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U.S. Department of Health and Human Services

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Trastuzumab

On October 20, 2010, the U. S. Food and Drug Administration granted approval for trastuzumab (Herceptin), Genentech, Inc.), in combination with cisplatin and a fluoropyrimidine (capecitabine or 5-fluorouracil), for the treatment of patients with HER2 overexpressing metastatic gastric or gastroesophageal (GE) junction adenocarcinoma, who have not received prior treatment for metastatic disease.

The approval is based on a significant improvement in median overall survival (OS) of 2.5 months with trastuzumab plus chemotherapy treatment compared to chemotherapy alone demonstrated in a single, international, multicenter, open-label, randomized clinical trial, BO18255 (ToGA trial). A total of 594 patients with locally advanced or metastatic HER2 overexpressing adenocarcinoma of the stomach or GE junction were randomized (1:1) to receive either trastuzumab plus chemotherapy or chemotherapy alone

Trastuzumab was administered at an initial dose of 8 mg/kg intravenously (IV) followed by 6 mg/kg every three weeks until disease progression or intolerable toxicity. The chemotherapy regimen included cisplatin 80 mg/m2 IV day 1 every three weeks for six cycles and a fluoropyrimidine (either capecitabine 1000 mg/m2 orally twice daily for fourteen days or 5-fluorouracil 800 mg/m2 /day continuous intravenous infusion (CIV) days 1-5 every three weeks for six cycles.) All tumors were confirmed to be HER2 gene amplified by FISH or protein overexpressing (IHC 3+) using validated assays performed at a central laboratory.

Among the 594 patients, 82% had primary gastric cancer, 18% had primary GE junction adenocarcinoma; 97% had metastatic disease. The median age was 60 years (range 2183) and 76% were male. Asians comprised 53% of the study population, Caucasians 38%; and Hispanics 5%. Nearly all patients (95%) had tumors with HER2 gene amplification by FISH. With HER2 IHC tumor staining 47% of tumors stained 3+, 30% were 2+, and 22% were 0 or 1+. Approximately 91% of patients had an ECOG PS <1. Prior therapies included gastrectomy (23%), prior neoadjuvant and/or adjuvant therapy (7%) and prior radiotherapy (2%.)

The trial was closed after the second interim analysis when 167 deaths had occurred on the trastuzumab arm and 184 deaths on the control arm. In the final OS analysis, the median OS was 13.5 months (95% CI: 11.7, 15.7) and 11.0 months (95% CI: 9.4, 12.5) in the trastuzumab and control arms, respectively. The hazard ratio (HR) was 0.73 [(95% CI: 0.60, 0.91); p-value, two sided = 0.0038 (nominal significance level of 0.0193)] in favor of the trastuzumab arm.

An updated OS analysis (227 and 221deaths in the trastuzumab and control arms, respectively) demonstrated median OS of 13.1 (95% CI: 11.9, 15.1 mos.) and 11.7 months (95% CI: 10.3, 13.0) in the trastuzumab and control arms, respectively (HR 0.8, 95% CI 0.67, 0.97.) Exploratory OS analyses in subgroups defined by protein expression (IHC testing) suggest that trastuzumab was most effective in prolonging survival in the 294 patient subgroup with HER2 IHC 3+ tumors (HR 0.66, 95% CI 0.50, 0.87) and less effective in the 160 patient subgroup with IHC 2 + tumors (HR 0.78, 95% CI 0.55, 1.10). No trastuzumab treatment effect was apparent in the 133-patient subgroup with HER2 gene amplified, ICH 0 or 1+ tumors (HR 1.33, 95% CI 0.92, 1.92).

The most common adverse reactions (< 10%) associated with trastuzumab were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common grade 3 and 4 adverse reactions (>5%) related to trastuzumab were neutropenia (35%), anemia (12%), diarrhea (9%), nausea (8%), anorexia (7%), and vomiting (6%). About 37% of patients receiving trastuzumab plus chemotherapy had infusion-related reactions. No grade 4 infusion reactions or deaths related to infusion reactions were reported. Cardiac adverse reactions occurred at the same incidence on both study arms. The incidence of cardiac failure was < 1%. Over 90% of the deaths in both arms were due to disease progression or disease-related complications. The most common adverse reactions resulting in treatment discontinuation in the trastuzumab arm were infection, diarrhea, and febrile neutropenia.

HER2 overexpression and gene amplification should be determined using FDA-approved tests with an indication for the specific tumor type being tested. Interpretation of the test results may be affected by differences in tumor histopathology (breast, gastric, or GE junction cancer). Limitations in assay precision make it inadvisable to rely on a single method to rule out potential Herceptin benefit.

Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at:

http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/103792s5250lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).