Updated Data Continues to Support Adjuvant Trastuzumab

Adding 1-year of adjuvant trastuzumab to chemotherapy continues to demonstrate an improvement in overall survival (OS) and disease-free survival (DFS) for patients with early-stage HER2-positive breast cancer, according to an updated joint analysis published in the Journal of Clinical Oncology.

The median 8.4-year analysis showed that adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (HR = 0.63; 95% CI, 0.54-0.73; P < .001) and an increase in 10-year OS rate from 75.2% to 84%. The analysis also showed an improvement in DFS of 40% (HR = 0.60; 95% CI, 0.53- 0.68; P < .001) and an increase in 10-year DFS rate from 62.2% to 73.7%.

In a podcast that accompanied the analysis, Harold J. Burstein, MD, PhD, an associate professor of Medicine at Harvard Medical School and medical oncologists at the Dana-Farber Cancer Institute, explained that the updated results contained important information on the impact of treatment with trastuzumab.

“First and foremost, we learn that the benefits of trastuzumab are robust and durable. There remains a 40% reduction in disease recurrence and a 37% improvement in overall survival. These proportional risk reductions translate into meaningful differences for all identified clinical subsets of HER2-positive breast cancers,” Burstein said. ”The report…provides important information on the long-term effects of adjuvant trastuzumab. The current data represent over 8 years of median follow-up and include a larger percentage of patients with 10 or more years of follow-up.”

Data from the joint analysis of NCCTG N9831 and NSABP B-31 were first presented at the 2005 ASCO Annual Meeting. These studies assessed the addition of 1-year of trastuzumab to standard anthracycline/taxane-based chemotherapy compared with standard chemotherapy alone (control) in a combined 4046 patients. In the updated analysis, a statistically significant benefit was seen with the addition of trastuzumab to doxorubicin and cyclophosphamide followed by paclitaxel across all subgroups of patients.

Patients randomly assigned to the trastuzumab-containing arm had a significantly increased OS relative to those randomly assigned to the control arm when the stratification factors were taken into account (stratified HR = 0.63; 95% CI, 0.54-0.73; P < .001) as well as when the stratification factors plus age, tumor size, and extent of surgery were considered (adjusted HR = 0.61; 95% CI, 0.52-0.71; P < .001)

Distant recurrence was detected alone or in combination with other-disease events in 416 patients (20.6%) in the control arm and 241 (11.9%) in the trastuzumab arm. Patients who were randomly assigned to the trastuzumab-containing arm had a significantly improved DFS relative to those randomly assigned to the control arm when the stratification factors are taken into account (stratified HR = 0.60; 95% CI, 0.53 to 0.68; P < .001).

“These findings provide a handsome bookend to the adjuvant trastuzumab story that began in 2005,” Burstein said. “We are probably on the cusp of a new era in the management of HER2-positive breast cancer as a new generation of anti-HER2 targeted drugs seems poised to enter adjuvant therapy for early-staged disease. But before moving on to those hot new drugs, it’s appropriate to reflect on these trials of adjuvant trastuzumab which were superb models of clinical research.”

The overall incidence of cardiac dysfunction, a known risk associated with trastuzumab, was further characterized by the updated analysis. Overall, the benefits of the agent continue to outweigh the risk.

“We also see important confirmation of the long-term safety of trastuzumab,” Burstein said. “There were no suggestions of an increase in the incidence of secondary cancers associated with trastuzumab.”

In the analysis, the 8-year cumulative incidence rate of death as a result of cardiac causes was 0.2% for patients with the trastuzumab-containing regimen and 0.1% for patients in the control arm.

“Cardiac toxicity has been the most concerning known side effect of trastuzumab,” Burstein said. “There was a small, numerical increase in the incidence of death from cardiac conditions with the use of trastuzumab. The absolute risk of cardiac death is exceedingly small…[and] is dwarfed by the survival advantages of trastuzumab overall.”

Perez EA, Romond EH, Suman VJ, et al. Trastuzumab Plus Adjuvant Chemotherapy for Human Epidermal Growth Factor Receptor 2—Positive Breast Cancer: Planned Joint Analysis of Overall Survival From NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014; 33: 3744-3752.