SABCS-NEOADJUVANT TREATMENT OF HER2+ BREAST CANCER

First results of the NeoALTTO, NEOSPHERE and GeparQuinto studies
14.12.10
Category: Scientific News
Trials in the neoadjuvant arena using pCR as a surrogate end point for overall or disease-free survival presented at the 33rd San Antonio Breast Cancer Symposium

The NeoALTTO trial is a phase III, randomized, open-label, neoadjuvant study of lapatinib, trastuzumab, or their combination together with paclitaxel as neoadjuvant therapy for women with HER2-positive primary breast cancer. The first results from the study were reported at the 33rd San Antonio Breast Cancer Symposium by Dr José Baselga, who led this study at the Vall d’Hebron University Hospital, Barcelona, Spain.

From January 2008, to December 2009, 455 patients from 99 participating sites were randomized to receive either lapatinib (154 patients), or trastuzumab (149 patients), or lapatinib with trastuzumab for a total of 6 weeks (152 patients). After this biological window, patients continued on the same targeted therapy plus weekly paclitaxel for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). After surgery, patients received 3 cycles of adjuvant FEC followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy). The primary objective of the study was to evaluate and compare among the 3 arms the rate of pCR, defined as the absence of invasive cancer in the breast at the time of surgery. Secondary objectives include objective response rate, safety, pathologic node-negative status, rate of conversion to breast conservation, disease-free survival, and overall survival. All patients underwent tumor biopsies for comparative pharmacodynamic analyses before beginning therapy and on day 15 of the biological therapy window. A subset of patients also participated in PET/CT and circulating tumor cells substudies.

Overall, more than one-third of patients in the lapatinib-containing treatment arms did not complete therapy as planned, compared with only 8% of patients in the trastuzumab arm. The most noteworthy serious adverse event was diarrhea at grade 3 or higher, which occurred in 23% of patients receiving lapatinib and 21% of patients receiving lapatinib plus trastuzumab, but only 2% of patients receiving trastuzumab alone. Hepatic events and neutropenia were also substantially higher in the treatment arms containing lapatinib.

The pCR rate in the lapatinib/trastuzumab/paclitaxel arm was significantly higher than in the trastuzumab/paclitaxel arm (51.3% vs 29.5%, respectively; p=0.0001), while the pCR rate in the lapatinib/docetaxel arm (24.7%) was not significantly different from the trastuzumab arm. Corresponding objective (clinical) response rates at 6 weeks (biological window) were 67.1%, 30.2%, and 52.6%, and those at surgery were 80.3%, 70.5%, and 74.0%. Response rates in all treatment arms were substantially higher in hormone receptor negative tumors compared with hormone receptor positive tumors. Data for correlation between pCR and disease-free and/or overall survival will be available in the future.

Dr Luca Gianni of the Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy, presented results from the NEOSPHERE trial, a randomized phase II study with 4 neoadjuvant treatment arms. The pCR in the docetaxel/trastuzumab/pertuzumab arm was significantly greater than in the docetaxel/trastuzumab arm (p=0.014), which in turn was significantly higher than in the trastuzumab/pertuzumab arm (p=0.019). An exploratory subset analysis showed a pCR in a consistently higher proportion of hormone receptor negative tumors compared with hormone receptor positive tumors. The addition of pertuzumab did not cause an increased risk of serious events.

Dr Michael Untch of the Helios Klinikum Berlin-Buch, Berlin, Germany, presented the primary efficacy end point analysis from the GeparQuinto study which looked at lapatinib versus trastuzumab in combination with neoadjuvant anthracycline/taxane-based chemotherapy for the treatment of patients with HER2-positive, untreated, primary breast cancer. The neoadjuvant chemotherapy consisted of epirubicin in combination with cyclophosphamide, followed by docetaxel (EC-Doc). The primary end point pCR was 31.3% in the EC-Doc plus trastuzumab arm compared with 21.7% in the EC-Doc plus lapatinib arm (p<0.05). Of special note in this trial was the grade 3/4 diarrhea that occurred in 7% of patients receiving lapatinib during the run-in phase of the trial. This and other toxicities resulted in discontinuation of treatment for 34.5% of patients receiving lapatinib during this phase of the trial and a reduction in dose.

Dr Eric Winer who discussed study results pointed out, however, that all of these trials are in the neoadjuvant arena, using pCR as a surrogate end point for overall survival or disease-free survival. He raised the issue of whether pCR, at this point in time, is an appropriate end point for drug approval or practice change, and suggested that it is not.