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HERceptin Adjuvant Trial Results Suggest Benefits as Monotherapy in Adjuvant Setting: Presented at IBCEF

By Chris Berrie

VIENNA, AUSTRIA -- February 20, 2006 -- Adjuvant trastuzumab (Herceptin) as a single agent shows significant improvement in disease-free survival (DFS) and a clear trend towards improved overall survival with low incidence of severe congestive heart failure (CHF) in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer, according to the HERceptin Adjuvant trial (HERA).

Richard Bell, MD, senior clinical consultant, professor and director of cancer services, medical oncology, Andrew Love Cancer Centre, Geelong, Victoria, Australia, presented the HERA findings here on February 11^th at the International Breast Cancer Expert Forum: Milestones in Management, Confidence and Care (IBCEF).

Trastuzumab is known to improve survival in women with metastatic breast cancer, Dr. Bell noted during his analysis of the international, multicentre, randomised study. Since HER2-positive breast cancer is associated with early progression and poor prognosis, the rationale for the HERA trial was to target the 25% of women with early breast cancer that have HER2-positive disease.

The HERA trial was designed to enrol patients with centrally confirmed HER2 overexpression or amplification who were node-positive or sentinel-node-negative, with a tumour diameter greater than 1.0 cm. Inclusion criteria also required completion of at least 4 cycles of a range of approved neoadjuvant chemotherapy regimen without or with radiotherapy, with or without anthracycline or taxane therapy. Finally, the patients needed to have a left ventricular ejection fraction (LVEF) of at least 55% and a known hormone status.

The primary efficacy endpoint was DFS, and secondary endpoints were time to recurrence, time to distant recurrence, and overall survival. Safety endpoints were tolerability and general safety (including cardiac safety).

Although the HERA trial design provided for an observation arm and 2 trastuzumab 3-times-weekly arms, for 1 year and 2 years of treatment, Dr. Bell presented the interim efficacy analysis after 475 events that considered observation and 1 year of trastuzumab treatment.

Patient age ranges for the observation (n = 1693) and trastuzumab (n = 1694) arms were well matched for age, prior neoadjuvant chemotherapy, postmenopausal status, hormone receptor status, and nodal status.

At a median follow-up of 1 year, the observation arm had 220 events with a 2-year DFS of 77.4%, as compared with 127 events in the 1-year trastuzumab arm, a significant reduction of 85.8% (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.67; P < .001).

Dr. Bell indicated that this benefit of trastuzumab was due largely to reduced distant events (85 vs 154), locoregional events (27 vs 50), and second nonbreast malignancy (3 vs 6), despite increases seen in central nervous system events (21 vs 15 of observation arm) and death as first event (6 vs 3).

Secondary efficacy endpoints showed that the trastuzumab arm had significantly better time to recurrence (HR, 0.51; 95% CI, 0.40-0.64) and time to distant recurrence (HR, 0.49; 95% CI, 0.38-0.63). Although the difference in overall survival between trastuzumab and observation did not reach significance, Dr. Bell stressed that there was indeed a trend towards benefit with trastuzumab (HR, 0.76; 95% CI, 0.47-1.23).

Although this interim analysis was not powered for subgroup analyses, Dr. Bell indicated that all subgroups with sufficient patient numbers showed statistically significant treatment effects with trastuzumab. These included the subgroups within age less than 60 years, menopausal status, nodal status, pathological tumour size 5 cm or greater, hormone receptor status of ER-negative plus PR-negative, histological grade, surgery carried out for primary tumour, radiotherapy, and a chemotherapy of anthracyclines without taxanes.

At the same time, the confidence intervals for these subgroups remained large due to the low number of events during this follow-up, Dr. Bell indicated, and there were indications of potential differing event rates over time, although further follow-up is needed.

Among the 1708 observation patients and 1678 trastuzumab patients evaluated for adverse events, rates were similar between the 2 groups for 1 or more grade 3/4 adverse event (4.4% vs 7.9%, respectively), 1 or more serious adverse events (4.7% vs 7.0%) and fatal adverse event (0.2% vs 0.4%). In addition, 8.5% of patients in the trastuzumab arm withdrew from treatment.

Significant differences were seen between the observation and 1-year trastuzumab arms in the following measures: 10 or greater decrease in EF points and an LVEF < 50% (2.27% vs 7.38%, respectively; P < .001); confirmed LVEF decrease (0.58% vs 3.19%, respectively; P < .001); severe CHF (0.0% vs 0.60%, respectively; P < .001).

Dr. Bell stressed that the majority of patients recovered from severe CHF and LVEF decrease, and he noted that in most cases, LVEF stabilised or returned to baseline following discontinuation of trastuzumab.

Thus, as there were significant improvements seen in DFS, distant DFS, and across many of the subgroups analysed, accompanied by low incidence (and reversibility) of severe CHF, Dr. Bell indicated that these data provide convincing evidence that trastuzumab can be used as a single agent in the adjuvant setting.

This conference was sponsored by Roche.

REFERENCE:
Piccart-Gebhart et al., (2005) New Engl J Med. 353 (16), 1659-1672.


[Presentation title: The HERA trial.]

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