The Potential of Antiangiogenictherapy in Non ^ Small Cell Lung Cancer Giuseppe Giaccone

Review

The Potential of AntiangiogenicTherapy in Non ^ Small Cell Lung Cancer Giuseppe Giaccone

Abstract The long-term prognosis for patients with advanced non ^ small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizu- mab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small- moleculeVEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.

Lung cancer is the most common malignancy and the leading The optimal therapeutic approach for patients with stage IV cause of cancer death worldwide (1, 2). The prognosis for lung disease, elderly (z70 years) patients with earlier stage disease, cancer is poor, with a 5-year survival rate of only 15% (2). and patients with poor performance is not fully defined, Standard treatment for non–small cell lung cancer (NSCLC), although many receive single-agent (third generation) chemo- which comprises 80% to 85% of all lung cancer cases, involves therapy or best supportive care (3, 7, 8). surgery, radiation therapy, and chemotherapy, with disease Docetaxel and pemetrexed are currently approved for use as stage determining therapeutic options (3, 4). Surgery of curative monotherapy in the treatment of locally advanced or metastatic intent is the mainstay treatment in patients with localized NSCLC after failure of at least one prior chemotherapy regimen. disease (stage I and II disease). Chemotherapy is the primary Second-line docetaxel showed a 1-year survival benefit com- first-line treatment option for the 70% to 80% of patients who pared with supportive care. Approval of pemetrexed was based present with locally advanced (stage III) or metastatic (stage IV) on demonstration of noninferiority versus docetaxel (9). disease. Chemotherapy is noncurative in stage IV disease. In recent years, the improved understanding of cancer Standard first-line chemotherapy for patients with good biology has led to the investigation of several new targeted performance status (0/1) is a platinum-based (i.e., cisplatin or therapies directed against key biological processes in NSCLC carboplatin) doublet regimen incorporating a third-generation development and progression. These agents, including mono- cytotoxic agent (e.g., gemcitabine, vinorelbine, paclitaxel, or clonal antibodies and small-molecule tyrosine kinase inhibitors docetaxel). This approach has improved survival compared (TKI), have the potential for increased selectivity and thereby with best supportive care; however, overall and 1-year survival reduced toxicity compared with standard chemotherapies. Two (8-11 months and 27-47%, respectively) for patients with epidermal growth factor receptors (EGFR) TKIs, erlotinib and advanced disease remain low and further improvements from gefitinib, are currently approved for second- or third-line currently available chemotherapy agents seem unlikely (5, 6). treatment of NSCLC in several countries. However, only erlotinib has shown improved survival versus best supportive care in this setting (10, 11). Interestingly, a subgroup analysis of a phase III survival study (ISEL) comparing gefitinib with Author’s Affiliation: Department of Medical Oncology,VU University Medical placebo revealed a significant survival benefit in Asian patients Center, Amsterdam, the Netherlands receiving gefitinib, although the trial did not meet its primary Received 9/12/06; revised 12/9/06; accepted1/25/07. end point of increasing overall survival benefit in the Grant support: F. Hoffmann-La Roche. The costs of publication of this article were defrayed in part by the payment of page population as a whole (11). In the BR.21 study of erlotinib charges. This article must therefore be hereby marked advertisement in accordance versus placebo, Asian patients also had a better survival than with 18 U.S.C. Section 1734 solely to indicate this fact. the other ethnicities, although the number of patients assessed Requests for reprints: Giuseppe Giaccone, Department of Medical Oncology,VU in this study was only 91 (10). Gefitinib is no longer University Medical Center, 1007 MB Amsterdam, the Netherlands. Phone: 31-20- 444-4352; Fax: 31-20-444-4079; E-mail: [email protected]. recommended in the National Comprehensive Cancer Network F 2007 American Association for Cancer Research. guidelines for NSCLC based on its failure to improve survival doi :10.1158/1078-0432.CCR-0 6-218 6 (4). Neither agent has shown any additional benefit when

www.aacrjournals.org 1961 Clin Cancer Res 2007;13(7) April1,2007 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2007 American Association for Cancer Research. Review combined with first-line chemotherapy for NSCLC (12–14). High intratumoral (evidenced by mRNA and immunohisto- Targeted agents that inhibit tumor-associated angiogenesis have chemical analyses) and/or circulating VEGF levels are associat- shown particular promise in preclinical and clinical studies and ed with poor prognosis in patients with NSCLC (26–33). In are the focus of this review. addition to promoting tumor growth and survival via localized angiogenic mechanisms, evidence suggests that VEGF plays a role in the promotion of malignant pleural effusion and pleural Antiangiogenesis in NSCLC: TargetingVascular dissemination in NSCLC (34, 35). Inhibition of VEGF or its Endothelial Growth Factor receptor(s) inhibits vascularization and growth of human lung tumor xenografts (36–41). This effect has been observed in Angiogenesis, the process of new blood vessel formation, is both newly implanted and well-established NSCLC tumors fundamental to the growth and dissemination of solid tumors. (37). In addition to inhibiting tumor angiogenesis, studies in Tumors that are <2 mm3 receive nutrients and growth factors lung cancer xenograft models suggest that antagonism of VEGF by diffusion; to grow any larger, tumors must establish a blood signaling promotes tumor cell apoptosis (42) and enhances the supply (15). Tumor cells also use newly formed blood vessels antitumor activity of chemotherapy (36). It has been suggested as a route for metastatic spread. The fact that tumors are that these effects result from inhibition of VEGF-mediated dependent on angiogenesis for growth and metastasis has led tumor survival signals (43). Importantly, inhibitors of VEGF- to the development of antiangiogenic strategies for cancer mediated angiogenesis have shown clinically meaningful treatment (see refs. 16–21 for recent reviews). survival benefits, both as monotherapy or in combination with Angiogenesis is a complex process that is tightly controlled chemotherapy, in clinical trials with other types of solid tumors by factors that stimulate or inhibit the formation of new blood (44–48). Collectively, these findings suggest that targeting vessels. To grow, tumors trigger the development of their own VEGF is a rational therapeutic approach in NSCLC. Several blood supply by disrupting the delicate balance of proangio- agents that inhibit angiogenesis by blocking the VEGF pathway genic and antiangiogenic factors (15, 22). Proangiogenic gene are in clinical development for NSCLC (Table 1; Fig. 1). These expression is increased by physiologic stimuli, such as hypoxia, agents take one of two approaches to inhibiting VEGF: targeting which results from tumors compressing blood vessels and the VEGF molecule itself or targeting the cell surface receptors outstripping their blood supply as tumor tissue mass increases for VEGF. (16, 22). Oncogene activation or tumor suppressor mutation Bevacizumab. The most clinically advanced of the targeted can also tip the balance in favor of proangiogenic factors, antiangiogenic agents is bevacizumab (Avastin, Roche, Basel, stimulating the development of new blood vessels in and Switzerland; Genentech, Inc., South San Francisco, CA), a recom- around the tumor, thus enabling the tumor to expand, invade binant humanized monoclonal antibody against VEGF (49). surrounding tissues, and metastasize (16, 22). Preclinical studies with bevacizumab or its parental murine Of the different proangiogenic factors, vascular endothelial antibody A4.6.1 have shown growth inhibition in a variety of growth factor (VEGF or VEGF-A) is a key mediator of normal tumor models (50), including NSCLC (36). Bevacizumab, and tumor angiogenesis; it promotes the proliferation and combined with 5-fluorouracil–based chemotherapy, is current- survival of endothelial cells and increases vascular permeabil- ly approved in Europe and the United States for the first-line ity (23). VEGF binds to two receptor tyrosine kinases, VEGF treatment of metastatic colorectal cancer and in the United receptor (VEGFR) 1 (Flt-1) and VEGFR2 (KDR/Flk-1), as well States for the first-line treatment of advanced nonsquamous as the neuropilin family of coreceptors. VEGFR2 is thought to NSCLC. A pivotal phase III trial in patients with untreated be the main receptor responsible for the mitogenic, angiogen- metastatic colorectal cancer showed that the addition of ic, and permeability enhancing effects of VEGF. The binding of bevacizumab (5 mg/kg every 2 weeks) to standard irinotecan/ VEGF to VEGFR2 promotes receptor dimerization and ligand- 5-fluorouracil/leucovorin chemotherapy significantly improved dependent receptor tyrosine kinase phosphorylation, with median overall survival by 30% (20.3 versus 15.6 months; P < subsequent activation of signaling pathways involved in 0.001; ref. 45). Similarly, the addition of bevacizumab to 5- endothelial cell proliferation, migration, and survival. fluorouracil/leucovorin or FOLFOX4 significantly improved The central role of VEGF in tumor angiogenesis makes it an overall survival compared with chemotherapy alone (44, 48). attractive target for anticancer therapy. VEGF inhibition has the Bevacizumab has shown a survival benefit in other solid potential to cause regression of immature tumor blood vessels tumor types, including metastatic breast cancer and renal cell and inhibit the development of new tumor vasculature without cancer. Bevacizumab monotherapy (10 mg/kg every 2 weeks) compromising healthy vasculature. Because the physiologic showed improved progression-free survival compared with role of angiogenesis in healthy adults is limited to wound placebo (4.8 versus 2.5 months; P < 0.001) in patients with healing and the menstrual cycle (24), inhibiting VEGF should metastatic renal cell cancer who were not optimal candidates have minimal undesired effects on normal physiologic pro- for, or who had not responded to, interleukin-2 therapy (51). cesses and thus have relatively few side effects. Two additional Additionally, an interim analysis from an ongoing phase III factors make VEGF an attractive therapeutic target. First, study in patients with metastatic breast cancer showed that because VEGF circulates in the blood and acts directly on bevacizumab plus paclitaxel significantly increased progression- vascular endothelial cells, drugs that target VEGF do not need to free survival compared with paclitaxel alone [11.40 versus 6.11 penetrate tumor tissue to inhibit tumor angiogenesis. Second, months; hazard ratio (HR), 0.51; P < 0.0001; ref. 52]. VEGF acts on endothelial cells, which may be less likely to Clinical trials have also established the efficacy and mutate to a treatment-resistant phenotype than genetically tolerability of bevacizumab in NSCLC. A randomized phase II unstable tumor cells (25). Thus, endothelial cells may be a trial in 99 patients with advanced or recurrent NSCLC evaluated more attractive target than tumor cells for long-term therapy. the efficacy and safety of carboplatin (area under the curve of 6)

Clin Cancer Res 2007;13(7) April 1, 20 07 1962 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2007 American Association for Cancer Research. Angiogenesis Inhibitors in NSCLC

Table 1. Angiogenesis inhibitors in clinical development for NSCLC

Drug Mechanism(s) of action Molecular target(s) Stage of clinical development Bevacizumab Anti-VEGF antibodyVEGF ligand Phase III Sorafenib TKI Raf-1, VEGFR2, VEGFR3, PDGFR-h, Flt-3, c-Kit Phase III Sunitinib TKI VEGFR1, VEGFR2, VEGFR3, Flt-3, PDGFR-a, PDGFR-h, c-Kit Phase II Vatalanib TKI VEGFR1, VEGFR2, VEGFR3, PDGFR-h, c-Kit, c-Fms Phase II AMG 706 Protein kinase inhibitor VEGFR1, VEGFR2, VEGFR3, PDGFR, c-Kit, c-Ret Phase II CP-547,632 TKI VEGFR2 Phase II AZD2171 TKI VEGFR2 Phase II-III AEE788 TKI VEGFR1, VEGFR2, EGFR, HER2 Phase I/II ZD6474 TKI VEGFR2, VEGFR3, EGFR Phase II

plus paclitaxel (200 mg/m2) with or without bevacizumab (7.5 features being common in patients with squamous cell or 15 mg/kg), administered every 3 weeks (53). Patients who NSCLC). The risk of bleeding seemed to be only slightly received 15 mg/kg bevacizumab every 3 weeks had an elevated in patients with nonsquamous histology (overall risk improved median time to progression (7.4 versus 4.2 months; was f4%). In contrast to NSCLC, pulmonary bleeding has not P = 0.023) and overall response rate (31.5% versus 18.8%) been reported in trials of bevacizumab in breast, colorectal, compared with chemotherapy alone. Additionally, 15 mg/kg prostate, or renal cell cancer. bevacizumab every 3 weeks showed a small increase in survival, A large phase III trial (Eastern Cooperative Oncology Group although this did not reach statistical significance (17.7 versus study 4599) evaluated bevacizumab plus chemotherapy in 878 14.9 months; P = 0.63). In this trial, 19 of 32 patients treatment-naive patients with advanced nonsquamous NSCLC randomized to chemotherapy alone crossed over to bevacizu- (54). Patients with brain metastases and patients with more mab monotherapy on disease progression; 5 of these patients than half a teaspoon of hemoptysis were excluded. Patients achieved stable disease and median survival at 1 year was were randomized to receive carboplatin (area under the curve 47.4%. Bevacizumab was generally well tolerated, although of 6) plus paclitaxel (200 mg/m2) with or without bevacizumab adverse events of bleeding were noted, including major (15 mg/kg) every 3 weeks for six cycles; bevacizumab pulmonary hemorrhage (hemoptysis) that was associated with monotherapy (15 mg/kg every 3 weeks) was then continued squamous cell histology, cavitated or necrotic tumors, and until progressive disease or intolerable toxicity. Patients tumors located close to major blood vessels (the latter two receiving bevacizumab had significantly improved median

Fig. 1. Approaches to targetingVEGF orVEGFRs.

www.aacrjournals.org 1963 Clin Cancer Res 2007;13(7) April1,2007 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2007 American Association for Cancer Research. Review overall survival (12.5 versus 10.2 months; P = 0.007), advanced in relapsed/refractory renal cell cancer, and a recent progression-free survival (6.4 versus 4.5 months; P < 0.0001), phase III study in patients with previously treated advanced renal and response rates (27.2% versus 10.0%; P < 0.0001) cell cancer showed increased progression-free survival compared compared with chemotherapy alone. Non-prespecified explor- with best supportive care (24 versus 12 weeks; P < 0.000001; atory analyses suggest that bevacizumab is associated with a ref. 47), leading to U.S. Food and Drug Administration and survival benefit in all patient subgroups, with the possible European Agency for the Evaluation of Medicinal Products exception of women: the HR for survival was 0.96 (P = 0.80) approval in this indication. Preliminary results from a phase I for women. However, it is important to note that the primary study of sorafenib (200 or 400 mg twice daily) plus gefitinib end point of the study was met and that the study was not (250 mg/d) in 32 patients with unresectable or recurrent powered to show efficacy differences between subgroups. In advanced NSCLC showed that the combination was well addition, women did show significantly improved progression- tolerated with no dose-limiting toxicities; 1 patient achieved a free survival and response rates, arguing in favor of an overall partial response and 20 (63%) had stable disease (mean benefit from the addition of bevacizumab. Other possible duration of response, 20.4 weeks; ref. 56). In a recent phase II explanations for this finding include potential imbalances of trial, sorafenib monotherapy (400 mg/d) showed promising prognostic factors and imbalances in the use of second- and efficacy in 52 patients with advanced NSCLC, with 59% of third-line therapies. patients achieving disease stabilization (57). A large randomized The treatment combination was well tolerated, although study is presently running comparing chemotherapy (carbopla- there was a slightly increased incidence of grade 4/5 neutrope- tin-paclitaxel) alone with chemotherapy plus sorafenib in nia, grade 3/4 hypertension, and treatment-related deaths in patients with advanced NSCLC. This study includes all the bevacizumab arm. An increased incidence of hemorrhage histologies, unlike the pivotal study done with bevacizumab. was also observed in the bevacizumab arm, particularly The planned targeted accrual is 900 patients and survival is the pulmonary hemoptysis (1.9% versus 0.2%). However, restrict- major end point in this study. ing the population to patients with nonsquamous histology Sunitinib malate. Sunitinib malate (Sutent, SU11248, Pfizer, and minimal baseline hemoptysis substantially decreased the Inc., New York, NY) is a small-molecule TKI with activity incidence of grade z3 hemoptysis from 6.1% (in the phase II against VEGFR1, VEGFR2, and VEGFR3 as well as Flt-3, PDGFR-a, study) to 1.9%. PDGFR-h, and c-Kit (58, 59). Sunitinib malate prevented blood E4599 was the first study to show that addition of a vessel formation in a tumor vascular window model but targeted agent to standard first-line chemotherapy improves produced minimal effects on established blood vessels (60). In survival in patients with advanced NSCLC; it was also the first a NSCLC xenograft model, sunitinib malate markedly reduced to suggest that triplet therapy is superior to doublet therapy. tumor growth with histologic evidence of extensive tumor Based on these positive results, the bevacizumab/carboplatin/ destruction, although no tumor regression was observed (61). paclitaxel regimen used in the trial has been adopted as the Studies in a Lewis lung carcinoma model showed reduced tumor new Eastern Cooperative Oncology Group standard of care for vascularization and reduced metastasis to the lung following the first-line treatment of advanced NSCLC. The National excision of the s.c. tumor (60, 62). Combined treatment with Comprehensive Cancer Network has also recently incorporat- sunitinib malate and radiation therapy or cisplatin in murine ed bevacizumab (in combination with chemotherapy) into its xenograft models showed enhanced antitumor activity com- treatment guidelines for NSCLC (4), and in October 2006, the pared with conventional therapy alone (58, 62). Food and Drug Administration granted approval for the use of Sunitinib malate was recently approved by the Food and bevacizumab in combination with carboplatin/paclitaxel as Drug Administration for the treatment of previously treated first-line treatment for patients with advanced nonsquamous patients with gastrointestinal stromal tumors and for metastatic NSCLC. renal cell cancer based on evidence from phase III and phase II A large phase III trial of cisplatin/gemcitabine with or trials, respectively (46, 63). Two ongoing phase II studies are without bevacizumab as first-line therapy in advanced non- evaluating sunitinib malate monotherapy in advanced NSCLC: squamous NSCLC (BO17704) has completed recruitment in the first in previously treated patients with metastatic disease Europe. A total of 1,044 patients was randomized to three arms and the second as consolidation therapy following first-line to receive cisplatin/gemcitabine with or without one of two treatment with carboplatin/paclitaxel in locally advanced/ doses of bevacizumab (either 7.5 or 15 mg/kg every 3 weeks). metastatic disease. The agent is also under investigation in This trial will evaluate the efficacy of different bevacizumab combination with erlotinib in previously treated advanced doses and assess whether the benefit of bevacizumab extends to NSCLC. other chemotherapy doublet regimens. Vatalanib. Vatalanib (PTK787/ZK 222584; Novartis Phar- Sorafenib. Sorafenib tosylate (Nexavar, Bayer Pharmaceuti- maceuticals Corp., Basel, Switzerland) has activity against cals, Inc., Westhaven, CT; Onyx Pharmaceuticals, Inc., Emery- VEGFR1, VEGFR2, VEGFR3, PDGFR-h, c-Kit, and c-Fms (64). ville, CA) is a multitargeted TKI with activity against Raf-1, Preclinical studies showed that vatalanib inhibited endothelial VEGFR2, VEGFR3, platelet-derived growth factor receptor cell proliferation, migration, and survival in vitro and down- (PDGFR)-h, Flt-3, and c-Kit (55). In preclinical studies, sorafenib regulated angiogenesis in vitro and in vivo (64). Vatalanib also showed antitumor activity in a variety of human tumor inhibited the growth of a variety of human tumor xenografts; xenograft models, including NSCLC, which was associated with histologic analysis of a human epidermal tumor xenograft down-regulation of the Raf/mitogen-activated protein kinase/ model showed that vatalanib inhibited the development of new extracellular signal-regulated kinase kinase/extracellular signal- microvessels in the interior of the tumor but did not affect regulated kinase tumor cell proliferation pathway and reduced larger, more established vessels (64). In mice with lung lesions vascularization (55). Clinical development of sorafenib is most and pleural effusion induced by injection of human NSCLC

Clin Cancer Res 2007;13(7) April 1, 20 07 1964 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2007 American Association for Cancer Research. Angiogenesis Inhibitors in NSCLC cells, vatalanib reduced the formation of pleural effusion, decoy receptor comprising portions of VEGFR1 and VEGFR2 primarily by reducing vascular permeability, and reduced fused to a Fc segment of IgG1. In animal xenograft models, tumor vascularization, although it did not significantly reduce VEGF Trap has been shown to block growth of new vessels and the number of lung lesions (65). disrupt preexisting vasculature (74). A phase II trial to Vatalanib has been studied in patients with a variety of determine the overall objective response rate of patients with cancers, including colorectal, pancreatic, renal cell, ovarian, and platinum- and erlotinib-resistant locally advanced or metastatic hematologic malignancies. A phase I study in patients with non–small cell lung adenocarcinoma receiving VEGF Trap advanced solid tumors established that the maximum tolerated (4 mg/kg every 2 weeks) is ongoing. oral dose was 750 mg/d, whereas the biologically active dose Enzastaurin. Enzastaurin (Eli Lilly, Indianapolis, IN) is an was z1,000 mg/d (66). Two large phase III trials in patients orally active inhibitor of protein kinase Ch, glycogen synthase with untreated (CONFIRM-1) and previously treated (CON- kinase-3, and Akt. An ongoing phase II trial will compare time FIRM-2) metastatic colorectal cancer are ongoing. An interim to disease progression in patients receiving docetaxel/carbopla- analysis of CONFIRM-1, by independent central review, tin or pemetrexed/carboplatin with or without enzastaurin. showed no increase in progression-free survival with vatalanib Thalidomide. Thalidomide is an oral inhibitor of the effects plus FOLFOX4 compared with FOLFOX4 alone (median, 7.7 of tumor necrosis factor-a. Phase II studies of thalidomide in versus 7.6 months; HR, 0.88; P = 0.118; ref. 67). However, an patients with advanced NSCLC have shown promising activity interim analysis of CONFIRM-2 found that vatalanib plus for this agent in terms of tumor remissions and stable disease FOLFOX4 improved progression-free survival compared with (75, 76). Several ongoing trials are examining the potential role FOLFOX4 alone (5.6 versus 4.1 months; P = 0.026) but did not of thalidomide for the treatment of advanced NSCLC. A phase improve overall survival (12.1 versus 11.8 months; P = 0.51; II trial will determine the response rates of 37 patients with ref. 68). Clinical evaluation is ongoing in NSCLC with a phase stage III or IV NSCLC treated with second-line docetaxel and II trial (GOAL) of vatalanib monotherapy in relapsed or thalidomide, whereas a second trial will determine the response refractory NSCLC currently recruiting patients. rates of 21 patients with stage II or IIIA NSCLC receiving neo- AMG 706. AMG 706 (Amgen, Inc., Thousand Oaks, CA) is adjuvant carboplatin, gemcitabine, and thalidomide. A phase an oral multikinase inhibitor of VEGFR1, VEGFR2, VEGFR3, III trial aims to recruit 588 patients with stage III NSCLC and PDGFR, c-Kit, and c-Ret. In preclinical studies, AMG 706 caused compare their survival and time to progression when treated regression of tumor xenografts and inhibited vascular blood with carboplatin/paclitaxel and radiotherapy with or without flow and/or permeability (69). A phase I/II trial of AMG 706 in thalidomide (Eastern Cooperative Oncology Group 3598). combination with paclitaxel/carboplatin and the anti-EGFR monoclonal antibody panitumumab in patients with advanced Combined Inhibition of the VEGF and EGFR NSCLC is ongoing, and a phase II trial of AMG 706 or Pathways bevacizumab in combination with chemotherapy in patients with advanced NSCLC is planned. Combined targeting of the VEGF and EGFR signaling CP-547,632. CP-547,632 (Pfizer/OSI Pharmaceuticals, Inc., pathways represents an attractive approach to treating NSCLC. Melville, NY) is a selective VEGFR2 TKI (70). Preliminary Preclinical studies have shown that combined treatment with results from a phase I trial of CP-547,632 (200 mg/d) in EGFR and VEGF signaling inhibitors has at least additive combination with carboplatin/paclitaxel as first-line therapy for antitumor activity (77–79), indicating that the mechanisms of advanced NSCLC indicated that this treatment was well action of such agents are different but complementary (80, 81). tolerated (71). Efficacy data from 30 evaluable patients revealed In addition, EGFR inhibitors could act to sensitize cells to a 20% partial response rate, a stable disease rate of 50%, and a antiangiogenic therapy by lowering the tumor survival thresh- progressive disease rate of 30%. Based on these results, a phase old because one of the signaling pathways leading to cell I/II trial in chemonaive NSCLC patients is ongoing. growth and survival is shut down (82). Moreover, it has been AZD2171. AZD2171 (AstraZeneca, Macclesfield, United postulated that ‘‘overactivation’’ of non-EGFR pathways driving Kingdom) is a potent inhibitor of VEGFR2 tyrosine kinase VEGF expression (independent of EGFR) results in resistance to activity (72). The growth of established tumor xenografts of EGFR inhibitors due to the inability of these agents to down- different tumor types, including NSCLC, is inhibited by regulate VEGF to ‘‘critical’’ nonangiogenic levels, thus reducing AZD2171. A phase I study determined good tolerability of this the antiangiogenic potential of these antagonists (82). This compound, although the classic class toxicities (i.e., hyperten- could potentially be overcome by combining EGFR inhibition sion) were noted. A phase I study of AZD2171 has been done in with an anti-VEGF agent. combination with standard carboplatin-paclitaxel in patients Two approaches to combining VEGF and EGFR inhibition with untreated advanced NSCLC, which has identified the are possible. First, these factors can be inhibited using two optimal dose for combination (45 mg/d; ref. 73). The National specific agents (e.g., bevacizumab and erlotinib). Second, a Cancer Institute of Canada cooperative group is running a single agent that inhibits both VEGF and EGFR can be used. randomized phase II study of AZD2171 in combination with Both approaches are being examined clinically and have carboplatin-paclitaxel, and the study will continue to full- potential benefits. Inhibition using two drugs allows for blown phase III if no unexpected toxicities are encountered in treatment individualization and potentially dose titration to the phase II part. All patients, including those with squamous ensure optimal target inhibition. Use of a dual inhibitor means carcinoma histology and brain metastases, are included in this that only one drug needs to be administered. However, whether study, as with all other studies with VEGFR TKIs in lung cancer. both targets are optimally inhibited is difficult to assess. VEGF Trap. VEGF Trap (Regeneron, Tarrytown, NY; Sanofi- AEE788. AEE788 (Novartis Pharmaceuticals) is an oral Aventis, Paris, France) is a composite, soluble recombinant EGFR and VEGFR TKI. Preclinical studies have shown that

AEE788 inhibits EGFR, HER2, HER4, KDR, and Flt-1 with alone, 0.66), and 4.4 months for bevacizumab plus erlotinib IC50 values of 2, 6, 160, 77, and 59 nmol/L, respectively, and (HR versus chemotherapy alone, 0.72). Median overall survival is antiproliferative in cells overexpressing EGFR and HER2 was 8.6 months for chemotherapy alone, 12.6 months for (83, 84). A phase I/II dose escalation trial of AEE788 in patients bevacizumab plus chemotherapy (HR versus chemotherapy with recurrent or relapsed glioblastoma multiforme is currently alone, 0.74), and 13.7 months for bevacizumab plus erlotinib ongoing; preliminary results indicate that it is generally well (HR versus chemotherapy alone, 0.76). The combination of tolerated (85). bevacizumab and erlotinib was generally well tolerated; no new ZD6474. ZD6474 (Zactima, AstraZeneca) is a small-mole- or unexpected safety signals were noted, and the rate of cule inhibitor of VEGFR2, VEGFR3, and EGFR (86, 87). pulmonary hemorrhage was consistent with previous trials of ZD6474 was shown to potently inhibit VEGF-induced prolif- bevacizumab in NSCLC. The toxicity profile of the bevacizu- eration of endothelial cells in vitro (87). It also inhibited the mab/erlotinib combination compares favorably with either growth of a variety of human tumor xenografts, including A549 chemotherapy-containing group. lung adenocarcinoma and Calu-6 NSCLC, even in large tumors Two ongoing phase II trials will evaluate bevacizumab plus with established vasculature (87). Studies in PC-9 human lung erlotinib in the first-line setting. The multicenter ML19389 adenocarcinoma xenografts suggest that the antitumor activity phase II trial (n = 109) will investigate the efficacy of of ZD6474 may largely reflect inhibition of the EGFR as bevacizumab (15 mg/kg every 3 weeks) plus erlotinib (150 evidenced by its cross-resistance with gefitinib (ZD6474 had mg/d) given until disease progression or toxicity followed by greater activity in gefitinib-sensitive tumors than those resistant chemotherapy [gemcitabine (1,250 mg/m2) plus cisplatin (80 to gefitinib, with no reduction in tumor cell proliferation or mg/m2) or carboplatin (area under the curve of 5)] every 3 vascular density in the latter tumor type; ref. 88). However, the weeks for six cycles or until progression. The MO18632 phase II antitumor activity of ZD6474 in Calu-6 xenografts, which are trial (n = 46) will evaluate the efficacy of bevacizumab (15 mg/ responsive to inhibitors of VEGFR but not EGFR, supports kg every 3 weeks) plus erlotinib (150 mg/d) as measured by the proposed mechanisms of additional antiangiogenic activity. rate of nonprogression at 6 weeks. A phase I dose escalation trial in 77 patients with solid In addition, a large phase III trial (ATLAS) will recruit 1,150 tumors established that a dose of 300 mg/d was well tolerated; patients with advanced or metastatic nonsquamous NSCLC to the most common dose-limiting toxicities were diarrhea, evaluate first-line bevacizumab with or without erlotinib, hypertension, and rash (89). A phase II study is evaluating whereas a second phase III trial (BeTa Lung) is accruing 650 docetaxel with or without ZD6474 (100 or 300 mg/d) in patients to investigate erlotinib with or without bevacizumab in patients with previously treated locally advanced or metastatic the second-line treatment of nonsquamous advanced NSCLC. NSCLC. The preliminary results from the run-in phases of two These two studies may provide an insight as to the relative phase II randomized trials indicate that ZD6474 plus docetaxel contribution of VEGF and EGFR inhibition to the clinical in patients with locally advanced or metastatic NSCLC, or outcome in the second-line setting and the potential role for ZD6474 plus carboplatin/paclitaxel in treatment-naive patients bevacizumab maintenance therapy. with locally advanced or metastatic NSCLC, are both generally AZD2171 plus gefitinib. This combination has been studied well tolerated (90, 91). ZD6474 (300 mg/d) has also been in a large phase I study, including several tumor types (95). investigated in comparison with gefitinib (250 mg/d) as Activity has been observed in patients, including those with second- or third-line treatment in patients with advanced lung cancer. However, there are presently no plans to develop NSCLC in a phase II study. Preliminary data from 168 patients this combination further in Western countries, given the fact showed that estimated median time to progression was that gefitinib is not readily available for this indication any significantly longer in patients receiving ZD6474 compared more in those countries. with gefitinib (11.9 versus 8.1 weeks; HR, 0.632; P = 0.011; ref. 92). A phase III study investigating ZD6474 plus docetaxel versus docetaxel alone (study 32) has started accruing patients Future Directions with advanced NSCLC who failed first-line chemotherapy. The planned accrual is 1,200 patients, and progression-free survival The wealth of new molecular therapies currently approved or is the major end point of this study. in clinical development indicates that antiangiogenic therapy Bevacizumab plus erlotinib. Bevacizumab (up to 15 mg/kg has enormous potential for improving patient outcomes in every 3 weeks) was evaluated in combination with erlotinib (up NSCLC, but several issues remain. First and foremost is the to 150 mg/d) in a phase I/II study in 40 patients with question of the best clinical setting for antiangiogenic agents. In previously treated advanced nonsquamous NSCLC (93). Eight the first-line setting, the monoclonal antibody bevacizumab is (20%) patients achieved a partial response, and 26 (65%) had the first agent of any kind to show a survival advantage in stable disease. The median progression-free survival and overall NSCLC when combined with a standard doublet chemotherapy survival were 7.0 and 12.6 months, respectively. Treatment was regimen. Consequently, bevacizumab plus carboplatin/pacli- well tolerated with generally mild-to-moderate adverse events, taxel have now become the new Eastern Cooperative Oncology and no dose-limiting toxicity was observed. A phase II trial has Group reference standard for future trials in advanced non- evaluated bevacizumab (15 mg/kg every 3 weeks) combined squamous NSCLC. To determine whether the benefits of with chemotherapy (75 mg/m2 docetaxel or 500 mg/m2 bevacizumab will extend to other platinum-based doublets in pemetrexed) or combined with erlotinib (150 mg/d) in patients the first-line setting, ongoing trials in the United States and with recurrent or refractory NSCLC (94). Median progression- Europe are investigating combinations of bevacizumab with free survival was 3 months for chemotherapy alone, 4.8 months several other chemotherapy regimens. Antiangiogenic agents for bevacizumab plus chemotherapy (HR versus chemotherapy may also have potential in the (neo)adjuvant setting. There is

Clin Cancer Res 2007;13(7) April 1, 20 07 1966 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2007 American Association for Cancer Research. Angiogenesis Inhibitors in NSCLC evidence to suggest that tumor dependence on angiogenesis bevacizumab has continued to be administered after the end may decrease as the cancer progresses (96), providing a of chemotherapy in the studies done to date. Studies rationale for early intervention with antiangiogenic agents. investigating the role of prolonged bevacizumab administration Moreover, applying antiangiogenic therapy earlier in the will have to be done in light of the potential hazard of disease process may help reduce the risk of metastases and prolonged treatment with angiogenesis inhibitors. A large bleeding. This concept is currently being investigated in the planned phase III trial (MO19390) will evaluate the safety ongoing BEACON trial, a phase II study of bevacizumab plus profile of 15 mg/kg bevacizumab every 3 weeks combined with chemotherapy (docetaxel/cisplatin) in the neoadjuvant setting platinum-based chemotherapy as first-line treatment for 2,000 for patients with resectable stage IB to IIIA NSCLC. patients with advanced nonsquamous NSCLC. Safety studies Given that lung cancer is a heterogeneous disease express- are also required to address the issue of bleeding events in ing many different targets, combinations of different biolog- bevacizumab-treated patients. In a planned phase II trial ical agents to target multiple pathways simultaneously may (AVASQ) to investigate the feasibility of bevacizumab and lead to novel treatment paradigms for NSCLC. Both VEGF chemotherapy in patients with squamous cell NSCLC, who are and EGFR inhibition have been shown to extend survival in considered to be at risk of pulmonary bleeding, patients will NSCLC, leading to the expectation that dual inhibition will receive radiotherapy to the central lesion as a preventive confer greater clinical benefit than inhibition of a single measure to reduce the risk of bleeding before receiving pathway. Encouraging results from phase I trials of AEE788 bevacizumab. A second phase II trial (BRIDGE) will determine and ZD6474, two small-molecule inhibitors of EGFR and whether delayed bevacizumab administration will improve VEGFRs, indicate that this approach has potential. An early safety in patients with squamous cell NSCLC; f40 patients will clinical trial of bevacizumab plus erlotinib has also shown receive two cycles of carboplatin/paclitaxel followed by four promise, and several phase II and III clinical trials of this cycles of chemotherapy plus bevacizumab (15 mg/kg every 3 combination in the first- and second-line setting are under weeks) and then bevacizumab until disease progression. The way to establish whether dual inhibition will become a future primary end point of these two studies is the incidence of grade treatment paradigm for NSCLC. Whether the use of a single z3 pulmonary hemorrhage. dual inhibitor or separate anti-VEGF and anti-EGFR agents Interestingly, the studies that are presently ongoing with will provide different efficacy and safety remains to be several TKIs of VEGFRs do not seem to induce the same degree determined. of bleeding as reported with bevacizumab, although formal Recent preclinical studies suggest that certain chemothera- comparisons have yet to be done. Most phase III studies of peutic agents have antiangiogenic activity if they are admin- novel VEGFR TKIs include all histologies. It will be interesting istered frequently at low doses (a tenth to a third of the to see whether the inhibition of receptor signaling has similar maximum tolerated dose), with no prolonged drug-free breaks efficacy as inhibiting the growth factor VEGF. (97, 98). This approach, referred to as ‘‘metronomic’’ Finally, how should patients be selected for treatment with chemotherapy, may reduce certain toxicities and have better antiangiogenic therapies? Bevacizumab is currently contra- efficacy than conventional maximum tolerated dose regimens indicated in patients with predominantly squamous cell (99). The efficacy of metronomic chemotherapy may be NSCLC due to the occurrence of severe pulmonary hemorrhage further enhanced by the addition of specific antiangiogenic in four patients with squamous cell histology in a phase II trial agents (99). Because metronomic chemotherapy targets the of bevacizumab plus carboplatin/paclitaxel. In addition, endothelial cells of the tumor, this approach has potential exclusion of patients with central nervous system metastases applications for tumors that have developed resistance to from bevacizumab trials became a regulatory requirement chemotherapy. The value of metronomic chemotherapy as following a single central nervous system bleeding event in a antiangiogenic therapy for patients with NSCLC remains to be patient with hepatocellular carcinoma in an early phase I/II validated by randomized phase III trials, but encouraging trial. Consequently, the risk of central nervous system bleeding preliminary data have been reported; in one trial, patients with in patients with central nervous system metastases receiving NSCLC responded to a more frequent but low-dose adminis- bevacizumab cannot be estimated. Data from ongoing trials tration of the topoisomerase enzyme inhibitor etoposide after will be analyzed to evaluate the risk of bleeding events in having progressed on a conventional schedule of the same patients who develop central nervous system metastases while drug (100). However, several challenges must be overcome to receiving bevacizumab therapy to provide further insight into enable the integration of metronomic chemotherapy into this issue. Interestingly, the large trials ongoing with small- clinical practice. If metronomic chemotherapy in combination molecule VEGFR inhibitors do not exclude patients with with angiogenesis inhibitors is to become a new paradigm for squamous cell histology or brain metastases. Several trials are controlling cancer by long-term therapy, future studies will ongoing to determine whether patients with predominantly need to ascertain which chemotherapeutic agents are the most squamous cell NSCLC can be safely treated with bevacizumab. effective for metronomic dosing regimens, identify more These analyses may expand the eligible patient population for effective ways to combine the newest antiangiogenic agents bevacizumab. Currently, few data are available to indicate that with metronomic chemotherapy, select optimal antiangiogenic any molecular biomarker is predictive of the effect of doses that are nontoxic yet effective, and design appropriate antiangiogenic therapy. A prospective analysis of biomarkers schedules. in the E4599 trial of bevacizumab in NSCLC indicated that Establishing the safety profile of new antiangiogenic agents baseline intercellular adhesion molecule levels are prognostic over prolonged periods will also become important. Due to the for survival and response to chemotherapy (101). However, cytostatic action of angiogenesis inhibitors, chronic therapy further prospective data from randomized trials will be may be required to prevent tumor progression. Indeed, necessary to determine the clinical relevance of these findings,

www.aacrjournals.org 1967 Clin Cancer Res 2007;13(7) April1,2007 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2007 American Association for Cancer Research. Review describe the sensitivity and specificity of a standardized test kit, selection. Because all tumors depend on angiogenesis to some and identify appropriate cutoffs for clinical use. It should be degree, it can be argued that all patients with solid tumors noted that, in metastatic colorectal cancer, the benefits of should be considered potential candidates for antiangiogenic bevacizumab treatment were found to be independent of therapy. Further studies are required to fully confirm this and to standard tumor markers and VEGF levels (102). This suggests define the optimal role of antiangiogenic agents in the NSCLC that factors other than VEGF expression level may be important treatment paradigm. in determining the response to therapy, such as the degree of dependence of tumors on VEGF signaling. At present, there is no consensus as to which form of VEGF (tumor versus Acknowledgments circulating) is the most clinically relevant to evaluate, and there is no standard detection method. These factors underscore I thank Yfke Hager (Gardiner-Caldwell Communications) for medical writing the current difficulties in using potential markers for patient support.

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Clin Cancer Res 2007;13(7) April 1, 20 07 1970 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2007 American Association for Cancer Research. The Potential of Antiangiogenic Therapy in Non−Small Cell Lung Cancer

Giuseppe Giaccone

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