2021, according to Deciphera Pharmaceuticals, Inc, the developer of ripretinib.

“We are looking forward to announcing top-line results for this study in the second half of 2021,” Sherman added. “I am grateful to the patients and their families, investigators, and our employees who have helped us reach this milestone.”

Previously, in May 2020, ripretinib was approved by the FDA for use as a fourth-line treatment of adult patients with advanced GIST who had received previous treatment with 3 or more kinase inhibitor therapies such as imatinib. The regulatory 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% versus placebo in heavily pretreated patients with advanced disease.3

The median PFS with ripretinib and placebo was 6.3 months and 1.0 months, respectively (HR, 0.15; 95% CI, 0.09-0.25; P <.0001). At 6 months, the PFS rates with ripretinib versus placebo were 51.0% (95% CI, 39.4%-61.4%) and just 3.2% (95% CI, 0.2%-13.8%), respectively. This benefit was reported across all subsets analyzed in the trial, including those who had received 3 prior therapies (HR, 0.15) and in those who had received 4 or more therapies (HR, 0.24).

Moreover, ripretinib resulted in a reduction in the risk of death of 64% versus placebo, which was the secondary end point of the research. Specifically, the median OS reported with the agent was 15.1 months compared with 6.6 months with placebo (HR, 0.36; 95% CI, 0.20-0.63; P = .0004). Although there was a numerical improvement observed, the hierarchical testing procedures used for the study prevented conclusive establishment of statistical significance with regard to OS.

At 6 months, the OS rates in the ripretinib and placebo arms were 84.3% (95% CI, 74.5%-90.6%) and 55.9% (95% CI, 39.9%-69.2%), respectively; at 12 months, these rates were 65.4% (95% CI, 51.6%-76.1%) and 25.9% (95% CI, 7.2%-49.9%), respectively.

Additionally, ripretinib elicited an ORR of 9.4% versus 0% with placebo (P = .0504), although this improvement was not determined to be statistically significant. The median duration of response had not yet been reached in the ripretinib arm. At the time of the May 31, 2019, data cutoff, 7 of 8 patients continued to respond to treatment with the investigational broad-spectrum KIT and PDGFRα inhibitor.

Regarding safety, 98.8% of patients in the investigative arm experienced all-grade treatment-emergent toxicities compared with 97.7% with placebo. Treatment-emergent adverse effects (TEAEs) that were grade 3 or 4 in severity, irrespective of cause, were reported in 49.4% and 44.2% of those in the ripretinib and placebo arms, respectively.

The most frequently reported all-grade, treatment-emergent toxicities in the investigative and control arms included alopecia (51.8% vs 4.7%, respectively), fatigue (42.4% vs 23.3%), nausea (38.8% vs 11.6%), abdominal pain (36.5% vs 30.2%), constipation (34.1% vs 18.6%), and myalgia (31.8% vs 11.6%). The most common TEAEs that were grade 3 or 4 in severity included anemia (9.4% vs 14%, respectively), hypertension (7.1% vs 0%), and abdominal pain (7.1% vs 4.7%).

About 7% of patients who receive ripretinib experienced TEAEs that required dose reductions vs 2.3% of those given placebo. Moreover, 8.2% versus 11.6% of patients in the investigative and control arms, respectively, ended up discontinuing treatment. Notably, more toxicities were reported in those who were given placebo vs those who were administered ripretinib, at 5.9% versus 23.3%, respectively.

Data from an exploratory analysis of INVICTUS during the 2020 CTOS Virtual Meeting showed that ripretinib had clinically meaningful activity in patients with fourth-line or later advanced GIST and several, heterogeneous genetic subsets of KIT/PDGFRA mutations.4

Ripretinib improved PFS in all primary mutation subsets examined compared with placebo. Specifically, the PFS rates with ripretinib versus placebo in patients whose tumors harbored KIT exon 11 mutations were 55.3% and 63.6%, respectively (HR, 0.15; 95% CI, 0.08-0.29); these rates were 16.5% versus 13.6%, respectively, in those with KIT exon 9 mutations.

Additionally, dose escalation with ripretinib following progressive disease on a 150-mg daily dose of the agent resulted in a clinically meaningful benefit in patients with advanced disease, according to data from a phase 1 trial also presented during the 2020 CTOS Annual Meeting.5 PFS benefit with ripretinib was reported in the second-, third-, and fourth-line settings, when delivered using an intra-patient dose-escalation method, which was a twice-daily dose of 150 mg.

References

  1. Deciphera Pharmaceuticals completes target enrollment in the INTRIGUE phase 3 clinical study of QINLOCK (ripretinib) in patients with second-line gastrointestinal stromal tumor. News release. Deciphera Pharmaceuticals, Inc. November 30, 2020. Accessed January 4, 2021. http://bwnews.pr/2MyVx9z.
  2. A study of DCC-2618 vs sunitinib in advanced GIST patients after treatment with imatinib (intrigue). ClinicalTrials.gov. Updated October 23, 2020. Accessed January 4, 2021. https://clinicaltrials.gov/ct2/show/NCT03673501.
  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. George S, Chi P, Heinrich M, et al. Ripretinib intra-patient dose escalation following disease progression provides clinically meaningful progression-free survival in gastrointestinal stromal tumor in phase 1 study. Presented at: 2020 CTOS Annual Meeting; November 18-21, 2020; virtual. Abstract 25.
  5. Schöffski P, Bauer S, Heinrich M, et al. Ripretinib demonstrated activity across all KIT/PDGFRA mutations in patients with fourth-line advanced gastrointestinal stromal tumor: analysis from the phase 3 INVICTUS study. Presented at: 2020 CTOS Virtual Meeting; November 18-21, 2020; Virtual. https://bit.ly/3fmC1Y6