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Cited by 399Lung Cancer Research StudiesPARP inhibition in cancer therapyLung Cancer Treatments and Mutations

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

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Pietanza, M. Catherine, Waqar, Saiama N., Krug, Lee M., Dowlati, Afshin, Hann, Christine L., Chiappori, Alberto, Owonikoko, Taofeek K., Woo, Kaitlin M. +16 more·2018·Journal of Clinical Oncology
DOI 10.1200/jco.2018.77.7672PMC PMC6085179
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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.

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Authors
Pietanza, M. C., Waqar, S. N., Krug, L. M., Dowlati, A., Hann, C. L., Chiappori, A., Owonikoko, T. K., Woo, K. M., Cardnell, R. J., Fujimoto, J., Long, L., Diao, L., Wang, J., Bensman, Y., Hurtado, B., de Groot, P., Sulman, E. P., Wistuba, I. I., Chen, A., Fleisher, M., Heymach, J. V., Kris, M. G., Rudin, C. M., & Byers, L. A.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • M. Catherine Pietanza, Lee M. Krug, Mark G. Kris, and Charles M. Rudin, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College; Kaitlin M. Woo, Yevgeniva Bensman, Brenda Hurtado, and Martin Fleisher, Memorial Sloan Kettering Cancer Center, New York, NY; Saiama N. Waqar, Washington University School of Medicine in St. Louis, St Louis, MO; Afshin Dowlati, Case Western Reserve University and University Hospitals Seidman Cancer Center, Cleveland, OH; Christine L. Hann, Johns Hopkins...
Corresponding author
Byers, Lauren Averett
ORCID
Venue
Journal of Clinical Oncology
Publisher
American Society of Clinical Oncology (ASCO)
Published
2018-08-10
Volume
36
Issue
23
Pages
2386-2394
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
DOI
10.1200/jco.2018.77.7672
PMC
PMC6085179
OpenAlex
W2808238124
Cited by
399
References
4
Citations by year
2026: 23 · 2025: 41 · 2024: 57 · 2023: 59 · 2022: 48 · 2021: 57 · 2020: 55 · 2019: 45 · 2018: 12
FWCI
15.88
Type
journal article
Language
en
Update notices
correction (2018-10-01)
Open access
Licence
cc-by-nc-nd
Locations
  • Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-nd)
Funders
  • LUNGevity Foundation
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • Sidney Kimmel Foundation for Cancer Research
  • Celgene
  • Puma Biotechnology
  • National Institutes of Health
  • Genentech
  • EMD Serono
  • Ignyta
  • National Cancer Institute (UM1CA186716, P50CA070907, P30CA008748, UM1CA186688, R01CA207295, P30CA016672, UM1CA186691)
  • Daiichi Sankyo Europe
Topics
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
  • Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords
temozolomide, veliparib, small cell lung cancer, relapsed small cell lung cancer, PARP inhibitors, PARP1, SLFN11, MGMT promoter methylation, progression-free survival, overall survival, thrombocytopenia, neutropenia, circulating tumor cells, combination chemotherapy, immunohistochemical markers, drug safety and tolerability
MeSH terms
Poly (ADP-Ribose) Polymerase-1, Temozolomide, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, DNA Mutational Analysis, Double-Blind Method, Female, Humans, Immunohistochemistry, Lung Neoplasms, Male, Middle Aged, Neoplastic Cells, Circulating, Nuclear Proteins, Placebos, Promoter Regions, Genetic, Biomarkers, Tumor, DNA Modification Methylases, Antineoplastic Agents, Alkylating, DNA Methylation, Tumor Suppressor Proteins, DNA Repair Enzymes, Small Cell Lung Carcinoma

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