Table 2. Recent phase III trials assessing antiangiogenic agents in a second- or third-line setting
Agent and study name [ref.]Target (s)Study designOverall response rateProgression-free survivalOverall survival
Multi-targeted antiangiogenic orally administered TKIs
    Nintedanib; LUME-Lung 1[44]VEGF-1–3, PDGF-α and β, and FGFR-1–3Stage 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 survivalOverall 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 = 0.002In 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-1–3Stage 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 survivalNo 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 = 0.04No significant difference (median values NR)
    Vandetanib; ZODIAC [46]VEGFR-1 and -2, RET and EGFRStage 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 survivalDocetaxel: 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<0.0001Docetaxel: 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 EGFRStage 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 survivalPemetrexed: 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 = 0.108Pemetrexed: 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 EGFRStage 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 survivalPlacebo: 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<0.001Placebo: 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 EGFRStage 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 survivalErlotinib: 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 = 0.721Erlotinib: 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-3Stage IIIB/IV non-squamous NSCLC Patients randomised to: placebo (n = 353) or sorafenib (400 mg twice daily; n = 350) Primary end-point: overall survivalPlacebo: 0.9% Sorafenib: 4.9% (p<0.001)Placebo: 43 days Sorafenib: 84 days HR 0.61; p<0.0001Placebo: 253 days Sorafenib: 248 days HR 0.99; p = 0.4687
    Sunitinib [51]VEGF-1–3, PDGFR-α and β, and RETStage 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 survivalErlotinib: 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 = 0.0023Erlotinib: 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]VEGFStage 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 survivalErlotinib: 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 NRErlotinib: 9.2 months Erlotinib + bevacizumab: 9.3 months HR 0.97 (95% CI 0.80–1.18); p = 0.758
    Aflibercept; VITAL [53]VEGFNon-squamous NSCLC Patients randomised to: docetaxel (n = 457) or docetaxel + aflibercept (6 mg·day−1; n = 456) Primary end-point: overall survivalDocetaxel: 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 = 0.0035Docetaxel: 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.