FDA Approval for Trastuzumab

Brand name(s): Herceptin®

• Approved for HER2-overexpressing Metastatic Gastric or Gastroesophageal (GE) Junction Adenocarcinoma
• Approved for HER2-overexpressing Breast Cancer

Full prescribing information ¹ is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

HER2-overexpressing Metastatic Gastric or Gastroesophageal (GE) Junction Adenocarcinoma

On October 20, 2010, the Food and Drug Administration (FDA) granted approval for trastuzumab (Herceptin®, made by Genentech, Inc.), in combination with cisplatin and a fluoropyrimidine (either 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 results of a single international multicenter open-label randomized clinical trial, BO18255 (ToGA trial), which enrolled 594 patients with locally advanced or metastatic HER2-overexpressing adenocarcinoma of the stomach or GE junction. Patients were randomly assigned (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 3 weeks until disease progression or intolerable toxicity. The chemotherapy regimen included cisplatin 80 mg/m² IV day 1 every 3 weeks for six cycles and a fluoropyrimidine (either capecitabine 1000 mg/m² orally twice daily for 14 days or 5-fluorouracil 800 mg/m² /day continuous intravenous infusion (CIV) days 1-5 every 3 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 percent had primary gastric cancer, 18 percent had primary GE junction adenocarcinoma; 97 percent had metastatic disease. The median age was 60 years (range 21 to 83 years), and 76 percent were male. The study population comprised Asians (53 percent), Caucasians (38 percent), and Hispanics (5 percent). Nearly all patients (95 percent) had tumors with HER2 gene amplification by FISH. With HER2 IHC tumor staining 47 percent of tumors stained 3+, 30 percent were 2+, and 22 percent were 0 or 1+. Approximately 91 percent of patients had an ECOG performance status (PS) of 1 or less. Prior therapies included gastrectomy (23 percent), neoadjuvant and/or adjuvant therapy (7 percent), and radiotherapy (2 percent.)

The trial was closed after the second interim analysis, when 167 deaths had occurred in patients receiving trastuzumab plus chemotherapy and 184 deaths had occurred in patients receiving chemotherapy alone. The median survival was 13.5 months for patients treated with trastuzumab and chemotherapy and 11.0 months for patients treated with chemotherapy alone [HR 0.73 (95 percent CI: 0.60, 0.91); p=0.0038 (nominal significance level of 0.0193)].

An updated survival analysis was done after 227 deaths had occurred in patients receiving trastuzumab plus chemotherapy and 221 deaths had occurred in patients receiving chemotherapy alone. The analysis demonstrated median survival of 13.1 months for patients receiving trastuzumab and chemotherapy and 11.7 months for patients receiving chemotherapy alone (HR 0.8, 95 percent 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 percent CI 0.50, 0.87) and less effective in the 160-patient subgroup with IHC 2 + tumors (HR 0.78, 95 percent 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 percent CI 0.92, 1.92).

The most common adverse reactions in at least 10 percent of patients in the trastuzumab plus chemotherapy group were neutropenia, diarrhea, fatigue, anemia, stomatitis, weight loss, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, and dysgeusia. The most common grade 3 and 4 adverse reactions in at least 5 percent of patients receiving trastuzumab plus chemotherapy were neutropenia (35 percent), anemia (12 percent), diarrhea (9 percent), nausea (8 percent), anorexia (7 percent), and vomiting (6 percent). About 37 percent 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 for patients in both groups. The incidence of cardiac failure was less than 1 percent. Over 90 percent of the deaths in both study groups were due to disease progression or disease-related complications. The most common adverse reactions resulting in treatment discontinuation in patients receiving trastuzumab plus chemotherapy 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.

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HER2-overexpressing Breast Cancer

On November 16, 2006, the FDA granted approval to trastuzumab (Herceptin®, made by Genentech, Inc.) as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel for the adjuvant treatment of women with node-positive, HER2-overexpressing breast cancer. The approval is based on evidence of a significant prolongation in disease-free survival in women receiving trastuzumab and chemotherapy compared to those receiving chemotherapy alone.

An integrated interim analysis of 3752 women from two NCI-Cooperative Group trials (NSABP B31 ² and NCCTG N9831 ³) were reviewed. Both studies restricted enrollment to women whose breast cancer demonstrated 3+ overexpression of HER2 by immunohistochemistry or amplification of the HER2 gene by fluorescence in situ hybridization (FISH). All women received standard adjuvant chemotherapy [four 21-day cycles of doxorubicin and cyclophosphamide (AC) followed by paclitaxel administered weekly or every 3 weeks for a total of 12 weeks]. As appropriate, women also received hormonal therapy and local radiotherapy. Patients were randomly assigned to receive either no additional therapy or to receive trastuzumab at 4 mg/kg on the day of paclitaxel initiation and subsequently at 2 mg/kg weekly for a total of 52 weeks.

Disease-free survival (DFS), defined as the time from randomization to recurrence, occurrence of contralateral breast cancer, other second primary cancer, or death, was the primary endpoint of the combined efficacy analysis. There were 401 patients without follow-up assessment for DFS at the interim analysis and were censored at study day 1.

At the time of the interim analysis, there were 261 events among 1880 women in the chemotherapy alone arm and 133 events among 1872 women in the trastuzumab plus chemotherapy arm. The reduction in the risk of recurrence, second primary cancer or death was 52 percent (hazard ratio 0.48, 95 percent CI: 0.39; 0.59). An analysis of overall survival was conducted showing fewer deaths in the trastuzumab plus chemotherapy arm; however, the findings were not significantly different and were based on small number of deaths with 96 percent of the population alive.

The most serious trastuzumab toxicities were

• cardiomyopathy
• pulmonary toxicity (respiratory failure, pneumonitis, pulmonary infiltrates
• infusion reactions
• febrile neutropenia/exacerbation of chemotherapy-induced neutropenia

• fever
• vomiting
• infusion reactions
• diarrhea
• infections
• increased cough
• headache
• fatigue
• dyspnea
• rash
• neutropenia
• anemia
• myalgia

Adverse reactions requiring trastuzumab interruption or discontinuation included severe infusion reactions, congestive heart failure, and significant declines in left ventricular cardiac function.

Serial measurement of left ventricular ejection fraction (LVEF) was obtained in the two clinical trials. Six percent of patients were unable to receive trastuzumab following completion of AC chemotherapy due to cardiac dysfunction (LVEF 50 percent or 15 point decline in LVEF from baseline to end of AC).

Following initiation of trastuzumab therapy, the incidence of new-onset, dose-limiting myocardial dysfunction was higher among patients receiving trastuzumab and paclitaxel as compared to those receiving paclitaxel alone. Of those patients with normal LVEF prior to initiation of trastuzumab/paclitaxel, 16 percent discontinued trastuzumab therapy due to clinical evidence of myocardial dysfunction or significant declines in LVEF. Approximately 2 percent in the trastuzumab plus chemotherapy arm and 0.4 percent in the chemotherapy experienced clinically symptomatic, laboratory-confirmed cardiomyopathy determined by an external review committee. One death was observed among 32 trastuzumab-treated patients with clinical evidence of cardiomyopathy. Among the 31 surviving patients, all were receiving cardiac medication at last follow-up and approximately half had evidence of recovery to a normal LVEF (defined as 50 percent) on continuing medical management.