Veliparib in Combination With Platinum-Based Chemotherapy for First-Line Treatment of Advanced Squamous Cell Lung Cancer: A Randomized, Multicenter Phase III Study

Abstract

PURPOSE Squamous non–small-cell lung cancer (sqNSCLC) is genetically complex with evidence of DNA damage. This phase III study investigated the efficacy and safety of poly (ADP-ribose) polymerase inhibitor veliparib in combination with conventional chemotherapy for advanced sqNSCLC ( NCT02106546 ). PATIENTS AND METHODS Patients age ≥ 18 years with untreated, advanced sqNSCLC were randomly assigned 1:1 to carboplatin and paclitaxel with veliparib 120 mg twice daily (twice a day) or placebo twice a day for up to six cycles. The primary end point was overall survival (OS) in the veliparib arm versus the control arm in current smokers, based on phase II findings. Archival tumor samples were provided for biomarker analysis using a 52-gene expression histology classifier (LP52). RESULTS Overall, 970 patients were randomly assigned to carboplatin and paclitaxel plus either veliparib (n = 486) or placebo (n = 484); 57% were current smokers. There was no significant OS benefit with veliparib in current smokers, with median OS 11.9 versus 11.1 months (hazard ratio [HR], 0.905; 95% CI, 0.744 to 1.101; P = .266). In the overall population, OS favored veliparib; median OS was 12.2 versus 11.2 months (HR, 0.853; 95% CI, 0.747 to 0.974), with no difference in progression-free survival (median 5.6 months per arm). In patients with biomarker-evaluable tumor samples (n = 360), OS favored veliparib in the LP52-positive population (median 14.0 v 9.6 months; HR, 0.66; 95% CI, 0.49 to 0.89), but favored placebo in the LP52-negative population (median 11.0 v 14.4 months; HR, 1.33; 95% CI, 0.95 to 1.86). No new safety signals were observed in the experimental arm. CONCLUSION In current smokers with advanced sqNSCLC, there was no therapeutic benefit of adding veliparib to first-line chemotherapy. The LP52 signature may identify a subgroup of patients likely to derive benefit from veliparib with chemotherapy.

Veliparib Plus Carboplatin and Paclitaxel Versus Investigator's Choice of Standard Chemotherapy in Patients With Advanced Non–Squamous Non–Small Cell Lung Cancer

“…The study did not meet its primary endpoint, with no significant OS improvement observed with veliparib + carboplatin/paclitaxel versus chemotherapy alone in LP52+ patients. The original primary endpoint in the current smoker population was amended in light of emerging data from LP52+ populations in other studies, 28 which occurred following randomization and treatment in this study.…”

“…LP52 analysis was carried out on available tumor samples as previously described. 24,28 The current analysis used the same set of genes as the LP52 classifier assay in M11-089 and the original LSP. 24,28 While retrospective use of LP52 in M11-089 was based on an RNA sequencing (RNAseq) platform normalized within M11-089 samples, to define LP52+ patients for the primary analysis of M14-359, we collaborated with Qiagen (Hilden, Germany) and HTG Molecular Diagnostics (Tucson, AZ) to develop an Investigational Use Only (IUO) RNA assay for LP52 classification.…”

“…24,28 The current analysis used the same set of genes as the LP52 classifier assay in M11-089 and the original LSP. 24,28 While retrospective use of LP52 in M11-089 was based on an RNA sequencing (RNAseq) platform normalized within M11-089 samples, to define LP52+ patients for the primary analysis of M14-359, we collaborated with Qiagen (Hilden, Germany) and HTG Molecular Diagnostics (Tucson, AZ) to develop an Investigational Use Only (IUO) RNA assay for LP52 classification. The IUO version of LP52 is based on HTG EdgeSeq (or HTGseq) technology, which uses a quantitative nuclease protection assay chemistry combined with next-generation sequencing to produce a simple and reproducible platform that is more compatible with clinical use than RNAseq.…”

“…This change was to enable the prospective application of a biomarker assay following the emergence of data from a Phase 2 study of veliparib + carboplatin/paclitaxel in NSCLC (M10-898; NCT01560104) and a Phase 3 study of veliparib + chemotherapy in squamous NSCLC (M11-089; NCT02106546) that suggested the assay may have utility across NSCLC subtypes, with LP52 positivity identifying patients more likely to benefit from veliparib treatment. 28 Secondary endpoints included OS in the overall population, PFS in LP52+ patients and the overall population, and objective response rate (ORR) in LP52+ patients and the overall population with veliparib + carboplatin/paclitaxel versus chemotherapy alone. PFS was defined as the time from randomization to disease progression (within 26 weeks from last tumor assessment) or death from any cause (within 12 weeks of the last tumor assessment) according to RECIST version 1.1, as assessed by the local investigator.…”

“…The predictive value of the LP52 classifier for improved efficacy with veliparib was initially identified in exploratory analyses of a Phase 2 veliparib trial in NSCLC (NCT01560104) 21 and was verified in a Phase 3 veliparib trial in squamous NSCLC, which demonstrated a potential benefit in overall survival (OS) in patients with an LP52 positive (LP52+) status receiving veliparib. 28 Following prospective-retrospective verification of the LP52 classifier, 27 we hypothesized that this predictive value of LP52 to identify patients who have poorer outcomes and who may demonstrate an improved response to veliparib therapy may also be applicable to patients with non-squamous NSCLC.…”