Tumor genomes in tobacco users with non-small cell lung cancer (NSCLC) have genetic alterations that are associated with poor outcomes from standard chemotherapy, as well as factors that can make the tumors vulnerable to veliparib, according to results presented at the International Association for the Study of Lung Cancer (IASLC) 17th Annual World Conference on Lung Cancer in Austria.

Veliparib is a poly(ADP-ribose) polymerase (PARP) -1 and -2 inhibitor with chemo-sensitizing and antitumor activities. It has a synthetic lethality interaction with cancers that harbor homologous recombination deficiency, and was shown in preclinical models to delay the repair of chemotherapy-induced DNA damage.

In the phase 2 M10-898 (ClinicalTrials.gov Identifier: NCT01560104) study of veliparib with carboplatin/paclitaxel in previously untreated metastatic or advanced NSCLC, clinically meaningful improvements in progression-free survival (PFS) and overall survival (OS) were observed. Smoking history had a beneficial effect from veliparib, and suggested a genetic basis for the effect.

In the study presented at the conference, researchers subjected tumor samples from the M10-898 trial to whole exome and RNA sequencing analysis to comprehensively identify genes and genomic features that are associated with smoking status and response to veliparib. They compared their results to genomic signatures in NSCLC that are associated with smoking status in The Cancer Genome Atlas (TCGA) Lung Cancer Project.

Of the 38 patients with whole exome data, 26 were determined to be positive for a smoking-related genetic signature (TCGA signature 4). Researchers also observed an elevated mutational burden in current and former smokers (199 somatic mutations vs 60 in never smokers).

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The small sample size of the study’s genomic cohort precluded conclusive association of genomic signatures and veliparib benefits. In future phase 3 veliparib trials, a targeted sequencing assay to detect key DNA damage and repair genes as well as key genomic signatures will be used to validate the study’s results.

Reference

  1. He L, Huang X, Sun Y, et al. Evaluating genomic signatures predicting veliparib sensitivity in non-small cell lung cancer (NSCLC). Paper presented at: International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer; December 2016; Vienna, Austria.