Targeting Angiogenesis in Solid Tumors

A growing number of novel antiangiogenic agents are entering clinical trials to study their clinical safety and efficacy. A few, such as bevacizumab (Avastin), sorafenib (Nexavar), and sunitinib (Sutent), have received US Food and Drug Administration approval and are already in widespread clinical use. As knowledge about the intricacies of intracellular signaling within multiple tumor types expands, agents with the capacity to impact these pathways are being incorporated into additional clinical trials alone and in combination with other targeted and/or traditional antineoplastic agents. Early clinical trials have focused on highly vascular tumor types, as well as those known to significantly overexpress the VEGF (vascular endothelial growth factor) receptor family. This article aims to review the status of antiangiogenic therapy in selected tumor types and discuss areas for further research.

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.[1] 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

Colorectal cancer, the third most commonly diagnosed cancer in the United States for both men and women,[2] expresses VEGF approximately 50% of the time, and studies have indicated that this expression negatively impacts the likelihood of metastasis and survival.[3] 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.[4] 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.[5] 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.[6] 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.[7]

NON–SMALL-CELL LUNG CANCER

Lung cancer is the number 1 cause of cancer death among male and female Americans.[1] 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.[8]

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.[9]

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.[10] 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[11] 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.[12] 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[13] 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.

RENAL CELL CARCINOMA

Prior to the advent of antiangiogenic agents, first-line standard of care regimens for metastatic renal cell carcinoma (RCC) generally included interleukin-2 or interferon alfa, and historically produced response rates of about 15%.[14] Yang and colleagues[15] were among the first to demonstrate clinically significant efficacy of an antiangiogenic agent, bevacizumab, in this patient population, spurring intense interest in this drug class. However, the duration of progression-free survival in that study-4.8 months in the bevacizumab arm vs 2.5 months in those receiving placebo (P < .001)-was relatively short-lived, indicating further study was necessary to produce more sustainable improvements.

In an attempt to model the traditional concept of combining several agents that demonstrate clinical activity, yet have differing mechanisms of action, a study of bevacizumab combined with erlotinib (Tarceva, an epidermal growth factor [EGF] receptor tyrosine kinase inhibitor) was undertaken in January 2003 in 63 patients with metastatic clear cell RCC.[16] Preclinical evidence of a relationship between the VEGF and EGF pathways led to this combination, with a rationale that blockade of both pathways simultaneously might lead to improved outcomes over single-pathway inhibition. There was a 25% objective response rate noted, with 1 complete response, 14 partial responses, and 36 patients with stable disease. At the time of manuscript publication in November 2005, the 12- and 18-month survival rates were 78% and 60%, respectively.

In 2006, both sunitinib and sorafenib were approved by the FDA for advanced RCC due to their evidence of activity as single agents.[17,18] Even as the initial approvals for these agents were sought from the FDA, additional randomized trials were being launched to further characterize the activity of these agents, and to contrast response vs available therapies.

In a randomized, double-blind phase III trial in patients with advanced clear-cell renal cell carcinoma, 903 patients whose disease was resistant to other therapies received either sorafenib 400 mg twice daily or placebo.[18] Accrual for this study began in November 2003 and continued until March 2005. At the first interim data analysis in January 2005, median progression-free survival was 5.5 months in patients receiving sorafenib, vs 2.8 months in the placebo group (P < .01). Due to this statistically and clinically significant difference, patients assigned to the placebo group were allowed to cross over to receive sorafenib. In an analysis of overall survival in November 2005, median overall survival, the primary endpoint, was 19.3 months in the sorafenib group vs 15.9 months for those receiving placebo (P < .02).

Due to the strength of the earlier response data for this drug class, and the known low historical responses to cytokine therapies, interest in identifying a more effective initial therapy for patients presenting with newly diagnosed, previously untreated metastatic RCC led to a randomized phase III trial to compare sunitinib with the current standard of care for the time: standard interferon alfa therapy.[19] Sunitinib 50 mg, given by mouth once daily for 6 weeks followed by a 2-week rest, was compared with 9 million units of interferon alfa as a subcutaneous injection three times per week. Median progression-free survival in the sunitinib group was 11 months vs 5 months in the group who received interferon alfa (P < .001), and the sunitinib group's objective response rate was 31% vs 6% in the control group (P < .001).

These study results collectively represent the advent of a new standard of care for patients with metastatic renal cell carcinoma. Further advances may be seen as researchers study and refine the optimal combinations of multitargeted regimens in this tumor types. These advances represent significant hope for a disease previously considered to convey a uniformly dismal prognosis.

BREAST CANCER

Another area of intense clinical interest to test antiangiogenic agents is in patients with breast cancer. An early study of capecitabine (Xeloda) alone vs in combination with bevacizumab in patients with metastatic breast cancer refractory to other therapies revealed less than expected results in terms of the trial's primary end point-time to disease progression.[20] However, there was a significant benefit in response rates in the combination arm (19.8% vs 9.1% P < .001).

A similar study conducted in newly diagnosed, treatment-naive metastatic breast cancer was successful in illustrating a significant improvement in progression-free survival.[21] This finding suggests that if utilized earlier in the course of disease, when tumor cells have not yet become resistant to previous treatment mechanisms, the combination of capecitabine 1,000 mg/m² twice daily for 15 days and bevacizumab 15 mg/kg on day 1 of each 21-day cycle may be more active than when employed as a second- or third-line regimen.

Another important trial report in this population relates to the outcomes of the phase III ECOG 2100 study, where 722 patients who had received no prior therapy for their locally advanced or metastatic breast cancer were randomized to paclitaxel alone vs paclitaxel plus bevacizumab.[22] Paclitaxel was administered at 90 mg/m² on days 1, 8, and 15 of each 28-day cycle, and in the combination arm, patients received paclitaxel as above concurrent with bevacizumab 10 mg/kg on days 1 and 15. Patients continued on therapy until progression or unacceptable toxicity.

Patients in the combination arm experienced significantly higher response rates (28.2% vs 14.2% in the paclitaxel alone arm, P < .0001) as well as a longer progression-free survival time (10.97 vs 6.11 mo, P < .001). Overall survival appeared to be improved in earlier analyses; however, a recent independent review revealed that this parameter no longer reached significance (P < .14).[23]

CONCLUSION

In summary, there is tremendous excitement related to the broad applicability of the antiangiogenic drug class. In November 2007, the FDA granted approval for sorafenib to treat inoperable hepatocellular carcinoma, and current trials are ongoing in ovarian, pancreatic, and thyroid cancers. Additional agents under investigation include pazopanib, motesanib, vatalanib, vandetanib, and many others not yet named. Translational research efforts over the next decade will shed new light on the previously uncharacterized inner drivers of cancer cells, and the optimal treatment agents and combinations to dramatically improve survival. Our challenge as nurses will be to continually expand our knowledge base, in order to be able to safely administer and educate patients and family about these new agents.

References:

1. Folkman J: Tumor antiangiogenesis: Therapeutic implications. N Engl J Med 285(21):1182-1186, 1971.

2. American Cancer Society: Cancer Facts & Figures. Accessed November 8, 2007, from http://www.cancer.org.

3. Lee JC, Chow NH, Wang ST, et al: Prognostic value of vascular endothelial growth factor expression in colorectal cancer patients. Eur J Cancer 36:748-753, 2000.

4. Kabbinavar F, Hurwitz H, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leuocovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 21:60-65, 2003.

5. Jain RK: Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy. Science 307:58-62, 2005.

6. Giantonio BJ, Catalano PJ, Meropol NJ, et al: Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 25:1539-1544, 2007.

7. Avastin Prescribing Information: Genentech, October 2006.

8. Carney DN, Hansen HH: Non-small-cell lung cancer: Stalemate or progress? N Engl J Med 343:1261-1262, 2000.

9. Johnson DH, Fehrenbacher L, Novotny W, et al: Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced pr metastatic non-small cell lung cancer. J Clin Oncol 22(11):2184-2191, 2004.

10. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 355(24):2542-2550, 2006.

11. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology, Non-Small Cell Lung Cancer, v2.2008. Accessed on November 9, 2007, from www.nccn.org.

12. Socinski MA, Novello S, Sanchez JM: Efficacy and safety of sunitinib in previously treated, advanced non-small cell lung cancer (NSCLC): Preliminary results of a multicenter phase II trial (abstract 7001). J Clin Oncol 24(suppl 18S):364s, 2006.

13. Gatzemeier U, Blumenschein G, Fosella F: Phase II trial of single-agent sorafenib in patients with advanced NSCLC (abstract 7002). J Clin Oncol 24(suppl 18S):364s, 2006.

14. Coppin C, Porzsolt F, Awa A, et al: Cochrane Database Syst Rev (1):CD001425, Jan 25, 2005.

15. Yang JC, Haworth L, Sherry RM et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003.

16. Hainsworth JD, Sosman JA, Spigel DR, et al: Treatment of metastatic renal cell carcinoma with a combination of bevacizumab and erlotinib. J Clin Oncol 23:7889-7896, 2005.

17. Motzer RJ, Rini BI, Bukowski RM, et al: Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295:2516-2124, 2006.

18. Escudier B, Eisen T, Stadler W, et al: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125-134, 2007.

19. Motzer RJ, Hutson TE, Tomcak P, et al: Sunitinib versus interferon alfa in metastatic renal cell carcinoma. N Engl J Med 356(2):115-124, 2007.

20. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23(4):792-799, 2005.

21. Sledge G, Miller K, Moisa C, et al: Safety and efficacy of capecitabine (C) and bevacizumab (B) as first-line in metastatic breast cancer (abstract 1013). J Clin Oncol 25(suppl 18S):35s, 2007.

22. Miller KD, Wang M, Gralow J, et al: A randomized phase III trial of paclitaxel vs paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: A trial coordinated by the ECOG (E2100) (abstract 3). Breast Cancer Res Treat 94(suppl 1):S6, 2005.

23. Genentech press release, 12/5/07. http://www.gene.com/gene/news/press-releases/display.do?method=detail&id=10927