Role of Anti-angiogenesis Agents in Treating NSCLC: Focus on Bevacizumab and VEGFR Tyrosine Kinase Inhibitors

OPINION STATEMENT: Successful inhibition of angiogenesis with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab has improved the efficacy seen with standard cytotoxic therapy in NSCLC. The addition of bevacizumab to first-line chemotherapy improved response rate and progression free survival and added 2 months to median overall survival for those patients with advanced stage NSCLC on the treatment arm of E4599. Bevacizumab is now a standard agent to add to frontline carboplatin and paclitaxel for patients with newly diagnosed NSCLC who meet the eligibility criteria from the landmark E4599 trial. Unfortunately about half of all patients are not eligible either because they have squamous histology, brain metastases, or are on anti-coagulation. Ongoing trials are further exploring the safety of bevacizumab in these patient populations, as well as in combination with other cytotoxic regimens. Exploration of other applications of bevacizumab in the second-line and adjuvant setting are ongoing as well. The largest class of drugs that block angiogenesis are the multi-targeted tyrosine kinase inhibitors (TKIs) that target the VEGF receptor (VEGFR). These drugs are still in development, and though two are now on the market for treating other malignancies, their role in NSCLC is under investigation. These agents have the advantages of hitting multiple targets, convenient oral administration, and potential for lower cost. Their lack of target specificity leads to unexpected toxicity, but also promising efficacy. For example, the overall objective response rate of 9.5% with single agent sunitinib compares similarly to that of pemetrexed or docetaxel in previously treated NSCLC patients, but toxicity, notably fatigue, lead to discontinuation in 38% of patients. Hypertension, hemorrhage and cavitation are common toxicities amongst this class of agents. Rash, fatigue, myalgia, and hand-foot syndrome are more specifically seen with TKIs. These compounds may also be synergistic or additive with traditional cytotoxic chemotherapy drugs and other novel compounds. In early trials sorafenib as a single agent has shown no clinical response in previously treated NSCLC patients, whereas clinical benefit in combination with erlotinib or chemotherapy has been seen in early studies. Vandetanib has demonstrated objective responses as a single agent and in combination with chemotherapy in previously treated NSCLC patients. A phase I trial of AZD2171 with carboplatin and paclitaxel in newly diagnosed advanced stage NSCLC also demonstrated promising results with 6 of 15 patients achieving partial responses. NSCLC specific trials are also underway, or in development for pazopanib, axitinib, AMG 706, XL647, enzastaurin, and other TKIs. Other anti-angiogenesis agents with different mechanisms of action include thalidomide and its derivatives, monoclonal antibodies to the VEGFRs, and VEGF Trap, a chimeric molecule which combines extracellular portions of VEGFR1 and VEGFR2 with the Fc portion of immunoglobulin G1 to form a molecule that binds and "traps" VEGF. Despite modest improvements, prognosis continues to be poor for patients with advanced NSCLC. Bevacizumab is a first step into the world of angiogenesis inhibitors for NSCLC and though it only offers a modest survival benefit in a limited patient population, it paves the way for the development of the next generation of anti-angiogenesis inhibitors. We can hope that further improvements in survival will follow.     

Chemotherapy for advanced non-small cell lung cancer

It is well-known that cisplatin-based chemotherapy can prolong the survival of patients with advanced non-small cell lung cancer (NSCLC). This report reviews the recently published clinical trials of chemotherapy for advanced NSCLC. New agents developed in the 1990s such as paclitaxel, docetaxel, gemcitabine, vinorelbine and irinotecan prolonged the survival of patients with advanced NSCLC by single-agent chemotherapy, and combinations of platinum and one of the new agents were superior to existing platinum-based combinations. Accordingly, the current standard chemotherapy for previously untreated patients with advanced NSCLC is considered to be a two-drug combination consisting of cisplatin and one of the new agents. For elderly patients, single-agent chemotherapy using vinorelbine or gemcitabine is recommended. However, the usefulness of platinum-containing chemotherapy for elderly patients has not yet been throughly evaluated. As salvage chemotherapy for patients previously treated with chemotherapy, the effectiveness of docetaxel is confirmed by two randomized trials. However, since many promising agents including pemetrexed and molecular targeting agents such as gefitinib, erlotinib and bevacizumab have been currently developed, we have to evaluate the usefulness of these agents by well-designed clinical trials.     

Advances in the treatment of second-line non-small-cell lung cancer

Treatment with third-generation chemotherapy agents improves survival and quality of life of patients with non-small-cell lung cancer (NSCLC). Despite these favorable outcomes, most patients receiving front-line therapy experience disease progression. The availability of many new novel agents with activity in NSCLC has prompted investigators to explore second-line chemotherapy options. For many years, docetaxel was the only approved agent for the second-line treatment of NSCLC. More recently, the multi-targeted antifolate pemetrexed has demonstrated activity in patients previously treated with chemotherapy with locally advanced or metastatic NSCLC. The findings of a phase III trial comparing pemetrexed to docetaxel led to the regulatory approval of pemetrexed as monotherapy for the second-line treatment of NSCLC. Several other novel therapies, including molecular targeting agents such as erlotinib, are under development in clinical trials in patients with NSCLC. One of these trials has subsequently led to the approval of erlotinib as second- or third-line therapy in advanced NSCLC.     

Perspectives on salvage therapy for non-small-cell lung cancer

Platinum-based chemotherapy offers a modest survival advantage over best supportive care in chemotherapy-naive patients with a good performance status and advanced/metastatic non-small-cell lung cancer (NSCLC). Despite the survival benefit associated with first-line chemotherapy, the majority of patients will experience relapse or disease progression. In clinicalpractice, an increasing number of patients maintain a good performance status after first-line treatment and are eligible for further treatments. Docetaxel (Taxotere) at 75 mg/m2 given once every 3 weeks has been the standard of care for second-line chemotherapy since the year 2000. Pemetrexed (Alimta) is a novel multitargeted antifolate agent with single-agent activity in first- and second-line treatment of NSCLC. A large phase 111 study comparing docetaxel to pemetrexed in second-line therapy demonstrated that pemetrexed is equally active and less toxic than docetaxel. Based on these results, pemetrexed is a reasonable second-line chemotherapy option for patients with recurrent, advanced NSCLC. Progress made in the field of molecular biology has led to the identification of drugs active against specific cellular targets. Gefitinib (Iressa) and erlotinib (Tarceva) are both orally active tyrosine kinase inhibitors of the epidermal growth factor receptor. Phase II and III trials have demonstrated that these agents are active particularly in a subgroup of patients with specific biologic characteristics. Both drugs have been approved for the treatment of pretreated NSCLC. Other drugs, such as cetuximab (Erbitux) and bevacizumab (Avastin) have shown promising activity in NSCLC and are currently being tested in clinical trials.     

Docetaxel in the treatment of advanced non-small-cell lung cancer

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non-small-cell lung cancer (NSCLC). Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platinum–docetaxel regimens for the first-line treatment of advanced NSCLC. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II trials. This review article summarizes recent studies of docetaxel as a single agent and in combination regimens with cytotoxic or targeted therapies in the management of patients with advanced NSCLC.     

Optimal Duration of Chemotherapy in Advanced Non-Small Cell Lung Cancer

Opinion statement NSCLC is the leading cause of cancer mortality in the United States. Approximately 30–40% of patients present with advanced stage disease (Stage IIIb with malignant effusion and Stage IV) and the majority of those who present with “earlier” disease will ultimately develop and succumb to metastatic lung cancer. Although platinum-based combination chemotherapy has been shown to impact overall survival and quality of life, it is not curative and less than 25% of patients survive 2 years. Therefore, the benefits of chemotherapy must be weighed against toxicity, inconvenience, and cost. Several randomized trials have shown that there is no added benefit of extending first line, platinum-based chemotherapy beyond four cycles. There was no additional survival benefit and patients experienced increased toxicity with longer durations of therapy. Attempts to improve outcome by planned sequential therapy, i.e. shifting from one cytotoxic regimen to another after a fixed number of cycles have also not been successful. Several new so-called “targeted” therapeutic agents have recently been evaluated in clinical trials to assess whether the efficacy of first line chemotherapy with platinum doublets can be improved with the addition of these agents. These include bevacizumab, epidermal growth factor receptor inhibitors (erlotinib and gefitinib), bexarotene, matrix metalloproteinase inhibitors, and others. Other than bevacizumab, none have demonstrated benefit in this scenario. The design of most of these trials employed the concurrent use of the new agent with six cycles of platinum-based chemotherapy (usually either carboplatin/paclitaxel or cisplatin/gemcitabine) and then continued the new agent until relapse. Three agents have demonstrated benefit in randomized studies in the second line setting, docetaxel, pemetrexed, and erlotinib. No study has evaluated the optimal duration of therapy for these agents, though for erlotinib, it appears that use until progression is optimal. Future studies of novel agents will need to explore not only the potential use of these agents in combination or in comparison with standard therapy, but also the duration of therapy and consider issues of survival, quality of life, and cost.     

Docetaxel in the treatment of advanced non-small-cell lung cancer

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non-small-cell lung cancer (NSCLC). Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platinum-docetaxel regimens for the first-line treatment of advanced NSCLC. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II trials. This review article summarizes recent studies of docetaxel as a single agent and in combination regimens with cytotoxic or targeted therapies in the management of patients with advanced NSCLC.     

First-line treatment for advanced non-small-cell lung cancer

With best supportive care alone, patients with metastatic non-small-cell lung cancer (NSCLC) have a median survival of 4 to 5 months and a 1-year survival rate of approximately 10%. Trials carried out in the 1980s and 1990s comparing chemotherapy to best supportive care reported variable efficacy results; however, a pivotal meta-analysis of these data indicated that cisplatin-based chemotherapy provided a survival benefit in advanced NSCLC. In the past decade newer agents such as gemcitabine (Gemzar), vinorelbine, paclitaxel, and docetaxel (Taxotere) have all demonstrated activity in NSCLC as single agents; consequently these agents have been combined with cisplatin or carboplatin. Randomized phase III trials comparing these "newer" platin-based doublets have failed to identify an optimal platinum-based doublet therapy regimen. Though it is clear that chemotherapy is an appropriate treatment for many patients with lung cancer, there a sense in which the use of traditional chemotherapeutic agents has reached a therapeutic plateau. Increased understanding of cancer biology has revealed numerous potential therapeutic strategies, including targeting the epidermal growth factor receptor, protein kinase C, rexinoid receptors, and the angiogenesis pathway. The Eastern Cooperative Oncology Group study E4599 comparing paclitaxel/carboplatin with/without bevacizumab is the first phase III randomized trial to show a survival advantage with the addition of a molecularly targeted agent to chemotherapy in the chemotherapy-naive patient population. Future studies will involve the evaluation of additional targeted agents plus chemotherapy as well as looking at combinations of these targeted agents alone or with chemotherapy.     

The place of targeted therapy in the patient management of non-small cell lung cancer

There is much interest in the use of targeted therapies for the management of non-small cell lung cancer (NSCLC). To date, four targeted therapies - bevacizumab, cetuximab, erlotinib and gefitinib - have been investigated in randomised trials, in the treatment of advanced NSCLC. In the first-line setting, bevacizumab has been shown to significantly prolong survival when added to carboplatin/paclitaxel, as demonstrated in a large phase III study. However, issues of toxicity limit this treatment regimen to selected patients. The addition of bevacizumab to gemcitabine/cisplatin will be reported at ASCO 2007. The addition of cetuximab to cisplatin/vinorelbine has also been shown to improve survival in a randomised phase II study. Erlotinib has been investigated as monotherapy in first-line chemo-na?ve patients and has demonstrated objective response rates of 10-23%. However, in a study comparing erlotinib versus chemotherapy, the outcome was less favourable for patients who had received erlotinib. Erlotinib monotherapy has also been investigated in recurrent disease, and has been shown to improve overall survival over that achieved with placebo. The greatest benefit was observed in never-smokers with epidermal growth factor receptor-positive tumours. In a further phase II randomised study, the effect of combining two targeted therapies has been investigated. This study compared erlotinib/bevacizumab versus bevacizumab/chemotherapy versus chemotherapy alone. Both regimens including targeted therapy were comparable and superior to chemotherapy alone. However, these are preliminary data and further research is required to clarify the role of targeted therapies in the management of advanced NSCLC.     

Docetaxel in advanced non-small cell lung cancer

Based on the survival benefit demonstrated in large randomized clinical trials, docetaxel is approved for the treatment of advanced non-small cell lung cancer (NSCLC) in both the first- and second-line settings. The efficacy of docetaxel in combination with cisplatin is equivalent to some, and superior to other, platinum-based doublets for first-line management of NSCLC, and has a manageable toxicity profile. Carboplatin-based regimens and nonplatinum combinations with docetaxel also have proven efficacy in first-line therapy of patients with advanced NSCLC. Combinations of docetaxel with various novel targeted agents have produced encouraging data in Phase II studies. This article reviews recent studies of docetaxel as a single agent and in combination regimens with cytotoxic and more recent targeted agents in the management of advanced NSCLC.     

Salvage therapy for advanced non-small cell lung cancer: factors influencing treatment selection

Novel chemotherapies and molecularly targeted agents have improved outcomes for patients with advanced non-small cell lung cancer (NSCLC). Several efficacious regimens are available, which allows for selection of therapy based on factors such as schedule, toxicity profile, patient-specific needs, and individual preferences of the patient. Treatment guidelines recommend platinum-based chemotherapy first line for patients with a good performance status. These regimens offer a modest survival advantage over best supportive care. The role of targeted biologic agents in this setting is being assessed in phase II trials. Results to date show promising activity and tolerability. Erlotinib, docetaxel, and pemetrexed are all approved for patients who progress following one prior regimen for advanced NSCLC. These agents have different tolerability profiles and routes of administration but appear to have similar effects on tumor response and survival, though comparative trials are required to confirm this. Based on the results of a phase III trial, erlotinib is also recommended for third-line use in patients with NSCLC. Identifying predictive markers of clinical response to therapy may provide an opportunity to better select patient subsets appropriate for specific treatment. Recent data have linked various clinical characteristics and biologic markers with outcome to HER-1/EGFR-targeted agents. However, many of these studies are retrospective and based on small patient numbers, and there is evidence of broad benefit across diverse patient subgroups with erlotinib. Prospective, randomized trials are required to validate potential predictive markers fully before they are applied to clinical practice.     

Second-line Treatment for Non–Small-Cell Lung Cancer: One Size Does Not Fit All

After progression following first-line treatment, many patients with advanced non–small-cell lung cancer (NSCLC) still have a good performance status and can be considered for further treatments. Based on 2 randomized phase III trials, docetaxel was the first approved second-line therapy associated with longer survival and better quality of life compared with best supportive care alone and vinorelbine or ifosfamide. Since then, other agents have been approved for the second-line treatment of NSCLC (ie, pemetrexed, erlotinib, and gefitinib). Recently, new molecular-targeted agents are being increasingly considered in this setting, above all, bevacizumab and vandetanib. The discovery and validation of predictive markers of efficacy for both chemotherapy drugs and the new targeted therapies is of primary importance for the selection of second-line treatment for all patients with advanced NSCLC.     

Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions

Systemic therapy improves the survival and quality of life of patients with advanced stage non-small cell lung cancer (NSCLC). Several new therapeutic options have emerged for advanced NSCLC, incorporating novel cytotoxic agents (taxanes, gemcitabine, pemetrexed) and molecular-targeted agents (erlotinib, bevacizumab). Efforts to improve the outcome of first-line therapy for advanced and metastatic NSCLC have primarily focused on the addition of targeted agents to platinum-based two-drug regimens. Bevacizumab, an antibody against vascular endothelial growth factor, is the first drug to demonstrate superior outcomes when added to systemic chemotherapy in advanced disease. Evaluation of the role of maintenance therapy following four to six cycles of first-line combination chemotherapy is ongoing. Both cytotoxic agents and targeted agents are suitable for evaluation in the maintenance setting. Promising results have been noted with single-agent paclitaxel as maintenance therapy following four cycles of combination therapy with carboplatin and paclitaxel. Phase III studies are now under way to evaluate the roles of gemcitabine, pemetrexed, and erlotinib as maintenance therapies for patients who experience a response or disease stabilization after four cycles of combination chemotherapy. Whether this approach will be successful in extending the survival of a select group of patients remains to be seen.     

The Role of Anti–Epidermal Growth Factor Receptor and Anti–Vascular Endothelial Growth Factor Therapies in the Treatment of Non–Small-Cell Lung Cancer

Standard first-line therapy for non–small-cell lung cancer (NSCLC) with platinum-based agents, given in combination with cytotoxic compounds, has reached a relative plateau in its therapeutic efficacy. Novel molecular targeted agents acting on specific pathways have emerged as effective agents for treating NSCLC; some have already produced positive results in phase III trials. Notably, inhibition of the vascular endothelial growth factor (VEGF) pathway with an anti-VEGF antibody, bevacizumab, and targeting the epidermal growth factor receptor (EGFR) pathway with a small-molecule EGFR tyrosine kinase inhibitor erlotinib or a monoclonal antibody (cetuximab) have demonstrated prolonged survival in patients with advanced disease in both the first- and second-line settings. The heterogeneity of signaling processes leading to tumor cell survival and proliferation supports the targeting of multiple signaling pathways as an effective anticancer treatment strategy. Consequently, rational combinations of molecular targeted agents might offer superior clinical efficacy and an alternative treatment option to patients refractory to, or unable to tolerate, standard chemotherapy. The challenge lies in determining which molecular entities should be pursued and the best approach to combine them. This review discusses the potential clinical utility of combining bevacizumab and erlotinib to inhibit both angiogenesis and EGFR signaling as a valid nonchemotherapeutic approach for the treatment of NSCLC. Other combinations of novel therapies that block EGFR and angiogenic pathways, as well as complementary signaling pathways, with unique modes of action and low toxicity profiles could offer an increased repertoire of individualized treatment options for patients with advanced NSCLC.     

Incorporating novel agents with gemcitabine-based treatment of NSCLC

First-line treatment with a two-drug combination chemotherapy regimen comprising of a platinum-based agent with a third-generation agent has been the accepted standard of care in most countries for the treatment of advanced non-small-cell lung cancer (NSCLC). Previously, the addition of a third agent to standard chemotherapy regimens has failed to improve survival in the majority of randomized trials that have been conducted. However, recent findings suggest that the addition of the novel targeted agent bevacizumab to a standard paclitaxel/carboplatin regimen significantly improves survival. The addition of novel agents to gemcitabine-based regimens is therefore a logical approach to improving the treatment of advanced NSCLC. Several trials of gemcitabine-based regimens with bevacizumab are ongoing.     

Optimizing chemotherapy for advanced non-small cell lung cancer: focus on docetaxel

Systemic chemotherapy with platinum-based combinations provides modest improvements in both survival and quality of life for patients with advanced non-small cell lung cancer (NSCLC). For first-line treatment of advanced NSCLC patients with a good performance status, the accepted standard of care is a platinum agent combined with docetaxel, paclitaxel, gemcitabine, vinorelbine or irinotecan. Several studies have attempted to identify an optimal platin-based regimen, however, all regimens offer some combination of clinical benefit with characteristic toxicities and no regimen appears clearly superior. Non-platinum regimens have also shown equivalent efficacy compared to platinum combinations, but again, none are clearly superior. Most recently, the existing standard of care is being amended to reflect the survival advantage gained from adding a new targeted agent, bevacizumab, to traditional platinum-doublet therapy for patients with non-squamous NSCLC. Docetaxel is the only agent currently approved for both first- and second-line treatment of advanced NSCLC. Multiple randomized clinical trials have established the efficacy of platin-docetaxel regimens for first-line treatment of advanced NSCLC. Improvements in various lung cancer related symptoms and global quality of life indices have also been noted with docetaxel-based regimens. Based on the efficacy of platin-docetaxel regimens in advanced disease, they are now being incorporated into the adjuvant and neoadjuvant treatment of early-stage disease.     

Optimizing first-line treatment options for patients with advanced NSCLC

The median survival time for advanced non-small cell lung cancer (NSCLC) remains poor, despite years of research into new chemotherapy combinations. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. While no one particular platinum-based chemotherapy regimen is definitely superior to the others (as demonstrated in the Eastern Cooperative Oncology Group's E1594 trial), three randomized phase III trials (the Southwest Oncology Group 9509, Italian Lung Cancer Project, and TAX326 trials) have recently demonstrated that taxane-platinum doublets are better tolerated than a combination of vinorelbine and cisplatin (VC). Moreover, a combination of docetaxel and cisplatin produced superior survival and quality of life than VC in the TAX326 study. Nonplatinum combinations, such as a taxane-gemcitabine doublet, appear promising and better tolerated than their platinum-based comparators in other studies. Efforts to evaluate chemotherapy specifically in elderly patients and in those with poor performance status (PS) have increased. Single-agent chemotherapy has been safely administered to these populations, but platinum-based doublet therapy may also be feasible in both elderly patients and patients with PS scores of 2. The addition of the monoclonal antibody against vascular endothelial growth factor, bevacizumab, to standard chemotherapy for patients with non-squamous cell advanced NSCLC significantly extended median survival in the E4599 randomized trial. Each incremental advance demonstrates that progress can be made in first-line treatment of advanced NSCLC.     

Investigating the potential of bevacizumab in other indications: metastatic renal cell, non-small cell lung, pancreatic and breast cancer

Bevacizumab (Avastin) has unprecedented survival benefit in patients with metastatic colorectal cancer. Trials are already in progress to investigate the potential of bevacizumab in indications including metastatic renal cell cancer (RCC), non-small cell lung cancer (NSCLC), pancreatic cancer, breast and ovarian cancer. Bevacizumab offers the potential to increase survival without substantially altering the toxicity profile in these tumor types. Bevacizumab has shown activity in patients with refractory metastatic RCC, where progression-free survival (PFS) was significantly longer in patients treated with bevacizumab (10 mg/kg every 2 weeks) than those treated with placebo (hazard ratio=2.55, p<0.001). In addition, combining bevacizumab with erlotinib (Tarceva) has shown a median time to progression of more than 11 months. In NSCLC, a phase II trial revealed that adding bevacizumab to chemotherapy increased therapeutic benefit compared with chemotherapy alone. Adverse events were mild and easily managed, but six patients receiving bevacizumab developed severe hemoptysis. Entry criteria for NSCLC trials have been adjusted to exclude patients with squamous cell histology to try to avoid this issue. Adding bevacizumab (10 mg/kg) to the current standard of care, gemcitabine, in stage IV pancreatic cancer has also shown promising efficacy. Partial responses were seen in 19% of patients, with a further 48% having stable disease. Several ongoing clinical trials are also studying bevacizumab with various chemotherapy and radiotherapy regimens. Bevacizumab combined with carboplatin (Paraplatin)/paclitaxel (Taxol) was further examined in a phase III randomized trial that accrued 878 patients with advanced non-squamous cell NSCLC. Patients given chemotherapy (paclitaxel and carboplatin) plus bevacizumab had a higher response rate, longer PFS and an increase in survival compared with patients on chemotherapy alone. Both regimens were generally well tolerated. Bevacizumab has also shown activity in patients with metastatic breast cancer. In 715 patients, a significant, 2-fold increase in response rate was observed in patients receiving bevacizumab plus paclitaxel compared with paclitaxel alone. Median PFS was also significantly increased (p<0.001). Bevacizumab has the potential to provide significant efficacy benefits for patients with metastatic RCC, NSCLC, pancreatic cancer, and other tumor types when used first line in combination with standard therapy.     

Complex Decisions for First‐Line and Maintenance Treatment of Advanced Wild‐Type Non‐Small Cell Lung Cancer

Until recently, the first-line treatment of advanced non-small cell lung cancer (NSCLC) required minimal clinical decision making. Patients who were eligible for chemotherapy received a platinum-based doublet, and 5-year survival rates were poor. With the advent of molecularly targeted agents and better tolerated chemotherapies—namely, bevacizumab, erlotinib, and pemetrexed—new therapeutic opportunities have emerged. Some of the strategies that have proven to be successful for the treatment of patients with NSCLC are targeting of the vascular endothelial growth factor, use of maintenance chemotherapy for patients without progression of disease after initial therapy, and tailoring of cytotoxic agents specific to the histology of an individual patient’s cancer. Each approach has been independently shown to improve overall survival, but integrating the data from a number of complicated trials into the “best” approach for patients remains challenging. This review attempts to address three fundamental questions clinicians face in choosing first-line and maintenance treatment for advanced NSCLC, particularly nonsquamous histology: Is pemetrexed or a taxane agent better for combination with platinum therapy? Should bevacizumab be used, and is it beneficial when added to pemetrexed chemotherapy? When is maintenance therapy indicated, and which agent is best?     

Preliminary Treatment Patterns and Safety Outcomes for Non—Small-Cell Lung Cancer from ARIES,a Bevacizumab Treatment Observational Cohort Study

BackgroundBevacizumab, a monoclonal antibody against vascular endothelial growth factor, provides benefit in advanced non—smallcell lung cancer (NSCLC), prolonging progression-free and overall survival. Observational cohort studies such as ARIES (“Avastin® Regimens: Investigation of Treatment Effects and Safety”) provide valuable safety and effectiveness data for a broader patient population than controlled trials, such as Eastern Cooperative Oncology Group (ECOG) 4599, which have strict eligibility criteria required for study participation. The ARIES study objective is to further delineate clinical outcomes associated with bevacizumab use in a real-world setting in patients with advanced NSCLC.Patients and MethodsPatients with locally advanced/metastatic nonsquamous NSCLC, whose first therapy includes bevacizumab, may enroll. There are no protocol-specified treatments or assessments. Data are collected at baseline, then quarterly, including targeted safety events, until death, consent withdrawal, loss to follow-up, or study closure. ARIES is conducted at 276 US sites. Planned NSCLC accrual is 2000 patients.ResultsAs of February 14, 2008, 996 evaluable patients with NSCLC have been enrolled. Median follow-up is 6.1 months; 84% of patients have ≥ 1 quarterly update. Key demographics are shown in Table 1. Targeted serious adverse events (SAEs) to date include venous thromboembolic events and other events, 2%; grade 3/4 bleeding and arterial thromboembolic events, 1% each; gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome, pulmonary hemorrhage, hypertension, and wound complications, < 1% each. The most common chemotherapy regimens are carboplatin/paclitaxel, 63%; carboplatin/docetaxel, 11%; non—platin-based, 10%.ConclusionLow rates of targeted SAEs were preliminarily observed despite the inclusion of patients underrepresented in E4599, including those with ECOG performance status ≥ 2, brain metastasis, therapeutic anticoagulation at baseline, and older age. Updated safety data, treatment patterns (with bevacizumab dose and duration), and demographics will be provided at the meeting, based on > 1300 patients.