NDA for Ripretinib Submitted to FDA for Treatment of GIST

December 16, 2019

Article

A New Drug Application for ripretinib was submitted to the FDA for the treatment of patients with advanced gastrointestinal stromal tumor who have received a prior treatment of imatinib, sunitinib, and regorafenib, according to a press release from Deciphera Pharmaceuticals, Inc.

A New Drug Application (NDA) for ripretinib (DCC-2618) was submitted to the FDA for the treatment of patients with advanced gastrointestinal stromal tumor (GIST) who have received a prior treatment of imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga), according to a press release from Deciphera Pharmaceuticals, Inc.¹

The NDA was submitted based on data from the phase III INVICTUS trial, which demonstrated improvement in progression-free survival (PFS) compared with placebo in heavily pretreated patients with heavily advanced GIST. Thesedata were presented at the 2019 ESMO Congress.

Median PFS was 6.3 months with ripretinib versus 1.0 months with placebo, which led to an 85% reduction in the risk of disease progression or death (HR, 0.15; 95% CI, 0.09-0.25; P <.0001). There was also a 64% reduction in the risk of death, which was a secondaryend pointof the trial.²

The objective response rate (ORR) was 9.4% with ripretinib compared with 0.0% in the placebo arm (P= .0504). Because these findings were not statistically significant, the ability to effectively test the significance of the overall survival (OS) data was impacted. The median OS was 15.1 months with ripretinib versus 6.6 months with placebo (HR, 0.36; 95% CI, 0.20-0.63; P= .0004).

The 6-month PFS rate was 51.0% with ripretinib (95% CI, 39.4%-61.4%) and 3.2% with placebo (95% CI, 0.2%-13.8%). The PFS benefit was observed across all patient subgroups who were evaluated. In patients who received previous treatment with 3 therapies, the HR for PFS was 0.15 in favor of ripretinib (95% CI, 0.08-0.29), while patients who were treated with 4 or more therapies, had an HR of 0.24 in favor of the novel targeted therapy (95% CI, 0.12-0.51).

The 6-month OS rates were 84.3% (95% CI, 74.5%-90.6%) and 55.9% (95% CI, 39.9%-69.2%) for ripretinib and placebo, respectively. The 12-month OS rate was 65.4% for ripretinib (95% CI, 51.6%-76.1%) versus 25.9% for placebo (95% CI, 7.2%-49.9%). After further analysis was added to adjust for crossover, the median 11.6 months for those who crossed over to ripretinib versus 1.8 months in the placebo arm.

Overall, 98.8% of patients in the ripretinib experienced a treatment-emergent adverse event (TEAE) of any grade, regardless of causality, compared with 97.7% in the placebo arm. Grade 3/4 TEAEs of any cause were experienced by 49.4% and 44.2% of patients, respectively.

The most common TEAEs of any grade in the ripretinib versus placebo arms, respectively, included alopecia (51.8% vs 4.7%), 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 grade 3/4 TEAEs between the ripretinib arm and the placebo group, respectively, were anemia (9.4% vs 14%), hypertension (7.1% vs 0%), and abdominal pain (7.1% vs 4.7%).

In the ripretinib arm, TEAEs led to a dose reduction in 7.1% of patients compared with 2.3% in the placebo arm. Treatment disconsolations due to TEAEs occurred in 8.2% of patients receiving treatment with ripretinib versus 11.6% with placebo. Additionally, there were more TEAEs in the placebo arm compared with the ripretinib arm.

INVICTUS was a double-blind phase III study in which patients were randomized 2:1 to receive either 150 mg of ripretinib daily (n = 85) or placebo (n = 44). The median age of patients was 60 years with more aged 75 years or older in the placebo arm (23%) compared with the ripretinib arm (9%). Two-thirds of patients received 3 previous lines of therapy, and one-third received 4 or more prior therapies.

Ripretinib is an investigational tyrosine kinase switch control inhibitor, which was engineered to inhibitKIT- andPDGFRα-mutated kinases with a dual mechanism of action to regulate the kinase switch pocket and activation loop. The agent is currently in clinical development for the treatment of cancers driven by these mutations. Ripretinib inhibitsKITmutations in exons 9, 11, 13, 14, 17, and 18, as well as the primary exon of 17 D816V, and PDGFRαmutations in exons 12, 14, and 18, including exon 18 D842V mutation.

Under the FDA, the Oncology Center of Excellence Real-Time Oncology Review (RTOR) pilot program is reviewing the NDA. This program aims to evaluate efficient review processes to ensure treatments that are both safe and effective come to market as early as possible for patients while maintaining a quality review process.

Ripretinib was previously granted a Breakthrough Therapy Designation from the FDA in October 2019 for the treatment of patients with advanced GIST who have already received a prior treatment of imatinib, sunitinib, and regorafenib.

References:

Deciphera Pharmaceuticals Announces Submission of New Drug Application to U.S. FDA for Ripretinib in Patients with Advanced Gastrointestinal Stromal Tumors. Business Wire website.https://www.businesswire.com/news/home/20191216005211/en/. Published December 16, 2019. Accessed December 16, 2019.
van Mehren M, Attia S, 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). Presented at: 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA87.