Trastuzumab Bests Lapatinib for HER2 Breast Cancer
FROM THE LANCET AND THE LANCET ONCOLOGY
Major Finding: In the GeparQuinto trial, 30% of 307 HER2-positive patients treated with trastuzumab had a pathological complete response, compared with only 23% of 308 HER2-positive patients treated with lapatinib. In NeoALTTO, trastuzumab was more effective than lapatinib alone for the treatment of HER2-positive breast cancer, but it was most effective in combination with lapatinib. Pathological complete response occurred in 51% of 152 patients in the combination treatment group, compared with 30% of the 149 patients in the trastuzumab group and 25% of the 154 patients in the lapatinib group, for an adjusted odds ratio of 2.6 for the combination vs. trastuzumab alone.
Data Source: Two randomized phase III trials – GeparQuinto and NeoALTTO.
Disclosures: GeparQuinto was funded by GlaxoSmithKline, Roche, and Sanofi-Aventis; lapatinib was provided free of charge. Dr. Untch said he had no relevant financial disclosures, but several other GeparQuinto investigators made financial disclosures relating to these and other pharmaceutical companies. The NeoALTTO trial was funded by GlaxoSmithKline. Dr. Baselga said he has received honoraria from Roche, and his institution has received funding from GlaxoSmithKline and Roche. Several other NeoALTTO investigators made financial disclosures involving GlaxoSmithKline and/or other pharmaceutical companies. Dr. Chia, the author of the editorial that accompanied the article in the Lancet Oncology on the GeparQuinto trial, disclosed that he has received honoraria from GlaxoSmithKline, manufacturer of lapatinib, and F. Hoffmann-La Roche, manufacturer of trastuzumab, as well as an unrestricted research grant from Hoffmann-La Roche.
Trastuzumab is significantly more effective alone or in combination with lapatinib than is lapatinib alone for the treatment of human epidermal growth factor receptor 2–positive breast cancer in patients receiving neoadjuvant chemotherapy, according to findings from two randomized phase III trials.
The studies – GeparQuinto and the NeoALTTO (Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial – underscore the value of testing new therapies in the neoadjuvant setting.
In the GeparQuinto trial, 30% of 307 HER2-positive patients treated with the anti-HER2 humanized monoclonal antibody trastuzumab had a pathological complete response, compared with only 23% of 308 HER2-positive patients treated with the tyrosine kinase inhibitor lapatinib, which targets both HER1 and HER2 (odds ratio, 0.68).
Although the patients randomized to receive trastuzumab had significantly more edema (39% vs. 29%) and dyspnea (30% vs. 21%), those randomized to receive lapatinib experienced significantly more diarrhea (75% vs. 47%) and skin rash (55% vs. 32%), and significantly more patients in the lapatinib group discontinued treatment (33% vs. 14%), Dr. Michael Untch and his colleagues reported in the Jan. 17 issue of the Lancet Oncology.
Women with previously untreated unilateral or bilateral primary invasive breast carcinoma were enrolled in the study between Nov. 7, 2007, and July 9, 2010, at 126 centers in Germany and 1 center in Switzerland. Patients were eligible for inclusion if they had locally advanced tumor stages cT3 or cT4, hormone receptor (HR)-negative tumors, or HR-positive tumors with clinically positive axillary nodes (cN+ for cT2) or pNSLN+ for cT1 disease (Lancet Oncol. 2012 Jan. 17 [doi:10.1016/S1470-2045(11)70397-7]).
They received neoadjuvant treatment including four cycles of epirubicin given at 90 mg/m2 intravenously along with cyclophosphamide at a dose of 600 mg/m2 intravenously, every 3 weeks, and four cycles of docetaxel at 100 mg/m2 intravenously every 3 weeks, plus either trastuzumab or lapatinib throughout all cycles prior to surgery. Trastuzumab was given at a starting loading dose of 8 mg/kg and then at 6 mg/kg intravenously every 3 weeks; the lapatinib dose was 1,000-1,250 mg/day orally.
"Pathological complete response rates were significantly lower with lapatinib treatment than with trastuzumab, irrespective of the definitions of pathological complete response that were used. These results confirm the efficacy of a neoadjuvant regimen containing trastuzumab," wrote Dr. Untch, of Helios-Klinikum, Berlin-Buch, Berlin, and his colleagues from the German Breast Group and the Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) Study Group.
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Rethinking Trials in the Neoadjuvant Setting
In an accompanying editorial, Dr. Michael Gnant and Dr. Guenther G. Steger highlighted the NeoALTTO study’s design as a "crucial scientific strength."
Delaying chemotherapy for 6 weeks while the targeted anti-HER2 treatment was initiated enabled collection of samples for translational research, as well as assessment of early tumor response without confounding by cytotoxic therapy.
"Such approaches should be used more often in pivotal trials of new drugs that target specific biological pathways, to enable unbiased efficacy assessments to be made. Equally important, such trials could help to identify clinically useful markers of early response, with the ultimate goal of tailoring neoadjuvant treatments for individual patients," they wrote (Lancet 2012 Jan. 17 [doi:10.106/S0140-6736(12)60068-3]).
In addition, on the basis of such neoadjuvant trials, the traditional sequence of drug testing first in advanced disease, then in the neoadjuvant setting, and finally in the adjuvant setting, could be revised.
"In the future, assessment of a pathway-directed therapeutic intervention in rigorous neoadjuvant trials might be sufficient for validity in a biomarker-defined population of patients to be accepted," Dr. Gnant and Dr. Steger suggested. Trials in such a setting, after drug safety is established, could lead to large savings in drug development costs, and to much quicker availability of promising new drugs for the treatment of early breast cancer, they noted.
Dr. Gnant and Dr. Steger are with the Comprehensive Cancer Centre of the Medical University of Vienna. Dr. Gnant has served on advisory boards for and has received consulting fees from AstraZeneca and Novartis, and has received lecture fees and/or research support from Roche, Schering, Pfizer, Novartis, AstraZeneca, Sanofi-Aventis, GlaxoSmithKline, and Amgen. Dr. Steger has served on advisory boards for and has received consulting fees from AstraZeneca, Roche, and Amgen, and has received lecture fees and research support from AstraZeneca, Novartis, Roche, GlaxoSmithKline, and Amgen.