Cancer
The safety and efficacy of trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabine or5-fluorouracil) were studied in patients previously untreated for metastatic gastric or gastroesophageal junctionadenocarcinoma (Study 7). In this open-label, multi-center trial, 594 patients were randomized 1:1 to
trastuzumab in combination with cisplatin and a fluoropyrimidine (FC+T) or chemotherapy alone (FC).
Randomization was stratified by extent of disease (metastatic vs. locally advanced), primary site (gastric vs.
gastroesophageal junction), tumor measurability (yes vs. no), ECOG performance status (0,1 vs. 2), andfluoropyrimidine (capecitabine vs. 5-fluorouracil). All patients were either HER2 gene amplified (FISH+) orHER2 overexpressing (IHC 3+). Patients were also required to have adequate cardiac function(e.g., LVEF > 50%).
On the trastuzumab-containing arm, trastuzumab was administered as an IV infusion at an initial dose of8 mg/kg followed by 6 mg/kg every 3 weeks until disease progression. On both study arms cisplatin wasadministered at a dose of 80 mg/m2 Day 1 every 3 weeks for 6 cycles as a 2 hour IV infusion. On both studyarms, capecitabine was administered at 1000 mg/m2 dose orally twice daily (total daily dose 2000 mg/m2) for
14 days of each 21 day cycle for 6 cycles. Alternatively, continuous intravenous infusion (CIV) 5-fluorouracilwas administered at a dose of 800 mg/m2
/day from Day 1 through Day 5 every three weeks for 6 cycles.
The median age of the study population was 60 years (range: 21 to 83); 76% were male; 53% were Asian,38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% had ECOG PS of 0 or 1; 82% had primarygastric cancer and 18% had primary gastroesophageal adenocarcinoma. Of these patients, 23% had undergone
prior gastrectomy, 7% had received prior neoadjuvant and/or adjuvant therapy, and 2% had received priorradiotherapy.
The main outcome measure of Study 7 was overall survival (OS), analyzed by the unstratified log-rank test.
Thefinal OS analysis based on 351 deaths was statistically significant (nominal significance level of 0.0193). Anupdated OS analysis was conducted at one year after the final analysis. The efficacy results of both the final andthe updated analyses are summarized in Table 13 and Figure 7.
Table 13
Study 7: Overall Survival in ITT Population
FC Arm
N = 296
FC + T Arm
N = 298
Definitive (Second Interim) Overall Survival
No. Deaths (%) 184 (62.2%) 167 (56.0%)
Median 11.0 13.5
95% CI (mos.) (9.4, 12.5) (11.7, 15.7)
Hazard Ratio 0.73
95% CI (0.60, 0.91)
p-value*, two-sided 0.0038
Updated Overall Survival
No. Deaths (%) 227 (76.7%) 221 (74.2%)
Median 11.7 13.1
95% CI (mos.) (10.3, 13.0) (11.9, 15.1)
Hazard Ratio 0.80
95% CI (0.67, 0.97)
* Comparing with the nominal significance level of 0.0193.
Figure 7
Updated Overall Survival in Patients with Metastatic Gastric Cancer (Study 7)
An exploratory analysis of OS in patients based on HER2 gene amplification (FISH) and protein overexpression(IHC) testing is summarized in Table 14.
Table 14
Exploratory Analyses by HER2 Status Using Updated Overall Survival Results
FC
(N = 296)a
FC + T
(N = 298)b
FISH+ / IHC 0, 1+ subgroup (N=133)
No. Deaths / n (%) 57/71 (80%) 56/62 (90%)
Median OS Duration (mos.) 8.8 8.3
95% CI (mos.) (6.4, 11.7) (6.2, 10.7)
Hazard ratio (95% CI) 1.33 (0.92, 1.92)
FISH+ / IHC2+ subgroup (N= |
