Randomized phase II study of carboplatin and paclitaxel with either linifanib or placebo for advanced nonsquamous non-small-cell lung cancer

• Published in: Journal of clinical oncology Vol. 33; no. 5; pp. 433 - 441
• Main Authors: Ramalingam, Suresh S, Shtivelband, Mikhail, Soo, Ross A, Barrios, Carlos H, Makhson, Anatoly, Segalla, José G M, Pittman, Kenneth B, Kolman, Petr, Pereira, Jose R, Srkalovic, Gordan, Belani, Chandra P, Axelrod, Rita, Owonikoko, Taofeek K, Qin, Qin, Qian, Jiang, McKeegan, Evelyn M, Devanarayan, Viswanath, McKee, Mark D, Ricker, Justin L, Carlson, Dawn M, Gorbunova, Vera A
• Format: Journal Article
• Language: English
• Published: United States American Society of Clinical Oncology 10.02.2015
• Subjects: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carboplatin - administration & dosage; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - mortality; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Indazoles - administration & dosage; Indazoles - adverse effects; Kaplan-Meier Estimate; Lung Neoplasms - drug therapy; Lung Neoplasms - mortality; Male; Middle Aged; ORIGINAL REPORTS; Paclitaxel - administration & dosage; Phenylurea Compounds - administration & dosage; Phenylurea Compounds - adverse effects; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Treatment Outcome; Vascular Endothelial Growth Factor A - antagonists & inhibitors
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2014.55.7173

Linifanib, a potent, selective inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, has single-agent activity in non-small-cell lung cancer (NSCLC). We evaluated linifanib with carboplatin and paclitaxel as first-line therapy of advanced nonsquamous NSCLC. Patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned to 3-week cycles of carboplatin (area under the curve 6) and paclitaxel (200 mg/m(2)) with daily placebo (arm A), linifanib 7.5 mg (arm B), or linifanib 12.5 mg (arm C). The primary end point was progression-free survival (PFS); secondary efficacy end points included overall survival (OS) and objective response rate. One hundred thirty-eight patients were randomly assigned (median age, 61 years; 57% men; 84% smokers). Median PFS times were 5.4 months (95% CI, 4.2 to 5.7 months) in arm A (n = 47), 8.3 months (95% CI, 4.2 to 10.8 months) in arm B (n = 44), and 7.3 months (95% CI, 4.6 to 10.8 months) in arm C (n = 47). Hazard ratios (HRs) for PFS were 0.51 for arm B versus A (P = .022) and 0.64 for arm C versus A (P = .118). Median OS times were 11.3, 11.4, and 13.0 months in arms A, B, and C, respectively. HRs for OS were 1.08 for arm B versus A (P = .779) and 0.88 for arm C versus A (P = .650). Both linifanib doses were associated with increased toxicity, including a higher incidence of adverse events known to be associated with VEGF/PDGF inhibition. Baseline plasma carcinoembryonic antigen/cytokeratin 19 fragments biomarker signature was associated with PFS improvement and a trend toward OS improvement with linifanib 12.5 mg. Addition of linifanib to chemotherapy significantly improved PFS (arm B), with a modest trend for survival benefit (arm C) and increased toxicity reflective of known VEGF/PDGF inhibitory effects.