Smoking History Predicts Sensitivity to PARP Inhibitor Veliparib in Patients with Advanced Non-Small Cell Lung Cancer

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Tobacco-related non-small cell lung cancer (NSCLC) is linked to poorer survival and increased genomic instability.
• Veliparib, a poly(adenosine diphosphate-ribose) polymerase inhibitor, enhances DNA damage caused by platinum chemotherapy.
• A prior phase 2 trial indicated a trend towards improved outcomes with veliparib addition to carboplatin/paclitaxel in advanced NSCLC.

Purpose of the Study:

• To conduct an exploratory analysis of a phase 2 trial to determine if smoking history influences the efficacy of veliparib combined with carboplatin/paclitaxel in untreated advanced NSCLC.
• To identify patient subgroups that may derive greater benefit from the veliparib and chemotherapy combination.

Main Methods:

• Patients with advanced NSCLC were randomized to receive carboplatin/paclitaxel with either veliparib (120 mg) or placebo.
• Patients were stratified by histologic subtype and smoking history: recent smokers, former smokers, and never-smokers.
• Plasma cotinine levels and mutation status (via whole exome sequencing) were analyzed.

Main Results:

• Smoking history, along with other factors, predicted veliparib benefit in univariate analyses, with recent smoking history being the most predictive in multivariate analysis.
• Recent smokers receiving veliparib demonstrated significantly greater progression-free survival and overall survival benefits compared to former and never-smokers.
• While the rate of severe adverse events was higher in recent smokers on veliparib, overall and serious adverse events were similar between treatment arms.

Conclusions:

• Smoking history is a significant predictor of efficacy for the veliparib-chemotherapy combination in NSCLC.
• The combination therapy demonstrated acceptable toxicity across different smoking history groups.
• A prespecified analysis focusing on recent smokers is planned for ongoing phase 3 NSCLC studies involving veliparib.