Shorter Duration of Trastuzumab May Reduce Cardiac Toxicity, Costs

Shorter Duration of Trastuzumab May Reduce Cardiac Toxicity, Costs

Dr. Pier F. Conte presents Abstract 501.
The superiority of adding trastuzumab to adjuvant chemotherapy for HER2-positive, early-stage breast cancer is well known, Pier Franco Conte, MD, of the Istituto Oncologico Veneto IRCCS, in Italy, said during an Oral Abstract Session on June 5. However, results from the Short-HER study suggest a shorter course may reduce the rate of severe cardiac toxicity (Abstract 501).

Dr. Conte said the rationale for the shorter duration was shown previously in the FinHER study, which found the same magnitude of benefit among the two treatment durations.1

In the Short-HER study, patients were randomly selected to receive 1 year of trastuzumab plus chemotherapy (“long” group) or 9 weeks of trastuzumab plus chemotherapy (“short” group). Dr. Conte said patients older than age 65 received 80 mg/m2 of docetaxel and 11% of the patients in the long group received 175 mg/m2 of paclitaxel. The primary endpoints were disease-free survival (DFS) and overall survival (OS). Secondary endpoints included failure rate at 2 years and the incidence of cardiac events. The study planned both frequentist and Bayesian analyses; primary endpoints were analyzed after 198 events or at a median follow-up of 5 years.

From December 2007 to October 2013, the study enrolled 1,253 patients; there were 189 DFS events reported over a median of 5.2 years. Baseline characteristics between the two treatment groups were similar.

DFS and OS Outcomes

Dr. Carey K. Anders discusses Abstract 501.
There were 89 DFS events in the long group (627 patients) and 100 in the short group (626 patient). The 5-year DFS did not achieve noninferiority in the frequentist analysis (87.5% vs. 85.4% in the long and short groups, respectively, hazard ratio [HR] 1.15, 90% CI [0.91, 1.46]), as the upper limits of the confidence interval crossed the noninferiority margin of 1.289, he said.

However, a subgroup analysis of DFS comparing stage III with stages I and II and nodal status 2 to 3 with 0 to 1 did reach significance (HR 2.30, 90% CI [1.35, 3.94]; p < 0.001 and HR 2.25, 90% CI [1.33, 3.83]; p < 0.001, respectively). These two groups each represent about 15% of the entire study population, he said.

“The probability that short is not inferior to long treatment has an HR of 0.78 in Bayesian approach,” he said.

There were 37 OS events in the long group and 38 in the short group. The 5-year OS was virtually identical between the two arms (95.1% vs. 95.0% in the long and short groups, respectively; HR 1.06, 90% CI [0.73, 1.55]).

There was an ongoing decline in left ventricular ejection fraction for the long group but a much slower decline in the short group over 18 months (p = 0.023). There were substantially more cardiac events in the long group compared with the short group: 90 and 32, respectively (HR 0.32, 95% CI [0.21, 0.50]; p < 0.0001).

Is Less Better?

According to the results of the Short-HER study, “There may be a protective effect from a shorter duration of trastuzumab therapy” against cardiac toxicity, discussant Carey K. Anders, MD, of The University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center, said.

There was no difference in OS at 5 years, and the smaller subset analysis found that patients with stage III disease with multiple positive lymph nodes “appeared to derive greater benefit from the longer duration of trastuzumab.”

From a financial perspective, she said 1 year of trastuzumab is about $55,000, based on Medicare estimates.

“One would save close to $50,000 for 9 weeks of therapy compared to 1 year,” Dr. Anders said. “If you compare these estimates to commonly accepted additions to adjuvant therapy, 10 years versus 5 years of letrozole adds approximately $15,000, while the addition of paclitaxel to [doxorubicin and cyclophosphamide] is about $12,500.”

For select patients who cannot tolerate 12 months of trastuzumab therapy, Dr. Anders said the shorter duration “may be reasonable.”  

–Michelle Dalton, ELS