Targeted genomic profiling of blood from patients with NSCLC after classification with a poor prognosis.

Abstract

e23051 Background: Proteomic signatures have clinical utility, with one example, VeriStrat (VS), measuring acute phase reactant proteins in blood. Patients with EGFRwt tumors and a POOR (VS-P) prognostic classification have worse clinical outcomes relative to those with a GOOD (VS-G) status. A VS-P prognostic result limits standard of care therapeutic options, thus clinical trials may be a good option. A global Phase II study, FOCAL is being conducted that examines the addition of ficlatuzumab to erlotinib for first line EGFR sensitizing mutation positive, VS-P patients. In contrast, treatment options for patients with NSCLC and EGFR wildtype, VS-P status are limited. From this latter group we profiled cell-free DNA (cfDNA) with a targeted NGS panel to identify actionable somatic variant mutations. Methods: Plasma samples previously determined to be EGFRwt by ddPCR and VS-P by MALDI-ToF were analyzed by NGS with a targeted 15-gene panel. Screening of cfDNA isolated from the plasma of 11 VS-P patients with advanced stages of NSCLC are presented. Results: As expected, EGFR sensitizing variants were detected only in the positive control but not among any of the EGFRwt pre-screened VS-P cohort. Six of the 11 plasma samples contained TP53 mutations, which included missense, splice-site and frame-shifts. Although targeted therapies for p53 are not currently approved by the FDA, several pre-clinical and clinical trials are underway with either compounds such as the p53 re-activating agent APR-246 (a PRIMA-1 analogue), or with wild-type p53 gene-therapy such as SGT-53. Conclusions: Targeted profiling using NGS on cfDNA from plasma can identify actionable mutations in patient samples with a poor prognosis as determined by the VS-P status. This is the first study to profile EGFRwt/VS-P patient samples. It is likely that other targets associated with current therapy may be uncovered with additional profiling. Additional profiling of EGFRwt/VS-P patients with a 35-gene NGS panel that measures additional somatic variants, indels and amplifications is warranted. We expect that these studies will yield targets that could provide options for patients with NSCLC and a poor prognosis.