Computational Systems Biology Methods and Protocols.7z

monitored by circulating tumor DNA (ctDNA) using serial plasma

samples from NSCLC patients. Monitoring T790M gatekeeper

mutation will further impact on treatment decision and patient

survival. Importantly, the standard care in the clinical practice is

rapidly changing owing to the availability of third-generation

EGFR TKI, which is designed to have low activity against wild-

type EGFR while retaining activity against EGFR isoforms with

resistant mutations (including T790 M mutation) (Table 1)

[51, 52]. A seminal study retrospectively established that patients

with T790M-positive tumors treated with osimertinib, a third-

generation EGFR TKI that binds irreversibly to EGFRs harboring

common activating mutations and the T790M resistance mutation,

had equivalent outcomes whether the mutation was detected in

tumor tissue or blood [53]. They further prospectively confirmed

and expanded these findings in patients with newly diagnosed

NSCLC and those with acquired resistance to EGFR TKI therapy.

Table 1
First-, second-, and third-generation EGFR TKIs

Drug Indications Targets Approval

First-

generation

EGFR TKI

Gefitinib IRESSA First line for EGFR exon 19 deletions

or exon 21 (L858R) substitution

mutations, second line or third line

for patients with regionally advanced

or metastatic NSCLC who had failed

one or two prior treatment regimens

19 del

L858R

2003

Erlotinib TARCEVA First line for EGFR exon 19 deletions

or exon 21 (L858R) substitution

mutations, second line or third line

for patients with regionally advanced

or metastatic NSCLC who had failed

one or two prior treatment regimens

19 del

L858R

2004

Icotinib CONMANA First line for EGFR-sensitive mutations

in locally advanced or metastatic

NSCLC patients with first-line

treatment

2011

Second-

generation

EGFR TKI

Afatinib GILOTRIF First-line metastatic NSCLC whose

tumors have EGFR exon

19 deletions or exon 21 (L858R)

substitution mutations

Metastatic, squamous NSCLC

progressing after platinum-based

chemotherapy

19 del

L858R

2013

Third-

generation

EGFR TKI

Osimertinib TAGRISSO Metastatic EGFR T790 M-positive

NSCLC, as detected by an

FDA-approved test, whose disease

has progressed on or after EGFR TKI

therapy

T790M 2015

54 Jun Li et al.