Bevacizumab has become a standard of care for first line therapy in a subgroup of advanced NSCLC patients. With the advent of other effective therapies in bevacizumab-eligible patients and the ongoing development and testing of biomarkers for cytotoxic agents, it remains to be seen whether continued use of bevacizumab will be justified in the absence of predictive biomarkers.
Lung cancer is the leading cause of cancer death worldwide, responsible for over one million deaths annually. In the United States in 2010, it is estimated that 219,440 cases will be diagnosed and 159,390 deaths will be attributable to the disease. In advanced non–small-cell lung cancer (NSCLC), survival has plateaued around 12 months with standard platinum doublet-based regimens.
In this issue of ONCOLOGY, Gridelli and Rossi provide a comprehensive review of clinical data and controversy surrounding the use of monoclonal antibodies in advanced NSCLC. To date, the introduction of monoclonal antibodies (mAbs) that target the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) pathways have marginally increased survival in the populations deemed eligible for these agents. Given the toxicity and immense economical costs of these novel agents, however, the challenge remains to find the appropriate patient population that may gain a substantial and meaningful benefit from them.
The anti-VEGF recombinant humanized mAb, bevacizumab, was first approved by the Food and Drug Administration in 2004 for metastatic colorectal cancer and, since that time, has gained indications for metastatic breast cancer, lung cancer, renal cell carcinoma and glioblastoma. Thus far, an overall survival benefit has only been observed in metastatic colorectal cancer and lung cancer; approval for metastatic breast cancer is currently under review by the FDA. With regard to NSCLC, the Eastern Cooperative Oncology Group (ECOG) 4599 study, found a two-month increase in overall survival and a 1.7-month benefit in progression-free survival, which enabled bevacizumab to gain approval for use in patients with advanced NSCLC with non-squamous histologies and no evidence of hemoptysis. In addition, follow-up studies have suggested that treated brain metastases and use of anticoagulation may not be absolute contraindications to the use of bevacizumab with chemotherapy.[4,5] Disappointingly, a second large phase III trial, the AVAiL (AVAstin in Lung) trial failed to show an overall survival benefit for the addition of bevacizumab to chemotherapy, but did show a modest but statistically significant difference in PFS of about 2.5 weeks.[6,7] One particularly interesting hypothesis that has been proposed to explain the lack of OS advantage and smaller PFS in the AVAiL study was the differing chemotherapy regimens used in the two studies. In E4599, carboplatin and paclitaxel were combined with bevacizumab, while in the AVAiL trial, cisplatin and gemcitabine were used. There is preclinical data that suggests that taxanes may be synergistic with bevacizumab (because of their ability to act as vascular disrupting agents (VDAs)) while gemcitabine is not. If true, this raises the question of whether bevacizumab will be effective with other platinum-based regimens-most notably platinum-pemetrexed doublet, which is a commonly used regimen in adenocarcinomas. Although the safety of the carboplatin, pemetrexed, and bevacizumab combination has been reported, efficacy data on this combination will hopefully be provided from current phase III trials that are comparing this combination to carboplatin-paclitaxel. Whether bevacizumab will be as effective with non-taxane-containing regimens remains an open question.
Given the estimated cost (about $100,000 for a treatment course of bevacizumab), the infrequent but serious toxicities (hemorrhage and venous/arterial thromboembolism); and the modest survival benefit observed, predictive clinical and/or biological markers are clearly needed. Interestingly, a retrospective analysis of E4599 did find that patients with adenocarcinomas appeared to benefit more from bevacizumab than did patients with other eligible histologies, with a median survival 14.2 months vs 10.3 months  and a similar effect was seen for PFS but not OS in the AVAil Trial.[6,7] The development of hypertension during the first cycle of therapy was also associated with a better PFS and OS in the bevacizumab group. However, this represented only 6.2 % of patients, and patients who did not develop hypertension also benefited from the therapy.
In an attempt to identify predictive biomarkers, the E4599 investigators examined VEGF, basic fibroblast growth factor (bFGF), soluble intercellular adhesion molecule-1 (ICAM) and E-selectin in pretreatment plasma and did not find a correlation between any of these markers and survival. Efforts to develop predictive biomarkers have been complicated by the realization that response to anti-angiogenic therapy may depend not only on tumor-derived features, but on host factors (serum levels of VEGF and other angiogenic factors, degree of mobilization of proangiogenic bone marrow-derived cells, and tumor microenvironment and/or stromal cell activation) as well. Work from Schneider and colleagues looked at germline variability by examining single nucleotide polymorphisms (SNPs) in the VEGF locus from patients treated in the E2100 trial, which tested bevacizumab in combination with paclitaxel in patients with metastatic breast cancer. In their study, an exploratory analysis revealed at least one polymorphism that correlated with increased overall survival in bevacizumab-treated patients. Interestingly, a limited retrospective analysis was performed on 133 samples from E4599. This analysis, performed by Zhang et al, looked for SNPs that would be predictive of response, PFS and OS. Zhang and his colleagues were able to identify several candidate SNPs that were involved with the angiogenesis pathway and correlated with increased OS (VEGF G-634C, ICAM1 T469C) and for PFS (ICAM1 T469C, EGF A-61G). Interestingly, although in some cases the identical SNPs were examined in patients from E2100 (metastatic breast) and E4599 (metastatic lung), different SNPs within the same gene (VEGF) appeared to be predictive for increased overall survival after treatment with bevacizumab in the two studies. Clearly these findings need to be validated in a larger, prospective fashion but this suggests that potential biomarkers may exist to guide our use of bevacizumab therapy.
Angiogenesis is required for tumorigenesis in a variety of solid tumor types including NSCLC. The monoclonal antibody, bevacizumab, as well as several small tyrosine kinase inhibitors and other therapeutic strategies have thus far been tested in the treatment of NSCLC. To date, however, only marginal benefit has been seen from the inhibition of this critical pathway. Furthermore, despite over a decade of clinical investigation and use, it is still not clear which patients benefit most from bevacizumab; what the optimal chemotherapy regimen is; or the optimal duration of bevacizumab treatment that should be administered. Clinical trials are now underway that will hopefully address at least some of these questions. Bevacizumab has become a standard of care for first line therapy in a subgroup of advanced NSCLC patients. With the advent of other effective therapies in bevacizumab-eligible patients and the ongoing development and testing of biomarkers for cytotoxic agents, it remains to be seen whether continued use of bevacizumab will be justified in the absence of predictive biomarkers.
Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin. 2010; 60(5):277-300.
2. Van Meter ME, Kim ES. Bevacizumab: current updates in treatment. Curr Opin Oncol. 2010; 22(6):586-91.
3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer. N Engl J Med. 2006;355(24):2542-50.
4. Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non–small-cell lung cancer and brain metastases. J Clin Oncol. 2009;27(31):5255-61.
5. Crino L, Dansin E, Garrido P, et al. Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non–small-cell lung cancer (SAiL, MO19390): a phase 4 study. Lancet Oncol. 2010;11(8):733-40.
6. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non–small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol. 2010;21(9):1804-9.
7. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer: AVAil. J Clin Oncol. 2009;27(8):1227-34.
8. Shaked Y, Henke E, Roodhart JM, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 2008;14(3):263-73.
9. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-51.
10. Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for nonsquamous non–small-cell lung cancer. J Clin Oncol. 2009;27(20):3284-9.
11. Fojo T, Grady C. How much is life worth: cetuximab, non–small-cell lung cancer, and the $440 billion question. J Natl Cancer Inst. 2009;101(15):1044-8.
12. Sandler A, Yi J, Dahlberg S, et al. Treatment outcomes by tumor histology in Eastern Cooperative Group Study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non–small-cell lung cancer. J Thorac Oncol, 2010;5(9):1416-23.
13. Dahlberg SE, Sandler AB, Brahmer JR, et al. Clinical course of advanced non–small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol. 2010;28(6):949-54.
14. Dowlati A, Gray R, Sandler AB, et al. Cell adhesion molecules, vascular endothelial growth factor, and basic fibroblast growth factor in patients with non–small-cell lung cancer treated with chemotherapy with or without bevacizumab--an Eastern Cooperative Oncology Group Study. Clin Cancer Res. 2008;14(5):1407-12.
15. Ebos JML, Lee CR, Kerbel RS. Tumor and Host-Mediated Pathways of Resistence and Disease Progression in Response to Antiangiogenic Therapy. Clin Cancer Res. 2009;15(16):5020-25.
16. Schneider BP, Wang M, Radovich M, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol. 2008;26(28):4672-8.
17. Zhang W, Dahlberg, SE,. Yang, D, et al. Genetic variants in angiogenesis pathway associated with clinical outcome in NSCLC patients (pts) treated with bevacizumab in combination with carboplatin and paclitaxel: subsetpharmacogenetic analysis of ECOG 4599 [abstract #8032]. J Clin Oncol. 2009;27 (15 suppl).
18. Ramalingam SS, Belani CP. Antiangiogenic agents in the treatment of non–small-cell lung cancer: reality and hope. Curr Opin Oncol. 2010;22(2):79-85.
19. Ceppi P, Papotti M, Scagliotti G. New strategies for targeting the therapy of NSCLC: the role of ERCC1 and TS. Adv Med Sci. 2010;55(1):22-5.