(P 48) SIGNIFICANCE OF MONITORING PLASMA CONCENTRATION OF RIPRETINIB IN CHINESE PATIENTS WITH GASTROINTESTINAL STROMAL TUMORS

Objective: Ripretinib, has been approved as a fourth-line and above treatment for advanced gastrointestinal stromal tumors (GIST) with the standard dose of 150 mg daily. Upon disease progression, ripretinib intrapatient dose escalation (IPDE) to 150 mg twice daily was recommended by the NCCN and CSCO guidelines. In phase I study of ripretinib, the peak concentration (Cmax, 502ng/ml) was reached at an average of 4.02 hours (range, 1.95-24.05 hours) after a single dose of 150 mg daily, and on day 15, the Cmax (761ng/ml) was reached at an average of 2.08 hours (range, 1.02-8.13 hours). The steady-state of ripretinib was achieved after 14 days. Currently, no reports exist on blood concentrations of ripretinib during real-world treatment of advanced GIST patients. This study aims to explore the significance of monitoring plasma concentration of ripretinib in the treatment of Chinese GIST patients.

Methods: Advanced GIST patients who received ripretinib treatment from June 2021 to April 2023 were included. In patients with advanced GIST who had reached a steady-state (＞2 weeks) of ripretinib treatment, peripheral venous blood samples were collected before drug administration and at 4 hours following drug administration. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect patients' ripretinib plasma concentrations. Correlations of ripretinib plasma concentration with dosage, clinical efficacy and adverse reactions were analyzed.

Results: A total of 34 patients with 38 specimens were included, with a median age of 59.5 years (range, 33-85 years). The overall mean±SD of the steady-state plasma trough concentrations (Cmin) for ripretinib was 412.62±280.88 ng/mL. The Cmin (mean±SD) were 299 ± 193 ng/mL, 392 ± 253 ng/mL, and 809 ± 431 ng/mL in patients who underwent dose reduction (50 or 100 mg daily), standard dose (150 mg daily), and IPDE (200 mg daily or 150 mg twice daily), respectively. The differences of ripretinib Cmin between standard dose and IPDE group were significant (P < 0.05). The median follow-up time was 5.3 months (95% CI, 1.53-9.07 months), and the median progression-free survival (mPFS) is not mature. In patients with assessable efficacy, the objective response rate (ORR) was 6% and 12%, while the disease control rate (DCR) was 71% and 88% for patients with Cmin below or above the mean value, respectively. No significant correlation was observed between ripretinib Cmax and common adverse reactions, including alopecia, fatigue, muscle pain, diarrhea, constipation, and anemia.

Conclusion: The ripretinib Cmin in Chinese GIST patients with dose escalation following disease progression was significantly higher than patients treated with the standard dose. A higher ripretinib Cmin appears to be associated with improved disease control. Furthermore, this study revealed no significant correlation between ripretinib Cmax and common adverse reactions. Further validation is required in the future.