Genentech, Inc. informed about an updated cardiotoxicity information related to the use of Herceptin ( Trastuzumab ), obtained from the National Surgical Adjuvant Breast and Bowel Project ( NSABP ) study ( B-31 ), a randomized, Phase III trial that was conducted in 2043 women with operable, HER2 overexpressing breast cancer ( IHC 3+ or FISH+ ).

This study demonstrated a significant increase in cardiotoxicity in patients who were randomized to the Herceptin-containing arm as compared to patients who received chemotherapy alone.

A preliminary analysis of the safety data from Study NSABP B-31 was presented at the annual meeting of the American Society of Clinical Oncology ( ASCO ) in May 2005, during the presentation of a joint analysis of Study NSABP B-31 and the North Central Cancer Treatment Group ( NCCTG ) study ( N9831 ).

Study NSABP B-31 was intended, in part, to characterize cardiotoxicity associated with Herceptin use and to assess the value of serial cardiac monitoring during Herceptin therapy as a predictor of cardiotoxicity and as an aid to early identification of cardiac toxicity.

Study NSABP B-31 evaluated the addition of Herceptin to standard adjuvant chemotherapy.
The chemotherapy regimen consisted of four cycles of Doxorubicin and Cyclophosphamide ( AC ) followed by four cycles of Paclitaxel every 3 weeks; patients were randomized to receive 1 year of Herceptin, at the approved dose and schedule, during and following Paclitaxel ( Arm 2 ) or to Paclitaxel alone ( Arm 1 ).

Patients in this study were required to have a baseline assessment of cardiac function with either multigated acquisition scan ( MUGA ) or echocardiogram and to have follow-up assessments at the completion of AC and at 6, 9, and 18 months after the initiation of Paclitaxel with or without Herceptin.
Eligible patients had a left ventricular ejection fraction ( LVEF ) measurement at baseline ( prior to any therapy ) that was within normal limits and no history of or active cardiac disease, including cardiomyopathy, congestive heart failure, prior myocardial infarction, or arrhythmia.

Prior to initiation of Herceptin ( Arm 2 ), LVEF measurements were required to be at or above the radiology facility's lower limit of normal and be no more than 15 points below baseline measurements.

Herceptin was permanently discontinued in patients with symptomatic cardiac toxicity. In the event that Herceptin administration was withheld or discontinued because of cardiotoxicity, Paclitaxel was administered at the investigator's discretion.

A total of 1019 patients were randomized to the Herceptin-containing arm ( Arm 2 ). Based on preliminary data and analyses through April 2005, 6.8% of patients were unable to initiate Herceptin per the protocol because of decreased LVEF or symptoms of cardiac toxicity experienced during the AC portion of therapy.

Among the evaluable patients who had adequate cardiac function and initiated Herceptin, 30.5% required at least one dose delay because of asymptomatic decrease in LVEF or cardiac symptoms.

In 18.6% of patients, Herceptin was discontinued prior to the completion of 1 year of therapy because of asymptomatic decrease in LVEF ( 14.3% ) and symptomatic cardiac dysfunction/other cardiac toxicity ( 4.3% ).

In addition, a statistically significant increase in the 3-year cumulative incidence of New York Heart Association ( NYHA ) Class III and IV congestive heart failure and cardiac death was observed in patients who received the Herceptin-containing regimen ( 4.1% ) compared with control ( 0.8% ).

There were no cardiac deaths observed in patients who received the Herceptin-containing regimen and 1 cardiac death was observed in the control arm.

A preliminary exploratory analysis performed by NSABP investigators suggests that age and LVEF following AC chemotherapy may identify patients at greatest risk for symptomatic cardiac dysfunction.

Herceptin as a single agent is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease.
Herceptin in combination with Paclitaxel is indicated for treatment of patients with metastatic breast cancer whose tumors overexpress the HER2 protein and who have not received chemotherapy for their metastatic disease.
Herceptin should be used in patients whose tumors have been evaluated with an assay validated to predict HER2 protein overexpression.

Source: FDA, 2005


XagenaMedicine2005