Smoking History Predicts Sensitivity to PARP Inhibitor Veliparib in Patients with Advanced Non–Small Cell Lung Cancer Martin Reck, MD, PhD, Normand Blais,

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Smoking History Predicts Sensitivity to PARP Inhibitor Veliparib in Patients with Advanced Non–Small Cell Lung Cancer Martin Reck, MD, PhD, Normand Blais, MD, Erzsebet Juhasz, MD, Vera Gorbunova, MD, C. Michael Jones, MD, Laszlo Urban, MD, Sergey Orlov, MD, PhD, Fabrice Barlesi, MD, PhD, Ebenezer Kio, MD, Ulrich Keilholz, MD, Qin Qin, MS, Jiang Qian, PhD, Caroline Nickner, MSc, Juliann Dziubinski, MBA, Hao Xiong, PhD, Rajendar K. Mittapalli, PhD, Martin Dunbar, PhD, Peter Ansell, PhD, Lei He, PhD, Mark McKee, MD, Vincent Giranda, MD, Suresh S. Ramalingam, MD Journal of Thoracic Oncology Volume 12, Issue 7, Pages 1098-1108 (July 2017) DOI: 10.1016/j.jtho.2017.04.010 Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Veliparib pharmacokinetics (PK) by cotinine level at screening. (A) Dose-normalized veliparib concentration-time profile. (Data are dose-normalized veliparib mean [± SD] concentration-time profile at cycle 1 day 3 between patients with a cotinine level of 10 ng/mL or lower and those with a level higher than 10 ng/mL at screen on linear [left panel] and log-linear [right panel] scale.) (B) Dose-normalized PK parameters of veliparib-treated patients. (Data represent mean ± SD [percent coefficient of variation]; three patients in the group with a low cotinine level were excluded from PK analyses, as no measurable veliparib concentrations were observed in these patients.) AUC0–12, area under the concentration-time curve from 0 to 12 hours; Cmax, maximum plasma-concentration observed; Tmax, time after administration of drug to reach Cmax. Journal of Thoracic Oncology 2017 12, 1098-1108DOI: (10.1016/j.jtho.2017.04.010) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Progression-free survival (PFS) and overall survival (OS) Kaplan-Meier curves are shown for recent smokers (A and B), patients with a high cotinine level (C and D), and heavy smokers (E and F). In all patients with a low cotinine level (n = 57 who received veliparib and 30 who received placebo), the hazard ratios (HRs) were 0.97 (95% confidence interval [CI]: 0.51–1.87) for PFS and 1.07 (95% CI: 0.63–1.81) for OS. In light smokers (n = 36 who received veliparib and 28 who received placebo), the HRs were 0.97 (95% CI: 0.49–1.92) for PFS and 0.92 (95% CI: 0.63–1.6) for OS. BID, twice daily. Journal of Thoracic Oncology 2017 12, 1098-1108DOI: (10.1016/j.jtho.2017.04.010) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 Best percentage change from baseline in the sum of tumor sizes. (A) Patients treated with placebo and carboplatin/paclitaxel. (B) Patients treated with veliparib and carboplatin/paclitaxel. Data are the best percentage change from baseline in the sum of target lesion sizes for individual patients. Journal of Thoracic Oncology 2017 12, 1098-1108DOI: (10.1016/j.jtho.2017.04.010) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 Hazard ratios for progression-free survival and overall survival (univariate Cox proportional hazard model). Plots show hazard ratio (95% confidence interval [CI]) for baseline factors predictive of progression-free survival or overall survival benefit of a veliparib and chemotherapy combination (p < 0.10 in at least one subgroup of a baseline factor). EGFR status was not included from the original demographics table because of the low number of patients with unknown values. ECOG PS, Eastern Cooperative Oncology Group performance status. Journal of Thoracic Oncology 2017 12, 1098-1108DOI: (10.1016/j.jtho.2017.04.010) Copyright © 2017 International Association for the Study of Lung Cancer Terms and Conditions