[Advances in Treatment of Non-small Cell Lung Cancer Harboring EGFR Exon 20 Insertion Mutations]

Abstract

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations are the third most prevalent activating EGFR mutation in non-small cell lung cancer (NSCLC), accounting for 5%-12% of all EGFR mutations in NSCLC cases. Patients harboring EGFR exon 20 insertion mutations exhibit similar clinical characteristics except for worse prognosis as compared to those with 'classic' EGFR mutations. EGFR exon 20 insertion mutations are considered as a heterogeneous class of alterations that cause different conformational changes in EGFR. The majority of mutations (almost 90% of cases) is positioned in the loop that immediately follows the C-terminal of the C-helix, and the most widely reported subtype of insertion mutations is D770_N771>ASVDN(A767_V769dupASV) with frequency of 21%-28%. NSCLC patients with EGFR exon 20 insertion mutations show primary drug resistance to previously approved EGFR tyrosine kinase inhibitors and are generally insensitive to conventional chemotherapy and immunotherapy. The recently approved targeted drugs Amivantamab and Mobocertinib shift the treatment paradigm for NSCLC patients harboring EGFR exon 20 insertion mutations. There are also several new compounds targeting NSCLC EGFR exon 20 insertion mutations are in development. In this article, we provide a through overview on the treatment development in EGFR exon 20 insertion mutant NSCLC. .

Keywords: EGFR exon 20 insertion mutations; Epidermal growth factor receptor; Lung neoplasms; Targeted treatment.

图 1

EGFR外显子20插入突变位置^[11]。 Insertion site of EGFR exon 20 insertion mutants^[11]. EGFR: epidermal growth factor receptor.

图 2

常见EGFR外显子20插入突变类型的发生频率^{[3, 5, 6]} Frequency of common EGFR exon 20 insertion mutations^{[3, 5, 6]}

图 3

Mobocertinib在EGFR外显子20插入阳性NSCLC中的Ⅰ期/Ⅱ期研究设计^[15]。 Design of mobocertinib phase 1/2 study in NSCLC patients with EGFR exon 20 insertions^[15]. CNS: central nervous system; iORR: intracranial objective response rate; QD: daily; RP2D: recommended phase 2 dose.

图 4

Mobocertinib在Ⅰ期/Ⅱ期研究PPP人群中对不同EGFR外显子20插入突变亚型的有效性^[15]。 Objective response by EGFR exon 20 insertion mutation category (PPP cohort) in mobocertinib phase 1/2 study^[15]. PD: progressed disease; PR: partial response; PPP: platinum-pretreated patient; SD: stable disease.

图 5

CHRYSALIS研究设计^[47]。 Study design of CHRYSALIS^[47]. C: cycle; SOC: standard of chemotherapy.

图 6

CHRYSTALIS有效性人群中不同EGFR外显子20插入突变位点与插入结构区亚组的肿瘤缩小与缓解情况^[47]。 Tumor reduction and responses by insert site of EGFR exon 20 insertion mutation in efficacy population of CHRYSTALIS^[47]. SoD: sum of lesion diameters; ctDNA: circulating tumor DNA.