Randomized, double-blind, phase II study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer

• Type of Material: Article
• Authors: M.Catherine Pietanza, Memorial Sloan-Kettering Cancer Center; Saiama N. Waqar, Washington University School of Medicine in St. Louis; Lee M. Krug, Memorial Sloan-Kettering Cancer Center; Afshin Dowlati, University Hospitals Case Medical Center; Christine L. Hann, Johns Hopkins University; Alberto Chiappori, Moffitt Cancer Center; Taofeek K Owonikoko, Emory University; Kaitlin M. Woo, Memorial Sloan-Kettering Cancer Center; Robert J. Cardnell, University of Texas MD Anderson Cancer Center; Junya Fujimoto, University of Texas MD Anderson Cancer Center; Lihong Long, University of Texas MD Anderson Cancer Center; Lixia Diao, University of Texas MD Anderson Cancer Center; Jing Wang, University of Texas MD Anderson Cancer Center; Yevgeniva Bensman, Memorial Sloan-Kettering Cancer Center; Brenda Hurtado, Memorial Sloan-Kettering Cancer Center; Patricia de Groot, University of Texas MD Anderson Cancer Center; Erik P. Sulman, University of Texas MD Anderson Cancer Center; Ignacio I. Wistuba, University of Texas MD Anderson Cancer Center; Alice Chen, National Institutes of Health, Bethesda; Martin Fleisher, Memorial Sloan-Kettering Cancer Center; John V. Heymach, University of Texas MD Anderson Cancer Center; Mark G. Kris, Memorial Sloan-Kettering Cancer Center; Charles M. Rudin, Memorial Sloan-Kettering Cancer Center; Lauren Averett Byers, University of Texas MD Anderson Cancer Center
• Language: English
• Date: 2018-08-10
• Publisher: American Society of Clinical Oncology
• Publication Version: Final Published Version
• Copyright Statement: © 2018 by American Society of Clinical Oncology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1200/JCO.2018.77.7672
• Title of Journal or Parent Work: Journal of Clinical Oncology
• ISSN: 0732-183X
• Volume: 36
• Issue: 23
• Start Page: 2386
• End Page: 2394
• Grant/Funding Information: Supported by the Cancer Therapy Evaluation Program at the National Cancer Institute (NCI; Grant No. UM1CA186691); National Institutes of Health (NIH)/NCI Grants No. CCSG P30-CA008748 and NIH/NCI CCSG P30-CA016672; University of Texas-Southwestern and MD Anderson Cancer Center Lung SPORE (Grant No. 5 P50 CA070907); through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program (J.W., J.V.H., L.A.B.); MD Anderson Cancer Center Physician Scientist Award (L.A.B.); The LUNGevity Foundation (L.A.B.); Lee Clark Fellowship of The University of Texas MD Anderson Cancer Center, supported by the Jeane F. Shelby Scholarship Fund (L.A.B.); NIH/NCI award No. 1-R01-CA207295 (L.A.B.); an NCI Cancer Clinical Investigator Team Leadership Award (No. P30-CA016672; L.A.B.); The Rexanna Foundation (J.V.H, L.A.B.); The Sidney Kimmel Foundation for Cancer Research (L.A.B.); and The Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (L.A.B.).
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m2/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved significantly with TMZ/veliparib (8.2 months; 95% CI, 6.4 to 12.2 months; v 7.0 months; 95% CI, 5.3 to 9.5 months; P = .50). However, ORR was significantly higher in patients receiving TMZ/veliparib compared with TMZ/placebo (39% v 14%; P = .016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred with TMZ/veliparib: 50% versus 9% and 31% versus 7%, respectively. Significantly prolonged PFS (5.7 v 3.6 months; P = .009) and OS (12.2 v 7.5 months; P = .014) were observed in patients with SLFN11-positive tumors treated with TMZ/veliparib. Conclusion Four-month PFS and median OS did not differ between the two arms, whereas a significant improvement in ORR was observed with TMZ/veliparib. SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.