Thomas J. Lynch, Jr, MD, Chief, Hematology/Oncology
Massachusetts General Hospital Cancer Center, Boston
Targeted therapy holds great promise in lung cancer, but until the advent of agents that attack vascular endothelial growth factor (VEGF), outcome has been largely disappointing in the majority of patients with the disease.1 Epidermal growth factor receptor (EGFR) inhibitors have been able to dramatically help a small portion of patients with lung cancer, but have not improved survival in the far larger group of unselected patients when added to chemotherapy.2 Strategies that have been tried to improve on chemotherapy include anti-ras agents, retinoids, antisense agents to protein kinase C, and drugs that inhibit matrix metalloproteinase. All such strategies have failed to improve survival when added to standard chemotherapy in the first-line treatment of patients with stage IV non-small cell lung cancer (NSCLC), though certainly not for lack of trying. Thousands of patients worldwide have participated in trials of chemotherapy plus a targeted agent vs. chemotherapy alone.
To date, only bevacizumab, a monoclonal antibody against VEGF, has proven to be an effective agent when combined with chemotherapy in advanced lung cancer. The pioneering Eastern Cooperative Oncology Group E4599 study by Sandler and colleagues 3 validated VEGF as a target for lung cancer therapy and showed a clear and meaningful survival advantage with bevacizumab plus chemotherapy vs. chemotherapy alone. Bevacizumab has changed the way oncologists approach metastatic lung cancer, but many feel that the Sandler et al. study raised more questions than it answered. For example, how important is maintenance therapy with single-agent bevacizumab? We will need additional trials to determine the optimal duration of treatment. Most concerning is how oncologists can apply the lessons learned from E4599 to patients who have squamous cell carcinoma, brain metastasis, or the need for anticoagulation—all of which were key exclusion criteria. Currently, patients with these characteristics are not offered bevacizumab unless enrolled in a clinical trial. If we are to realize the optimal benefit of this agent, these important groups of patients will have tobe addressed.
What makes this such an exciting time in lung cancer therapy is that, as seen in Table 1, bevacizumab is likely to be just the first of many anti-VEGF treatments to help patients with lung cancer. Small molecule tyrosine kinase inhibitors (TKIs) of VEGF promise several advantages to a monoclonal antibody strategy. The smaller size of TKIs allows potential activity in the central nervous system, and their mechanisms of action might explain their single-agent activity. As a single agent, sunitinib has shown a response rate comparable to that of single-agent erlotinib or gefitinib.4 AZD2171 is a highlypotent and fairly specific oral inhibitor of VEGF 5 and is currently under phase II/III investigation in lung cancer in a trial led by the National Cancer Institute-Canada. Sorafenib, technically a multikinase inhibitor, derives much of its antitumor activity from VEGF interaction and has shown some single-agent promise.6 Investigations of sorafenib have shown an encouraging time to tumor progression, as well as characteristic tumor "cavitation," which is very hard to quantify as a tumor response, but indicates anti- tumor activity.7 Both of these agents hold great promise in lung cancer, and their combination with chemotherapy is compelling. In addition, vascular-targeting agents (e.g., VEGF-trap) also seem promising.
Although paradigm-changing results have been obtained in trials of anti-VEGF agents, the importance of VEGF as a target in tumor biology and the antitumor properties of these drugs remain areas of intense discussion. In this monograph, we review potential mechanisms of action of anti-VEGF drugs and their implications for choosing novel antivascular combinations in the future. A key controversy is the phenomenon of "tumor vascular normalization," suggested by Jain and colleagues.8 Their elegant work may help to explain the potent synergy seen when chemotherapy is used with bevacizumab. Alternative theories suggest that inhibiting VEGF signaling can lead directly to cellular apoptosis, which may explain the single-agent activity seen with oral TKIs. This area of research will enhance our understanding of how these drugs should be combined with each other and how agents that target other key pathways, such as EGFR and ras, are integrated with anti-VEGF agents.
Ultimately, progress against lung cancer is likely to come not from blocking a single pathway, but rather from a multitargeted approach. The latter approach is being pursued in studies of bevacizumab and erlotinib (now in phase III) and in the development of agents with multiple targets, such as ZD6474, that demonstrate potent anti-VEGF kinase action and modest anti-EGFR properties.9 Despite only modest single-agent activity, ZD6474 met its key time to progression endpoint in a critical randomized phase II study when administered with docetaxel in previously treated patients with lung cancer.10 The results have led to a large phase III study examining its role in the second- and third-line treatment of patients with advanced lung cancer.
Doctors will face significant toxicity concerns with all of these drugs. Hypertension is a class-related effect of VEGF inhibitors and has been seen with all of the above- mentioned drugs. Fortunately, management with oral antihypertensives is usually direct and effective. Increased vascular events, both arterial and venous, have been seen with bevacizumab in patients with colon cancer and need to be considered in patients with lung cancer. Bleeding in the form of hemoptysis is the most worrisome toxicity seen with bevacizumab in patients with lung cancer. We have much less experience with the small molecule inhibitors, but toxicity is also a key area of concern in their development.
Several important questions remain to be answered: Will patients who are currently ineligible for bevacizumab (i.e., those with squamous cell histology, brain metastasis, or the need for anticoagulation) be able to be treated safely? Will the small molecule VEGF TKIs improve survival when combined with chemotherapy? Will they offer a safety advantage compared with bevacizumab? And will other vascular-targeting antibodies prove superior to bevacizumab?