A. Passaro et al.
Annals of Oncology
however, evidence remains limited and/or conflicting in
some specific areas where the optimal approach remains
controversial, both in metastatic and early settings. In 2021,
the European Society for Medical Oncology (ESMO) held a
virtual consensus-building process on this topic to gain in-
sights from a multidisciplinary group of experts and develop
recommendations on controversial topics that cannot be
adequately addressed in the current evidence-based ESMO
Clinical Practice Guideline.
METHODS
The aim of this consensus-building process was to discuss
controversial issues relating to the management of patients
with EGFR-mutant NSCLC. The virtual meeting included a
multidisciplinary panel of 32 leading experts from 16
countries and was chaired by AP and SP. All experts were
allocated to four different working groups. Each working
group covered a specific subject area and was appointed a
chair as follows:
1. Tissue and biomarkers analyses (Chair: KK)
2. Early and locally advanced disease (Chair: SP)
3. Metastatic disease (Chair: NL)
4. Clinical Trial Design, patients’ perspective, miscellaneous
(Chair: FB)
Planning, preparation and execution of the consensus
process was conducted according to the ESMO standard
operating procedures. No systematic literature search was
undertaken. All recommendations compiled by the group
were accompanied by a level of evidence and strength of
recommendation based on the ‘Infectious Diseases Society
of America-United States Public Health Service Grading
System’ (Supplementary Table S1, available at https://doi.
org/10.1016/j.annonc.2022.02.003). The final manuscript
was reviewed and approved by all panel members.
RESULTS
Tissue and biomarker analysis
1: Is there a need to accurately identify all EGFR mutations
with clinical utility, covering those considered as common
and atypical/uncommon?
STATEMENT: Broad screening of exons 18-21 for all muta-
tions with established or potential clinical significance is
recommended, preferably by next-generation sequencing
(NGS) [ESCAT I-A] [I,A].
DISCUSSION: Comprehensive reflex biomarker testing,
including EGFR, is recommended for all patients with a
diagnosis of non-squamous NSCLCs, regardless of disease
stage and should be initiated by the pathologist at the time
of initial diagnosis.
The most common type of activating EGFR mutation is
the in-frame deletion of exon 19 around the LREA motif
(amino acids residues 747 to 750; w45% of EGFR muta-
tions), followed by p.L858R point mutation of exon 21
(w40% of EGFR mutations).1
Volume 33 - Issue 5 - 2022
Tumors with these activating mutations or less frequent
mutations, defined as atypical/uncommon, such as in-
sertions in exon 19, point mutations in exon 18 at position
G719 (w3% of EGFR mutations), the exon 21 p.L861Q
mutant (w2% of EGFR mutations) and the S768I mutation
in exon 20 (w2% of EGFR mutations), showed variable
sensitivity to EGFR tyrosine kinase inhibitors (TKIs).2,3
On the other hand, most in-frame insertion mutations
within exon 20 of EGFR, which accounts for (w4%-10% of
all EGFR mutations), and other uncommon mutations
including exon 19 insertions, p.L747S, p.D761Y, p.T790M
and p.T854A confer resistance to EGFR TKIs.
Considering the need to identify mutations affecting EGFR
and other targetable genes, parallel testing with a compre-
hensive next-generation sequencing (NGS) panel, rather than
single-gene EGFR testing, using tissuedor plasma/blood if
tumor tissue is not availabledis recommended. The use of
NGS makes efficient sample use, improves timely access to
results, bypasses delays for ordering follow-up testing and
can be cost-effective if enough targets are included. Consid-
ering the clinical application of NGS to examine tumors in
NSCLC, rare EGFR mutations of unknown biological and
clinical significance are encountered in clinical practice.
Interestingly, distinct response rates to EGFR TKIs are re-
ported even for mutations at the same location within the
genomic DNA. Compound mutations are defined as double or
multiple independent mutations of the EGFR tyrosine kinase
domain, in which the EGFR TKI sensitizing or other mutation is
identified together with a mutation of unknown clinical sig-
nificance. Advances in tumor genotyping methodology pro-
vide a higher probability of identifying atypical and
compound mutations in the EGFR tyrosine kinase domain in
w20% of the same tumor sample. More attention and
collaborative efforts are required to elucidate these rare
compound mutations’ biological and clinical significance.
Level of consensus: 96.8% (30) agree; 3.2% (1) abstain.
Total: 31 voters.
2: What is the role of tissue rebiopsy at disease progres-
sion in patients on TKI therapy for EGFR-mutant NSCLC?
STATEMENT: In all patients with EGFR-mutant NSCLC who are
progressing on TKI therapy, a tissue rebiopsy is recommended
(when feasible) to assess for actionable mechanisms of
resistance and potential histologic transformation [I,A].
DISCUSSION: Nearly all EGFR-mutated NSCLC patients
eventually develop resistance to TKI therapy.4 There are
three main mechanisms of acquired resistance that are
important for clinical practice:
(i) On-target resistance involving EGFR
(ii) Off-target resistance through activation of bypass
oncogenic pathways
(iii) Histologic transformation.
Characterization of these resistance mechanisms at pro-
gression can reveal actionable insights for selecting subse-
quent treatments and clinical trials.
https://doi.org/10.1016/j.annonc.2022.02.003 467