The China National Medical Products Administration has accepted a new drug application for ripretinib as a treatment for adult patients with advanced gastrointestinal stromal tumor who have received previous treatment with 3 or more kinase inhibitors, including imatinib.
The China National Medical Products Administration (NMPA) has accepted a new drug application (NDA) for ripretinib (Qinlock) as a treatment for adult patients with advanced gastrointestinal stromal tumor (GIST) who have received previous treatment with 3 or more kinase inhibitors, including imatinib (Gleevac).1
“There is a significant unmet medical need for patients with GIST in China, especially for those who are refractory to prior therapies. Based on the recent full US FDA approval and compelling clinical data from the INVICTUS trial, we believe ripretinib has the potential to alter the treatment landscape for [patients with] GIST in China,” Samantha Du, PhD, founder, chairperson, and chief executive officer of Zai Lab, stated in a press release. “We look forward to working closely with the NMPA to make a profound impact on the way GIST is treated in China.”
In May 2020, the FDA approved the investigational broad-spectrum KIT and PDGFRα inhibitor for use as a fourth-line treatment in this patient population based on data from the pivotal phase 3 INVICTUS trial. Results from the trial demonstrated that treatment with the agent led to an 85% reduction in the risk of disease progression or death versus placebo in heavily pretreated patients with advanced GIST.
Specifically, the median progression-free survival (PFS) with ripretinib was 6.3 months versus 1.0 months with placebo (hazard ratio [HR], 0.15; 95% CI, 0.09-0.25; P <.0001).2 Moreover, a 64% reduction in the risk of death with the agent versus placebo, which was a secondary end point of the trial. The median overall survival (OS) reported with ripretinib was 15.1 months compared with 6.6 months with placebo (HR, 0.36; 95% CI, 0.20-0.63; P = .0004). The hierarchical testing procedures used for the trial prevented the conclusive establishment of statistical significance for OS.
The objective response rate achieved with ripretinib and placebo was 9.4% versus 0%, respectively (P = .0504). The data were not determined to be statistically significant, which impacted the ability to adequately evaluate the significance of OS findings, given the design of the trial’s statistical analysis. Moreover, the median duration of response with ripretinib had not yet been reached at the time of data cutoff, which was May 31, 2019. At that time, 7 of 8 patients continued to respond to treatment.
The 6-month PFS rates with ripretinib and placebo were 51.0% and 3.2%, respectively, and benefit was observed across all patient subgroups that had been evaluated. In patients who had received 3 prior therapies, the HR for PFS was 0.15, which favored the investigational drug (95% CI, 0.08-0.29). In participants who had received ≥4 therapies, the HR was 0.24 in favor of ripretinib (95% CI, 0.12-0.51).
The 6-month OS rate reported with ripretinib was 84.3% versus 55.9% with placebo, and the 12-month OS rates were 65.4% and 25.9%, respectively. A further analysis of OS was added to adjust for crossover. The median OS in the placebo arm without crossover was 1.8 months versus 11.6 months for those who crossed over to the ripretinib arm.
With regard to safety, all-grade treatment-emergent adverse effects (TEAEs) were reported in 98.8% of those who received ripretinib and 97.7% of those given placebo. Treatment-emergent grade 3/4 toxicities were observed in 49.4% and 44.2% of those on the ripretinib and placebo arms, respectively.
The most commonly reported all-grade TEAEs in the ripretinib and placebo arms, respectively, 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 grade 3/4 TEAEs experienced by patients on the investigational and placebo arms, respectively, included anemia (9.4% vs 14%, respectively), hypertension (7.1% vs 0%), and abdominal pain (7.1% vs 4.7%).
TEAEs resulted in a dose reduction in 7.1% of patients who received ripretinib compared with 2.3% in those who were given placebo. TEAEs led to treatment discontinuations in 8.2% of patients on the ripretinib arm and 11.6% of those on the placebo arm. Notably, more TEAEs were reported on the placebo arm versus the ripretinib arm, at 5.9% versus 23.3%, respectively.
“The earlier than expected acceptance of the ripretinib NDA in China underscores its potential and follows the recent FDA approval in the United States,” Steve Hoerter, president and chief executive officer of Deciphera. “The magnitude of the unmet need for [patients with] GIST in China is striking, with over 30,000 Chinese patients reportedly diagnosed each year. We look forward to our continued collaboration with Zai as we work to bring ripretinib to patients who are waiting for an additional treatment option.”
In the phase 3 INTRIGUE (NCT03673501), investigators will examine ripretinib compared with sunitinib (Sutent) in patients with GIST who received previous treatment with imatinib. The study plans to recruit a total of 358 patients with advanced disease. The estimated completion date of the randomized trial is June 2021.
The agent was previously granted a breakthrough therapy designation from the FDA for the treatment of patients with advanced disease who had received previous treatment with imatinib, sunitinib, and regorafenib (Stivarga).