ngle agent in a multicenter, open-label, single-arm clinical trial (Study 6)in patients with HER2 overexpressing metastatic breast cancer who had relapsed following one or twoprior chemotherapy regimens for metastatic disease. Of 222 patients enrolled, 66% had received prioradjuvant chemotherapy, 68% had received two prior chemotherapy regimens for metastatic disease, and25% had received prior myeloablative treatment with hematopoietic rescue. Patients were treated with aloading dose of 4 mg/kg IV followed by weekly doses of trastuzumab at 2 mg/kg IV.
The ORR (complete response + partial response), as determined by an independent Response eva luationCommittee, was 14%, with a 2% complete response rate and a 12% partial response rate. Completeresponses were observed only in patients with disease limited to skin and lymph nodes. The overallresponse rate in patients whose tumors tested as CTA 3+ was 18% while in those that tested as CTA 2+, itwas 6%.
14.3 Metastatic Gastric Cancer
The safety and efficacy of trastuzumab in combination with cisplatin and a fluoropyrimidine (capecitabineor 5-fluorouracil) were studied in patients previously untreated for metastatic gastric or gastroesophagealjunction adenocarcinoma (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+H) or chemotherapy alone (FC).
Randomization was stratified by extent of disease (metastatic vs. locally advanced), primary site (gastricvs. 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+) or HER2 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 cisplatinwas administered at a dose of 80 mg/m2Day 1 every 3 weeks for 6 cycles as a 2 hour IV infusion. Onboth study arms capecitabine was administered at 1000 mg/m2 dose orally twice daily (total daily dose2000 mg/m2) for 14 days of each 21 day cycle for 6 cycles. Alternatively, continuous intravenousinfusion (CIV) 5-fluorouracil was administered at a dose of 800 mg/m2/day from Day 1 through Day 5every three weeks for 6 cycles.
The median age of the study population was 60 years (range: 21-83); 76% were male; 53% were Asian,38% Caucasian, 5% Hispanic, 5% other racial/ethnic groups; 91% hadECOG PS of 0 or 1; 82% hadprimary gastric 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% hadreceived prior radiotherapy.
The main outcome measure of Study 7 was overall survival (OS), analyzed by the unstratified log-ranktest. The final OS analysis based on 351 deaths was statistically significant (nominal significance level of0.0193). An updated OS analysis was conducted at one year after the final analysis. The efficacy results
of both the final and the updated analyses are summarized in Table 13 and Figure 7.
Table 13
Study 7: Overall Survival in ITT Population
FC Arm
N = 296
FC + H Arm
N = 298
Definitive (Second Interim) Overall Survival
No. Deaths (%) 184 (62.2%) 167 (56.0%)
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