Randomized Phase II Study of Carboplatin and Paclitaxel With Either Linifanib or Placebo for Advanced Nonsquamous Non–Small-Cell Lung Cancer

• Authors: Suresh Ramalingam, Emory University; Mikhail Shtivelband, Ironwood Cancer and Research Centers, Chandler, AZ; Ross A. Soo, National University Cancer Institute, National University Health System, Singapore; Carlos H. Barrios, Pontifícia Universidade Católica do Rio Grande; Anatoly Makhson, Moscow City Oncology Hospital; Jose G. M. Segalla, Hospital Amaral Carvalho, Jau; Kenneth B. Pittman, he Queen Elizabeth Hospital, Woodville, South Australia; Petr Kolman, Hospital Kyjov, Kyjov, Czech Republic; Jose R. Pereira, Instituto Brasileiro de Cancerologia Toracica, Sao Paulo, Brazil; Gordan Srkalovic, Sparrow Regional Cancer Center, Lansing, MI; Chandra P. Belani, Penn State Hershey Cancer Institute; Rita Axelrod, Thomas Jefferson University Hospital, Philadelphia, PA; Taofeek Owonikoko, Emory University; Qin Qin, AbbVie, North Chicago, IL.; Jiang Qian, AbbVie, North Chicago, IL.; Evelyn M. McKeegan, AbbVie, North Chicago, IL.; Viswanath Devanarayan, AbbVie, North Chicago, IL.; Mark D. McKee, AbbVie, North Chicago, IL.; Justin L. Ricker, AbbVie, North Chicago, IL.; Dawn M. Carlson, AbbVie, North Chicago, IL.; VA Gorbunova, N.N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia
• Journal Title: Journal of Clinical Oncology
• Volume: Volume 33, Number 5
• Publisher: American Society of Clinical Oncology | 2015-02-10, Pages 433-441
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1200/JCO.2014.55.7173
• Subjects: Health Sciences, Oncology; Biology, Cell; Health Sciences, Rehabilitation and Therapy; Health Sciences, Toxicology
• Keywords: Linifanib; inhibitor; vascular endothelial growth factor; VEGF; platelet-derived growth factor; PDGF; non-small-cell lung cancer; advanced stage cancer; nonsquamous NSCLC; carboplatin; paclitaxel; progression-free survival; chemotherapy; toxicity

Abstract

Purpose: 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 and Methods: 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/m2) 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. Results: 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. Conclusion: 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.