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Targeting Angiogenesis in Advanced Non-Small Cell Lung Cancer

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Targeting Angiogenesis in Advanced Non-Small Cell Lung Cancer Original 1235 Article CE Targeting Angiogenesis in Advanced Non–Small Cell Lung Cancer Philip E. Lammers, MD, MSCI, and Leora Horn, MD, MSc Abstract stage IIIB/IV adenocarcinoma have a molecular muta- Lung cancer is the leading cause of cancer-related mortality in the tion thought to drive tumor growth.4 However, only United States. Over the past 40 years, treatments with standard patients with epidermal growth factor receptor (EGFR) chemotherapy agents have not resulted in substantial improve- ments in long-term survival for patients with advanced lung can- mutations (approximately 10%–15%) or anaplastic lym- cer. Therefore, new targets have been sought, and angiogenesis is phoma kinase (ALK) rearrangements (approximately a promising target for non–small cell lung cancer (NSCLC). Bevaci- 5%) have an FDA-approved therapy available. Other zumab, a monoclonal antibody targeted against the vascular en- potential targets have been identified, such as c-ros on- dothelial growth factor, is the only antiangiogenic agent currently cogene 1 (ROS1) gene fusions and BRAF mutations, recommended by NCCN for the treatment of advanced NSCLC. However, several antibody-based therapies and multitargeted ty- and clinical trials using targeted agents are ongoing. rosine kinase inhibitors are currently under investigation for the Alternative targets continue to be investigated, one of treatment of patients with NSCLC. This article summarizes the avail- which is angiogenesis, a necessary process in the growth able clinical trial data on the efficacy and safety of these agents in and metastasis of solid tumors.5 Bevacizumab is the only patients with advanced lung cancer. (JNCCN 2013;11:1235–1247) antiangiogenic therapy FDA-approved for NSCLC,6 but other agents have been tested in advanced NSCLC. Currently, NCCN recommends that bevacizumab be considered in the first-line treatment setting for stage IV disease in combination with a platinum doublet, with Lung cancer is the leading cause of cancer-related continuation of bevacizumab until progression.2 mortality in the United States, with an estimated The use of antiangiogenic agents is a rational ap- 228,190 new cases and 159,480 deaths in 2013.1 More proach to treating lung cancer, but must be balanced than two-thirds of patients with lung cancer will pres- against the potential risks involved, which can be life- ent with advanced disease.2 The 5-year survival rate threatening. Researchers have been searching for po- is approximately 15%. Standard platinum-based che- tential biomarkers to identify patients for whom therapy motherapy regimens are associated with survival with antiangiogenic inhibitors may be most beneficial. of approximately 1 year in patients with advanced The current data for antiangiogenic agents vary widely lung cancer.3 Approximately 60% of patients with among the studied drugs, and safety data are especially limited for many of the agents studied. This review sum- From Vanderbilt-Ingram Cancer Center, Vanderbilt University, marizes the available efficacy and safety/tolerability data Nashville, Tennessee from clinical trials of antiangiogenic agents in advanced Submitted January 16, 2013; accepted for publication June 24, 2013. NSCLC. (For consistency, efficacy data have been con- Dr. Lammers is supported by the NIH (K12 CA 0906525). Financial verted to months using the following: 1 month = 4.2 support for editorial assistance was provided by Boehringer Ingelheim Pharmaceuticals, Inc. The authors have disclosed that weeks for data reported in weeks; 12 months = 365 days they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products for data reported in days. For consistency, where nec- discussed in this article or their competitors. essary, progression-free and overall survivals have been Correspondence: Leora Horn, MD, MSc, Vanderbilt-Ingram Cancer Center, Vanderbilt University, 2220 Pierce Avenue, 777 Preston rounded to the nearest tenth, and hazard ratio, confi- Research Building, Nashville, TN 37232. dence interval, and P values have been rounded to 2 E-mail: [email protected] decimal places.) © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 11 Number 10 | October 2013 1236 Original Article Lammers and Horn Efficacy and Safety of Antiangiogenic Bevacizumab is the most studied antiangiogenic Agents for NSCLC agent in advanced NSCLC (Tables 1 and 2). After promising results from a phase II study,8 ECOG 4599 Antibody-Based Therapeutics was conducted as a randomized phase III trial com- Bevacizumab: Bevacizumab is a humanized mono- paring carboplatin/paclitaxel with or without beva- clonal antibody with a high affinity for vascular en- cizumab in 878 patients with recurrent or advanced 7 dothelial growth factor (VEGF). Bevacizumab binds nonsquamous NSCLC.9 Improvements in median to circulating VEGF, preventing it from binding to overall survival (OS), median progression-free sur- the VEGF receptor (VEGFR) and thereby inhibiting vival (PFS), and response rate (RR) occurred in pa- downstream signaling. The sites of action of bevaci- tients treated with bevacizumab compared with those zumab and other antiangiogenic agents described in in the chemotherapy arm: 12.3 versus 10.3 months; this article are depicted in Figure 1. Bevacizumab has 6.2 versus 4.5 months; and 35% versus 15%, respec- been studied extensively in various malignancies, and tively. In an unplanned subset analysis, median PFS certain adverse events (AEs), such as bleeding and and RR were significantly improved with bevaci- thrombosis, are known to be associated with its use. zumab versus chemotherapy for both sexes; however, In addition, hypertension and proteinuria are com- median OS was not improved in the female cohort mon throughout treatment, although these are gener- but was improved among men (11.7 vs 8.7 months ally manageable with antihypertensive therapies. with chemotherapy).10 In another unplanned subset Aflibercept VEGF Bevacizumab c-KIT FGFR PDGFR FLT-3 RET VEGFR EGFR Bavituximab Ramucirumab Phosphatidylserine Sorafenib Pazopanib Sorafenib Sorafenib Sorafenib Sunitinib Vandetanib Sunitinib Cediranib Sunitinib Sunitinib Sunitinib Vandetanib Pazopanib Nintedanib Pazopanib Pazopanib Nintedanib Motesanib Vandetanib Cediranib Cediranib ABT-869 Cediranib Nintedanib Motesanib Nintedanib Motesanib Axitinib Motesanib Axitinib ABT-869 Axitinib ABT-869 ABT-869 PI3K RAS SRC Nintedanib RAF Sorafenib AKT MEK Ombrabulin ERK Microtubules Proliferation Angiogenesis Figure 1 Targeting angiogenesis in lung cancer. Receptors and downstream signaling pathways involved in angiogenesis and sites of action of antiangiogenic antibody-based therapies and multitargeted tyrosine kinase inhibitors. Abbreviations: AKT, protein kinase B; c-KIT, stem cell factor receptor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; FGFR, fibroblast growth factor receptor; FLT-3, fms-like tyrosine kinase 3; MEK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositol-3-kinase; RAF, v-raf 1 murine leukemia viral oncogene homolog 1; RAS, retrovirus-associated DNA sequences; RET, rearranged during transfection; SRC, v-src sarcoma viral oncogene homolog; TKIs, tyrosine kinase inhibitors; VEGF, vascular endothe- lial growth factor; VEGFR, vascular endothelial growth factor receptor. © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 11 Number 10 | October 2013 Table 1 Overall Survival and Response Rate Data Reported in Selected Phase II and III Trials of Antiangiogenic Agents in NSCLC Study Treatment Response Rate Overall Survival Bevacizumab Previously untreated locally Carboplatin (AUC 6 day 1) + paclitaxel (200 mg/m2 day 1) q21d x 18.8% vs 28.1% (BEV, 7.5 14.9 vs 11.6 mo (BEV, 7.5 advanced or metastatic NSCLC 6 cycles vs carboplatin/paclitaxel + BEV (7.5 or 15 mg/kg) → BEV mg/kg); 31.5% (BEV, 15 mg/kg; P=.84 vs CT alone); (N=99)8 (15 mg/kg) q21d mg/kg) 17.7 mo (BEV, 15 mg/kg; © JNCCN—Journal ofthe NationalComprehensive Cancer Network P=.63) ECOG 4599: recurrent or Carboplatin (AUC 6 day 1) + paclitaxel (200 mg/m2 day 1) q21d x 15% vs 35% 10.3 vs 12.3 mo (HR, 0.79; advanced nonsquamous NSCLC 6 cycles vs carboplatin/paclitaxel + BEV (15 mg/kg day 1) q21d x 6 95% CI, 0.67–0.92; P=.003) (N=878)9 cycles → BEV (15 mg/kg) q21d AVAiL: recurrent or advanced Cisplatin (80 mg/m2 day 1) + gemcitabine (1250 mg/m2 day 1, 34.6% vs 37.8% vs 21.6% 13.4 mo (P=.42 vs PBO) vs nonsquamous NSCLC (N=1043)13 day 8) + BEV (15 mg/kg day 1) q21d x 6 cycles → BEV (15 mg/kg) 13.6 mo (P=.76 vs PBO) vs q21d vs cisplatin/ gemcitabine + BEV (7.5 mg/kg day 1) q21d x 13.1 mo 6 cycles → BEV (7.5 mg/kg) q21d vs cisplatin/ gemcitabine + PBO q21d x 6 cycles → PBO q21d AngiogenesisinAdvancedNSCLC Targeting Previously untreated advanced Pemetrexed (500 mg/m2 day 1) + carboplatin (AUC 6 day 1) + 55% 14.1 mo nonsquamous NSCLC (N=50)14 BEV (15 mg/kg day 1) q21d x 6 cycles → pemetrexed (500 mg/m2) + BEV (15 mg/kg) q21d Previously untreated advanced Pemetrexed (500 mg/m2) + carboplatin (AUC 6) + BEV (15 mg/kg) 34.1% vs 33.0% 12.6 vs 13.4 mo (HR, 1.00; nonsquamous NSCLC (N=939)15 q21d x 4 cycles → pemetrexed (500 mg/m2) + BEV (15 mg/kg) P=.949) q21d vs paclitaxel (200 mg/m2) + carboplatin (AUC 6) + BEV (15 mg/kg) q21d x 4 cycles → BEV (15 mg/kg) q21d Advanced nonsquamous NSCLC Carboplatin (AUC 6) + paclitaxel (200 mg/m2) + BEV (15 mg/kg) q21d 63% or 13% 16.0 or 12.0 mo Original Article and asymptomatic,
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