ESMO 2022 EGFR Mutant Non-Small-Cell Lung Cancer 11

Annals of Oncology A. Passaro et al.
Management of Systemic Acquired Resistance to Osimertinib
Re-Biopsy
(liquid vs. tissue vs. both)
Comprehensive biomarker analysis

(NGS preferred)
Histological transformation Off-target alterations EGFR on-target alterations No target

[12-15%] [30-60%] [10-20%] [40 – 50%]
Pathology review
e.g. MET, HER2,HER3, e.g. EGFR p.C797S,

Small Cell Squamous
BRAF, RET other EGFR mutations
Informed discussion with patient,

aligning expectations
Preferred: Molecular-driven clinical trial Preferred: Molecular-agnostic clinical trial

Preferred: Clinical trial Alternative: Platinum-based chemotherapy Alternative: Platinum-based chemotherapy
Alternative: Platinum-based chemotherapy or or
Atezolizumab plus Bevacizumab and Platinum-based Atezolizumab plus Bevacizumab and Platinum-based
chemotherapy (or similar combination) chemotherapy (or similar combination)
Preferred: Clinical trial

Alternative: Standard chemotherapy or Off label drug / Consider EGFR TKI rechallenge in absence of valid therapeutic alternative
Immune checkpoint inhibitors not before other standard therapeutic options are exhausted
Figure 2. Management of systemic acquired resistance to osimertinib.

EGFR, epidermal growth factor receptor; NGS, next-generation sequencing; TKI, tyrosine kinase inhibitor.
of OS benefit was less pronounced among Asian patients Level of consensus: 96.8% (30) agree; 3.2% (1) abstain. To-
and those with an p.L858R mutation.67,81 The panel, tal: 31 voters.
however, considers this should not restrict the use of
2. What is the optimal management of patients with CNS
osimertinib in first-line therapy for these patient sub-
disease and/or with leptomeningeal involvement?
groups. Beyond osimertinib, other third-generation in-
hibitors are being developed such as almonertinib (now STATEMENT: Third-generation EGFR TKIs should be priori-
aumolertinib), lazertinib, alflutinib, rezivertinib, tized for those patients with CNS metastasis, including
ASK120069, SH-1028, D-0316 and abivertinib. Some of leptomeningeal disease, as initial therapy. The benefit of
these agents are approved in Asian countries like lazertinib radiotherapy in addition to EGFR TKIs is not supported by
(approved in the Republic of Korea) and almonertinib prospective controlled trials data. For those with intracra-
(approved in China) for the treatment of patients with nial progression despite osimertinib 80 mg, delivery of local
EGFR p.T790M resistance mutation-positive NSCLC.104,105 stereotactic radiation, avoiding whole brain radiotherapy
In the absence of access to third-generation EGFR TKIs, (WBRT), with the continuation of standard dose osimertinib
patients should receive first- or second-generation EGFR is standard, while increasing the osimertinib dose to 160 mg
TKIs. can be considered if accessible. Patients who present with
New combination strategies have shown interesting re- leptomeningeal disease may benefit from osimertinib at a
sults frontline, but have not been adopted as standards. preferred dose of 160 mg, if available [II,A].
Adding vascular endothelial growth factor inhibitors to the
standard first-generation TKIs has been shown to prolong DISCUSSION: Osimertinib is the preferred agent for com-
PFS but not OS.106-109 The combination of chemotherapy mon EGFR-mutant patients with CNS metastasis. Previously,
with gefitinib resulted in improved OS compared with gefitinib, erlotinib and afatinib all demonstrated intracranial
gefitinib as first-line therapy in two randomized trials from responses in patients with brain metastasis, despite their
Asia. This approach, however, has not been compared with relatively low CNS penetration.
the use of a third-generation EGFR TKI as initial therapy. A In the FLAURA trial, osimertinib demonstrated a better CNS
similar randomized trial using a backbone of osimertinib is control over gefitinib or erlotinib in patients with brain me-
underway (FLAURA2dNCT04035486).110,111 tastases and delayed the emergence of brain metastases in
476 https://doi.org/10.1016/j.annonc.2022.02.003 Volume 33 - Issue 5 - 2022

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Annals of Oncology A. Passaro et al.

Management of Systemic Acquired Resistance to Osimertinib

Comprehensive biomarker analysis

Histological transformation Off-target alterations EGFR on-target alterations No target

e.g. MET, HER2,HER3, e.g. EGFR p.C797S,

Informed discussion with patient,

Preferred: Molecular-driven clinical trial Preferred: Molecular-agnostic clinical trial

Preferred: Clinical trial

Figure 2. Management of systemic acquired resistance to osimertinib.

476 https://doi.org/10.1016/j.annonc.2022.02.003 Volume 33 - Issue 5 - 2022

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