SUMMARY: The American Cancer Society estimates that in the US, about 4000-5000 cases of Gastro Intestinal Stromal Tumors (GISTs) are diagnosed each year. GI Stromal Tumor (GIST) is one of the most common types of Soft Tissue Sarcoma and can develop anywhere along the GI tract, but are primarily found in the stomach (60%) and small intestine (30%). GISTs originate from the interstitial cells of Cajal or related stem cells and are associated with activating mutations in KIT-CD117 (80%) or PDGFRA- Platelet-Derived Growth Factor Receptor-A (5-10%). These two mutations are mutually exclusive and are important in the molecular pathogenesis of these tumors. Approximately two thirds of the patients with GISTs are cured with surgery but recurrences are frequent and this risk of relapse is dependent on the tumor size, mitotic rate and primary tumor site. The risk stratification of GISTs by Joensuu, unlike the NIH criteria, takes into account primary tumor site and tumor rupture as well, which can influence outcomes.
Treatment of patients with advanced or metastatic GIST with Tyrosine Kinase Inhibitor GLEEVEC® (Imatinib) achieves high Objective Response and diseases stabilization rates. Patients with KIT exon 9 mutation have a poor prognosis compared to those with KIT exon 11 mutation (most common) and benefit from a higher dose of GLEEVEC® (800 mg daily). The majority of PDGFRA mutations affect exon 18. It should also be noted that patients with PDGFRA D842V mutation are GLEEVEC® resistant. Following progression on GLEEVEC®, FDA approved therapies include SUTENT® (Sunitinib) and STIVARGA® (Regorafenib).
Ripretinib is an orally administered kinase switch-control inhibitor of KIT and PDGFRA at the JuxtaMembrane Domain (JMD), and the main activation loop switch. The agent restores the inhibitory JMD switch, which is often deactivated in GIST, and helps to stabilize the kinase in an inactive state. Ripretinib is a KIT and PDGFRA inhibitor that blocks initiating KIT mutations in exons 9, 11, 13, 14, 17, and 18, known to be present in GIST patients, and the D816V exon 17 mutation known to be present in patients with Advanced Systemic Mastocytosis. Ripretinib inhibits PDGFRA mutations in exon 18, including the D842V mutation that drives a subset of GIST. Ripretinib was specifically designed to improve the outcomes in GIST patients by inhibiting the full spectrum of known mutations in KIT and PDGFRA.
The INVICTUS trial is an international, multicenter, randomized, double-blind, placebo-controlled Phase III trial, in which the safety, efficacy and tolerability of Ripretinib was compared to placebo, among heavily pretreated patients with advanced GIST. In this study, 129 patients were randomized in a 2:1 ratio to receive Ripretinib at 150 mg orally daily (N=85) or placebo (N=44). Previous therapies for enrolled patients included at least GLEEVEC®, SUTENT® and STIVARGA®. Two-thirds of patients had received 3 prior therapies, and a third had received more than 4 lines of therapy. The median patient age was 60 years and the most common mutation was at KIT exon 11 (58%) followed by KIT exon 9 (16%). Patients with disease progression on placebo were allowed to cross over to receive Ripretinib. The Primary endpoint was Progression Free Survival.
It was noted that Ripretinib significantly reduced the risk of disease progression or death by 85% compared to placebo, with a median PFS of 6.3 months compared to 1.0 month in the placebo group (HR=0.15, P<0.0001). This PFS benefit was consistent across all assessed patient subgroups. Additionally, Ripretinib reduced the risk of death by 64% compared to placebo, with a median OS of 15.1 months compared to 6.6 months in the placebo group (HR=0.36; P=0.0004). According to the pre-specified hierarchical testing procedure of the endpoints for the study, statistical significance for OS could not be established. The most common Adverse Events with Ripretinib included alopecia, nausea, abdominal pain, constipation and myalgias.
It was concluded that Ripretinib significantly improves Progression Free Survival and very likely also improves Overall Survival in heavily pretreated patient population with Gastrointestinal Stromal Tumors. INVICTUS: A Phase 3, International, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Ripretinib as 4th Line Therapy or more in Patients with Advanced Gastrointestinal Stromal Tumors (GIST) Who Have Received Treatment with Prior Anticancer Therapies (NCT03353753). van Mehren M, Attia S, Bauer S, et al. Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract LBA87.
