SABCS 2011 Report – Tumour markers for patient selection in treatment with VEGF inhibitors

by Dr Sunil Upadhyay – It is well known that HER2-positive marker positively regulates VEGF expression and VEGR levels correlate with HER2 over-expression. There is emerging evidence to suggest that trastuzumab with bevacizumab with or without chemotherapy in local recurrent or metastatic breast cancers has a synergistic effect and encouraging clinical activity. Professor Luca Gianni from the Instituto Nazionale Tumori, Milan presented the results of AVEREL, a randomised, Phase III trial to evaluate bevacizumab in combination with trastuzumab + docetaxel as first-line therapy for HER2-positive, locally recurrent/metastatic breast cancer at SABCS 2011.

The treatment was allowed until disease progression or toxicity and the planned minimum number of docetaxel was 6 cycles. The primary end point was PFS and the secondary end points were efficacy (OS, ORR, duration of response and time to treatment failure), safety and quality of life.

The results from the trial presented by Prof. Gianni showed that the baseline characteristics between the two arms were well balanced. Many of the patients recruited had not received prior chemotherapy and very few had received prior adjuvant anti-HER2 therapy, simply because of the time of this trial when adjuvant anti-HER2 therapy was not available in many countries.

The investigator assessed PFS which was found to be superior for the bevacizumab arm (n=216) at 16.5 months compared to the no bevacizumab arm (n=208) at 13.7 months with HR 0.82 but not significant (p=0.0775). However, the independent review committee that assessed PFS noted that the addition of bevacizumab was associated with significant prolongation of median PFS (HR 0.72) and the difference was statistically significant (p=0.0162) confirming the additional gain from bevacizumab. The subgroup analysis did not show any surprises. The objective response rate was also better with the addition of bevacizumab. However, interim analysis showed that there was no overall survival gain with the addition of bevacizumab. Similarly, there were no safety concerns and toxicity related deaths in either arm. An exploratory analysis of the PFS according to baseline plasma VEGF-A levels showed that the patients with high baseline plasma VEGF-A level derived the most pronounced improvement with the addition of bevacizumab.

In conclusion, AVEREL demonstrated longer median PFS when bevacizumab was combined with trastuzumab plus docetaxel in patients with HER2-positive local recurrent/metastatic breast cancer without any safety signals but no overall survival gain either. Lack of survival gain is not unusual in a metastatic setting. These results show that selecting patients with high baseline plasma VEGF-A confers greater benefit and therefore greater cost-efficiency. Global biomarker study MERiDiAN and BETH adjuvant trial will provide further data on the use of bevacizumab and patient selection criteria for optimum outcome in metastatic breast cancer. (Abstract S4.8)