Treatment of uncommon EGFR mutations in non-small cell lung cancer: new evidence and treatment

Abstract

Sensitizing mutations in epidermal growth factor receptor (EGFR) are associated with positive responses to anti-EGFR-targeted therapy, leading to a new era of treatment for non-small cell lung cancer (NSCLC). Exon 19 deletions and exon 21 L858R substitutions are the most common mutations, accounting for approximately 90% mutations in NSCLC; these are termed classic mutations and result in high sensitivity to tyrosine kinase inhibitors (TKIs). Other EGFR mutations are termed uncommon EGFR mutations, of which G719X, S768I, L861Q, exon 20 insertions, and complex mutations are the most frequent. G719X, S768I, and L861Q are point mutations and those that exist with complex mutations are sensitive to first-generation TKIs. A prospective analysis demonstrated that afatinib, a second-generation TKI, led to a better prognosis in some patients with NSCLC compared to first-generation TKIs. Chemotherapy used to be the traditional choice for patients carrying exon 20 insertions; however, with the development of novel targeted drugs, the role of chemotherapy is changing. Tremendous progress has also been made in clinical trials on immunotherapy treatment of uncommon EGFR mutations. The treatment for patients with NSCLC harboring uncommon EGFR mutations remains a subject of debate and the sensitivity of uncommon EGFR mutations to TKIs is still unclear. Here, we summarized recent data in the literature and provide an overview of the clinical characteristics, incidence, and outcomes of patients harboring G719X, S768I, L861Q, exon 20 insertions, and complex mutations who were treated with TKIs, chemotherapy, or immunotherapy.

Keywords: Non-small cell lung cancer (NSCLC); immunotherapy; treatment; tyrosine kinase inhibitors (TKIs); uncommon epidermal growth factor receptor mutations (uncommon EGFR mutations).

Figure 1

EGFR somatic mutations within exon 18–21 of the tyrosine kinase domain of the gene. Common and uncommon EGFR mutations are represented by orange and purple background respectively. EGFR, epidermal growth factor receptor.

Figure 2

Progression-free survival to EGFR-TKI of NSCLC patients harboring common and common EGFR mutations. EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; NSCLC, non-small cell lung cancer.

Figure 3

Flow diagram of the study selection. Other references include reviews and meta-analysis.

Figure 4

A comprehensive view of uncommon EGFR mutations from five studies: (A) a summary of frequency of G719X, S768I, L861Q, Exon 20 insertions and other mutations (complex mutations included); (B) a summary of these single point mutations and exon 20 insertions. EGFR, epidermal growth factor receptor.

Figure 5

Efficacy of EGFR-TKIs in each uncommon EGFR mutation in different studies. EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.