Combined Antiangiogenesis and Antiepidermal Growth Factor Receptor Targeting in the Treatment of Cancer: Hold Back, We Are Not There Yet

Abstract

This issue of the Journal of Clinical Oncology (JCO) contains the results of two randomized phase II studies evaluating the activity of combined targeted therapy directed at the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). In the first study, Bowel Oncology and Cetuximab Antibody (BOND)-2, 83 patients with metastatic colorectal carcinoma (CRC) refractory to irinotecan-based chemotherapy were randomly assigned to receive the combination of the anti-EGFR monoclonal antibody cetuximab, the anti-VEGF monoclonal antibody bevacizumab, and irinotecan (CBI) or cetuximab plus bevacizumab (CB). Both arms demonstrated promising activity compared with historical controls, and there was a suggestion that the addition of bevacizumab improved the antitumor activity of cetuximab either alone or in combination with irinotecan. In the second study, 104 patients with previously untreated renal cell carcinoma (RCC) received bevacizumab in combination with the EGFR tyrosine kinase inhibitor erlotinib or with placebo. In this study, the addition of erlotinib to bevacizumab was well tolerated, but did not provide additional clinical benefit compared with bevacizumab alone. In summary, the combination of the antiVEGF antibody bevacizumab with an anti-EGFR agent was positive in patients with CRC, whereas it did not provide any additional benefit to bevacizumab alone in patients with RCC. In this editorial, we review the potential reason(s) for these discordant results and explore the implications of these studies for future research and daily clinical practice. First, both studies were designed based on a strong rationale exploring combined antiangiogenesis and anti-EGFR approaches. Solid tumors are genetically complex, and with rare exceptions, it is unlikely that a given tumor will be entirely dependent on one abnormally activated kinase or signaling pathway for its malignant behavior. There is also a considerable level of compensatory cross talk among receptors within one signaling pathway, as well as cross talk among distinct signaling pathways regulating cell proliferation, trafficking, and survival. As with conventional chemotherapeutic agents, which are often most effective when administered as combination therapies, rationally developed combinations of molecularly targeted agents are likely to be more potent than singleagent therapies. In the case of the potential interactions between EGFR signaling and angiogenesis, several studies have shown that both EGFR monoclonal antibodies and tyrosine kinase inhibitors reduce VEGF levels and microvessel density in tumors that regress on EGFR blockade. Interestingly, tumor cells with acquired resistance to cetuximab exhibit increased expression and secretion of VEGF, and forced expression of VEGF in sensitive cancer cells renders them resistant to cetuximab in vivo. These data suggest that inhibition of EGFR-dependent tumor neoangiogenesis is central for the antitumor effect of EGFR inhibitors; in turn, enhanced angiogenesis may endow tumors with resistance to EGFR blockade. Therefore, it is not surprising that the combination of antiangiogenic and anti-EGFR agents has showed greater antitumor activity than when these agents are administered alone. However, even carefully characterized preclinical models have limitations. For example, renal carcinoma cell lines are sensitive to cetuximab in vitro, whereas a series of clinical trials in RCC with anti-EGFR agents uniformly have shown lack of activity in patients. In this regard, the findings from the study by Bukowski et al in this issue of JCO provide one more piece of evidence for the lack of activity of anti-EGFR agents in RCC, and also raises the question as to whether single-agent activity may be required for any anti-EGFR agent to be incorporated into a combined-therapy approach. Conversely, the interpretation of the BOND-2 study in patients with refractory CRC seems to be more complex. This study follows the same approach as the initial BOND study, in which a total of 329 patients with EGFR-expressing colorectal cancer refractory to irinotecan-based chemotherapy were randomly assigned to receive cetuximab or irinotecan plus cetuximab. The combination treatment was superior to cetuximab as a single agent, both in terms of response rate (23% v 11%; P .007) and median progression-free survival (PFS; 4.1 v 1.5 months; P .001). The trial was not powered to demonstrate any advantage in overall (OS) survival, and half of the patients receiving cetuximab as a single agent were switched to the combination treatment when progression of the disease was documented. Nevertheless, a better median OS was observed in those patients receiving the combination as first-line treatment (8.6 v 6.9 months). In the BOND-2 study, patients refractory to irinotecan-based chemotherapy were randomly assigned to receive CBI or CB. Although the study was closed to accrual before the completion of target size (150 patients) due to poor accrual after the commercialization of bevacizumab, the results of the study showed promising activity: the CBI arm had JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 29 OCTOBER 1