Tobacco users with non-small cell lung cancer (NSCLC) have genetic alterations in their tumors that may underlie their increased responsiveness to veliparib, according to new research.
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Veliparib, a poly(ADP-ribose) polymerase (PARP) -1 and -2 inhibitor with chemo-sensitizing and antitumor characteristics, is an effective treatment for tumors that have homologous recombination deficiency. This genomic signature has been associated with a history of smoking in The Cancer Genome Atlas Lung Cancer Project.
In a randomized, phase II study comparing the effects of veliparib versus placebo in combination with carboplatin and paclitaxel in patients with previously untreated metastatic or advanced NSCLC, clinically significant improvements in progression-free survival and overall survival were observed for patients treated with veliparib, and the improvements were greater for patients with a smoking history. Researchers proposed that the beneficial effect of smoking history likely had a genetic basis.
To explore this possibility, the researchers evaluated 38 tumor samples from the trial using whole exome and RNA sequencing analysis in an effort to identify genes and genomic features associated with smoking history and response to veliparib. Researchers compared the results of the analysis to genomic signatures in NSCLC associated with smoking history in The Cancer Genome Atlas Lung Cancer Project. The data were presented at the International Association for the Study of Lung Cancer (IASLC) 17TH Annual World Conference (December 4-7; Vienna, Austria).
Twenty-six of the samples were determined to be positive for a smoking-related genetic signature in TCGA. An elevated mutational burden in current as well as former smokers was determined (199 somatic mutations vs 60 in never-smokers). The researchers concluded that genetic alterations in the tumors of tobacco users with NSCLC may be linked to poor outcomes from standard chemotherapy treatment as well as increased response to veliparib.
The association between response to veliparib and NSCLC genetic alterations will require further research, due to the relatively small sample size of the study’s genetic cohort. The authors state that a targeted sequencing assay will be included in future phase III trials of veliparib in order to validate the study’s results.
