first neoaltto, now GEPARTRIO results-- Herceptin beats Lapatinib as agent combined w

[Lani]

chemo in neoadjuvant therapy. (Neo Altto showed the combination was even better)

I think the exclusion of triple positives without + lymph nodes may scew the gepartrio results


Trastuzumab Bests Lapatinib for HER2 Breast Cancer
Elsevier Global Medical News. 2012 Jan 17, S Worcester

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.

Pathological complete response in this parallel groups, open-label study, 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 (Lancet 2012 Jan. 17 [doi:10.106/S0140-6736(11)61847-3]).

As in the GeparQuinto Trial, no major cardiac dysfunction occurred, and diarrhea was more frequent in the patients receiving lapatinib (23% and 21% of those in the lapatinib and combination groups, respectively, vs. 2% in the trastuzumab group who had grade 3 diarrhea).

NeoALTTO participants were enrolled between Jan. 5, 2008, and May 27, 2010, at 86 sites in 23 countries. Participants had histologically confirmed invasive HER2-positive breast cancer with tumors at least 2 cm in diameter. Lapatinib was given at 1,500 mg orally to those in the lapatinib-only group, and at 1,000 mg for those in the combination group; trastuzumab was given at a loading dose of 4 mg/m² followed by 2 mg/kg on subsequent doses for both groups.

The anti-HER2 treatments were given alone for 6 weeks, and paclitaxel at 80 mg/m² weekly was then added for an additional 12 weeks.

"Dual targeting of HER2-positive tumors with trastuzumab and lapatinib is undertaken because of primary and acquired resistance to both agents, their partly non-overlapping mechanisms of action, and the well characterized synergistic interaction between them in HER2 breast-cancer models," the investigators noted.

These findings provide proof of concept that dual inhibition of HER2 is better than a single-agent approach, Dr. Baselga and his colleagues said, noting that the higher pathological complete response rate for the combination was clear across all subgroups tested, which is consistent with the findings from other studies of anti-HER2 treatment in HER2-positive tumors.

"Our study also supports investigation of novel targeted agents for breast cancer in the neoadjuvant setting, when tumors have not yet acquired resistance to therapy and when chances of clinical benefit are highest," they said.

In an accompanying editorial, Dr. Michael Gnant and Dr. Guenther G. Steger highlighted the NeoALTTO study's design as a "crucial scientific strength" (Lancet 2012 Jan. 17 [doi:10.106/S0140-6736(12)60068-3]). 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, wrote Dr. Gnant and Dr. Steger of 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.

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.

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