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

Analysis of predictive factors of unforeseen nodal metastases in resected clinical stage I NSCLC

“…In our present analysis, our focus was directed at clinical stage I NSCLC including the squamous histology. We meticulously examined both histological and clinical factors that are readily accessible within routine medical practice (16). However, looking ahead, it is imperative to delve further into this specific population.…”

Landscape of Genomic Alterations and PD-L1 Expression in Early-Stage Non-Small-Cell Lung Cancer (NSCLC)—A Single Center, Retrospective Observational Study

“…To date, there are limited data on the specific types of EGFR mutations and co-mutations in early-stage NSCLC [ 22 , 35 , 36 , 37 , 38 , 39 , 40 ]. Studies of NSCLC in advanced stages (IIIB–IV) have shown that both the type of mutation (common or rare mutations, compound mutations, primary resistant mutations) and co-occurring mutations have an impact on prognosis and response to TKI therapy.…”

“…As much as we know about the genomic landscape and antitumor immune response in advanced-stage NSCLC, little has been published on the prevalence and nature of EGFR mutations and other driver alterations and PD-L1 expression in early-stage NSCLC [ 22 , 35 , 36 , 37 , 38 , 39 , 40 ]. Therefore, in our study, we investigated the frequencies of genomic alterations and PD-L1 status in patients with primary diagnosed stage I–IIIA NSCLC to elucidate potential biomarkers for precision oncology and to explore the importance of broad-range sequencing in early tumor stages.…”

Developments in predictive biomarker testing and targeted therapy in advanced stage non-small cell lung cancer and their application across European countries

“…In NSCLC, the prevalence of KRAS mutations ranges from 26 to 41%. 42 , 43 , 44 , 45 Directly targeting mutated KRAS has posed a significant challenge due to the high affinity of KRAS for GDP/GTP and the absence of identified allosteric regulatory binding sites. 46 However, in 2013, the discovery of the switch-II pocket in KRAS G12C provided a breakthrough for the development of clinically effective KRAS G12C inhibitors.…”