Randomized Phase II Study in Patients with HER2-Positive Breast Cancer

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Published: 16 Dec 2011
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Dr Luca Gianni - Ospedale San Raffaele, Milan, Italy

Speaking at a press conference, Dr Gianni presents results showing that pertuzumab with trastuzumab and docetaxel had a significantly higher pCR rate (45.8%) compared with TH (29%) or other pertuzumab combinations.

 HER2+/ER+ and HER2+/ER– BC have different patterns of gene expression, and treatment response seems to be driven by different biologic pathways . This effect was also seen. A broad panel of biomarkers was assessed in tumour specimens and in sera to characterise the molecular profile of the ITT population and to explore biomarkers with different treatments and in different subsets of patients.

2011 SABCS, San Antonio Breast Cancer Symposium, 6-10 December, San Antonio, USA


Randomized Phase II Study in Patients with HER2-Positive Breast Cancer


Dr Luca Gianni – Ospedale San Raffaele, Milan, Italy

Good morning everybody. It is this time when options for treating women with HER2 positive breast cancer are really many and very effective. One of the possibilities is that of improving by adding modulators of the activity of HER2 directed therapies and at these meetings over the years there have been presentations of evidence, both pre-clinical and clinical, indicating that there is a rationale for combining bevacizumab, which is the antiangiogenic monoclonal antibody directed against VEGF, with trastuzumab. Indeed, VEGF expression is positively related by HER2 and the levels of the VEGF correlate with HER2 over-expression. In animals and in animal models the combination of the two monoclonal antibodies produced synergistic results. In addition to that, single arm phase II studies of trastuzumab with bevacizumab with or without chemotherapy in women with locally recurrent or metastatic breast cancer showed encouraging activity despite progression with trastuzumab containing chemotherapy.


All this has justified the conduct of a prospective randomised trial that is known as AVEREL. AVEREL randomised 424 women with previously untreated HER2 positive locally recurrent or metastatic breast cancer to receive either the conventional treatment of every three weeks trastuzumab with docetaxel at the dose of 100mg/m2 or the same combination of chemotherapy and trastuzumab with the addition of bevacizumab given at 50mg/kg every three weeks. Treatment was planned until progression of disease or intolerable toxicity and, in the case of docetaxel, there was a suggestion to try and deliver at least six cycles of chemotherapy, knowing in advance that it’s usually difficult to proceed beyond the sixth cycle with this type of chemotherapy. The primary endpoint of the study was the investigator assessed progression free survival; secondary endpoints were additional efficacy elements such as overall survival, objective response rate, duration of response, safety and quality of life. And finally there were exploratory endpoints, the most important of which was an independent review committee assessment of progression free survival to comply with regulatory recommendations in the United States by the Food and Drug Administration and biomarker assessment. The participation to this biomarker assessment was optional.


Let’s go to the results without dwelling too much into the characteristics of the patient population that was classical for HER2 positive metastatic breast cancer at first presentation. If you consider the investigator assessed progression free survival that is the primary analysis of the study you can see that administration of bevacizumab prolonged the progression free survival for median 13.7 months to median 16.5 months and that difference corresponded to a hazard ratio of 0.82 and a p-value that was not statistically significant of 0.0775.


If you consider the independent review committee assessment of progression free survival, as done for US regulatory purposes, again you observe basically the same difference from 13.9 to 16.8 months of progression free survival. You have to consider that the most relevant difference in this assessment by the independent review committee was that patients were censored for non-protocol therapy, something that was not done in the case of the investigators assessment. In this case the hazard ratio stratified was 0.72 and the p-value was statistically significant, it was 0.0162.


The improvement is there. What we wanted also to know if there was a subset of cases and patients who derived benefit out of the entire population. To do so we repeated the same study that has been conducted in HER2 negative disease and, starting from the concept that a high expression of vascular endothelial growth factor A is associated with poor prognosis, we wanted to know whether the measurement of vascular endothelial growth factor A could be a marker of a subset of patients who might derive more benefit than in others. 


Here you see from this line what is the progression free survival in cases that were exposed to the standard docetaxel and trastuzumab therapy and had low vascular endothelial growth factor alpha. If they had high VEGF-alpha, as you can see, the median progression free survival was only 8.5 months, however, in both high and low VEGF-alpha administration of bevacizumab corresponded to an abrogation of the poor prognosis and both patient groups had a more than 16 month progression free survival.


These numbers are not statistically significant and couldn’t be because the study was limited to a subset of the entire patient population corresponding to about 160 patients overall but they’re really interesting because they are the first evidence that, in this population of HER2 positive cancer, we have the same behaviour that has already been observed in the AVADO trial in HER2 negative disease.


In conclusion, the AVEREL demonstrated longer median progression free survival when bevacizumab was combined with trastuzumab and docetaxel in patients with HER2 positive metastatic breast cancer. The difference in terms of primary endpoint was not statistically significant but it was statistically significant when assessed by an independent review committee. The data on overall survival that I didn’t show are really immature because it’s too early to derive any conclusion on overall survival; at this time the two curves for overall survival are not different at the interim analysis. There were no new receptor signals observed in this patient population with respect to what we already know from other patient populations exposed to Avastin. In perspective, in the AVEREL, exploratory analysis of plasma VEGF-A suggests a potentially predictive effect with greater benefit with high VEGF-A levels that are consistent with observation in the HER2 negative group of patients. Because of that, a global biomarker study, known as MERiDIAN, is planned where patients will be treated with bevacizumab plus paclitaxel and stratified by plasma level of VEGF-A to confirm or dispute the concept that this marker has anything to do with prediction of benefit from addition of bevacizumab. On top of that we have, now that has been completed, the BETH adjuvant trial where in HER2 positive disease patients were randomised to receive chemotherapy and trastuzumab with or without bevacizumab and this will provide additional evidence on the potential benefit of adding the antiangiogenic monoclonal antibody in women with HER2 positive disease.


Thank you for your attention.