China’s National Medical Products Administration has granted priority review status to a new drug application for ripretinib for the treatment of adult patients with advanced gastrointestinal stromal tumor who received previous treatment with 3 or more kinase inhibitors, including imatinib.
China’s National Medical Products Administration has granted priority review status to a new drug application (NDA) for ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who received previous treatment with 3 or more kinase inhibitors, including imatinib (Gleevec), according to Zai Lab Limited.1
“The grant of this priority review for the ripretinib NDA underscores the potential of ripretinib to alter the treatment landscape for [patients with] GIST, especially for those who are refractory to prior therapies,” Samantha Du, PhD, founder, chairwoman, and chief executive officer of Zai Lab, stated in a press release. “The magnitude of the unmet need for [patients with] GIST in China is significant, with over 30,000 Chinese patients diagnosed each year. We thank the agency for their commitment and continued support to patients in need and look forward to working closely with them to advance this important therapy toward approval.”
Ripretinib, a switch-control TKI, was developed to broadly inhibit KIT and PDGFRα–mutated kinases through a dual mechanism of action that both regulates the kinase switch pocket and activation loop, according to Zai Lab Limited. The agent inhibits primary and secondary KIT mutations in exons 9, 11, 13, 14, 17, and 18 that are associated with GIST, in addition to the primary exon 17 D816V mutation that plays a role in systemic mastocytosis.
In May 2020, the FDA approved ripretinib for use as a fourth-line treatment option in patients with advanced GIST who received previous treatment with 3 or more kinase inhibitors, including imatinib based on data from the phase 3 INVICTUS trial (NCT03353753). In this trial, the investigational broad-spectrum KIT and PDGFRα inhibitor resulted in an 85% reduction in the risk of disease progression or death versus placebo in heavily pretreated patients with advanced disease.2
Specifically, data demonstrated that the median progression-free survival (PFS) with ripretinib was 6.3 months versus just 1.0 month with placebo (hazard ratio [HR], 0.15; 95% CI, 0.09-0.25; P <.0001). Moreover, a 64% reduction in the risk of death was observed with ripretinib versus placebo, which was the secondary end point of the trial. The median overall survival (OS) with ripretinib versus placebo was 15.1 months versus 6.6 months, respectively (HR, 0.38; 95% CI, 0.20-0.63; P = .0004). Despite that benefit, the hierarchical testing procedures used for the trial prevented a conclusive establishment of statistical significance for OS.
The objective response rate with the agent was 9.4% versus no responses experienced with placebo (P = .0504). However, these data were not determined to be statistically significant, and this impacted the ability to adequately assess the significance of the OS data, given the design of the trial’s statistical analysis. The median duration of response with ripretinib had not yet been reached; 7 of 8 patients continued to respond to treatment at the May 31, 2019 data cutoff.
Moreover, the PFS rate at 6 months was 51.0% with ripretinib (95% CI, 39.4%-61.4%) versus just 3.2% with placebo (95% CI, 0.2%-13.8%). Notably, PFS benefit with the targeted therapy was observed across all patient subgroups evaluated. The HR for PFS in heavily pretreated patients who had received 3 previous therapies was 0.15 in favor of ripretinib (95% CI, 0.08-0.29). In patients who received 4 or more prior treatments, the HR was 0.24, again in favor of ripretinib (95% CI, 0.12-0.51).
The 6-month OS rate with the switch kinase inhibitor was 84.3% (95% CI, 74.5%-90.6%) versus 55.9% with placebo (95% CI, 39.9%-69.2%). At 12 months, the OS rate was 65.4% (95% CI, 51.6%-76.1%) and 25.9% (95% CI, 7.2%-49.9%) with ripretinib and placebo, respectively. To adjust for crossover, investigators analyzed OS even further. The median OS in the placebo arm without crossover was 1.8 months versus 11.6 months in those who crossed over to the investigational arm.
With regard to safety, all-grade treatment-emergent adverse effects (TEAEs) were reported in 98.8% of patients who received ripretinib versus 97.7% of those who received placebo. All-cause grade 3/4 TEAEs were observed in 49.4% of patients on the investigational arm versus 44.2% of those on the control arm.
The most commonly reported all-grade effects reported in the ripretinib and placebo 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 grade 3/4 TEAEs between the investigational and control arms were anemia (9.4% vs 14%, respectively), hypertension (7.1% vs 0%), and abdominal pain (7.1% vs 4.7%).
Moreover, 7.1% of patients on ripretinib experienced TEAEs that resulted in a dose reduction compared with 2.3% of those on placebo. Additionally, 8.2% of patients on ripretinib had TEAEs that led to treatment discontinuation versus 11.6% of those on placebo. Notably, more TEAEs were reported in those receiving placebo compared with those receiving ripretinib, at 5.9% versus 23.3%, respectively.
The phase 3 randomized INTRIGUE trial (NCT03673501), which is examining ripretinib compared with sunitinib (Sutent) in patients with GIST who progressed on imatinib, is currently enrolling participants. The target enrollment for the trial is 358 patients with advanced disease and the estimated completion date is June 2021.