Suresh S Ramalingam1, Mikhail Shtivelband2, Ross A Soo2, Carlos H Barrios2, Anatoly Makhson2, José G M Segalla2, Kenneth B Pittman2, Petr Kolman2, Jose R Pereira2, Gordan Srkalovic2, Chandra P Belani2, Rita Axelrod2, Taofeek K Owonikoko2, Qin Qin2, Jiang Qian2, Evelyn M McKeegan2, Viswanath Devanarayan2, Mark D McKee2, Justin L Ricker2, Dawn M Carlson2, Vera A Gorbunova2. 1. Suresh S. Ramalingam and Taofeek K. Owonikoko, Winship Cancer Institute of Emory University, Atlanta, GA; Mikhail Shtivelband, Ironwood Cancer and Research Centers, Chandler, AZ; Ross A. Soo, National University Cancer Institute, National University Health System, Singapore, Singapore; Carlos H. Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre; José G.M. Segalla, Hospital Amaral Carvalho, Jau; Jose R. Pereira, Instituto Brasileiro de Cancerologia Toracica, Sao Paulo, Brazil; Anatoly Makhson, Moscow City Oncology Hospital No. 62; Vera A. Gorbunova, N.N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia; Kenneth B. Pittman, The Queen Elizabeth Hospital, Woodville, South Australia, Australia; Petr Kolman, Hospital Kyjov, Kyjov, Czech Republic; Gordan Srkalovic, Sparrow Regional Cancer Center, Lansing, MI; Chandra P. Belani, Penn State Hershey Cancer Institute, Hershey; Rita Axelrod, Thomas Jefferson University Hospital, Philadelphia, PA; Qin Qin, Jiang Qian, Evelyn M. McKeegan, Viswanath Devanarayan, Mark D. McKee, Justin L. Ricker, and Dawn M. Carlson, AbbVie, North Chicago, IL. suresh.ramalingam@emory.edu. 2. Suresh S. Ramalingam and Taofeek K. Owonikoko, Winship Cancer Institute of Emory University, Atlanta, GA; Mikhail Shtivelband, Ironwood Cancer and Research Centers, Chandler, AZ; Ross A. Soo, National University Cancer Institute, National University Health System, Singapore, Singapore; Carlos H. Barrios, Pontifícia Universidade Católica do Rio Grande do Sul School of Medicine, Porto Alegre; José G.M. Segalla, Hospital Amaral Carvalho, Jau; Jose R. Pereira, Instituto Brasileiro de Cancerologia Toracica, Sao Paulo, Brazil; Anatoly Makhson, Moscow City Oncology Hospital No. 62; Vera A. Gorbunova, N.N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, Moscow, Russia; Kenneth B. Pittman, The Queen Elizabeth Hospital, Woodville, South Australia, Australia; Petr Kolman, Hospital Kyjov, Kyjov, Czech Republic; Gordan Srkalovic, Sparrow Regional Cancer Center, Lansing, MI; Chandra P. Belani, Penn State Hershey Cancer Institute, Hershey; Rita Axelrod, Thomas Jefferson University Hospital, Philadelphia, PA; Qin Qin, Jiang Qian, Evelyn M. McKeegan, Viswanath Devanarayan, Mark D. McKee, Justin L. Ricker, and Dawn M. Carlson, AbbVie, North Chicago, IL.
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/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. 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.
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/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. 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.
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