Retrospective efficacy analysis of immune checkpoint inhibitors in patients with EGFR‐mutated non‐small cell lung cancer

Abstract

Background Treatment with epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) leads to initial response in most patients with EGFR‐mutated non‐small cell lung cancer (NSCLC). In contrast, little is known of the subpopulation of patients with NSCLC with EGFR mutations who exhibit clinical outcomes that require treatment with immune checkpoint inhibitors (ICIs). Therefore, to identify eligible cases to treat with ICIs, we retrospectively analyzed the correlation between clinical features and the efficacy of ICIs in patients with EGFR mutations. Patients and Methods We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who were treated with ICIs after developing resistance to EGFR‐TKIs between February 2016 and April 2018 at 6 institutions in Japan. The association between clinical outcomes and the efficacy of ICIs was investigated. Results We enrolled 27 patients who harbored EGFR‐activating mutations. The objective response and disease control rates were higher in patients with uncommon EGFR mutations than in those with common EGFR mutations (71% vs 35.7% and 57% vs 7%, P = 0.14 and P < 0.01, respectively). Patients with uncommon EGFR mutations or without T790M mutations exhibited a significantly longer median progression‐free survival than those with common EGFR mutations or with T790M mutations (P = 0.003 and P = 0.03, respectively). Conclusion Patients with uncommon EGFR mutations and without T790M mutations are associated with the best outcomes for treatment with immunotherapy among those with EGFR‐mutated NSCLC, based on retrospective analysis. Further research is needed to validate the clinical biomarkers involved in ICI responders with EGFR mutations.

Role of the dynamic tumor microenvironment in controversies regarding immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) with EGFR mutations

“…Additionally, T790 M(−) patients had significantly lower FOXP3+ TILs than did T790 M(+) patients (P = 0.013). Furthermore, in a retrospective study by Yamada et al [118] including 27 patients with EGFR-TKI resistance who were treated with ICIs, subgroup findings supported that T790 M(−) patients were more likely to derive greater benefit from PD-1 inhibitor treatment (median PFS: 86 days vs 48 days, P = 0.03; median TTP: 97 days vs 48 days, P = 0.03) than were T790 M(+) patients. In the study of 67 EGFR-mutant NSCLC patients, the prevalence of PD-L1 expression was significantly lower in T790 M(+) tumors than in T790 M(−) tumors (P = 0.0149), and better survival was associated with PD-L1(−) / T790 M(+) tumors [152].…”

“…The G719X mutation in exon 18 (3%) [113] and the L861X mutation in exon 21 (2%) [114] are the most common uncommon mutation types; G719X, L861X, and additional mutations in exon 20 and exon 19 are also considered favorable for effective EGFR-TKI treatment [115][116][117]. Recently, multiple studies have shown that NSCLC patients with uncommon EGFR mutations are more likely to benefit from immunotherapy than are those with common EGFR mutations [118,119].…”

“…Yamada et al [118] reported that NSCLC patients with uncommon EGFR mutations showed a good response to ICIs compared with patients with common EGFR mutations, with prolonged median PFS (256 days vs 50 days, P = 0.003) and median time to progression (TTP) (256 days vs 48 days, P = 0.008). A 5-year follow-up of the CA209-003 study on nivolumab, a phase I single-arm study, was reported by Brahmer and colleagues [120], who observed that 2 patients with uncommon EGFR mutations (2/8, 25%) had a survival of more than 5 years; the mutations were the EGFR exon 20 insertion and exon 18 missense mutation G719A.…”

“…The data showed that no EGFRmutant NSCLC patients received a benefit from pembrolizumab administration prior to EGFR-TKI treatment [180]. Second, ICIs may be a promising approach for some cases with high PD-L1 expression or some uncommon EGFR-mutated NSCLC cases due to intratumor heterogeneity among PD-L1-expressing and EGFRmutant clones [30,[118][119][120]. Third, tumor microenvironmental changes, a rather small window, may be most beneficial for combination EGFR blockade with immune-mediated anticancer approaches, which were found to only be temporary and disappeared as treatment continued [47].…”

Identification of a gene signature closely related to immunosuppressive tumor microenvironment predicting prognosis of patients in EGFR mutant lung adenocarcinoma

“…Recently, immunotherapy represented by immune-checkpoint inhibitors (ICIs) have impressively achieved success and anti-programmed cell death-1 (PD-1)/anti-programmed cell death ligand-1 (PD-L1) inhibitors have been approved by the United States Food and Drug Administration (FDA) for the treatment of advanced NSCLC. However, EGFR-mutant NSCLC patients rarely derive a signi cant bene t from ICIs therapy [7][8].…”