Phase II trial of S-1 plus leucovorin in patients with advanced gastric cancer and clinical prediction by S-1 pharmacogenetic pathway

Abstract

BackgroundThe first one-arm phase II trial aimed to evaluate and predict efficacy and safety of S-1 plus oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach.Patients and methodsA total of 39 patients orally took S-1 at conventional dose and LV simultaneously at a dose of 25 mg twice daily for a week, within a 2-week cycle. The primary endpoint was overall response rate (ORR), while the secondary endpoints were progression-free survival (PFS), time to failure (TTF), overall survival (OS), disease control rate (DCR), and adverse events (AEs). Peripheral blood was sampled prospectively for baseline expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics.ResultsThe ORR and DCR were 41.0 and 76.9%. The median PFS, TTF, and OS were 4.13, 3.70, and 11.40 months. Grade 3–4 AEs occurred in only 13 patients, and grade 4 AEs occurred in only 1 of them. High OPRT/TS and peritoneal metastasis (vs. liver metastasis) independently predicted responding. High OPRT/DPD independently predicted grade 3–4 AEs. High AUC0–24h of 5-FU and metastatic/recurrent sites ≤2 (vs. >3) independently predicted prolonged PFS. Low baseline plasmic DPD independently predicted prolonged OS.ConclusionsTwo-week, oral S-1/LV regimen demonstrated promising efficacy and safety as first-line chemotherapy for AGC.ClinicalTrials.gov identifierNCT02090153Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3209-1) contains supplementary material, which is available to authorized users.

Variation in CYP2A6 Activity and Personalized Medicine

“…However, in patients with metastatic biliary tract cancer who were given a combination therapy of oxalipatin and S-1, CYP2A6 genotype was not associated with clinical efficacy or toxicity, despite CYP2A6 genotype reduced metabolizers exhibiting higher tegafur C max (maximal plasma drug concentration) and AUC 0–24 , and lower 5-fluoruracil C max and AUC 0–24 , compared to patients without CYP2A6 reduce-of-function variants [ 144 ]. Similar negative results have been observed for other tegafur or S-1 combination therapies [ 145 , 146 ]. These results suggest that the impact of CYP2A6 genotype on the efficacy of tegafur-containing cancer treatments may be dependent on cancer type as well as the other chemotherapies given in combination with tegafur or S-1.…”

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021

“… c There is no sufficient evidence to recommend chemotherapeutic drugs based on the prediction of chemotherapeutic response according to the Lauren classification, molecular classification, in vitro drug susceptibility test, xenograft transplantation model, xenobiotic metabolism, or metabolomics. Patients suspected of fluoropyrimidine‐associated metabolic disorders are advised to undergo a dihydropyrimidine dehydrogenase deficiency (DPD) test [ 140 ], and those suspected of irinotecan‐associated metabolic disorders can undergo the UGT1A1 gene polymorphism testing [ 141 ]. d The standard treatment for late‐stage gastric cancer usually lasts 4‐6 months, and these patients should be regularly followed‐up after disease control.…”

Pharmacogenomic-guided dosing of fluoropyrimidines beyond DPYD: time for a polygenic algorithm?

“…Based on pharmacokinetic data, the relative risk for tegafur-induced toxicity may be decreased for CYP2A6 poor metabolizers. Indeed, the majority of the studies that assessed the effect of CYP2A6 defective alleles on tegafur-induced toxicity did not find an association ( Kaida et al, 2008 ; Kong et al, 2009 ; Hirose et al, 2010 ; Ishii et al, 2010 ; Kim et al, 2011 ; Park et al, 2011 ; Choi et al, 2012 ; Fang et al, 2012 ; Kim et al, 2013 ; Kim et al, 2016 ; He et al, 2017 ; Jeong et al, 2017 ; Kim et al, 2018 ) ( Table 6 ). Some sparse associations that have been published for common CYP2A6 defective alleles did not remain significant in multivariate analyses ( Tsunoda et al, 2011 ; Kim et al, 2017 ) and the authors suggest that CYP2A6 defective alleles are not involved in tegafur-induced toxicity.…”