Immunotherapy for EGFR-mutant advanced non-small-cell lung cancer: Current status, possible mechanisms and application prospects

Abstract

Immune checkpoint inhibitors (ICIs) are effective against advanced and even perioperative non-small-cell lung cancer (NSCLC) and result in durable clinical benefit, regardless of programmed death ligand-1 (PD-L1) expression status in cancer. Existing clinical evidence shows that the effect of immunotherapy in patients with EGFR-mutant NSCLC after the development of tyrosine kinase inhibitor (TKI) resistance is not satisfactory. However, compared with monotherapy, ICIs combined with chemotherapy can improve the efficacy. Encouragingly, compared with that of patients with sensitive mutations, the progression-free survival of patients with rare mutations who were treated with ICIs was increased. Adequately maximizing the efficacy of ICIs in EGFR-mutant NSCLC patients is worth exploring. In this review, we described preclinical and clinical studies of ICIs or combined therapy for EGFR-mutant NSCLC. We further focused on EGFR mutations and the cancer immune response, with particular attention given to the role of EGFR activation in the cancer-immunity cycle. The mechanisms for the natural resistance to ICIs were explored to identify corresponding countermeasures that made more EGFR-mutant NSCLC patients benefit from ICIs.

Immunotherapy or antiangiogenic therapy plus chemotherapy as first‐line treatment of patients with PD‐L1(‐) advanced non‐squamous non‐small cell lung cancer in a Chinese cohort

“…And, bevacizumab improved PFS in patients with common EGFR mutations 18 . PFS was improved in patients with rare EGFR mutations treated with immunotherapy compared with those with sensitive EGFR mutations 19 . This can affect group‐to‐group comparability, which is why we use PSM.…”

ERBB signalling contributes to immune evasion in KRAS-driven lung adenocarcinoma

“…Given that α-PD1 resistance in our model is associated with elevated expression of EGFR/ERBB ligands, which may engage EGFR heterodimers with ERBB2 or ERBB3, or ERBB2/3 heterodimers at high localised ligand concentrations, broad spectrum inhibition of the ERBB family would be more effective than selective targeting of EGFR alone, as we previously showed for development of KRAS G12D -driven lung tumours (30). Moreover, our data were generated using 2 brief rounds of Afatinib treatment to trigger α-PD1 responsiveness, suggesting that brief transient pulses of ERBB blockade can combine well with ICB and may thereby mitigate some of the clinical toxicity associated with prolonged EGFR inhibition in the context of ICB therapy (64). Further refinement of dosing schedules may thus yield greater therapeutic benefit.…”

Anti-EGFR aptamer exhibits direct anti-cancer effects in NSCLC cells harboring EGFR L858R mutations

“…Resistance mechanisms most common to anti-EGFR therapy include (i) secondary/tertiary mutations in the TKD that disrupt TKI binding affinity (e.g., EGFR T790M or C797X mutations), (ii) downregulation of the targeted oncogene, (iii) clonal selection of cells with mutation or amplification in an untargeted oncogene (e.g., activation of downstream oncogenes such as KRAS or other oncogenic pathways such as c-Met and AXL), or (iv) phenotype transformation (e.g., epithelial mesenchymal transition or histological transformation to small cell lung cancer) [22][23][24][25] . The five-year survival for relapsed patients remains low, especially as immunotherapy and salvage chemotherapy, which are the go-to second and third-line treatment options for TKI resistant NSCLC, have proven to be ineffective 24,26,27 or to induce life-threatening side effects 28 . This again highlights an unmet need for the development of alternative or adjuvant NSCLC therapies.…”

“…, epithelial mesenchymal transition or histological transformation to small cell lung cancer) 22–25 . The five-year survival for relapsed patients remains low, especially as immunotherapy and salvage chemotherapy, which are the go-to second and third-line treatment options for TKI resistant NSCLC, have proven to be ineffective 24,26,27 or to induce life-threatening side effects 28 . This again highlights an unmet need for the development of alternative or adjuvant NSCLC therapies.…”