The Correlation Between Ripretinib Exposure and the Efficacy and Safety in Patients with Advanced Gastrointestinal Stromal Tumors: an Observational Study

INTRODUCTION AND RATIONALE:

Gastrointestinal stromal tumors (GISTs) are a rare mesenchymal sarcoma that most commonly occur in the stomach and small intestine, but can occur in any region of the entire gastrointestinal tract. For advanced GISTs that cannot be surgically removed or metastasized, imatinib, sunitinib, and regorafenib are recommended TKIs in the current clinical guidelines for the first-, second-, and third-line therapy respectively. Although imatinib has significant effect in the first-line treatment of GIST, improving the prognosis and survival outcome, GISTs often develop primary or secondary drug resistance, resulting in disease progression.Ripretinib is a broad-spectrum switch-control kinase inhibitor that specifically inhibits KIT and PDGFRA kinase signaling through dual mechanisms of action. In clinical studies of advanced GIST patients, Ripretinib has shown good safety and efficacy. In the phase III clinical study INVICTUS, Ripretinib 150 mg QD was used to treat patients with metastatic or unresectable GIST who failed to treatment with imatinib, sunitinib, and regorafenib. The median progression-free survival (mPFS) was 6.3 months in the Ripretinib group and 1.0 month in the placebo group. The phase III clinical trial INTRIGUE showed that although there was no significant advantage in progression-free survival (PFS) compared with sunitinib, Ripretinib had better safety, lower incidence of adverse events, and better patient tolerability. In May 2020, Ripretinib was approved by the US FDA for the treatment of adult patients with advanced GIST who have failed to three or more kinase inhibitors including imatinib. It is also recommended as a preferred fourth-line drug in the 2023 version of the NCCN guidelines and the 2022 version of the CSCO guidelines for GISTs.

In vitro kinase and cell studies have shown that Ripretinib is effective against wild-type KIT and PDGFRA, as well as a wide range of KIT and PDGFRA mutations, including major and resistant mutations in KIT exons 9, 11, 13, 14, 17, and 18, as well as the regorafenib-resistant D816V mutation. It is more effective than other type I and type II TKI inhibitors. However, the inhibitory effect of Ripretinib varies depending on the mutation type. At the same time, in the phase III clinical study INVICTUS gene mutation analysis, it was found that patients with primary mutations in KIT exon 11 and secondary mutations in KIT exon 17 had a relatively longer PFS.

The preclinical study of Ripretinib suggests that its inhibitory effect on KIT is concentration-dependent and time-dependent. With the increase of in vivo concentration, the inhibitory effect of KIT phosphorylation also increases. Increasing the dosage or dosing frequency can increase tumor regression and survival rates. In the phase I clinical study of Ripretinib, it was found that increasing the dose to 150 mg BID after oral administration of 150mg QD with disease progression (PD) can obtain a further benefit. The median progression-free survival (mPFS) of second-line, third-line, and fourth-line patients was 5.6, 3.3, and 4.6 months, respectively, indicating that the increase of Ripretinib's exposure in vivo is associated with improved efficacy.

Preclinical and clinical studies have found that the main metabolic pathway of Ripretinib is N-demethylation. Ripretinib and its active metabolite DP-5439 are mainly metabolized in the liver through CYP3A4 metabolic enzymes, and DP-5439 has pharmacological activity similar to the parent drug Ripretinib. In a phase I clinical study of pharmacokinetics, there was significant inter-patient variability in PK parameters after administration of Ripretinib. The variation (CV%) of Cmax and AUC0-24h reached 35% to 60%. The AUC of DP-5439 after a single dose of 150 mg was about 49% of Ripretinib, and the AUC after 15 days of dosing at 150 mg QD was about 129% of Ripretinib. At the same time, the AUC0-24h of Ripretinib increased proportionally with dose within the range of 20-250 mg, but the Cmax increased less than dose proportionally. The Cmax and AUC0-24h of DP-5439 increased less than dose proportionally within the range of 50-250 mg.The above findings suggest that therapeutic drug monitoring (TDM) may be clinically relevant for patients receiving Ripretinib treatment, and further exploration of the relationship between blood concentration or exposure level of Ripretinib and clinical efficacy is warranted.