Clinical significance of serum factors relating to ERBB signal pathways in a phase II trial of S-1 plus cisplatin combined with trastuzumab for HER2-positive advanced gastric or esophagogastric junction cancer: WJOG7212G (T-SPACE) TR study

Background: No biomarker other than HER2 expression for anti-HER2 therapy has been established in gastric cancer. We explored serum ERBB-related biomarkers for efficacy in a phase II trial (WJOG7212G) of triweekly trastuzumab (Tmab) (first dose 8 mg/kg then 6mg/kg) in combination with 5-weekly S-1 (40-60mg, twice daily, for 21 days) plus cisplatin (60mg/m2, on day 8) for HER2-positive (IHC3 + , or IHC2+ and FISH+) advanced gastric or esophagogastric junction cancer. Methods: Serum samples were collected in 31 of 44 patients enrolled in the phase II study. Serum HER2, EGF, TGF-alpha, neuregulin 1 (NRG1), HGF, IGF1 and TIMP1 were measured by ELISA at following 4 points; pre-treatment, immediately before 2nd and 4th Tmab administration, and after PD. Pre-treatment serum levels were compared between responders (CR + PR) and non-responders (SD + PD). Progression free survival (PFS) and overall survival (OS) were compared between the high and low groups divided at median of pre-treatment value of each serum marker. Results: Patient characteristics were: median age 65.0 years, males 23 (74%), PS 0-1 29 (93%), primary site of stomach 27 (87%), histology of diffuse type 14 (45%), IHC 3+ 22 (71%) patients. The response rate was 68% (95% CI 50 - 81). The median PFS was 183 days (95% CI 133 - 420). The median OS was 515 days (95% CI 373 - not reached). Pre-treatment HER2 and NRG1 levels were higher in responders than in non-responders (Mean; HER2 96 ± 68 ng/ml vs. 12 ± 2 ng/ml, p = 0.026, NRG1 2467 ± 886 pg/ml vs. 186 ± 186 pg/ml, p = 0.012). HER2, NRG1 and EGF levels decreased after treatment (p < 0.05). Patients with high pre-treatment NRG1 levels showed significantly longer PFS (median; 322 vs. 160 days, p = 0.022) and marginally longer OS (median; not reached vs. 373 days, p = 0.09) than those with the low levels. Pre-treatment HER2 level was not associated with either PFS (median; 247 vs. 177 days, p = 0.50) or OS (median; 544 vs. 503 days, p = 0.53). Conclusions: Serum NRG1 may be a candidate of a predictive marker for the efficacy of Tmab in combination with S-1 plus cisplatin in patients with HER2 positive gastric or esophagogastric junction cancer.