The concept of angiogenesis as a potential therapeutic target in cancer therapy dates back to 1971, when Dr. Judah Folkman first published an article in the New England Journal of Medicine describing the theory. Since then, a small number of agents have been noted to possess properties that discourage new blood vessel formation during tumor development, such as thalidomide and interferon, but it was not until the discovery of vascular endothelial growth factor (VEGF) that the expansion of antiangiogenic therapies occurred. In June 2004, bevacizumab (Avastin) was approved for use in metastatic colorectal cancer, and over just the past 3 years, this drug and others in its class have been found efficacious in non–small-cell lung cancer, renal cell carcinoma, and breast cancer.
Colorectal cancer, the third most commonly diagnosed cancer in the United States for both men and women, expresses VEGF approximately 50% of the time, and studies have indicated that this expression negatively impacts the likelihood of metastasis and survival. One of the first trials in this patient population was a randomized phase II study adding bevacizumab to fluorouracil (5-FU) and leucovorin (FU/LV), vs FU/LV alone, which was the standard of care at the time. A total of 104 previously untreated patients with metastatic colorectal cancer were assigned to one of three groups: FU/LV alone, or bevacizumab at either 5 mg/kg or 10 mg/kg every 2 weeks with FU/LV weekly, each for 6 weeks of an 8-week cycle. The response rate in the 5-mg/kg bevacizumab arm was significantly improved vs FU/LV (40% vs 17%, P < .029) and the median time to progression was 3.8 months longer in this group compared to the controls as well (P < .005).
Interestingly, the patients randomized to receive "high-dose" bevacizumab in this study did not achieve statistically significant improvements in response rate, progression-free, or overall survival, and the reason for this finding was unclear. One possibility noted by the authors relates to a theory that the lower dose of bevacizumab, instead of completely obliterating the tumor's neovasculature, might actually have promoted temporary vessel "normalization," permitting better delivery of chemotherapy agents into the tumor itself, thereby impacting response. Further characterization of the mechanisms of action of varying doses of antiangiogenic agents, alone and in combination with traditional chemotherapeutic agents, over both the short and long term, is warranted to more completely explore and subsequently exploit these features.
As the chemotherapeutic standard of care for metastatic colorectal cancer advanced to incorporate oxaliplatin (Eloxatin) and the FOLFOX (leucovorin/5-FU/oxaliplatin) family of regimens, an Eastern Cooperative Oncology Group (ECOG) randomized phase III trial was put forth to examine outcomes in previously treated patients receiving FOLFOX4 alone, bevacizumab 10 mg/kg alone, or the two in combination every 14 days. Overall response rates in the combination group were 22.7%, vs 8.6% and 3.3% in the FOLFOX4 alone and bevacizumab alone arms, respectively (P < .0001). Median survival improved by approximately 2 months in those receiving the combination (12.9 vs 10.8 months for those receiving FOLFOX4 alone, P < .0011) and these positive data contributed to the eventual US Food and Drug Administration (FDA)-approved indication in this population.
NON–SMALL-CELL LUNG CANCER
Lung cancer is the number 1 cause of cancer death among male and female Americans. Non–small-cell lung cancer (NSCLC), which includes predominantly the cellular subtypes adenocarcinoma, squamous cell, and large-cell carcinoma, comprise more than 75% of the histology commonly presented; approximately 70% of these patients present with surgically unresectable disease.
One of the first studies of bevacizumab in NSCLC illustrated the potential benefit of the antiangiogenic drug class in combination with a traditional taxane/platinum doublet regimen, but also revealed a significant caution. A phase II trial of paclitaxel and carboplatin was conducted with or without bevacizumab in patients with advanced or recurrent NSCLC, randomizing 99 patients to one of three groups: paclitaxel 200 mg/m2 and carboplatin at an area under the concentration-time curve (AUC) of 6, or the doublet plus either 7.5 mg/kg or 15 mg/kg of bevacizumab once every 3 weeks.
The results clearly indicated a clinical benefit to the 15 mg/kg bevacizumab plus paclitaxel/carboplatin arm as compared to chemotherapy alone, with a higher response rate (31.5% vs 18.8%), longer median time to disease progression (7.4 vs 4.2 mo), and what was described as a "modest" but not statistically significant improvement in survival (17.7 vs 14.9 mo). However, despite excluding patients with a recent history of surgery or biopsy, six patients experienced a major bleeding complication, described as hemoptysis or hematemesis, resulting in four patient deaths. All six patients had tumors that were located in the central bronchus, adjacent to major blood vessels, and five either began the study with or developed cavitations or necrosis of the tumors during treatment. Four of the six patients involved had tumors of squamous cell histology, prompting the study authors to launch a subsequent study excluding patients with this tumor histology.
Through collaboration with other ECOG investigators, 878 patients with NSCLC were accrued and again randomized to receive paclitaxel 200 mg/m2 and carboplatin at an AUC of 6 alone or in combination with bevacizumab 15 mg/kg, the most active dose level noted in the prior trial. Patients with squamous cell histology, history of hemoptysis of greater than one-half teaspoon, or central nervous system metastases (to reduce risk of intracranial hemorrhage, which had not been fully evaluated in the earlier trial) were excluded. Response rates and survival in this study were again statistically and clinically significant, prompting FDA approval for bevacizumab in this indication, as well as a recommendation by the National Comprehensive Cancer Network to utilize bevacizumab plus chemotherapy as first-line therapy in advanced or metastatic nonsquamous NSCLC.
Other antiangiogenic agents are under active study in NSCLC, including sorafenib (Nexavar) and sunitinib (Sutent), due in large part to their multikinase inhibitory properties, but also related to their ease of oral administration and overall good tolerability profile. Two recent reports from a special session at the 2006 annual meeting of the American Society of Clinical Oncology (ASCO) highlighted single-agent activity for both of these drugs in this patient population, an important precursor to combined therapy trials.
The 2006 ASCO Clinical Science Symposium on Angiogenesis Inhibitors in Lung Cancer included presentations of preliminary data on two phase II trials with oral antiangiogenic agents. In the first, 64 patients with advanced NSCLC were recruited to receive sunitinib 50 mg daily in a 4-weeks-on, 2-weeks- off pattern. This population comprised all histologic subtypes, with 22% of the patients diagnosed with squamous cell carcinoma.
At the time of the symposium presentation, the majority of the patients had received fewer than five cycles of the regimen, but were tolerating therapy well overall. There were 6 confirmed partial responses, and 12 patients with stable disease. This study illustrated the potential of this drug in an advanced disease population as a single agent; it was well tolerated even by those patients who would otherwise have been excluded from bevacizumab-based antiangiogenic therapy.
The second study focused not only on the clinical outcomes related to continuous daily dosing of sorafenib 400 mg twice daily, but on identifying a number of protein biomarkers in the patient's serum that might be predictive for response to this type of therapy. While there were no confirmed partial responses seen in this study, 29% of patients experienced some tumor shrinkage. Importantly, 10 proteins were identified that correlated with tumor shrinkage and time to progression; continued study of these markers may provide a better prognostic tool to judge potential signs of disease response or resistance to antiangiogenic therapies much earlier as compared to traditional radiologic imaging.
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