TY - JOUR
T1 - 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
AU - Pietanza, M. Catherine
AU - Waqar, Saiama N.
AU - Krug, Lee M.
AU - Dowlati, Afshin
AU - Hann, Christine L.
AU - Chiappori, Alberto
AU - Owonikoko, Taofeek K.
AU - Woo, Kaitlin M.
AU - Cardnell, Robert J.
AU - Fujimoto, Junya
AU - Long, Lihong
AU - Diao, Lixia
AU - Wang, Jing
AU - Bensman, Yevgeniva
AU - Hurtado, Brenda
AU - de Groot, Patricia
AU - Sulman, Erik P.
AU - Wistuba, Ignacio I.
AU - Chen, Alice
AU - Fleisher, Martin
AU - Heymach, John V.
AU - Kris, Mark G.
AU - Rudin, Charles M.
AU - Byers, Lauren Averett
N1 - 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.). We thank Andy Ni, Amy Quinterio, Isabella Bergagnini, Gianna McArthur, Patrick Nolan, Lakeisha Lubin, Sarah Riva, and Hazem Karabeber for the collection and organization of data.
Publisher Copyright:
Copyright © 2018 by American Society of Clinical Oncology.
PY - 2018/8/10
Y1 - 2018/8/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85052011208&partnerID=8YFLogxK
U2 - 10.1200/JCO.2018.77.7672
DO - 10.1200/JCO.2018.77.7672
M3 - Article
C2 - 29906251
AN - SCOPUS:85052011208
SN - 0732-183X
VL - 36
SP - 2386
EP - 2394
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 23
ER -