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Tumor Mutation Burden and Efficacy of Nivolumab Monotherapy and in Combination With Ipilimumab in Small Cell Lung Cancer using strelka somatic variant calls

ABSTRACT: Whole exome sequencing was used to evaluate the impact of tumor mutation burden (TMB) on efficacy of nivolumab monotherapy or combined with ipilimumab in patients with SCLC from the nonrandomized or randomized cohorts of CheckMate 032.

INSTRUMENT(S): -

ORGANISM(S): Homo Sapiens

SUBMITTER: Bristol-Myers Squibb

PROVIDER: PRJEB25808 | EVA | 2018-03-31

REPOSITORIES: EVA

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Project description:BackgroundThe usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC).Research questionHow does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC?MethodsWe retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution.ResultsA total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.InterpretationAlthough ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.

Dataset Information

Tumor Mutation Burden and Efficacy of Nivolumab Monotherapy and in Combination With Ipilimumab in Small Cell Lung Cancer using strelka somatic variant calls

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