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Shorter duration of trastuzumab for breast cancer halves severe cardiac toxicity, but fails to meet noninferiority
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CHICAGO — Shortening adjuvant trastuzumab receipt from 1 year to 9 weeks halved the rate of severe toxicity in women with HER-2–positive breast cancer, according to results of the phase 3 Short-HER study presented at the ASCO Annual Meeting.
However, the shorter treatment schedule did not meet noninferiority criteria for DFS.
One-year of trastuzumab (Herceptin, Genentech) with chemotherapy is standard adjuvant treatment for HER-2–positive breast cancer.
“The same magnitude of benefit [with 1 year of trastuzumab] was reported by the small FinHER study with 9 weeks of trastuzumab,” Pier-Franco Conte, MD, of the departments of surgery, oncology and gastroenterology at University of Padua in Italy, said during his presentation. “There also is synergism of trastuzumab when combined with chemotherapy. Real-world patients tend to be at lower risk for relapse and higher risk for cardiac toxicity.”
Conte and colleagues compared a long- and short-course of trastuzumab in 1,254 patients (median age, 55 years; range, 25-78) from 82 centers in Italy.
Patients had stage I (37.3%), IIa (40%), IIb (20.6%) or III (2.1%) disease. Thirty percent of patients had one to three positive nodes, whereas 16% had four or more. Most patients (68%) had ER–positive tumors.
Patients in the long treatment arm received adriamycin and cyclophosphamide or epirubicin and cyclophosphamide chemotherapy for four cycles followed by four courses of three-weekly docetaxel with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab. Patients in the short arm received three courses of three-weekly docetaxel plus trastuzumab for nine doses followed by three courses of 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy.
DFS served as the primary endpoint, and OS served as the second primary endpoint.
Researchers originally set a noninferiority margin of HR less than 1.29 based on 2,500 patients; however, they amended the protocol based on 1,250 patients (alfa, 0.05; power, 0.56). The analysis of the primary endpoint would occur after 198 events or a median follow-up of 5 years.
After median follow-up of 5.2 years, researchers reported 5-year DFS rates of 87.5% in the long arm and 85.4% in the short arm (HR = 1.15; 90% CI, 0.91-1.46).
Five-year OS rates were 95.1% in the long arm and 95% in the short arm (HR = 1.05; 95% CI, 0.73-1.55).
Cardiac adverse events occurred in 14.4% of patients on the long arm and 5.1% of patients on the short arm. More patients on the short arm experienced grade 2 (11.2% vs. 3.5%) and grade 3 (2.7% vs. 1.1%) cardiac events.
Time to first cardiac event greater than grade 2 appeared significantly delayed in patients assigned the short arm (HR = 0.32; 95% CI, 0.21-0.5).
“One year of trastuzumab is still standard,” Conte said. “[This] trial, however, reinforces the hypothesis that treatment de-escalation retains efficacy with less toxicity. A shorter treatment might be an option for patients at low risk for relapse and/or higher risk for cardiac toxicity.”
These results also may increase access to trastuzumab in low- and middle-income countries, Conte said. – by Alexandra Todak
Reference: Conte P-F, et al. Abstract 501. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Disclosure: Conte reports speakers bureau roles with AstraZeneca, Lilly, Novartis and Roche/Genentech; research funding or travel expenses from Merck, Novartis and Roche; and travel expenses from AstraZeneca, Celgene and Novartis.
Perspective
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Derek Raghavan, MD, PhD, FACP, FRACP, FASCO
This study and corresponding perspective illustrate one of the problems in modern oncology. The concept of the study was fine, but the execution was flawed. When a noninferiority study is designed, it is not kosher to change the size and power halfway through the study, particularly when such a vastly heterogeneous population of patients is included. It is correct that the data, as presented, do not support noninferiority. However, the design precludes an assessment of noninferiority in a clinically or statistically meaningful way. It is more appropriate to state that the question has simply not been answered. We also should not forget that the OS, notwithstanding population heterogeneity, was identical! Given the costs of such treatment, this type of study should be completed adequately and accurately, and the failure of design and execution of this study should not dissuade others from attempting to ask the crucial question: Are high-dose pharmaceutical company drug regimens worth the cost to the community and the fiscal toxicity for patients?Perspective
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Kevin Kalinsky, MD, MS
A shorter trastuzumab (Herceptin, Genentech) treatment regimen had the potential to decrease cost and cardiac events. However, efficacy is highly important and, based on these data, I agree with the conclusion of the researchers that 1 year of trastuzumab remains preferred. At this time, there is no indication that any patients should receive the shorter duration of treatment, if they are tolerating it. This was a large, randomized trial. I do not think there is a potential role for future trials to further explore this question.
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