Critical Review of EGFR-Mutated NSCLC: What We Do and Do ... · Over the past decade numerous...

Over the past decade numerous large-scale sequencing approaches have identified increasingly more oncogenic driver mutations in non-small cell lung cancer (NSCLC) (Figure 1A)1, which have facilitated the rational development of targeted therapies and led to marked survival benefits compared to classical treatment approaches with chemotherapy (Figure 1B).2 Mutations in the epidermal growth factor receptor (EGFR) gene are amongst the most frequently observed1,3,4, but significant differences in mutation frequency exist depending on histology, gender, smoking status and ancestry. The highest rate of EGFR mutations (≥50%) has been found in Asian female non-smokers with adenocarcinoma histology and a bronchioalveolar subtype.5-7

The EGFR family, also referred to as HER or ErbB receptors, comprises four receptor tyros-ine kinases: EGFR (HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4).5 Ligand binding to the extracellular region of EGFR leads to autophosphorylation, activation and EGFR dimerization, which in turn initiates intracellular signalling cascades.5 Signal transduction subsequently leads to cell proliferation and survival via activation of RAS/RAF/MEK and PI3K/AKT pathways, among others.5 EGFR became a prime therapeutic target in NSCLC in 2004, following the discovery that somatic mutations in the EGFR gene enhance tyrosine kinase activity in lung cancer patients.5 These somatic EGFR mutations activate the kinase receptor in the absence of ligand binding, and can trigger oncogenesis by inducing a constitutively active state that leads to sustained downstream signalling.8 Subsequently, targeted therapy with tyrosine kinase inhibitors (TKIs) has emerged as the mainstay treatment for advanced NSCLC patients with activating mutations (Figure 1C).9

Three generations of EGFR-TKIs are currently approved but they are not all equal in terms of EGFR binding, metabolism, anti-tumor activity (Table 1A) and safety.10 First-generation EGFR-TKIs (e.g., gefitinib and erlotinib) reversibly bind to EGFR and inhibit the binding of adenosine triphosphate (ATP) to the tyrosine kinase domain (Figure 2A-B). Although gefitinib and erlotinib have shown efficacy in first-, second-, and third-line treatment of NSCLC, the benefit seen is usually transient because NSCLC with EGFR-activating mutations treated with first-generation EGFR-TKIs inevitably develop resistance.11 Up to half of patients treated with first-generation EGFR-TKIs develop acquired resistance through a T790M EGFR substitution mutation.12

Second-generation EGFR-TKIs (e.g., afatinib and dacomitinib) form irreversible, covalent attachments to the EGFR kinase domain and have demonstrated improvements in progression- free survival (PFS) relative to those treated with first-generation EGFR-TKIs.13, 14 Moreover, the third-generation EGFR-TKI, osimertinib, is highly active in NSCLC patients with the EGFR T790M mutation who had disease progression with first- and second-generation EGFR-TKIs.15

Although the treatment landscape of advanced NSCLC has dramatically changed with the introduction of EGFR-TKIs, identifying methods to best select patients who are more likely to benefit from EGFR inhibition as well as selecting the optimal sequence of EGFR-TKIs, especially how best to use the third-generation EGFR-TKI, osimertinib, are emerging issues that still need to be addressed.

Critical Review of EGFR-Mutated NSCLC: What We Do and Do Not Know

Alexander Meisel1,2 and Maximillian Hochmair3

1University Hospital Zurich, Zurich, Switzerland2ETH Zurich, Zurich, Switzerland

3Karl Landsteiner Institute of Lung Research and Pulmonary Oncology, Vienna, Austria

healthbook TIMES Oncology Hematology

hb TIMES Onco Hema healthbook.ch March 18, 2020

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Corresponding author: Alexander MeiselAssociate Researcher, Department of Nuclear Medicine, University Hospital Zurich,ETH Zurich, E-mail: alexander.meisel@usz.ch

DOI: 10.36000/hbT.OH.2020.03.012ISSN: 2673-2092 (Print) and 2673-2106 (Online)

This article was published on March 18, 2020

Meisel et al. Critical review of EGFR-mutated NSCLC:What we do and do not know. healthbook TIMES Onco Hema 2020;(3):20-35

INTRODUCTION

202020

This critical review considers the evolving landscape of EGFR-TKI therapy and discusses the optimal sequence schedule to improve survival outcomes for EGFR-mutant positive (EGFR M+) advanced NSCLC patients.

FIRST-LINE EGFR-TKI THERAPY IN NSCLCFor almost a decade now, first- and second-generation EGFR-TKIs have been widely established in place of traditional standard platinum-based chemotherapy as the first-line treatment of choice for patients with newly diagnosed EGFR M+ advanced NSCLC.16

Several randomized trials have demon-strated that first-line EGFR-TKI therapy can improve objective response rates (ORR) and promote longer PFS compared to standard chemotherapy (Table 1B).14,17-

24 Median PFS in phase 3 trials comparing gefitinib with platinum-based chemo-therapy as first-line treatment of patients with advanced NSCLC is about 9 months versus 6 months, respectively.18,19 However, no overall survival (OS) benefit was identi-fied in these first-generation EGFR-TKI trial populations, which may be partly due to high crossover rates following disease progression (Table 1C).9,14,17-24

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Figure 1. A) Distribution of oncogenic driver mutations in NSCLC (adapted from Skoulidis F et al. 20191); B) OS targeted versus non-targeted treatment (adapted from Kris MG et al. 20142); and C) History of EGFR-mutant positive (EGFR M+) NSCLC (adapted from Rotow J et al. 201733).

healthbook TIMES Oncology Hematology 21

Figure 1A

Fig. 1A

FGR1 or FGFR2 0.7%

ALK fusion 4.4%

ERBB2 3.8%

NF1 truncation 1.9%

MET splice 3.0%

HRAS 1.2%

MAP2K1 0.7%

ROS1 fusion 1.9%

RIT1 0.2%

RET fusion 2.3%MET amplification 2.5%ERBB2 amplification 2.7%

NRAS 1.2%

Fig. 1B

No targetedtherapy

00 1 2 3 4 5

Targeted therapy

No driver

Log-rank p<0.001

19771978

Identification of EGFRFDA approval of cisplatin

First report of an EGFR TKI

Report of nivolumab activity in NSCLC

FDA approval of gefitinib (second line, unselected)

EGFRT790M resistance mutation reported

• FDA approval of erlotinib and afatinib (first line, EGFR-mutant NSCLC)

• Response of third-generation TKIs in EGFR-T790M-positive patients

• FDA approval of osimertinib (first line, EGFR-mutant NSCLC)

• Progression-free and overall survival benefit shown in EGFR/ALK mutant subgroup for combination treatment with Atezolizumab/Bevacizumab/chemotherapy

• FDA approval of osimertinib (second line, EGFR-T790M-mutant NSCLC)

• EGFRC797S identified at resistance to third-generation EGFR TKIs

• FDA breakthrough designation for the EGFR/c-MET bi-specific antibody JNJ-61186372

• FDA approval of EGFRT790M ctDNA assay• First report of a fourth-generation

allosteric TKI EAI045 inhibiting triplemutant EGFRL858R/T790M/C797S or EGFRL858R/T790M/C797S

• First report on EGFRM766Q mutation mediating resistance to osimertinib but sensitizing to neratinib and poziotinib

• FDA approval of erlotinib (second line, unselected)

• EGFR mutation associated with response to EGFR TKIs

Figure 2. A) EGFR TKI-generations; and B) Schematic representation of EGFR signalling and EGFR-TKI inhibition. Adapted from Hsu PC et al. 2019.154 The Epidermal growth factor receptor (EGFR) pathway in non-small cell lung cancer (NSCLC). EGFR kinase domain mutations including Del19, L858R and T790M increase kinase activity of EGFR, leading to the hyperactivation of downstream signalling pathways including MAPK, PI3K/AKT/mTOR, and IL-6/JAK/STAT3 which promote tumori-genesis of NSCLC cells. The three generations of EGFR-TKIs differ with respect to how they bind to different EGFR mutations and which EGFR mutations are active or inactive.

4th-generation TKIEIA045

*reversible binding to EGFR, allosteric inhibition *no biological activity without dimerization

inhibitor cetuximab (accessability of binding site)

2nd-generation TKIsAfatinib, dacomitinib

*irreversible covalent binding to allErbB receptors (EGFR, ErbB2, ErbB4)

*inactive on T790M mutation

1st-generation TKIsGefitinib, erlotinib

*reversible binding to mutant EGFR*inactive on T790M mutation

3rd-generation TKIosimertinib

*reversible covalent binding to EGFR

*specificity to T790M mutation

T790M, C797S mutation

Exon 19 deletionL858R mutation

mTOR ERK STAT

RAS JAK

T790M mutation

Cell proliferation, survival and migrationGene transcriptionNucleus

Cell membrane

First generation Second generation Third generation Forth generation

Quinazoline-based Quinazoline-based Pyrimidine-based Thiazole amid-based

MoA Reversible ATP competitive Irreversible, covalent

(Cys 797)Irreversible, covalent

(Cys 797) Reversible, allosteric

• Improved RR/PFS over chemotherapy

• Dose limited by rash (caused by EGFR wild type inhibition)

• Preclinical activity against T790M and Exon 20 insertions

• Pan-HER inhibition can disrupt heterodimeristation

• Targets HER2/HER3 mediated resistance

• Higher potency against L858R

• PFS and/or OS benefits observed in phase-III clinical trials compared to 1st-generation EGFR-TKIs

• Low CNS penetration but significant clinical activity (afatinib)

• T790M specific activity• Wild type sparing• Targets HER2/HER3

mediated resistance• CNS penetration• PFS and/or OS benefits

observed in phase-III clinical-trials compared to 1st- generation EGFR-TKIs

• Clinical development stopped due to lower response rates in phase-II and safety profile (hyperglycemia due to IGFR inhibition)

• T790M modest activity• T790M/C797S specific

activity• Unaffected ATP binding• No biological activity

without further inhibition of EGFR-dimerization with cetuximab

• Currently no further clinical development

Erlotinib

Gefitinib Afatinib

Dacomitinib

Osimertinib EAI045

Rociletinib*

EGFR MUTATIONS AND OUTCOMESWITH EGFR-TKIs First-generation EGFR-TKIs were serendipitously found to be most effective in advanced NSCLC patients with tumors harboring recurrent activating mutations (mainly somatic)25, 26 occurring in the exons encoding the kinase domain of EGFR.27-29 Approximately 93% of EGFR activating mutations occur in exons 19 to 21. Of these, deletions in exon 19 (Del19) and a point mutation in exon 21 leading to substitution of leucine for arginine at position 858 (L858R) are particularly common (44.8% and 39.8%, respectively).30 Indeed, the presence of an EGFR mutation in NSCLC patients is the strongest and most reliable predictor of improved PFS and ORR with EGFR-TKIs compared with chemotherapy in the first-line setting. The 2009 landmark IPASS (Iressa Pan-Asia Study) study reported significantly longer PFS with gefitinib versus standard chemotherapy in a subgroup of advanced lung tumor patients with EGFR mutations (hazard ratio [HR] for progression to death: 0.48; 95% CI: 0.36−0.64; p <0.001) but not in patients with EGFR wild-type tumors (HR for pro-gression to death: 2.85; 95% CI: 2.05 − 3.98; p<0.001).31

Much later in 2015, a pooled analysis of the LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6) trial populations showed superiority of afatinib to platinum-based chemotherapy in terms of median OS in a subset of patients with EGFR Del19

mutations but not in patients with EGFR L858R mutations: 27.3 versus 24.3 months, respectively (HR: 0.81; 95% CI: 0.66 to 0.99; p=0.037).32 This data revealed for the first time that EGFR-TKIs in the first-line setting could prolong OS in patients harbouring Del19 EGFR mutations, and that Del19 and L858R EGFR mutations constitute two distinct patient subgroups.32

In a small proportion of patients, primary resistance mutations can already be detected at diagnosis (Figure 3). The most prevalent are EGFR exon 20 insertions (4 %) and EGFR T790M mutations (5%).1,3,4,33,34 While the latter are sensitive to third-generation EGFR-TKIs, EGFR exon 20 insertions can be targeted with the specific inhibitor TAK-788.35 Initial results from a phase I/II trial (NCT02716116) showed a disease control rate (DCR) of 89% with 54% of the patients achieving a partial response (confirmed + unconfirmed) and 35% stable disease. Overall, 23 of 24 evaluable patients (93%) showed a reduction in the tumor volume; side effects were consistent with other EGFR-TKIs. Therefore, a phase III trial (n=318, 1:1 randomization) comparing TAK-788 with platinum/pemetrexed combination chemotherapy was initiated with enrolment starting in late 2019 (NCT04129502).35 Furthermore, in March 2020 JNJ-61186372, a bi-specific antibody targeting EGFR and c-MET, received FDA breakthrough designation for the poor-prognosis subpopulation of EGFR M+ patients

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PFS achieved in trials of patients with EGFR mutation-positive non-small cell lung cancer treated with EGFR-TKIs in a first-line settinga

EGFR TKI Study Comparator

Median PFS, mo (HR [95% CI])

Common Mutations Del19 L858R

Erlotinib ENSURE Gemcitabine + cisplatin n=110 11.0(0.34[0.22−0.51])b n=57 11.1(0.20[0.11−0.37])b n=52 8.3(0.57[0.31−1.05])b

EURTAC Platinum doublet n=86 9.7(0.37[0.25−0.54])b n=57 11.0(0.30[0.18−0.50])b n=29 8.4(0.55[0.29−1.02])b

OPTIMAL Platinum doublet n=82 13.1(0.16[0.10−0.26])b n=43 15.3(0.13[0.07−0.25])b n=39 12.5(0.26[0.14−0.49])b

Gefitinib IPASS Carboplatin + paclitaxel n=132 NR n=66 11.0(0.38[0.26−0.56])b n=64 9.2(0.55[0.35−0.87])b

NEJ002 Carboplatin + paclitaxel n=114 10.8(0.30[0.22−0.41])b n=58 11.5b n=49 10.8b

WJTOG3405 Cisplatin + docetaxel n=86 9.2(0.49[0.34−0.71])b n=50 NR(0.45[0.27−0.77])b n=36 NR(0.51[0.29−0.90])b

Afatinib LUX-Lung 3 Pemetrexed + cisplatin n=204 13.6(0.47[0.34−0.65]) n=113 13.7(0.28[0.18−0.44]) n=91 10.8(0.73[0.46−1.17])

LUX-Lung 6 Gemcitabine + cisplatin n=216 11.0(0.25[0.18−0.35]) n=124 13.7(0.20[0.13−0.33]) n=92 9.6(0.32[0.19−0.52])

LUX-Lung 7 Gefitinib n=160 11.0(0.73[0.57−0.95]) n=93 12.7(0.76[0.55−1.06]) n=67 10.9(0.71[0.48−1.06])

Dacomitinib ARCHER 1050 Gefitinib n=227 14.7(0.59[0.47−0.74]) n=134 16.5(0.55[0.41−0.75]) n=93 12.3(0.63[0.44−0.88])b

Osimertinib FLAURA Gefitinib or erlotinib n=279 17.7(0.45[0.36−0.57]) n=175 21.4(0.43[0.32−0.56])b n=104 14.4(0.51[0.36−0.71])b

IC50 values of reversible EGFR-TKIs and afatinib

EGFR Wildtype EGFR L858R EGFR Exon 19 Deletion

LoVo A431 H2073 H3255 H1975 EGFR T790M PC-9 PC-9/VanR EGFR T790M

Afatinib 15 33 25 0.9 22 0.6 3

Gefitinib 59 73 61 11 3100 7 740

Erlotinib 91 250 110 9 6100 6 1300

Table 1. A) IC 50 values of reversible EGFR-TKIs and afatinib (adapted from Hoffknecht P et al. 2015)125 B) Progres-sion-free survival (PFS) in EGFR M+ NSCLC patients achieved in phase III trials for first-line EGFR-TKIs (adapted from Shah R et al. 2019153); aCentral inde-pendent review, unless stated otherwise; bInvestigator review. C) Overall survival (OS) in EGFR M+ NSCLC patients achieved in phase III trials for first-line EGFR-TKIs. Adapted from Shah R et al. 2019.153

harboring EGFR exon 20 insertions. This status was grant-ed after promising phase I results. JNJ-61186372 will be further evaluated in combination with Lazertinib.36

CO-MUTATIONS AND OUTCOMES WITHEGFR-TKIsAlthough EGFR mutant NSCLC represents a prototypical oncogene-addicted cancer with a single driver, co-muta-tions are a frequent event.37 The most commonly mutated genes are TP53 (55–65%), RB1 (10%), PI3KCA/PTEN (9–12%) and CTNNB1 (5-10%).1,38 TP53 alterations are associated with a poorer prognosis (lower ORR, shorter PFS and OS).38,39 Similar findings have been made for

PTEN, MDM2 and RB1 mutations, especially for patients with EGFR mutations and RB1 loss; PFS with EGFR tyros-ine kinase inhibition was extremely short (median PFS of 1.9 months).38 Alterations in TP53, RB1, and the combina-tion of both in particular, are associated with increased genetic instability eventually leading to small cell transfor-mation.38,39

SECOND-GENERATION VERSUS FIRST-GENERATION EGFR-TKIs Recent head-to-head trials have demonstrated that second- generation EGFR-TKIs are preferable to first-generation EGFR-TKIs as first-line treatment for patients with EGFR

Figure 3. Resistance mechanisms in EGFR-mutant positive (EGFR M+) NSCLC.31 Adapted from Rotow J et al. 2017.33

OS (overall data set and stratified mutation) achieved in trials of patients with EGFR- mutation positive non-small cell lung cancer treated with EGFR-TKIs in a first-line setting

EGFR TKI Study

Median OS, mo (HR [95% CI])

Common mutations Del19 L858R

Erlotinib ENSURE 26.3(0.91[0.63−1.31]) NR(0.79[0.48−1.30]) NR(1.05[0.60−1.84])

EURTAC 22.9(0.92[0.63−1.35]) NR(0.94[0.57−1.54]) NR(0.99[0.56−1.76])

OPTIMAL 22.8(1.19[0.83−1.71]) 27.0(1.52[0.92−2.52]) 21.5(0.92[0.55−1.54])

Gefitinib IPASS NR(1.00[0.76−1.33]) 27.2(0.79[0.54−1.15]) 18.7(1.44[0.90−2.30])

NEJ002 27.7(0.89[0.63−1.24]) 28.9(0.83[0.52−1.34]) 28.0(0.82[0.49−1.38])

WJTOG3405 34.8(1.25[0.88−1.78]) 35.2 (NR) 32.2 (NR)

Afatinib LUX-Lung 3 31.6(0.78[0.58−1.06]) 33.3(0.54[0.36−0.79]) 27.6(1.30[0.80−2.11])

LUX-Lung 6 23.6(0.83[0.62−1.09]) 31.4(0.64[0.44−0.94]) 19.6(1.22[0.81−1.83])

LUX-Lung 7 27.9(0.86[0.66−1.12]) 30.7(0.83[0.58−1.17]) 25.0(0.91[0.62−1.36])

Dacomitinib ARCHER 1050 34.1(0.76[0.58−0.99]) 34.1(0.88[0.61−1.26]) 32.5(0.71[0.48−1.05])

Osimertinib FLAURA 38.6(0.80[0.64−1.00]) NR(0.68[0.51−0.90]) NR(1.00[0.74−1.40])

EGFR activating mutations• Exon 19 deletions 45%• L858R 40%• G719X 5%• L861X 1%• S768I 1%• Other uncommon

mutations

Second-site mutations• T790M >50%• T854A• D761Y• L747S• G796S/R• L792F/H• L718Q

Primary resistance• Exon 20 insertions 4%• T790M Other

• EMT• Small-cell transformation

Second-site mutations• C797S

EGF EGF IL-6

EGFR EGFR

EGFR AXL IGF1RHER2HER3

BCL-2 p53

RASNF1

P13K SRC

Multipleligands

Bypass signallingpathways

Osimertinibresistance

Loss ofEGFR-T790M

Cell survival andproliferation

Downstreampathway alterations

Cell survival

ApoptosisYAP1CDK4/6

ProliferationMutation

EGFR amplification andautocrine signalling

EGFR kinasedomain mutations

Changes insurvival andapoptosispathways

PD-L1IL-6R METEGF

3–4%

M+ NSCLC since they may prolong PFS and OS. First-line efficacy of erlotinib or gefitinib has been compared with second-generation EGFR-TKIs in randomized clinical trials. In the LUX-Lung 717 and ARCHER-1050 trials,14 gefitinib was compared with second-generation agents afatinib and dacomitinib, respectively. The LUX-Lung 7 was a large (N=319), multicentre and multi-ethnic phase 2b trial that showed a trend toward improved OS with afatinib vs. gefitinib in treatment-naïve patients harbouring Del19 or L858R mutations.17 Overall, analysis of the LUX-Lung 7 data together with the LUX-Lung 3 and LUX-Lung 6 data show that afatinib results in approximately 10% of patients achieving long-term clinical benefit (long term response ≥3 year PFS and OS), which is greater than that observed with first-generation EGFR-TKIs.13 Stratification factors in these trials included: Del19 versus L858R EGFR and vs. other ‘uncommon’ mutations in LUX-Lung 3 and LUX-Lung 6; race (Asian versus non-Asian) in LUX-Lung 3 only, and brain metastases (presence versus absence) in LUX-Lung 7 only.13 The frequency of Del19 mutation-pos-itive NSCLC was slightly higher among long-term respond-ers in the LUX-Lung 3,6,7 analysis, which supports its known role as a biomarker for improved outcomes with EGFR-TKIs vs other mutation types.13 These studies also demon-strate that afatinib can provide clinical benefit in advanced NSCLC patients with brain metastases or uncommon muta-tions.17,22,23 Although the LUX-Lung 7 trial showed that afatinib compared to gefitinib significantly improves PFS and the time-to-treatment failure, more serious drug-re-lated adverse events were reported in the afatinib group than in the gefitinib group.40 Indeed, second-generation EGFR-TKIs typically have more frequent side effects than other EGFR-TKIs because of their broad inhibitory profile.10 However, post-hoc analyses from LUX-Lung 3 and LUX-Lung 6 suggest that tolerability-guided dose adjustment of afatinib is an effective measure to reduce treatment-related adverse events, as well as reduce interpa-tient variability of afatinib exposure, without affecting treatment efficacy.41 A more recent study by Yokoyama et al. shows that a low starting dose of afatinib therapy (20 mg daily) with dose modification according to severity of adverse events is a better strategy in treatment-naïve patients who have NSCLC associated with common acti-vating EGFR mutations, both in terms of effectiveness and tolerability, than starting with a standard afatinib dose (40 mg daily).42 In this phase II trial, the PFS was 15.2 months, which was similar to previous reports with the standard 40 mg dose of afatinib, and toxicities were generally mild. Impor-tantly, the low starting dose of afatinib was also effective in high-risk patients with common EGFR M+ NSCLC who had asymptomatic brain metastasis.42

The ARCHER 1050 trial is the first randomized, phase III study that directly compared a second-gen vs. a first-generation EGFR-TKI to demonstrate an OS benefit.43 Although, in contrast to the LUX-Lung 3,22 6,23 and 717 trials, the ARCHER 1050 trial identified a significant improvement in OS with dacomitinib versus gefitinib (median OS: 34.1

v 26.8 months, respectively; HR: 0.76; 95% CI, 0.582 to 0.993; p=0.044), it did not include patients with uncommon mutations or brain metastases.43

ACQUIRED RESISTANCE MECHANISM TO FIRST- OR SECOND-GENERATION EGFR-TKIs The majority of NSCLC patients who harbor EGFR acti-vating mutations show an initial pronounced response to EGFR-TKI treatment, but ultimately acquire resistance to these drugs after approximately 9 to 14 months of therapy.44

The threonine 790 to methionine (T790M) secondary mutation in exon 20 of EGFR is the most common mecha-nism conferring acquired resistance; it is detected in approx-imately 50% of patients treated with first-generation EGFR-TKIs.12 Several other EGFR-dependent and EGFR- independent mechanisms of acquired resistance have been described, including secondary site EGFR mutations (T290M, C797S), mesenchymal-epithelial transition factor (MET) amplification, human receptor tyrosine kinase epidermal growth factor receptor-2 (HER2) amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations or amplification, phos-phatase and tensin homolog (PTEN) loss, mitogen-activated protein kinase (MAPK) pathway activation, BRAF mutation, insulin-like growth factor receptor -1 (IGF-1R), fibroblast growth factor receptor (FGFR) activation, and small cell lung cancer (SCLC) transformation, among others.45-47 It has been proposed that the common T790M resistance mutation reduces the potency of ATP-competitive kinase inhibitors and that irreversible inhibitors could overcome this resistance via covalent binding, rather than an alternative binding mode.48 Amplification of MET occurs in approxi-mately 5% to 20% of patients whereas HER2 amplification is estimated to occur in up to 8% of patients.49 Lineage plasticity, specifically small cell histologic transformation, occurs in 5%–14% of patients with resistance to earlier generation EGFR inhibitors.50,51

Second-generation irreversible EGFR-TKIs were initially designed and developed to delay or overcome T790M- mediated resistance, however evidence from the literature indicates a similar frequency of T790M-mediated resistance in patients receiving first-line treatment with the second-genera-tion EGFR-TKI afatinib.52,53 Despite a delay in the expression of T790M when used in the first-line setting, the T790M mutation is still detected in 36.4% or 47.6% of patients treated with afatinib.52,53 Although preclinical data showed promising results of afatinib against EGFR T790M,54 the clinical trial data was disappointing, showing no OS benefit in patients after failure of platinum doublet chemotherapy and first- generation EGFR-TKIs.55 Notably, T790M is rarely identified in tumors before exposure to EGFR-TKIs concurrently with other more common activating mutations.45

Presently, the clinical efficacy of dacomitinib and osimertinib against uncommon mutations is being evaluated in ongoing phase II trials.56 In addition, an exploratory phase II trial (ZENITH20) with poziotinib, a new pan-HER TKI, in

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NSCLC patients harboring exon 20 insertions failed to reach its primary endpoint in a cohort of 115 patients.57

Patients with wild-type EGFR may present concurrent oncogenic mutations in KRAS proto-oncogene GTPase (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA), and tumour protein p53, resulting in differential clinical features, treatment outcomes and survival prognoses.58 Zhao et al. (2019) showed that patients with the wild-type genes experienced longer PFS times than those with KRAS, TP53, KRAS/TP53 or PIK-3CA/TP53 mutations.58 Moreover, the authors suggest that patients with NSCLC should receive routine KRAS, PIK-3CA and TP53 gene sequencing to determine mutations for the analysis of clinical characteristics and prognosis.58 As men-tioned above, these mutations may be detected as part of the initial mutational spectrum where they mediate primary resistance, but they may also emerge during the course of EGFR-TKI treatment (i.e., secondary resistance)(Figure 3).1

EXTENDING SURVIVAL WITH THIRD-GENERATION EGFR-TKIs IN TREATMENT-NAÏVE NSCLC PATIENTSOsimertinib is an irreversible, third-generation EGFR-TKI that was developed based on its ability to inhibit the T790M resistance mutation and its selectivity for the mutant receptor. Since it also inhibits the common EGFR-activating mutations, namely Del19 and L858R, its role as first-line therapy represents a new milestone for patients with EGFR mutations.9,15

In the recent phase III FLAURA study, median OS was positive for osimertinib compared to older generation EGFR-TKIs in patients with Del19 or L858R EGFR mutated advanced NSCLC (38.6 months versus 31.8 months; HR: 0.80 [95.05% CI: 0.64−1.00]; p=0.046).59 In the first-line setting when compared with gefitinib or erlo-tinib, osimertinib met its primary endpoint showing signif-icant improvement in PFS (10.2 versus 18.9 months, respectively; HR: 0.46; 95% CI: 0.37–0.57; p<0.001)9 and OS (31.8 versus 38.6 months; HR: 0.8, 95% CI: 0.641–0.997; p=0.0462).59 The superior PFS results with osimer-tinib were consistent across common types of EGFR muta-tions, namely Del19 and L858R, and against patients with or without baseline brain metastases. Osimertinib is also highly active against confirmed metastatic or recurrent NSCLC with uncommon activating EGFR mutations, e.g. mutations other than Del19, L858R, T790M and exon 20 insertions; notably, 63% of patients in this study received first-line osimeritinib.60 Taken together these data suggest that osimertinib is more effective and better tolerated than first-generation EGFR-TKIs, and thus osimertinib mono-therapy has emerged as the new standard-of-care for first-line treatment of EGFR mutated NSCLC patients.9,59

Notably, however, FLAURA compared osimertinib with either gefitinib or erlotinib but not with afatinib.61

STRATEGIES TO FURTHER IMPROVE SURVIVAL OUTCOMES FOR NSCLC PATIENTS IN THE FIRST-LINE SETTINGIn addition to monotherapy, EGFR-TKIs in combination with chemotherapy62 or immunotherapy63,64 have shown improvement in PFS in patients with advanced NSCLC harboring EGFR mutations.

One strategy that attempts to decrease the emergence of resistance involves combining cytotoxic chemotherapy with an EGFR-TKI.65,66 A recent study by Noronha et al. (2019) demonstrated that first-line gefitinib combined with peme-trexed and carboplatin chemotherapy significantly improved PFS compared with gefitinib alone (16 months vs. 8 months [95% CI, 7.0 to 9.0 months], respectively; HR for disease progression or death, 0.51 [95% CI, 0.39 to 0.66]; P< 0.001) and OS (not reached v 17 months [95% CI, 13.5 to 20.5 months]; hazard ratio for death, 0.45 [95% CI, 0.31 to 0.65]; P< 0.001), but increased toxicity in patients with NSCLC.68 However, results with the first-generation EGFR-TKI and pemetrexed as first-line treatment for NSCLC does not exceed osimertinib monotherapy in terms of PFS in this set-ting.9,65,67 Moreover, grade ≥3 toxicities occurred in 34% and 51% of patients in the osimertinib trial versus the gefitinib plus chemotherapy trial, respectively.9,67

Results from the randomized phase III RELAY trial showed that in the first-line setting erlotinib in combination with ramucirumab reduces the risk of disease progression or death by over 40% versus erlotinib alone in EGFR-positive NSCLC.68 At a median follow-up of 20.7 months, the median PFS was 19.4 months (95% CI, 15.4–21.6) with the ramucirumab combination compared with 12.4 months (95% CI, 11.0–13.5) with erlotinib alone (HR: 0.591; 95% CI, 0.461–0.760; p<0.0001).68

Bevacizumab is a promising antibody for blocking vascular endothelial growth factor receptor 2 (VEGFR2). It is being evaluated in combination with EGFR-TKI as a first-line treatment for NSCLC in clinical trials.69 Compared with erlotinib alone, bevacizumab plus erlotinib combination therapy improved PFS in patients with EGFR-positive NSCLC. This study is ongoing and further follow-up is required to assess OS and overall efficacy of this combination in the first-line setting.63

TREATING NSCLC PATIENTS WITH UNCOMMON EGFR MUTATIONSUncommon mutations may occur singularly or co-exist with a common or another uncommon EGFR mutation.70

Up to 25% of all EGFR mutation-positive tumors may have uncommon mutations together with a common EGFR mutation within the same tumor.70-72 Moreover, individuals with EGFR co-mutations exhibit shorter PFS and lower response rates than those with single EGFR-mutations.70 The substitution mutations of G719X in exon 18, L861Q in exon 21, S768I in exon 20, and exon 20 insertions are

most prevalent among uncommon mutations described to date.73 Patients with these uncommon substitution muta-tions benefit from first-generation EGFR-TKIs such as erlotinib and gefitinib,75-77 however based on extensive and robust data, afatinib is the preferred agent for the first-line treatment of NSCLC harboring these mutations.71

Afatinib has demonstrated clinical activity against G719X, L861Q and S768I in a post-hoc analysis of the LUX-Lung trials78 as well as in the real-world.71 Of 75/600 (12%) NSCLC patients with uncommon EGFR mutations in a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6 clinical trials, the ORR was 78% with a PFS of 13.8 months for G719X (n=14), 56% with a PFS of 8.2 months for L861Q (n=9), and 100% with a PFS of 14.7 months for S768I (n=8).32 In a recent large, real-world dataset identifying patients with 98 different uncommon mutations, the ORR with afatinib was 60% in EGFR-TKI naïve patients (G719X: 63.4%; L861Q: 59.6%; and S768I: 62.5%) and 25% in EGFR-TKI pretreated patients.68 Seven (6.8%) EGFR-TKI naïve patients in the real-world dataset continued with afatinib treatment for more than three years; this is only marginally lower than reported in clinical trials (10–12%).13 Furthermore, whilst exon 20 insertions are traditionally not considered responsive to EGFR-TKIs based on retrospective analyses77,79,80, analysis of the aforementioned real-world dataset demonstrated that some exon 20 insertions are clinically sensitive to afatinib; analysis of 70 NSCLC patients with exon 20 insertions treated with afatinib showed an ORR of 24.3% with a median duration of response (DoR) of 11.9 months.71

In a preclinical study by Kohsaka et al. (2019), it was shown that afatinib, possibly due to its alternative mechanism of action, reduced the viability of cells expressing numerous compound mutations, including those involving Del19, G719X and/or S768I mutations; only compound mutations involving T790M were considered to be resistant to afatinib.81

SECOND-LINE TREATMENT OPTIONS FOR NSCLC PATIENTS AND THE NEED FOR SENSITIVE T790M DETECTION ASSAYS Osimertinib monotherapy has demonstrated superior activity versus platinum-pemetrexed chemotherapy as sec-ond-line treatment for EGFR T790M M+ NSCLC and is the current standard treatment in this setting.15,82 In addition, afatinib and osimertinib have been shown to inhibit EGFR phosphorylation in cells harboring uncommon secondary resistance mutations.83-86 For patients without EGFR T790M mutations, platinum-based chemotherapy is the currently recommended second-line treatment.87-89

Unlike the emergence of EGFR T790M in response to earlier generation EGFR TKIs, there is no predominant mechanism of resistance to target on progression to osimertinib.49 Hence, there is no established targeted treat-ment following the failure of osimertinib, so it is widely debated whether osimertinib should be reserved for

second-line use following progression with a second- generation EGFR-TKI.90

In the confirmatory phase III AURA 3 trial, osimertinib was superior to platinum-pemetrexed in patients with T790M- positive advanced NSCLC, who had disease progression after first- or second- generation EGFR-TKI therapy.15 The median PFS was 10.1 months in the osimertinib arm and 4.4 months in the platinum-pemetrexed arm (HR: 0.30; 95% CI, 0.23–0.41; p<0.001]. The ORR was significantly better with osimertinib (71%; 95% CI, 65–76) than with platinum-pemetrexed (31%; 95% CI, 24–40) (odds ratio: 5.39; 95% CI, 3.47–8.48; p<0.001). The medianduration of response was 9.7 months (95% CI, 8.3–11.6) with osimertinib and 4.1 months (95% CI, 3.0–5.6) with plat-inum-pemetrexed.15 At data cut-off, the median OS was 26.8 months (95% CI: 23.5, 31.5) versus 2.5 months (95% CI: 20.2, 28.8) respectively (HR=0.87; 95% CI: 0.67, 1.12; p = 0.277); the survival rate at 24 months was 55% versus 43% and at 36 months was 37% versus 30%, respectively.91

In a real-world clinical practice setting, EGFR-TKI-naive patients who received first-line afatinib and went on to develop T790M-positive acquired resistance subsequently received second-line osimertinib.90 At the initial database lock the median time to treatment failure (TTF), the primary outcome, was 27.6 months (90% CI: 25.9–31.3 months).92 Results were also promising in patients with an EGFR Del19 activating mutation (30.3 months) and Asian patients (46.7 months).92 An interim analysis has demon-strated a median OS of 41.3 months (90% CI: 36.8–46.3) overall and 45.7 months (90% CI: 45.3–51.5) in patients with Del19-positive tumors (n=149).93 The 2-year survival was 80% and 82%, respectively, for patients overall and those with Del19 tumors.93

A key challenge of the second line use of osimertinib is to ensure that all patients who develop T790M-driven resistance are identified; this requires re-biopsy, and the wide-spread availability of sensitive T790M detection assays. EGFR mutations can be analyzed in tumor biopsies and in cell-free plasma DNA from blood samples (liquid biopsy).94, 95

Selection of EGFR-mutated NSCLC patients for osimertinib treatment using liquid biopsy supported by tumor tissue analyses in plasma-negative cases may now be the preferred strategy.94,95 Highly sensitive genotyping assays have also been developed to use with liquid biopsy samples, e.g., the droplet digital polymerase chain reaction (ddPCR) can reliably detect mutations with high sensitivity and specificity.94,95 In a recent comparative study, ddPCR was more sensitive than Cobas® EGFR Mutation Test v2 for detecting EGFR T790M mutations in cell-free plasma DNA.95 Notably, in patients who progressed under treatment with an EGFR-TKI, the T790M positivity rate was 66% using ddPCR, but only 24% using Cobas.95 Overall in this real-world setting, 60% of all T790M-positive patients, as assessed by ddPCR and Cobas®, were subsequently treated with osimertinib.95

REVIEW

COMBINATION STRATEGIESStudies with other exploratory second-line treatments are ongoing. For example, activity of EGFR-TKI and anti- EGFR-antibody, chemotherapy96,97 and immunotherapy98 combinations are being explored in the second-line NSCLC setting. Exploratory combinations with immunotherapies such as programmed death ligand-1 (PD-L1) inhibitors have been generally disappointing, i.e., they have failed to demonstrate a clinical benefit, plus they have been limited by the toxicity rates leading in many instances to treatment discontinuation99; only the IMPOWER 150 study, evaluating the combination of carboplatin, paclitaxel and bevacizumab plus or minus the PD-L1 inhibitor, atezolizumab, has shown encouraging results to date.100,101

EGFR inhibition combined with afatinib and the mono-clonal anti-EGFR antibody, cetuximab, showed a beneficial response in resistant tumors harboring the EGFR T790M mutations in a phase Ib clinical trial.102 This trial included advanced EGFR M+ NSCLC patients with acquired resist-ance to erlotinib or gefitinib who were administered afatin-ib plus cetuximab.102 The ORR in the T790M-positive and negative subgroups were comparable (32% versus 25%; p=0.341), while the median duration of response and median PFS were 5.7 and 4.7 months, respectively.102 More-over, afatinib-cetuximab demonstrated a manageable safety profile in this setting.102 Interestingly, triplet therapy, including afatinib, cetuximab, and bevacizumab induced pathological complete remission (CR) repeatedly in lung cancer cells harboring EGFR T790M mutations in vivo.103

Combination strategies with other TKIs such as BRAF, MEK and MET TKIs are also being evaluated. Crizotinib, for example, is a multitargeted MET/ALK/ROS1 inhibitor that is currently used as a MET-inhibitor; notably ALK mutations are found at low frequency in NSCLC (approxi-mately 5%).104 Several case reports have already described the successful use of osimertinib combined with dabrafenib plus trametinib following an acquired BRAF V600E mutation105, 106, or osimertinib combined with crizotinib for EGFR M+ NSCLC with a treatment-emergent MET amplification.107 The TATTON multi-arm phase Ib study is the first trial to report the safety and efficacy of the combination osimertinib plus savolitinib in pretreated EGFR M+, MET amplified NSCLC.108 Response rates up to 67% and a median PFS of up to 11.0 months (depending on mutational profile and preceding therapy) together with an acceptable safety profile were observed.108

Despite the lack of an overall benefit, the randomized phase II trial evaluating the c-MET monoclonal antibody emibetuzum-ab is a landmark trial.109 The trial suggests that the negative prognostic impact of a biomarker (c-MET overexpression) can be completely reversed by a rational, biomarker-driven combi-nation, which turns into a predictive biomarker at the same time.109 An exploratory post-hoc analysis showed an improvement of 15.3 months in median PFS (20.7 with emibetuzumab plus erlotinib versus 5.4 months with erlotinib

[HR 0.39, 90% CI: 0.17 – 0.91]) for the 24 patients with the highest MET expression (MET expression level of 3+ in ≥90% of tumor cells).109

THIRD- AND SUBSEQUENT-LINE TREATMENT OPTIONS Results from a retrospective analysis of subsequent therapy outcomes in patients with common EGFR mutations in LUX-Lung 3,6 and 7 trials supported treatment sequencing with first-line afatinib followed by subsequent therapies, including first-generation EGFR-TKIs and osimertinib (n=37; mostly in the ≥ third-line setting; 10 patients received second-line osimertinib). The median duration of osimertinib therapy in any treatment line was 20.2 months (95% CI: 12.8–31.5). Median PFS on afatinib in 37 patients receiving subsequent osimertinib was 21.9 months; median OS was not reached after a median follow-up of 4.7 years.110 Notably, only a few patients received osimertinib fol-lowing afatinib because the availability of osimertinib at the time these LUX-Lung studies were undertaken was restricted, plus testing for T790M was not required or documented.110

EFFICACY OF EGFR-TKIs IN BRAIN METASTASES AND LEPTOMENINGEAL DISEASEAbout 20–40% of patients with NSCLC develop brain metastases (BM) during the course of their disease and his-torically their prognosis is generally poor.111,112 The median survival of patients with untreated brain metastases is reported to be 1–3 months.113-115 Moreover, approximately one-third of NSCLC patients develop central nervous system (CNS) metastases after acquiring EGFR-TKI resistance.116,117 Despite preclinical data suggesting poor blood-brain-barrier (BBB) penetrance,118 EGFR-TKIs have demonstrated systemic efficacy and CNS activity in patients with BM.119

Studies have shown that EGFR-TKIs, namely afatinib and osimertinib, are able to cross the BBB.119,120 For example, Tamiya et al. (2018) investigated the efficacy of afatinib in a prospective study of 11 patients with EGFR-mutated NSCLC with leptomeningeal carcinomatosis.119 The median cerebrospinal fluid concentration of afatinib in this study was 3.16 ± 1.95 nM.119 This equates to a median concentration of 2.9 nM, which is clearly above the IC50 value for the EGFR (0.5 nM).119,121

The Cambridge Brain Mets Trial 1 (CamBMT1) was the first proof-of-principle trial examining the concentration of afatin-ib in operable BM of patients treated with afatinib for 11 days plus irradiation (2 or 4 Gy) on day 10 prior to resection.122 The phase Ib results of the 10 patients investigated in the phase Ib study showed that in the resected BM, the concentration of afatinib was a median of 405 ng/g, i.e., more than 15 times higher than in the plasma (median 22.7 ng/mL).122 The subsequent phase II study is still ongoing, with data from a total of 60 patients being investigated.122 CNS efficacy has also been demonstrated in several subanalyses of clinical studies.123 For example, in a prespecified subanalysis of the

LUX-LUNG 3 and 6 studies, it was shown that the extent of PFS benefit with afatinib vs. first-line chemotherapy in patients with EGFR-mutated NSCLC was comparable between patients with and without brain metastases.123 In a combined analysis, afatinib significantly prolonged PFS compared to chemotherapy in patients with brain metastases (8.2 versus 5.4 months, respectively; HR: 0.50; p=0.0297).123

Recent additional analyses of the LUX-LUNG 3 and 6 studies have shown that patients with CNS involvement on afatinib had a lower risk of progression in the CNS than patients with progression elsewhere.124 Likewise, the risk of CNS progression de novo under afatinib was low; observed in only 6% of patients without CNS involvement at base-line.124 Data are also available supporting the activity of afatinib in the CNS for pretreated patients with EGFR M+ NSCLC, and with at least two previous lines of EGFR-TKI plus platinum-based chemotherapy.125 Hoffknecht et al. (2015) showed that the median time to treatment failure of 3.6 months was comparable between patients with and without CNS metastases. In addition, cerebral disease control was achieved in 66% of patients with CNS involve-ment.125 This data is also supported by a number of cases from daily clinical practice.126 Hochmair et al. (2016), for example, report on five patients with symptomatic brain metastases in whom a complete remission could be achieved under afatinib, which according to magnetic resonance imaging (MRI) lasted for at least five months and was accompanied by a correspondingly large clinical benefit. 126

Most recently, Gottfried et al. presented data demonstrating the efficacy of afatinib in patients, both Asian and non-Asian, with BM.127 The median time to symptomatic progression (TTSP) was 13.7 months in this combined real-world data analysis, which shows consistency with data from the phase III LUX-Lung 3 and LUX-Lung 6 studies.127

The AURA studies have demonstrated CNS activity of osi-mertinib in pre-specified subgroup analyses of patients with EGFR T790M-positive NSCLC who had progressed while on previous EGFR-TKI treatment.128, 129 Moreover, the consistent CNS efficacy observed across analyses in the FLAURA study, provides strong evidence for the superior CNS efficacy of osimertinib.9

Leptomeningeal disease is another CNS metastatic manifestation involving the leptomeninges and cerebro-spinal fluid (CSF). Among EGFR M+ NSCLC patients, leptomeningeal metastases (LM) occur in approximately 9% of cases, which is double the 3.8% incidence in the overall NSCLC population.130 The prognosis for EGFR M+ NSCLC with LM is very dismal with a median OS rang-ing between 3 and 10 months from the time of diagnosis.131-133

This can be partially explained by the diffuse nature of the disease, making it less accessible for local interventions like surgery or radiotherapy, which are typically applied in emergency situations or only when patients are very symptomatic.134

In the BLOOM phase I trial (n=41) simertinib was evaluated in patients with LM from EGFR-mutated advanced NSCLC whose disease had progressed on previous EGFR-TKI therapy. Yang et al. (2020) reported an ORR of 62% with a median DoR of 15.2 months.135 Osimertinib further led to an improvement of neurological symptoms and CSF clearance in 57% and 28% of the patients, respectively.135 Notably, the median OS of 11.0 months slightly surpassed historical reported results.135

DISCUSSIONThe overall survival benefit observed in the FLAURA trial is an important milestone in EGFR M+ NSCLC. The improved PFS and the OS benefit of > 6 months 9,136 has led to Level I/Grade A recommendations in international guidelines.87,88,137 But does this make osimertinib the standard of care for every patient or just one of many different options? From the subgroup analysis of the FLAURA trial there seems to be no clinical or molecular determinant showing any detrimental outcomes of osimertinib com-pared to first-generation TKIs.136 On the other hand, the observed OS benefits seem to be mainly driven by, or at least more pronounced in, non-Asian patients with EGFR Del19 mutations and WHO performance status 1 plus detectable EGFR mutations in circulating tumor DNA (ctDNA).136 The detection of EGFR genetic alterations in ctDNA seems to be a poor-risk factor at any stage of the disease (shorter PFS when initially detected and shorter OS at relapse).138 Since the OS is not only influenced by the efficacy of the first-line treatment but also by subsequent treatments, it is worth looking at the reported data on factors changing the effectiveness of sequential therapy lines.

There seem to be no obvious differences in the FLAURA trial in terms of patients which received no subsequent sec-ond-line treatment due to death (22% in both arms) or patients alive not receiving any treatment (9% osimertinib arm [n=279] and 8% comparator arm [n=277]).136 The higher rate of patients still on study treatment in the osimertinib arm (22% versus 5%) also explains the lower rate of patients receiving a second-line treatment (48% in the osimertinib versus 65% in comparator arm).136 Second-line treatments mainly consisted of cytotoxic chemotherapy (68%) in the osimertinib arm, while in the comparator arm the majority of patients crossed over to osimertinib (47%) or received another EGFR-TKI (27%).136

Although no data are available to date on the second-line treatment outcomes, the numbers reflect the rate of mutations (approx. 50%) after first-generation TKI therapy, as reported in previous trials.12,44 Third-line therapy was consistent in both arms in terms of frequency (54% osimertinib arm versus 51% comparator arm) and composition.136 It is therefore highly unlikely that the estimated OS benefit is biased by lower subsequent treatment rates or the lack of accessibility to novel treatments.

REVIEW

No conclusions can be drawn for second-generation TKIs like afatinib32 or dacomitinib,43 where improvements in pro-gression-free and overall survival were observed as well. The results of the GioTag database93 and pooled post-hoc analysis of the LUX-LUNG 3,6 and 7 trials110 suggest that the sequence afatinib followed by osimertinib provides excellent outcomes with a median OS of 41.3 months in the GioTag study and an OS that was not reached in LUX-LUNG 3, 6 and 7 after a median follow-up of 4.7 years (Figure 4A).

The crux of the matter is that these analyses also excluded patients with a poor prognosis, i.e., patients without second-line therapy or a EGFR T790M negative progression. Therefore in our opinion, the sequence afatinib followed by osimertinib can only be justified if we can better predict the type of progression and if we have OS data including afatinib patients receiving alternative second-line therapy (e.g., chemotherapy, immunotherapy, chemoimmunotherapy, or no therapy). The issue remains another important and debatable point139, especially when the short PFS of 2.8 months with osimertinib as second-line treatment (AURA trial) is taken into account (Figure 4B).50 Notably, efficacy of second-line chemotherapy seems to be unaffected by the

type of resistance (EGFR T790M negative versus EGFR T790M positive).140

It also remains an open question of how to best integrate immune checkpoint inhibitors into the treatment algorithm of EGFR M+ NSCLC. The IMPOWER 150 phase III trial has shown an impressive OS benefit for the combination of atezolizumab, bevacizumab, carboplatin and paclitaxel in patients with at least one prior TKI treatment.101 However, the US Food and Drug Administration (FDA) label for this active regimen is restricted to patients who have exhausted other FDA-approved therapies.141 According to the European Medicines Agency (EMA) label, the regimen is indicated only after failure of appropriate targeted therapies.142 Since combination trials with osimertinib and durvalumab have been terminated due to severe side effects143, it will be important to answer the question of when immune check-point inhibitors are optimally given, i.e., before or after a third-generation TKI. Although responses to PD-(L)1 monotherapy are generally low, outcomes seem to differ between EGFR Del19 and EGFR L858R NSCLC.144 The lowest response rates (7%) along with a significantly shorter PFS and OS were reported for EGFR Del19.144

Figure 4. A) Overall survival of sequential therapy for afatinib followed by osimertinib in the real-world GioTag study and the combined LUX-LUNG 3, 6 and 7 analysis. Adapted from Hochmair MJ et al. 201990 and Park K et al. 2019110; and B) Theoretical comparison of the overall duration of response with two different EGFR-TKI sequencing paradigms. Adapted from Le T et al. 2019139. Pictured is the sequencing strategy in which the second-generation EGFR-TKI, afatinib, is used in the first line, followed by the later-generation EGFR-TKI osimertinib after progression in the setting of acquired T790M mutation. Pro-gression-free survival (PFS) for first-line afatinib is drawn from the LUX-LUNG 3, 6 and 7 trial data, which compared afatinib to conventional chemotherapy or gefitinib (LUX-LUNG 7) in the first-line setting. The median PFS for osimertinib after progression on afatinib in T790M-positive patients was derived from the GioTag trial. The median PFS for osimertinib and atezolizumab after progression on EGFR-TKIs in T790M-negative patients was derived from the AURA and IMPOWER150 trials, respectively. The lower picture is the sequencing strategy in which the third-generation TKI, osimertinib, was used as a first-line treatment based on the PFS demonstrated in the FLAURA trial followed by atezolizumab based on the PFS demonstrated in the IMPOWER150 trial. This figure illustrates that the superior efficacy of third-generation therapies in the front line may not lead to superior overall survival despite a clearly superior PFS when comparing front-line therapies in isolation.

T790M+

Time (months)

6 12 18 24 30 36 42 48 54

42% maturity

Afatinib followedby osimertinib

Events

Median OS, months(90% CI)

n = 203

41.3(36.8–46.3)

GioTag LUX Lung 3, 6 & 7

Afatinib Osimertinib

Osimertinib

TTF 2 = 15.6 months (GioTag)

PFS = 10.2 months (IMPOWER150)

Atezolizumab + CPB*

PFS = 18.9 months (FLAURA)

*Carboplatin, Paclitaxel & Bevacizumab(Median OS @ 24 months not reached)

TTF 1 & 2 = 27.6 months (GioTag)

AfatinibPFS = 2.8 months (AURA)

PFS = 10.2 months (IMPOWER150)

Atezolizumab + CPB*

Osimertinib

PFS 1 = 11.0 months (LUX Lung 3, 6 & 7)

T790M-

Survival time (months)0

6 12 18 24 30 36 42 48 60 66 7254

Afatinib

Number at riskAfatinib 37 37 37 37 37 37 37 37 37 37 37 36 36 36 35 32 28 25 20 16 12 6 3 1 0

25th59.3

MedianNE

75thNE

Hastings et al. (2019) tried to explain these findings in relation to a lower mutational burden in EGFR Del19 NSCLC, which the authors subsequently observed in this subgroup of patients.144 In-vitro studies also indicate a direct immunosuppressive effect of dendritic cells mediated by exosomes of EGFR Del19 cells.145 Together these results suggest that further stratification of EGFR M+ NSCLC might allow a better patient stratification and selection for immune checkpoint inhibitor treatment.

Whether the use of chemotherapy plus TKI combinations is justified remains another matter of debate. After trials in molecularly unselected patients have failed to demonstrate any benefit, two recent trials have rekindled the discussion.146 Although a study by Noronha et. al. (2019) has shown an PFS and OS benefit, it has been criticized that the PFS (16 months) and OS (not reached after a median follow-up of 17 months) does not exceed the results of the FLAURA trial.147 The fact that only 15% received a third-generation EGFR-TKI was seen as another methodological issue.67

Therefore, the increased toxicities might not be justified when other modern treatment options are available.67 Despite the comparably low rate of third-generation EGFR-TKI treatment (22%), the PFS (20.9 months) and OS (50.9 months) in the NEJ009 phase III trial is unprecedented.66 Whether the infrequent application of third-generation EGFR-TKIs in the above mention trials might be explained by a different mutational spectrum at progression is still an open question. It will be also important to answer if co-mutations or certain mutational profiles will be able to identify patients who are able to obtain an extraordinary benefit through the addition of chemotherapy. In this context the results of the FLAURA 2 trial (NCT04035486) combining osmertinib plus platinum/pemetrexed are highly anticipated.

Finally, treatment beyond progression along with the integration of local interventions like radiotherapy is another important question to be discussed, especially for patients with oligo-progressive disease. An observational study with 577 EGFR M+ patients suggested that treating patients beyond progression does not negatively impact survival.148 Smaller trials and retrospective analyses suggested that radiotherapy (RT) or multi-site stereotactic body radiotherapy (SBRT) is able to induce responses (50% ORR, >80% local DCR) and extend the PFS about 4–10 months, delaying the change of second-line treatment.149-151

The combination of radiotherapy and treatment beyond progression might even extend OS, as suggested in the ret-rospective analysis of 118 patients cohorts from two cohorts from the University of Texas MD Anderson Lung Cancer Moonshot GEMINI and Moffitt Cancer Center lung can-cer databases.152 Furthermore, a randomized phase III trial (n=300, NCT03944772) started to recruit patients in 2019 and will investigate the role of early SBRT (50 – 60 Gy) to the primary tumor.

CONCLUSIONS

The recent advances in EGFR M+ NSCLC and the availa-bility of different treatment options enables physicians to follow a patient-centric treatment approach. Osimertinib is now an option in the first-line setting, and approximately 1 in 4 patients will remain on treatment after 3 years. Approxi-mately 50% of NSCLC patients will, however, require second-line therapy after about 1.5 years with osimertinib; for the majority of cases in the FLAURA trial, cytotoxic chemo-therapy was the second-line treatment. In our opinion, cytotoxic chemotherapy in the second-line setting will most probably be replaced by the quadruple chemoimmunotherapy regimen of the IMPOWER 150 trial. The observed plateau in the survival curves in the NSCLC subpopulation with activating mutations together with the aforementioned benefits are rational arguments that would justify this approach.

If one of the most important treatment goals for NSCLC patients is to delay giving cytotoxic chemotherapy for as long as possible, a second-generation EGFR-TKIs (e.g., afatinib) followed by osimertinib with a median treatment duration of approximately 30 months might be an alterna-tive option. Interestingly, the treatment duration of osim-ertinib as second- or later-line therapy was 20.2 months in the pooled analysis of the LUX-LUNG 3, 6 and 7 tri-als, which is almost identical to the treatment duration when given in the first-line setting. The AURA study highlights that activity of osimertinib in patients with tumors negative for T790M is less favorable than for EGFR T790M+ patients, and chemotherapy seems to be a better choice for these patients. It is likely that question of the best sequence can only be answered, when different EGFR mutations are seen as distinct diseases and additional biomarkers (e.g. c-MET overexpression, co-mutations, loss of EGFR T790M at progression) will be implemented into clinical decision making.

• Optimizing the treatment sequence of first-, second- and third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is important to maximize benefits and prolong resistance for patients with EGFR mutant-positive non-small cell lung cancer (NSCLC).

• Immunotherapy combination regimens, as demon-strated in the IMPOWER 150 trial, are fast emerging as a second- or subsequent-line treatment option for EGFR M+ NSCLC patients.

• Targeted therapy based on individual EGFR mutation profiles (EGFR mutations & co-mutations) has the potential to further improve outcomes and be more cost-effective.

TAKE-HOME MESSAGES

The submission of this review has been supported by Boehringer Ingelheim, while Boehringer Ingelheim has had no influence over the content. Also the authors did not receive any honoraria for writing this review.

REVIEW

1. Skoulidis, F.; Heymach, J. V., Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nature reviews. Cancer 2019, 19 (9), 495-509.2. Kris, M. G.; Johnson, B. E.; Berry, L. D.; Kwiatkow-ski, D. J.; Iafrate, A. J.; Wistuba, I. I.; Varella-Garcia, M.; Franklin, W. A.; Aronson, S. L.; Su, P.-F.; Shyr, Y.; Camidge, D. R.; Sequist, L. V.; Glisson, B. S.; Khuri, F. R.; Garon, E. B.; Pao, W.; Rudin, C.; Schiller, J. H.; Haura, E. B.; Socinski, M. A.; Shirai, K.; Chen, H.-J.; Giaccone, G.; Ladanyi, M.; Kugler, K.; Minna, J. D.; Bunn, P. A., Using Multiplexed Assays of Onco-genic Drivers in Lung Cancers to Select Targeted Drugs. JAMA 2014, 311 (19), 1998-2006.3. Frampton, G. M.; Ali, S. M.; Rosenzweig, M.; Ch-mielecki, J.; Lu, X.; Bauer, T. M.; Akimov, M.; Bu-fill, J. A.; Lee, C.; Jentz, D.; Hoover, R.; Ou, S.-H. I.; Salgia, R.; Brennan, T.; Chalmers, Z. R.; Jaeger, S.; Huang, A.; Elvin, J. A.; Erlich, R.; Fichtenholtz, A.; Gowen, K. A.; Greenbowe, J.; Johnson, A.; Khaira, D.; McMahon, C.; Sanford, E. M.; Roels, S.; White, J. L.; Greshock, J.; Schlegel, R.; Lipson, D.; Yelensky, R.; Morosini, D.; Ross, J. S.; Collisson, E.; Peters, M.; Ste-phens, P. J.; Miller, V. A., Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov 2015, 5 (8), 850-859.4. Jordan, E. J.; Kim, H. R.; Arcila, M. E.; Barron, D.; Chakravarty, D.; Gao, J. J.; Chang, M. T.; Ni, A.; Kundra, R.; Jonsson, P.; Jayakumaran, G.; Gao, S. P.; Johnsen, H. C.; Hanrahan, A. J.; Zehir, A.; Rekhtman, N.; Ginsberg, M. S.; Li, B. T.; Yu, H. A.; Paik, P. K.; Drilon, A.; Hellmann, M. D.; Reales, D. N.; Benayed, R.; Rusch, V. W.; Kris, M. G.; Chaft, J. E.; Baselga, J.; Taylor, B. S.; Schultz, N.; Rudin, C. M.; Hyman, D. M.; Berger, M. F.; Solit, D. B.; Ladanyi, M.; Riely, G. J., Prospective Comprehensive Molecular Character-ization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies. Cancer Discov 2017, 7 (6), 596-609.5. Hynes, N. E.; Lane, H. A., ERBB receptors and can-cer: the complexity of targeted inhibitors. Nature re-views. Cancer 2005, 5 (5), 341-354.6. Campbell, J. D.; Lathan, C.; Sholl, L.; Ducar, M.; Vega, M.; Sunkavalli, A.; Lin, L.; Hanna, M.; Schubert, L.; Thorner, A.; Faris, N.; Williams, D. R.; Osarogiag-bon, R. U.; van Hummelen, P.; Meyerson, M.; Mac-Conaill, L., Comparison of Prevalence and Types of Mutations in Lung Cancers Among Black and White Populations. JAMA Oncology 2017, 3 (6), 801-809.7. Rosell, R.; Moran, T.; Queralt, C.; Porta, R.; Carde-nal, F.; Camps, C.; Majem, M.; Lopez-Vivanco, G.; Isla, D.; Provencio, M.; Insa, A.; Massuti, B.; Gonza-lez-Larriba, J. L.; Paz-Ares, L.; Bover, I.; Garcia-Cam-pelo, R.; Moreno, M. A.; Catot, S.; Rolfo, C.; Reguart, N.; Palmero, R.; Sánchez, J. M.; Bastus, R.; Mayo, C.; Bertran-Alamillo, J.; Molina, M. A.; Sanchez, J. J.; Taron, M., Screening for Epidermal Growth Factor Re-ceptor Mutations in Lung Cancer. New England Journal of Medicine 2009, 361 (10), 958-967.8. Du, Z.; Lovly, C. M., Mechanisms of receptor tyro-sine kinase activation in cancer. Molecular Cancer 2018, 17 (1), 58.9. Soria, J. C.; Ohe, Y.; Vansteenkiste, J.; Reungwet-wattana, T.; Chewaskulyong, B.; Lee, K. H.; Decha-phunkul, A.; Imamura, F.; Nogami, N.; Kurata, T.; Okamoto, I.; Zhou, C.; Cho, B. C.; Cheng, Y.; Cho, E. K.; Voon, P. J.; Planchard, D.; Su, W. C.; Gray, J. E.; Lee, S. M.; Hodge, R.; Marotti, M.; Rukazenkov, Y.; Ramalingam, S. S., Osimertinib in Untreated EG-FR-Mutated Advanced Non-Small-Cell Lung Cancer. The New England journal of medicine 2018, 378 (2), 113-125.10. Girard, N., Optimizing outcomes and treatment se-quences in EGFR mutation-positive non-small-cell lung cancer: recent updates. Future Oncology 2019, 15 (25), 2983-2997.11. Cheng, X.; Chen, H.-J., Tumor heterogeneity and resistance to EGFR-targeted therapy in advanced nons-mall cell lung cancer: challenges and perspectives. Onco Targets Ther 2014, 7, 1689-1704.12. Kobayashi, S.; Boggon, T. J.; Dayaram, T.; Janne, P. A.; Kocher, O.; Meyerson, M.; Johnson, B. E.; Eck, M. J.; Tenen, D. G.; Halmos, B., EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. The New England journal of medicine 2005, 352 (8), 786-92.13. Schuler, M.; Paz-Ares, L.; Sequist, L. V.; Hirsh, V.; Lee, K. H.; Wu, Y.-L.; Lu, S.; Zhou, C.; Feng, J.; Ellis, S. H.; Samuelsen, C. H.; Tang, W.; Märten, A.; Ehrnrooth, E.; Park, K.; Yang, J. C.-H., First-line afatinib for advanced EGFR m+ NSCLC: Analysis of long-term responders in the LUX-Lung 3, 6, and 7 trials. Lung Cancer 2019, 133, 10-19.14. Wu, Y. L.; Cheng, Y.; Zhou, X.; Lee, K. H.; Na-kagawa, K.; Niho, S.; Tsuji, F.; Linke, R.; Rosell, R.; Corral, J.; Migliorino, M. R.; Pluzanski, A.; Sbar, E. I.; Wang, T.; White, J. L.; Nadanaciva, S.; Sandin, R.; Mok, T. S., Dacomitinib versus gefitinib as first-line

treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a ran-domised, open-label, phase 3 trial. The Lancet. Oncology 2017, 18 (11), 1454-1466.15. Mok, T. S.; Wu, Y. L.; Ahn, M. J.; Garassino, M. C.; Kim, H. R.; Ramalingam, S. S.; Shepherd, F. A.; He, Y.; Akamatsu, H.; Theelen, W. S.; Lee, C. K.; Sebas-tian, M.; Templeton, A.; Mann, H.; Marotti, M.; Ghi-orghiu, S.; Papadimitrakopoulou, V. A., Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer. The New England journal of medicine 2017, 376 (7), 629-640.16. Felip, E.; Gridelli, C.; Baas, P.; Rosell, R.; Stahel, R., Metastatic non-small-cell lung cancer: consensus on pathology and molecular tests, first-line, second-line, and third-line therapy: 1st ESMO Consensus Confer-ence in Lung Cancer; Lugano 2010. Annals of oncology : official journal of the European Society for Medical Oncol-ogy 2011, 22 (7), 1507-19.17. Park, K.; Tan, E. H.; O’Byrne, K.; Zhang, L.; Boy-er, M.; Mok, T.; Hirsh, V.; Yang, J. C.; Lee, K. H.; Lu, S.; Shi, Y.; Kim, S. W.; Laskin, J.; Kim, D. W.; Arvis, C. D.; Kolbeck, K.; Laurie, S. A.; Tsai, C. M.; Shahidi, M.; Kim, M.; Massey, D.; Zazulina, V.; Paz-Ares, L., Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, ran-domised controlled trial. The Lancet. Oncology 2016, 17 (5), 577-89.18. Maemondo, M.; Inoue, A.; Kobayashi, K.; Suga-wara, S.; Oizumi, S.; Isobe, H.; Gemma, A.; Harada, M.; Yoshizawa, H.; Kinoshita, I.; Fujita, Y.; Okinaga, S.; Hirano, H.; Yoshimori, K.; Harada, T.; Ogura, T.; Ando, M.; Miyazawa, H.; Tanaka, T.; Saijo, Y.; Hagiwara, K.; Morita, S.; Nukiwa, T., Gefitinib or che-motherapy for non-small-cell lung cancer with mutated EGFR. The New England journal of medicine 2010, 362 (25), 2380-8.19. Mitsudomi, T.; Morita, S.; Yatabe, Y.; Negoro, S.; Okamoto, I.; Tsurutani, J.; Seto, T.; Satouchi, M.; Tada, H.; Hirashima, T.; Asami, K.; Katakami, N.; Takada, M.; Yoshioka, H.; Shibata, K.; Kudoh, S.; Shimizu, E.; Saito, H.; Toyooka, S.; Nakagawa, K.; Fukuoka, M., Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJ-TOG3405): an open label, randomised phase 3 trial. The Lancet. Oncology 2010, 11 (2), 121-8.20. Zhou, C.; Wu, Y. L.; Chen, G.; Feng, J.; Liu, X. Q.; Wang, C.; Zhang, S.; Wang, J.; Zhou, S.; Ren, S.; Lu, S.; Zhang, L.; Hu, C.; Hu, C.; Luo, Y.; Chen, L.; Ye, M.; Huang, J.; Zhi, X.; Zhang, Y.; Xiu, Q.; Ma, J.; Zhang, L.; You, C., Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTI-MAL, CTONG-0802): a multicentre, open-label, ran-domised, phase 3 study. The Lancet. Oncology 2011, 12 (8), 735-42.21. Rosell, R.; Carcereny, E.; Gervais, R.; Vergnenegre, A.; Massuti, B.; Felip, E.; Palmero, R.; Garcia-Gomez, R.; Pallares, C.; Sanchez, J. M.; Porta, R.; Cobo, M.; Garrido, P.; Longo, F.; Moran, T.; Insa, A.; De Ma-rinis, F.; Corre, R.; Bover, I.; Illiano, A.; Dansin, E.; de Castro, J.; Milella, M.; Reguart, N.; Altavilla, G.; Jimenez, U.; Provencio, M.; Moreno, M. A.; Terrasa, J.; Munoz-Langa, J.; Valdivia, J.; Isla, D.; Domine, M.; Molinier, O.; Mazieres, J.; Baize, N.; Garcia-Campelo, R.; Robinet, G.; Rodriguez-Abreu, D.; Lopez-Vivan-co, G.; Gebbia, V.; Ferrera-Delgado, L.; Bombaron, P.; Bernabe, R.; Bearz, A.; Artal, A.; Cortesi, E.; Rolfo, C.; Sanchez-Ronco, M.; Drozdowskyj, A.; Queralt, C.; de Aguirre, I.; Ramirez, J. L.; Sanchez, J. J.; Mo-lina, M. A.; Taron, M.; Paz-Ares, L., Erlotinib versus standard chemotherapy as first-line treatment for Euro-pean patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. The Lancet. Oncol-ogy 2012, 13 (3), 239-46.22. Sequist, L. V.; Yang, J. C.; Yamamoto, N.; O’Byrne, K.; Hirsh, V.; Mok, T.; Geater, S. L.; Orlov, S.; Tsai, C. M.; Boyer, M.; Su, W. C.; Bennouna, J.; Kato, T.; Gor-bunova, V.; Lee, K. H.; Shah, R.; Massey, D.; Zazulina, V.; Shahidi, M.; Schuler, M., Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013, 31 (27), 3327-34.23. Wu, Y. L.; Zhou, C.; Hu, C. P.; Feng, J.; Lu, S.; Huang, Y.; Li, W.; Hou, M.; Shi, J. H.; Lee, K. Y.; Xu, C. R.; Massey, D.; Kim, M.; Shi, Y.; Geater, S. L., Afati-nib versus cisplatin plus gemcitabine for first-line treat-ment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. The Lancet. Oncology 2014, 15 (2), 213-22.24. Wu, Y. L.; Zhou, C.; Liam, C. K.; Wu, G.; Liu, X.; Zhong, Z.; Lu, S.; Cheng, Y.; Han, B.; Chen, L.;

Huang, C.; Qin, S.; Zhu, Y.; Pan, H.; Liang, H.; Li, E.; Jiang, G.; How, S. H.; Fernando, M. C.; Zhang, Y.; Xia, F.; Zuo, Y., First-line erlotinib versus gemcit-abine/cisplatin in patients with advanced EGFR muta-tion-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study. Annals of oncology : official journal of the European Soci-ety for Medical Oncology 2015, 26 (9), 1883-9.25. Berry, D. K.; Wang, X.; Michalski, S. T.; Kang, H. C.; Yang, S.; Creelan, B. C.; McLeod, H. L.; Hicks, J. K., Clinical Cohort Analysis of Germline EGFR T790M Demonstrates Penetrance Across Ethnicities and Races, Sexes, and Ages. JCO Precision Oncology 2020, (4), 170-175.26. Centeno, I.; Blay, P.; Santamaría, I.; Astudillo, A.; Pitiot, A. S.; Osorio, F. G.; González-Arriaga, P.; Igle-sias, F.; Menéndez, P.; Tardón, A.; Freije, J. M.; Balbín, M., Germ-line mutations in epidermal growth factor receptor (EGFR) are rare but may contribute to onco-genesis: a novel germ-line mutation in EGFR detected in a patient with lung adenocarcinoma. BMC cancer 2011, 11, 172-172.27. Lynch, T. J.; Bell, D. W.; Sordella, R.; Gurubhaga-vatula, S.; Okimoto, R. A.; Brannigan, B. W.; Harris, P. L.; Haserlat, S. M.; Supko, J. G.; Haluska, F. G.; Louis, D. N.; Christiani, D. C.; Settleman, J.; Haber, D. A., Activating mutations in the epidermal growth factor re-ceptor underlying responsiveness of non-small-cell lung cancer to gefitinib. The New England journal of medicine 2004, 350 (21), 2129-39.28. Paez, J. G.; Janne, P. A.; Lee, J. C.; Tracy, S.; Greu-lich, H.; Gabriel, S.; Herman, P.; Kaye, F. J.; Linde-man, N.; Boggon, T. J.; Naoki, K.; Sasaki, H.; Fujii, Y.; Eck, M. J.; Sellers, W. R.; Johnson, B. E.; Meyerson, M., EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science (New York, N.Y.) 2004, 304 (5676), 1497-500.29. Pao, W.; Miller, V.; Zakowski, M.; Doherty, J.; Politi, K.; Sarkaria, I.; Singh, B.; Heelan, R.; Rusch, V.; Fulton, L.; Mardis, E.; Kupfer, D.; Wilson, R.; Kris, M.; Varmus, H., EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and er-lotinib. Proceedings of the National Academy of Sciences of the United States of America 2004, 101 (36), 13306-11.30. Kobayashi, Y.; Togashi, Y.; Yatabe, Y.; Mizuuchi, H.; Jangchul, P.; Kondo, C.; Shimoji, M.; Sato, K.; Suda, K.; Tomizawa, K.; Takemoto, T.; Hida, T.; Nishio, K.; Mitsudomi, T., EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs. Clinical cancer re-search : an official journal of the American Association for Cancer Research 2015, 21 (23), 5305-13.31. Mok, T. S.; Wu, Y. L.; Thongprasert, S.; Yang, C. H.; Chu, D. T.; Saijo, N.; Sunpaweravong, P.; Han, B.; Margono, B.; Ichinose, Y.; Nishiwaki, Y.; Ohe, Y.; Yang, J. J.; Chewaskulyong, B.; Jiang, H.; Duffield, E. L.; Watkins, C. L.; Armour, A. A.; Fukuoka, M., Gefi-tinib or carboplatin-paclitaxel in pulmonary adenocar-cinoma. The New England journal of medicine 2009, 361 (10), 947-57.32. Yang, J. C.-H.; Wu, Y.-L.; Schuler, M.; Sebastian, M.; Popat, S.; Yamamoto, N.; Zhou, C.; Hu, C.-P.; O’Byrne, K.; Feng, J.; Lu, S.; Huang, Y.; Geater, S. L.; Lee, K. Y.; Tsai, C.-M.; Gorbunova, V.; Hirsh, V.; Bennouna, J.; Orlov, S.; Mok, T.; Boyer, M.; Su, W.-C.; Lee, K. H.; Kato, T.; Massey, D.; Shahidi, M.; Za-zulina, V.; Sequist, L. V., Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adeno-carcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 tri-als. The Lancet Oncology 2015, 16 (2), 141-151.33. Rotow, J. K.; Bivona, T. G., Understanding and targeting resistance mechanisms in NSCLC. Nature Reviews Cancer 2017, 17 (11), 637-658.34. van Veggel, B.; Madeira R Santos, J. F. V.; Hashemi, S. M. S.; Paats, M. S.; Monkhorst, K.; Heideman, D. A. M.; Groves, M.; Radonic, T.; Smit, E. F.; Schuuring, E.; van der Wekken, A. J.; de Langen, A. J., Osimertinib treatment for patients with EGFR exon 20 mutation positive non-small cell lung cancer. Lung Cancer 2020, 141, 9-13.35. Janne, P. A.; Neal, J. W.; Camidge, D. R.; Spira, A. I.; Piotrowska, Z.; Horn, L.; Costa, D. B.; Tsao, A. S.; Patel, J. D.; Gadgeel, S. M.; Bazhenova, L.; Zhu, V. W.; West, H.; Vincent, S.; Zhu, J.; Li, S.; Riely, G. J., Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions. Journal of Clinical Oncology 2019, 37 (15_suppl), 9007-9007.36. Study of JNJ-61186372, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer. https://clinicaltrials.gov/ct2/show/NCT02609776 (accessed 16th March 2020). 37. Arceci, R. J., Somatic CEBPA Mutations Are a Fre-quent Second Event in Families With Germline CEBPA Mutations and Familial Acute Myeloid Leukemia. Year-

323232

book of Oncology 2009, 2009, 116-117.38. Kim, Y. H.; Lee, B.; Shim, J. H.; Lee, S.-H.; Park, W.-Y.; Choi, Y.-L.; Sun, J.-M.; Ahn, J. S.; Ahn, M.-J.; Park, K., Con-current Genetic Alterations Predict the Progression to Target Therapy in EGFR-Mutated Advanced NSCLC. Journal of Thoracic Oncology 2019, 14 (2), 193-202. 39. Roeper, J.; Falk, M.; Chalaris-Rißmann, A.; Lu-eers, A. C.; Ramdani, H.; Wedeken, K.; Stropiep, U.; Diehl, L.; Tiemann, M.; Heukamp, L. C.; Ot-to-Sobotka, F.; Griesinger, F., TP53 co-mutations in EGFR mutated patients in NSCLC stage IV: A strong predictive factor of ORR, PFS and OS in EGFR mt+ NSCLC. Oncotarget 2020, 11 (3). 40. Paz-Ares, L.; Tan, E. H.; O’Byrne, K.; Zhang, L.; Hirsh, V.; Boyer, M.; Yang, J. C. H.; Mok, T.; Lee, K. H.; Lu, S.; Shi, Y.; Lee, D. H.; Laskin, J.; Kim, D. W.; Lau-rie, S. A.; Kölbeck, K.; Fan, J.; Dodd, N.; Märten, A.; Park, K., Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial. Annals of oncology : official journal of the Europe-an Society for Medical Oncology 2017, 28 (2), 270-277. 41. Yang, J. C.-H.; Sequist, L. V.; Zhou, C.; Schuler, M.; Geater, S. L.; Mok, T.; Hu, C.-P.; Yamamoto, N.; Feng, J.; O’Byrne, K.; Lu, S.; Hirsh, V.; Huang, Y.; Sebastian, M.; Okamoto, I.; Dickgreber, N.; Shah, R.; Märten, A.; Massey, D.; Wind, S.; Wu, Y.-L., Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: post hoc analyses of the randomized LUX-Lung 3 and 6 trials. Annals of Oncology 2016, 27 (11), 2103-2110. 42. Yokoyama, T.; Yoshioka, H.; Fujimoto, D.; Demu-ra, Y.; Hirano, K.; Kawai, T.; Kagami, R.; Washio, Y.; Ishida, T.; Kogo, M.; Tomii, K.; Okuno, T.; Akai, M.; Hirabayashi, M.; Nishimura, T.; Nakahara, Y.; Kim, Y. H.; Miyakoshi, C.; Yoshimura, K.; Hirai, T., A phase II study of low starting dose of afatinib as first-line treatment in patients with <em>EGFR</em> mutation-positive non-small-cell lung cancer (KTORG1402). Lung Cancer 2019, 135, 175-180. 43. Mok, T. S.; Cheng, Y.; Zhou, X.; Lee, K. H.; Na-kagawa, K.; Niho, S.; Lee, M.; Linke, R.; Rosell, R.; Corral, J.; Migliorino, M. R.; Pluzanski, A.; Sbar, E. I.; Wang, T.; White, J. L.; Wu, Y. L., Improvement in Overall Survival in a Randomized Study That Com-pared Dacomitinib With Gefitinib in Patients With Advanced Non-Small-Cell Lung Cancer and EGFR-Ac-tivating Mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018, 36 (22), 2244-2250.44. Takeda, M.; Nakagawa, K., First- and Second-Gen-eration EGFR-TKIs Are All Replaced to Osimertinib in Chemo-Naive EGFR Mutation-Positive Non-Small Cell Lung Cancer? Int J Mol Sci 2019, 20 (1), 146.45. Morgillo, F.; Della Corte, C. M.; Fasano, M.; Ciar-diello, F., Mechanisms of resistance to EGFR-targeted drugs: lung cancer. ESMO open 2016, 1 (3), e000060.46. Engelman, J. A.; Zejnullahu, K.; Mitsudomi, T.; Song, Y.; Hyland, C.; Park, J. O.; Lindeman, N.; Gale, C. M.; Zhao, X.; Christensen, J.; Kosaka, T.; Holmes, A. J.; Rogers, A. M.; Cappuzzo, F.; Mok, T.; Lee, C.; Johnson, B. E.; Cantley, L. C.; Janne, P. A., MET am-plification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, N.Y.) 2007, 316 (5827), 1039-43.47. Lavacchi, D.; Mazzoni, F.; Giaccone, G., Clinical evaluation of dacomitinib for the treatment of met-astatic non-small cell lung cancer (NSCLC): current perspectives. Drug Des Devel Ther 2019, 13, 3187-3198.48. Yun, C. H.; Mengwasser, K. E.; Toms, A. V.; Woo, M. S.; Greulich, H.; Wong, K. K.; Meyerson, M.; Eck, M. J., The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proceedings of the National Academy of Sciences of the United States of America 2008, 105 (6), 2070-5.49. Schoenfeld, A. J.; Yu, H. A., The Evolving Landscape of Resistance to Osimertinib. Journal of Thoracic Oncolo-gy 2020, 15 (1), 18-21.50. Jänne, P. A.; Yang, J. C. h.; Kim, D. W.; Planchard, D.; Ohe, Y.; Ramalingam, S. S.; Ahn, M. J.; Kim, S. W.; Su, W. C.; Horn, L.; Haggstrom, D.; Felip, E.; Kim, J.-H.; Frewer, P.; Cantarini, M.; Brown, K. H.; Dick-inson, P. A.; Ghiorghiu, S.; Ranson, M., AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Can-cer. New England Journal of Medicine 2015, 372 (18), 1689-1699.51. Yu, H. A.; Arcila, M. E.; Rekhtman, N.; Sima, C. S.; Zakowski, M. F.; Pao, W.; Kris, M. G.; Miller, V. A.; Ladanyi, M.; Riely, G. J., Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clinical cancer research : an official journal of the American As-sociation for Cancer Research 2013, 19 (8), 2240-2247.52. Campo, M.; Gerber, D.; Gainor, J. F.; Heist, R. S.; Temel, J. S.; Shaw, A. T.; Fidias, P.; Muzikansky, A.; Engelman, J. A.; Sequist, L. V., Acquired Resistance to First-Line Afatinib and the Challenges of Prearranged

Progression Biopsies. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2016, 11 (11), 2022-2026.53. Wu, S. G.; Liu, Y. N.; Tsai, M. F.; Chang, Y. L.; Yu, C. J.; Yang, P. C.; Yang, J. C.; Wen, Y. F.; Shih, J. Y., The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcino-ma patients. Oncotarget 2016, 7 (11), 12404-13.54. Li, D.; Ambrogio, L.; Shimamura, T.; Kubo, S.; Takahashi, M.; Chirieac, L. R.; Padera, R. F.; Shap-iro, G. I.; Baum, A.; Himmelsbach, F.; Rettig, W. J.; Meyerson, M.; Solca, F.; Greulich, H.; Wong, K. K., BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Onco-gene 2008, 27 (34), 4702-11.55. Miller, V. A.; Hirsh, V.; Cadranel, J.; Chen, Y. M.; Park, K.; Kim, S. W.; Zhou, C.; Su, W. C.; Wang, M.; Sun, Y.; Heo, D. S.; Crino, L.; Tan, E. H.; Chao, T. Y.; Shahidi, M.; Cong, X. J.; Lorence, R. M.; Yang, J. C., Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of er-lotinib, gefitinib, or both, and one or two lines of che-motherapy (LUX-Lung 1): a phase 2b/3 randomised trial. The Lancet. Oncology 2012, 13 (5), 528-38.56. Ahn, M.-J.; Cho, J. H.; Sun, J. M.; Lee, S.-H.; Ahn, S. H.; Park, K.; Park, K. U.; Kang, E. J.; Choi, Y. H.; Kim, K. H.; An, H. J.; Lee, H. W., An open-label, mul-ticenter, phase II single arm trial of osimertinib in non-small cell lung cancer patients with uncommon EGFR mutation (KCSG-LU15-09). Journal of Clinical Oncol-ogy 2018, 36 (15_suppl), 9050-9050.57. Precision Oncology News Spectrum’s Poziotinib Failed to Meet Primary Phase II Trial Endpoint. https://www.precisiononcologynews.com/drug-discovery-de-velopment/spectrums-poziotinib-failed-meet-primary-phase-ii-trial-endpoint#.XlkQEss3aVM (accessed 28th February).58. Zhao, J.; Han, Y.; Li, J.; Chai, R.; Bai, C., Prog-nostic value of KRAS/TP53/PIK3CA in non-small cell lung cancer. Oncol Lett 2019, 17 (3), 3233-3240.59. Ramalingam, S. S.; Gray, J. E.; Ohe, Y.; Cho, B. C.; Vansteenkiste, J.; Zhou, C.; Reungwetwattana, T.; Cheng, Y.; Chewaskulyong, B.; Shah, R.; Lee, K. H.; Cheema, P.; Tiseo, M.; John, T.; Lin, M. C.; Imamura, F.; Hodge, R.; Rukazenkov, Y.; Soria, J.-C.; Planchard, D., LBA5_PROsimertinib vs comparator EGFR-TKI as first-line treatment for EGFRm advanced NSCLC (FLAURA): Final overall survival analysis. Annals of Oncology 2019, 30 (Supplement_5).60. Cho, J. H.; Sun, J.; Lee, S.; Ahn, J. S.; Park, K.; Park, K. U.; Kang, E. J.; Choi, Y. H.; Kim, K. H.; An, H. J. A.; Lee, H. W.; Ahn, M., OA10.05 An Open-La-bel, Multicenter, Phase II Single Arm Trial of Osimerti-nib in NSCLC Patients with Uncommon EGFR Mu-tation(KCSG-LU15-09). Journal of Thoracic Oncology 2018, 13 (10), S344.61. NICE TA 621: Osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer. https://www.nice.org.uk/guidance/ta621/resources/osimerti-nib-for-untreated-egfr-mutationpositive-nonsmall-cell-lung-cancer-pdf-82609012217797 (accessed 29th January).62. Nakamura, A.; Inoue, A.; Morita, S.; Hosomi, Y.; Kato, T.; Fukuhara, T.; Gemma, A.; Takahashi, K.; Fujita, Y.; Harada, M.; Minato, K.; Takamura, K.; Kobayashi, K.; Nukiwa, T., Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for un-treated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). Journal of Clinical Oncology 2018, 36 (15_suppl), 9005-9005.63. Saito, H.; Fukuhara, T.; Furuya, N.; Watanabe, K.; Sugawara, S.; Iwasawa, S.; Tsunezuka, Y.; Yamaguchi, O.; Okada, M.; Yoshimori, K.; Nakachi, I.; Gemma, A.; Azuma, K.; Kurimoto, F.; Tsubata, Y.; Fujita, Y.; Nagashima, H.; Asai, G.; Watanabe, S.; Miyazaki, M.; Hagiwara, K.; Nukiwa, T.; Morita, S.; Kobayashi, K.; Maemondo, M., Erlotinib plus bevacizumab versus er-lotinib alone in patients with EGFR-positive advanced non-squamous non-small-cell lung cancer (NEJ026): interim analysis of an open-label, randomised, multi-centre, phase 3 trial. The Lancet. Oncology 2019, 20 (5), 625-635.64. Seto, T.; Kato, T.; Nishio, M.; Goto, K.; Atagi, S.; Hosomi, Y.; Yamamoto, N.; Hida, T.; Maemondo, M.; Nakagawa, K.; Nagase, S.; Okamoto, I.; Yamanaka, T.; Tajima, K.; Harada, R.; Fukuoka, M.; Yamamoto, N., Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations ( JO25567): an open-label, randomised, multicentre, phase 2 study. The Lancet. Oncology 2014, 15 (11), 1236-44.65. Noronha, V.; Patil, V. M.; Joshi, A.; Menon, N.; Chougule, A.; Mahajan, A.; Janu, A.; Purandare, N.; Kumar, R.; More, S.; Goud, S.; Kadam, N.; Daware, N.; Bhattacharjee, A.; Shah, S.; Yadav, A.; Trivedi, V.;

Behel, V.; Dutt, A.; Banavali, S. D.; Prabhash, K., Gefi-tinib Versus Gefitinib Plus Pemetrexed and Carboplatin Chemotherapy in EGFR-Mutated Lung Cancer. Journal of Clinical Oncology 2019, 38 (2), 124-136.66. Hosomi, Y.; Morita, S.; Sugawara, S.; Kato, T.; Fukuhara, T.; Gemma, A.; Takahashi, K.; Fujita, Y.; Harada, T.; Minato, K.; Takamura, K.; Hagiwara, K.; Kobayashi, K.; Nukiwa, T.; Inoue, A., Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non–Small-Cell Lung Cancer With Mutated Epidermal Growth Factor Receptor: NEJ009 Study. Journal of Clinical On-cology 2019, 38 (2), 115-123.67. Tanaka, T.; Ishiki, H.; Kubo, E.; Yokota, S.; Shi-mizu, M.; Kiuchi, D.; Satomi, E., Is Gefitinib Com-bined With Platinum-Doublet Chemotherapy a Coun-terpart to Osimertinib Monotherapy in Advanced EGFR-Mutated Non-Small-Cell Lung Cancer in the First-Line Setting? Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2020, JCO1902509-JCO1902509.68. Nakagawa, K.; Garon, E. B.; Seto, T.; Nishio, M.; Ponce Aix, S.; Paz-Ares, L.; Chiu, C.-H.; Park, K.; No-vello, S.; Nadal, E.; Imamura, F.; Yoh, K.; Shih, J.-Y.; Au, K. H.; Moro-Sibilot, D.; Enatsu, S.; Zimmermann, A.; Frimodt-Moller, B.; Visseren-Grul, C.; Reck, M.; Investigators, R. S., Ramucirumab plus erlotinib in pa-tients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, dou-ble-blind, placebo-controlled, phase 3 trial. The Lancet. Oncology 2019, 20 (12), 1655-1669.69. Gentzler, R. D.; Yentz, S. E.; Patel, J. D., Bevacizum-ab in advanced NSCLC: chemotherapy partners and duration of use. Current treatment options in oncology 2013, 14 (4), 595-609.70. Kim, E. Y.; Cho, E. N.; Park, H. S.; Hong, J. Y.; Lim, S. H.; Youn, J. P.; Hwang, S. Y.; Chang, Y. S., Compound EGFR mutation is frequently detected with co-mutations of actionable genes and associated with poor clinical outcome in lung adenocarcinoma. Cancer Biol Ther 2016, 17 (3), 237-245.71. Chih-Hsin Yang, J.; Schuler, M.; Popat, S.; Miura, S.; Heeke, S.; Park, K.; Märten, A.; Kim, E. S., Afati-nib for the Treatment of Non-Small Cell Lung Cancer Harboring Uncommon EGFR Mutations: A Database of 693 Cases. Journal of thoracic oncology : official pub-lication of the International Association for the Study of Lung Cancer 2020, S1556-0864(20)30014-9.72. Kohsaka, S.; Nagano, M.; Ueno, T.; Suehara, Y.; Hayashi, T.; Shimada, N.; Takahashi, K.; Suzuki, K.; Takamochi, K.; Takahashi, F.; Mano, H., A method of high-throughput functional evaluation of EGFR gene variants of unknown significance in cancer. Sci Transl Med 2017, 9 (416), eaan6566.73. Barnet, M. B.; O’Toole, S.; Horvath, L. G.; Se-linger, C.; Yu, B.; Ng, C. C.; Boyer, M.; Cooper, W. A.; Kao, S., EGFR-Co-Mutated Advanced NSCLC and Response to EGFR Tyrosine Kinase Inhibitors. Journal of thoracic oncology : official publication of the Interna-tional Association for the Study of Lung Cancer 2017, 12 (3), 585-590.74. Shen, Y.-C.; Tseng, G.-C.; Tu, C.-Y.; Chen, W.-C.; Liao, W.-C.; Chen, W.-C.; Li, C.-H.; Chen, H.-J.; Hsia, T.-C., Comparing the effects of afatinib with gefitinib or Erlotinib in patients with advanced-stage lung adenocarcinoma harboring non-classical epidermal growth factor receptor mutations. Lung Cancer 2017, 110, 56-62.75. Zhang, Y.; Wang, Z.; Hao, X.; Hu, X.; Wang, H.; Wang, Y.; Ying, J., Clinical characteristics and response to tyrosine kinase inhibitors of patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations. Chin J Cancer Res 2017, 29 (1), 18-24.76. Shi, J. H.; Yang, H.; Jiang, T.; Li, X.; Zhao, C.; Zhang, L.; Zhao, S.; Liu, X.; Jia, Y.; Wang, Y.; Xi, L.; Zhang, S.; Su, C.; Ren, S.; Zhou, C., Uncommon EGFR mutations in a cohort of Chinese NSCLC pa-tients and outcomes of first-line EGFR-TKIs and plat-inum-based chemotherapy. Chin J Cancer Res 2017, 29 (6), 543-552.77. Xu, J.; Jin, B.; Chu, T.; Dong, X.; Yang, H.; Zhang, Y.; Wu, D.; Lou, Y.; Zhang, X.; Wang, H.; Han, B., EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC) harbor-ing uncommon EGFR mutations: A real-world study in China. Lung cancer (Amsterdam, Netherlands) 2016, 96, 87-92.78. Yang, J. C.; Sequist, L. V.; Geater, S. L.; Tsai, C. M.; Mok, T. S.; Schuler, M.; Yamamoto, N.; Yu, C. J.; Ou, S. H.; Zhou, C.; Massey, D.; Zazulina, V.; Wu, Y. L., Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncom-mon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6. The Lan-cet. Oncology 2015, 16 (7), 830-8.79. Wu, J.-Y.; Yu, C.-J.; Chang, Y.-C.; Yang, C.-H.; Shih, J.-Y.; Yang, P.-C., Effectiveness of Tyrosine Kinase

Inhibitors on “Uncommon” Epidermal Growth Factor Receptor Mutations of Unknown Clinical Significance in Non–Small Cell Lung Cancer. Clinical Cancer Re-search 2011, 17 (11), 3812-3821.80. Kuiper, J. L.; Hashemi, S. M. S.; Thunnissen, E.; Snijders, P. J. F.; Grünberg, K.; Bloemena, E.; Sie, D.; Postmus, P. E.; Heideman, D. A. M.; Smit, E. F., Non-classic EGFR mutations in a cohort of Dutch EG-FR-mutated NSCLC patients and outcomes following EGFR-TKI treatment. Br J Cancer 2016, 115 (12), 1504-1512.81. Kohsaka, S.; Petronczki, M.; Solca, F.; Maemon-do, M., Tumor clonality and resistance mechanisms in EGFR mutation-positive non-small-cell lung cancer: implications for therapeutic sequencing. Future Oncol 2019, 15 (6), 637-652.82. Yang, J. C.-H.; Ahn, M.-J.; Kim, D.-W.; Ramalin-gam, S. S.; Sequist, L. V.; Su, W.-C.; Kim, S.-W.; Kim, J.-H.; Planchard, D.; Felip, E.; Blackhall, F.; Hagg-strom, D.; Yoh, K.; Novello, S.; Gold, K.; Hirashima, T.; Lin, C.-C.; Mann, H.; Cantarini, M.; Ghiorghiu, S.; Jänne, P. A., Osimertinib in Pretreated T790M-Pos-itive Advanced Non-Small-Cell Lung Cancer: AURA Study Phase II Extension Component. Journal of clin-ical oncology : official journal of the American Society of Clinical Oncology 2017, 35 (12), 1288-1296.83. Costa, D.; Kobayashi, S.; Halmos, B.; Schumer, S.; Huberman, M.; Kumar, A.; Boggon, T. J.; Tenen, D. G., Bim mediates EGFR tyrosine kinase inhibitor induced apoptosis in non-small cell lung cancers and is linked to the resistance conferred by secondary EGFR mutations, T790M and the novel L747S. Cancer Research 2007, 67 (9 Supplement), LB-61-LB-61.84. Bean, J.; Riely, G. J.; Balak, M.; Marks, J. L.; Ladanyi, M.; Miller, V. A.; Pao, W., Acquired resistance to epidermal growth factor receptor kinase inhibitors as-sociated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clinical cancer re-search : an official journal of the American Association for Cancer Research 2008, 14 (22), 7519-7525.85. Chiba, M.; Togashi, Y.; Bannno, E.; Kobayashi, Y.; Nakamura, Y.; Hayashi, H.; Terashima, M.; De Velasco, M. A.; Sakai, K.; Fujita, Y.; Mitsudomi, T.; Nishio, K., Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A. BMC Cancer 2017, 17 (1), 281-281.86. Balak, M. N.; Gong, Y.; Riely, G. J.; Somwar, R.; Li, A. R.; Zakowski, M. F.; Chiang, A.; Yang, G.; Ouerfelli, O.; Kris, M. G.; Ladanyi, M.; Miller, V. A.; Pao, W., Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to ki-nase inhibitors. Clinical cancer research : an official jour-nal of the American Association for Cancer Research 2006, 12 (21), 6494-6501.87. Wu, Y. L.; Planchard, D.; Lu, S.; Sun, H.; Yama-moto, N.; Kim, D. W.; Tan, D. S. W.; Yang, J. C. H.; Azrif, M.; Mitsudomi, T.; Park, K.; Soo, R. A.; Chang, J. W. C.; Alip, A.; Peters, S.; Douillard, J. Y., Pan-Asian adapted Clinical Practice Guidelines for the manage-ment of patients with metastatic non-small-cell lung cancer: a CSCO-ESMO initiative endorsed by JSMO, KSMO, MOS, SSO and TOS. Annals of oncology : offi-cial journal of the European Society for Medical Oncology 2019, 30 (2), 171-210.88. Planchard, D.; Popat, S.; Kerr, K.; Novello, S.; Smit, E. F.; Faivre-Finn, C.; Mok, T. S.; Reck, M.; Van Schil, P. E.; Hellmann, M. D.; Peters, S.; Committee, E. G., Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology 2018, 29 (Suppl 4), iv192-iv237.89. Hanna, N.; Johnson, D.; Temin, S.; Baker, S., Jr.; Brahmer, J. R.; Ellis, P. M.; Giaccone, G.; Hesketh, P. l. J.; Jaiyesimi, I.; Leighl, N. B.; Riely, G. J.; Schiller, J. H.; Schneider, B. J.; Smith, T. J.; Tashbar, J.; Biermann, W. A.; Masters, G., Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of clinical oncology : official journal of the American Soci-ety of Clinical Oncology 2017, 35 (30), 3484-3515.90. Hochmair, M. J.; Morabito, A.; Hao, D.; Yang, C.-T.; Soo, R. A.; Yang, J. C. H.; Gucalp, R.; Halmos, B.; Wang, L.; Märten, A.; Cufer, T., Sequential afatinib and osimertinib in patients with EGFR mutation-posi-tive non-small-cell lung cancer: updated analysis of the observational GioTag study. Future Oncol 2019, 15 (25), 2905-2914.91. Wu, Y.-L.; Mok, T. S. K.; Han, J.-Y.; Ahn, M.-J.; Delmonte, A.; Ramalingam, S. S.; Kim, S.-W.; Shep-herd, F. A.; Laskin, J.; He, Y.; Akamatsu, H.; Theel-en, W. S. M. E.; Su, W.-C.; John, T.; Sebastian, M.; Mann, H.; Miranda, M.; Laus, G.; Rukazenkov, Y.; Papadimitrakopoulou, V., 475OOverall survival (OS) from the AURA3 phase III study: Osimertinib vs

platinum-pemetrexed (plt-pem) in patients (pts) with EGFR T790M advanced non-small cell lung cancer (NSCLC) and progression on a prior EGFR-tyrosine kinase inhibitor (TKI). Annals of Oncology 2019, 30 (Supplement_9).92. Hochmair, M. J.; Morabito, A.; Hao, D.; Yang, C. H.; Soo, R. A.; Yang, C. H.; Gucalp, R.; Halmos, B.; Wang, C.; Golembesky, A.; Märten, A.; Cufer, T., Se-quential treatment with afatinib and osimertinib in pa-tients with EGFR mutation-positive non-small-cell lung cancer: an observational study. Future Oncology 2018, 14 (27), 2861-2874.93. Hochmair, M. J.; Morabito, A.; Hao, D.; Yang, C. H.; Soo, R. A.; Yang, C. H.; Gucalp, R.; Halmos, B.; Wang, L.; Märten, A.; Cufer, T., Sequential afatinib and osimertinib in patients with EGFR mutation-pos-itive non-small-cell lung cancer: updated analysis of the observational GioTag study. Future Oncology 2019, 15 (25), 2905-2914.94. Hochmair, M. J.; Buder, A.; Schwab, S.; Burghu-ber, O. C.; Prosch, H.; Hilbe, W.; Cseh, A.; Fritz, R.; Filipits, M., Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afa-tinib Treatment in Patients with Advanced EGFR Mu-tation-Positive NSCLC, and Subsequent Response to Osimertinib. Target Oncol 2019, 14 (1), 75-83.95. Buder, A.; Setinek, U.; Hochmair, M. J.; Schwab, S.; Kirchbacher, K.; Keck, A.; Burghuber, O. C.; Pirk-er, R.; Filipits, M., EGFR Mutations in Cell-free Plasma DNA from Patients with Advanced Lung Adenocarci-noma: Improved Detection by Droplet Digital PCR. Target Oncol 2019, 14 (2), 197-203.96. Mok, T. S. K.; Kim, S. W.; Wu, Y. L.; Nakagawa, K.; Yang, J. J.; Ahn, M. J.; Wang, J.; Yang, J. C. H.; Lu, Y.; Atagi, S.; Ponce, S.; Shi, X.; Rukazenkov, Y.; Haddad, V.; Thress, K. S.; Soria, J. C., Gefitinib Plus Chemother-apy Versus Chemotherapy in Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer Resistant to First-Line Gefitinib (IMPRESS): Overall Survival and Biomarker Analyses. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2017, 35 (36), 4027-4034.97. Soria, J. C.; Wu, Y. L.; Nakagawa, K.; Kim, S. W.; Yang, J. J.; Ahn, M. J.; Wang, J.; Yang, J. C. H.; Lu, Y.; Atagi, S.; Ponce, S.; Lee, D. H.; Liu, Y. N.; Yoh, K.; Zhou, J. Y.; Shi, X.; Webster, A.; Jiang, H.; Mok, T. S. K., Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. The Lancet. Oncology 2015, 16 (8), 990-998.98. Gettinger, S.; Hellmann, M. D.; Chow, L. Q. M.; Borghaei, H.; Antonia, S.; Brahmer, J. R.; Goldman, J. W.; Gerber, D. E.; Juergens, R. A.; Shepherd, F. A.; Laurie, S. A.; Young, T. C.; Li, X.; Geese, W. J.; Rizvi, N., Nivolumab Plus Erlotinib in Patients With EGFR-Mutant Advanced NSCLC. Journal of Thoracic Oncology 2018, 13 (9), 1363-1372.99. Velez, M. A.; Burns, T. F., Is the game over for PD-1 inhibitors in EGFR mutant non-small cell lung cancer? Translational Lung Cancer Research 2019, S339-S342.100. Socinski, M. A.; Jotte, R. M.; Cappuzzo, F.; Orlandi, F.; Stroyakovskiy, D.; Nogami, N.; Rodrí-guez-Abreu, D.; Moro-Sibilot, D.; Thomas, C. A.; Barlesi, F.; Finley, G.; Kelsch, C.; Lee, A.; Coleman, S.; Deng, Y.; Shen, Y. C.; Kowanetz, M.; Lopez-Chavez, A.; Sandler, A.; Reck, M.; Group, I. M. S., Atezolizum-ab for First-Line Treatment of Metastatic Nonsquamous NSCLC. The New England journal of medicine 2018, 378 (24), 2288-2301.101. Reck, M.; Mok, T. S. K.; Nishio, M.; Jotte, R. M.; Cappuzzo, F.; Orlandi, F.; Stroyakovskiy, D.; Nogami, N.; Rodríguez-Abreu, D.; Moro-Sibilot, D.; Thomas, C. A.; Barlesi, F.; Finley, G.; Lee, A.; Coleman, S.; Deng, Y.; Kowanetz, M.; Shankar, G.; Lin, W.; So-cinski, M. A.; Group, I. M. S., Atezolizumab plus bevaci-zumab and chemotherapy in non-small-cell lung cancer (IMpower150): key subgroup analyses of patients with EGFR mutations or baseline liver metastases in a ran-domised, open-label phase 3 trial. Lancet Respir Med 2019, 7 (5), 387-401.102. Janjigian, Y. Y.; Smit, E. F.; Groen, H. J. M.; Horn, L.; Gettinger, S.; Camidge, D. R.; Riely, G. J.; Wang, B.; Fu, Y.; Chand, V. K.; Miller, V. A.; Pao, W., Dual inhibition of EGFR with afatinib and cetuximab in ki-nase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov 2014, 4 (9), 1036-1045.103. Kudo, K.; Ohashi, K.; Makimoto, G.; Higo, H.; Kato, Y.; Kayatani, H.; Kurata, Y.; Takami, Y.; Min-ami, D.; Ninomiya, T.; Kubo, T.; Ichihara, E.; Sato, A.; Hotta, K.; Yoshino, T.; Tanimoto, M.; Kiura, K., Triplet therapy with afatinib, cetuximab, and bevaci-zumab induces deep remission in lung cancer cells har-boring EGFR T790M in vivo. Mol Oncol 2017, 11 (6), 670-681.104. Soda, M.; Choi, Y. L.; Enomoto, M.; Takada, S.;

Yamashita, Y.; Ishikawa, S.; Fujiwara, S.; Watanabe, H.; Kurashina, K.; Hatanaka, H.; Bando, M.; Ohno, S.; Ishikawa, Y.; Aburatani, H.; Niki, T.; Sohara, Y.; Sugi-yama, Y.; Mano, H., Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007, 448 (7153), 561-566.105. Zhou, F.; Zhao, W.; Chen, X.; Zhang, J.; Zhou, C., Response to the combination of dabrafenib, trame-tinib and osimertinib in a patient with EGFR-mutant NSCLC harboring an acquired BRAF V600E muta-tion. Lung Cancer 2020, 139, 219-220.106. Huang, Y.; Gan, J.; Guo, K.; Deng, Y.; Fang, W., Acquired BRAF V600E Mutation Mediated Resistance to Osimertinib and Responded to Osimertinib, Dab-rafenib, and Trametinib Combination Therapy. Journal of Thoracic Oncology 2019, 14 (10), e236-e237.107. Zhu, V. W.; Schrock, A. B.; Ali, S. M.; Ou, S.-H. I., Differential response to a combination of full-dose osimertinib and crizotinib in a patient with EGFR-mu-tant non-small cell lung cancer and emergent MET am-plification. Lung Cancer (Auckl) 2019, 10, 21-26.108. Han, J. Y.; Sequist, L. V.; Ahn, M. J.; Cho, B. C.; Yu, H.; Kim, S. W.; Yang, J. C. H.; Lee, J. S.; Su, W. C.; Kowalski, D.; Orlov, S.; Cantarini, M.; Verheijen, R. B.; Mellemgaard, A.; Frewer, P.; Ou, X.; Oxnard, G., TATTON expansion cohorts: A phase Ib study of osimertinib plus savolitinib in patients (pts) with EG-FR-mutant, MET-positive NSCLC following disease progression on a prior EGFR-TKI. Annals of Oncology 2019, 30, ix196-ix197.109. Scagliotti, G.; Moro-Sibilot, D.; Kollmeier, J.; Favaretto, A.; Cho, E. K.; Grosch, H.; Kimmich, M.; Girard, N.; Tsai, C.-M.; Hsia, T.-C.; Brighenti, M.; Schumann, C.; Wang, X. A.; Wijayawardana, S. R.; Gruver, A. M.; Wallin, J.; Mansouri, K.; Wacheck, V.; Chang, G.-C., A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Com-bination with Erlotinib as First-Line Treatment for <em>EGFR</em> Mutation–Positive NS-CLC Patients. Journal of Thoracic Oncology 2020, 15 (1), 80-90.110. Park, K.; Bennouna, J.; Boyer, M.; Hida, T.; Hirsh, V.; Kato, T.; Lu, S.; Mok, T.; Nakagawa, K.; O’Byrne, K.; Paz-Ares, L.; Schuler, M.; Sibilot, D. M.; Tan, E. H.; Tanaka, H.; Wu, Y. L.; Yang, J. C. H.; Zhang, L.; Zhou, C.; Märten, A.; Tang, W.; Yamamo-to, N., Sequencing of therapy following first-line afati-nib in patients with EGFR mutation-positive non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 2019, 132, 126-131.111. Villarreal-Garza, C.; de la Mata, D.; Zavala, D. G.; Macedo-Perez, E. O.; Arrieta, O., Aggressive treat-ment of primary tumor in patients with non-small-cell lung cancer and exclusively brain metastases. Clin Lung Cancer 2013, 14 (1), 6-13.112. Socinski, M. A.; Evans, T.; Gettinger, S.; Hensing, T. A.; VanDam Sequist, L.; Ireland, B.; Stinchcombe, T. E., Treatment of stage IV non-small cell lung can-cer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013, 143 (5 Suppl), e341S-e368S.113. Louie, A. V.; Rodrigues, G.; Yaremko, B.; Yu, E.; Dar, A. R.; Dingle, B.; Vincent, M.; Sanatani, M.; Younus, J.; Malthaner, R.; Inculet, R., Management and Prognosis in Synchronous Solitary Resected Brain Me-tastasis from Non–Small-Cell Lung Cancer. Clin Lung Cancer 2009, 10 (3), 174-179.114. Penel, N.; Brichet, A.; Prevost, B.; Duhamel, A.; Assaker, R.; Dubois, F.; Lafitte, J. J., Pronostic factors of synchronous brain metastases from lung cancer. Lung cancer (Amsterdam, Netherlands) 2001, 33 (2-3), 143-154.115. Flannery, T. W.; Suntharalingam, M.; Kwok, Y.; Koffman, B. H.; Amin, P. P.; Chin, L. S.; Nicol, B.; Fowler, Z.; Young, A. B.; Regine, W. F., Gamma knife stereotactic radiosurgery for synchronous versus meta-chronous solitary brain metastases from non-small cell lung cancer. Lung cancer (Amsterdam, Netherlands) 2003, 42 (3), 327-333.116. Omuro, A. M. P.; Kris, M. G.; Miller, V. A.; Franceschi, E.; Shah, N.; Milton, D. T.; Abrey, L. E., High incidence of disease recurrence in the brain and leptomeninges in patients with nonsmall cell lung carci-noma after response to gefitinib. Cancer 2005, 103 (11), 2344-2348.117. Eichler, A. F.; Kahle, K. T.; Wang, D. L.; Joshi, V. A.; Willers, H.; Engelman, J. A.; Lynch, T. J.; Sequist, L. V., EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro Oncol 2010, 12 (11), 1193-1199.118. Ballard, P.; Yates, J. W. T.; Yang, Z.; Kim, D. W.; Yang, J. C. H.; Cantarini, M.; Pickup, K.; Jordan, A.; Hickey, M.; Grist, M.; Box, M.; Johnström, P.; Varnäs, K.; Malmquist, J.; Thress, K. S.; Jänne, P. A.; Cross, D., Preclinical Comparison of Osimertinib with Other EG-FR-TKIs in EGFR-Mutant NSCLC Brain Metastases

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Models, and Early Evidence of Clinical Brain Metasta-ses Activity. Clinical cancer research : an official journal of the American Association for Cancer Research 2016, 22 (20), 5130-5140.119. Tamiya, A.; Tamiya, M.; Nishihara, T.; Shiroya-ma, T.; Nakao, K.; Tsuji, T.; Takeuchi, N.; Isa, S. I.; Omachi, N.; Okamoto, N.; Suzuki, H.; Okishio, K.; Iwazaki, A.; Imai, K.; Hirashima, T.; Atagi, S., Cerebro-spinal Fluid Penetration Rate and Efficacy of Afatinib in Patients with EGFR Mutation-positive Non-small Cell Lung Cancer with Leptomeningeal Carcinomatosis: A Multicenter Prospective Study. Anticancer Res 2017, 37 (8), 4177-4182.120. Wang, J.; Kim, D. W.; Kim, S. W., Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study. ASCO Meeting Abstracts 2016, 34.121. Solca, F.; Dahl, G.; Zoephel, A.; Bader, G.; Sand-erson, M.; Klein, C.; Kraemer, O.; Himmelsbach, F.; Haaksma, E.; Adolf, G. R., Target binding properties and cellular activity of afatinib (BIBW 2992), an ir-reversible ErbB family blocker. J Pharmacol Exp Ther 2012, 343 (2), 342-350.122. Baird, R.; Garcia-Corbacho, J.; Linossi, C.; Smith, D.; Williams, M.; Machin, A.; Ahmad, S.; Matys, T.; Jena, R.; Pacey, S.; Jefferies, S.; Price, S. In Cambridge Brain Mets Trial 1 (CamBMT1): A proof of principle study of afatinib penetration into cerebral metas-tases (mets) for patients (pts) undergoing neurosurgical resection, combined with low-dose, targeted radiotherapy (RT)—Phase 1b results. Oral presentation, ASCO, Chi-cago, Illinois, Chicago, Illinois, 2017.123. Schuler, M.; Wu, Y. L.; Hirsh, V.; O’Byrne, K.; Yamamoto, N.; Mok, T.; Popat, S.; Sequist, L. V.; Massey, D.; Zazulina, V.; Yang, J. C. H., First-Line Afa-tinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2016, 11 (3), 380-390.124. Girard, N., Optimizing outcomes in EGFR muta-tion-positive NSCLC: which tyrosine kinase inhibitor and when? Future Oncol 2018, 14 (11), 1117-1132.125. Hoffknecht, P.; Tufman, A.; Wehler, T.; Pelzer, T.; Wiewrodt, R.; Schütz, M.; Serke, M.; Stöhlmach-er-Williams, J.; Märten, A.; Maria Huber, R.; Dick-greber, N. J.; Afatinib Compassionate Use, C., Efficacy of the irreversible ErbB family blocker afatinib in epi-dermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal dis-ease. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2015, 10 (1), 156-163.126. Hochmair, M. J.; Holzer, S.; Burghuber, O. C., Complete remissions in afatinib-treated non-small-cell lung cancer patients with symptomatic brain metastases. Anticancer Drugs 2016, 27 (9), 914-915.127. Gottfried, M.; de Marinis, F.; Tu, H.; Laktion-ov, K. K.; Feng, J.; Poltoratskiy, A.; Zhao, J.; Tan, E.-H.; Lee, V.; Kowalski, D.; Yang, C.-T.; Srinivasa, B.; Passaro, A.; Clementi, L.; Tang, W.; Huang, D. C.-L.; Cseh, A.; Park, K.; Zhou, C.; Wu, Y.-L., 484PActivity of afatinib in patients (pts) with EGFR mutation-posi-tive (EGFRm+) NSCLC and baseline brain metastases: Pooled analysis of three large phase IIIb trials. Annals of Oncology 2019, 30 (Supplement_9).128. Goss, G.; Tsai, C. M.; Shepherd, F. A.; Ahn, M. J.; Bazhenova, L.; Crinò, L.; de Marinis, F.; Felip, E.; Morabito, A.; Hodge, R.; Cantarini, M.; Johnson, M.; Mitsudomi, T.; Jänne, P. A.; Yang, J. C. H., CNS re-sponse to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials. Annals of oncology : official journal of the European Soci-ety for Medical Oncology 2018, 29 (3), 687-693.129. Wu, Y. L.; Ahn, M.; Garassino, M. C.; Han, J.; Katakami, N.; Kim, H. R.; Hodge, R.; Kaur, P.; Brown, A.; Ghiorghiu, D.; Papadimitrakopoulou, V. A.; Mok, T. S. K., CNS Efficacy of Osimertinib in Pa-tients With T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3). Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2018, 36 (26), 2702-2709.130. Remon, J.; Le Rhun, E.; Besse, B., Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era. Cancer Treatment Reviews 2017, 53, 128-137.131. Li, Y. S.; Jiang, B.-Y.; Yang, J.-J.; Tu, H.-Y.; Zhou, Q.; Guo, W.-B.; Yan, H.-H.; Wu, Y.-L., Leptomenin-geal Metastases in Patients with NSCLC with EGFR Mutations. Journal of Thoracic Oncology 2016, 11 (11), 1962-1969.132. Kuiper, J. L.; Hendriks, L. E.; van der Wekken, A.

J.; de Langen, A. J.; Bahce, I.; Thunnissen, E.; Heide-man, D. A. M.; Berk, Y.; Buijs, E. J. M.; Speel, E.-J. M.; Krouwels, F. H.; Smit, H. J. M.; Groen, H. J. M.; Ding-emans, A.-M. C.; Smit, E. F., Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: A retrospective cohort analysis. Lung cancer (Amsterdam, Netherlands) 2015, 89 (3), 255-261.133. Liao, B.-C.; Lee, J.-H.; Lin, C.-C.; Chen, Y.-F.; Chang, C.-H.; Ho, C.-C.; Shih, J.-Y.; Yu, C.-J.; Yang, J. C.-H., Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non-Small-Cell Lung Cancer Pa-tients with Leptomeningeal Carcinomatosis. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2015, 10 (12), 1754-1761.134. Cheng, H.; Perez-Soler, R., Leptomeningeal me-tastases in non-small-cell lung cancer. The Lancet Oncol-ogy 2018, 19 (1), e43-e55.135. Yang, J. C. H.; Kim, S.-W.; Kim, D.-W.; Lee, J.-S.; Cho, B. C.; Ahn, J.-S.; Lee, D. H.; Kim, T. M.; Gold-man, J. W.; Natale, R. B.; Brown, A. P.; Collins, B.; Chmielecki, J.; Vishwanathan, K.; Mendoza-Naranjo, A.; Ahn, M.-J., Osimertinib in Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study. Journal of clinical oncology : official jour-nal of the American Society of Clinical Oncology 2020, 38 (6), 538-547.136. Ramalingam, S. S.; Vansteenkiste, J.; Planchard, D.; Cho, B. C.; Gray, J. E.; Ohe, Y.; Zhou, C.; Reun-gwetwattana, T.; Cheng, Y.; Chewaskulyong, B.; Shah, R.; Cobo, M.; Lee, K. H.; Cheema, P.; Tiseo, M.; John, T.; Lin, M.-C.; Imamura, F.; Kurata, T.; Todd, A.; Hodge, R.; Saggese, M.; Rukazenkov, Y.; Soria, J.-C., Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. New England Jour-nal of Medicine 2019, 382 (1), 41-50.137. National Comprehensive Cancer Network (NCCN) Clinical practice guidelines in oncology: NCCN guidelines for non-small cell lung cancer V7. https://www.nccn.org (accessed 24th February).138. Molina-Vila, M.-A.; Stahel, R. A.; Dafni, U.; Jordana-Ariza, N.; Balada-Bel, A.; Garzón-Ibáñez, M.; García-Peláez, B.; Mayo-de-las-Casas, C.; Felip, E.; Curioni Fontecedro, A.; Gautschi, O.; Peters, S.; Massutí, B.; Palmero, R.; Ponce Aix, S.; Carcereny, E.; Früh, M.; Pless, M.; Popat, S.; Cuffe, S.; Bidoli, P.; Kammler, R.; Roschitzki-Voser, H.; Tsourti, Z.; Kara-chaliou, N.; Rosell, R., Evolution and Clinical Impact of EGFR Mutations in Circulating Free DNA in the BELIEF Trial. Journal of Thoracic Oncology 2020, 15 (3), 416-425.139. Le, T.; Gerber, D. E., Newer-Generation EGFR Inhibitors in Lung Cancer: How Are They Best Used? Cancers (Basel) 2019, 11 (3), 366.140. Yoshida, T.; Kuroda, H.; Oya, Y.; Shimizu, J.; Horio, Y.; Sakao, Y.; Hida, T.; Yatabe, Y., Clinical out-comes of platinum-based chemotherapy according to T790M mutation status in EGFR-positive non-small cell lung cancer patients after initial EGFR-TKI failure. Lung Cancer 2017, 109, 89-91.141. FDA TECENTRIQ (atezolizumab) prescribing information. https://www.accessdata.fda.gov/drugsatf-da_docs/label/2018/761034s009lbl.pdf (accessed 24th February).142. EMA TECENTRIQ - Summary of Product Char-acteristics. https://www.ema.europa.eu/en/documents/product-information/tecentriq-epar-product-informa-tion_en.pdf (accessed 24 February).143. Yang, J. C.-H.; Shepherd, F. A.; Kim, D.-W.; Lee, G.-W.; Lee, J. S.; Chang, G.-C.; Lee, S. S.; Wei, Y.-F.; Lee, Y. G.; Laus, G.; Collins, B.; Pisetzky, F.; Horn, L., Osimertinib Plus Durvalumab versus Osimertinib Monotherapy in EGFR T790M-Positive NSCLC fol-lowing Previous EGFR TKI Therapy: CAURAL Brief Report. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2019, 14 (5), 933-939.144. Hastings, K.; Yu, H. A.; Wei, W.; Sanchez-Vega, F.; DeVeaux, M.; Choi, J.; Rizvi, H.; Lisberg, A.; Tru-ini, A.; Lydon, C. A.; Liu, Z.; Henick, B. S.; Wurtz, A.; Cai, G.; Plodkowski, A. J.; Long, N. M.; Halpenny, D. F.; Killam, J.; Oliva, I.; Schultz, N.; Riely, G. J.; Arcila, M. E.; Ladanyi, M.; Zelterman, D.; Herbst, R. S.; Goldberg, S. B.; Awad, M. M.; Garon, E. B.; Get-tinger, S.; Hellmann, M. D.; Politi, K., EGFR mutation subtypes and response to immune checkpoint blockade treatment in non-small-cell lung cancer. Annals of oncol-ogy : official journal of the European Society for Medical Oncology 2019, 30 (8), 1311-1320.145. Yu, S.; Sha, H.; Qin, X.; Chen, Y. M.; Li, X.; Shi, M.; Feng, J., EGFR E746-A750 deletion in lung cancer represses antitumor immunity through the exo-some-mediated inhibition of dendritic cells. Oncogene 2020, 10.1038/s41388-020-1182-y.

146. Rotow, J. K.; Jänne, P. A., What’s Old Is New Again: Revisiting Up-Front Chemotherapy in EG-FR-Mutated Non–Small-Cell Lung Cancer. Journal of Clinical Oncology 2020, 38 (2), 107-110.147. Noronha, V.; Joshi, A.; Patil, V. M.; Chougule, A.; Mahajan, A.; Janu, A.; Purandare, N.; Kumar, R.; More, S.; Goud, S.; Kadam, N.; Daware, N.; Shah, S.; Yadav, A.; Dutt, A.; Trivedi, V.; Behel, V.; Banavali, S. D.; Prabhash, K., Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin che-motherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C). Jour-nal of Clinical Oncology 2019, 37 (15_suppl), 9001-9001.148. Goto, Y.; Tanai, C.; Yoh, K.; Hosomi, Y.; Sakai, H.; Kato, T.; Kaburagi, T.; Nishio, M.; Kim, Y. H.; Inoue, A.; Hasegawa, Y.; Isobe, H.; Tomizawa, Y.; Mori, Y.; Minato, K.; Yamada, K.; Ohashi, Y.; Kuni-toh, H., Continuing EGFR-TKI beyond radiological progression in patients with advanced or recurrent, EGFR mutation-positive non-small-cell lung can-cer: an observational study. ESMO open 2017, 2 (4), e000214-e000214.149. Basler, L.; Kroeze, S. G. C.; Guckenberger, M., SBRT for oligoprogressive oncogene addicted NSCLC. Lung cancer (Amsterdam, Netherlands) 2017, 106, 50-57.150. Wang, Y.; Li, Y.; Xia, L.; Niu, K.; Chen, X.; Lu, D.; Kong, R.; Chen, Z.; Sun, J., Continued EGFR-TKI with concurrent radiotherapy to improve time to pro-gression (TTP) in patients with locally progressive non-small cell lung cancer (NSCLC) after front-line EGFR-TKI treatment. Clin Transl Oncol 2018, 20 (3), 366-373.151. Kim, C.; Hoang, C. D.; Kesarwala, A. H.; Schrump, D. S.; Guha, U.; Rajan, A., Role of Local Ab-lative Therapy in Patients with Oligometastatic and Oli-goprogressive Non-Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 2017, 12 (2), 179-193.152. Le, X.; Puri, S.; Negrao, M. V.; Nilsson, M. B.; Robichaux, J. P.; Boyle, T.; Hicks, J. K.; Lovinger, K. L.; Roarty, E.; Rinsurongkawong, W.; Tang, M.; Sun, H.; Elamin, Y. Y.; Lacerda, L. C.; Lewis, J.; Roth, J. A.; Swisher, S. G.; Lee, J. J.; William, W. N., Jr.; Glisson, B. S.; Zhang, J.; Papadimitrakopoulou, V. A.; Gray, J. E.; Heymach, J. V., Landscape of EGFR-Dependent and -Independent Resistance Mechanisms to Osimertinib and Continuation Therapy Beyond Progression in EG-FR-Mutant NSCLC. Clinical cancer research : an official journal of the American Association for Cancer Research 2018, 24 (24), 6195-6203.153. Shah, R.; Lester, J. F., Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer: A Clash of the Generations. Clin Lung Cancer 2019.154. Hsu, P. C.; Jablons, M. D.; Yang, C. H.; You, L., Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC). Int J Mol Sci 2019, 20 (15).

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