Figures
- Figure 1.
Molecular pathways underlying angiogenesis. A: Tumour cells produce vascular endothelial growth factor (VEGF)-A and other angiogenic factors, such as basic fibroblast growth factor (bFGF), angiopoietins, interleukin-8, placental growth factor and VEGF-C. These stimulate resident endothelial cells to proliferate and migrate. B: An additional source of angiogenic factors is the stroma. This is a heterogeneous compartment, comprising fibroblastic, inflammatory and immune cells. Recent studies indicate that tumour-associated fibroblasts produce chemokines, such as stromal cell-derived factor (SDF)-1, which may recruit bone-marrow-derived angiogenic cells (BMC). VEGF-A or placental growth factor may also recruit BMC. Tumour cells may also release stromal cell-recruitment factors, such as platelet-derived growth factor (PDGF)-A, PDGF-C or transforming growth factor (TGF)-β. A well-established function of tumour-associated fibroblasts is the production of growth/survival factor for tumour cells, such as epidermal growth factor (EGF) receptor ligands, hepatocyte growth factor and heregulin. C: Endothelial cells produce PDGF-B, which promotes recruitment of pericytes in the microvasculature after activation of PDGF receptor-β. HGF: hepatocyte growth factor. Reproduced from [10] with permission.
Tables
- Table 1. Recent phase III trials assessing antiangiogenic agents in a first-line setting
Agent and study name [ref.] Target (s) Study design Overall response rate Progression-free survival Overall survival Monoclonal antibodies Bevacizumab; ECOG 4599 [14] VEGF Stage IIIB/IV non-squamous NSCLC Patients randomised to: carboplatin/paclitaxel (n = 444) or carboplatin/paclitaxel + bevacizumab (15 mg·kg−1; n = 434) Primary end-point: overall survival Carboplatin/paclitaxel: 15% Carboplatin/paclitaxel + bevacizumab: 35% (p<0.001) Carboplatin/paclitaxel: 4.5 months Carboplatin/paclitaxel + bevacizumab: 6.2 months HR 0.66 (95% CI 0.57–0.77); p<0.001 Carboplatin/paclitaxel: 10.3 months Carboplatin/paclitaxel + bevacizumab: 12.3 months HR 0.79 (95% CI 0.67–0.92); p = 0.003 Bevacizumab; AVAiL [21, 22] VEGF Stage IIIB/IV non-squamous NSCLC Patients randomised to: cisplatin/gemcitabine (n = 347), cisplatin/gemcitabine + bevacizumab (7.5 mg·kg−1; n = 345) or cisplatin/gemcitabine + bevacizumab (15 mg·kg−1; n = 351) Primary end-point: progression-free survival Cisplatin/gemcitabine: 20.1% Cisplatin/gemcitabine + bevacizumab (7.5 mg·kg−1): 34.1% Cisplatin/gemcitabine + bevacizumab (15 mg·kg−1): 30.4% (p<0.0001 and p = 0.0023, respectively) Cisplatin/gemcitabine: 6.1 months Cisplatin/gemcitabine + bevacizumab (7.5 mg·kg−1): 6.7 months Cisplatin/gemcitabine + bevacizumab (15 mg·kg−1): 6.5 months HR 0.75 (95% CI 0.62–0.91); p = 0.003 and HR 0.92 (95% CI 0.68–0.98); p = 0.03, respectively Cisplatin/gemcitabine: 13.1 months Cisplatin/gemcitabine + bevacizumab (7.5 mg·kg−1): 13.6 months Cisplatin/gemcitabine + bevacizumab (15 mg·kg−1): 13.4 months HR 0.92 (95% CI 0.78–1.11); p = 0.420 and HR 1.03 (95% CI 0.86–1.23); p = 0.761, respectively Multi-targeted antiangiogenic orally administered TKIs Cediranib; BR24 [23] VEGFR-1–3, PDGFR-β, FGFR-1 and c-kit Stage IIIB/IV NSCLC all histologies Patients randomised to: carboplatin/paclitaxel (n = 125) or carboplatin/paclitaxel + cediranib (30 mg·day−1; n = 126) Primary end-point: progression-free survival Carboplatin/paclitaxel: 16% Carboplatin/paclitaxel + cediranib: 38% (p<0.0001) Carboplatin/paclitaxel: 5.0 months Carboplatin/paclitaxel + cediranib: 5.6 months HR 0.77 (95% CI 0.56–1.08); p = 0.13 Carboplatin/paclitaxel: 10.1 months Carboplatin/paclitaxel + cediranib: 10.5 months HR 0.78 (95% CI 0.57–1.06); p = 0.11 Cediranib; BR29 [24] VEGFR-1–3, PDGFR-β, FGFR-1 and c-kit Stage IIIB/IV NSCLC all histologies Patients randomised to: carboplatin/paclitaxel or carboplatin/paclitaxel + cediranib (20 mg·day−1) Primary end-point: overall survival Carboplatin/paclitaxel: 34% Carboplatin/paclitaxel + cediranib: 52% (p = 0.001) Carboplatin/paclitaxel: 5.5 months Carboplatin/paclitaxel + cediranib: 5.5 months HR 0.91 (95% CI 0.71–1.18); p = 0.5 Carboplatin/paclitaxel: 12.1 months Carboplatin/paclitaxel + cediranib: 12.2 months HR 0.95 (95% CI 0.69–1.30); p = 0.74 Sorafenib; ESCAPE [25] VEGFR-2–3, PDGFR-β, c-kit, Raf and flt-3 Stage IIIB/IV NSCLC all histologies Patients randomised to: carboplatin/paclitaxel (n = 462) or carboplatin/paclitaxel + sorafenib (400 mg; n = 464) Primary end-point: overall survival Carboplatin/paclitaxel: 27% Carboplatin/paclitaxel + sorafenib: 24% (p = 0.102) Carboplatin/paclitaxel: 5.4 months Carboplatin/paclitaxel + sorafenib: 4.6 months HR 0.99 (95% CI 0.84–1.16); p = 0.433 Carboplatin/paclitaxel: 10.6 months Carboplatin/paclitaxel + sorafenib: 10.7 months HR 1.15 (95% CI 0.94–1.41); p = 0.915 Sorafenib; NExUS [26] VEGFR-2–3, PDGFR-β, c-kit, Raf and flt-3 Stage IIIB/IV non-squamous NSCLC Patients randomised to: gemcitabine/cisplatin (n = 387) or gemcitabine/cisplatin + sorafenib (400 mg; n = 385) Primary end-point: overall survival Gemcitabine/cisplatin: 26% Gemcitabine/cisplatin + sorafenib: 28% (p = 0.27) Gemcitabine/cisplatin: 5.5 months Gemcitabine/cisplatin + sorafenib: 6.0 months HR 0.83 (95% CI 0.71–0.97); p = 0.008 Gemcitabine/cisplatin: 12.5 months Gemcitabine/cisplatin + sorafenib: 12.4 months HR 0.98 (65% CI 0.83–1.16); p = 0.401 Motesanib; MONET1 [27] VEGFR-1–3, PDGFR-β, c-kit and RET Stage IIIB/IV non-squamous NSCLC Patients randomised to: carboplatin/paclitaxel (n = 549) or carboplatin/paclitaxel + motesanib (125 mg; n = 541) Primary end-point: overall survival Carboplatin/paclitaxel: 26% Carboplatin/paclitaxel + motesanib: 40% (p<0.001) Carboplatin/paclitaxel: 5.4 months Carboplatin/paclitaxel + motesanib: 5.6 months HR 0.79 (95% CI 0.61–0.98); p<0.001 Carboplatin/paclitaxel: 11.0 months Carboplatin/paclitaxel + motesanib: 13.0 months HR 0.90 (95% CI 0.78–1.04); p = 0.14 Vascular disrupting agents Vadimezan; ATTRACT-1 [28] Stage IIIB/IV NSCLC all histologies Patients randomised to: carboplatin/paclitaxel (n = 650) or carboplatin/paclitaxel + vadimezan (1800 mg·m−2; n = 649) Primary end-point: overall survival Carboplatin/paclitaxel: 25% Carboplatin/paclitaxel + vadimezan: 25% (p = 1.0) Carboplatin/paclitaxel: 5.5 months Carboplatin/paclitaxel + vadimezan: 5.5 months HR 1.04 (95% CI 0.91–1.19); p = 0.727 Carboplatin/paclitaxel: 12.7 months Carboplatin/paclitaxel + vadimezan: 13.4 months HR 1.01 (95% CI 0.85–1.19); p = 0.535 ECOG: Eastern Cooperative Oncology Group; AVAiL: Avastin in Lung Cancer; TKI: tyrosine kinase inhibitor; ESCAPE: Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC; NExUS: NSCLC research Experience Utilising Sorafenib; MONET1: Motesanib NSCLC Efficacy and Tolerability Study; ATTRACT-1: Antivascular Targeted Therapy: Researching ASA404 in Cancer Treatment; VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; PDGFR: platelet-derived growth factor receptor; FGFR: fibroblast growth factor receptor; RET: Rearranged during Transfection; NSCLC: nonsmall cell lung cancer; HR: hazard ratio.
- Table 2. Recent phase III trials assessing antiangiogenic agents in a second- or third-line setting
Agent and study name [ref.] Target (s) Study design Overall response rate Progression-free survival Overall survival Multi-targeted antiangiogenic orally administered TKIs Nintedanib; LUME-Lung 1[44] VEGF-1–3, PDGF-α and β, and FGFR-1–3 Stage IIIB/IV NSCLC all histologies Patients randomised to: docetaxel (n = 659) or docetaxel + nintedanib (200 mg twice daily; n = 655) Primary end-point: progression-free survival Overall response rate not reported DCR was significantly greater in the docetaxel + nintedanib arm in patients with adenocarcinoma (p<0.0001) Docetaxel: 2.7 months Docetaxel + nintedanib: 3.4 months HR 0.79 (CI 0.68–0.92); p = 0.002 In patients with adenocarcinoma: Docetaxel: 10.3 months Docetaxel + nintedanib: 12.6 months HR 0.83; p = 0.036 In overall population: Docetaxel: 9.1 months Docetaxel + nintedanib: 10.1 months HR 0.94; p = 0.272 Nintedanib; LUME-Lung 2 [45] VEGF-1–3, PDGF-α and β, and FGFR-1–3 Stage IIIB/IV non-squamous NSCLC Patients randomised to: pemetrexed (n = 360) or pemetrexed + nintedanib (200 mg twice daily; n = 353) Primary end-point: progression-free survival No difference in overall response rate between pemetrexed and pemetrexed + nintedanib (9%) Pemetrexed: DCR 53% Pemetrexed + nintedanib: DCR 61% (p = 0.039) Pemetrexed: 3.6 months Pemetrexed + nintedanib: 4.4 months HR 0.83 (95% CI 0.7–0.99); p = 0.04 No significant difference (median values NR) Vandetanib; ZODIAC [46] VEGFR-1 and -2, RET and EGFR Stage IIIB/IV NSCLC all histologies Patients randomised to: docetaxel (n = 697) or docetaxel + vandetanib (100 mg·day−1; n = 694) Primary end-point: progression-free survival Docetaxel: 10% Docetaxel + vandetanib: 17% (p = 0.0001) Docetaxel: 3.2 months Docetaxel + vandetanib: 4.0 months HR 0.79 (97.6% CI 0.70–0.90); p<0.0001 Docetaxel: 10.0 months Docetaxel + vandetanib: 10.6 months HR 0.91 (97.5% CI 0.78–1.07); p = 0.196 Vandetanib; ZEAL [47] VEGFR-1 and -2, RET and EGFR Stage IIIB/IV NSCLC all histologies Patients randomised to: pemetrexed (n = 278) or pemetrexed + vandetanib (100 mg·day−1; n = 256) Primary end-point: progression-free survival Pemetrexed: 8% Pemetrexed + vandetanib: 19% (p<0.001) Pemetrexed: 11.9 weeks Pemetrexed + vandetanib: 17.6 weeks HR 0.86 (97.6% CI 0.69–1.06); p = 0.108 Pemetrexed: 9.2 months Pemetrexed + vandetanib: 10.5 months HR 0.86 (97.5% CI 0.65–1.13); p = 0.219 Vandetanib; ZEPHYR [48] VEGFR-1 and -2, RET and EGFR Stage IIIB/IV NSCLC all histologies Pre-treated with EGFR inhibitor and one or two chemotherapy regimens Patients randomised to: placebo (n = 307) or vandetanib (300 mg·day-1; n = 617) Primary end-point: overall survival Placebo: 0.7% Vandetanib: 2.6% (p = 0.028) Placebo: 1.8 months Vandetanib: 1.9 months HR 0.63 (95.2% CI 0.54–0.74); p<0.001 Placebo: 7.8 months Vandetanib: 8.5 months HR 0.95 (95.2% CI 0.81–1.11); p = 0.527 Vandetanib; ZEST [49] VEGFR-1 and -2, RET and EGFR Stage IIIB/IV NSCLC all histologies Patients randomised to: erlotinib (150 mg·day−1; n = 617) or vandetanib (300 mg·day−1; n = 623) Primary end-point: progression-free survival Erlotinib: 12% Vandetanib: 12% (p = 0.98) Erlotinib: 2.0 months Vandetanib: 2.6 months HR 0.98 (95.2% CI 0.87–1.10); p = 0.721 Erlotinib: 7.8 months Vandetanib: 6.9 months HR 1.01 (95.1% CI 0.89–1.16); p = 0.830 Sorafenib; MISSION [50] VEGFR-2–3, PDGFR-β, c-kit, Raf and flt-3 Stage IIIB/IV non-squamous NSCLC Patients randomised to: placebo (n = 353) or sorafenib (400 mg twice daily; n = 350) Primary end-point: overall survival Placebo: 0.9% Sorafenib: 4.9% (p<0.001) Placebo: 43 days Sorafenib: 84 days HR 0.61; p<0.0001 Placebo: 253 days Sorafenib: 248 days HR 0.99; p = 0.4687 Sunitinib [51] VEGF-1–3, PDGFR-α and β, and RET Stage IIIB/IV NSCLC all histologies Patients randomised to: erlotinib (150 mg·day−1; n = 480) or erlotinib + sunitinib (37.5 mg·day−1; n = 480) Primary end-point: overall survival Erlotinib: 6.9% Erlotinib + sunitinib: 10.6% (p = 0.048) Erlotinib: 2.0 months Erlotinib + sunitinib: 3.6 months HR 0.81 (95% CI 0.70–0.94); p = 0.0023 Erlotinib: 8.5 months Erlotinib + sunitinib: 9.0 months HR 0.92 (95% CI 0.80–1.07); p = 0.139 Monoclonal antibodies, decoy receptors Bevacizumab; BeTa [52] VEGF Stage IIIB/IV NSCLC all histologies Patients randomised to: erlotinib (150 mg·day−1; n = 317) or erlotinib + bevacizumab (n = 319) Primary end-point: progression-free survival Erlotinib: 6% Erlotinib + bevacizumab: 13% (p-value NR) Erlotinib: 1.7 months Erlotinib + bevacizumab: 3.4 months HR 0.62 (95% CI 0.52–0.75); p-value NR Erlotinib: 9.2 months Erlotinib + bevacizumab: 9.3 months HR 0.97 (95% CI 0.80–1.18); p = 0.758 Aflibercept; VITAL [53] VEGF Non-squamous NSCLC Patients randomised to: docetaxel (n = 457) or docetaxel + aflibercept (6 mg·day−1; n = 456) Primary end-point: overall survival Docetaxel: 8.9% Docetaxel + aflibercept: 23.3% (p<0.001) Docetaxel: 4.1 months Docetaxel + aflibercept: 5.2 months HR 0.82 (95% CI 0.72–0.94); p = 0.0035 Docetaxel: 10.4 months Docetaxel + aflibercept: 10.1 months HR 1.01 (95% CI 0.87–1.17); p = 0.9 TKI: tyrosine kinase inhibitor; ZODIAC: Zactima in Combination with Docetaxel in NSCLC; ZEAL : Zactima Efficacy with Alimta in Lung Cancer; ZEPHYR: Zactima Efficacy Trial for NSCLC Patients with a History of EGFR-TKI and Chemoresistance; ZEST: Zactima Efficacy Study versus Tarceva; VEGF: vascular endothelial growth factor; PDGF: platelet-derived growth factor; FGFR: fibroblast growth factor receptor; VEGFR: VEGF receptor; EGFR: epidermal growth factor receptor; PDGFR: PDGF receptor; NSCLC: nonsmall cell lung cancer; NR: not reported; DCR: disease control rate; HR: hazard ratio.
Vol 23 Issue 131
Table of Contents
Therapeutic options targeting angiogenesis in nonsmall cell lung cancer
