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Lung Cancer

The Role of Bevacizumab in the Treatment of Non-Small Cell Lung Cancer: Current Indications and Future Developments

^aDivision of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy; ^bI Division of Oncological Pneumology, Department of Lung Diseases, San Camillo-Forlanini Hospitals, Roma, Italy

Key Words. Bevacizumab • NSCLC • Angiogenesis • Targeted therapy

Correspondence: Cesare Gridelli, M.D., Division of Medical Oncology, "S.G. Moscati" Hospital, Contrada Amoretta, 83100 Avellino, Italy. Telephone: 39-0825-203573; Fax: 39-0825-203556; e-mail: cgridelli{at}libero.it

Received July 9, 2007; accepted for publication August 14, 2007.

Disclosure: C.G. and F.DeM. have acted as consultants to and have financial interests in Roche. No other potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.

	Learning Objectives

Top Learning Objectives Abstract Introduction Angiogenesis and Lung Cancer VEGF and Bevacizumab Bevacizumab and NSCLC Treatment Conclusions References

 
After completing this course, the reader will be able to:

1. Describe the main clinical trials of bevacizumab combined with chemotherapy in the treatment of advanced NSCLC.
   
2. Describe the main clinical trials of bevacizumab combined with other targeted therapies in the treatment of advanced NSCLC.
   
3. Describe some ongoing trials of bevacizumab in the treatment of NSCLC and try to define future developments of bevacizumab in this clinical setting.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Angiogenesis and Lung Cancer VEGF and Bevacizumab Bevacizumab and NSCLC Treatment Conclusions References

 
The majority of non-small cell lung cancer (NSCLC) patients present with advanced disease, and despite the improvement in efficacy and safety outcomes with platinum-based chemotherapy, this standard cytotoxic approach has reached a therapeutic plateau, with the prognosis for this clinical condition remaining poor. Advances in the knowledge of tumor biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment. Bevacizumab, an anti–growth factor vascular endothelial growth factor (VEGF) monoclonal antibody, is the antiangiogenic agent at the most advanced stage of development in the treatment of solid tumors and also in NSCLC treatment. Bevacizumab, combined with platinum-based chemotherapy, has been demonstrated to improve efficacy outcomes over chemotherapy alone in the treatment of nonsquamous advanced NSCLC in two phase III randomized trials. These represent the first evidence of improvement in treatment outcomes of chemotherapy with targeted therapies in the first-line treatment of advanced NSCLC. Future clinical developments of bevacizumab in NSCLC treatment will include the combination of this agent with other targeted therapies in advanced disease (especially with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor) and the integration of this agent into combined modality approaches for the treatment of early-stage and locally advanced disease.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Angiogenesis and Lung Cancer VEGF and Bevacizumab Bevacizumab and NSCLC Treatment Conclusions References

 
Lung cancer is the leading cause of cancer-related mortality in both men and women [1], with 1.2 million new cases diagnosed every year and with 1 million deaths being recorded worldwide in 2001 [2]. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. The majority of NSCLC patients present with advanced disease at diagnosis and a large portion of those diagnosed with early-stage disease eventually recur, experiencing metastatic disease, with the prognosis for this clinical condition remaining poor.

Although chemotherapy has recently produced promising results as an adjuvant strategy for early-stage patients [3], and some progress has been made in the treatment of locally advanced and advanced disease [4, 5], treatment outcomes for NSCLC are still to be considered disappointing. Advances in the knowledge of tumor biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment. The first generation of clinical trials of targeted agents in NSCLC treatment has been concluded, and some considerations can now be drawn. To date, only few of these new agents can offer hope of a substantial impact on the natural history of the disease, and negative results are more commonly reported than positive ones. Nevertheless, clinically meaningful advances have already been achieved. In chemotherapy-refractory advanced NSCLC patients, erlotinib (Tarceva®; OSI Pharmaceuticals, Inc., Melville, NY), an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), represents a further chance of tumor control and symptom palliation for pretreated patients [6].

One of the targeted approaches most widely studied in the treatment of NSCLC is the inhibition of angiogenesis [7]. Among angiogenesis inhibitors, the anti–vascular endothelial growth factor (VEGF) monoclonal antibody (mAb) bevacizumab (Avastin ®; Genentech Inc., South San Francisco, CA) represents the most successful targeted therapy. In fact, in chemotherapy-naive advanced NSCLC patients with nonsquamous histology, the combination of bevacizumab with chemotherapy has demonstrated, in two large phase III randomized trials, better efficacy outcomes than with chemotherapy alone [8, 9]. These represent the first evidence of improvement in treatment outcomes of chemotherapy with targeted therapies in the first-line treatment of advanced NSCLC. On the basis of the results in first-line treatment, bevacizumab is, at the moment, the most promising targeted agent for the treatment of NSCLC, and its role in combination with other targeted agents or in other settings, such as second-line treatment of advanced disease, early-stage disease (as adjuvant and neoadjuvant treatment), and locally advanced disease, must be defined. In this review we summarize the main clinical experience with bevacizumab in NSCLC treatment and we try to hypothesize its future clinical development in this disease, by describing some ongoing clinical trials.

	ANGIOGENESIS AND LUNG CANCER

Top Learning Objectives Abstract Introduction Angiogenesis and Lung Cancer VEGF and Bevacizumab Bevacizumab and NSCLC Treatment Conclusions References

 
Generally, tumors cannot grow beyond 2 mm in diameter without developing a vascular supply [10]. Not only does neovascularization permit further growth of the primary tumor, but it also provides a pathway for migrating tumor cells to gain access to the systemic circulation and to establish distant metastases. In the absence of a functional vascular supply tumors remain dormant and are unable to metastasize [11, 12]. Normally, angiogenesis is well controlled and limited to physiologic processes. In contrast, solid tumors secrete a range of proangiogenic factors that favor angiogenesis, and as a consequence their development and metastasis. Among these proangiogenic factors, VEGF is the most potent and specific of the endothelial cell mitogens [13, 14].

The role of angiogenesis is well established in the progression of lung cancers, and high microvessel density has been widely studied as a prognostic factor predictive of metastasis and poor survival [15, 16]. Specifically, high vascularity at the tumor periphery has been correlated with tumor progression [17]. In NSCLC, the majority of studies support correlation among VEGF expression, microvessel density, and poor prognosis. However, the role of microvessel density as a prognostic factor remains controversial. In fact, a very recent meta-analysis of individual patient data from published and unpublished datasets has not demonstrated a prognostic value for microvessel density in patients with nonmetastatic surgically treated NSCLC [18].

	VEGF AND BEVACIZUMAB

Top Learning Objectives Abstract Introduction Angiogenesis and Lung Cancer VEGF and Bevacizumab Bevacizumab and NSCLC Treatment Conclusions References

 
Neovascularization stimulates tumor growth, invasion, and metastasis [10], and this process is controlled by stimulatory (VEGF, basic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-, GM-CSF) and inhibitory (angiostatin, endostatin) factors whose balance determines the degree of angiogenesis. VEGF is the single most commonly upregulated angiogenic factor in both grafted and naturally occurring tumors, thus being a prime target for antivascular therapy [19]. VEGF and VEGF receptors (VEGFRs) play a pivotal role in normal and pathologic angiogenesis. Activation of the VEGF–VEGFR axis triggers multiple signaling networks that result in endothelial cell survival, mitogenesis, migration, and differentiation, and vascular permeability and mobilization of endothelial progenitor cells from the bone marrow into the peripheral circulation. In addition, VEGF mediates vessel permeability and has been associated with malignant effusions [20, 21]. The VEGF-related gene family of angiogenic and lymphangiogenic growth factors comprises six secreted glycoproteins referred to as VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor (PlGF)-1 and PlGF-2 [22, 23]. VEGF-A, commonly referred to as VEGF, is a 45-kDa homodimeric glycoprotein with a diverse range of angiogenic activities. VEGF has two identified receptors: Flt-1 (fms-like tyrosine kinase-1) and Flk-1/KDR (fetal liver kinase-1/kinase domain region) [24]. More recently, an additional tyrosine kinase receptor, VEGFR-3 (also referred to as fms-like tyrosine kinase 4 [Flt-4]), was identified and has been found to be primarily associated with lymphangiogenesis [25, 26].

Because of its central role in tumor angiogenesis, the VEGF–VEGFR pathway has been a major focus of basic research and drug development in the field of oncology.

Bevacizumab is an anti-VEGF recombinant humanized mAb. It contains the human IgG₁ framework (93%) and murine VEGF-binding complementarity-determining regions (7%), which block the binding of all VEGF-A isoforms to the receptors, inhibiting the biologic activities of VEGF.

Bevacizumab is the antiangiogenic agent at the most advanced stage of development in the treatment of cancer. In fact, bevacizumab, combined with chemotherapy, has already been demonstrated, in phase III randomized trials, to improve efficacy outcomes over those seen with chemotherapy alone in the treatment of advanced colorectal cancer, breast cancer, and NSCLC [8, 9, 27, 28].

	BEVACIZUMAB AND NSCLC TREATMENT

Top Learning Objectives Abstract Introduction Angiogenesis and Lung Cancer VEGF and Bevacizumab Bevacizumab and NSCLC Treatment Conclusions References

 
Advanced Disease: Combination with Chemotherapy
A randomized phase II study of bevacizumab (7.5 mg/kg or 15 mg/kg) in combination with carboplatin and paclitaxel compared with carboplatin plus paclitaxel alone in 99 patients with stage IIIB or IV NSCLC was performed [29]. Response rates with the antibody administered at 15 mg/kg were about 10% higher (31.5%, 28.1%, and 18.8% in the high-dose antibody group, the low-dose antibody group, and the chemotherapy-alone group, respectively), and the time to tumor progression was approximately 3 months longer (7.4, 4.3, and 4.2 months, respectively). A trend toward a longer survival time was also reported (17.7, 11.6, and 14.9 months, respectively). Bevacizumab therapy appeared to be associated with a higher risk for bleeding, which included two distinct patterns: minor mucocutaneous hemorrhage that did not require any change in bevacizumab treatment and major hemoptysis. A development warranting concern was that six patients developed severe hemoptysis (four episodes were fatal). Bleeding arose from centrally located tumors close to major blood vessels, and cavitation or necrosis had occurred in most cases. In an evaluation of potential risk factors, it was found that the squamous histologic subtype, because of its anatomical position often near the central vessels, and bevacizumab treatment were the only factors associated with hemoptysis. On this basis, all the following trials performed with bevacizumab in the treatment of advanced NSCLC excluded patients with squamous histology.

Based on the promising results of the above-mentioned phase II randomized trial [29], the Eastern Cooperative Oncology Group (ECOG) conducted a randomized study (E4599) in which 878 patients with recurrent or advanced nonsquamous NSCLC were assigned to either chemotherapy with paclitaxel and carboplatin alone (n = 444) or paclitaxel and carboplatin plus bevacizumab (n = 434) [8]. Patients with squamous cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status (ECOG performance status [PS] score >1) were excluded. Squamous histology was excluded because of the risk for grade 5 hemoptysis reported in the previous phase II randomized study. Patients were randomized to receive paclitaxel (200 mg/m²) and carboplatin (to an area under the concentration–time curve of 6) plus bevacizumab (15 mg/kg) on day 1 every 3 weeks or the same chemotherapy regimen alone. Patients in the bevacizumab arm continued bevacizumab after six cycles until progressive disease or intolerable toxicity. The primary endpoint was overall survival. The median survival time was 12.3 months in the group assigned to chemotherapy plus bevacizumab, compared with 10.3 months in the chemotherapy-alone group (hazard ratio [HR] for death, 0.79; p = .003). The median progression-free survival times in the two groups were 6.2 and 4.5 months, respectively (HR for disease progression, 0.66; p < .001), with corresponding response rates of 35% and 15% (p < .001). No difference among different subgroups of patients was found, except for gender. In fact, the median overall survival times in the paclitaxel–carboplatin group and the paclitaxel–carboplatin–bevacizumab group were 8.7 and 11.7 months, respectively, among men and 13.1 and 13.3 months, respectively, among women. Possible explanations for this finding include imbalances between the two groups with respect to known or unknown baseline prognostic factors, imbalances in the use of second- and third-line therapies (men received more second-line chemotherapy), statistical chance, or a true sex-based difference. Although it has been postulated that baseline VEGF levels correlate with the clinical outcome of bevacizumab treatment, in this trial, baseline plasma VEGF levels did not correlate with survival. The experimental regimen was globally well tolerated, but more toxic than chemotherapy alone. In the bevacizumab plus chemotherapy and the chemotherapy-alone arms the following toxicities were reported: grade 3 or 4 neutropenia (24% versus 16.4%), grade 3 or 4 thrombosis/embolism (3.8% versus 3%), and grade 3 or 4 hemorrhage (4.1% versus 1.0%). The rates of clinically significant bleeding were 4.4% and 0.7%, respectively (p < .001). In summary, the rates of hypertension, proteinuria, bleeding, neutropenia, febrile neutropenia, thrombocytopenia, hyponatremia, rash, and headache were significantly higher in the paclitaxel–carboplatin–bevacizumab group than in the paclitaxel–carboplatin group (p < .05). There were two treatment-related deaths in the chemotherapy group (from gastrointestinal hemorrhage and febrile neutropenia) and 15 treatment-related deaths in the chemotherapy-plus-bevacizumab group; the difference between the groups was significant (p = .001). Of the 15 deaths in the paclitaxel–carboplatin–bevacizumab group, five were attributed to pulmonary hemorrhage, 5 were a result of complications of febrile neutropenia, two were each attributed to a cerebrovascular event or gastrointestinal hemorrhage, and one was a result of a probable pulmonary embolus. Sandler et al. [8] concluded that the addition of bevacizumab to paclitaxel plus carboplatin in the treatment of selected patients with NSCLC has a significant survival benefit, with the risk for more treatment-related deaths. That study represents the first evidence of superior efficacy of targeted therapy combined with chemotherapy over chemotherapy alone in the treatment of NSCLC.

Very recently, another randomized, placebo-controlled, phase III study (the Avastin in Lung [AVAiL] trial) evaluated the addition of bevacizumab to chemotherapy (cisplatin plus gemcitabine) in the treatment of advanced NSCLC. Manegold et al. [9] compared two doses of bevacizumab plus cisplatin and gemcitabine with cisplatin and gemcitabine plus placebo. The primary endpoint was progression-free survival; secondary endpoints included overall survival, response rate, and safety. Eligibility criteria included, as in the ECOG trial, previously untreated advanced nonsquamous NSCLC patients with an ECOG PS score of 0–1 and no brain metastases. About 1,000 patients were randomized to receive cisplatin and gemcitabine every 3 weeks for up to six cycles plus bevacizumab, continued to progression, at 7.5 mg/kg every 3 weeks, or 15 mg/kg every 3 weeks, or placebo. The study was designed to include the number of patients required to observe a 30% reduction in the risk for a progression-free survival event in the bevacizumab arms compared with control, using a two-sided log-rank test with 80% power.

Progression-free survival was significantly longer with bevacizumab, as analyzed both in a primary analysis (without censoring for nonprotocol antineoplastic therapy [NPT] prior to progression) and in a prespecified analysis with censoring for NPT. The median progression-free survival times were 6.1, 6.7, and 6.5 months, respectively, for chemotherapy alone, chemotherapy plus bevacizumab 7.5 mg/kg, and chemotherapy plus bevacizumab 15 mg/kg (HR, 0.75; 95% confidence interval [CI], 0.62–0.90; p = .002 for bevacizumab 7.5 mg/kg and HR, 0.82; 95% CI, 0.68–0.98; p = .03 for bevacizumab 15 mg/kg). The response rate and response duration were also significantly greater with bevacizumab. Response rates were 20%, 34%, and 30%, respectively, for chemotherapy alone, chemotherapy plus bevacizumab 7.5 mg/kg, and chemotherapy plus bevacizumab 15 mg/kg. The response durations were 4.7, 6.1, and 6.1 months, respectively, for chemotherapy alone, chemotherapy plus bevacizumab 7.5 mg/kg, and chemotherapy plus bevacizumab 15 mg/kg. No difference according to gender was observed, minimizing the gender issue of the ECOG 4599 trial. The median survival time had not been reached. Manegold et al. [9] concluded that both doses of bevacizumab significantly improved the progression-free survival time and response rate over those seen with chemotherapy alone (cisplatin and gemcitabine), as observed in the earlier phase III trial E4599, against carboplatin and paclitaxel. No unexpected safety signals were detected in this trial, with grade 3 adverse events occurring in 75%, 76%, and 81% of the three treatment groups, respectively (chemotherapy alone, chemotherapy plus bevacizumab 7.5 mg/kg, and chemotherapy plus bevacizumab 15 mg/kg). Adverse events leading to death occurred in 4%, 4%, and 5% of the three groups, respectively; grade 3 hemoptysis occurred in <1%, 1.5%, and <1% and grade 3 hypertension occurred in 4%, 4%, and 5%, respectively (Table 1).

Dalsania et al. [31] evaluated the combination of bevacizumab, pemetrexed, and carboplatin in a phase II trial on 14 patients. The treatment has shown promising activity (response rate, 60%; disease control rate, 75%) and a good toxicity profile to date. Patel et al. [32] also evaluated the combination of pemetrexed and carboplatin plus bevacizumab in this patient population, but with a different schedule. Patients received pemetrexed in addition to bevacizumab until disease progression or toxicity. The regimen appeared feasible and active. In 39 patients (of a planned 50) enrolled, there was no grade 4 hematologic toxicity. One patient with diverticulitis experienced bowel perforation that required surgical intervention. The only risk factor identified was previous history of diverticulitis. One complete response and 20 partial responses were observed for an overall response rate of 55% (95% CI, 43%–75%).

Davila et al. [33] evaluated the combination of gemcitabine and oxaliplatin plus bevacizumab in a phase II trial. Preliminary results among 26 evaluable patients showed no bleeding complications and minimal hematologic toxicity. However, selected nonhematologic toxicities have been noted (one patient had ischemic bowel and one patient died from liver failure in the first cycle). A response rate of 31% was observed.

Waples et al. [34] recently reported preliminary data on safety of the combination of bevacizumab, oxaliplatin, and pemetrexed as first-line treatment for NSCLC from a phase II study. Among 53 subjects, grade 3 neutropenia occurred in 10.4% of patients and grade 4 thrombocytopenia and neutropenia occurred in 3.0% of the patients, demonstrating an acceptable safety profile.

Reynolds et al. [35] treated 50 advanced NSCLC patients with the combination of nanoparticle albumin bound (nab)-paclitaxel, carboplatin, and bevacizumab in a phase II trial. The development of nab-paclitaxel has circumvented many of the infusion difficulties that are associated with standard solvent-based paclitaxel (in cremophor). The authors reported a response rate of 30% (with no complete responses) and a stable disease rate of 48%. The median progression-free survival time was 7.1 months (range, <1–10.6). Grade 3–4 treatment-related toxicities included neutropenia (52%), thrombocytopenia (10%), febrile neutropenia (4%), and hemoptysis (4%) (Table 2).

At the moment, a relevant proportion of advanced NSCLC patients are not eligible for bevacizumab treatment. Thus, there is interest in determining if patients with brain metastases and with squamous histology can be, at least partially, recandidated to this effective targeted therapy. Moreover, the risk related to these two conditions, although not negligible, is not completely clear. A phase II trial of bevacizumab in combination with first- or second-line therapy in patients with treated brain metastases from nonsquamous NSCLC (the PASSPORT trial) has been initiated. Another phase II trial, the BRIDGE trial, will treat patients with squamous cell histology with two cycles of carboplatin and paclitaxel, and then initiate treatment with carboplatin, paclitaxel, and bevacizumab for an additional four cycles. The AVASQ (Avastin in Squamous NSCLC) phase I/II trial will evaluate the safety of administering thoracic radiotherapy to central lung lesions before carboplatin and paclitaxel plus bevacizumab in the first- and second-line treatment of advanced squamous NSCLC.

Many doubts exist on the feasibility of bevacizumab in elderly patients. This topic is particularly relevant if we consider that a great proportion of lung cancers are diagnosed in patients >70 years old [37]. Merza et al. [38] have retrospectively studied 106 male elderly patients diagnosed with advanced NSCLC in the past 3 years in their institution and identified the factors that would have excluded patients from participating in clinical trials with bevacizumab. The authors used the exclusion criteria as per ECOG trial 4599 [8] and an open industry-sponsored trial (erlotinib with or without bevacizumab for second-line treatment of NSCLC). Patients with squamous predominant histology (n = 26) were excluded. Of the remaining 80 patients evaluated for use of bevacizumab, 72 patients (90%) met one or more exclusion criteria. The majority of the factors that would have contraindicated bevacizumab use in this patient population were cardiovascular comorbidities, which are reported with a high incidence in elderly NSCLC patients [39]. This retrospective analysis, although performed in a small population, suggests that the use of bevacizumab may be further limited in elderly NSCLC patients.

Ramalingam et al. [40] retrospectively analyzed the ECOG 4599 [8] database to compare outcomes in elderly patients treated with paclitaxel and carboplatin plus bevacizumab versus paclitaxel and carboplatin alone. Out of 850 eligible patients, 26% (n = 224) were 70 years of age (1.6% were 80 years). For the elderly patients, there was a trend toward a superior response rate (29% versus 17%; p = .067) and median progression-free survival time (5.9 months versus 4.9 months; p = .063) with chemotherapy plus bevacizumab when compared with chemotherapy alone, although there was no difference in overall survival (chemotherapy plus bevacizumab, 11.3 months; chemotherapy, 12.1 months; p = .4). Grade 3–5 toxicities were noted in 87% of elderly patients treated with paclitaxel and carboplatin plus bevacizumab compared with 61% of patients treated with paclitaxel and carboplatin (p < .001). The treatment-related death rates with chemotherapy plus bevacizumab and paclitaxel plus carboplatin were 6.3% versus 1.8% (not significant) for the elderly. Febrile neutropenia (6% versus 0.9%), proteinuria (8% versus 0), and hypertension (6% versus 0.9%) were more common with chemotherapy plus bevacizumab than with chemotherapy alone among the elderly. When compared with younger patients, the elderly experienced more neutropenia (34% versus 22%), bleeding (7.9% versus 3.2%), proteinuria (7.9% versus 1.3%), muscle weakness (7.9% versus 2.2%), and motor neuropathy (3.5% versus 0.6%) with chemotherapy plus bevacizumab. Greater toxicity with the addition of bevacizumab in patients 70 years may have contributed to the absence of survival benefit for chemotherapy plus bevacizumab over chemotherapy alone in the elderly population.

Advanced Disease: Combination with Other Targeted Therapies
Combining targeted agents that block multiple signaling pathways may reveal a very useful therapeutic approach leading to better outcomes [41]. Human epidermal growth factor receptor (HER)-1/EGFR and VEGF share common downstream signaling pathways. They exert effects both directly and indirectly on tumor cells, and combining drugs that target these molecules may confer additional clinical benefit. VEGF is also downregulated by HER-1/EGFR inhibition [42], and a recent study suggested that blockade of VEGF may also inhibit HER-1/EGFR autocrine signaling [43]. Therefore, it is rational to suggest that dual blockade of these molecular targets may produce additive and even synergistic cytostatic effects. Several preclinical studies have investigated the antitumor activity of combined anti-HER-1/EGFR and anti-VEGF agents [44]. A recent phase I/II study examined erlotinib and bevacizumab in patients with nonsquamous stage IIIB/IV NSCLC pretreated with one or more prior chemotherapy regimens [45]. In phase I, erlotinib (150 mg/day orally) plus bevacizumab (15 mg/kg i.v. every 21 days) was established as the phase II dose, although no dose-limiting toxicities were observed. Forty patients were enrolled in this trial (34 treated at the phase II dose); 21 were female, 30 had adenocarcinoma histology, and nine were never-smokers. The most common adverse events were mild-to-moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between bevacizumab and erlotinib. Data on antitumor activity of this combination have to be considered very promising. In fact, eight patients (20%; 95% CI, 7.6%–32.4%) had partial responses and 26 (65%; 95 CI, 50.2%–79.8%) had stable disease as their best response. The median overall survival time for the 34 patients treated at the phase II dose was 12.6 months, with a progression-free survival duration of 6.2 months. The same authors, given recent evidence of a somatic mutation in the gene encoding the EGFR-TK domain and correlation with response to EGFR-TKIs, analyzed available archival tissue from their study for the presence of this mutation. EGFR exons 18–21 and 23 were sequenced in tumors from nine patients [46]. Outcomes were correlated with EGFR mutations. By Response Evaluation Criteria in Solid Tumors, three patients achieved partial responses, three had stable disease, and three had progressive disease. An EGFR-TK mutation in exon 20 was found in one tumor. Although a high degree of correlation between response to TKI therapy and the EGFR-TK mutation has been previously noted [47, 48], in this study, thus far, the mutation has been identified in only one of three tumors. Although these results are preliminary, they suggest that the combination of bevacizumab and erlotinib may provide benefit in a broader population than each agent individually.

A randomized phase II trial was performed in the second-line setting to investigate the safety and efficacy of bevacizumab with chemotherapy or erlotinib versus standard chemotherapy [49]. Patients with a PS score of 2 were eligible for this trial. One hundred twenty patients were randomized to one of three treatment arms: chemotherapy (docetaxel or pemetrexed) alone, bevacizumab and chemotherapy (docetaxel and pemetrexed), or bevacizumab plus erlotinib. There was a trend toward a longer progression-free survival interval with bevacizumab and chemotherapy (HR, 0.66; 95% CI, 0.38–1-16) and with bevacizumab plus erlotinib (HR, 0.72; 95% CI, 0.42–1.23) than with chemotherapy alone; however, the progression-free survival and overall survival times did not reach statistical significance. The preliminary safety data indicate a rate of grade 3–5 hemorrhage of 5.1%, and the overall rate of neutropenia was similar between the chemotherapy treatment arms. This randomized phase II trial provides valuable safety data about bevacizumab in the second-line setting, and the trend toward a longer progression-free survival interval is intriguing.

Groen et al. [50] evaluated the combination of erlotinib and bevacizumab in a phase II study as first-line treatment. Patients (PS score, 0–2) with advanced nonsquamous NSCLC who had received no prior chemotherapy were treated with erlotinib (150 mg/day) plus bevacizumab (15 mg/kg every 21 days) until progressive disease or unacceptable toxicity. Among 38 patients enrolled into the trial, 33 patients are evaluable for safety and 32 are available for efficacy. Only 4 of 33 were never-smokers. Grade 3 or 4 adverse events were rash (9.9%), thrombosis (1.8%), diarrhea (0.9%), and hypertension (0.9%). The rate of nonprogression at 6 weeks (primary study objective) was 75%. The median time to progression was 5.5 months (95% CI, 1.9–9.2). The authors concluded that the erlotinib plus bevacizumab regimen is well tolerated, with a low rate of grade 3 or 4 adverse events and no unexpected toxicities, and offers a promising rate of nonprogression at 6 weeks in the first-line treatment of advanced nonsquamous NSCLC.

Some very interesting clinical trials on the combination of bevacizumab and erlotinib are ongoing. The study BO20571 is a randomized, phase II trial that compares, in terms of progression-free survival and safety, erlotinib plus bevacizumab with platinum-based chemotherapy plus bevacizumab in the first-line treatment of nonsquamous stage IIIB/IV NSCLC patients. In arm 1, patients are treated with erlotinib (150 mg/day) plus bevacizumab (15 mg/kg every 21 days) until progressive disease or unacceptable toxicity. In arm 2, patients are treated with 4–6 cycles of chemotherapy (carboplatin and paclitaxel or cisplatin and gemcitabine) plus bevacizumab (15 mg/kg every 21 days) until progressive disease or unacceptable toxicity. The enrollment of 200 patients is planned.

The ATLAS trial is a phase III, randomized trial comparing bevacizumab plus erlotinib with bevacizumab as maintenance treatment after four cycles of chemotherapy plus bevacizumab in the first-line treatment of nonsquamous stage IIIB/IV NSCLC. The primary endpoint of the trial is progression-free survival after the end of first-line chemotherapy. Secondary endpoints are safety and overall survival. Obviously, only patients who are progression free at the end of four cycles of chemotherapy plus bevacizumab are eligible for the trial. In arm 1, patients are treated with bevacizumab (15 mg/kg every 21 days) and in arm 2, patients are treated with erlotinib (150 mg/day) plus bevacizumab (15 mg/kg every 21 days). To date, about 300 of the 1,150 planned patients have been enrolled.

The BeTA Lung trial is a phase III, randomized trial comparing erlotinib plus bevacizumab with erlotinib alone in terms of efficacy (survival) and safety in the second-line treatment of nonsquamous stage IIIB/IV NSCLC. Among the secondary endpoints is the search for molecular markers predictive of clinical outcome. In arm 1, patients are treated with erlotinib (150 mg/day) and in arm 2 patients are treated with erlotinib (150 mg/day) plus bevacizumab (15 mg/kg every 21 days). At the moment, 350 of the 650 planned patients have been enrolled.

Finally, a phase II study of the Southwest Oncology Group (SWOG 0536) will evaluate the addition of the anti-EGFR mAb cetuximab to the combination of carboplatin, paclitaxel, and bevacizumab.

Adjuvant Treatment
Based on the results in advanced disease, some studies have been planned and others are already ongoing aimed at extending the benefit of bevacizumab into the adjuvant and neoadjuvant settings. A pilot trial of adjuvant bevacizumab in resected IIIAN2 NSCLC is being conducted to assess the safety and feasibility of the addition of bevacizumab to radiotherapy and cisplatin-based chemotherapy (cisplatin plus docetaxel and cisplatin plus gemcitabine) in the postoperative setting. In this trial, bevacizumab is administered simultaneously with chemotherapy and with radiotherapy, and after as maintenance therapy for 1 year. The Bevacizumab and Chemotherapy for Operable NSCLC (BEACON) trial, opened at Memorial Sloan Kettering Cancer Center, involves stage IB–IIIA patients with resectable NSCLC. It makes a distinction between nonsquamous, noncentral tumors on the one hand and tumors that are either squamous or large and central on the other. Patients with squamous or central tumors receive chemotherapy without bevacizumab; the others receive bevacizumab plus chemotherapy. Bevacizumab is not administered with the final cycle of chemotherapy before surgery. Postoperatively, all patients (including those with squamous tumors) receive maintenance bevacizumab for 1 year. This trial represents a good example of the problems connected with the use of bevacizumab in early-stage NSCLC. In fact, in early bevacizumab trials, patients with squamous tumors tended to have the greatest benefit from treatment but were also at greatest risk for hemoptysis resulting from bevacizumab disintegration of the tumor. Following surgical removal of the primary lesions, patients with squamous tumors may be able to benefit from the use of bevacizumab to attack microscopic residual disease remaining after surgery. In conclusion, the benefit from bevacizumab may be potentially extended preoperatively to nonsquamous tumors and postoperatively to both squamous and nonsquamous tumors.

A U.S. Intergroup trial, ECOG 1505, is ongoing and will compare cisplatin-based chemotherapy (carboplatin and paclitaxel or cisplatin and gemcitabine or cisplatin and docetaxel) with cisplatin-based chemotherapy plus bevacizumab for 1 year in patients with resected stage IB (with tumors 4 cm), stage II, and stage III disease. The target accrual for this trial is 1,500 patients.

At the moment, the role of bevacizumab in the adjuvant setting is completely undefined and its use in this condition must be limited to clinical trials.

Neoadjuvant Treatment
Rizvi et al. [51] very recently reported on the feasibility of the combination cisplatin and docetaxel plus bevacizumab in the neoadjuvant setting. Patients with resectable stage IB–IIIA NSCLC were eligible. Patients with adenocarcinoma (cohort 1) received preoperative bevacizumab plus docetaxel and cisplatin. Patients with squamous histology, central location, or recent hemoptysis received induction chemotherapy without bevacizumab (cohort 2). Cohort 1 received bevacizumab (15 mg/kg) followed by chemotherapy 2 weeks later to assess single-agent bevacizumab response. Cohort 2 received docetaxel and cisplatin alone followed by resection. Both cohorts received adjuvant bevacizumab for 1 year. At the moment, 19 patients of a planned 70 have been enrolled. Interestingly, after single-agent bevacizumab, a >10% reduction in tumor size was observed after 2 weeks in 6 of 11 patients. To date, bevacizumab has been safely administered in the neoadjuvant and adjuvant phase of this clinical trial with no unexpected toxicities. However, the study is ongoing.

Locally Advanced Disease
Bevacizumab also may be integrated into the treatment of locally advanced disease, potentially improving overall survival [36]. A phase I/II trial investigating the role of bevacizumab in the treatment of patients with unresectable IIIA/B disease is being coordinated by the University of North Carolina. Interestingly, patients with squamous histology are eligible, but patients with squamous tumors that abut or invade major blood vessels are excluded. Patients will receive induction therapy with two cycles of carboplatin, paclitaxel, and bevacizumab, and then will receive weekly carboplatin and paclitaxel and biweekly bevacizumab with concurrent thoracic radiotherapy. If the initial cohorts of patients have a tolerable toxicity profile, erlotinib will be integrated into the treatment. Another phase I/II trial will evaluate concurrent radiotherapy and weekly carboplatin and paclitaxel plus triweekly bevacizumab followed by consolidation with two cycles of carboplatin and paclitaxel plus bevacizumab. The SWOG is also performing a phase I/II trial in patients with unresectable IIIA/B disease. Patients will receive cisplatin and etoposide plus thoracic radiotherapy and docetaxel plus bevacizumab as consolidation therapy. Two cohorts of patients will receive bevacizumab, on different schedules, with cisplatin and etoposide during radiotherapy. Patients with squamous histology and tumor cavitation or tumor located within 1 cm of a major blood vessel will be excluded from the trial (Table 3).

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Angiogenesis and Lung Cancer VEGF and Bevacizumab Bevacizumab and NSCLC Treatment Conclusions References

	REFERENCES

Top Learning Objectives Abstract Introduction Angiogenesis and Lung Cancer VEGF and Bevacizumab Bevacizumab and NSCLC Treatment Conclusions References

 

1. Jemal A, Siegel R, Ward E et al. Cancer Statistics, 2007. CA Cancer J Clin 2007;57:43–66.[Abstract/Free Full Text]
2. Parkin DM, Bray F, Ferlay J et al. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94:153–156.[CrossRef][Medline]
3. Bria E, Cuppone F, Cecere FL et al. Adjuvant chemotherapy for non-small cell lung cancer. J Thorac Oncol 2007;2;(5) (suppl):S7–S11.
4. Rigas JR, Kelly K. Current treatment paradigms for locally advanced non-small cell lung cancer. J Thorac Oncol 2007;2(suppl 2):S77–S85.
5. Scagliotti G. Optimizing chemotherapy for patients with advanced non-small cell lung cancer. J Thorac Oncol 2007;2(suppl 2):S86–S91.[CrossRef]
6. Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small cell lung cancer. N Engl J Med 2005;353:123–132.[Abstract/Free Full Text]
7. Gridelli C, Rossi A, Maione P. New antiangiogenetic agents and non-small cell lung cancer. Crit Rev Oncol Hematol 2006;60:76–86.[CrossRef][Medline]
8. 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;355:2542–2550.[Abstract/Free Full Text]
9. Manegold 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-naïve patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704. J Clin Oncol 2007;25;(18) (suppl):LBA7514.
10. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990;82:4–6.[Free Full Text]
11. Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182–1186.[Medline]
12. Folkman J. Endothelial cells and angiogenic growth factors in cancer growth and metastasis. Introduction. Cancer Metastasis Rev 1990;9:171–174.[CrossRef][Medline]
13. Herbst RS, Onn A, Sandler A. Angiogenesis and lung cancer: Prognostic and therapeutic implications. J Clin Oncol 2005;23:3243–3256.[Abstract/Free Full Text]
14. Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 2005;23:1011–1027.[Abstract/Free Full Text]
15. Meert AP, Paesmans M, Martin B et al. The role of microvessel density on the survival of patients with lung cancer: A systematic review of the literature with meta-analysis. Br J Cancer 2002;87:694–701.[CrossRef][Medline]
16. Fontanini G, Lucchi M, Vignati S et al. Angiogenesis as a prognostic indicator of survival in non-small-cell carcinoma: A prospective study. J Natl Cancer Inst 1997;89:881–886.[Abstract/Free Full Text]
17. Ushijima C, Tsukamoto S, Yamazaki K et al. High vascularity in the peripheral region of non-small cell lung cancer tissue is associated with tumor progression. Lung Cancer 2001;34:233–241.[CrossRef][Medline]
18. Trivella M, Pezzella F, Pastorino U et al. Microvessel density as a prognostic factor in non-small-cell lung carcinoma: A meta-analysis of individual patient data. Lancet Oncol 2007;8:488–499.[CrossRef][Medline]
19. Keshet E, Ben-Sasson SA. Anticancer drug targets: Approaching angiogenesis. J Clin Invest 1999;104:1497–1501.[Medline]
20. Zebrowski BK, Yano S, Liu W et al. Vascular endothelial growth factor levels and induction of permeability in malignant pleural effusions. Clin Cancer Res 1999;5:3364–3368.[Abstract/Free Full Text]
21. Zebrowski BK, Liu W, Ramirez K et al. Markedly elevated levels of vascular endothelial growth factor in malignant ascites. Ann Surg Oncol 1999;6:373–378.[CrossRef][Medline]
22. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003;9:669–676.[CrossRef][Medline]
23. Houck K, Ferrara N, Winer J et al. The vascular endothelial growth factor family: Identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol 1991;5:1806–1814.[Abstract/Free Full Text]
24. Ferrera N. Vascular endothelial growth factor. Trends Cardiovasc Med 1993;3:244–250.[CrossRef]
25. Kaipainen A, Korhonen J, Mustonen T et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 1995;92:3566–3570.[Abstract/Free Full Text]
26. Paavonen K, Puolakkainen P, Jussila L et al. Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 2000;156:1499–1504.[Abstract/Free Full Text]
27. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–2342.[Abstract/Free Full Text]
28. Miller KD, Sledge GW, Burstein HJ. Angiogenesis inhibition in the treatment of breast cancer: A review of studies presented at the 2006 San Antonio Breast Cancer Symposium. Clin Adv Hematol Oncol 2007;5:1–12.[Medline]
29. Johnson 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;22:2184–2191.[Abstract/Free Full Text]
30. William WN, Kies MS, Fossella SV et al. Phase II study of bevacizumab in combination with docetaxel and carboplatin in patients with metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 2007;25;(18) (suppl):691S.
31. Dalsania CJ, Hageboutros A, Harris E et al. Phase II trial of bevacizumab plus pemetrexed and carboplatin in previously untreated advanced nonsquamous non-small cell lung cancer. J Clin Oncol 2007;25;(18) (suppl):697S.
32. Patel JD, Hensing TA, Villafor V. Pemetrexed and carboplatin plus bevacizumab for advanced non-squamous non-small cell lung cancer (NSCLC): Preliminary results. J Clin Oncol 2007;25;(18) (suppl):409S.
33. Davila E, Lilenbaum R, Raez L et al. Phase II trial of oxaliplatin and gemcitabine with bevacizumab in first-line advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2006;24;(18) (suppl):673S.
34. Waples JM, Auerbach M, Boccia R et al. A phase II study of oxaliplatin and pemetrexed plus bevacizumab in advanced non-squamous non-small cell lung cancer. J Clin Oncol 2007;25;(18) (suppl):685S.
35. Reynolds C, Barrera D, Vu DQ. 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). J Clin Oncol 2007;25;(18) (suppl):611S.[CrossRef]
36. Heist RS, Fidias P, Huberman M. Phase II trial of oxaliplatin, pemetrexed, and bevacizumab in previously-treated advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2007;25;(18) (suppl):634S.[CrossRef]
37. Havlik RJ, Yancik R, Long S et al. The National Institute on Aging and the National Cancer Institute SEER collaborative study on comorbidity and early diagnosis of cancer in the elderly. Cancer 1994;74;(7) (suppl):2101–2106.[CrossRef][Medline]
38. Merza T, Howard LM, Junagadhwalla M. Exclusions to use of bevacizumab in elderly veterans with advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2007;25;(18) (suppl):687S.
39. Gridelli 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;95:362–372.[Abstract/Free Full Text]
40. Ramalingam SS, Dahlberg SE, Langer CJ et al. Outcomes for elderly advanced stage non-small cell lung cancer (NSCLC) patients (pts) treated with bevacizumab (B) in combination with carboplatin (C) and paclitaxel (P): Analysis of Eastern Cooperative Oncology Group (ECOG) 4599 study. J Clin Oncol 2007;25;(18) (suppl):393S.
41. Maione P, Gridelli C, Troiani T et al. Combining targeted therapies and drugs with multiple targets in the treatment of NSCLC. The Oncologist 2006;11:274–284.[Abstract/Free Full Text]
42. Hirata A, Ogawa S, Kometani T et al. ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 2002;62:2554–2560.[Abstract/Free Full Text]
43. Ciardiello F, Caputo R, Damiano V et al. Antitumor effects of ZD6474, a small molecule vascular endothelial growth factor receptor tyrosine kinase inhibitor, with additional activity against epidermal growth factor receptor tyrosine kinase. Clin Cancer Res 2003;9:1546–1556.[Abstract/Free Full Text]
44. Ciardiello F, Bianco R, Damiano V et al. Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res 2000;6:3739–3747.[Abstract/Free Full Text]
45. Herbst 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;23:2544–2555.[Abstract/Free Full Text]
46. Tsao AS, Herbst R, Sandler A et al. Phase I/II trial of bevacizumab plus erlotinib for patients with recurrent non-small cell lung cancer: Correlation of treatment response with mutations of the EGFR tyrosine kinase gene. J Clin Oncol 2005;23;(16) (suppl):643s.
47. Lynch TJ, Bell DW, Sordella R et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129–2139.[Abstract/Free Full Text]
48. Paez JG, Janne PA, Lee JC et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497–1500.[Abstract/Free Full Text]
49. Fehrenbacher L, O'Neill V, Belani C et al. A phase II, multicenter, randomized clinical trial to evacuate the efficacy and safety of bevacizumab in combination with either chemotherapy (docetaxel or pemetrexed) or erlotinib hydrochloride compared with chemotherapy alone for treatment of recurrent or refractory non-small cell lung cancer. J Clin Oncol 2006;24(suppl 18S):379S.[CrossRef]
50. Groen 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). J Clin Oncol 2007;25;(18) (suppl):415S.
51. Rizvi NA, Rusch V, Zhao B. Single agent bevacizumab and bevacizumab in combination with docetaxel and cisplatin as induction therapy for resectable IB-IIIA non-small cell lung cancer. J Clin Oncol 2007;25;(18) (suppl):687S.

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