Targeted Therapy and Immunotherapy in Early-Stage Non-Small Cell Lung Cancer: Current Evidence and Ongoing Trials

Abstract

The scenario of neoadjuvant and adjuvant settings in non-small cell lung cancer (NSCLC) is rapidly evolving. As already happened for the advanced disease, also early stages have entered the era of precision medicine, with molecular analysis and Programmed death-ligand 1 (PD-L1) evaluation that by now can be considered a routine assessment. New treatment options have been recently approved, with osimertinib now part of clinical practice for Epidermal Growth Factor Receptor mutated (EGFRm) patients, and immune checkpoint inhibitors (ICIs) available after FDA approval both in the adjuvant (atezolizumab) and neoadjuvant (nivolumab) setting. No mature data on overall survival benefits are available yet, though. Several clinical trials with specific-tyrosine kinase inhibitors (TKIs) and ICIs are currently ongoing, both with and without concomitant chemotherapy. As therapeutic strategies are rapidly expanding, quite a few questions remain unsettled, such as the optimal duration of adjuvant targeted therapy or the effective benefit of ICIs in early-stage EGFRm or ALK (Anaplastic Lymphoma Kinase) rearranged patients, or the possibility to individuate high-risk patients after surgical resection assessing minimal residual disease (MRD) by ctDNA evaluation. We hereby report already available literature data and summarize ongoing trials with targeted therapy and immunotherapy in early-stage NSCLC, focusing on practice-changing results and new perspectives for potentially cured patients.

Keywords: ALK rearrangements; EGFR mutations; adjuvant therapy; early stage; immune checkpoint inhibitors; immunotherapy; neoadjuvant therapy; non-small cell lung cancer; targeted therapy; tyrosine kinase inhibitors.

Figure 1

Mechanisms of action of main drugs evaluated in the adjuvant and neoadjuvant setting in NSCLC patients (created with BioRender.com (accessed on 15 June 2022)). Abbreviations: EGFR, Epidermal Growth Factor Receptor; ALK, Anaplastic Lymphoma Kinase; TKIs, tyrosine kinase inhibitors; PD-(L)1, Programmed death-(ligand) 1; ICIs, immune checkpoint inhibitors; TCR, T-cell receptor; MHC II, major histocompatibility complex.

Figure 2

Main clinical trials in the adjuvant/neoadjuvant setting with EGFR-TKIs and ICIs with available literature data (created with BioRender.com (accessed on 15 June 2022)). Abbreviations: y, years; CT, chemotherapy; DFS, disease-free survival; OS, overall survival; neoadj, neoadjuvant; MPR, major pathological response; EGFR-TKIs, Epidermal Growth Factor Receptor tyrosine kinase inhibitors; ICIs, immune checkpoint inhibitors.