Bevacizumab, an antibody against human vascular endothelial growth factor (VEGF), was recently approved in combination regimens for first line therapy of metastatic colorectal, adeno and large cell lung and breast cancer. In clinical trials combination of Bevacizumab with Paclitaxel showed an increase in progression free survival in breast cancer patients. We have investigated the efficacy of Bevacizumab in 99 patient-derived human tumor xenografts, growing sc in nude mice in order to compare the preclinical with the clinical activity pattern and to investigate if 8 proteins associated with angiogenesis correlate with the activity. Bevacizumab was applied iv at a loading dose of 40 mg/kg/d on day 0, followed by two applications of 20 mg/kg/d on day 7 and 14, respectively. Antitumor activity was evaluated at the minimum T/C value or after 28 days. A marked inhibition (optimal T/C< 20%) occurred in 9 tumors (10%), 20 tumors (21%) showed T/C values between 20% and 34%, whereas 64 tumors (69%) were resistant to single agent treatment with Bevacizumab with T/C values > 34%.
Therefore as a single agent Bevacizumab showed moderate activity at the stronger cut off point of T/C <20% and a broader activity at the weaker cut-off of T/C < 34%. Antitumor activity (T/C < 34%) was found in 4/20 colon, 12/36 NSCLC, 3/11 breast, 2/10 renal and 7/22 miscellaneous tumor entities mimicking the activity pattern seen in the clinic. Within the group of miscellaneous tumor types Bevacizumab was active in 2/5 head and neck cancers, 1/2 ovarian, 1/3 pancreas, 1/1 bladder, 1/1 small cell lung, 1/6 gastric cancer, and in 1/1 sarcoma carcinoma models. Nevertheless most of the tumors grew progressively and doubled the initial tumor volume within 2-3 weeks. A regression of more than 50% was found only in 1 NSCLC. In the clinic the remission rates observed in different tumor types were always < 5 - 10% when Bevacizumab was administered as single agent. The real benefit was evident in combination with cytotoxic drugs when the progression free survival or the overall survival was significantly prolonged in colon, breast and lung (adeno and large cell) cancers leading to registration in the USA, in Europe, and in part Japan.
Using a bead suspension assay levels of human and murine VEGF as well as 7 other factors and signal transduction proteins involved in angiogenesis were determined in 54 - 58 of the 99 tested xenografts. In addition microvessel density was examined in 20 xenografts by fluorescence microscopy. Up to now no correlation was found between Bevacizumab activity and the expression of 8 angiogenic proteins mainly human and mouse VEGF and vessel density suggesting that the compound might act via additional mechanism of action. In the clinic Bevacizumab activity could also not be correlated to the VEGF status of the patient. Our approach should be helpful to identify a pattern of proteomic biomarkers being predictive for Bevacizumab activity. In conclusion the preclinical antitumor activity corresponded well to clinical experience with efficacy in colon, NSCL, breast and renal cancers and also additional tumor entities responded.
- American Association for Cancer Research