Randomized Phase II Trial of Cisplatin and Etoposide in Combination With Veliparib or Placebo for Extensive-Stage Small-Cell Lung Cancer: ECOG-ACRIN 2511 Study.

Abstract

PURPOSE:

Veliparib, a poly (ADP ribose) polymerase inhibitor, potentiated standard chemotherapy against small-cell lung cancer (SCLC) in preclinical studies. We evaluated the combination of veliparib with cisplatin and etoposide (CE; CE+V) doublet in untreated, extensive-stage SCLC (ES-SCLC).

MATERIALS AND METHODS:

Patients with ES-SCLC, stratified by sex and serum lactate dehydrogenase levels, were randomly assigned to receive four 3-week cycles of CE (75 mg/m2 intravenously on day 1 and 100 mg/m2 on days 1 through 3) along with veliparib (100 mg orally twice per day on days 1 through 7) or placebo (CE+P). The primary end point was progression-free survival (PFS). Using an overall one-sided 0.10-level log-rank test, the study had 88% power to demonstrate a 37.5% reduction in the PFS hazard rate.

RESULTS:

A total of 128 eligible patients received treatment on protocol. The median age was 66 years, 52% of patients were men, and Eastern Cooperative Oncology Group performance status was 0 for 29% of patients and 1 for 71%. The respective median PFS for the CE+V arm versus the CE+P arm was 6.1 versus 5.5 months (unstratified hazard ratio [HR], 0.75 [one-sided P = .06]; stratified HR, 0.63 [one-sided P = .01]), favoring CE+V. The median overall survival was 10.3 versus 8.9 months (stratified HR, 0.83; 80% CI, 0.64 to 1.07; one-sided P = .17) for the CE+V and CE+P arms, respectively. The overall response rate was 71.9% versus 65.6% (two-sided P = .57) for CE+V and CE+P, respectively. There was a significant treatment-by-strata interaction in PFS: Male patients with high lactate dehydrogenase levels derived significant benefit (PFS HR, 0.34; 80% CI, 0.22 to 0.51) but there was no evidence of benefit among patients in other strata (PFS HR, 0.81; 80% CI, 0.60 to 1.09). The following grade ≥ 3 hematology toxicities were more frequent in the CE+V arm than the CE+P arm: CD4 lymphopenia (8% v 0%; P = .06) and neutropenia (49% v 32%; P = .08), but treatment delivery was comparable.

CONCLUSION:

The addition of veliparib to frontline chemotherapy showed signal of efficacy in patients with ES-SCLC and the study met its prespecified end point.

• Authors: Taofeek K Owonikoko, Suzanne E Dahlberg, Gabriel L Sica, Lynne I Wagner, James L Wade 3rd, Gordan Srkalovic, Bradley W Lash, Joseph W Leach, Ticiana B Leal, Charu Aggarwal, Suresh S Ramalingam
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 37 Issue 3 Pg. 222-229 (01 20 2019) ISSN: 1527-7755 [Electronic] United States
• PMID: 30523756 (Publication Type: Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• Benzimidazoles
• Placebos
• veliparib
• Etoposide
• Cisplatin

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Benzimidazoles (administration & dosage, adverse effects)
• Cisplatin (administration & dosage, adverse effects)
• Double-Blind Method
• Etoposide (administration & dosage, adverse effects)
• Female
• Humans
• Lung Neoplasms (drug therapy)
• Male
• Middle Aged
• Placebos
• Progression-Free Survival
• Small Cell Lung Carcinoma (drug therapy)
• Survival Rate