EGFR-mutated stage IV non-small cell lung cancer: What is the role of radiotherapy combined with TKI?

Abstract

Lung cancer is the leading cause of cancer-related death globally and poses a considerable threat to public health. Asia has the highest prevalence of epidermal growth factor receptor (EGFR) mutations in patients with non-small cell lung cancer (NSCLC). Despite the reasonable response and prolonged survival associated with EGFR-tyrosine kinase inhibitor (TKI) therapy, the acquisition of resistance to TKIs remains a major challenge. Additionally, patients with EGFR mutations are at a substantially higher risk of brain metastasis compared with those harboring wild-type EGFR. The role of radiotherapy (RT) in EGFR-mutated (EGFRm) stage IV NSCLC requires clarification, especially with the advent of next-generation TKIs, which are more potent and exhibit greater central nervous system activity. In particular, the feasible application of RT, including the timing, site, dose, fraction, and combination with TKI, merits further investigation. This review focuses on these key issues, and provides a flow diagram with proposed treatment options for metastatic EGFRm NSCLC, aiming to provide guidance for clinical practice.

Keywords: EGFR mutation; TKI; radiotherapy.

FIGURE 1

Preliminary treatment outlines for driver oncogene‐positive NSCLC with brain metastases. ALK, anaplastic lymphoma kinase; BM, brain metastasis; EGFR, epidermal growth factor receptor; NSCLC, non‐small cell lung cancer; PD, progressive disease; ROS1, c‐Ros oncogene 1 receptor tyrosine kinase; SIB, simultaneous integrated boost; SRS, stereotactic radiosurgery; TKI, tyrosine kinase inhibitor; WBRT, whole‐brain radiotherapy

FIGURE 2

Pooled survival results from retrospective studies in this review mentioned about the effect of first‐ or second‐generation EGFR‐TKI combined with cranial RT before progression. iPFS ranges from 8.1 to 25 months,, , , , , , , , and OS ranges from 14.3 to 48 months., , , , , , , , EGFR: epidermal growth factor receptor; iPFS, intracranial progression‐free survival; RT, radiotherapy; TKI, tyrosine kinase inhibitor

FIGURE 3

The EGFR signaling pathway is involved in irradiation (IR)‐induced DNA damage repair. ATM, ataxia telangiectasia mutation; ATR, ataxia‐telangiectasia and RAD3‐related; BER, base excision repair; DNA‐PKcs, DNA‐dependent protein kinase catalytic subunit; EGFR, epidermal growth factor receptor; ERK, extracellular‐regulated protein kinase; GSK3β; glycogen synthase kinase 3 beta; HR, homologous recombination; LEF‐1, lymphoid enhancer factor 1; MEK, mitogen‐activated extracellular signal‐regulated kinase; NHEJ, non‐homologous end joining; PARP, poly ADP‐ribose polymerase; PCNA, proliferating cell nuclear antigen; PI3K, phosphatidylinositol 3‐kinase; XRCC, x‐ray repair complementing defective repair in Chinese hamster cells

FIGURE 4

Flow diagram with therapeutic options in EGFR‐mutated stage IV NSCLC. BM, brain metastasis; ChT, chemotherapy; CR, complete remission; EGFR, epidermal growth factor receptor; NGS, next‐generation sequencing; NSCLC, non‐small cell lung cancer; PD, progressive disease; PR, partial remission; RP, radiation pneumonitis; RT, radiotherapy; SD, stable disease; SRS, stereotactic radiosurgery; TKI, tyrosine kinase inhibitor; TRT, thoracic radiotherapy; WBRT, whole‐brain radiotherapy