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 improvements 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.)

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 endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Targeting Angiogenesis in Advanced NSCLC =.90) =.003) P P =.42 vs PBO) =.76 vs PBO) P P

=.84 vs CT alone); P =.63) =.949) Overall Survival 7.5 14.9 vs 11.6 mo (BEV, mg/kg; 15 mg/kg; 17.7 mo (BEV, P 10.3 vs 12.3 mo (HR, 0.79; 95% CI, 0.67–0.92; 13.4 mo ( 13.6 mo ( 13.1 mo 14.1 mo 12.6 vs 13.4 mo (HR, 1.00; P 16.0 or 12.0 mo NR NR NR 6.2 mo 10.1 vs 10.4 mo (HR, 1.01; 95.1% CI, 0.87–1.17; Response Rate 7.5 18.8% vs 28.1% (BEV, 15 mg/kg); 31.5% (BEV, mg/kg) 15% vs 35% 34.6% vs 37.8% 21.6% 55% 34.1% vs 33.0% 63% or 13% 55% 44% vs 37% 32% vs 31% 2% 23.3% vs 8.9%

) 2

BEV → day 1, 2 day 1) q21d x day 1) q21d x day 1) + 2 2 2 ramucirumab BEV (15 mg/kg) → → ) + BEV (15 mg/kg) q21d ) + BEV (15 mg/kg) 2 2 pemetrexed (500 mg/m → ) + carboplatin (AUC 6) BEV 2 BEV (15 mg/kg) q21d → day 1) + carboplatin (AUC 6 ) + carboplatin (AUC 6) BEV (15 mg/kg) 2 2 ) + aflibercept (6 mg/kg) q3wk vs docetaxel 2 day 1) + gemcitabine (1250 mg/m 2 PBO q21d pemetrexed (500 mg/m → → BEV (15 mg/kg) q21d (first-line) or ) q21d x 6 cycles vs carboplatin (AUC 6)/paclitaxel ) q21d x 6 cycles 2 2 BEV (7.5 mg/kg) q21d vs cisplatin/ gemcitabine + PBO → BEV (15 mg/kg) q21d → → Treatment Carboplatin (AUC 6 day 1) + paclitaxel (200 mg/m 6 cycles vs carboplatin/paclitaxel + BEV (7.5 or 15 mg/kg) (15 mg/kg) q21d Carboplatin (AUC 6 day 1) + paclitaxel (200 mg/m 6 cycles vs carboplatin/paclitaxel + BEV (15 mg/kg day 1) q21d x cycles Cisplatin (80 mg/m day 8) + BEV (15 mg/kg 1) q21d x 6 cycles q21d vs cisplatin/ gemcitabine + BEV (7.5 mg/kg day 1) x 6 cycles q21d x 6 cycles Pemetrexed (500 mg/m BEV (15 mg/kg day 1) q21d x 6 cycles + BEV (15 mg/kg) q21d Pemetrexed (500 mg/m q21d x 4 cycles q21d vs paclitaxel (200 mg/m (15 mg/kg) q21d x 4 cycles Carboplatin (AUC 6) + paclitaxel (200 mg/m x 6 cycles + erlotinib (150 mg qd) (second-line) Carboplatin (AUC 6 day 1) + paclitaxel (200 mg/m ramucirumab (10 mg/kg day 1) q21d x 6 cycles (10 mg/kg) q21d Ramucirumab + pemetrexed either carboplatin or cisplatin vs pemetrexed + either carboplatin or cisplatin Bavituximab (3 mg/kg) q7d + carboplatin (AUC 6)/paclitaxel (200 mg/m (200 mg/m Aflibercept (4 mg/kg) q2wk Docetaxel (75 mg/m + PBO q3wk

15 20 14

19 22 Overall Survival and Response Rate Data Reported in Selected Phase II and III Trials of Antiangiogenic Agents Overall Survival and Response Rate Data Reported in Selected Phase II III Trials in NSCLC

9 8 24 Table 1 Table Study Bevacizumab Previously untreated locally advanced or metastatic NSCLC (N=99) ECOG 4599: recurrent or advanced nonsquamous NSCLC (N=878) recurrent or advanced AVAiL: nonsquamous NSCLC (N=1043) Previously untreated advanced nonsquamous NSCLC (N=50) Previously untreated advanced nonsquamous NSCLC (N=939) Advanced nonsquamous NSCLC and asymptomatic, untreated brain metastases (N=91) Ramucirumab Previously untreated advanced NSCLC (N=40) Previously untreated advanced nonsquamous NSCLC (N=140) Bavituximab Previously untreated advanced or metastatic nonsquamous NSCLC (N=86) Aflibercept Platinum and erlotinib resistant advanced or metastatic NSCLC (N=98) 1 prior platinum-based VITAL: therapy (N=913) Abbreviations: AUC, area under the curve; BEV, bevacizumab; CT, chemotherapy; HR, hazard ratio; NR, not reported; NSCLC, non–small cell lung cancer; PBO, placebo. bevacizumab; CT, Abbreviations: AUC, area under the curve; BEV,

Lammers and Horn

=.14) =.11) =.92) =.14) P P P P =NR) P

=.272) 13.0 vs 11.0 mo (HR, 0.90; 95% CI, 0.78–1.04; Overall Survival NR (HR, 1.03; 10.5 vs 10.1 mo (HR, 0.78; 95% CI, 0.57–1.06; 11 mo HR, 14.0 mo (vs CT/BEV: 1.05; 95% CI, 0.67–1.63) vs HR, 12.8 mo (vs CT/BEV: 1.18; 95% CI, 0.76–1.83) vs 14.0 mo 6.7 mo 10.7 vs 10.6 mo (HR, 1.15; 95% CI, 0.94–1.41; 12.4 vs 12.5 mo (HR, 0.98; 95% CI, 0.83–1.16) 5.6 mo 8.6 mo 9.0 vs 8.5 mo (HR, 0.92; 95% CI, 0.80–1.07; 5.2 mo 10.1 vs 9.1 mo (HR, 0.94; P

40% vs 26% Response Rate 29% 1.4% 5% vs 3% 9% vs 38% vs 16% 30% vs 23% 37% 0% 27.4% vs 24.0% 28% vs 26% 11.1% 2.1% 10.6% vs 6.9% days 1, 8) + 2 q21d vs 2 day 1) + day 1) + 2 2 PBO daily PBO daily day 1) + motesanib day 1) + cediranib q21d vs docetaxel → 2 2 → 2 sorafenib (400 mg sorafenib (400 mg BEV (15 mg/kg) q21d motesanib (125 mg → → → cediranib (45 or 30 mg → → PBO bid PBO bid → →

motesanib (125 mg daily) vs → day 8) + cediranib (30 mg daily) q21d 2 day 1) + gemcitabine (1250 mg/m 2 motesanib (75 mg bid) x 36 mo vs carboplatin/ → Carboplatin (AUC 6 day 1) + paclitaxel (200 mg/m (125 mg daily) q21d x 6 cycles carboplatin/paclitaxel + PBO daily q21d x 6 cycles Treatment pemetrexed + PBO Carboplatin (AUC 6 day 1) + paclitaxel (200 mg/m (either 45 or 30 mg daily) q21d x 6–8 cycles daily) vs carboplatin/paclitaxel + PBO x 6–8 cycles Pemetrexed (500 mg/m Carboplatin (AUC 6 day 1) + paclitaxel (200 mg/m motesanib (125 mg daily) q21d x 6 cycles daily) x 36 mo vs carboplatin/paclitaxel + motesanib (75 mg bid) q21d x 6 cycles paclitaxel + BEV (15 mg/kg) q21d x 6 cycles x 36 mo Sorafenib (400 mg bid) Carboplatin (AUC 6 day 1) + paclitaxel (200 mg/m sorafenib (400 mg bid days 2–19) x 6 cycles bid) vs carboplatin/paclitaxel + PBO Cisplatin (75 mg/m sorafenib (400 mg bid days 1–21) x 6 cycles bid) vs cisplatin/gemcitabine + PBO Sunitinib (50 mg daily x 4 wk followed by 2 no treatment) Sunitinib (37.5 mg daily) Erlotinib (150 mg daily) + sunitinib (37.5 vs erlotinib PBO Nintedanib (150 or 250 mg bid) Nintedanib (200 mg bid) + docetaxel, 75 mg/m + PBO Nintedanib (200 mg bid) + pemetrexed, 500 mg/m

31 38

41 35 34 37 Overall Survival and Response Rate Data Reported in Selected Phase II and III Trials of Antiangiogenic Agents Overall Survival and Response Rate Data Reported in Selected Phase II III Trials in NSCLC (cont.)

44 30 39 28 Cediranib advanced NCIC BR24: CT-naïve NSCLC (N=296) Previously treated NSCLC without prior BEV (N=38) Motesanib advanced NSCLC CT-naïve (N=186) advanced CT-naïve MONET-1: nonsquamous NSCLC (N=1090) Table 1 Table Study Sorafenib Relapsed or refractory NSCLC (N=54) advanced NSCLC ESCAPE: CT-naïve (N=926) advanced NEXUS: CT-naïve nonsquamous NSCLC (N=904; n=772 evaluable for efficacy) Sunitinib Previously treated NSCLC (N=63) Previously treated advanced NSCLC (N=47) Previously untreated advanced NSCLC (N=960) Nintedanib Previously treated advanced NSCLC (N=73) LUME-Lung 1: previously treated advanced NSCLC (N=1314) LUME-Lung 2: previously treated advanced nonsquamous NSCLC (N=713) Abbreviations: AUC, area under the curve; BEV, bevacizumab; CT, chemotherapy; HR, hazard ratio; NR, not reported; NSCLC, non–small cell lung cancer; PBO, placebo. bevacizumab; CT, Abbreviations: AUC, area under the curve; BEV,

Targeting Angiogenesis in Advanced NSCLC =.20)

=.53) =.22) =.83) P P P P

=.61) =.70) =NR) =.54) P P P P =.89) vs 15.9 mo

P =.63) vs 14.7 mo (vs CT Overall Survival 6.8 vs 6.7 mo (HR, 1.1; 95% CI, 0.77–1.55; 14.8 mo 16.6 mo (vs CT alone: HR, 1.08; 95% CI, 0.66–1.76; P alone: HR, 1.39; 95% CI, 0.87–2.22; 10.6 vs 13.3 mo (HR, 1.12; 95% CI, 0.74–1.69; 10.5 vs 9.2 mo (HR, 0.86; 97.54% CI, 0.65–1.13; 7.8 vs 6.9 mo (HR, 1.01; 95.08% CI, 0.89–1.16; 10.6 vs 10.0 mo. (HR, 0.91; 97.52% CI, 0.78–1.07; 8.5 vs 7.8 mo (HR, 0.95; 95.2% CI, 0.81–1.11; 9.0 mo (both doses combined) 11.0 vs mo (HR, 0.96; 60% CI, 0.76–1.21; 13.4 vs 12.7 mo (HR, 1.01; 95% CI, 0.85–1.19; Response Rate 6% vs 0% 9% 45.5% vs 39.7% 26.3% 29.3% vs 43.3% 19% vs 8% 12% vs 17% vs 10% 2.6% vs 0.7% 3.1% vs 6.8% 32% vs 31% 25% vs

→ ) 2 ) day ) 2

2 )/cisplatin 2 PBO q21d → )/cisplatin (75 mg/m 2 )/carboplatin (AUC 6) day 2 ) q21d vs PBO + carboplatin 2 ) q21d x 6 cycles 2 )/carboplatin (AUC 6) day 2 q21d 2 day 1) + vandetanib (100 mg daily) q21d x 2 ) + carboplatin (AUC 6)/paclitaxel (200 mg/m day 1) + docetaxel (75 mg/m 2 2 ) + vandetanib (100 mg daily) q21d x 6 cycles 2 vadimezan (1800 mg/m → ) q21d 2 ) day 2 or paclitaxel (200 mg/m 2 PBO daily Treatment Pazopanib (600 mg qd) + erlotinib (150 vs PBO (150 mg qd) Axitinib (5 mg bid) Cisplatin + pemetrexed axitinib (5 mg bid [starting dose] continuous) q21d x 6 cycles vs cisplatin + pemetrexed axitinib (5 mg bid [starting dose] days 2–19) q21d x 6 cycles vs cisplatin/ pemetrexed q21d x 6 cycles Axitinib (5 mg bid) + carboplatin (AUC 6)/paclitaxel (200 mg/m q21d vs bevacizumab (15 mg/kg) + carboplatin (AUC 6)/paclitaxel (200 mg/m Pemetrexed (500 mg/m 6 cycles vs pemetrexed + PBO q21d x Erlotinib (150 mg daily) vs vandetanib (300 Docetaxel (75 mg/m vandetanib (100 mg daily) vs docetaxel + PBO daily q21d x 6 cycles → (300 mg daily) vs PBO daily Vandetanib Linifanib (0.10 mg/kg daily) vs linifanib (0.25 Ombrabulin (35 mg/m (75 mg/m 2 q21d vs PBO day 1 + docetaxel (75 mg/m 2 or paclitaxel (200 mg/m (1800 mg/m Vadimezan q21d x 6 cycles (AUC 6)/paclitaxel (200 mg/m

50 51

63 58

56 49 47 53 60 Overall Survival and Response Rate Data Reported in Selected Phase II and III Trials of Antiangiogenic Agents Overall Survival and Response Rate Data Reported in Selected Phase II III Trials in NSCLC (cont.)

54 55 Table 1 Table Study Pazopanib Previously treated advanced NSCLC (N=192) Axitinib or previously treated CT-naïve NSCLC without prior angiogenic therapy (N=32) Previously untreated nonsquamous NSCLC (N=170) Previously untreated advanced nonsquamous NSCLC (N=118) Vandetanib ZEAL: previously treated advanced NSCLC (N=534) previously treated advanced ZEST: NSCLC (N=1240) ZODIAC: previously treated locally advanced or metastatic NSCLC (N=1391) ZEPHYR: previously treated locally advanced or metastatic NSCLC (N=924) Linifanib (ABT-869) Previously treated advanced or metastatic NSCLC (N=139) Ombrabulin (AVE8062) Previously untreated metastatic NSCLC (N=176) (ASA404) Vadimezan Previously untreated advanced or metastatic NSCLC (N=1204) Abbreviations: AUC, area under the curve; BEV, bevacizumab; CT, chemotherapy; HR, hazard ratio; NR, not reported; NSCLC, non–small cell lung cancer; PBO, placebo. bevacizumab; CT, Abbreviations: AUC, area under the curve; BEV,

Lammers and Horn

analysis, elderly patients (age ≥70 years) had improved and OS (12.6 vs 13.4 months) did not show superior- median PFS and RR but no improvement in median ity. The toxicities differed between arms; more grade OS.11 The most common grade 3 or higher AEs in the 3/4 thrombocytopenia (23.3% vs 5.6%), anemia bevacizumab arm were neutropenia (26%), hyperten- (14.5% vs 2.7%), and fatigue (10.9% vs 5.0%) were sion (7%), febrile neutropenia (5%), and bleeding seen in the pemetrexed group, whereas more grade events (4%).9 Compared with chemotherapy alone, 3/4 neutropenia (40.6% vs 25.8%), febrile neutrope- bevacizumab plus chemotherapy was associated with nia (4.1% vs 1.4%), and sensory neuropathy (4.1% vs higher rates of grade 4 neutropenia (26% vs 17%) 0%) were seen in the paclitaxel group. and thrombocytopenia (1.6% vs 0.2%), and grade 3/4 Several studies have evaluated bevacizumab in pa- febrile neutropenia (4.0% vs 1.8%), hyponatremia tients who have historically been excluded from other (3.5% vs 1.1%), hypertension (7.0% vs 0.7%), head- trials. The phase II BRIDGE trial studied carboplatin/ ache (3.0% vs 0.5%), rash or desquamation (2.3% vs paclitaxel and delayed bevacizumab in 31 previously 0.5%), and bleeding events (4.4% vs 0.7%). untreated patients with advanced squamous NSCLC.16 The AVAIL trial was a similarly designed phase Efficacy results have not been published, but the 4 most III trial conducted in Europe and Canada to evalu- common grade 3/4 AEs were hypertension (16%), dys- ate the efficacy of cisplatin and gemcitabine with or pnea (10%), deep vein thrombosis (7%), and arthralgia without bevacizumab (7.5 or 15.0 mg/kg) in 1043 (7%). One patient had grade 3 or higher pulmonary patients with advanced or recurrent nonsquamous hemorrhage and another had grade 1 pulmonary hem- NSCLC.12 Median PFS (6.7 months in the bevaci- orrhage. zumab, 7.5-mg/kg arm and 6.5 months in the bevaci- The phase II BRAIN trial evaluated the safety of zumab, 15.0-mg/kg arm vs 6.1 months in the placebo bevacizumab given in the first-line setting with carbo- arm) and RR (38% in the bevacizumab, 7.5-mg/kg platin/paclitaxel, or in the second-line setting in com- arm and 35% in the bevacizumab, 15.0-mg/kg arm bination with erlotinib in patients with nonsquamous vs 22% in the placebo arm) were significantly im- NSCLC and asymptomatic, untreated brain metastases. proved in both bevacizumab-containing arms, but Grade 1 intracranial hemorrhage occurred in 1 of 67 pa- OS was not improved in either bevacizumab-con- tients in the first-line setting and 0 of 24 patients in the taining arm compared with placebo (13.6, 13.4, and second-line setting, and the RR for intracranial metas- 13.1 months, respectively).13 Grade 3/4 AEs in the tases was 61% in first-line therapy and 21% in second- bevacizumab, 15.0-mg/kg arm included hypertension line therapy.17 (9%), vomiting (9%), neutropenia (36%), bleeding Ramucirumab: Ramucirumab (IM-1121B), a human (4%), and proteinuria (1%). Grade 3/4 AEs in the monoclonal anti–VEGFR-2 antibody,18 is currently bevacizumab, 7.5-mg/kg arm included hypertension being evaluated in patients with diverse histologic (6%), vomiting (7%), neutropenia (40%), bleeding subtypes of NSCLC, including those with squamous (4%), and proteinuria (<1%). Pulmonary hemor- cell histology and/or treated brain metastases. Re- rhage was observed in 1.5% of patients in the beva- sults from a single-arm phase II trial of 40 patients cizumab, 7.5-mg/kg arm; 0.9% in the bevacizumab, treated with carboplatin, paclitaxel, and ramucirum- 15.0-mg/kg arm; and 0.6% in the placebo arm. ab reported an RR of 55% and a median PFS of 7.9 A phase II study of pemetrexed/carboplatin/bev- months.19 Grade 3/4 AEs included thrombocytopenia acizumab followed by maintenance pemetrexed and (10%), febrile neutropenia (7.5%), peripheral neu- bevacizumab showed impressive results14 and led inves- ropathy, and pulmonary embolism (5% each). tigators to conduct a large randomized phase III trial of In a separate phase II randomized study in pa- 939 patients to evaluate for superiority of pemetrexed/ tients with nonsquamous NSCLC, ramucirumab carboplatin/bevacizumab followed by pemetrexed/ plus pemetrexed was given in combination with bevacizumab maintenance compared with pacli- either carboplatin or cisplatin versus single-agent taxel/carboplatin/bevacizumab followed by single- pemetrexed in combination with carboplatin or agent bevacizumab maintenance.15 Only PFS was cisplatin.20 An interim analysis showed an RR of statistically superior in the pemetrexed/carboplatin/ 44% and aPFS of 6.3 months in the ramucirumab bevacizumab arm (6.0 vs 5.6 months for paclitaxel/ arm versus an RR of 37% and a PFS of 4.3 months carboplatin/bevacizumab), but RR (34.1% vs 33.0%) in the chemotherapy-alone arm. Grade 3 AEs in

Targeting Angiogenesis in Advanced NSCLC

Table 2 Ongoing Phase II and Phase III Trials in the United States of Approveda and Investigational Antiangiogenic Agents in Advanced or Metastatic NSCLCb Trial Phase Description Statusa Bevacizumab NCT01107626 III Bevacizumab or pemetrexed or bevacizumab plus pemetrexed after Recruiting at least stable disease after 4 cycles of induction therapy in patients with advanced nonsquamous NSCLC NCT00948675 III Pemetrexed and carboplatin followed by pemetrexed maintenance Active, no longer therapy or paclitaxel, carboplatin, and bevacizumab followed by recruiting bevacizumab maintenance therapy in patients with advanced nonsquamous NSCLC NCT00946712 III Carboplatin and paclitaxel with or without bevacizumab and/or Recruiting cetuximab in patients with stage IV or recurrent NSCLC

NCT01351415 III Investigator’s choice of standard of care treatment with or without Recruiting bevacizumab in patients with advanced nonsquamous NSCLC

Ramucirumab NCT01168973 III Ramucirumab plus docetaxel as second-line treatment in patients Active, no longer with stage IV NSCLC recruiting NCT01160744 II Ramucirumab plus cisplatin or carboplatin with paclitaxel or Recruiting gemcitabine as first-line treatment in patients with stage IV NSCLC Bavituximab NCT01160601 II Carboplatin and paclitaxel with or without bavituximab in patients Active, no longer with previously untreated advanced nonsquamous NSCLC recruiting Sorafenib NCT00609804 II Sorafenib plus erlotinib or sorafenib alone in patients with advanced Active, no longer NSCLC after failure of erlotinib recruiting Sunitinib NCT00693992 III Sunitinib maintenance in patients with advanced NSCLC after first- Recruiting line combination chemotherapy NCT00698815 II Sunitinib plus pemetrexed or sunitinib monotherapy as second-line Active, no longer treatment in patients with advanced NSCLC recruiting Cediranib NCT00795340 III Cediranib plus paclitaxel/carboplatin in patients with advanced Active, no longer NSCLC recruiting NCT00410904 II Cediranib plus pemetrexed in patients with previously treated NSCLC Active, no longer recruiting Pazopanib NCT01027598 II Pazopanib plus erlotinib in patients with previously treated Active, no longer advanced NSCLC recruiting NCT01179269 II Pazopanib plus paclitaxel as first-line treatment in patients with Recruiting advanced NSCLC NCT01262820 II Pazopanib as second-line treatment in patients with advanced Recruiting NSCLC after failure of bevacizumab

Abbreviation: NSCLC, non–small cell lung cancer. aTrials of bevacizumab listed are limited to phase III. bBased on information on ClinicalTrials.gov as of June 2013. the ramucirumab arm included thrombocytopenia randomized phase II study of 86 patients with non- (15%), neutropenia (13%), fatigue (12%), and nau- squamous histology compared carboplatin/paclitaxel sea (10%). with or without bavituximab.22 In the bavituximab Bavituximab: Bavituximab is a monoclonal anti- group, the RR was 32% and PFS was 5.8 months, and body against phosphatidylserine that causes selec- in the chemotherapy alone group, the RR was 31% tive shutdown of existing tumor blood vessels.21 A and PFS was 4.6 months. OS was not yet reached at

Lammers and Horn

the time of reporting. The most common grade 3/4 vs 13.7 months) compared with patients receiving AEs were anemia (6.8% with bavituximab vs 7.1% chemotherapy alone. The 4 most common grade 3/4 with chemotherapy alone), neutropenia (6.8% vs AEs in the sorafenib arm were neutropenia (9%), 9.5%), and thrombocytopenia (6.8% vs 2.4%). rash/desquamation (8%), hand-foot skin reaction Aflibercept: Aflibercept (AV0005), an angiogenesis (8%), and fatigue (5%), whereas in the chemothera- inhibitor composed of portions of the extracellular py arm, these were neutropenia (6%), fatigue (3%), domains of human VEGFR-1 and VEGFR-2 fused and diarrhea, sensory neuropathy, vomiting, and to the Fc portion of human immunoglobulin G, is nausea (2% each). Four of the 6 fatal hemorrhagic/ currently being evaluated in NSCLC.23 In a single- bleeding events observed in the study occurred in arm, phase II trial, aflibercept was administered to 98 patients with squamous histology (2 in each arm). patients with platinum- and erlotinib-resistant lung A second phase III trial (NEXUS) excluded pa- adenocarcinoma, and results showed an RR of 2%, tients with squamous cell histology, subsequent to a median PFS of 2.7 months, and a median OS of a protocol amendment.31 This trial combined cis- 6.2 months.24 The most common grade 3/4 AEs were platin/gemcitabine with or without sorafenib in 904 hypertension (23%), dyspnea (21%), proteinuria patients with advanced NSCLC, showing no differ- (10%), and fatigue (7%). A phase III trial (VITAL) ence in median OS with sorafenib versus placebo in of docetaxel plus aflibercept versus docetaxel alone nonsquamous disease (12.4 vs 12.5 months), but a as second-line therapy in advanced NSCLC showed statistically significant increase in median PFS (6.0 an improvement in RR (23% vs 9%) and median vs 5.5 months). Reported grade 3 or higher AEs at- PFS (5.2 vs 4.1 months), but OS was not improved tributable to sorafenib included thrombocytopenia (10.1 vs 10.4 months).25 The most common grade (10%), hand-foot skin reaction (9%), fatigue (7%), 3/4 AEs were neutropenia (28% in the aflibercept and rash (6%). arm vs 21% in the chemotherapy-alone arm), fatigue Sunitinib: Sunitinib is a multitargeted TKI that (11% vs 4%), and stomatitis (9% vs 1%). inhibits VEGFR-2, PDGFR-β, rearranged during 32 Tyrosine Kinase Inhibitors transfection (RET), c-KIT, and FLT-3. Sunitinib Resistance to VEGF inhibition has been shown to be has shown single-agent activity in phase II trials multifactorial.26 Receptor tyrosine kinase inhibitors in patients with previously treated NSCLC.33,34 A (TKIs), many of which target several angiogenesis phase III trial of sunitinib plus erlotinib versus er- pathways, are a class of agents in clinical development lotinib alone as second- or third-line therapy in 960 for various malignancies. Many of the multitargeted patients (90% with unknown EGFR mutational sta- agents will theoretically inhibit several angiogen- tus) showed no significant differences in the primary esis pathways and may specifically overcome resis- end point of OS (9.0 vs 8.5 months).35 The most tance to VEGF inhibition. Several of these multi- common grade 3/4 toxicities with sunitinib plus er- targeted TKIs have been investigated for use in the lotinib were rash/dermatitis (17%), diarrhea (16%), treatment of NSCLC in clinical trials. and hypophosphatemia (13%), all higher than with Sorafenib: Sorafenib is a multitargeted TKI that in- erlotinib alone (10%, 3%, and 4%, respectively). hibits VEGFR-2, VEGFR-3, platelet-derived growth Nintedanib: Nintedanib (BIBF 1120) is a multi- factor receptor-β (PDGFR-β), v-raf1 murine leuke- targeted TKI that targets VEGFR-1, VEGFR-2, mia viral oncogene homolog 1 (Raf), fms-like tyro- VEGFR-3, PDGFR-α, PDGFR-β, fibroblast sine kinase 3 (FLT-3), and stem cell factor receptor growth factor receptor (FGFR)-1, FGFR-2, and (c-KIT).27 Sorafenib showed single-agent activity FGFR-3. In addition, nintedanib has activity in several phase II trials in patients with previous- against FLT-3 and the v-src sarcoma viral onco- ly treated advanced nonsquamous NSCLC,28,29 but gene homolog (src) family.36 A phase II study of large randomized phase III trials have been disap- nintedanib dosed at either 250 mg twice daily or pointing.30,31 A phase III trial (ESCAPE) of 926 pa- 150 mg twice daily in 73 patients with relapsed tients with advanced nonsquamous and squamous NSCLC showed mild activity.37 A phase III study cell NSCLC was halted because of lack of efficacy on (LUME-Lung 1) randomized 1314 patients with interim analysis.30 Patients with squamous histology advanced or metastatic squamous and nonsqua- receiving sorafenib had a shorter median OS (8.9 mous NSCLC that had progressed on first-line

Targeting Angiogenesis in Advanced NSCLC chemotherapy to either nintedanib or placebo in c-KIT, and RET.43 A phase II trial of motesanib in combination with docetaxel.38 An improvement combination with doublet chemotherapy44 and a was seen in median PFS (3.4 vs 2.7 months) but phase III trial of carboplatin and paclitaxel with or not in median OS (10.1 vs 9.1 months) in the without motesanib (MONET1) were performed. nintedanib/docetaxel arm versus the docetaxel/ The phase III study was initially suspended because placebo arm. Grade 3/4 AEs were similar in each of a higher incidence of hemoptysis and mortality in arm, the most common included elevated alanine patients with squamous cell histology. The trial re- aminotransferase (ALT) (8% vs 1%) and diarrhea sumed in patients with only nonsquamous histology, (7% vs 3%). A separate phase III study (LUME- and did not show a statistically significant improve- Lung 2) comparing nintedanib or placebo in com- ment in median OS.45 The RR was 40%, median PFS bination with pemetrexed in patients with ad- was 5.6 months, and median OS was 13.0 months vanced or metastatic nonsquamous NSCLC that in the motesanib arm, versus 26%, 5.4 months, and had progressed on first-line chemotherapy was 11.0 months, respectively, in the placebo arm. Grade stopped early because of a signal for futility on 3 or higher AEs with motesanib included neutro- an interim analysis.39 The analysis of 713 enrolled penia (22% vs 15% with placebo), diarrhea (9% vs patients (initial enrollment planned for 1300 pa- 1%), hypertension (7% vs 1%), and cholecystitis tients) showed an increase in median PFS (4.4 vs (3% vs 0%). The incidence of grade 5 AEs was 14% 3.6 months) but no difference in RR (9% vs 9%) with motesanib versus 9% with placebo. or median OS (HR 1.03). Reported grade 3/4 AEs Pazopanib: Pazopanib is a multitargeted TKI that included elevated ALT (23% vs 7%), elevated as- inhibits VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- partate aminotransferase (12% vs 2%), and diar- α/β, FGFR-1, FGFR-3, and c-KIT,46 and is currently rhea (3% vs 1%). being evaluated. In a phase II trial, 192 patients Cediranib: Cediranib inhibits VEGFR-1, VEGFR-2, with advanced NSCLC for whom 1 to 2 prior lines VEGFR-3, PDGFR-α/β, FGFR-1, and c-KIT.40 A of therapy failed were randomized to pazopanib plus phase II/III trial comparing carboplatin/paclitaxel erlotinib versus placebo plus erlotinib.47 A statisti- with or without cediranib, 30 mg, in 296 patients cally significant improvement in PFS was seen in the with advanced NSCLC was halted early because combination arm (2.6 vs 1.8 months with erlotinib of imbalances in the number of deaths observed in alone), but both arms showed similar RR (6% vs cediranib-treated patients.41 The RR was 38%, me- 0%) and OS (6.8 vs 6.7 months). Severe nonhema- dian PFS was 5.6 months, and median OS was 10.5 tologic toxicities in the combination group were fa- months in the cediranib group compared with an RR tigue (20%), diarrhea (19%), and proteinuria (5%). of 16%, median PFS of 5.0 months, and median OS of Axitinib: Axitinib is a multitargeted TKI that targets 10.1 months in the placebo group. The 4 most com- VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, and c- mon grade 3/4 AEs in the cediranib arm were neu- KIT.48 A phase II study of axitinib in 32 patients with tropenia (49%), fatigue (29%), increased thyroid- NSCLC showed an RR of 9%, a median PFS of 4.9 stimulating hormone (27%), and hypertension months, and a median OS of 14.8 months.49 Grade 3 (19%). A phase II trial evaluating pemetrexed and hypertension (9%) and diarrhea and vomiting (3% cediranib in 2 cohorts of patients (a bevacizumab- each) were reported. In a randomized phase II study naïve group and a bevacizumab-pretreated group) has of 2 dosing schedules (continuous or intermittent) completed accrual of bevacizumab-naïve patients.42 of axitinib with first-line pemetrexed/cisplatin in Preliminary results in the bevacizumab-naïve group 170 patients with nonsquamous NSCLC, the ax- showed an RR of 29%, median PFS of 5.6 months, itinib arms were associated with higher RRs versus and median OS of 11 months. The 4 most common chemotherapy alone (45.5% in the continuous arm grade 3/4 AEs in the bevacizumab-naïve cohort were and 39.7% in the intermittent arm vs 26.3% in the fatigue (22%), neutropenia (14%), diarrhea (14%), chemotherapy-alone arm), but with no significant and infection (8%). Three treatment-related deaths prolongation of PFS (8.0, 7.9, and 7.1 months, re- have been reported. spectively) or OS (16.6, 14.7, and 15.9 months, re- Motesanib: Motesanib is a multitargeted TKI that spectively).50 The most common grade 3 AEs were targets VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, hypertension (20%), neutropenia (18%), and nau-

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sea (16%) with continuous axitinib, and hyperten- was 11.0 months in each arm. The safety profile was sion (17%), fatigue (16%), and anemia (14%) with reported to be similar, with a 57% incidence of un- intermittent axitinib, and grade 4 asthenia (1%) and specified grade 3/4 AEs in the ombrabulin arm versus pulmonary embolism (1%) were also reported with 52% in the placebo arm. the latter schedule. Vadimezan: Vadimezan (ASA404) is a vascular dis- A phase II randomized study of axitinib or beva- rupting agent of the flavonoid class.61 After promis- cizumab combined with paclitaxel/carboplatin as ing results in a phase II trial in untreated patients,62 first-line therapy for patients with nonsquamous it was tested in a phase III trial in advanced or meta- NSCLC failed to show an improvement in RR (29% static NSCLC in combination with carboplatin/ vs 43%, respectively), PFS (5.7 vs 6.1 months), or paclitaxel versus carboplatin/paclitaxel alone. A to- OS (10.6 vs 13.3 months) for axitinib versus beva- tal of 1299 patients were enrolled and the trial was cizumab. The most common grade 3/4 AE in both stopped early because of futility. No statistical differ- arms was neutropenia, and axitinib was associated ences in OS (13.4 vs 12.7 months), PFS (5.5 vs 5.5 with a higher rate of treatment discontinuation be- months), or RR (25% vs 25%) were seen in the vadi- cause of AEs compared with bevacizumab (41% vs mezan arm versus the chemotherapy-alone arm.63 31%, respectively).51 Vandetanib: Vandetanib is a TKI that inhibits VEGFR signaling, EGFR signaling to a lesser extent, Lack of Predictive Biomarkers for and RET tyrosine kinases.52 Vandetanib is no longer Antiangiogenic Therapy in Lung Cancer in development for the treatment of NSCLC. Sev- Many antiangiogenic agents have shown an increase eral phase III trials failed to show a significant im- in RR or PFS when compared with placebo, but in provement in OS among previously treated patients most cases this has not translated into an OS benefit. with advanced NSCLC when vandetanib was com- Predictive biomarkers are greatly needed to identify bined with chemotherapy (ZEAL, ZODIAC),53,54 the subset of patients who may benefit from antian- given as a single agent after failure of an EGFR TKI giogenic therapy or those likely to experience side (ZEPHYR),55 or compared with erlotinib (ZEST).56 effects, such as thrombosis and bleeding. Several Linifanib: Linifanib (ABT-869) is a multitargeted molecular mediators of angiogenesis and inflamma- TKI that is being evaluated in NSCLC. It inhibits tory signaling have been investigated as potential VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-β, c-KIT, biomarkers of antiangiogenic therapy in lung can- CSF-1R, and FLT-3.57 Results from a phase II trial cer, such as circulating VEGF,64 intercellular adhe- evaluating 2 doses of linifanib (0.10 mg/d and 0.25 sion molecule (ICAM),64 IL-2,65 IL-8,66 IL-12,65 and mg/d) in 139 patients with chemorefractory NSCLC IL-16,65 but no biomarker has yet been prospectively showed an RR of 5.0%, median PFS of 3.6 months, validated to correlate with outcomes. and median OS of 9.0 months overall.58 The incidence of grade 3/4 hypertension was 1.5% in the 0.10-mg/d group and 24.3% in the 0.25-mg/d group; Conclusions no other grade 3/4 AEs were observed in more than As the field of lung cancer moves further into the 10% of patients overall. age of personalized medicine, it will be imperative Vascular Disrupting Agents to target the entire milieu surrounding the tumor Ombrabulin: Ombrabulin (AVE8062) is a vascu- environment, and not merely the mutations within lar disrupting agent and analog of combretastatin the cancer cell itself. Preclinical models and selected A4 that damages tumor vasculature.59 The phase II clinical trials have shown benefits for targeting an- DISRUPT trial randomized 176 patients with either giogenesis in lung cancer. Currently, bevacizumab squamous or nonsquamous histology to either thera- is the only antiangiogenic agent recommended by py with ombrabulin or placebo combined with a che- the NCCN for use in the treatment of advanced motherapy backbone of either cisplatin/docetaxel or NSCLC. A significant knowledge deficit exists in carboplatin/paclitaxel for 6 cycles.60 The RR was the understanding of the molecular basis of antian- 32% in the ombrabulin arm versus 31% in the pla- giogenic therapy and the AEs seen with these agents. cebo group, PFS was 5.7 versus 5.5 months, and OS A more thorough understanding of the mechanisms

Targeting Angiogenesis in Advanced NSCLC of benefit and AEs is needed to better predict who therapy for nonsquamous non-small-cell lung cancer: AVAiL. J will benefit from this treatment strategy. Predictive Clin Oncol 2009;27:1227–1234. 13. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with biomarkers are needed to help select patients who cisplatin-gemcitabine and bevacizumab or placebo as first-line will benefit most from or be least likely to experience therapy for nonsquamous non-small-cell lung cancer: results from the toxicities associated with these drugs. a randomised phase III trial (AVAiL). Ann Oncol 2010;21:1804– 1809. 14. Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance Acknowledgments pemetrexed and bevacizumab as first-line therapy for nonsquamous Editorial assistance was provided by Allison Michaelis, non-small-cell lung cancer. J Clin Oncol 2009;27:3284–3289. 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Targeting Angiogenesis in Advanced NSCLC

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JNCCN-N-0186-1013 Patient and JNCCN-N-0186-1013 OCT-HP-A.inddCaregiver 1 9/30/13 5:21 PM © ResourcesJNCCN—Journal of the National Comprehensive Cancer Network | Volume 11 Number 10 | October 2013