Fast Facts: EGFR Exon 20 Insertion Mutations in NSCLC

G. Troncone, P. Pisapia, P. Cheema, J. Rotow

Description

Lung cancer is still a major cause of death globally, but the development of personalized, precision medicine has had a marked effect on treatment management and improved clinical outcomes, particularly for those with advanced stage non-small-cell lung cancer (NSCLC). EGFR mutations are the third most common mutation found in patients with advanced stage NSCLC. First-line treatment with a traditional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is indicated for most patients, but not for patients with EGFR exon 20 insertion mutations (ex20ins). Instead, recent approvals of an EGFR ex20ins-specific TKI (mobocertinib) and a bispecific antibody (amivantamab) targeting both EGFR and mesenchymalepithelial transition factor (MET) offer the potential for improved outcomes in this patient population. Furthermore, new approaches to treatment continue to be developed and trials for new agents with greater activity against ex20ins mutations are ongoing.

Sujets

• Medical
• Médecine
• Oncology

Informations

• Publié par: S. Karger AG
• Date de parution: 13 juin 2022
• Nombre de lectures: 0
• EAN13: 9783318071368
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Fast Facts: EGFR Exon 20 Insertion Mutations in NSCLC
First published 2022
Text 2022 Julia Rotow, Parneet Cheema, Pasquale Pisapia, Giancarlo Troncone
2022 in this edition S. Karger Publishers Ltd
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ISBN 978-3-318-07020-0
Rotow J (Julia)
Fast Facts: EGFR Exon 20 Insertion Mutations in NSCLC/
Julia Rotow, Parneet Cheema, Pasquale Pisapia, Giancarlo Troncone
Medical illustrations by Graeme Chambers, Belfast, UK.
Typesetting by Amnet, Chennai, India.
Printed in the UK with Xpedient Print.
Made possible by a contribution from Takeda Pharmaceuticals Company Limited. Takeda did not have any influence on the content and all items were subject to independent peer and editorial review.
List of abbreviations
Introduction
EGFR and mutations
EGFR mutation testing
Treatment decisions
Therapies in development
Useful resources
Index
List of abbreviations
AMP: Association for Molecular Pathology
ASCO: American Society of Clinical Oncology
ATP: adenosine triphosphate
CAP: College of American Pathologists
CR: cysteine-rich
CT: computed tomography
ctDNA: circulating tumor DNA
dPCR: digital polymerase chain reaction
EGFR: epidermal growth factor receptor
ErbB: erythroblastic leukemia oncogene B
ex20ins: exon 20 insertions
FDA: Food and Drug Administration
HER: human epidermal growth factor receptor
Hsp: heat shock protein
IASLC: International Association for the Study of Lung Cancer
LR: leucine-rich
LRE: Leu-Arg-Glu (motif)
MET: mesenchymal-epithelial transition factor
NCCN: National Comprehensive Cancer Network
NGS: next-generation sequencing
NSCLC: non-small-cell lung cancer
(NSCLC) NOS: not otherwise specified
ORR: objective response rate
OS: overall survival
PCR: polymerase chain reaction
PFS: progression-free survival
PR: partial response
PS: performance status
RR: response rate
RT-PCR: real-time polymerase chain reaction
SD: stable disease
TK: tyrosine kinase
TKI: tyrosine kinase inhibitor
WT: wild type
Introduction
Lung cancer is still a major cause of death globally, but the development of personalized, precision medicine has had a marked effect on treatment management and improved clinical outcomes, particularly for those with advanced stage non-small-cell lung cancer (NSCLC). However, such novel medicines need to be tailored to patients individual (molecular) tumor alterations to avoid unnecessary or inadequate treatment. Molecular testing is therefore essential as is the ongoing development of more efficacious drugs and treatment models.
EGFR mutations are the third most common mutation found in patients with advanced stage NSCLC. First-line treatment with a traditional epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is indicated for most patients, but not for patients with EGFR exon 20 insertion mutations (ex20ins). Instead, recent approvals of an EGFR ex20ins-specific TKI (mobocertinib) and a bispecific antibody (amivantamab) targeting both EGFR and mesenchymal-epithelial transition factor (MET) offer the potential for improved outcomes in this patient population. Furthermore, new approaches to treatment continue to be developed and trials for new agents with greater activity against ex20ins mutations are ongoing.
This is a time of change in the field of NSCLC treatment and this small volume is packed with updates on progress in the treatment of patients with NSCLC harboring EGFR ex20ins. It will be invaluable for oncologists, oncology nurses and trainees, and also pathologists who, with the continuing growth in precision medicine, are becoming an even more important member of the healthcare team for patients with this disease.
1 EGFR and mutations

Epidermal growth factor receptor
The EGFR gene encodes for the epidermal growth factor receptor (EGFR), a 170 kDa type I transmembrane protein with a tyrosine kinase (TK) function. EGFR protein is one of four proteins that belong to the erythroblastic leukemia oncogene B (ErbB) family, also known as human epidermal growth factor receptor (HER). 1
EGFR (HER1 or ErbB1)
HER2 (ErbB2 or neu)
HER3 (ErbB3)
HER4 (ErbB4).
The ErbB family of proteins is part of a larger family of receptor TKs.
Structure. All four HER/ErbB proteins have a similar structure, comprising an extracellular ligand-binding domain with cysteine-rich (CR) and leucine-rich (LR) regions, a transmembrane domain with a single hydrophobic -helix structure, a juxtamembrane domain with a regulatory function, an intracellular domain with TK activity (except for HER3), and a carboxy-terminal domain with a regulatory function ( Figure 1.1 ). 2
Extracellular domain . Within the EGFR protein structure, the extracellular region (also known as the ectodomain) is composed of two LR (L1 and L2) and two CR (CR1 and CR2) domains. 1 Ligand binding happens between the L1 and L2 domains, 3 and is favored by highly conserved tryptophan residues in the CR1 and CR2 domains. 4 The CR1 domain also plays a key role in the receptor dimerization process. 3
Transmembrane/juxtamembrane domains . The hydrophobic -helix transmembrane domain continues directly into the juxtamembrane domain, which is involved in different regulatory activities, including downregulation, ligand-dependent internalization and association with proteins, including calmodulin. 5
Intracellular domain . This region has TK activity. It is characterized by the presence of tyrosine residues where phosphorylation takes place. 6

Figure 1.1 EGFR structure.
Carboxy-terminal domain . This region comprises tyrosine residues, which modulate signal transduction (after phosphorylation), 5 serine-threonine residues, which are fundamental for receptor downregulation and endocytosis (after phosphorylation), 5 and a binding site for actin. 7
Amino acid sequences. EGFR consists of 1186 amino acids. It is produced after cleavage of the N-terminal sequence of a 1210-amino acid precursor. 8 Amino acid sequences can be defined by a percentage of identity, that is, the number of identical residues over a defined length in a given alignment (identical proteins have 100% sequence identity). They can also be defined by a percentage of similarity, which counts similar residues in addition to identical ones. The sequence identity (similarity) in the HER/ErbB protein family ranges from 37% (53% similarity) for EGFR and HER3 to 49% (64% similarity) for EGFR and HER2. 5 As far as amino acid similarity is concerned, the intracellular TK domains show the highest sequence similarity (average 59-81%), whereas the carboxy-terminal domains feature the lowest sequence similarity (average 12-30%). 8
Mechanism of action. EGFR binds to at least seven different ligands. Binding of a specific ligand determines whether homo- or heterodimerization occurs (attachment to one or more other EGFR proteins) and activates the TK domain through transautophosphorylation of the tyrosine residues. 9 , 10 This leads to direct or indirect (through adaptor proteins) activation of downstream signaling pathways.
The EGFR signaling pathway regulates cell growth, survival, proliferation and differentiation ( Figure 1.2 ).
EGFR mutations in NSCLC
EGFR is situated on chromosome 7 (7p11.2) ( Figure 1.3 ). Somatic mutations, involving the TK domain, were first reported in two independent studies in 2004 in patients with non-small-cell lung cancer (NSCLC) 11 and can be found in exons 18-21. 12
Epidemiology. EGFR mutations are more prevalent in Asian (30-50%) than Caucasian (10-15%) patients with NSCLC. They are mainly, but not only, associated with adenocarcinoma histology and female sex, and occur in non-, former and light smokers. 12 - 14

Figure 1.2 EGFR downstream signaling pathways. Ligand binding activates signaling pathways that promote cell growth, proliferation and survival. AKT, protein kinase B; ERK, extracellular-regulated kinase; GRB-2, growth factor receptor-bound protein 2; JAK, Janus kinase; MEK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3-K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; RAF, rapidly accelerated fibrosarcoma; RAS, rat sarcoma; SOS, Son of Sevenless; STAT, signal transducer and activator of transcription.

Figure 1.3 Chromosomal location and exon structure of EGFR . Somatic mutations involve exons 18-21 within the TK domain (exons 18-24).
Classification. In general, mutations within the EGFR TK domain have been classified into three groups ( Table 1.1 ).
Class I encompasses short in-frame deletions that determine the loss of 4-6 amino acids (E746 to S752) within exon 19.
Class II includes point mutations in exons 18-