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The Oncologist, Vol. 9, Suppl 1, 19–26, June 1, 2004
© 2004 AlphaMed Press

Non-Small Cell Lung Cancer and Antiangiogenic Therapy: What Can Be Expected of Bevacizumab?

Roy S. Herbsta, Alan B. Sandlerb

a M.D. Anderson Cancer Center, Department of Head and Neck Medical Oncology, Houston, Texas, USA; b Vanderbilt University Medical Center, Division of Hematology/Oncology, Nashville, Tennessee, USA

Correspondence: Roy S. Herbst, M.D., M.D. Anderson Cancer Center, Department of Head and Neck Medical Oncology, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. Telephone: 713-792-6363; Fax: 713-796-8655; e-mail: rherbst{at}mdanderson.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Why Target Vascular Endothelial...
 Anti-VEGF Strategies
 Bevacizumab in NSCLC
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Identify the role of angiogenesis in non-small cell lung cancer (NSCLC).
  2. Explain the role of bevacizumab in apparently producing greater response, time to progression, and overall survival rates in a randomized phase II trial comparing carboplatin, paclitaxel, and bevacizumab with carboplatin and paclitaxel without bevacizumab and the limitations of this interpretation.
  3. Define the main toxicity concerns with the use of bevacizumab in the treatment of NSCLC.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit atCME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Why Target Vascular Endothelial...
 Anti-VEGF Strategies
 Bevacizumab in NSCLC
 Conclusions
 References
 
There is an urgent need for new therapies to treat non-small cell lung cancer (NSCLC), as progress with current chemotherapy regimens has been limited. The roles of vascular endothelial growth factor (VEGF) in promoting tumor angiogenesis, maintaining existing vasculature, and contributing to resistance to traditional therapies, together with its negative prognostic significance in NSCLC, make it an appropriate target for therapy. Bevacizumab (AvastinTM; Genentech Inc., South San Fransisco, CA), a monoclonal antibody directed against VEGF, has shown promise in treating a number of different cancers. In a recent phase II trial in patients with advanced metastatic NSCLC, the addition of bevacizumab to standard carboplatin/paclitaxel chemotherapy produced a significantly longer time to progression (32.1 versus 18.4 weeks) and greater response rate (31% versus 19% [not significant]) than chemotherapy alone. In the subset of patients with nonsquamous histologies, response rates and survival were further enhanced, with a mean survival time of 17.9 months versus 12.3 months with chemotherapy alone.

Bevacizumab was generally well tolerated and did not appear to increase the incidences or severities of the nausea/vomiting, neuropathy, and renal toxicity that are typically associated with carboplatin/paclitaxel chemotherapy. Adverse events in phase I and II studies included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. Serious tumor-related bleeding episodes (hemoptysis/hematemesis) appear to be the main safety concern in patients with NSCLC, with squamous cell histology as a possible risk factor.

Further work is needed to identify the best way to use bevacizumab in NSCLC, including use in combination with other biologic agents and in the adjuvant setting.

Key Words. Vascular endothelial growth factor • Clinical trial • Non-small cell lung cancer • Monoclonal antibody • Bevacizumab


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Why Target Vascular Endothelial...
 Anti-VEGF Strategies
 Bevacizumab in NSCLC
 Conclusions
 References
 
Non-small cell lung cancer (NSCLC) comprises over 75% of lung cancers and has proven to be particularly difficult to treat. Surgery provides the only curative treatment, but resection is possible in only 30% of patients at diagnosis, with metastatic disease developing in 50% of patients within 5 years [1]. Despite the development of new chemotherapy regimens, including platinum-based regimens, the prognosis for advanced inoperable NSCLC remains poor. A recent Eastern Cooperative Oncology Group clinical trial compared a standard regimen of cisplatin/paclitaxel with three other platinum-based regimens in 1,155 patients. The overall response rate was 19% and median survival was only 8.0 months, with a 33% survival rate at 1 year and an 11% survival rate at 2 years. No significant differences in these parameters were found among the different treatments. The median time to progression (TTP) was 3.4 months with cisplatin/paclitaxel; only the cisplatin/gemcitabine group showed a significantly better result (4.2 months) [2]. Similar results were reported in another recent comparative study involving carboplatin/paclitaxel and vinorelbine/cisplatin [3]. As these data represent the best care available at present, there is clearly a pressing need for new therapeutic approaches for NSCLC. Indeed, we may be approaching a ceiling with respect to the benefit that can be gained from combination chemotherapeutic interventions.


   WHY TARGET VASCULAR ENDOTHELIAL GROWTH FACTOR IN LUNG CANCER?
Top
 Learning Objectives
 Abstract
 Introduction
 Why Target Vascular Endothelial...
Anti-VEGF Strategies
 Bevacizumab in NSCLC
 Conclusions
 References
 
Treatment for cancer is now moving beyond traditional chemotherapy, with the advent of specific targeted therapies, and much research is focused on developing treatments based on inhibiting tumor angiogenesis. Generally, tumors cannot grow beyond approximately 2 mm in diameter without developing a vascular supply [4]. 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 establish distant metastases. Angiogenesis, whether physiological or pathological, is governed by a host of proangiogenic and antiangiogenic factors [5]. Among these, vascular endothelial growth factor (VEGF) is the most potent and specific of the endothelial cell mitogens, acting both as an endothelial cell survival factor and as a key factor in mobilizing circulating endothelial cell precursors to nascent blood vessels [5–8]. Not only does VEGF promote the vascularization and growth of the primary tumor, but it also appears to play a key role in the early establishment of new metastatic foci [9]. VEGF mRNA is upregulated in the majority of human tumors (Table 1Go), and this tends to correlate with poor prognosis (Table 2Go) [10]. Inhibition of VEGF, therefore, provides a particularly attractive strategy for antiangiogenic therapy in cancer [5, 11].


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  		Table 1. Human tumors overexpressing VEGF mRNA in situ
 

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  		Table 2. Prognostic value of VEGF as determined for breast cancer
 
In NSCLC, the majority of studies supports a correlation among VEGF expression, microvessel density (MVD), and poor prognosis. However, several studies suggest that angiogenesis has little or no predictive value [12, 13], although this may reflect methodologic differences, such as the use of different monoclonal antibodies [12]. In a study of the significance of the various VEGF isoforms in NSCLC, Yuan et al. reported that a high VEGF-189 level correlated with high intratumoral MVD, short survival, and early postoperative relapse, while VEGF-121 was correlated with short survival and relapse. In contrast, expression of two other isoforms, VEGF-165 and VEGF-206, had no predictive value [14].

Vascularity also varies within a tumor. Ushijima et al. found a strong correlation between peripheral, but not central, MVD counts and poor prognosis; moreover, high peripheral MVD values carried an especially poor prognosis when associated with a high expression level of VEGF [15]. A similar correlation between poor prognosis and localized elevated MVD at the advancing front of NSCLC tumors, accompanied by increased localized staining of VEGF and its receptor, was also reported by Koukourakis et al. [16]. Furthermore, these workers were able to differentiate between a standard MVD (sMVD) and an activated MVD (aMVD), with the latter composed of blood vessels that expressed the VEGF/VEGF receptor (VEGFR) complex. Although the sMVD level was higher in nontumorous areas of the lung, aMVD levels were higher in the tumor, particularly at the advancing tumor front. Multivariate analysis showed that aMVD was the most important independent prognostic factor.

Finally, it should be noted that some NSCLC tumors do not appear to require any neoangiogenesis for their progression. Passalidou et al. reported that nine of 113 tumors showed no evidence of new blood vessel growth, but instead filled up the alveoli and appropriated existing blood vessels within the trapped alveolar septa [17].


   ANTI-VEGF STRATEGIES
Top
 Learning Objectives
 Abstract
 Introduction
 Why Target Vascular Endothelial...
 Anti-VEGF Strategies
Bevacizumab in NSCLC
 Conclusions
 References
 
A variety of therapeutic strategies aimed at blocking VEGF or its receptor-signaling system is currently being developed for the treatment of cancer (Table 3Go). The best-studied approaches are VEGF/VEGFR blockade by monoclonal antibodies (MAbs) and inhibition of receptor signaling by tyrosine-kinase inhibitors.


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  		Table 3. Angiogenesis inhibitors in phase II/III development
 
VEGF receptor tyrosine-kinase (RTK) inhibitors in development include SU6668, vatalanib (PTK787/ ZK 222584), and ZD6474. These agents vary in their receptor specificities. SU6668 inhibits the platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptors in addition to VEGFR-2 [18, 19]. Vatalanib also inhibits other class III kinases, albeit at higher concentrations [20]. ZD6474 inhibits VEGFR-1 and VEGFR-2 tyrosine kinase activities, but has also been reported to inhibit a range of other tyrosine and serine-threonine kinases [21].

SU6668 and vatalanib inhibited growth of a range of human-tumor xenografts in mice and inhibited neovascularization within these tumors [19, 20]. ZD6474 was also shown to inhibit tumor growth in vivo [21]. Significant toxicity and poor clinical efficacy led to the withdrawal of SU5416, a selective and potent inhibitor of VEGFR-1 and VEGFR-2, from further development [22]. Phase I clinical trials of SU6668 found serious dose-limiting myelosuppression (grade 3 thrombocytopenia) at doses of 400–800 mg/m2/d. However, 300 mg/m2/d was found to be tolerable (mild-to-moderate nausea, diarrhea, fatigue, and dyspnea observed) and was selected for phase II development. Early results for vatalanib showed that stable disease was achieved in several patients with colorectal cancer [23].

Bevacizumab (rhuMAb VEGF; AvastinTM; Genentech, Inc.; South San Francisco, CA) is a recombinant humanized monoclonal antibody to VEGF composed of human IgG1 framework regions and antigen-binding complementarity-determining regions from a murine antibody (A.4.6.1) that blocks binding of human VEGF to its receptors [24]. Bevacizumab is being assessed in a range of cancer types, including NSCLC. Promising results have been seen in breast cancer, and, in particular, colorectal cancer and renal cell cancer [25–28]. Results from a recent phase III study in patients with untreated metastatic colorectal cancer demonstrate a significant survival benefit conferred by the addition of bevacizumab to irinotecan/5-fluorouracil/leucovorin (IFL) chemotherapy, and provide the first phase III validation of the antiangiogenic approach for the treatment of human cancer [27]. The renal cancer study was stopped early because of a highly significant longer TTP with bevacizumab monotherapy [28]. Moreover, long-term disease stabilization was achieved in several patients with various tumor types who were treated with bevacizumab under an extension protocol [29]. Thirty-five patients received bevacizumab for >=1 year and six patients received the drug for >=2 years. There were three complete and 15 partial responses, and 14 patients had disease stabilization. The median survival was not reached, but was >27.5 months, with 25 patients (71%) still alive at 2 years. Ongoing studies are evaluating bevacizumab in a range of cancer types, mostly in combination with chemotherapy or other modalities [30].

The remainder of this review focuses on the potential of bevacizumab in the treatment of NSCLC.


   BEVACIZUMAB IN NSCLC
Top
 Learning Objectives
 Abstract
 Introduction
 Why Target Vascular Endothelial...
 Anti-VEGF Strategies
 Bevacizumab in NSCLC
Conclusions
 References
 
Preclinical Studies
Bevacizumab, or its parent murine antibody A.4.6.1, inhibits the growth of various human tumor cell types in murine xenograft models [31–33], including the CALU-6 NSCLC model [34]. There was no inhibitory effect exerted on the growth of cancer cells in vitro, and treated tumors showed reduced vascularity [33] and reduced interstitial pressure [32, 35]. In addition to inhibition of the primary tumor, reduction in metastases was also observed in some studies [36–38].

Hypoxia-induced production of VEGF is believed to be important in mediating tumor resistance to radiotherapy and chemotherapy [39], and the antibody A.4.6.1 significantly augments the antitumor effects of both modalities [31, 34]. Administration of bevacizumab was able to reverse the protective effect of VEGF against the antiangiogenic effects of docetaxel in endothelial cells in vitro and in vivo [40].

Finally, VEGF has been shown to inhibit differentiation of dendritic cells, and this inhibition can be reversed by an anti-VEGF antibody, with a corresponding increase in antitumor immune responses [41, 42].

Phase II Clinical Trial in NSCLC
A randomized, multicenter, phase II trial was conducted involving 99 patients with newly diagnosed stage IIIB (with pleural effusion), stage IV, or recurrent NSCLC [43]. Patients were randomized to receive either carboplatin (target area under the concentration-time curve of 6 mg/ml/min) plus paclitaxel (200 mg/m2) chemotherapy every 3 weeks or carboplatin plus paclitaxel chemotherapy with bevacizumab at a dose of 7.5 mg/kg (low dose) or 15 mg/kg (high dose) every 3 weeks. The principal efficacy end points were TTP and best tumor response rates (complete or partial response), as determined both by the investigators and by an independent review facility. The results of that study are shown in Table 4Go. Bevacizumab, 15 mg/kg, plus carboplatin/paclitaxel produced a greater response rate (31.5% versus 18.8%) and longer median TTP (7.4 months versus 4.2 months) than chemotherapy alone. A modestly longer survival time, 17.7 versus 14.9 months (Fig. 1Go), was also evident. Nineteen patients in the control group who showed disease progression were allowed to cross over to receive high-dose bevacizumab monotherapy; no objective responses were observed in those patients, although 5 of the 19 had one measurement of stable disease [43].


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  		Table 4. Efficacy of bevacizumab (BEV) when added to carboplatin/paclitaxel (CP) in patients with locally advanced or metastatic NSCLC
 


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  		Figure 1. Kaplan-Meier curve showing overall survival of patients receiving bevacizumab, 7.5 mg/kg or 15 mg/kg, plus paclitaxel/carboplatin versus paclitaxel/carboplatin alone (control).

 
Tolerability
In phase I trials, bevacizumab did not display dose-limiting toxicities when administered alone, nor did it lead to synergistic toxicities when combined with standard chemotherapy regimens [44, 45]. Adverse events in phase I and II studies, including the phase II NSCLC trial (see above), included hypertension, thrombosis, proteinuria (with occasional nephrotic syndrome), and epistaxis. In the extension study, no unexpected adverse events were observed after 1 year of therapy. Deep venous thrombosis occurred after 1 year of treatment, but patients were able to remain on bevacizumab with anticoagulant therapy [29].

Tolerability data for the phase II NSCLC trial are shown in Table 5Go. Bevacizumab was generally well tolerated and did not appear to increase the incidences or severities of the nausea/vomiting, neuropathy, and renal toxicity that are typically associated with carboplatin/paclitaxel chemotherapy. However, a dose-related increase in the incidence of leukopenia, including grade 3 and 4 events, was seen [43]. The main tolerability concern in this study was the occurrence of bleeding episodes. Classified as hemoptysis/hematemesis, they occurred in six patients (five in the low-dose group), four of whom died. All six cases appeared to be tumor related, originating from centrally located pulmonary tumors close to major blood vessels. Cavitation or necrosis of the tumor had occurred in five cases (Fig. 2Go). Such bleeding episodes have not been reported in patients receiving bevacizumab in breast, colorectal, prostate, or renal cell cancer trials [43].


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  		Table 5. Main adverse events associated with bevacizumab (BEV) plus carboplatin/paclitaxel (CP) in patients with advanced or metastatic NSCLC
 


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  		Figure 2. Example of tumor cavitation in phase II trial of bevacizumab plus paclitaxel/carboplatin in advanced or metastatic NSCLC patients.

 
Exploratory analysis found squamous-cell histology as a possible risk factor in patients receiving bevacizumab, as this characteristic was found in tumors of four of the six patients (67%) with serious bleeding, while only 20/99 (20%) enrolled patients had squamous-cell histologies [46]. Accordingly, patients with this tumor type have been excluded from the ongoing trial, E4599. Further information as to whether this issue is of particular concern in lung cancer may come from planned trials of bevacizumab in combination with etoposide plus platinum in patients with small cell lung cancer, in whom central tumors are common.

There was a higher incidence of thrombotic events associated with bevacizumab. However, when thrombotic events related to occlusion of central lines were considered separately, the numbers of events were similar across the three treatment arms.

Ongoing Studies
Several ongoing trials are assessing bevacizumab in combination with other therapies in NSCLC [47]. These include:


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Why Target Vascular Endothelial...
 Anti-VEGF Strategies
 Bevacizumab in NSCLC
 Conclusions
References
 
In targeting VEGF, bevacizumab is directed against one of the key factors that promotes tumor growth and spread, not only by mediating tumor angiogenesis but also by promoting development of resistance to standard therapies. The encouraging results achieved by adding bevacizumab to standard combination chemotherapy in patients with advanced metastatic NSCLC justify further studies, particularly evaluations in earlier-stage disease. Ongoing trials will provide more detailed information on the most effective use of this new drug, including the optimal dosage and scheduling with chemotherapy and other targeted therapies, as well as minimizing the risk of bleeding episodes.

There are compelling reasons for using antiangiogenic therapy in combination with other drugs [26, 49, 50]. The profusion of angiogenic factors that can be produced by tumors suggests that inhibition of angiogenesis may require the combined action of several inhibitors. Secondly, traditional chemotherapeutic agents exert antiangiogenic effects of their own, and these effects can be potentiated by agents such as antibodies to VEGF [5].

Contrary to the assumption that inhibition of angiogenesis would impede delivery of chemotherapeutic agents to tumors by reducing their vascularity, the efficacy of chemotherapy is potentiated by the coadministration of antiangiogenic therapy [51]. Antiangiogenic agents act to prune and normalize the vascular supply that is typically aberrant in tumors [52]. Finally, inhibiting VEGF can counter tumor resistance to chemotherapy and radiotherapy and, possibly, to other antiangiogenic therapies [53], as well as reduce the enhanced tumor interstitial pressures that impede drug delivery.

It is possible that we are reaching the limits of what conventional chemotherapy can achieve in patients with advanced NSCLC. The advent of targeted therapies, such as bevacizumab, looks likely to improve prospects for such patients.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Why Target Vascular Endothelial...
 Anti-VEGF Strategies
 Bevacizumab in NSCLC
 Conclusions
 References
 

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Received November 25, 2003; accepted for publication January 15, 2004.




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