To be, or not to be: the dilemma of immunotherapy for non-small cell lung cancer harboring various driver mutations

J Cancer Res Clin Oncol. 2023 Sep;149(12):10027-10040. doi: 10.1007/s00432-023-04919-4. Epub 2023 Jun 1.

Abstract

Introduction: Lung cancer is one of primary cancer type with high incidence and mortality, non-small cell lung cancer (NSCLC) is the most common type of lung cncer. For advanced lung cancer, traditional chemotherapy and targeted therapy become difficult to solve the dilemma of further progress. In recent years, with the clinical application of immunotherapy, the therapeutic strategy of lung cancer has changed dramatically. At present, immunotherapy has shown conspicuous efficacy in NSCLC patients with high expression of programmed death-ligand 1 (PD-L1) and high tumor mutational burden (TMB). The discovery of driver mutations brings delightful hope for targeted cancer therapy. However, it remains controversial whether immunotherapy can be used in NSCLC patients with these specific driver mutations.

Method: This article summarized the latest research progresses of immunotherapy in advanced NSCLC. We paid close attention to the relevance of various driver mutations and immunotherapy in NSCLC patients, and summarized the predictive effects of several driver mutations and immunotherapy.

Results: The mutations of KRAS, KRAS+TP53, EPHA (especially EPHA5), ZFHX3, ZFHX3+TP53, NOTCH, BRAF and LRP1B+FAT3 have potential to be used as biomarkers to predict the positive effectiveness of immunotherapy. ZFHX3, ZFHX3+TP53, STKII/LKB1+KEAP1+SMARCA4+PBRM1 mutations in LUAD patients get more positive effect in immunotherapy. While the mutations of EGFR, KEAP1, STKII/LKB1+KRAS, EML4-ALK, MET exon 14 skipping mutation, PBRM1, STKII/LKB1+KEAP1+SMARCA4+PBRM1, ERBB2, PIK3CA and RET often indicate poor benefit from immunotherapy.

Conclusion: Many gene mutations have been shown to be associated with immunotherapy efficacy. Gene mutations should be combined with PD-L1, TMB, etc. to predict the effect of immunotherapy.

Keywords: Common mutation; Driver mutations; Immunotherapy; Non-small cell lung cancer (NSCLC); Rare mutation.

Publication types

  • Review

MeSH terms

  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Carcinoma, Non-Small-Cell Lung* / therapy
  • DNA Helicases / genetics
  • Humans
  • Immunotherapy
  • Kelch-Like ECH-Associated Protein 1 / genetics
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / therapy
  • Mutation
  • NF-E2-Related Factor 2 / metabolism
  • Nuclear Proteins / genetics
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Transcription Factors / genetics

Substances

  • B7-H1 Antigen
  • Kelch-Like ECH-Associated Protein 1
  • Proto-Oncogene Proteins p21(ras)
  • NF-E2-Related Factor 2
  • SMARCA4 protein, human
  • DNA Helicases
  • Nuclear Proteins
  • Transcription Factors