REVIEW For reprint orders, please contact: [email protected]

Common EGFR-mutated subgroups (Del19/L858R) in advanced non-small-cell lung cancer: chasing better outcomes with tyrosine kinase inhibitors Noemi Reguart*,‡,1 & Jordi Remon‡,2 ABSTRACT Ten years ago, somatic mutations in EGFR were identified in patients with non-small-cell lung cancer. Demonstration of the antitumor efficacy of EGF receptordirected tyrosine kinase inhibitors resulted in their approval for the treatment of advanced non-small-cell lung cancer. Insights into the role of EGFR-sensitizing mutations and acquired and de novo T790M resistance mutations followed, and differences in progression-free survival for patients with EGFR Del19- and L858R-mutated tumors treated with reversible first-generation EGF receptor tyrosine kinase inhibitors were reported. Recently, overall survival benefit in patients with Del19- but not L858R-mutated tumors has been demonstrated after treatment with afatinib, an irreversible ErbB family blocker. Although the biology underlying this difference in survival is currently unclear, this review examines several hypotheses. The introduction of targeted therapies based on recognition of the significance of acquired genetic driver mutations, such as somatic mutations in EGFR/ErbB-1 and rearrangements of ALK , has changed the treatment paradigm for patients with non-small-cell lung cancer (NSCLC). Indeed, tumor genotyping is now an essential routine diagnostic tool in clinical practice [1] . Adenocarcinoma is the most common type of NSCLC, and approximately half of these tumors have a known, actionable, oncogenic driver, the most common being KRAS (∼25%), sensitizing EGFR (∼17%), ALK (8%) and other EGFR (4%) mutations [2] . These oncogenic drivers are almost always mutually exclusive in patients with NSCLC. Targeted agents currently approved for the treatment of NSCLC include the first-generation, reversible EGF receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib; the second-generation irreversible ErbB family-targeted TKI, afatinib; and the ALK inhibitor, crizotinib. Recently it has been reported that individuals with NSCLC with known oncogenic drivers receiving a matched targeted agent live significantly longer than those who have a driver mutation but do not receive personalized treatment (hazard ratio [HR]: 0.69; 95% CI: 0.53–0.9; p = 0.006) [2] . In addition to KRAS, EGFR and ALK, other oncogenic drivers have been identified in adenocarcinomas, including ERBB2, BRAF, PIK3CA, MET, NRAS, MEK1 and AKT1. However, as these aberrations are generally rare (1–2%) [3] , meaningful clinical trials are difficult to undertake, given the challenge of recruiting sufficient patient numbers to allow demonstration of a statistically significant survival benefit [4] . Systematic characterization of genetic aberrations will foster the development of targeted agents and facilitate meaningful studies of these agents in patients with NSCLC. In this review we present recently published data on specific EGFR mutations and their differing clinical impact in patients treated with EGFR-TKIs.

KEYWORDS 

• afatinib • chemotherapy • Del19 • EGFR • erlotinib • gefitinib • L858R • mutations • NSCLC • TKI

Medical Oncology Department, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain Medical Oncology Department, Hospital de Mataró, Carretera de la Cirera, s/n, 08304 Mataró, Barcelona, Spain *Author for correspondence: Tel.: +34 932 275 400; Fax: +34 934 546 500; [email protected] ‡ Authors contributed equally 1 2

10.2217/FON.15.15 © 2015 Future Medicine Ltd

Future Oncol. (2015) 11(8), 1245–1257

part of

ISSN 1479-6694

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Review  Reguart & Remon Biological characteristics of EGFR mutations ●●The EGFR signaling pathway & somatic

mutations

EGFR is a member of the ErbB family of receptors, a subfamily of closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4). Genetic mutations affecting EGFR protein expression or activity can lead to unregulated proliferation and malignancy in humans. The tyrosine kinase domain contains an activation loop, a C-helix and ATP-binding cleft. During kinase activation the activation loop is extended away to allow the ‘catalytic’ glutamate residue on the C-helix to interact with a lysine residue that coordinates the proper orientation of the α and β phosphate of ATP. In the inactive state, the activation loop changes conformation to preclude the binding of the peptide substrate, while the C-helix rotates away, acting upon the ‘catalytic’ glutamate residue [5] . Ligand binding to the extracellular portion of the receptor is followed by its dimerization allowing activation of the kinase, and, subsequently activation of several downstream signaling pathways such as Ras–Raf–Mek and PI3K–AKT, which regulate cell proliferation and antiapoptotic activity, respectively [6] . Dysregulation of ErbB family kinase activity has been described in a range of human cancers, including NSCLC, resulting in constitutive signaling through ErbB family proteins. Mutations of EGFR have been validated as cancer-promoting mechanisms, and EGFR mutation-positive (EGFRm) tumors are not

dependent on functional EGFR for their survival [7] . These mutations surround the ATP binding site of the kinase, resulting in an activated state leading to malignant transformation through selective activation of AKT and STAT signaling pathways in in vivo models [6,8] . There are several classes of activating somatic EGFR mutations: in-frame deletions in exon 19 (LREA, Del19); single point mutations in exon 21 (L858R, L861Q) or exon 18 (G719S/A/C); and in-frame duplications and/or insertions in exon 20 (Figure 1) . Collectively, in-frame Del19 and L858R point mutations are referred to as common sensitizing mutations and account for 85–90% of all EGFR mutations. Common mutations have been widely studied in clinical trials as predictors of response to TKIs [9–18] . Several less frequent mutations of EGFR, also known as uncommon mutations, have been described at exons 18–21. However, their clinical significance is not well defined as they have generally not been considered in randomized clinical trials. Different patterns of sensitivity and resistance to TKIs have been associated with uncommon EGFR mutations as well as complex mutations in diverse exons of EGFR [19] . EGFR somatic mutations occur in around 30–50% of patients with NSCLC who are of East Asian ethnicity, compared with around 10% of patients from other ethnicities [20] . In Asian and Northern American populations, deletions in exon 19 (Del19) account for 45–50% of all EGFR mutations and a further 35–40% derive from the L858R mutation in exon 21 [7–9] (Figure 1) . In a Caucasian population, Del19 and

Exon 19

Exon 20

Exon 21 (activation loop)

Exon 2

5

7

EGF binding

13

16 17

EGF binding TM

18–21 Tyrosine kinase

22–24

875

Exon 18 (nucleotide-binding loop)

823 824

(40–45%)

761 762

(5%)

728 729

(45%)

688

(5%)

28

Autophosphorylation

Figure 1. Distribution of sensitizing mutations of EGFR within the tyrosine kinase domain in non-small-cell lung cancer.

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Differences in efficacy between Del19 & L858R EGFR mutation-positive non-small-cell lung cancer  L858R mutations were also the most prevalent mutation of EGFR, but with slightly different frequencies (61.9 and 33.0%, respectively) [10] . Currently, EGFR testing is recommended at diagnosis of advanced disease in all adenocarcinoma and mixed adenocarcinoma tumors regardless of smoking habits or gender. In nonadenocarcinoma histology, EGFR testing is not routinely recommended except in nonsmokers, adeno-squamous mixed tumors or small biopsy specimens [21] . ●●EGFR mutations & TKI efficacy

With the exception of the most prevalent exon 20 insertions, the majority of EGFR mutations have been associated with enhanced efficacy of at least one EGFR-TKI agent. Presence of L858R and Del19 mutations cause EGFR to have less affinity for ATP compared with the wild-type (wt) receptor, leading to less competition for binding sites and, consequently, lower concentrations of TKIs are sufficient for pathway inhibition [22] . However, there is evidence to suggest that sensitivity to TKIs may be stratified according to the particular type of activating mutation [23] . There are several factors that may influence this phenomenon. Del19 mutations remove between three and eight residues from the loop ATP binding cleft of the kinase, resulting in greater sensitivity to TKIs. Conversely, localization of the L858R mutation, remote to the ATP-binding cleft, may be a factor in the lack of response observed following treatment of L858R-positive NSCLC with TKIs that target the ATP site (Figure 2) [24] . It is possible that repositioning of critical residues on the tyrosine kinase domain, as a consequence of deleting residues in the α-helix, may be implicated in the greater sensitivity of Del19-mutant cells relative to the L858R-mutant cells [22] . There is evidence to support this hypothesis, in the form of IC50 values for afatinib, erlotinib and gefitinib against EGFR-wt, L858R- and Del19-mutated cell lines (Table 1) [26] . First-line treatment with TKIs in EGFRm non-small-cell lung cancer patients: Phase III trials results ●●Erlotinib & gefitinib

The reversible EGFR-TKIs erlotinib and gefitinib are currently standard first-line treatments in EGFRm NSCLC, demonstrating improved overall response rate (ORR) and progression-free

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Review

survival (PFS) over standard platinum-doublet chemotherapy in several randomized Phase III trials (Table 2) [9–16] . The majority of these studies consisted of patients harboring the common sensitizing EGFR mutations (L858R and Del19) only [11,14–15] . To date, no differences in overall survival (OS) versus standard platinum-doublet chemotherapy have been reported in these trials, possibly due to the high crossover rate to the TKI arm following disease progression in chemotherapy-treated patients. Furthermore, the use of chemotherapy schedules as a control arm in these trials was not an optimal strategy, as neither pemetrexed, antiangiogenic therapy nor a viable maintenance strategy was employed. In a recent randomized Phase II trial of 154 patients with EGFRm recurrent and advanced NSCLC, bevacizumab in combination with erlotinib improved PFS over erlotinib alone. However the bevacizumab plus erlotinib combination was associated with increased toxicity [27] . It is generally accepted that EGFRm patients live longer following treatment with reversible EGFR-TKIs. However, no randomized trial has yet shown a statistically significant survival advantage of first-line reversible TKIs over chemotherapy in any mutational EGFR subgroup with median OS of approximately 20 months (Table 2) [9–16] . In EGFR-positive lung cancer subpopulations, data from Phase III trials suggest that reversible EGFR-TKI efficacy varies according to EGFR mutation subtype with a trend toward higher efficacy in terms of PFS for Del19 over L858R (0.28 vs 0.47, respectively), with a statistically significant indirect comparison (HR: 0.59; p = 0.019) [29] . These data suggest two distinct populations predicted by EGFRm subtype. Thus far, however, the PFS benefit observed following treatment with reversible EGFR-TKIs has not been translated into a statistically significant OS benefit (Figure 3) . ●●Afatinib

Recently, the second-generation TKI afatinib, an irreversible ErbB family inhibitor [30] , demonstrated superior efficacy over standard of care chemotherapy in two randomized Phase III trials conducted in the largest number of EGFRm NSCLC patients to date (LUX-Lung 3 [17] and LUX-Lung 6 [18]) (Table 2) . In contrast to the erlotinib and gefitinib trials, LUX-Lung 3 and LUX-Lung 6 recruited patients with uncommon and common mutations of EGFR; the majority of patients (∼90%) had common Del19 and

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N-lobe

Deletions

G719

Insertions

C-helix

T790 P-loop

L858

A-loop

C-lobe

Figure 2. Structure of the EGF receptor kinase domain, highlighting the sites of oncogenic mutations.   Reproduced with permission from [25] © Elsevier (2010).

L858R mutations (∼50 and 40%, respectively). In LUX-Lung 3, 345 patients were randomly assigned (2:1 ratio) to receive afatinib 40 mg daily, or pemetrexed/cisplatin every 21 days for up to six cycles with no maintenance therapy. Patients were stratified according to their EGFR mutation status (Del19, L858R, vs others) and race (Asian or non-Asian [28% non-Asian]). LUX-Lung 6 randomized 364 similarly stratified Asian-only patients to receive either afatinib 40 mg daily, or gemcitabine/cisplatin in a 21-day schedule for up to six cycles. In both trials, approximately 11% of

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participants had tumors with uncommon mutations. Afatinib-treated patients achieved a consistent advantage over standard chemotherapy in terms of PFS (11 months by independent review), ORR (60–67%) and health-related quality of life [31] . Twelve months’ PFS of 47% was reported in both studies. In a preplanned subgroup analysis of LUX-Lung 3, PFS was improved in patients with tumors harboring a common EGFR-activating mutation; 13.6 months for afatinib versus 6.9 months in the chemotherapy group (HR: 0.47; p = 0.001) (Table 2) . However, in LUX-Lung 6,

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Differences in efficacy between Del19 & L858R EGFR mutation-positive non-small-cell lung cancer 

Review

Table 1. IC50 values in different lung cancer cell lines (EGFR-wt, L858R, Del19, T790M) treated with reversible (gefitinib, erlotinib) and irreversible (afatinib) tyrosine kinase inhibitors†. Tyrosine kinase inhibitor  

EGFR-wt 

EGFR L858R 

EGFR Del19 

 

LoVo

A431

H2073

H3255

H1975 T790M+

PC-9

PC-9 VanR T790M+

Afatinib Gefitinib Erlotinib

15 59 91

28 73 250

25 61 108

0.9 11 9

22 3102 6073

0.6 7 6

3 741 1262

Data taken from [26].

†

PFS in patients with common mutations was similar to that reported in the overall population. In LUX-Lung 3 and 6 the HR for PFS favored Del19 compared with L858R (LUX-Lung 3 HR: 0.28 and 0.73; LUX-Lung 6 HR: 0.20 and 0.32, respectively) [17,18] (Figure 3) . Improvement of common lung cancer-related symptoms such as cough, dyspnea and pain, as well as prolonged time to deterioration, were observed independent of the underlying EGFR mutation [31] . Recently, Yang et al. [28] reported OS data from LUX-Lung 3 and LUX-Lung 6 (Table 3) . In a prespecified analysis, both trials reported individually an OS benefit for afatinib versus chemotherapy in the Del19 subgroup, LUX-Lung 3 (33.3 vs 21.1 months; HR: 0.54; p = 0.0015) and LUX-Lung 6 (31.4 vs 18.4 months; HR: 0.64; p = 0.0229) (Figure 3) . Individually, LUX-Lung 3

and 6 did not report an OS survival benefit of afatinib over chemotherapy in patients with common (Del19 and L858R) mutations (31.6 vs 28.2 months; HR: 0.78; p = 0.109; and 23.6 vs 23.5 months; HR: 0.83; p = 0.1756, respectively). However, exploratory combined analyses of data from both trials, encompassing a total of 631 common EGFRm patients, reported for the first time a significant improvement in OS in afatinib- versus chemotherapy-treated patients (27.3 vs 24.3 months; HR: 0.81; p = 0.0374). The combined subgroup analysis confirmed that there was a survival benefit with afatinib versus chemotherapy in Del19 mutant patients with an absolute improvement of 11 months (31.7 vs 20.7 months; HR: 0.59; p = 0.0001) but this was not reproduced in the L858R mutant group (22.1 vs 26.9 months; HR: 1.25; p = 0.16). An

Table 2. Randomized Phase III trials comparing first-line reversible (gefinitib, erlotinib) and irreversible (afatinib) EGF receptor tyrosine kinase inhibitors with platinum-based chemotherapy in advanced non-small-cell lung cancer harboring EGFR-activating mutations. Study

 Treatment randomization

n

RR (%)

IPASS†

Gefitinib vs carboplatin/paclitaxel

261

71.2 vs 47.3; p < 0.001

First-SIGNAL‡

Gefitinib vs gemcitabine/cisplatin

42

WJTOG 3405

Gefitinib vs cisplatin/docetaxel

177

NEJ002

Gefitinib vs carboplatin/paclitaxel

228

OPTIMAL

ENSURE

Erlotinib vs gemcitabine/ 154 carboplatin Erlotinib vs first-line chemotherapy 173 regimens Erlotinib vs gemcitabine/cisplatin 148

LUX-Lung 3

Afatinib vs cisplatin/pemetrexed

345

LUX-Lung 6

Afatinib vs cisplatin/gemcitabine

364

EURTAC

PFS (months)

9.5 vs 6.3; HR: 0.48; p < 0.001 84.6 vs 37.5; p = 0.002 8.0 vs 6.3; HR: 0.54; p = 0.086 62.1 vs 32.2; p < 0.001 9.2 vs 6.3; HR: 0.49; p < 0.001 73.7 vs 30.7; p < 0.001 10.8 vs 5.4; HR: 0.30; p < 0.001 83 vs 36; p < 0.0001 13.1 vs 4.6; HR: 0.16; p < 0.0001 58 vs 15; p < 0.0001 9.7 vs 5.2; HR: 0.37; p < 0.0001 68.2 vs 39.3; p < 0.0001 11 vs 5.5; HR: 0.33; p < 0.0001 56.0 vs 23.0; p = 0.001 13.6 vs 6.9§; HR: 0.47; p < 0.001 67.0 vs 23.0; p < 0.0001 11.0 vs 5.6§; HR: 0.25; p < 0·0001

OS (months)

Ref.

21.6 vs 21.9; HR: 1.00; p = 0.99 27.2 vs 25.6; HR: 1.043

[10]

36 vs 39; HR: 1.185

[12]

27.7 vs 26.6; HR: 0.887; p = 0.483 22.6 vs 28.8; HR: 1.065; p = 0.685 19.3 vs 19.5; HR: 1.04; p = 0.87 NR

[13]

31.6 vs 28.2§; HR: 0.78; p = 0.1090 23.6 vs 23.5§; HR: 0.83; p = 0.1756

[9]

[14] [15] [16] [17,28] [18,28]

Included patients with uncommon mutations. First-SIGNAL: primary end point was OS. § In patients with common activating mutations only (LUX-Lung 3, n = 308; LUX-Lung 6, n = 324). HR: Hazard ratio; OS: Overall survival; PFS: Progression-free survival; RR: response rate. † ‡

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PFS HR (95% CI)

Trial LUX-Lung 3 Del19 L858R LUX-Lung 6 Del19 L858R IPASS Del19 L858R NEJ002 Del19 L858R WJTOG3405 Del19 L858R EURTAC Del19 L858R OPTIMAL Del19 L858R ENSURE Del19 L858R 0

OS HR (95% CI)

0.28 (0.18–0.44) 0.73 (0.46–1.17)

0.54 (0.36–0.79) 1.30 (0.80–2.11)

0.20 (0.13–0.33) 0.32 (0.19–0.52)

0.64 (0.44–0.94) 1.22 (0.81–1.83)

0.38 (0.26–0.56) 0.55 (0.35–0.87)

0.79 (0.54–1.15) 1.44 (0.90–2.30)

0.35 (0.23–0.52) 0.32 (0.20–0.50)

0.83 (0.52–1.34) 0.82 (0.49–1.38)

0.45 (0.27–0.77) 0.51 (0.29–0.90)

NA NA

0.30 (0.18–0.50) 0.55 (0.29–1.02)

0.94 (0.57–1.54) 0.99 (0.56–1.76)

0.13 (0.07–0.25) 0.26 (0.14–0.49)

NA NA

0.20 (0.12–0.33) 0.54 (0.32–0.90)

NA NA

0.5 1.0 1.5 Favors TKI Favors chemotherapy

0 1.0 2 3 Favors TKI Favors chemotherapy

Figure 3. Hazard ratio for progression-free survival and overall survival in patients with non-small-cell lung cancer harboring Del19 and L858R mutations in trials of EGF receptor tyrosine kinase inhibitors. NA: Not available; HR: Hazard ratio; OS: Overall survial; PFS: Progression-free survival; TKI: Tyrosine kinase inhibitor.

exploratory analysis revealed that the OS benefit in the Del19 subgroup was maintained independently of subsequent treatment with EGFR-TKIs and country-specific reimbursement policies. These data reinforce the concept of two distinct molecular populations Del19 and L858R, which may benefit to different extents from first-line afatinib treatment. Collectively, these findings confirm the efficacy of afatinib as standard treatment in EGFRm patients in a first-line setting. However, there are important factors to consider when comparing erlotinib, gefitinib and afatinib Phase III studies. Their study designs incorporated substantial differences in important variables, including mutation testing, EGFRm subtype (common and/or uncommon), assessment of progression (independent vs investigator), comparator choice (schedule, number of cycles) and inclusion criteria [32] . The higher incidence of EGFRm in Asian patients is reflected by the focus on Asian patients in the majority of studies conducted in this setting. The EURTAC trial [15] was the only randomized, Phase III trial conducted in an exclusively Caucasian population. The randomized LUX-Lung 3 trial was the only study designed to

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recruit globally, with predetermined subanalyses using race as a stratification showing no significant differences between Asian and non-Asian patients (HR for PFS in Asian patients was 0.54, compared with 0.68 in non-Asian patients; p = 0.65 per independent review) [17] . To date, no comparator trials have been reported that compare the efficacy of the irreversible broad ErbB family blockers, such as afatinib and dacomitinib to reversible EGFR-TKIs (erlotinib or gefitinib) in an EGFR-stratified population. A recent network meta-analysis in a subgroup of EGFRm advanced NSCLC patients reinforced afatinib as a viable treatment alternative to reversible EGFR-TKIs, with an estimated HR in patients with common mutations of 0.73 (0.42–1.24) for afatinib versus erlotinib, and 0.60 (0.34–0.99) for afatinib versus gefitinib [33] . However, OS findings were not significantly different between treatments. Afatinib will be compared with gefitinib in the first-line setting in a Phase IIb trial, LUX-Lung 7 (NCT01466660). Dacomitinib will be compared with gefitinib in treatment-naive EGFRm patients in a Phase III trial, ARCHER 1050 (NCT01774721). It should be noted that irreversible EGFR inhibition with dacomitinib was

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Differences in efficacy between Del19 & L858R EGFR mutation-positive non-small-cell lung cancer 

Review

Table 3. Overall survival analysis by common EGFR mutations (Del19/L858R) in LUX-lung 3 and LUX-Lung 6†.  n/OS/HR  

LUX-Lung 3  Afatinib

n (Del19) OS (months) HR; p OS in Del19 HR; p OS in L858R HR; p

Chemotherapy

203 (112) 104 (57) 31.6 28.2 0.78 (0.58–1.06); p = 0.109 33.3 21.1 0.54 (0.36–0.79); p = 0.0015 – – – –

LUX-Lung 6  Afatinib

Chemotherapy

216 (124) 108 (62) 23.6 23.5 0.83 (0.62–1.09); p = 0.1756 31.4 18.4 0.64 (0.44–0.94); p = 0.0229 – – – –

LUX-Lung 3 and 6 combined analysis for common mutations (Del19/L858R) Afatinib

Chemotherapy

419 212 27.3 24.3 0.81 (0.66–0.99); p = 0.0374 31.7 20.7 0.59 (0.45–0.77); p = 0.0001 22.1 26.9 1.25 (0.92–1.71); p = 0.160

Data taken from [28]. HR: Hazard ratio; OS: Overall survival; p: Probability. †

not superior to erlotinib in unselected lung cancer patients as second-line treatment in a Phase III trial, (ARCHER 1009); and data for EGFRm patients subgroup are not yet mature [34] .

●●Higher prevalence of de novo T790M-

its affinity for EGFR-TKI, thereby mediating primary resistance [37] . Since the allelic frequency of pretreatment T790M is very low (2% with direct sequencing), the detection rate rises with highly sensitive methods (60%) [38,39] . Currently, quantification of T790M is performed using detection kits such as Qiagen’s Therascreen. De novo T790M is a predictor of shorter EGFR reversible TKI response duration compared with T790M mutation-negative patients [39,40] . Interestingly, Yu et al. [41] found that de novo T790M mutations occur concurrently with L858R mutations in around 80% of cases, but only occur concurrently with Del19 mutations in around 20% of cases. Moreover, Lee et al. reported that among T790M-positive patients, there was a higher proportion of never smokers (83 vs 62%; p = 0.047) and L858R mutations (75 vs 25%; p = 0.051; for L858R and Del19, respectively) compared with the opposite group [42] . These findings may suggest a role for de novo T790M mutations in the outcomes observed following EGFR-TKI therapy in patients harboring L858R mutations. If this hypothesis holds true, routine assessment of de novo T790M mutation in the diagnostic biopsy may be warranted, particularly in tumors harboring L858R mutation. It would be of interest to discover whether the use of new generation compounds such as CO1686 [43] and AZD9291 [44] , with proven efficacy in patients with acquired T790M, will lead to superior outcomes compared with reversible EGFR-TKIs or irreversible ErbB family blockers in the first-line setting of L858R/T790M double mutations.

resistant mutation in L858R-mutated lung tumors

●●Other molecular markers of resistance

Rationale for the difference in observed activity of TKIs in EGFRm patient subgroups (Del19/L858R) Although the direct biological cause for the less pronounced effect of EGFR-TKIs on L858R compared with Del19 remains unclear, there are several hypotheses worthy of consideration. ●●Ethnicity: L858R mutation in Asian versus

non-Asian populations

Only LUX-Lung 3 enrolled Asian and nonAsian patients with predominantly Asian patients (28% non-Asian) [28] . The HR for OS in common mutations in the combined analysis favored afatinib over chemotherapy in both ethnicities: Asian (n = 548; HR: 0.82) and non-Asian (n = 83; HR: 0.68). A recent subset analysis of OS by EGFR-mutation type (Del19, L858R) and race (Asian, non-Asian) showed that the difference according to mutational subtype is irrespective of ethnicity [35,36] . The EURTAC (Caucasian only) trial [15] also revealed a correlation between PFS and EGFRm subgroups favoring Del19 over L858R mutation (HR: 0.30 vs HR: 0.55, respectively), with a minor influence on OS outcome (Figure 3) . It is therefore perhaps unlikely that the absence of any OS benefit in L858R-mutant patients is a result of ethnicity.

The T790M mutation produces a conformational change of the ATP pocket that increases receptor affinity for its natural substrate while decreasing

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(BRCA1 & BIM)

Other important primary predictive markers of outcome in NSCLC patients treated

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Review  Reguart & Remon with EGFR-TKIs are breast cancer type 1 susceptibility protein (BRCA1) and levels of BCL-2 interacting mediator of cell death (BIM), a proapoptotic member of the BCL-2 protein family. High BRCA1 expression levels correlate significantly with lower PFS in EGFRm patients treated with erlotinib. However, no differences according to BRCA1 mRNA expression and the type of EGFR mutation have yet been reported [45] . Consequently, BRCA1 levels do not appear to be a likely cause of the different sensitivity of Del19 and L858R to EGFR-TKIs. Expression and upregulation of BIM protein is required for induction of apoptosis by EGFR-TKIs in EGFRm NSCLC cells [46] . BIM mRNA expression is also implicated as an early adaptive biomarker of resistance in EGFRm NSCLC patients [39] ; a subset analysis by EGFR-mutation type was not provided for this study. Similarly, BIM deletion polymorphisms were associated with shorter PFS in EGFRm patients treated with an EGFRTKI [47,48] . As BIM polymorphisms constitute a germ-line alteration, their pattern of distribution should not differ significantly between EGFRmutation subtypes [49] , thereby falling short of a plausible hypothesis to explain the lower efficacy of EGFR-TKIs in L858R-mutated patients. ●●Higher doses of TKIs are needed to target

L858R/T790M

Preclinical data show that higher concentrations of EGFR-TKIs are required to inhibit EGFR in L858R compared with Del19-mutated cells, irrespective of the agent used (Table 1) [26] . As such, it could therefore be hypothesized that higher concentrations of EGFR-TKIs may improve outcomes in L858R-mutant disease. However, the Phase II LUX-Lung 2 trial [50] included EGFRm patients treated with either 50 mg or 40 mg of afatinib, and no dose dependent effects were observed between EGFR-mutation subtypes. It therefore seems unlikely that higher doses will improve outcomes in an L858R subset of patients. Moreover, gefitinib, which is generally prescribed at doses below the maximum tolerable dose [51,52] , showed only minor differences in PFS by common exon mutations [9,53] . ●●Differential EGF-induced tyrosine

phosphorylation patterns in L858R-mutated lung tumors

Distinctive EGF-induced tyrosine phosphorylation patterns have been described between EGFR-wt and the two EGFR-mutant receptors [6] .

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Of note, tyrosine 845 is highly phosphorylated in the L858R mutant, but not in the wt or the deletion mutant, and hence it appears to be unique in distinguishing between the two types of EGFR mutations. Tyrosine phosphorylation regulates STAT3/5 activity, a survival pathway activated in EGFR-mutated tumors in association with the AKT pathway. An alternative hypothesis to explain the lower efficacy of reversible and irreversible EGFR-TKIs in L858R mutation patients could be that STAT3 activation is not sufficiently abrogated by a single EGFR-TKI treatment [54–56] . Moreover, in TKI-resistant cell lines, EGFR-TKIs may induce STAT3 phosphorylation via interleukin-6 secretion, activating interleukin-6 receptor (IL-6R)/JAK1/STAT3 signaling. Inhibition of afatinib-induced STAT3 activation may therefore reverse sensitivity to afatinib [57] . ●●Different oncogene addiction patterns

after progression in L858R-mutated lung tumors

In a combined analysis of LUX-Lung 3 and 6 OS data, it was shown that survival curves for afatinib and chemotherapy in the L858Rmutant subgroup cross over in the time window of PFS once afatinib is discontinued. Conversely, in the Del19-mutant subgroup, these curves remain separate. This interesting observation may be evidence that the numerically derived superior OS in L858R-mutant patients treated with upfront chemotherapy is initiated once afatinib is discontinued in patients treated with upfront afatinib. From these data it could be hypothesized that, after a therapeutic switch to chemotherapy following radiological progression, oncogene-addicted L858R cells remain. Whereas those patients who switched from chemotherapy first-line to second-line therapy containing a TKI experienced benefit. However, there is currently no preclinical data to support this theory. Working within this paradigm, in an L858R-mutant patient group Response Evaluation Criteria In Solid Tumors (RECIST) criteria alone may not be the optimal approach to decide when to resume EGFR-TKI blockade. If in fact this hypothesis explains the observed inferior OS benefit in L858R mutation patients, maintaining EGFR suppression in combination with chemotherapy beyond RECIST progression may present a preferable therapeutic strategy in L858R patients. It is known that in EGFRm patients’ continuation of EGFR-TKI beyond progression prevents the

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Differences in efficacy between Del19 & L858R EGFR mutation-positive non-small-cell lung cancer  disease–flare phenomenon. However, this phenomenon has been described in almost 21% of patients irrespective of EGFR-mutant subtype [58,59] . In an institutional database with 78 EGFRm patients, continuation of an EGFR-TKI along with chemotherapy improved ORR but not PFS or OS compared with chemotherapy alone. However, patient numbers were not sufficient for an analysis of the outcome by mutation subtype [60] . In the Phase III LUX-lung 5 trial [59] afatinib plus chemotherapy beyond tumor progression on afatinib significantly improved PFS and ORR over chemotherapy alone in heavily pretreated patients. Unfortunately, no data on EGFR mutational status of patients were available. ASPIR ATION investigated treatment beyond progression with erlotinib and 93 of 207 patients who started first-line erlotinib continued after radiological progression. These patients were treated for a further 3 months before reaching PFS [61] . In contrast, an analysis of the data from the IMPRESS trial, comparing cisplatin/pemetrexed + gefitinib versus cisplatin/ pemetrexed + placebo after failure of first-line gefitinib, did not reveal a PFS benefit (HR: 0.86) [62] . In summary, data on efficacy of treatment beyond progression are heterogeneous and not reported for EGFR-mutational subgroups. Therefore, it remains unclear if L858R-mutated cells have an increased oncogene addiction and prolonged treatment might help to improve outcome. ●●L858R-mutated patients respond better

on chemotherapy

Data from Phase III clinical trials conducted in EGFRm patients indicate that L858Rmutant tumors respond better to chemotherapy compared with Del19-mutant tumors (Figure 3) . This may be related to the hypothesis that L858R-mutant tumors have a greater association with de novo T790M mutation and it has been suggested that the negative predictive value of the initial T790M mutation differs whether EGFR-TKI is introduced upfront or following chemotherapy [45] . In the EURTAC trial, the presence of de novo T790M had a detrimental effect on PFS for patients treated with upfront erlotinib but not for patients treated with upfront chemotherapy [39] . These results suggest that the use of upfront chemotherapy plus EGFRTKI in L858R EGFRm patients may be a viable option if this was the underlying cause of the inferior benefit in OS observed with irreversible

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Review

TKIs. Unfortunately, in the FASTACT-2 trial [63] , the benefit of combination treatment was not reported by EGFR-mutated subtypes, thus this trial did not shed more light on this question. Conversely, a noncomparative study from a Spanish Lung Cancer Group suggested that second-line EGFR-TKIs could attain PFS similar to that of first-line therapy, irrespective of EGFR mutation subtype [64] . ●●Tumor heterogeneity in EGFR-mutated

tumors

EGFR mutation heterogeneity between primary lung tumors and their metastases may be a factor contributing to the inferior responses to EGFR-TKIs observed in L858R-mutated NSCLC patients. Taniguchi et al. [65] tested EGFR mutation in multiple areas within 21 resected tumors: 71% had exclusively EGFRmutated cells, whereas 29% had both EGFRmutated and EGFR-wt NSCLC cells within the same primary tumor. Times to disease progression and OS after gefitinib treatment were significantly shorter in those patients with EGFR-mutation heterogeneity. In an Asian study, the overall discordance rate of EGFRmutation heterogeneity was 13.9 and 7.5% in synchronous tumors [66] . Conversely, in a different study cases of Asian patient discordances were extremely rare which could suggest that these discrepancies were associated with the methodological procedure [67] . In a retrospective series of Caucasian patients, the accuracy of EGFR-mutation screening of single tumor-biopsy samples before first-line EGFRTKI was validated. However, for half of the samples, tumor loci showed different EGFR copy numbers which may have affected the mutation detection threshold, thus implicating the methodology and justifying implementation of methods with greater sensitivity [68] . Whether a polyclonal cell population which causes EGFR-mutation heterogeneity does exist, and whether its rate is higher in L858Rmutant patients is yet unknown. Moreover, different subtypes of EGFR mutations demonstrate variant outcomes to first-line EGFR-TKI therapy, suggesting that detailed sequencing of mutations could impact on the prognosis of EGFRm patients [69] . Conclusion & future perspective Based on the results of numerous trials in EGFRm NSCLC patients, it is evident that

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Review  Reguart & Remon targeted treatment with TKIs is associated with clinical benefit over traditional chemotherapy in terms of ORR, PFS and health-related quality of life. This has changed our understanding of NSCLC tumors such that lung cancer is now considered to comprise of distinct entities defined by molecular characterization. As a result of the accumulating evidence, several reversible EGFR-TKIs (erlotinib, gefitinib) and irreversible ErbB family blockers (afatinib) are currently used in the first-line setting for treatment of NSCLC. However, it is increasingly evident that inherent molecular differences exist which underlie distinct outcomes following the use of different TKIs. The recent report of significantly increased OS beyond one year with the irreversible TKI, afatinib, specifically in Del19 EGFR-mutated subgroups compared with chemotherapy (LUX-Lung 3 and 6 trials), has highlighted a clear need to understand the molecular mechanisms underlying these data.

The recognition of such molecular mechanisms, other than common EGFR mutation itself, may inform the development of novel strategies to improve outcomes in the L858R EGFRm patient subgroup. Thus far, however, treatment with the irreversible ErbB family blocker afatinib in firstline treatment appears to be the treatment option of choice in the EGFR Del19 patient subgroup and remains a treatment option for EGFR L858R advanced NSCLC patients. Financial & competing interests disclosure Part of the KnowledgePoint360 Group, an Ashfield company, was supported financially by Boehringer Ingelheim during the preparation of this manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Medical writing assistance provided by Shaun Villa of GeoMed, supported financially by Boehringer Ingelheim.

EXECUTIVE SUMMARY ●●

EGF receptor (EGFR) is a member of the ErbB family of receptors, a subfamily of closely related receptor tyrosine kinases: EGFR (ErbB-1), HER2/c-neu (ErbB-2), Her 3 (ErbB-3) and Her 4 (ErbB-4).

●●

Genetic mutations affecting EGFR protein expression or activity can lead to unregulated proliferation and malignancy in humans and are found in around 30–50% of patients with non-small-cell lung cancer (NSCLC) who are of East Asian ethnicity, and around 10% of patients from other ethnicities.

●●

Collectively, EGFR Del19 and L858R point mutations, referred to as common sensitizing mutations, are the most

frequent EGFR mutations in NSCLC (85–90%). The majority of Phase III randomized studies, examining the first-line treatment of EGFR mutation-positive (EGFRm) NSCLC, have consisted of patients harboring common mutations only. ●●

The reversible EGFR tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, and the irreversible ErbB family blocker,

afatinib, are currently standard first-line treatments in EGFRm NSCLC based on the demonstration of an improved overall response rate (ORR) and progression-free survival (PFS) over standard platinum-doublet chemotherapy. To date, no differences in overall survival (OS) versus standard platinum-doublet chemotherapy have been reported with reversible TKIs. ●●

Differences in PFS for patients with EGFR Del19- and L858R-mutated NSCLC treated with reversible first-generation EGFR-TKIs over chemotherapy have been reported.

●●

Recently, two randomized trials with afatinib (LUX-Lung 3 and LUX-Lung 6) reported individually an OS benefit

(>1 year) over chemotherapy in the EGFR Del19 subgroup. Despite improvement in PFS, ORR and symptom control in the L858R subgroup, no significant differences in OS compared with standard chemotherapy could be demonstrated in this mutational subgroup. These data suggest that Del19- and L858R-mutated patients are two distinct populations that should be considered separately in the future. ●●

Currently, the biology underlying the difference in observed activity of erlotinib, gefitinib and afatinib in EGFR-mutated patient subgroups (Del19/L858R) is unclear, but several hypotheses are emerging from the available literature.

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