204P - Phase II trial of S-1 plus leucovorin in patients with advanced gastric cancer and clinical prediction by S-1 pharmacogenetic pathway

Date 19 December 2015
Event ESMO Asia 2015 Congress
Session Poster presentation 1
Topics Anti-Cancer Agents & Biologic Therapy
Gastric Cancer
Presenter Ruihua Xu
Citation Annals of Oncology (2015) 26 (suppl_9): 42-70. 10.1093/annonc/mdv523
Authors R. Xu1, Y. Zeng2, M. He1, D. Zhang1, F. Wang1
  • 1Medical Oncology, Cancer Centre Sun Yat-Sen University, 510060 - Guangzhou/CN
  • 2State Key Laboratory Of Oncology In South China, Cancer Centre Sun Yat-Sen University, 510060 - Guangzhou/CN

Abstract

Aim/Background

As the first phase II trial, it aimed to evaluate and predict the efficacy and safety of S-1 combined with oral leucovorin (S-1/LV) as first-line chemotherapy for patients with advanced gastric cancer (AGC), using S-1 pharmacogenetic pathway approach.

Methods

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 endpoints were overall response rate (ORR), 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 plasmic expression of dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP), and thymidylate synthase (TS), CYP2A6 gene polymorphisms, and 5-FU pharmacokinetics.

Results

The ORR and the DCR were 41.0% and 76.9%. The median PFS, median TTF, and median OS were 4.13 (95% CI, 3.44-4.83), 3.70 (2.60-4.80), and 11.40 (7.76-15.05) months. Grade 3 ∼ 4 AEs occurred in only 13 patients, and grade 4 AE (neutropenia) occurred in only one of them. High OPRT/TS (Odd Ratio (OR) 16.962 (1.781-161.581), P = 0.014) and peritoneal metastasis (OR 25.604 (1.852-353.979), P = 0.016) independently predicted responding. High OPRT/DPD (OR 15.566 (1.490-162.605), P = 0.022) independently predicted grade 3 ∼ 4 AEs. Response to S-1/LV (Hazards Ratio (HR) 0.275 (0.124-0.609), P = 0.001) and high area under the curve (AUC0-24h) of 5-FU (HR 0.272 (0.114-0.645), P = 0.003) independently predicted prolonged PFS. Low baseline plasmic DPD (HR 2.726 (1.045-7.113), P = 0.040) and second-line treatment (HR 0.259 (0.091-0.736), P = 0.011) independently predicted prolonged OS. See table. Table:

Univariate analysis Multivariate analysis
HR 95% CI P HR 95% CI P
PFS/Variates
Response to S-1/LV 0.011 0.001
no 1 reference 1 reference
yes 0.391 0.190-0.803 0.275 0.124-0.609
Metastatic/recurrent sites 0.040 0.111
≤ 2 1 reference 1 reference
3 2.728 1.049-7.092 1.866 0.867-4.013
AUC0-24h of 5-FU 0.026 0.003
≤ 1281.800 1 reference 1 reference
> 1281.800 0.404 0.182-0.898 0.272 0.114-0.645
TTF/Variates Univariate analysis Multivariate analysis
HR 95% CI P HR 95% CI P
Response to S-1/LV 0.016 0.007
no 1 reference 1 reference
yes 0.434 0.220-0.857 0.362 0.172-0.762
Metastatic/recurrent sites 0.013 0.107
≤ 2 1 reference 1 reference
3 2.487 1.210-5.019 1.840 0.877-3.859
AUC0-24h of 5-FU 0.051 0.028
≤ 1281.800 1 reference 1 reference
> 1281.800 0.492 0.234-1.033 0.403 0.179-0.907
OS/Variates Univariate analysis Multivariate analysis
HR 95% CI P HR 95% CI P
Baseline CEA (continuous) 1 1.000-1.001 0.041 1 1.000-1.001 0.176
Secondline chemotherapy 0.001 0.011
no 1 reference 1 reference
Yes 0.192 0.071-0.520 0.259 0.091-0.736
Baseline plasmic DPD 0.009 0.040
≤ 119.200 pg/ml 1 reference 1 reference
> 119.200 pg/ml 1.014 1.003-1.025 2.726 1.045-7.113
Baseline plasmic TP 0.033 0.078
≤ 137.900 ng/ml 1 reference 1 reference
> 137.900 ng/ml 0.365 0.145-0.920 0.412 0.154-1.104

Conclusions

S-1/LV demonstrated promising efficacy and satisfactory safety in AGC. Patients with high OPRT/TS, high AUC0-24h of 5-FU, low DPD and second-line chemotherapy may benefit most from S-1/LV.

Clinical trial identification

NCT02090153

Disclosure

All authors have declared no conflicts of interest.