Next-Generation Sequencing-Based Evaluation of the Actionable Mutational Landscape in Solid Tumors: the “MOZART” Prospective Observational Study

Abstract

Abstract Background The identification of the most appropriate targeted therapies for advanced cancers is challenging. We performed a molecular profiling of metastatic solid tumors utilizing a comprehensive next-generation sequencing (NGS) assay to determine mutations’ type, frequency and actionability and potential correlations with PD-L1 expression. Methods 304 adult patients with heavily-pretreated metastatic cancers treated between 01/2019-03/2021 were recruited. The CLIA-/UKAS-accredit Oncofocus® assay targeting 505 genes was used on newly-obtained or archived biopsies. Chi-square, Kruskal-Wallis and Wilcoxon rank-sum test were used where appropriate. Results were significant for p < 0.05. Results A total of 237 tumors (78%) harbored actionable mutations. Tumors were positive for PD-L1 in 68.9% cases. The median number of mutant genes/tumor was of 2.0 (IQR: 1.0–3.0). Only 34.5% were actionable ESCAT Tier I-II with different prevalence according to cancer type. The DNA damage repair (14%), the PI3K/AKT/mTOR (14%) and the RAS/RAF/MAPK (12%) pathways were the most frequently altered. No association was found between PD-L1, ESCAT, age, sex and tumor mutational status. Sixty-two patients underwent targeted treatment, with 37.1% obtaining objective responses. Conclusions We highlight the clinical value of molecular profiling in metastatic solid tumors using comprehensive NGS-based panels to improve treatment algorithms in situations of uncertainty and facilitate clinical trial recruitment.