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.

Conflict of interest statement

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Figures

FIG 1.

CONSORT diagram of all patients enrolled in the study and their contribution to the primary end point of the study. (*) Reasons for ineligibility were unconfirmed diagnosis, abnormal laboratory values, and no measurable disease. Per protocol, four of the six ineligible patients excluded from efficacy assessment who received treatment were included in the toxicity data in Table 3. (†) Reasons for not starting assigned therapy included patient refusal or withdrawal of consent, medical reasons, adverse events, disease progression, treatment delay, and death. CE, cisplatin and etoposide; P, placebo; V, veliparib.

FIG 2.

Kaplan-Meier plots for (A) PFS and (B) OS in eligible patients. The estimated median PFS was 6.1 months (95% CI, 5.9 to 6.7 months) for the CE+V arm and 5.5 months (95% CI, 5.0 to 6.1 months) for the CE+P arm (unstratified hazard ratio [HR], 0.75 [one-sided P = .06); stratified PFS HR, 0.63 [one-sided P = .01]). The estimated median OS was 10.3 months (95% CI, 8.9 to 12.0 months) and 8.9 months (95% CI, 8.3 to 11.3 months) for arms CE+V and CE+P, respectively. The stratified OS HR comparing the CE+V and CE+P arms was 0.83 (80% CI, 0.64 to 1.07; one-sided P = .17). CE, cisplatin and etoposide; OS, overall survival; P, placebo; PFS, progression-free survival; V, veliparib.

FIG 3.

Kaplan-Meier plots for PFS in the four stratification groups of the study. Multivariable Cox analysis showed significant benefit of veliparib added to CE in the stratum of men with abnormal LDH levels (n = 46; adjusted hazard ratio [HR], 0.34; 80% CI, 0.22 to 0.51; one-sided P < .001). There was no significant treatment effect of veliparib in the other strata (adjusted PFS HR, 0.81; 80% CI, 0.60 to 1.09; one-sided P = .18): male patients with normal LDH levels (n = 20), female patients with normal LDH levels (n = 18), and female patients with abnormal LDH levels (n = 44). CE, cisplatin and etoposide; LDH, lactate dehydrogenase; P, placebo; PFS, progression-free survival; V, veliparib.