A Real-World Systematic Analysis of Driver Mutations’ Prevalence in Early- and Advanced-Stage NSCLC: Implications for Targeted Therapies in the Adjuvant Setting

SIMPLE SUMMARY: The development of oncogene-targeted drugs has radically changed the course of non small cell lung carcinoma (NSCLC) in the advanced stage. Recently, the ADAURA trial demonstrated the efficacy of Osimertinib also in the adjuvant setting of EGFR-mutated NSCLC. This raises the question regarding whether the same paradigm applies also to currently approved drugs directed against non-EGFR NSCLC drivers. Herein we compared actionable genomic alterations in early- and advanced-stage NSCLC in 1961 unselected single-institution cases analyzed by routine molecular diagnostics procedures. Our data add significantly to the currently limited real-world data on actionable mutations in surgically resectable NSCLC. Our finding that distinct NSCLC genomic drivers are mutated at similar frequencies in early- and advanced-stage tumors implies that the relative biological potency of currently actionable NSCLC genomic drivers is conserved throughout clinical evolution and supports the hypothesis that genotype-matched therapies are likely to provide significant benefit in an adjuvant setting ABSTRACT: The approval of osimertinib for adjuvant treatment of stage I–II–III EGFR-mutated NSCLC (early stage) represents a paradigm shift, raising the question of whether other genotype-matched therapeutics approved for advanced-stage NSCLC can also provide clinical benefit in the adjuvant setting. However, there is a paucity of real-world data on the prevalence of actionable genomic alterations (GAs) in early-stage NSCLC. We used next-generation sequencing, complemented by immunohistochemistry and fluorescence in situ hybridization, to screen our single-institution cohort of 1961 NSCLC consecutive cases for actionable molecular targets. The prevalence of actionable GAs was comparable in early versus advanced-stage NSCLC, the only exception being KRAS mutations (more frequent in early-stage cases). Consistent with advanced-stage tumors being more aggressive, co-occurrence of TP53 and EGFR GAs as well as copy number gains were less frequent in early-stage tumors. EGFR mutations and high expression of PD-L1 were inversely associated, whereas KRAS mutations and high PD-L1 reactivity showed positive association. Recapitulating advanced-stage tumors, early-stage NSCLC had the highest share of EGFR mutations in lepidic and acinar subtypes. Resected lepidic tumors contained the highest proportion of the KRAS G12C actionable variant. These results, obtained with routine diagnostic technologies in an unselected clinical setting, provide a significant addition of real-world data in early-stage NSCLC.