Veliparib in combination with whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer: results of a randomized, global, placebo-controlled study

Pierre Chabot, Te-Chun Hsia, Jeong-Seon Ryu, Vera Gorbunova, Cristobal Belda-Iniesta, David Ball, Ebenezer Kio, Minesh Mehta, Katherine Papp, Qin Qin, Jane Qian, Kyle D Holen, Vince Giranda, John H Suh, Pierre Chabot, Te-Chun Hsia, Jeong-Seon Ryu, Vera Gorbunova, Cristobal Belda-Iniesta, David Ball, Ebenezer Kio, Minesh Mehta, Katherine Papp, Qin Qin, Jane Qian, Kyle D Holen, Vince Giranda, John H Suh

Abstract

Veliparib is a potent, orally bioavailable, poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor that crosses the blood-brain barrier and has been shown to potentiate the effects of radiation in preclinical and early clinical studies. This phase 2, randomized, global study evaluated the efficacy and safety of veliparib in combination with whole-brain radiation therapy (WBRT) in patients with brain metastases from non-small cell lung cancer (NSCLC). Three-hundred and seven patients with brain metastases from NSCLC were randomized 1:1:1 to WBRT (30 Gy in 10 fractions) plus 50 mg veliparib twice daily (BID; n = 103), 200 mg veliparib BID (n = 102), or placebo BID (n = 102). Treatment began within 28 days of diagnosis. Tumor response and safety were assessed; the primary endpoint was overall survival (OS). Patients who received ≥1 dose of treatment were included in the safety analysis. All randomized patients were included in the efficacy endpoint analyses. Patient characteristics were well balanced between treatment arms. Median OS was 185 days for patients treated with WBRT plus placebo and 209 days for WBRT plus veliparib (50 or 200 mg). No statistically significant differences in OS, intracranial response rate, and time to clinical or radiographic progression between any of the treatment arms were noted. No differences were observed in adverse events (all grades) across treatment arms; nausea, fatigue, alopecia, and headache were the most commonly reported. No new safety signals were identified for veliparib. A significant unmet need for therapies that improve the outcomes of patients with brain metastases from NSCLC remains.

Keywords: Brain metastases; Non-small cell lung cancer; PARP inhibitor; Randomized clinical trial; Veliparib; Whole-brain radiation therapy.

Conflict of interest statement

PC, T-CH, J-SR, VG, CB, and EK have no conflict of interest to disclose. DB has participated as an investigator for AbbVie, his institution was reimbursed by AbbVie for expenses incurred, he received research funding from AbbVie and has participated on advisory boards for Boehringer Ingelheim, AstraZeneca, and Lilly Oncology. MM has received consultant honoraria from BMS, Cavion, Celldex, Elekta, Novartis, Novocure, and has served on the Board of Directors of Pharmacyclics, with stock options, and has institutional research funding from Novocure and Cellectar. JHS has received consultant honoraria and has received research funding from Varian Medical Systems and has had travel and lodging covered by Elekta. KP, QQ, JQ, KDH, and VG are AbbVie employees and may own stock. Ethical approval This study was approved by an Independent Ethics Committee/Independent Review Board before initiation and was performed in accordance with the 1964 Declaration of Helsinki and its later amendments. Informed consent All patients provided written informed consent before their participation.

Figures

Fig. 1
Fig. 1
Study design. BID twice daily, ITT intent to treat, NSCLC non-small cell lung cancer, WBRT whole-brain radiation therapy
Fig. 2
Fig. 2
Overall survival—all randomized patients and subgroup analysis. GPA graded prognostic assessment, KPS Karnofsky performance score, mets, metastases, neruo neurologic, PSY psychologic, WBRT whole-brain radiation therapy

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