Management of locally advanced non-small cell lung cancer: State of the art and future directions

Abstract

Lung cancer is the second most common and the deadliest type of cancer worldwide. Clinically, non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer; approximately one-third of affected patients have locally advanced NSCLC (LA-NSCLC, stage III NSCLC) at diagnosis. Because of its heterogeneity, LA-NSCLC often requires multidisciplinary assessment. Moreover, the prognosis of affected patients is much below satisfaction, and the efficacy of traditional therapeutic strategies has reached a plateau. With the emergence of targeted therapies and immunotherapies, as well as the continuous development of novel radiotherapies, we have entered an era of novel treatment paradigm for LA-NSCLC. Here, we reviewed the landscape of relevant therapeutic modalities, including adjuvant, neoadjuvant, and perioperative targeted and immune strategies in patients with resectable LA-NSCLC with/without oncogenic alterations; as well as novel combinations of chemoradiation and immunotherapy/targeted therapy in unresectable LA-NSCLC. We addressed the unresolved challenges that remain in the field, and examined future directions to optimize clinical management and increase the cure rate of LA-NSCLC.

Keywords: adjuvant therapy; immunotherapy; locally advanced; neoadjuvant therapy; non-small cell lung cancer; targeted therapy.

FIGURE 1

Current evidence and perspectives of the clinical management for resectable LA‐NSCLC with and without driver mutations. Summary of the main outcomes of clinical trials evaluating perioperative, neoadjuvant, and adjuvant therapy strategies, with a special focus on the enrolled stage III populations. Current challenges and future trends in field are also presented. ^*Due to the small size of the subgroup population, data should be interpreted with caution. Abbreviations: ALK, anaplastic lymphoma kinase; chemo, chemotherapy; ctDNA, circulating tumor DNA; CTLA‐4, cytotoxic T lymphocyte‐associated antigen‐4; DFS, disease‐free survival; EFS, event free survival; EGFR, epidermal growth factor receptor; HR, hazard ratio; ICIs, immune checkpoint inhibitors; LAG3, Lymphocyte activation gene 3; MRD, minimal residual disease; MPR, major pathological response; NA, not available; NR, not reached; OS, overall survival; pCR, pathological complete response; PD‐1, programmed death 1; RT, radiotherapy; TIGIT, T cell immunoglobulin and ITIM domain; TKIs, tyrosine kinase inhibitors.

FIGURE 2

Ongoing phase III clinical trials of immunotherapy and targeted therapy for LA‐NSCLC. ^#Concurrent. Abbreviations: cCRT, concurrent chemoradiotherapy; CRT, chemoradiotherapy; CT, chemotherapy; DFS, disease‐free survival; EFS, event‐free survival; FAS, full analysis set; MPR, major pathological response; MRD, minimal residual disease; OS, overall survival; pCR, pathological complete response; PD, progressive disease; PD‐L1, programmed cell death‐Ligand 1; PFS, progression‐free survival; PPAS, PD‐L1‐positive analysis set; sCRT, sequential chemoradiotherapy.

FIGURE 3

Current evidence and perspectives of clinical management for unresectable LA‐NSCLC with and without EGFR mutations. ^†Concurrent chemoradiotherapy. ^‡Sequential chemoradiotherapy. ^§Concurrent chemoradiotherapy/sequential chemoradiotherapy. ^*Due to the small size of the subgroup population, data should be interpreted with caution. Abbreviations: chemo, chemotherapy; CRT, chemoradiotherapy; DFS, disease‐free survival; EGFR, epidermal growth factor receptor; EFS, event free survival; HR, hazard ratio; ICIs, immune checkpoint inhibitors; NR, not reached; NA, not available; ORR, objective response rate; OS, overall survival; PD‐L1, programmed cell death‐Ligand 1; PFS, progression free survival; RT, radiotherapy; TKIs, tyrosine kinase inhibitors.