Ripretinib Improves PFS in Advanced GIST

Margaret von Mehren, MD

Ripretinib (DCC-2618) improved progression-free survival (PFS) compared with placebo in patients with fourth-line and fourth-line plus advanced gastrointestinal stromal tumors (GIST), according to topline findings of the phase III INVICTUS study (NCT03353753).

In the trial, the broad-spectrum KIT and PDGFRα inhibitor led to a median PFS of 6.3 months compared with 1.0 months with placebo in this patient population, translating to an 85% reduction in the risk of disease progression or death (HR, 0.15; P <.0001).

Based on these data, Deciphera, the manufacturer of ripretinib, plans to submit a new drug application to the FDA in the first quarter of 2020 for the drug as a treatment for patients with advanced GIST who previously received imatinib (Gleevec), sunitinib (Sutent) and regorafenib (Stivarga). Full findings from the INVICTUS study are expected to be presented at an upcoming medical meeting.

“There is a dire unmet need for new therapies that can deliver effective disease control for patients with advanced GIST who have failed currently approved treatment options,” Margaret von Mehren, MD, Department of Medical Oncology, Fox Chase Cancer Center, stated in a press release.

“These top-line data from a phase III, randomized, placebo-controlled study are highly impressive and suggest that ripretinib’s approach of targeting the broad spectrum of KIT and PDGFRα mutations known to drive GIST can significantly improve progression free survival in the most heavily pretreated patients. Particularly notable is the magnitude of benefit observed for overall survival in this study,” added von Mehren.

In the international, multicenter, double-blind, placebo-controlled, phase III study, investigators evaluated the efficacy, safety, and tolerability of ripretinib compared with placebo in 129 patients with advanced GIST who received prior treatment with imatinib, sunitinib, and regorafenib. Patients were randomized 2:1 to either ripretinib at 150 mg or placebo once daily.

To be eligible for enrollment, patients had to have a histologic diagnosis of GIST; have progressed on or were intolerant to imatinib, sunitinib, and regorafenib; have an ECOG performance status of 0 to 2 at screening; have at least 1 measurable lesion according to modified RECIST v1.1 criteria; and have adequate organ function.

The primary endpoint was PFS as assessed by blinded independent central radiologic review via modified RECIST v1.1 criteria; key secondary endpoints were overall response rate (ORR), overall survival (OS), quality of life, disease control rate, and time to tumor progression.

Additional results showed that the ORR was 9.4% with ripretinib compared with 0% for placebo (P = .0504), which was not found to be statistically significant. Moreover, ripretinib did show a clinically meaningful improvement in OS versus placebo at 15.1 months compared with 6.6 months, respectively (HR, 0.36; P = .0004). However, since the statistical significance for ORR was not achieved, the hypothesis testing of OS was not formally performed due to a prespecified hierarchical testing procedure of the endpoints. In the placebo arm, the OS data included patients who crossed over to receive ripretinib following disease progression.

Regarding safety, ripretinib was well tolerated and adverse events (AEs) were found to be consistent with prior data with the investigational agent. Treatment-emergent AEs (TEAEs) were similar between the ripretinib (99%) and placebo (98%) arms. Grade 3/4 TEAEs occurred in 42 patients (49%) receiving ripretinib versus 19 patients (44%) on placebo. The grade 3/4 TEAS >5% of patients on ripretinib included anemia (9%), abdominal pain (7%), and hypertension (7%). In the placebo arm, the grade 3/4 TEAE >5% was anemia (14%).

“Today’s announcement represents a significant milestone in our mission to deliver important new medicines for the treatment of cancer,” Steve Hoerter, president and chief executive officer of Deciphera, stated in the press release. “The data from INVICTUS reinforce our belief that ripretinib has the potential to transform the treatment of GIST, and our focus now turns to working closely with the FDA as they evaluate ripretinib for those patients with GIST who, having failed all currently approved therapies, are in desperate need of a treatment option.”

Deciphera Pharmaceuticals Announces Positive Top-line Results from INVICTUS Pivotal Phase 3 Clinical Study of Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumors. Deciphera. Published August 13, 2019. https://bit.ly/2OTQIsg. Accessed August 13, 2019.