Heterogeneous Responses to Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) in Patients with Uncommon EGFR Mutations: New Insights and Future Perspectives in this Complex Clinical Scenario

Abstract

Uncommon Epidermal Growth Factor Receptor (EGFR) mutations represent a distinct and highly heterogeneous subgroup of Non-Small Cell Lung Cancers (NSCLCs), that accounts for approximately 10% of all EGFR-mutated patients. The incidence of uncommon EGFR mutations is growing, due to the wider adoption of next-generation sequencing (NGS) for diagnostic purposes, which enables the identification of rare variants, usually missed with available commercial kits that only detect a limited number of EGFR mutations. However, the sensitivity of uncommon mutations to first- and second-generation EGFR Tyrosine Kinase Inhibitors (TKIs) is widely heterogeneous and less well known, compared with classic mutations (i.e., exon 19 deletions and exon 21 L858R point mutation), since most of the pivotal studies with EGFR TKIs in the first line, with few exceptions, excluded patients with rare and/or complex variants. Recently, the third generation EGFR TKI osimertinib further revolutionized the therapeutic algorithm of EGFR-mutated NSCLC, but its role in patients harboring EGFR mutations besides exon 19 deletions and/or L858R is largely unknown. Therefore, a better knowledge of the sensitivity of uncommon mutations to currently available EGFR TKIs is critical to guiding treatment decisions in clinical practice. The aim of this paper is to provide a comprehensive overview of the treatment of NSCLC patients harboring uncommon EGFR mutations with currently approved therapies and to discuss the emerging therapeutic opportunities in this peculiar subgroup of patients, including chemo-immunotherapy combinations, next-generation EGFR TKIs, and novel targeted agents.

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

“…These receptors have specific growth factors as ligands and are involved in several fundamental functions for cell survival and activation, such as growth, differentiation, and apoptosis [13][14][15][16]. The oncogenic role of their alterations is well documented, as well as their possible exploitation as therapeutic targets [17][18][19][20][21][22][23][24][25].…”

Molecular Diagnostics in Non-Small Cell Lung Carcinoma

“…[49][50][51][52] Less common alterations scattered throughout exons 18, 19 and 21 confer variable degrees of EGFR activation and sensitivity to EGFR TKI therapy. 53 Mutations within exon 20 lead to receptor activation but in general predict primary resistance to TKIs. 54 The EGFR T790M mutation, a well-characterized variant that arises in the setting of first generation TKI therapy and leads to drug resistance and disease relapse, also falls within exon 20.…”

Outcomes of Afatinib in Non-small Cell Lung Cancer Patients Harboring Uncommon Epidermal Growth Factor Receptor Mutations

“…A number of clinical studies [6][7][8][9][10][11][12] have con rmed that, compared with traditional chemotherapy, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR mutations have an objective response rate (ORR) as high as 70%-80%, a median progression-free survival (mPFS) ranging from 9.6 months to 18.9 months, and an overall survival (OS) ranging from 21.6 months to 34.1 months; thus, EGFR-TKIs have become the rst-line standard treatment for EGFR-sensitive mutations in NSCLC. In addition to the two most common types of EGFR mutations mentioned above, other types of EGFR mutations were also found in the region between exons 18-21 of the EGFR gene, called uncommon or nonclassical mutations, accounting for approximately 10-15% of EGFR mutations [13][14][15]. Since uncommon mutations in EGFR are relatively insensitive to the treatment of EGFR-TKIs, which may have a negative impact on research results, most clinical trials investigating the e cacy of EGFR-TKIs do not include patients with uncommon mutations [13][14][15][16].…”

“…In addition to the two most common types of EGFR mutations mentioned above, other types of EGFR mutations were also found in the region between exons 18-21 of the EGFR gene, called uncommon or nonclassical mutations, accounting for approximately 10-15% of EGFR mutations [13][14][15]. Since uncommon mutations in EGFR are relatively insensitive to the treatment of EGFR-TKIs, which may have a negative impact on research results, most clinical trials investigating the e cacy of EGFR-TKIs do not include patients with uncommon mutations [13][14][15][16]. Only a post hoc analysis of the LUX-Lung series trials evaluated the activity of EGFR-TKIs in NSCLC patients with uncommon mutations [14,15].…”

“…Since uncommon mutations in EGFR are relatively insensitive to the treatment of EGFR-TKIs, which may have a negative impact on research results, most clinical trials investigating the e cacy of EGFR-TKIs do not include patients with uncommon mutations [13][14][15][16]. Only a post hoc analysis of the LUX-Lung series trials evaluated the activity of EGFR-TKIs in NSCLC patients with uncommon mutations [14,15]. Due to the small sample size and high heterogeneity of patients with uncommon EGFR mutations, the e cacy of EGFR-TKIs for patients with rare EGFR mutations is still unclear.…”