Abstract 445
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.