FDA Grants Ripretinib Priority Review for Advanced GIST

Steve Hoerter, president and chief executive officer of Deciphera

Steve Hoerter

The FDA has granted a priority review designation to a new drug application (NDA) for ripretinib for the treatment of patients with advanced gastrointestinal stromal tumors (GIST).¹

The NDA is based on findings from the phase III INVICTUS trial, in which the investigational broad-spectrum KIT and PDGFRα inhibitor ripretinib led to an 85% reduction in the risk of disease progression or death compared with placebo for heavily pretreated patients with advanced GIST.²

Under the Prescription Drug User Fee Act, the FDA is scheduled to make a decision on the NDA by August 13, 2020.

“The FDA’s acceptance of our NDA brings us one step closer to our goal of providing patients with advanced GIST a potential new treatment option,” Steve Hoerter, president and chief executive officer of Deciphera Pharmaceuticals, Inc., the manufacturer of ripretinib, stated in a press release. “With commercial preparations already underway, we believe we will be well positioned for a potential US launch in 2020. We look forward to working with the FDA during their review of this application.”

In the double-blind INVICTUS trial, patients were randomized 2:1 to receive ripretinib at 150 mg daily (n = 85) or placebo (n = 44). The study was designed to assess open label ripretinib beyond progression but findings for this arm have not yet been presented. The median age of patients was 60 years, with more aged 75 or more in the placebo group (9% for ripretinib versus 23% for placebo). Two-thirds of patients had received 3 prior therapies, and a third had received ≥4 (range, 4-7). The most common mutation was at KIT exon 11 (58%) followed by KIT exon 9 (16%).

Results showed that the median progression-free survival (PFS) was 6.3 months with ripretinib compared with 1.0 months for placebo (HR, 0.15; 95% CI, 0.09-0.25; P <.0001). Additionally, there was a 64% reduction in the risk of death with ripretinib compared with placebo, which was a secondary endpoint. The median overall survival was 15.1 versus 6.6 months for ripretinib and placebo, respectively (HR, 0.36; 95% CI, 0.20-0.63; P = .0004). However, the hierarchical testing procedures utilized for the study prevented a conclusive establishment of statistical significance for OS.

Additionally, the objective response rate with ripretinib was 9.4% compared with no responses in the placebo group (P = .0504). These findings were not statistically significant, which impacted the ability to effectively test the significant of OS data, given the design of the INVICTUS statistical analysis. The median duration of response had not yet been reached, with 7 of 8 patients continuing to respond at the time of the data cutoff of May 31, 2019.

The 6-month PFS rate was 51.0% (95% CI, 39.4%-61.4%) for the novel targeted therapy compared with 3.2% for placebo (95% CI, 0.2%-13.8%). PFS benefit was observed across all assessed patient subgroups. In those treated with 3 therapies, the HR for PFS was 0.15, in favor of ripretinib (95% CI, 0.08-0.29). In those treated with ≥4 therapies, the HR was 0.24 in favor of the switch kinase inhibitor (95% CI, 0.12-0.51).

The 6-month OS rate with ripretinib was 84.3% (95% CI, 74.5%-90.6%) compared with 55.9% for placebo (95% CI, 39.9%-69.2%). The 12-month OS rate was 65.4% for ripretinib (95% CI, 51.6%-76.1%) compared with 25.9% for placebo (95% CI, 7.2%-49.9%). A further analysis of OS was added to adjust for crossover. For this, the median in the placebo arm without crossover was 1.8 months compared with 11.6 months for those who crossed over to the investigational arm.

All-grade treatment-emergent adverse events (TEAEs), regardless of causality, were experienced by 98.8% of patients in the ripretinib arm compared with 97.7% with placebo. Treatment-emergent grade 3/4 adverse events, regardless of cause, were experienced by 49.4% of patients in the ripretinib group compared with 44.2% for placebo.

The most common all-grade TEAEs in the ripretinib and placebo groups, respectively, were 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%).

TEAEs led to a dose reduction for 7.1% of patients in the ripretinib group versus 2.3% for the placebo arm. Treatment discontinuations due to TEAEs was required for 8.2% of patients in the investigational group versus 11.6% for the placebo arm. There were more TEAEs in the placebo arm than the ripretinib group (5.9% vs 23.3%).

Enrollment is currently ongoing in the phase III randomized INTRIGUE study (NCT03673501), which is looking at ripretinib versus sunitinib (Sutent) for patients with GIST following prior imatinib (Gleevec). The second-line study plans to recruit 358 patients with advanced GIST and has an estimated completion date of June 2021.

Ripretinib previously received an FDA breakthrough therapy designation for the treatment of patients with advanced GIST who have received prior treatment with imatinib, sunitinib, and regorafenib (Stivarga).

References

1. Deciphera Pharmaceuticals announces US Food and Drug Administration acceptance of new drug application and priority review for ripretinib in patients with advanced gastrointestinal stromal tumors [news release]. Waltham, MA: Deciphera Pharmaceuticals; February 12, 2020. bit.ly/2ULKpIo. Accessed February 12, 2020.
2. 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; abstr LBA87). doi: 10.1093/annonc/mdz394.087.