Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors For The Treatment of Non Small Cell Lung Cancer

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Expert Review of Anticancer Therapy

ISSN: 1473-7140 (Print) 1744-8328 (Online) Journal homepage: https://www.tandfonline.com/loi/iery20

Epidermal growth factor receptor tyrosine kinase


inhibitors for the treatment of non-small cell lung
cancer

Lara Kujtan & Janakiraman Subramanian

To cite this article: Lara Kujtan & Janakiraman Subramanian (2019) Epidermal growth factor
receptor tyrosine kinase inhibitors for the treatment of non-small cell lung cancer, Expert Review of
Anticancer Therapy, 19:7, 547-559, DOI: 10.1080/14737140.2019.1596030

To link to this article: https://doi.org/10.1080/14737140.2019.1596030

© 2019 The Author(s). Published by Informa


UK Limited, trading as Taylor & Francis
Group.

Published online: 14 Jun 2019.

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EXPERT REVIEW OF ANTICANCER THERAPY
2019, VOL. 19, NO. 7, 547–559
https://doi.org/10.1080/14737140.2019.1596030

REVIEW

Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of
non-small cell lung cancer
a,b a,c
Lara Kujtan and Janakiraman Subramanian
a
Department of Medicine, University of Missouri Kansas City, Kansas City, MO, USA; bThe Richard and Annette Bloch Cancer Center at Truman
Medical Center, Kansas City, MO, USA; cDivision of Oncology, Saint Luke’s Cancer Institute, Kansas City, MO, USA

ABSTRACT ARTICLE HISTORY


Introduction: Epidermal growth factor receptor (EGFR) mutations are well-described drivers of non- Received 15 November 2018
small cell lung cancer (NSCLC) and EGFR tyrosine kinase inhibitors (TKIs) have become key components Accepted 13 March 2019
of the NSCLC front-line treatment landscape. Tumors inevitably develop resistance to these agents, and KEYWORDS
development efforts continue to focus on identifying mechanisms of resistance and drugs to target Drug resistance; EGFR
these mechanisms. mutation; investigational
Areas covered: With several EGFR TKIs approved for use in the first-line or in later-line settings, an drugs; mutational testing;
understanding of the efficacy and safety of these inhibitors in various populations is warranted. treatment outcomes; non-
Furthermore, given the frequent emergence of drug resistance in NSCLC, examination of tumor tissue small cell lung cancer
throughout the disease course provides the opportunity to select treatments based on the tumor’s
mutation profile. Here, we discuss: key efficacy and safety findings for approved and investigational
EGFR TKIs; known mechanisms of resistance, particularly the T790M acquired EGFR mutation; and recent
advances in EGFR mutational testing that may facilitate less invasive tissue testing and guide treatment
selection.
Expert commentary: The expanding armamentarium of EGFR TKIs, improvements in the understanding
of resistance mechanisms and technological developments in the molecular analysis of tumors may
help render EGFR mutation-positive NSCLC a chronic disease in many patients by facilitating optimal
sequential therapy.

Video refs [1–9] afatinib and dacomitinib; the third-generation irreversible


EGFR TKI, osimertinib. Patients with EGFR mutation-positive
NSCLC are highly sensitive to EGFR TKIs with response rates
1. Introduction
and progression-free survival (PFS) typically ranging from 56%
An estimated 230,000 patients will be diagnosed with lung to 83% and 8.4‒18.9 months, respectively [12]. However,
cancer in the United States in 2018 [10]. Non-small cell lung regardless of which agent is chosen as first-line treatment,
cancer (NSCLC) is the most common type of lung cancer, and acquired resistance is inevitable. Third-generation EGFR TKIs
recent advances in the understanding of its biology have led were initially developed in an effort to combat resistance to
to the development of novel therapeutic strategies. An exam- first- and second-generation EGFR TKIs. Indeed, osimertinib is
ple of this was the identification of activated epidermal approved for the treatment of metastatic NSCLC harboring the
growth factor receptor (EGFR) as a driver in NSCLC [11], T790M EGFR resistance mutation, a common mechanism of
which led to the development of targeted EGFR inhibitors resistance to first- and second-generation EGFR TKIs [16–18],
and expanded the therapeutic options for this disease [12]. following progression on EGFR-TKI therapy. Resistance
The frequency of EGFR mutations varies depending on tumor mechanisms to third-generation TKIs are currently not as
histology and patient population, ranging from 7% to 14% in well characterized as those for first- and second-generation
Caucasian populations and 27% to 34% in Asian populations TKIs. Given the expanding armamentarium of highly effective
with adenocarcinoma [13–15]. EGFR mutations are more pre- TKIs for the treatment of EGFR mutation-positive NSCLC, it is
valent in females than males and never smokers than ever important that the characteristics of each agent are under-
smokers [14,15]. stood so that treatment can be tailored according to indivi-
Currently, five EGFR tyrosine kinase inhibitors (TKIs) are dual patient characteristics. Moreover, the assessment of the
approved by the US Food and Drug Administration and the molecular evolution of tumors at the point of acquired resis-
European Medicines Agency for the first-line treatment of tance is becoming increasingly important with respect to
patients with EGFR mutation-positive NSCLC: the first- optimizing the sequence of therapy. Here we review efficacy
generation reversible EGFR TKIs, erlotinib and gefitinib; and safety data for approved and investigational EGFR TKIs for
the second-generation irreversible ErbB family blockers, both the front-line treatment of NSCLC and for tumors

CONTACT Janakiraman Subramanian [email protected] Director of Thoracic Oncology, Saint Luke’s Cancer Institute, University of Missouri
Kansas City, 4321 Washington Street, Suite 4000, Kansas City, MO 64111, USA
© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
548 L. KUJTAN AND J. SUBRAMANIAN

Table 1. Mechanisms of resistance to EGFR TKIs [4]. randomized phase III trials, NEJ002 and WJTOG3405 demon-
Mechanism Approximate prevalence in NSCLC strated that gefitinib significantly improved PFS versus carbo-
T790M mutation 55% platin/paclitaxel (median 10.8 vs 5.4 months; HR, 0.30 [95% CI:
HER2 amplification 12% 0.22–0.41]; p < 0.001) and cisplatin/docetaxel (median 9.2 vs
MET amplification 5%
PIK3CA mutations 5% 6.3 months; HR, 0.49 [95% CI: 0.34–0.71]; p < 0.001), respec-
MAPK1 amplification 3% tively, in Japanese patients with EGFR mutation-positive
BRAF mutations 1% NSCLC [22,23]. Neither of these studies demonstrated an
EGFR = epidermal growth factor receptor, NSCLC = non-small cell lung cancer, improvement in OS with gefitinib versus chemotherapy.
TKI = tyrosine kinase inhibitor.
However, the recent Phase III NEJ009 trial demonstrated that
combining gefitinib with pemetrexed and carboplatin could
developing resistance to EGFR-TKI therapy (Table 1). In an improve PFS (median 20.9 vs 11.2 months; HR, 0.49 [95% CI:
effort to improve treatment selection and efficacy, newer 0.39–0.62]; p < 0.001) and OS (median 52.2 vs 38.8 months; HR,
and more convenient methods for detecting EGFR mutations, 0.70 [95% CI: 0.52–0.93]; p = 0.013), versus gefitinib alone [24].
including from circulating tumor cells (CTCs) and cell-free While gefitinib has proven activity against common activat-
tumor DNA (cftDNA), are evolving and are highlighted here. ing EGFR mutations (del19, L858R) few prospective data are
available that have assessed its activity against uncommon
mutations such as exon 18 mutations, exon 20 insertions,
2. FDA approved front-line EGFR tkis and mutations in the extracellular domain of EGFR, which
collectively account for >10% of all cases of EGFR mutation-
2.1. Gefitinib
positive NSCLC [25]. Available data from clinical trials [26], or
Gefitinib (IRESSA®, AstraZeneca) reversibly inhibits the kinase real-world studies [27,28], indicate that gefitinib is less active
activity of EGFR and has greater binding affinity for deletion against uncommon mutations such as G719X, L861Q and
19 (del19) and L858R mutant EGFR than for wild-type EGFR S768I than common mutations. Of note, certain uncommon
protein (Figure 1). It is indicated for the first-line treatment of mutations including exon 20 insertions and de novo T790M are
metastatic NSCLC harboring del19 or L858R EGFR mutations, intrinsically resistant to gefitinib [27,28].
as detected by a United States Food and Drug Administration
(FDA)-approved test. In the IPASS study, gefitinib led to longer
PFS than carboplatin/paclitaxel as first-line therapy in patients
2.2. Erlotinib
with advanced lung adenocarcinoma (hazard ratio [HR] for
progression or death, 0.74 [95% confidence interval (CI): Erlotinib (TARCEVA®, Genentech) also reversibly inhibits the
0.65–0.85]; p< 0.001) [19,20]. Overall survival (OS) was similar kinase activity of EGFR and has greater binding affinity for
for gefitinib compared to chemotherapy [19]. Subgroup ana- del19 – and L858R-mutant EGFR than for wild-type EGFR
lyses of IPASS demonstrated significantly longer PFS and protein (Figure 1). Erlotinib is indicated for the treatment of
a higher objective response rate (ORR) with gefitinib com- patients with metastatic NSCLC harboring del19 or L858R EGFR
pared to carboplatin/paclitaxel in EGFR mutation-positive mutations (as detected by an FDA-approved test) who are
patients [19,20]. The efficacy of first-line gefitinib in receiving first-line, maintenance, or second- or later-line treat-
Caucasian patients was observed in a single-arm, Phase IV ment after disease progression following ≥1 prior chemother-
study in patients with advanced, EGFR mutation-positive apy regimen. Results from the BR.21 (previously treated
NSCLC. The ORR was 69.8% with gefitinib, and the disease patients) and SATURN (maintenance therapy) trials demon-
control rate (DCR) was 90.6%; median PFS and OS were strated the efficacy of erlotinib in unselected (i.e. wild-type
9.7 months and 19.2 months, respectively [21]. The and mutant EGFR) NSCLC patient populations [29,30],

Figure 1. Mechanism of action of EGFR TKIs. Reprinted with permission from Journal of the Advanced Practitioner in Oncology.
Note: EGFR = epidermal growth factor receptor, TKI = tyrosine kinase inhibitors, del19 = deletion 19.
EXPERT REVIEW OF ANTICANCER THERAPY 549

although erlotinib has recently become indicated only for demonstrated significantly longer PFS (11.1 months) compared
patients with del19 or L858R EGFR mutation-positive NSCLC. with cisplatin/pemetrexed (6.9 months) in NSCLC patients with
Approval in the first-line setting was based on results from the activating EGFR mutations (HR, 0.58 [95% CI: 0.43–0.78];
EURTAC trial, which compared erlotinib and standard che- p = 0.001) [9]. This PFS benefit was more pronounced with
motherapy (cisplatin/docetaxel and cisplatin/gemcitabine) in afatinib in patients with del19 and L858R EGFR mutations
Caucasian EGFR mutation-positive NSCLC patients. Erlotinib (median 13.6 vs 6.9 months for afatinib and cisplatin/peme-
demonstrated significantly longer PFS versus chemotherapy trexed, respectively; HR, 0.47 [95% CI: 0.34–0.65]; p = 0.001)
(9.7 vs 5.2 months, respectively; HR, 0.37 [95% CI: 0.25–0.54]; [9]. While OS benefit was not observed in the overall popula-
p < 0.0001) [31]. In subgroup analyses, PFS was also signifi- tion, in a pre-specified subgroup analysis by EGFR mutation
cantly longer with erlotinib compared with chemotherapy in type, afatinib significantly improved OS compared with che-
patients with del19 (11.0 vs 4.6 months, respectively; motherapy in patients with del19 mutation (median 33.3 vs
p < 0.0001), but not L858R (8.4 vs 6.0 months; p = 0.0539) 21.1 months; HR, 0.54 [95% CI: 0.36–0.79]; p = 0.0015) [40]. In
mutations [31]. Two randomized Phase III trials, ENSURE and the Phase III LUX-Lung 6 trial, afatinib significantly improved
OPTIMAL, demonstrated that erlotinib significantly improved PFS versus cisplatin/gemcitabine in Asian, predominantly
PFS versus gemcitabine/cisplatin (median 11.0 vs 5.5 months; Chinese, patients with EGFR mutation-positive NSCLC (median
HR, 0.34 [95% CI: 0.22–0.51]; p < 0.0001) and gemcitabine/ 11.0 vs 5.6 months; HR, 0.28 [95% CI: 0.20–0.39]; p < 0.0001)
carboplatin (median 13.1 vs 4.6 months; HR, 0.16 [95% CI: [41]. Notably, this study independently replicated the significant
0.10–0.26]; p < 0.0001) in Asian, predominantly Chinese, OS benefit observed in LUX-Lung 3 in del19-positive patients
patients with EGFR mutation-positive NSCLC [32,33]. Like gefi- (median 31.4 vs 18.4 months; HR, 0.64 [95% CI: 0.44–0.94];
tinib, erlotinib appears to have limited or no clinical activity p = 0.023) [40].
against most uncommon EGFR mutations, including exon 20 In contrast to many Phase III trials of EGFR TKIs, LUX-Lung 3
insertions and de novo T790M [27,28]. and 6 permitted the recruitment of patients whose tumors
The combination of erlotinib and bevacizumab recently harbored uncommon EGFR mutations. In a post hoc analysis of
gained approval in Europe for the first-line treatment of these trials, along with the Phase II LUX-Lung 2 trial, 75
patients with unresectable advanced, metastatic, or recurrent patients were identified with uncommon activating mutations
non-squamous, EGFR mutation-positive NSCLC. Approval was [42]. In patients with L861Q, G719X or S768I, the response rate
based on results from the Phase II JO25567 trial comparing to afatinib was 56.3, 77.8 and 100.0%, respectively. Based on
erlotinib plus bevacizumab with erlotinib alone in Japanese these findings, the indication for afatinib was recently
patients. The combination of erlotinib and bevacizumab led to expanded to include these mutations. In contrast, afatinib
significantly longer PFS compared with erlotinib alone (med- appeared to have poor activity against exon 20 insertions
ian 16.0 vs 9.7 months, respectively; HR, 0.54 [95% CI: and de novo T790M [42]. Patients with stable brain metastases
0.36–0.79]; p = 0.0015) [34]. The PFS benefit seen with the were also permitted in LUX-Lung 3 and 6. In a prespecified
combination was also significant in patients with del19 EGFR subgroup analysis, similar overall clinical benefit with afatinib
mutations (median 18.0 vs 10.3 months, respectively; versus chemotherapy was observed in patients with, or with-
p = 0.0011), and showed a non-significant trend in patients out, brain metastases [43]. Competing risk analysis of patients
with L858R mutations (median 13.9 vs 7.9 months; p = 0.1653) with brain metastases treated with afatinib indicated that the
[34]. However, there was no difference in OS with the combi- risk of CNS progression was lower than that of non-CNS
nation compared with erlotinib alone (median 48.4 vs progression (31% and 52%, respectively [12]). Moreover, the
48.5 months, respectively; HR, 0.91 [95% CI: 0.56–1.46]; frequency of de novo CNS progression in LUX-Lung 3 and 6
p = 0.6838) [35]. In the second-line setting, a meta-analysis was only 6%, compared with a non-CNS progression fre-
of five studies comparing combination treatment with erloti- quency of 78% [12]. These findings suggest that afatinib may
nib plus bevacizumab versus bevacizumab or erlotinib alone, protect against metastatic spread to the brain.
pooled estimates did not show significant improvement in OS The LUX-Lung 7 head-to-head trial compared afatinib with
with combination therapy (HR, 0.96 [95% CI: 0.83–1.11]; gefitinib as first-line treatment in EGFR mutation-positive
p = 0.573) [36]. The erlotinib plus bevacizumab combination NSCLC patients. Afatinib treatment led to longer PFS (median
resulted in greater PFS (HR, 0.63 [95% CI: 0.53–0.75]; p = 0.000) 11.0 vs 10.9 months for gefitinib; HR, 0.73 [95% CI: 0.57–0.95];
and ORR (risk ratio = 1.91 [95% CI: 1.19–3.06]; p = 0.007) p = 0.017) and time-to-treatment failure (median 13.7 vs
compared with either bevacizumab or erlotinib alone [36]. 11.5 months; HR, 0.73 [95% CI: 0.58–0.92]; p = 0.0073) com-
pared with gefitinib [1]. However, median OS was not signifi-
cantly different (27.9 vs 24.5 months; HR, 0.86 [95% CI:
2.3. Afatinib
0.66–1.12]; p = 0.258), regardless of mutational subtype
Afatinib (GILOTRIF®, Boehringer Ingelheim) is an irreversible (del19 or L858R) in subgroup analyses [44].
ErbB family blocker that targets EGFR/ErbB1, HER2/ErbB2, and Afatinib is also approved for the treatment of metastatic
HER4/ErbB4, which results in the inhibition of HER3/ErbB3 phos- squamous cell lung cancer, regardless of EGFR mutation status,
phorylation; afatinib can inhibit both wild-type and mutant based on results from the LUX-Lung 8 trial of afatinib versus
EGFR (Figure 1), with higher affinity for mutant EGFR [37–39]. erlotinib in patients who had progressed on ≥4 cycles of
Afatinib is indicated for the first-line treatment of metastatic platinum-based chemotherapy. Patients in the afatinib group
NSCLC harboring non-resistant EGFR mutations, as detected by had significantly longer PFS than those in the erlotinib group
an FDA-approved test. In the global LUX-Lung 3 study, afatinib (2.4 vs 1.9 months; HR, 0.82 [95% CI: 0.68–1.00]; p = 0.0427).
550 L. KUJTAN AND J. SUBRAMANIAN

OS was also significantly longer with afatinib (7.9 months) NCT02511106) or chemoradiation (LAURA; NCT03521154) in
compared with erlotinib (6.8 months; HR, 0.81 [95% CI: patients with non-metastatic EGFR mutation-positive NSCLC.
0.69–0.95]; p = 0.0077) and DCR was significantly higher Recent preplanned subgroup analyses of FLAURA indicated
(51% vs 40%, respectively; p = 0.002), although ORR was not that osimertinib has CNS activity. In patients with measurable
significantly different between the two groups (6% vs 3%, and/or non-measurable CNS lesions, CNS PFS was longer with
p = 0.0551) [45]. osimertinib than gefitinib/erlotinib (median not reached vs
13.9 months; HR, 0.48 [95% CI: 0.26–0.86]; p = 0.014 [52]).
CNS ORR was 66% and 43%, respectively. The frequency of
2.4. Dacomitinib CNS progression (20% vs 39%) and the development of de
novo CNS lesions (12% vs 30%), was lower with osimertinib
Dacomitinib (Pfizer) irreversibly inhibits tyrosine autopho-
than gefitinib/erlotinib, indicating a protective effect against
sphorylation of EGFR, HER2/ErbB2, and HER4/ErbB4 (Figure 1)
metastatic spread to the brain [52], These findings are consis-
[46]. In a single-arm, Phase II study, dacomitinib showed pro-
tent with preclinical observations that osimertinib effectively
mising activity with a four-month PFS rate of 95.5% in patients
crosses the blood-brain barrier [50,53].
with EGFR mutation-positive disease [47]. These data were
recently substantiated by the Phase III ARCHER 1050 trial [2].
In this study, dacomitinib significantly improved PFS versus 3. Treatment of EGFR TKI–resistant NSCLC
gefitinib in patients with EGFR mutation-positive (del19 or
Resistance to front-line EGFR-TKI therapy is a major challenge
L858R) NSCLC (median 14.7 vs 9.2 months; HR, 0.59 [95% CI:
that limits durable responses to these agents. Selected
0.47–0.74]; p < 0.0001). In contrast to the LUX-Lung 3, 6 and 7
patients with minimal or isolated progression may be able to
and FLAURA trials patients with stable brain metastases were
continue with front-line EGFR TKIs in conjunction with local
excluded. Dacomitinib improved duration of response versus
therapies, such as radiation, to address the site of disease
gefitinib (median 14.8 vs 8.3 months, respectively), but there
progression [54–56]. However, it is important to consider pos-
was no significant difference in response rate between the
sible systemic treatment options in the second-line setting
two groups (75 vs 72%; p = 0.4234). ARCHER 1050 had a hier-
and beyond, as well as potential combination strategies with
archical statistical testing order of PFS followed by ORR then
the aim of delaying resistance in a first-line setting or provid-
OS. No formal testing of OS was conducted because ORR was
ing novel treatment options following acquired resistance.
not statistically significant [48]. Nevertheless, exploratory OS
Accordingly, many experimental regimens are currently
analysis from ARCHER 1050 was recently reported [49]. After
being assessed in clinical trials (ongoing Phase 1b-3 trials are
a median follow-up of 31.3 months, dacomitinib significantly
summarized in Table 2). Central to the development of novel
prolonged OS versus gefitinib (median 34.1 vs 26.8 months;
treatments is an understanding of the key molecular resis-
HR, 0.76 [95% CI: 0.58–0.99]; p = 0.044). Similar OS benefit was
tance mechanisms to EGFR TKIs, which appear to be some-
observed across patient subgroups including age (<65 vs
what different between first-/second-generation TKIs and
≥65 years), race (Asian vs non-Asian) and EGFR mutation
third-generation TKIs.
type (del19 vs L858R).

3.1. Resistance to first – and second-generation EGFR


2.5. Osimertinib TKIs
Osimertinib (TAGRISSO™, AstraZeneca) covalently binds and Currently, multiple mechanisms of resistance to first-
inhibits mutant forms of EGFR, including T790M, del19, and and second-generation EGFR TKIs have been identified and
L858R, with minimal activity against wild-type EGFR (Figure 1) include secondary EGFR mutations and upregulation of various
[50,51]. In the Phase III FLAURA trial, undertaken in patients compensatory kinases or signaling pathways (Table 1)
with EGFR mutation-positive (del19 or L858R) NSCLC, includ- [4,57,58]. The first resistance mechanism discovered was the
ing patients with stable brain metastases, osimertinib con- T790M mutation, which results in increased affinity for adeno-
ferred superior investigator-assessed PFS versus erlotinib or sine triphosphate (ATP) over TKIs at their binding site to EGFR
gefitinib (median 18.9 vs 10.2 months; HR, 0.46 [95% CI: [57]. At least half of first- and second-generation EGFR TKI–
0.37–0.57]; p < 0.001) [3]. Consistent PFS benefit was observed resistant lung cancers arise through the T790M secondary
in patients with (HR, 0.47 [95% CI: 0.30–0.74]), or without (HR, EGFR mutation [58,59] and, as a result, there is a large focus
0.46 [95% CI: 0.36–0.59]), brain metastases. The response rate on developing EGFR TKIs that target this particular acquired
with osimertinib was similar to that observed with first- mutation.
generation EGFR TKIs; however, the duration of response was Osimertinib is highly effective in this setting and is approved
prolonged with osimertinib (median 17.2 vs 8.5 months, by the FDA for the treatment of metastatic NSCLC harboring
respectively). At data cutoff, OS data were immature. Based T790M EGFR mutations (detected by an FDA-approved test)
on the results of FLAURA, osimertinib has recently been after progression on EGFR-TKI therapy. In a Phase I trial of
approved by the US FDA for the first-line treatment of patients osimertinib in NSCLC patients who progressed on EGFR-TKI
with EGFR mutation-positive NSCLC Second-generation EGFR therapy (AURA), the confirmed ORR was 51% and DCR was
TKIs were not included in the comparator arm of FLAURA. 84%; median PFS was 8.2 months [60]. Additionally, patients
Phase III trials are currently assessing osimertinib in an adju- with detectable T790M EGFR mutation by central testing had
vant setting following surgical resection (ADAURA; a higher ORR (61% vs 21% for those without) and longer PFS
Table 2. Key ongoing trials of combination therapy with EGFR TKIs in NSCLC.
Trial Phase Treatment arms Patient population Primary endpoint
First-line therapy
NCT02411448 (RELAY) Ib, III Erlotinib ± ramucirumab EGFRm+ (del19/L858R) stage IV NSCLC (n = 543) PFS, AEs
NCT02438722 (SWOG II/III Afatinib ± cetuximab EGFRm+ (del19/L858R; can be T790M+) stage IV NSCLC (n = 174) OS, PFS
S1403)
NCT02655536 II Erlotinib ± bevacizumab EGFRm+ (del19/L858R) stage IV non-squamous NSCLC with brain metastases PFS
(BRILLIANT) (n = 109)
NCT02716311 II Afatinib + cetuximab EGFRm+ (del19/L858R/G719X/L861Q/S768I/exon 19 insertion; excludes T790M/ TTF
exon20 mutations) non-squamous NSCLC (n = 170)
NCT02824458 I, III Gefitinib ± apatinib Activating EGFRm+ (eg del19/L858R) non-squamous NSCLC (n = 246) PFS
NCT02976116 II Gefitinib + fruquintinib (HMP-013) Activating EGFRm+ (mutations not specified) non-squamous NSCLC (n = 50) ORR, AE
NCT03122717 I/II Osimertinib + gefitinib EGFRm+ (del19/L858R) stage IV NSCLC (n = 64) No. patients completing 6
cycles
NCT03126799 (AvaTa) II Erlotinib ± bevacizumab EGFRm+ (del19/L858R) non-squamous NSCLC (n = 128) PFS
NCT03267654 II Gefitinib + apatinib EGFRm+ (del19/L858R) with BIM deletion or low abundance for EGFR mutation non- PFS
squamous NSCLC (n = 300)
NCT03392246 II Osimertinib + selumetinib EGFRm+ (del19/L858R) NSCLC (n = 25) ORR
NCT03457337 II Gefitinib ± S-1 EGFRm+ (del19/L858R) non-squamous NSCLC (n = 200) PFS
NCT03736837 (ALTER- II Icotinib + anlotinib EGFRm+ (del19/L858R) ALK-negative, non-squamous NSCLC (n = 58) PFS
L004)
Second-line therapy
NCT02917993 I/II Osimertinib + INCB039110 EGFRm+ (eg del19/L858R/G719X/L861Q) NSCLC (n = 59); Ph I: progressed on AEs, DLTs, ORR
previous EGFR TKI (>1 prior line allowed); Ph II: T790M+ after progressing on first-
line EGFR TKI
NCT02954523 I/II Osimertinib + dasatinib EGFR TKI-naïve EGFRm+ (del19/L858R/G719X/L861Q) NSCLC (n = 10) AEs, no. patients not
progressing
NCT03157089 (LUX- II Afatinib + pembrolizumab Squamous NSCLC that progressed after at least 2 cycles of platinum-based ORR
Lung IO) chemotherapy (n = 24) (EGFR mutation not required)
NCT03292133 II Gefitinib + nazartinib (EGF816) Sensitizing EGFRm+ (del19/L858R; others TBC with PI); advanced NSCLC (n = 36) PFS
NCT03381274 Ib/II Osimertinib + oleclumab (MEDI9447) or oleclumab + AZD4635 EGFRm+ (mutations not specified) NSCLC; Includes T790M-negative and positive AEs, ORR
(n = 98)
NCT03450330 I/II Osimertinib + AZD4205 Activating EGFRm+ (mutations not specified) NSCLC with failure on prior EGFR TKIs Safety/tolerability/AEs
(JACKPOT1) (n = 120)
NCT03455829 I/II Osimertinib + lerociclib (G1T38) Sensitizing EGFRm+ (mutations not specified) NSCLC (Ph II: No prior chemotherapy/ DLTs, RP2D, TEAE, PFS
osimertinib; T790M+) (n = 144)
NCT03758287 I/II Gefitinib + ningetinib (CT053PTSA) EGFRm+ (mutations not specified) T790M-negative NSCLC with progression after MTD, ORR
EGFR TKI (n = 72)
NCT03778229 II Osimertinib + savolitinib Sensitizing EGFRm+ (del19/L858R) NSCLC with MET high expression and/or ORR
(SAVANNAH) amplification with progression on osimertinib; 1–3 prior lines (n = 172)
NCT03784599 II Osimertinib + trastuzumab (T-DM1) Activating EGFRm+ (mutations not specified), HER2-overexpressing non-squamous Safety, ORR
(TRAEMOS) NSCLC with progression on first/second (must be T790M-negative) or third
generation (can be T790M+ or -negative) EGFR TKIs (n = 58)
Multiple lines of therapy
NCT02520778 Ib Osimertinib + navitoclax EGFRm+ (del19/L858R/G719X/L861Q) NSCLC progressing after EGFR TKI; Expansion Toxicity
phase: must be T790M+ (n = 50)
NCT02803203 I/II Osimertinib + bevacizumab Activating EGFRm+ (mutations not specified) NSCLC; VEGF- and EGFR-inhibitor naïve MTD, PFS
(n = 58)
NCT02971501 II Osimertinib ± bevacizumab EGFRm+ (del19/L858R/any other known sensitizing mutation) NSCLC with brain PFS
metastases; T790M+ after progression on first – or second-generation EGFR TKI
(n = 98)
NCT03076164 I/II Erlotinib + trametinib Activating EGFRm+ (type not specified) lung adenocarcinoma with progression on ORR, safety
EXPERT REVIEW OF ANTICANCER THERAPY

erlotinib
NCT03133546 II Osimertinib ± bevacizumab EGFRm+ (del19/L858R), T790M+ non-squamous NSCLC with progression after prior PFS
(BOOSTER) EGFR TKI as most recent regimen (n = 154)
551

(Continued )
552 L. KUJTAN AND J. SUBRAMANIAN

(9.6 vs 2.8 months, respectively) than patients with no detect-

AEs = adverse events, ALK = anaplastic lymphoma kinase, BIM = bcl-2 interacting mediator of cell death, DCR = disease control rate; DFS = disease-free survival, DLT = dose-limiting toxicities, EGFR = epidermal growth factor

survival, RP2D, recommended phase 2 dose, TEAE = treatment-emergent adverse events, TBC = to be confirmed, TKI = tyrosine kinase inhibitor, TTF = time to failure, SD = stable disease, VEGF = vascular endothelial growth
receptor, EGFRm+ = EGFR mutation positive, MTD, maximum tolerated dose; NSCLC = non-small cell lung cancer, ORR = objective response rate, OS = overall survival, PI = principal investigator, PFS = progression-free
able T790M [60]. The single-arm, Phase II AURA2 study con-
firmed the clinical benefit of osimertinib in patients with T790M

Primary endpoint
mutation-positive NSCLC after progression on EGFR-TKI therapy,

DCR (18 weeks)


with an ORR of 70% [61]. The Phase III AURA3 study, which

AEs, ORR
compared osimertinib with platinum-based chemotherapy plus
pemetrexed in patients with T790M mutation-positive NSCLC

EGFR TKI (eg erlotinib, gefitinib) + anti-angiogenic therapy (eg endostatin, Non-squamous NSCLC (no requirement for EGFRm+) with ≥SD following 2 months PFS
after progression on EGFR-TKI therapy, reported significantly
deletions, includes acquired T790M, de novo T790M, or T790M-negative (n = 157) longer PFS (median 10.1 vs 4.4 months; HR, 0.30 [95% CI:
0.23–0.41]; p < 0.001) and significantly higher ORR (71% vs
Sensitizing EGFRm+ (eg del19/L858R) NSCLC; excludes exon 20 insertions or

31%; p < 0.001) with osimertinib versus chemotherapy, respec-


tively [62].
T790M-independent mechanisms of resistance to first-
and second-generation TKIs are heterogeneous and are gener-
ally unresponsive to EGFR blockade. Thus, treatment options for
T790M-negative tumors remains an area of unmet medical need
[63]. One T790M-independent resistance mechanism, the con-
stitutive activation of MET, activates the phosphatidylinositol
3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)
EGFR insertion 20-positive NSCLC (n = 37)

pathway, signaling cell proliferation and survival, which EGFR


inhibitors cannot overcome [57]. HER2 mutations allow HER2
receptor activation independent of heterodimerization with
EGFR and phosphorylate EGFR even when TKIs are present
[57]. Occasionally, resistance to TKIs is mediated by histologic
of EGFR TKI (n = 100)

changes in the tumor. In a study performed at the


Patient population

Massachusetts General Hospital, tumor biopsies were underta-


ken in 37 patients with EGFR-mutated NSCLC at diagnosis and at
the time of EGFR-TKI resistance. Of these patients, 5 (14%)
experienced transformation to small-cell lung cancer at the
time of clinical TKI resistance. In all 37 patients, the original
EGFR mutation was maintained at the time of TKI resistance [59].
Nazartinib + trametinib or ribociclib or LXH254 or INC280 or gefitinib

3.2. Resistance to osimertinib


With the approval of first-line osimertinib in patients with EGFR
mutation-positive NSCLC, it is important that resistance
mechanisms are defined, with a view to identifying targeted
treatment options following acquired resistance. There is an
Treatment arms

ongoing effort to identify resistance mechanisms. Small cohort


studies have identified several putative resistance mechanisms,
including the tertiary EGFR mutation, C797S, or molecular aber-
rations in other intracellular signaling pathways, such as ampli-
fication of MET, HER2 or KRAS [64–67]. A recent subanalysis of
the FLAURA study indicated that resistance mechanisms to first-
line osimertinib are highly heterogeneous. In 91 evaluable
apatinib, anlotinib)
Afatinib + cetuximab

patients treated with first-line osimertinib, the most common


resistance mechanism was MET amplification (15% of patients).
C797S was present in only 7% of patients. Other less common
resistance mechanisms were HER2 amplification and PIK3CA
and RAS mutations [5]. No putative resistance mechanisms
were identified in ~60% of patients. As expected, no osimerti-
Phase
Ib

II

II

nib-treated patients showed evidence of T790M-mediated


acquired resistance [5]. Some of the identified mechanisms of
Table 2. (Continued).

resistance offer rationale for potential targeted treatments. For


example, C797S-positive tumors could be sensitive to EAI045,
NCT03333343

NCT03461185

NCT03727724

an allosteric inhibitor of mutant EGFR in early stages of devel-


(AFACET)

opment (Figure 1) [68]. EAI045, when combined with cetuxi-


factor.

mab, has shown antitumor activity in preclinical models of


Trial

EGFR-mutated lung cancer, including C797S [68], suggesting


EXPERT REVIEW OF ANTICANCER THERAPY 553

that agents targeting this newly discovered resistance mutation nivolumab in patients with T790M-positive tumors following
may be viable treatment options. Furthermore, C797S-positive progression on an EGFR-TKI (Table 2).
tumors may be sensitive to first-generation EGFR TKIs [69,70] if
T790M is not present. However, recent data indicate that ter-
tiary EGFR mutations, including C797S, occur in tumors that 4.3. CK-101
remain T790M-positive at the point of resistance [55]. CK-101 (CheckPoint Therapeutics) is a novel third-generation
Moreover C797S and T790M generally occur in cis i.e. on the EGFR TKI. An ongoing phase I/II trial is assessing CK-101 for the
same allele [71], suggesting that first- and second-generation treatment of patients with EGFR mutation-positive NSCLC in
EGFR TKIs would have limited activity after osimertinib failure. both EGFR TKI treatment naïve and previously-treated (T70M
The involvement of other signaling pathways in patients with positive settings). In 37 patients treated to date there was
acquired resistance to osimertinib suggests that novel combi- 100% disease control. The PR rate in previously treated
nation strategies may be effective in some of these patients. patients was 75%. The PR rate in patients with brain metas-
Ongoing Phase I studies, for example, are assessing the combi- tases was 50% [80].
nation of osimertinib with MEK, MET, VEGFR2 or BCL-2 family
inhibitors (NCT02143466, NCT02789345, NCT02520778). At this
time, the most likely treatment following failure of osimertinib 5. Safety profile of EGFR TKIs
is a clinical trial or chemotherapy.
Across studies, treatment with EGFR TKIs has been associated
with specific adverse events (AEs) related to inhibition of this
key pathway. Not surprisingly, approved TKIs and those in
4. Other EGFR TKIs currently in development
development share similar safety profiles in the treatment of
4.1. Icotinib NSCLC; a summary of EGFR TKI–related AEs is provided in
Table 3. The most commonly reported AEs with EGFR TKIs
Icotinib (Beta Pharma), a reversible inhibitor of wild-type and
are mainly gastrointestinal and dermatologic in nature and
mutant forms of EGFR (Figure 1), is in development for the
include diarrhea, rash, mucosal inflammation (e.g. stomatitis,
treatment of patients with advanced, EGFR mutation-positive
mucositis), and paronychia [81]. Rates of diarrhea and stoma-
NSCLC, both in the first-line and later-line settings [72]. In
titis appear to be greater with afatinib and dacomitinib com-
a Phase III trial comparing icotinib with gefitinib in Chinese
pared to erlotinib or gefitinib, possibly reflecting their broader
patients with previously treated, advanced NSCLC (ICOGEN),
inhibitory profiles. Gefitinib appears to also have a slightly
icotinib was non-inferior to gefitinib (median PFS, 4.6 vs
lower rate of dermatologic AEs compared to erlotinib, afatinib
3.4 months, respectively; p = 0.13) [73]. The efficacy of icotinib
and dacomitinib. While rates of these events can be high with
was further demonstrated in patients with advanced or meta-
EGFR TKIs compared to cytotoxic chemotherapy, the vast
static NSCLC who failed ≥1 platinum-based chemotherapy
majority of events are of low severity and can be managed
regimen (median PFS, 5.0 months; ORR, 25.8%; DCR, 67.7%;
with appropriate supportive care [81]. Of note, tolerability-
median OS, >17.6 months) [74]. In a pharmacokinetic study,
guided dose adjustment appears to reduce the incidence of
ORR with icotinib was 25% in Chinese patients with advanced
AEs associated with afatinib, dacomitinib and gefitinib without
NSCLC [75]. Results from the recent CONVINCE trial in EGFR
compromising PFS [82–84]. For example, a recent retrospec-
mutation-positive NSCLC patients demonstrated significantly
tive analysis of 228 patients with EGFR mutation-positive
improved PFS (median 11.2 vs 7.9 months for icotinib and
NSCLC who received first-line afatinib in a ‘real world’ clinical
cisplatin/pemetrexed, respectively; HR 0.61 [95% CI:
setting demonstrated that while dose reductions were com-
0.43–0.87]; p = 0.006) although there was no difference in
mon (67% of patients) and effectively reduced frequency and
OS [76]. Icotinib is approved in China as first-line therapy in
intensity of adverse drug reactions, they did not adversely
patients with advanced NSCLC and activating EGFR mutations
affect time on treatment or time to progression [85].
[77]. Ongoing Phase III trials are evaluating adjuvant icotinib
Furthermore, an observational study in Japanese patients
versus placebo or vinorelbine in EGFR mutation-positive
(n = 22) suggested that erlotinib can be dose-adjusted for
NSCLC patients (NCT02125240, NCT02448797).
body surface area and poor performance status without
a significant effect on survival [86].
As osimertinib was engineered to specifically inhibit
4.2. Nazartinib
mutant forms of EGFR, and spare wild-type EGFR, it had
Nazartinib (Novartis) is an irreversible, mutant-selective EGFR a better tolerability profile than gefitinib in the FLAURA trial;
TKI in development for the treatment of T790M mutation- overall, the frequency of Grade ≥ 3 AEs was 34% and 45%,
positive NSCLC (Figure 1) [78]. A first-in-human study of nazar- respectively [46]. The most frequent AEs were rash/acne (all
tinib recently demonstrated an ORR of 55% and a DCR of 86% grades: 58% vs 78%; Grade ≥ 3: 1% vs 7%), diarrhea (all grades:
in NSCLC patients with T790M mutation-positive tumors; this 58% vs 57%; Grade ≥ 3: 2% vs 2%), and dry skin (all grades:
trial is ongoing [79]. Nazartinib is also being assessed in com- 36% vs 36%; Grade ≥ 3: <1% vs 1%).
bination with gefitinib in previously untreated patients with Of note, effective management of AEs with dose-reduction
EGFR mutation-positive NSCLC, and in combination with schemes and supportive care allow most patients to remain
554 L. KUJTAN AND J. SUBRAMANIAN

Table 3. Rates of common EGFR TKI–associated AEs from key randomized NSCLC trials.
Percentage of patients Percentage of patients
with any-grade AEs with grade ≥3 AEs
Common EGFR TKI–associated EGFR TKI Control EGFR TKI Control
Agent Study N Comparator AEs arm arm arm arm
Afatinib LUX-Lung 3 [9] 345 Cisplatin/pemetrexed Diarrhea 95.2 15.3 14.4 0
Rash/acne 89.1 6.3 16.2 0
Stomatitis/mucositis 72.1 15.3 8.7 0.9
Paronychia 56.8 0 11.4 0
LUX-Lung 6 [41] 364 Cisplatin/gemcitabine Diarrhea 88.3 10.6 5.4 0
Rash/acne 80.8 8.8 14.6 0
Stomatitis/mucositis 51.9 5.3 5.4 0
Paronychia 32.6 0 0 0
LUX-Lung 7 [1] 319 Gefitinib Diarrhea 90.0 61.0 12.5 1.0
Rash/acne 88.8 81.1 9.0 3.0
Stomatitis 64.4 24.0 4.0 0
Paronychia 55.6 17.0 2.0 1.0
LUX-Lung 8 [45] 795 Erlotinib Diarrhea 69.9 33.4 10.5 2.5
Rash/acne 67.1 67.3 6.0 10.0
Stomatitis 28.8 8.6 4.0 0
Paronychia 10.5 4.3 <1.0 <1.0
Dacomitinib ARCHER 1050 [2] 452 Gefitinib Diarrhea 71.5 55.8 8.8 <1.0
Paronychia 50.5 20.1 7.5 1.3
Dermatitis acneiform 48.9 28.6 13.7 0
Stomatitis 43.6 17.9 3.5 <1.0
Osimertinib AURA3 [62] 419 Platinum/pemetrexed Diarrhea 40.5 11.0 1.1 1.5
Rash 33.7 5.9 <1.0 0
Dry skin 23.3 4.4 0 0
Paronychia 21.9 1.5 0 0
FLAURA [3] 556 Gefitinib/erlotinib Rash/acne 57.7 78.0 1.1 6.9
Diarrhea 57.7 57.4 2.2 2.2
Dry skin 35.8 36.1 <1.0 1.1
Paronychia 34.8 32.9 <1.0 <1.0
Gefitinib IPASS [20] 1,217 Carboplatin/paclitaxel Rash/acne 66.2 22.4 3.1 0.8
Diarrhea 46.6 21.7 3.8 1.4
Stomatitis 17.0 8.7 0.2 0.2
Paronychia 13.5 0 0.3 0
NEJ002 [23] 230 Carboplatin/paclitaxel Rash 71.1 22.1 5.3 2.7
Elevated ALT/AST 55.3 32.7 26.3 <1.0
Diarrhea 34.2 6.2 <1.0 0
WJTOG3405 [22] 177 Cisplatin/docetaxel Rash 74 7 2 0
Elevated AST 61 17 14 1
Elevated ALT 61 35 24 2
Diarrhea 47 35 1 0
Erlotinib EURTAC [31] 173 Cisplatin/docetaxel or Rash 79.8 5.0 13.0 0
gemcitabine
Diarrhea 57.1 18.0 5.0 0
ENSURE [32] 217 Cisplatin/gemcitabine Rash 70.9 6.4 10.6 1.0
Diarrhea 45.5 – 8.7 –
OPTIMAL [33] 165 Carboplatin/gemcitabine Rash 73.5 19.4 2.4 0
Elevated ALT 37.3 33.3 3.6 1.4
Diarrhea 25.3 5.6 1.2 0
Icotinib CONVINCE [76] 296 Cisplatin/pemetrexed Rash 15.5 1.5 14.9 1.5
Diarrhea 9.5 4.4 4.4 4.4
AEs = adverse events, ALT = alanine aminotransferase, AST = aspartate transaminase, EGFR = epidermal growth factor receptor, NSCLC = non-small cell lung cancer,
TKI = tyrosine kinase inhibitor.

on TKI therapy for as long as they experience clinical benefit. methods for detecting EGFR mutations in NSCLC patients
In clinical trials, discontinuations due to treatment-related AEs [87]. Less invasive tumor sampling allows for repeat biopsies,
were generally low (around 10% or less) [2,3,9,20,22,31–33,41] which can guide treatment selection and monitor therapeutic
efficacy. Also, liquid biopsy techniques facilitate mutation test-
ing when tissue biopsy or repeat biopsies are not possible or
6. Advances in EGFR mutation testing refused.
Liquid biopsies can potentially be obtained from blood,
With the increased number of agents in development target- saliva, or urine [88], and cftDNA or DNA isolated from CTCs
ing specific resistance mutations in NSCLC, as well as our can undergo EGFR mutational testing by a variety of methods.
increased understanding of the mechanisms that drive EGFR Studies have demonstrated correlation between EGFR muta-
TKI resistance, it is becoming increasingly important to re- tions detected in plasma and urine tumor DNA and mutations
biopsy tumors at subsequent stages of treatment. In recent detected in tissue samples, suggesting cftDNA is a potentially
years, the development of techniques to isolate CTCs and valid screening tool for EGFR mutation detection [89–91].
cftDNA from liquid biopsies has provided less invasive
EXPERT REVIEW OF ANTICANCER THERAPY 555

Furthermore, in a prespecified analysis of the EURTAC trial, of EGFR resistance mutations, such as T790M, a common mechan-
L858R EGFR mutations detected in cftDNA were associated ism of resistance to EGFR-TKI therapy. Furthermore, with increased
with significantly shorter OS compared with del19 EGFR muta- use of T790M mutation-specific EGFR TKIs, additional resistance
tions [92]. The FDA approved testing of peripheral blood for mechanisms will need to be identified and targeted. There is
del19/L858R mutations in June 2016 and the T790M mutation a need to incorporate comprehensive tumor genomic testing in
in September 2016. the clinic to identify emerging resistance to EGFR TKIs, which
Many liquid biopsy platforms are now available, and the includes not only T790M mutations but also other mechanisms
advantages/disadvantages of specific assays have been such as MET and HER2 amplification [4], which can be targeted
reviewed in detail elsewhere [93]. At present, few assays with currently available agents. Also, it is becoming clear that
have been reliably and prospectively validated, so questions acquired resistance to the mutation-selective EGFR TKIs (e.g. osi-
remain about their clinical applicability. In general, while cur- mertinib) via C797S mutation represents a clinical challenge, and
rent assays have high specificity, sensitivity is more limited EAI045 is in development to target this particular resistance
[93]. Consequently, mutations detected by liquid biopsy are mechanism. Osimertinib has recently demonstrated striking clin-
actionable but negative results should be followed by tumor ical activity and favorable tolerability in a first-line setting, and is
biopsy testing in order to confirm the negative result [93,94]. thus a first-line treatment of choice in patients with EGFR muta-
Also, liquid biopsy does not provide information on possible tion-positive NSCLC. However, targeted therapeutic options fol-
coexisting resistance mechanisms. For example, while plasma lowing osimertinib are unclear at present because resistance
assays can detect T790M, they will not detect cases of con- mechanisms are not clearly defined at this time. There is some
comitant small-cell transformation [95]. Despite these limita- discussion whether to reserve osimertinib for second-line use,
tions, liquid biopsy can play an important complementary role since the majority of patients treated with first- or second-
to standard tissue biopsy and may, in cases, assist when tissue generation TKIs develop T790M-positive tumors. Post-hoc analysis
biopsy is unavailable at initial screening [96]. of LUX-Lung 7 demonstrated that around 90% of 43 patients
treated sequentially with afatinib or gefitinib followed by third-
generation EGFR TKIs survived for at least 3 years [44].
7. Expert opinion Furthermore, in a recent observational study of 204 patients
EGFR TKIs are an important component of the NSCLC treat- who received sequential afatinib and osimertinib, overall median
ment landscape. Resistance to EGFR TKIs is inevitable, and time on treatment was 27.6 months overall, 30.3 months in
effective treatment of resistant tumors depends on the ability patients with tumors harboring an EGFR del19 mutation, and
to easily obtain repeat tumor samples. Non-invasive liquid 46.7 months in Asian patients [8]. A recent study that utilized
biopsy methods are more convenient for repeated sampling, a highly sensitive droplet-digital PCR liquid biopsy technique
and we need to incorporate cftDNA testing into the NSCLC indicated that the frequency of T790M following afatinib may be
diagnostic pathway to improve our ability to identify the as high as 73%, with some tumors having a low allelic frequency of
patients who will benefit from EGFR-TKI therapy. T790M below the detection threshold of other platforms [6].
The promising efficacy of the combination of erlotinib and Importantly, response to osimertinib was independent of the
bevacizumab in NSCLC underscores the need to explore allelic frequency of T790M in this study. Therefore, sequential
newer combinations of EGFR TKIs with other targeted agents. afatinib followed by osimertinib may be an option for some
EGFR TKIs are being evaluated in NSCLC in combination with patients with EGFR mutation-positive NSCLC and could be facili-
programmed death 1 (PD1) and PD-L1 inhibitors, including tated by wider availability of sensitive liquid biopsy assays. Recent
nivolumab, pembrolizumab, and durvalumab. Subgroup ana- exploratory analysis of ARCHER 1050 demonstrated that dacomi-
lyses and a subsequent meta-analysis have demonstrated that tinib confers an OS benefit in a first-line setting, the first TKI to
the HRs for survival outcomes in EGFR mutation-positive demonstrate such a benefit against another TKI [49]. Only 22
NSCLC patients favored docetaxel rather than immune check- patients received a sequential third-generation TKI after dacomi-
point inhibitors (nivolumab, atezolizumab, or pembrolizumab) tinib, but OS (median of 36.7 months) in these patients was
[97–99], suggesting that patients with EGFR mutation-positive encouraging [49], thus suggesting that sequential dacomitinib
tumors may not respond well to PD1 and PD-L1 inhibitors and osimertinib could also be an attractive strategy. However,
when compared to wild-type. Indeed, a recent phase II study there are few data regarding the CNS activity of dacomitinib and
of 11 patients with EGFR mutation-positive NSCLC treated with real-world data assessing the activity of dacomitinib are limited at
pembrolizumab indicated that monotherapy with checkpoint present.
inhibitors is not an appropriate treatment choice in this set- While there is some evidence to support reserving osi-
ting [100]. Combination of checkpoint inhibitors with EGFR mertinib for second-line use, these findings have to be
TKIs in EGFR mutation-positive patients may overcome this balanced with the impressive improvement in PFS in
observation, though this remains to be seen. Of note, preli- patients receiving front-line osimertinib compared to erloti-
minary data suggest an increased risk of interstitial lung dis- nib and gefitinib in the FLAURA trial. In addition, data from
ease after sequential or combination treatment with a PD1/ the FLAURA trial indicates that osimertinib has a better
PD-L1 inhibitor (e.g. nivolumab, durvalumab) and osimertinib toxicity profile and CNS penetration than first-generation
and thus further investigation is warranted [101–104]. EGFR TKIs [3,52]. Also, up to a third of the patients receiving
The approval of osimertinib and continuing clinical develop- front-line EGFR-TKI therapy in Phase III trials do not go on to
ment of mutation-specific EGFR TKIs aim to target the emergence receive any second-line therapy [105]. Furthermore, if
556 L. KUJTAN AND J. SUBRAMANIAN

reserved for second-line use, a proportion of patients, i. demonstrated OS advantage over gefitinib. Osimertinib OS
e. those who develop T790M-independent mechanisms of data are immature.
acquired resistance, will not be eligible to receive osimerti- ● Regardless of which agent is chosen as first-line therapy,
nib and will therefore not benefit from its favorable efficacy most patients will become resistant to therapy so the avail-
and tolerability. Thus, there is a risk of reserving osimertinib ability of treatment options beyond progression is an
for second-line use. Ultimately, further studies will help important consideration.
determine whether there is any benefit in sequencing osi- ● At least half of patients treated with first- and second-
mertinib after second-generation EGFR TKIs rather than generation EGFR TKIs acquire the T790M resistance mutation
using it in a first-line setting. which can be effectively treated with second-line osimertinib.
In the last few years there has been significant progress in Resistance mechanisms to osimertinib are heterogeneous.
several fronts against EGFR TK mutation-positive NSCLC ● Targeted treatment options after failure of osimertinib, and for
including the ability to non-invasively detect EGFR TK muta- patients with T790M-independent acquired resistance to first-
tions and the development of third-generation EGFR TKIs. and second-generation EGFR TKIs, are an unmet medical need.
However, we need to better understand the resistance ● Further development of liquid biopsy techniques may help
mechanisms to EGFR-TKIs, and develop effective strategies to to facilitate the screening and monitoring of tumor evolu-
target them with the eventual goal of making EGFR mutation- tion in the clinic thus optimizing sequential treatment.
positive NSCLC a chronic disease.
Acknowledgments
8. Five-year view The authors would like to thank Lauren Fink, of MedErgy and Lynn
Pritchard, of GeoMed, an Ashfield Company, part of UDG Healthcare plc,
The development of EGFR TKIs represented a quantum leap for their medical writing assistance.
in terms of treatment options for patients with EGFR muta-
tion-positive NSCLC. A little over a decade ago, these
patients received front-line platinum doublet chemotherapy. Funding
Even contemporary doublets such as pemetrexed-cisplatin This manuscript has received medical writing assistance funded by
would only offer median OS of 12 months or less [106]. Boehringer Ingelheim.
EGFR TKIs have eliminated chemotherapy in the front-line
setting for these patients, and each new generation of drug
improves on the last. Given the ever expanding armamen- Declaration of interest
tarium of EGFR TKIs, including osimertinib, improvements in J Subramanian has served on the advisory boards for AstraZeneca, Bristol-
the understanding of resistance mechanisms to different Myers Squibb, Alexion, Pfizer, and Boehringer Ingelheim. They have also
agents, and technological developments in the molecular served on speaker bureaus for Lilly, AstraZeneca, and Boehringer
Ingelheim. The authors have no other relevant affiliations or financial
analysis of tumors, it is likely that median OS rates of at involvement with any organization or entity with a financial interest in
least three years will become commonplace, as effective or financial conflict with the subject matter or materials discussed in the
sequential regimens are employed according to individual manuscript apart from those disclosed.
patient and tumor characteristics. As such, EGFR mutation-
positive NSCLC could become a chronic manageable disease
in many patients. Reviewer disclosures
Key issues still need to be addressed, not least of which is Peer reviewers on this manuscript have no relevant financial or other
that no targeted treatment options have been defined follow- relationships to disclose.
ing osimertinib failure. It is likely that such treatment options
will be identified within the next five years such as fourth- ORCID
generation EGFR TKIs to target tertiary EGFR mutations or
Lara Kujtan http://orcid.org/0000-0001-9758-1777
novel combination regimens in patients with EGFR indepen-
Janakiraman Subramanian http://orcid.org/0000-0003-0083-9896
dent resistance mechanisms.

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