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.
The investigators noted that lapatinib may provide a lower pathological complete response because of a reduced ability to block the HER2 pathway, compared with trastuzumab. Also, trastuzumab may have additional antitumor efficacy "by inducing an immune response via antibody-derived cellular cytotoxicity," they wrote.
In addition to providing additional evidence of the feasibility – and low cardiac toxicity – of "exposing the tumor for as long as possible to the synergistic effect of chemotherapy and trastuzumab before surgery," these findings suggest lapatinib should not be used outside of clinical trials as single anti-HER2 treatment in patients undergoing neoadjuvant chemotherapy, the investigators concluded.
Indeed, these findings "should lead to the conclusion that this regimen [the combination of lapatinib with standard chemotherapy] does not seem to have any advantages compared with a standard trastuzumab-based regimen for the adjuvant treatment of HER2-positive, early-stage breast cancer," Dr. Stephen K. Chia of the British Columbia Cancer Agency, Vancouver, B.C., wrote in an accompanying editorial (Lancet Oncol. 2012 Jan. 17 [doi:10.106/S1470-2045(12)70013-X]).
Another lesson learned from the GeparQuinto trial, according to Dr. Chia, is that the preoperative setting, which the research community and patients "seem to have embraced as both standard of care therapy and as an important strategy to test new therapeutic regimens," is ideally suited for this purpose.
"Moving forward into the future, no adjuvant trials should be done without an adequate signal from preoperative trials showing safety, efficacy, target modulation, and, ideally, the identification of predictive biomarkers such that we no longer pick a loser to study in larger and more resource-intensive adjuvant trials," he said. Dr. Chia noted that the second study demonstrating improved efficacy of trastuzumab – NeoALTTO – is a good example of such a preoperative study supporting the rationale for adjuvant trials with the combination of these agents, in this case the ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial, which is underway. The lapatinib group for ALTTO has been closed due to the demonstration of futility.
In NeoALTTO, which was published concomitantly with GeparQuinto in the Lancet, trastuzumab was more effective – although not significantly – than lapatinib alone for the treatment of HER2-positive breast cancer, but it was most effective in combination with lapatinib, Dr. José Baselga of Massachusetts General Hospital Cancer Center, Boston, and his colleagues from the NeoALTTO Study Team reported.