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.