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Antibodies to Vascular Endothelial Growth Factor in Non-small Cell Lung Cancer

2008; Elsevier BV; Volume: 3; Issue: 6 Linguagem: Inglês

10.1097/jto.0b013e318174e993

1556-1380

Heather A. Wakelee,

PI3K/AKT/mTOR signaling in cancer

Angiogenesis, formation of new vasculature, is critical to cancer growth. Agents that block angiogenesis, in particular bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor, the key ligand in angiogenesis, have become an important option for many patients with non-small cell lung cancer (NSCLC). Activity was first demonstrated in Eastern Cooperative Oncology Group E4599, a large phase 3 trial that randomized patients with newly diagnosed, nonsquamous NSCLC to receive carboplatin/paclitaxel with or without bevacizumab at 15 mg/kg every 3 weeks. The study demonstrated significant improvements in response rate, progression-free survival, and overall survival with the addition of bevacizumab. Median overall survival improved from 10.3 to 12.3 months (p = 0.003). Significant toxic effects, including fatal hemoptysis, however, resulted in 15 treatment-related deaths in the bevacizumab arm. The beneficial results were recently confirmed in the European Avastin in Lung Cancer B017704 (AVAiL) trial. In AVAiL, patients with newly diagnosed nonsquamous NSCLC were randomized to receive cisplatin/gemcitabine with or without bevacizumab at doses of either 7.5 or 15 mg/kg every 3 weeks. Both doses resulted in statistically significant improvements in response rate and progression-free survival, but overall survival results have yet to be presented. Based on these encouraging results, the drug is now being studied in earlier-stage disease as neoadjuvant or adjuvant therapy and in locally advanced NSCLC. Exploration of the safety and efficacy of the drug in combination with other chemotherapeutics and targeted agents, and in previously excluded patient populations such as those with brain metastases, is also ongoing. Angiogenesis, formation of new vasculature, is critical to cancer growth. Agents that block angiogenesis, in particular bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor, the key ligand in angiogenesis, have become an important option for many patients with non-small cell lung cancer (NSCLC). Activity was first demonstrated in Eastern Cooperative Oncology Group E4599, a large phase 3 trial that randomized patients with newly diagnosed, nonsquamous NSCLC to receive carboplatin/paclitaxel with or without bevacizumab at 15 mg/kg every 3 weeks. The study demonstrated significant improvements in response rate, progression-free survival, and overall survival with the addition of bevacizumab. Median overall survival improved from 10.3 to 12.3 months (p = 0.003). Significant toxic effects, including fatal hemoptysis, however, resulted in 15 treatment-related deaths in the bevacizumab arm. The beneficial results were recently confirmed in the European Avastin in Lung Cancer B017704 (AVAiL) trial. In AVAiL, patients with newly diagnosed nonsquamous NSCLC were randomized to receive cisplatin/gemcitabine with or without bevacizumab at doses of either 7.5 or 15 mg/kg every 3 weeks. Both doses resulted in statistically significant improvements in response rate and progression-free survival, but overall survival results have yet to be presented. Based on these encouraging results, the drug is now being studied in earlier-stage disease as neoadjuvant or adjuvant therapy and in locally advanced NSCLC. Exploration of the safety and efficacy of the drug in combination with other chemotherapeutics and targeted agents, and in previously excluded patient populations such as those with brain metastases, is also ongoing. Despite dozens of phase 3 trials of novel targeted agents combined with first-line chemotherapy for advanced-stage non-small cell lung cancer (NSCLC), the only positive ones to date have been with bevacizumab (Avastin; Genentech, South San Francisco, CA). Bevacizumab is a recombinant humanized monoclonal antibody against the vascular endothelial growth factor (VEGF),1Presta LG Chen H O'Connor SJ et al.Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.Cancer Res. 1997; 57: 4599-4953Google Scholar a key ligand in the signaling cascade that leads to vascular formation. The success of an antiangiogenesis drug is not surprising given the dependence of solid tumor growth and metastases on neovascularization. Folkman first described the importance of tumor neoangiogenesis in tumor growth more than 30 years ago and hypothesized that inhibition of this pathway could potentially treat cancer.2Folkman J Tumor angiogenesis: therapeutic implications.N Engl J Med. 1971; 285: 1182-1186Crossref PubMed Scopus (219) Google Scholar The selectivity of VEGF inhibition was predicted based on the exceptionally high levels of VEGF found in many tumors and the uniqueness of the tumor vasculature.3Kolch W Martiny-Baron G Kieser A et al.Regulation of the expression of the VEGF/VPS and its receptors: tumor angiogenesis.Breast Cancer Res Treat. 1995; 36: 139-155Crossref PubMed Scopus (135) Google Scholar, 4Breier G Risau W The role of vascular endothelial growth factor in blood vessel.Trends Cell Biol. 1996; 6: 454-456Abstract Full Text PDF PubMed Scopus (146) Google Scholar Promising preclinical work with a VEGF antibody in a murine model5Ferrara N Davis-Smyth T The biology of vascular endothelial growth factor.Endocr Rev. 1997; 18: 4-25Crossref PubMed Scopus (3667) Google Scholar, 6Kim KJ Li B Winer J et al.Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo.Nature. 1993; 362: 841-844Crossref PubMed Scopus (3342) Google Scholar led to the development of the humanized version, bevacizumab, and in 2003 the results of a randomized phase 3 trial demonstrating improved survival with the addition of the drug to colorectal cancer therapy was presented.7Hurwitz H Fehrenbacher L Novotny W et al.Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer.N Engl J Med. 2004; 350: 2335-2342Crossref PubMed Scopus (9167) Google Scholar The pivotal trial that demonstrated activity of bevacizumab in the treatment of advanced-stage NSCLC was E4599. The study randomized patients with previously untreated advanced-stage NSCLC to receive bevacizumab at 15 mg/kg every 3 weeks or no additional therapy in combination with standard carboplatin and paclitaxel for six cycles.8Sandler 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: 2542-2550Crossref PubMed Scopus (5232) Google Scholar Bevacizumab was continued until disease progression based on promising disease stabilization seen in initial phase 2 development.9Johnson DH Fehrenbacher L Novotny WF et al.Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer.J Clin Oncol. 2004; 22: 2184-2191Crossref PubMed Scopus (1819) Google Scholar A total of 878 patients were entered into E4599, and clear improvements in response rate, progression-free survival (PFS), and overall survival were demonstrated in the bevacizumab arm. To minimize bleeding risk, including fatal hemoptysis that had been seen in the randomized phase 2 trial, patients with squamous cell histologic findings, brain metastasis, anticoagulant use, or history of gross hemoptysis were excluded. Despite the precautions, 15 treatment-related deaths occurred in the bevacizumab arm, five due to hemoptysis, compared with only two treatment-related deaths in the control arm. Common toxic effects with bevacizumab include hypertension, proteinuria, mild epistaxis, and worsening neutropenia. Rare and potentially fatal complications include bleeding, particularly hemoptysis, a reversible posterior leukoencephalopathy syndrome, fistula formation, and surgical wound dehiscence. Despite these toxic effects, the clinical benefit demonstrated in E4599 is significant, especially when one considers the number of negative trials with other targeted agents in this patient population. In October 2006, based on the results of this trial, bevacizumab, given in combination with carboplatin and paclitaxel, was granted a labeling extension by the Food and Drug Administration for the initial treatment of advanced-stage NSCLC. The benefit of bevacizumab in advanced-stage NSCLC has now been confirmed in a second large randomized phase 3 trial, Avastin in Lung Cancer B017704 (AVAiL), presented at the American Society of Clinical Oncology (ASCO) meeting in June 2007.10Manegold C von Pawel J Zatloukal P et al.Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naive patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): B017704 (abstract LBA7514).J Clin Oncol. 2007; 25: 967sGoogle Scholar The trial was also limited to those patients with untreated advanced-stage, nonsquamous NSCLC without brain metastases, without invasion of tumor into major vessels (although tumor in a central location was acceptable) and not receiving anticoagulation. In total, 1043 patients were enrolled in this study and randomized to one of three arms. All patients received cisplatin and gemcitabine, and were randomized to receive the chemotherapy with placebo, bevacizumab at 7.5 mg/kg, or bevacizumab at 15 mg/kg (the dose used in E4599). Patients received up to six cycles of chemotherapy plus bevacizumab or placebo, which were then continued until disease progression. The primary endpoint was PFS with disease evaluation every three cycles (9 weeks). Both bevacizumab arms met the primary endpoint of improved PFS compared with placebo. The hazard ratio for PFS was 0.75 (95% confidence interval, 0.62–0.91; p = 0.003) at the 7.5 mg/kg dose and 0.82 (95% confidence interval, 0.68–0.98; p = 0.03) at the 15 mg/kg dose. Response rates were also significantly improved with bevacizumab. Overall survival data have not yet been presented. The toxicity data from the study were also reassuring. Serious adverse events (including those leading to death) did not differ between the placebo arm and the 7.5 mg/kg dose of bevacizumab arm but were higher with the 15 mg/kg dose of bevacizumab arm (1% higher death rate from serious adverse events). Most of these fatalities were from hemoptysis. Central tumor location and use of therapeutic anticoagulation (allowed if started after patient was on trial) did not seem to increase bleeding risk. The incidences of neutropenia, vomiting, hypertension, and epistaxis were also higher with the addition of either dose of bevacizumab. Ischemic events (including arterial thrombosis) and venous thromboembolic events were not significantly changed with the bevacizumab though. Multiple other chemotherapeutic agents and targeted therapies are also being combined with bevacizumab. Posters given at the ASCO annual meeting in June 2007 included three phase 2 studies of bevacizumab with different platinum doublets. Dr. Patel presented preliminary results on 39 patients treated with bevacizumab at the standard 15 mg/kg dose in combination with carboplatin and pemetrexed, with an intriguing 55% response rate but some instances of bowel perforation in patients with diverticular disease.11Patel JD Hensing TA Villafor V et al.Pemetrexed and carboplatin plus bevacizumab for advanced non-squamous non-small cell lung cancer (NSCLC): preliminary results (abstract 7601).J Clin Oncol. 2007; 25: 409sGoogle Scholar Another trial of first-line therapy examined the combination of carboplatin with nanoparticle albumin bound (nab)-paclitaxel plus bevacizumab at 15 mg/kg, all given every 3 weeks.12Reynolds C Barrera D Vu DQ et al.An open-label, phase II trial of nanoparticle albumin bound paclitaxel (nab-paclitaxel), carboplatin, and bevacizumab in first-line patients with advanced non-squamous non-small cell lung cancer (NSCLC) (abstract 7610).J Clin Oncol. 2007; 25: 411sCrossref PubMed Scopus (67) Google Scholar Initial data on the first 50 patients have shown an encouraging response rate and high median survival time of nearly 16 months. In the second-line setting, a combination regimen of oxaliplatin, pemetrexed, and bevacizumab at 15 mg/kg every 3 weeks also showed very promising preliminary results in 32 patients.13Heist RS Fidias P Huberman M et al.Phase II trial of oxaliplatin, pemetrexed, and bevacizumab in previously-treated advanced non-small cell lung cancer (NSCLC) (abstract 7700).J Clin Oncol. 2007; 25: 434sCrossref Scopus (49) Google Scholar Ongoing bevacizumab/chemotherapy trials are outlined in Table 1. None of the trials have reported unexpected safety concerns with the exception of bowel perforation in those with diverticular disease mentioned earlier.TABLE 1Ongoing Trials of Bevacizumab with ChemotherapyTreatmentLocationPhaseAccrual GoalLine of TherapyCisplatin/vinorelbine, cisplatin/gemcitabine, cisplatin/docetaxelECOG—Lung Intergroup31500AdjuvantCisplatin/docetaxelMSKÌ270PreoperativeAny platinum doubletHoffmann-La Roche4>1000FirstCarboplatin/pemetrexedNorthwestern250FirstCarboplatin/pemetrexedCooper Health2FirstOxaliplatin/pemetrexedDana-Farber250SecondCarboplatin/gemcitabineStanford250FirstCarboplatin/gemcitabineProvidence245FirstCarboplatin/gemcitabineMinneapolis248FirstCarboplatin/docetaxelMD Anderson250FirstOxaliplatin/gemcitabineMt. Sinai, Miami255FirstOxaliplatin/docetaxelSanofi-Aventis275FirstOxaliplatin/pemetrexedInternational Oncology Network269FirstGemcitabine/pemetrexedKarmanos242FirstTopotecanUniversity of Minnesota260Second+Pemetrexed/gemcitabine vs. pemetrexed/carboplatinSarah Cannon2110First—elderlyPemetrexed/gemcitabineACORN248First—elderlyAny chemotherapyGenentech2110First or second—treated brain metastasesPemetrexedStanford240only Second—treated brain metastases onlyCarboplatin/paclitaxelGenentech240First—squamous onlyData are from www.clinicaltrials.gov accessed on 10/1/07.ACORN, Accelerated Community Oncology Research Network; ECOG, Eastern Cooperative Oncology Group; MSKCC, Memorial Sloan Kettering Cancer Center. Open table in a new tab Data are from www.clinicaltrials.gov accessed on 10/1/07. ACORN, Accelerated Community Oncology Research Network; ECOG, Eastern Cooperative Oncology Group; MSKCC, Memorial Sloan Kettering Cancer Center. The first targeted agent combined with bevacizumab is the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) erlotinib. A promising median survival time of more than 12 months, observed for 34 patients treated with this combination as second- or third-line therapy in the initial phase 2 study led to further development.14Herbst RS Johnson DH Mininberg E et al.Phase I/II trial evaluating the anti-vascular endothelial growth factor monoclonal antibody bevacizumab in combination with the HER-1/epidermal growth factor receptor tyrosine kinase inhibitor erlotinib for patients with recurrent non-small-cell lung cancer.J Clin Oncol. 2005; 23: 2544-2555Crossref PubMed Scopus (547) Google Scholar Another single-arm phase 2 study, reported at ASCO 2007 enrolled 46 patients and found a 20% relative risk reduction but only a 7.9-month median survival time.15Groen HJ Smit EF Dingemans A A phase II study of erlotinib (E) and bevacizumab (B) in patients (pts) with previously untreated stage IIIB/IV non-small cell lung cancer (NSCLC) (abstract 7625).J Clin Oncol. 2007; 25: 415sGoogle Scholar A randomized phase 2 study of 120 patients on three treatment arms, either erlotinib (150 mg daily) plus bevacizumab (15 mg/kg every 3 weeks), chemotherapy alone (docetaxel or pemetrexed), or chemotherapy with bevacizumab, reported a 57% 1-year survival for the erlotinib/bevacizumab arm, although the hazard ratios for disease progression were not statistically improved by the addition of bevacizumab.16Herbst RS O'Neill VJ Fehrenbacher L et al.Phase II study of efficacy and safety of bevacizumab in combination with chemotherapy or erlotinib compared with chemotherapy alone for treatment of recurrent or refractory non-small-cell lung cancer.J Clin Oncol. 2007; 25: 4743-4750Crossref PubMed Scopus (375) Google Scholar Genentech has opened two large phase 3 studies with this drug combination, including the Beta trial, which will include 650 patients who will receive second- or third-line erlotinib with or without bevacizumab. AVF3671g, commonly known as the "ATLAS" trial, is enrolling patients to receive first-line doublet chemotherapy plus bevacizumab then, after completion of four to six cycles of chemotherapy, to continue bevacizumab with or without erlotinib. Additionally, phase 2 trials of the combination are ongoing as first-line therapy in selected patient populations, such as those with a poor performance status, never-smokers, bronchioloalveolar carcinoma, elderly patients (with pemetrexed as a third agent) and others. Other targeted agents, including VEGFR-TKIs and the EGFR antibody cetuximab, are also being studied in combination with bevacizumab, often with chemotherapy as well. Table 2 includes many of these ongoing trials.TABLE 2Ongoing Trials of Bevacizumab with Targeted AgentsaData are from www.clinicaltrials.gov accessed on 10/1/2007.TreatmentSponsor/LocationPhaseAccrual GoalLine of TherapyErlotinibGenentech Beta3650Second or thirdErlotinibGenentech ATLAS31150Immediately after firstErlotinib vs. chemotherapybNot yet accruing.Hoffman-La Roche2100–500FirstErlotinib vs. gemcitabine/cisplatinbNot yet accruing.Germany2220FirstErlotinibHOG225First—PS2ErlotinibSWOG280First+—BACErlotinibSWOG280First+—never-smokersErlotinibSwitzerland2109FirstErlotinib/pemetrexedH. Lee Moffitt1/257First-elderlyApomab/carboplatin/paclitaxelGenentech2120FirstRAD001/carboplatin/paclitaxelNovartis1120FirstAMG951(rhAPO2L)/TRAIL/chemotherapybNot yet accruing.Amgen2200FirstEnzastaurin/carboplatin/pemetrexedbNot yet accruing.Eli Lilly290FirstSunitinib/carboplatin/paclitaxelGenentech2130FirstCetuximab/carboplatin/paclitaxelSWOG290FirstCetuximab/carboplatin/paclitaxelImClone2120FirstSorafenib/carboplatin/paclitaxelMD Anderson160FirstSorafenibNCI162Second+Bortezomib/carboplatinUniversity of Massachusetts1/255FirstImatinibUniversity of Washington250Immediately after firstBAC, bronchioloalveolar carcinoma; HOG, Hoosier Oncology Group; NCI, National Cancer Institute; PS2, performance status 2; SWOG, Southwest Oncology Group.a Data are from www.clinicaltrials.gov accessed on 10/1/2007.b Not yet accruing. Open table in a new tab BAC, bronchioloalveolar carcinoma; HOG, Hoosier Oncology Group; NCI, National Cancer Institute; PS2, performance status 2; SWOG, Southwest Oncology Group. Treatment of elderly patients with advanced-stage NSCLC is an area of controversy. Some trials have cast doubt on the benefit of doublet chemotherapy regimens in those older than 70 years,17Gridelli C Perrone F Gallo C et al.Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.J Natl Cancer Inst. 2003; 95: 362-372Crossref PubMed Scopus (774) Google Scholar whereas other trials have shown the same magnitude of benefit with platinum doublets for older versus younger patients.18Langer CJ Vangel M Schiller J et al.Age-specific subanalysis of ECOG 1594: fit elderly patients (70–80 YRS) with NSCLC do as well as younger pts (<70) (abstract 2571).Proc Am Soc Clin Oncol. 2003; 22: 639Google Scholar In the United States, many healthy elderly patients receive standard doublet chemotherapy at diagnosis of advanced-stage NSCLC. Many of these patients also fit the eligibility criteria for bevacizumab and would be considered for this therapy. An analysis of elderly patients in E4599, however, argues for caution with this approach.19Ramalingam SS Dahlberg SE Langer CJ et al.Outcomes for elderly advanced stage non-small cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group 4599 study.J Clin Oncol. 2008; 26: 60-65Crossref PubMed Scopus (328) Google Scholar Ramalingam et al.19Ramalingam SS Dahlberg SE Langer CJ et al.Outcomes for elderly advanced stage non-small cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group 4599 study.J Clin Oncol. 2008; 26: 60-65Crossref PubMed Scopus (328) Google Scholar analyzed patients in E4599 by age and found that patients at least 70-year-old (approximately 25% of total patient population) did not have the same survival advantage with the addition of bevacizumab as their younger counterparts but had higher toxicity rates. Results of a similar analysis from AVAiL are awaited. In an unplanned subset analysis of E4599, the hazard ratio for overall survival for women was 0.98 (95% confidence interval, 0.77–1.25), even though response rates (14% versus 41%) and PFS were higher with the addition of bevacizumab.20Brahmer JR Gray R Schiller JH et al.ECOG 4599 phase III trial of carboplatin and paclitaxel +/− bevacizumab: subset analysis of survival by gender (abstract 7036).J Clin Oncol. 2006; 24: 373sGoogle Scholar No significant differences in second-line therapy, including use of EGFR-TKIs, were identified that could explain this survival discrepancy.8Sandler 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: 2542-2550Crossref PubMed Scopus (5232) Google Scholar Again, results of a similar analysis from AVAiL are awaited. In colorectal cancer trials the survival benefits in women have equaled those in men.21Ramies DA Sandler A Gray R et al.Bevacizumab: analysis of clinical benefit in females across trials in colorectal cancer and non-small cell lung cancer (abstract 7634).J Clin Oncol. 2007; 25: 417sGoogle Scholar The potential differences in survival by sex need further exploration, but at this time the data do not support differential prescribing of bevacizumab by sex. Based on safety concerns, most trials with bevacizumab in patients with NSCLC have excluded patients with squamous cell histologic findings, known brain metastases, and those receiving therapeutic anticoagulation. As outlined with the AVAiL data, anticoagulation use can be considered cautiously with NSCLC patients receiving bevacizumab, but the study included small numbers of patients receiving anticoagulation, and further exploration of the safety in this population is warranted. Several ongoing trials are looking at the drug in patients with treated, stable brain metastases. The PASSPORT trial is a Genentech-led trial specifically in those with treated brain metastases, and other trials such as ATLAS allow for patients with treated brain metastases but do not select specifically for them. The preliminary safety data from 42 patients treated on these two trials have been presented.22Akerley W Hainsworth J Oh Y et al.Safety of bevacizumab therapy in subjects with brain metastases due to non-small cell lung cancer (NSCLC) (abstract PD463–3-3).J Thorac Oncol. 2007; 2: S467Crossref Google Scholar Although central nervous system hemorrhages have not been observed to date, one patient developed grade 3 leukoencephalopathy.22Akerley W Hainsworth J Oh Y et al.Safety of bevacizumab therapy in subjects with brain metastases due to non-small cell lung cancer (NSCLC) (abstract PD463–3-3).J Thorac Oncol. 2007; 2: S467Crossref Google Scholar A phase 2 study at Stanford University is exploring the use of bevacizumab in combination with pemetrexed in patients with treated stable brain metastases. To overcome the bleeding risk with squamous cell disease, two studies with radiation before initiation of chemotherapy and bevacizumab were begun, but were closed early due to toxicity concerns (hemoptysis in particular). There are several trials of bevacizumab that are proceeding cautiously, particularly in stage III disease, that allow for squamous histology. Therefore, although excluding those receiving anticoagulation or with treated brain metastases may be unwarranted, squamous cell disease may in fact be a true marker of an increased risk of bleeding with bevacizumab. Given the positive results with bevacizumab in patients with advanced-stage NSCLC, several trials have opened looking at the addition of bevacizumab to chemotherapy and radiation for locally advanced NSCLC. Trials led by the Southwest Oncology Group and the Sarah Cannon Cancer Center have been frequently on hold because of concerns about tracheoesophageal fistula formation, which has been seen in trials of bevacizumab with concurrent chemoradiation in limited-stage small cell lung cancer. A study at the University of North Carolina that includes bevacizumab with carboplatin/paclitaxel/erlotinib and radiation remains open but is being watched closely. In Europe, there is at least one ongoing trial of radiation with escalating doses of bevacizumab for NSCLC. Bevacizumab is also being studied in early-stage, resectable NSCLC. An ongoing trial at the Memorial Sloan Kettering Cancer Center is examining bevacizumab alone or in combination with cisplatin/docetaxel preoperatively.23Rizvi NA Rusch V Zhao B et al.Single agent bevacizumab and bevacizumab in combination with docetaxel and cisplatin as induction therapy for resectable IB-IIIA non-small cell lung cancer (abstract 18045).J Clin Oncol. 2007; 25: 687sGoogle Scholar By far the largest effort with bevacizumab in early-stage disease though is the intergroup adjuvant trial, E1505 (Figure 1). This study, which opened in June 2007, aims to enroll 1500 patients with completely resected stage IB (≥4 cm) to stage IIIA NSCLC. Patients will receive four cycles of one of three chemotherapy regimens (cisplatin/vinorelbine, cisplatin/docetaxel, or cisplatin/gemcitabine) with randomization to bevacizumab at 15 mg/kg every 3 weeks, starting with the first cycle of chemotherapy, for up to 1 year of therapy. Patients are stratified by stage, histologic findings, sex, and chemotherapy regimen. Patients with any histologic findings are eligible, as are those receiving anticoagulation. Extensive correlative analyses are planned to help provide a better understanding of both the biology of bevacizumab action and which patients are mostly likely to benefit from this agent. Development of other antibodies that target VEGF has not been as successful as the bevacizumab story. Considerable work was performed in Europe with HuMV833, but because of dose-finding difficulties (nonlinear pharmacokinetics) and other issues, development is currently on hold.24Jayson GC Zweit J Jackson A et al.Molecular imaging and biological evaluation of HuMV833 anti-VEGF antibody: implications for trial design of antiangiogenic antibodies.J Natl Cancer Inst. 2002; 94: 1484-1493Crossref PubMed Scopus (273) Google Scholar A slightly different approach has been taken with AVE0005, commonly known as VEGF-TRAP, a chimeric fusion molecule that contains portions of the extracellular domains of VEGFR1 and VEGFR2 fused to the Fc portion of IgG1.25Holash J Davis S Papadopoulos N et al.VEGF-Trap: a VEGF blocker with potent antitumor effects.Proc Natl Acad Sci USA. 2002; 99: 11393-11398Crossref PubMed Scopus (1476) Google Scholar This compound binds free VEGF and has shown early promise. When AVE0005 was used as a single agent at 4 mg/kg every 2 weeks, two responses were seen in the first 34 patients enrolled in a phase 2 NSCLC trial, with accrual ongoing.26Massarelli E Miller VA Leighl NB et al.Phase II study of the efficacy and safety of intravenous (IV) AVE005 (VEGF Trap) given every 2 weeks in patients (pts) with platinum- and erlotinib-resistant adenocarcinoma of the lung (NSCLA) (abstract 7627).J Clin Oncol. 2007; 25: 416sGoogle Scholar Ongoing randomized trials are examining this agent in combination with docetaxel as well as with combination chemotherapy. Other agents are in earlier stages of development. Bevacizumab is the first agent to provide a survival advantage when added to first-line chemotherapy for advanced-stage NSCLC. Its success in E4599 established the importance of antiangiogenic strategies in the treatment of NSCLC. The response rate and PFS benefit from this trial have since been validated in a second large randomized trial, and the drug is being studied in combination with an expanding list of chemotherapeutics and with targeted agents. Studies in populations previously excluded, such as those with treated brain metastases, as well as in patient with early stage disease, are also under way. The antibodies to VEGF, particularly bevacizumab, have opened a clear path for further investigation of the role of antiangiogenic agents in NSCLC.