Making the first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-generation TKI?

Abstract

The traditional approach to the treatment of patients with advanced-stage non-small-cell lung carcinoma (NSCLC) harbouring ALK rearrangements or EGFR mutations has been the sequential administration of therapies (sequential treatment approach), in which patients first receive first-generation tyrosine-kinase inhibitors (TKIs), which are eventually replaced by next-generation TKIs and/or chemotherapy upon disease progression, in a decision optionally guided by tumour molecular profiling. In the past few years, this strategy has been challenged by clinical evidence showing improved progression-free survival, improved intracranial disease control and a generally favourable toxicity profile when next-generation EGFR and ALK TKIs are used in the first-line setting. In this Review, we describe the existing preclinical and clinical evidence supporting both treatment strategies - the 'historical' sequential treatment strategy and the use of next-generation TKIs - as frontline therapies and discuss the suitability of both strategies for patients with EGFR-driven or ALK-driven NSCLC.

Full text

The treatment of patients with lung cancer is rapidly
evolving. In the past 20 years, the clinical management
of these patients has shifted from a histology- based
approach towards a molecularly driven approach, owing
to the development of targeted therapies against the
driver mutations of this disease, which affect a number
of kinases1–3; this strategy has improved the outcomes
for patients, which is important considering the high
incidence and mortality of this disease4.
Approximately 50% of Asian patients with non- small-
cell lung carcinoma (NSCLC) and 11–16% of patients in
Western countries harbour mutations in EGFR, which
affect the kinase domain of EGFR5–7. The majority of
these alterations (>90%) are deletions within exon 19
or L858R point mutation8. Genomic rearrangements
involving the ALK gene occur in 3–6% of patients with
NSCLC9,10. Other genomic alterations (in MET, ROS1,
HER2, BRAF, or RET) are less frequent.
In the past decade, the first- generation EGFR
tyrosine- kinase inhibitors (TKIs) gefitinib, erlotinib, and
icotinib, and the second- generation TKI afatinib were
established as standard- of-care first- line therapies for
patients with NSCLC harbouring activating mutations
in EGFR11. Despite high initial response and disease
control rates, virtually all the patients receiving these
TKIs eventually experience tumour progression owing
to the emergence of therapeutic resistance12. Resistance
to TKIs is most commonly acquired denovo during
treatment, but can also occur owing to the outgrowth of
pre- existing resistant subclones13. In approximately 50%
of patients, resistance was mediated by the acquisition of
the ‘gatekeeper’ mutation T790M, which results in steri-
cal blockade of first- generation or second- generation
TKI binding and also increases the kinase affinity for
ATP14–17. Osimertinib is an irreversible third- generation
EGFR TKI that is active against exon 19 deletions and
L858R mutation, regardless of the presence of T790M
mutation18. This TKI forms a covalent bond to the
cysteine residue at position 797 and has lower activ-
ity than the aforementioned TKIs against wild- type
EGFR protein. Osimertinib was initially approved by
the FDA and European Medicines Agency (EMA) as the
standard- of-care treatment for patients with tumours
harbouring the EGFRT790M mutation after progression
upon treatment with a first- line EGFR TKI19–21.
Since 2011, the first- generation TKI crizotinib has
been the frontline treatment for NSCLC harbouring
translocations involving ALK22. As with EGFR TKIs,
all patients ultimately develop resistance to this agent,
and secondary point mutations in the kinase domain are
responsible for drug resistance in approximately 20% of
patients23. Unlike mutations causing EGFR resistance,
a diverse range of mutations in ALK affect the kinase
domain, and their incidence increases to 56% with
Making the first move in EGFR- driven
or ALK- driven NSCLC: first- generation
or next- generation TKI?
GonzaloRecondo1, FrancescoFacchinetti2, KenA.Olaussen1, BenjaminBesse1,3
andLucFriboulet
1*
Abstract | The traditional approach to the treatment of patients with advanced- stage
non- small-cell lung carcinoma (NSCLC) harbouring ALK rearrangements or EGFR mutations has
been the sequential administration of therapies (sequential treatment approach), in which
patients firstreceive first- generation tyrosine- kinase inhibitors (TKIs), which are eventually
replaced by next- generation TKIs and/or chemotherapy upon disease progression, in a decision
optionally guided by tumour molecular profiling. In the past few years, this strategy has been
challenged byclinical evidence showing improved progression- free survival, improved
intracranial disease control and a generally favourable toxicity profile when next- generation
EGFR and ALK TKIs are used in the first- line setting. In this Review , we describe the existing
preclinical and clinical evidence supporting both treatment strategies — the ‘historical’
sequential treatment strategy and the use of next- generation TKIs — as frontline therapies and
discuss the suitability of both strategies for patients with EGFR- driven or ALK- driven NSCLC.
1INSERM U981, Gustave
Roussy Cancer Campus,
Université Paris Saclay,
Villejuif, France.
2Medical Oncology Unit,
University Hospital of Parma,
Parma, Italy.
3Department of Cancer
Medicine, Gustave Roussy
Cancer Campus,
Villejuif, France.
*e- mail: luc.friboulet@
gustaveroussy.fr
https://doi.org/10.1038/
s41571-018-0081-4
REviEwS
Nature reviews
|
CliniCal OnCOlOgy

sequential exposure to ALK TKIs23. Ceritinib, alectinib,
and brigatinib are second- generation ALK inhibitors
with activity against a wide spectrum of secondary resist-
ance mutations affecting the ALK kinase domain24–26.
These TKIs were first developed in the setting of cri-
zotinib resistance, in which they had shown potent
activity in preclinical studies24–26. Similarly, lorlatinib,
a third- generation ALK inhibitor, has been developed
to be administered after progression following treat-
ment with first- generation and/or second- generation
TKIs27. In this Review, ‘next- generation TKI’ refers to
the third- generation EGFR TKI osimertinib, the second-
generation ALK TKIs ceritinib, alectinib, and brigatinib,
and the third- generation ALK TKI lorlatinib.
In the ‘historical’ sequential treatment approach,
patients with NSCLC receive frontline therapy with a
first- generation TKI and ‘switch’ to next- generation TKIs
and/or chemotherapy upon disease progression. In 2017,
however, next- generation inhibitors have emerged as
treatment options in the first- line setting, on the basis of
the increased efficacy observed when directly compared
with historical first- line TKIs28–30. The lack of compara-
tive survival outcomes has hampered the elucidation of
the most beneficial strategy for patients in the long term.
Herein, we present the evidence currently available on
the antitumour activity of EGFR and ALK TKIs, reported
in both preclinical and clinical studies, and discuss the
advantages and drawbacks of both strategies for patients
with EGFR- driven or ALK- driven NSCLC.
Historical approach: sequential treatment
EGFR TKIs. The publication of two studies in 2004
(REFS31,32) describing the predictive value of sensitizing
mutations in EGFR on the activity of EGFR inhibitors
is a key landmark in the development of potent drugs
to treat molecularly selected patients with NSCLC31,32.
Multiple phase III trials comparing the first- generation
EGFR TKIs erlotinib, gefitinib, or icotinib, as well as
the second- generation TKI afatinib, with platinum-
based chemotherapy as frontline therapies for patients
with advanced- stage disease have been reported33–50
(TABLE1). A consistent benefit in favour of EGFR TKIs
is observed across studies in terms of progression- free
survival (PFS), response rates, and disease control rates.
The median PFS with these compounds ranged from
8.0–13.1 months, compared with 4.6–6.9 months with
chemotherapy (range of HRs 0.16–0.48). Given this
impressive PFS benefit, an important overall survival
benefit was expected51. Nevertheless, median overall
survival durations were equivalent for both trial arms
across studies (19.3–34.8 months), predominantly owing
to the high rates of treatment crossover (54−95%). The
findings of these studies also provided the first demon-
stration that, in the context of oncogene addiction,
the clinical benefit derived from treatment with TKIs
is independent of whether the patients were treated
upfront or after first- line chemotherapy.
For the treatment of patients with the most frequent
EGFR mutations (L858R and exon 19 deletions), the
choice of a first- generation or second- generation EGFR
inhibitor depends on the physician’s preference, the
toxicity profile, and the local availability of each agent.
No differences in the efficacy of erlotinib, gefitinib, or
afatinib in terms of PFS and overall survival have been
detected in comparative studies (CTONG 0901 (REF.52)
and LUX- Lung 7 (REFS53,54)). Icotinib has been demon-
strated to be non- inferior to gefitinib, leading to its
approval in 2014 in China as a frontline treatment for
patients with advanced- stage EGFR- mutant NSCLC but
its development in Western countries was not pursued45.
In the ARCHER 1050 trial, dacomitinib, another second-
generation irreversible EGFR TKI, was associated with
longer PFS and overall survival durations than gefitinib
(34.1 months versus 26.8 months, HR 0.76; P = 0.044)55,56
(TABLE1). This improvement was achieved at the cost
of higher toxicity (frequency of grade 3 adverse events
63% versus 41%) and a detrimental effect on quality
of life (QOL)55. Similarly, the addition of erlotinib to
bevacizumab extended PFS duration for an average
of 6 months compared with erlotinib monotherapy47,
although again at the expense of increased toxicity
(frequency of grade 3 adverse events 91% versus 53%);
the combination regimen was approved by the EMA in
2016 as a first- line treatment option46.
For patients treated with first- line EGFR TKIs,
blood- based and/or tumour sampling analysis upon
disease progression is mandatory to study the T790M
mutational status, owing to the clinical benefits shown
for patients in this subgroup who received sequential
treatment with osimertinib in multiple studies18,21,57–59
(TABLE1). In the AURA 3 randomized phase III trial21,
for example, osimertinib was associated with better
median PFS durations and overall response rates (ORRs)
than cisplatin plus pemetrexed in the second- line set-
ting (TABLE1). In comparison with the chemotherapy
regimen, patients receiving osimertinib also had an
improved QOL, with better scores for lung cancer symp-
toms and a lower incidence of grade ≥3 adverse events
(23% versus 47%). At a median follow- up duration of
8.3 months, 71% of patients receiving chemotherapy had
crossed over to receive osimertinib after disease pro-
gression, and the median overall survival had not been
reached in either treatment arm. The extended benefit of
the sequential administration of a first- generation EGFR
TKI followed by osimertinib observed in this study21
drove the approval of this compound for patients with
NSCLC harbouring the T790M mutation and disease
progression after treatment with first- generation or
second- generation EGFR TKIs.
Key points
•PatientswithEGFR-drivenorALK-drivennon-small-celllungcarcinoma(NSCLC)
benefitfromtherapiestargetingthosealterations,butrelapseoccurssystematically.
•Severalgenerationsoftyrosinekinaseinhibitors(TKIs)havebeendevelopedto
addresstheacquisitionoftherapeuticresistance.
•ThehistoricaltreatmentapproachinvolvingsequentialadministrationofTKIsis
associatedwithlongoverallsurvivaldurations.
•Clinicalevidencefromthepastfewyearsindicatesthattheuseofnext-generation
TKIsinthefrontlinesettingisassociatedwithmajorimprovementsinprogression-free
survival,controlofintracranialdiseaseandtolerability.
•FormostpatientswithEGFR-drivenorALK-drivenNSCLC,thechoiceoffirst-line
oftreatmentshouldfavournext-generationTKIs.
www.nature.com/nrclinonc
Reviews

Nature reviews
|
CliniCal OnCOlOgy
Reviews
Table 1 | Clinical trials testing EGFR TKIs in sequential strategy
Trial Trial design (phase, primary end point and
treatment arms, including number of patients
harbouring EGFR mutations)a
Median follow- up
duration (months)
Outcomes (ORR, median PFS and
median OS)
Refs
First generation
IPASS • III
• PFS
• Gefitinib (n = 132) versus carboplatin + paclitaxel
(n = 129)
17 • 71.2% versus 47.3%
• 9.5 mo versus 6.3 mo (HR 0.48; P < 0.001)
• 21.6 mo versus 21.9 mo (HR 1.00; P = 0.99)
33,34
First- SIGNAL • III
• OS
• Gefitinib (n = 26) versus cisplatin + gemcitabine
(n = 16)
35 • 84.6% versus 37.5%
• 8 mo versus 6.3 mo (HR 0.54; P = 0.086)
• 27.2 mo versus 25.6 mo (HR 1.04)
35
WJTOG3405 • III
• PFS
• Gefitinib (n = 86) versus cisplatin + docetaxel (n = 86)
34 (59.1 for OS
analysis)
• 62.1% versus 32.2%
• 9.2 mo versus 6.3 mo (HR 0.49; P < 0.0001)
• 34.8 mo versus 37.3 mo (HR 1.25)
36,37
NEJ002 • III
• PFS
• Gefitinib (n = 114) versus carboplatin + paclitaxel
(n = 114)
23.4 • 73.7% versus 30.7%
• 10.8 mo versus 5.4 mo (HR 0.30; P < 0.001)
• 27.7 mo versus 26.6 mo (HR 0.89; P = 0.48)
38,39
OPTIMAL
(CTONG-0802)
• III
• PFS
• Erlotinib (n = 82) versus carboplatin + gemcitabine
(n = 72)
25.9 • 83% versus 36%
• 13.1 mo versus 4.6 mo (HR 0.16; P < 0.0001)
• 22.8 mo versus 27.2 mo (HR 1.19; P = 0.27)
40,41
ENSURE • III
• PFS
• Erlotinib (n = 110) versus cisplatin + gemcitabine
(n = 107)
28.9 (erlotinib
arm) and 27.1
(chemotherapy
arm)
• 62.7% versus 33.6%
• 11 mo versus 5.5 mo (HR 0.34; P < 0.0001)
• 26.3 mo versus 25.5 mo (HR 0.91; P = 0.61)
42
EURTAC • III
• PFS
• Erlotinib (n = 86) versus platinum + gemcitabine or
paclitaxel (n = 87)
18.9 (erlotinib
arm) and 14.4
(chemotherapy
arm)
• 63.6% versus 17.8%
• 9.7 mo versus 5.2 mo (HR 0.37; P < 0.0001)
• 19.3 mo versus 19.5 mo (HR 1.04; P = 0.87)
43
BELIEF • I I
• PFS
• Erlotinib + bevacizumab (n = 109)
21.4 • 77%
• 13.2 mo whole cohort; 16.0 mo T790M+
• 28.2 months
46
JO25567 • I I
• PFS
• Erlotinib + bevacizumab (n = 75) versus erlotinib
(n = 77)
20.4 • 69% versus 64%
• 16 mo versus 9.7 mo (HR 0.54; P = 0.0015)
• NA
47
CTONG 0901 • III
• PFS
• Erlotinib (n = 128) versus gefitinib (n = 128)
22.1 • 56.3% versus 53.3%
• 13.0 mo versus 10.4 mo (HR 0.81, P = 0.11)
• 22.9 mo versus 20.1 mo (HR 0.84; P = 0.25)
52
CONVINCE • III
• PFS
• Icotinib (n = 148) versus cisplatin + pemetrexed
(up to four cycles) eventually followed by
pemetrexed maintenance (n = 137)
18 (icotinib
arm) and 15.7
(chemotherapy
arm)
• NR
• 11.2 mo versus 7.9 mo (HR 0.61; P = 0.006)
• 30.5 mo versus 32.1 mo (P = 0.89)
44
ICOGEN • III
• PFS (non- inferiority in full data set)
• Icotinib (n = 29) versus gefitinib (n = 39)
NA • 62.1% versus 53.8%
• 7.8 mo versus 5.3 mo (HR 0.78; P = 0.32)
• 20.9 mo versus 20.2 mo (HR 1.1; P = 0.76)
45
Second generation
LUX- Lung 3 • III
• PFS
• Afatinib (n = 230) versus cisplatin + pemetrexed
(n = 115)
41 • 56% versus 23%
• 11.1 mo versus 6.9 mo (HR 0.58: P = 0.001)
• Whole cohort: 28.2 mo versus 28.2 mo (HR
0.88; P = 0.39)
• Exon 19 deletion: 33.3 mo versus 21.1 mo
(HR 0.54; P = 0.002)
48,50
LUX- Lung 6 • III
• PFS
• Afatinib (n = 242) versus cisplatin + gemcitabine
(n = 122)
33 • 66.9% versus 23%
• 11.0 mo versus 5.6 mo (HR 0.28; P < 0.0001)
• 23.1 mo versus 23.5 mo (HR 0.93; P = 0.61)
49,50
LUX- Lung 7 • IIB
• PFS, TTF and OS
• Afatinib (n = 160) versus gefitinib (n = 159)
42.6 • 70% versus 56%
• 11.0 mo versus 10.9 mo (HR 0.73; P = 0.017)
• 27.9 mo versus 24.5 mo (HR 0.86; P = 0.26)
53,54
ARCHER-1050 • III
• IRC- assessed PFS
• Dacomitinib (n = 227) versus gefitinib (n = 225)
31.3 • 75% versus 70%
• 14.7 mo versus 9.2 mo (HR 0.59; P < 0.0001)
• 34.1 mo versus 26.8 mo (HR 0.76; P = 0.0438)
55,56

www.nature.com/nrclinonc
Reviews
ALK TKIs. Crizotinib is a first- generation TKI of ALK,
MET, and ROS1, and was the first agent to be approved
for the treatment of patients with NSCLC harbouring
ALK translocations60–63. Two randomized phase III tri-
als established the superiority of crizotinib over chemo-
therapy in patients with advanced- stage NSCLC, either
as a first- line therapy22 or in patients with disease pro-
gression after receiving a platinum- based regimen64. In
the PROFILE 1014 study22, greater response rates and
median PFS durations were achieved with crizotinib than
with platinum- based therapy (TABLE2). Again, no signifi-
cant differences in overall survival were observed, with a
4-year survival of 56.6% with crizotinib and 49.1% with
chemotherapy65. This effect was mostly due to the high
crossover rates (84.2%) from crizotinib to the experimen-
tal arm. In an exploratory analysis, after adjusting for
crossover, the median overall survival was 59.8 months
with crizotinib and 19.2 months with chemotherapy.
Sequential treatment strategies with ALK inhibitors
have been developed with the aim of extending overall
survival durations61–63,66–81 (TABLE2). Unlike EGFR inhibi-
tors, a wide repertoire of ALK TKIs is available for patients
with disease progression after treatment with crizotinib;
the second-generation ALK TKIs ceritinib, alectinib,
and brigatinib have been developed to overcome most
resistance mechanisms24–26. Treatment with ceritinib
was associated with improved outcomes compared with
second-line chemotherapy (ORR 39.1% versus 6.9%, and
a median PFS gain of ~4 months) in patients with dis-
ease relapse after receiving crizotinib and platinum-based
chemotherapy72 (TABLE2). In the same disease setting, the
results of the phase III ALUR trial77 and the phase II ALTA
trial76 demonstrated beneficial outcomes with alectinib
and brigatinib, respectively (TABLE2). The third-generation
ALK TKI lorlatinib has activity against resistance muta-
tions arising after treatment with first-generation and/or
second-generation TKIs, including the G1202R muta-
tion27. Lorlatinib has been tested in a dose-escalation
phase I study66 and in a phase II trial81 (TABLE2).
One of the major concerns in the management
of patients with ALK-translocated tumours is the
high risk of developing brain metastases; 22–33% of
patients present with central nervous system (CNS)
involvement at diagnosis, and the prevalence of brain
metastases increases to 45–70% upon progression on
crizotinib treatment68,69,73,75,82. The improved CNS activ-
ity of second-generation and third-generation ALK
TKIs results from both their higher CNS penetration
and increased potency compared with crizotinib27.
Intracranial responses have been observed in 45% of
patients receiving ceritinib69, 64% of those receiving
alectinib83, and 67% treated with brigatinib84. Brigatinib
was associated with an intracranial PFS of 18.4 months
with the standard dose84. Importantly, even 42% of
patients in a heavily pretreated cohort (≥2 lines of ALK
TKIs) had intracranial disease control with lorlatinib,
and the cerebrospinal fluid concentration documented
for lorlatinib was 75% of the plasma concentration66.
Translational studies of resistance
A number of ‘back-to-benchside’ studies have been
conducted with the aim of characterizing the mecha-
nisms underlying clinical resistance to EGFR or ALK
TKIs. The results from these studies can provide a
Trial Trial design (phase, primary end point and
treatment arms, including number of patients
harbouring EGFR mutations)a
Median follow- up
duration (months)
Outcomes (ORR, median PFS and
median OS)
Refs
Third generation
AURA (dose-
escalation and
expansion
cohorts)
• I
• Safety and efficacy
• Osimertinib
• First line (n = 60 patients), second line or beyond
(n = 193)
19.1 and NA • 77% and 61%
• 20.5 mo and 9.6 mo
• NA
18,120
AURA
(extension
cohort)
• Phase II
• ORR
• Osimertinib (n = 201)
• Second line or beyond, prior treatment
with erlotinib (58%), gefitinib (58%) and/or
second- generation EGFR TKI (24%)
13.2 • 62%
• 12.3 mo
• Pooled analysis OS: 26.8 mo
• Median treatment exposure: 16.4 mo
57,59
AURA 2 • Phase II
• ORR
• Osimertinib (n = 210)
• Second line or beyond, prior treatment
with erlotinib (57%), gefitinib (58%) and/or
second- generation EGFR TKI (20%)
13.0 • 70%
• 9.9 mo
• Pooled analysis OS: 26.8 mo
• Median treatment exposure: 16.4 mo
58,59
AURA 3 • Phase III
• ORR
• Osimertinib (n = 279) versus
platinum + pemetrexed (n = 140)
• Second line, prior treatment with gefitinib (59%),
erlotinib (34%) or afatinib (7%)
8.3 • 71% versus 31%
• 10.1 mo versus 4.4 mo (HR 0.30; P < 0.001)
• NA
21
IRC, independent review committee; mo, months; NA , not available; NR , not reported; ORR , overall response rate; OS, overall survival; PFS, progression- free
survival; T790M+, patients with NSCLC harbouring T790M mutation in EGFR; TKI, tyrosine- kinase inhibitor ; TTF, time to treatment failure. aLine of treatment only
stated for third- generation inhibitors; all the first- generation and second- generation inhibitors were tested in the first- line setting.
Table 1 (cont.) | Clinical trials testing EGFR TKIs in sequential strategy

Nature reviews
|
CliniCal OnCOlOgy
Reviews
Table 2 | Clinical trials testing ALK TKIs in sequential strategy
Trial Trial design (phase, primary end point and treatment
arms, including number of patients and dosing
schedule when relevant)a
Median
follow- up
duration
Outcomes (ORR, median PFS and OS) Refs
First generation
PROFILE
1001
• I
• ORR , DOR , TTR , PFS, 6–12 mo OS, and safety profile
• Crizotinib (n = 149)
16.3 • 60.8%
• 9.7 mo
• 1-year OS 74.8%
61,62
PROFILE
1005
• I I
• ORR
• Crizotinib (n = 1069)
NA • 54%
• 8.4 mo
• 21.8 mo
63
PROFILE
1007
• III
• PFS
• Crizotinib (n = 173) versus pemetrexed or docetaxel
(n = 174)
12.2 mo
(crizotinib)
and 12.1 mo
(chemotherapy)
• 65% versus 20%
• 7.7 mo versus 3.0 mo (HR 0.49; P < 0.001)
• 20.3 mo versus 22.8 mo (HR 1.02; P = 0.54)
64
PROFILE
1014
• III
• PFS
• Crizotinib (n = 172) versus platinum + pemetrexed (n = 171)
46 mo • 74% versus 45%
• 10.9 mo versus 7.0 mo (HR 0.45; P < 0.001)
• NR (45.8 mo–NR) versus 47.5 mo (32.2 mo–NR;
HR 0.76; P = 0.048)
22,65
Second generation
ASCEND-1 • I
• MTD
• Ceritinib (n = 246)
• First line (33%) or second line after crizotinib (66%)
11.1 mo • 72% or 56%
• 18.4 mo or 6.9 mo
• NR or 16.7 mo
67,68
ASCEND-2 • I I
• ORR
• Ceritinib (n = 140)
• Second line after crizotinib
11.3 mo • 38.6%
• 5.7 mo
• 14.9 mo
69
ASCEND-3 • I I
• ORR
• Ceritinib (n = 124)
• First line
8.3 mo • 63.7%
• 11.1 mo
• NA
70
ASCEND-4 • III
• PFS
• Ceritinib (n = 189) versus platinum + pemetrexed (n = 187)
• First line
19.7 mo • 72.5% versus 26.7%
• 16.6 mo versus 8.1 mo (HR 0.55; P < 0.00001)
• NE (29.3 mo–NE) versus 26.2 mo (22.8 mo–NR;
HR 0.73; P = 0.056)
71
ASCEND-5 • III
• PFS
• Ceritinib (n = 115) versus pemetrexed or docetaxel (n = 116)
• Second line after crizotinib
16.5 mo • 39.1% versus 6.9%
• 5.4 mo versus 1.6 mo (HR 0.49; P < 0.0001)
• 18.1 mo versus 20.1 mo (HR 1.00; P = 0.5)
72
AF-001JP • I/II
• DLT and MTD (phase I) or ORR (phase II)
• Alectinib (n = 46)
• First line
36 mob• 93.5%
• NR; 3-year PFS: 62%
• NE; 3-year OS: 78%
73,74
AF-002JG • I/II
• Recommended phase II dose
• Alectinib (n = 47)
• Second line after crizotinib
4.2 mo • 55%
• NA
• NA
75
NP28761/
NP28673
• I I
• ORR
• Alectinib (n = 225; n = 189 evaluable for response)
• Second line after crizotinib
92.3 weeks • 51.3%
• 8.3 mo
• 29.1 mo
76,146
ALUR • III
• PFS
• Alectinib (n = 72) versus docetaxel or pemetrexed (n = 35)
• Second line after crizotinib
6.5 mo • 37.5% versus 2.9%
• 9.6 mo versus 1.4 mo (HR 0.15; P < 0.001)
• 12.6 mo (9.7 mo–NR) versus NR (NR–NR;
HR0.89)
77
NCT01449461 • Recommended phase II dose (phase I) or ORR (phase II)
• Brigatinib (n = 79)
• First line (10%, n = 8), second line after crizotinib
(85%, n = 68) or third line after crizotinib and ceritinib
(5%, n = 3)
>31 mobFirst- line brigatinib (n = 8):
• 100%
• 34.2 mo
• NR (2-year OS 100%)
Brigatinib after crizotinib (n = 71):
• 73%
• 13.2 mo
• 30.1 mo (2-year OS 61%)
78,79

www.nature.com/nrclinonc
Reviews
rationale for optimizing sequential treatment strate-
gies, because a better understanding of the biological
implications of therapeutic resistance can guide clini-
cians to provide the most adequate treatment upon
disease progression (FIG.1).
As discussed, the acquisition of the gatekeeper T790M
mutation in EGFR is the most common mechanism of
resistance to first-generation EGFR TKIs (detected in
50–60% of patients)12,14,85,86. The activation of ‘bypass’
signalling mechanisms is also relevant in this scenario,
and involves potential therapeutic targets, such as MET,
AXL, IGF1R, and other members of the EGFR family87–90.
Resistance to third-generation EGFR TKIs has also been
described91: the most common tertiary mutation in EGFR
is C797S in 24–40% of patients, which affects the covalent
binding site of osimertinib92–94. This tertiary mutation
can be present in cis or trans with the T790M mutation95.
The results of preclinical studies suggest that combina-
tions of brigatinib or other novel EGFR inhibitors with
anti-EGFR monoclonal antibodies are an effective treat-
ment option when C797S is present in cis96,97. Resistance
dependent on the presence of the tertiary mutation in
trans can be overcome by combining first-generation and
third-generation EGFR TKIs98,99.
A range of secondary mutations affecting the kinase
domain of ALK confer resistance to different ALK TKIs.
The following mutations have been implicated in resist-
ance to crizotinib: G1269A, C1156Y, E1210K, I1171T,
L1152R, S1206C/Y, I1151T/N/S, F1174C/L/V, V1180L,
and L1196M23,100–104. F1174C/L/V, 1151Tins, L1152P,and
C1156Y mutations are associated with resistance to
ceritinib24. Both V1180L and I1171T/N/S alterations
confer resistance to alectinib, and double mutations in
E1210K and S1206C or D1203N have been reported
inpatients with resistance to brigatinib23,105. G1202R
is the most common resistance mutation emerging on
treatment with second-generation ALK inhibitors and is
only targetable with lorlatinib23,27,106,107. Interestingly, the
acquisition of both the C1156Y and L1198F mutations
upon lorlatinib treatment has been reported to resensi-
tize the tumour to crizotinib108. After the description of
this initial case report, the results of the first extensive
preclinical and clinical study of mutations causing resist-
ance to lorlatinib were published in 2018 by Yoda and
colleagues109. Using N-ethyl-N-nitrosourea-generated
mutagenesis screening to determine the secondary
mutations in ALK that can arise upon lorlatinib treat-
ment, these investigators found that single mutations in
ALK cannot cause resistance to lorlatinib. Indeed, only
double ALK mutations in cis were detected upon resist-
ance to lorlatinib, both in preclinical experiments and
in patient-derived samples. Thus, observations of the
stepwise accumulation of resistance mutations in ALK
suggest that upfront treatment with lorlatinib could
markedly delay the onset of on-target resistance, lead-
ing to a more durable clinical benefit than the current
sequential treatment approach.
Off-target resistance mechanisms, such as bypass
pathway activation, have also been reported in patients
with resistance to first-generation and second-generation
ALK TKIs23,102,110. The results of preclinical studies
revealed that treatment with second-generation ALK
TKIs could overcome resistance to crizotinib that devel-
ops without the acquisition of secondary mutations in
ALK24. This observation mainly suggests that crizo-
tinib has lower inhibitory potency against ALK than
do second-generation ALK TKIs, facilitating tumour
growth upon modest activation of bypass signalling
mechanisms. By contrast, treatment with lorlatinib
does not overcome resistance to second-generation
Trial Trial design (phase, primary end point and treatment
arms, including number of patients and dosing
schedule when relevant)a
Median
follow- up
duration
Outcomes (ORR, median PFS and OS) Refs
Second generation (cont.)
ALTA • II
• ORR
• Brigatinib 90 mg daily (n = 112) versus brigatinib
standard dosec (n = 110)
• Second line after crizotinib
19.6 mo (90 mg
daily) or 24.3
mo (standard
dose)
• 46% versus 56%
• 9.2 mo versus 15.6 mo
• 29.5 mo (18.2 mo–NR) versus 34.1 mo
(27.7 mo–NR)
80,147
Third generation
NCT01970865 • I
• MTD
• Lorlatinib (n = 41)
• First line (2.4%), second line (34.2%), third line (56.1%) or
fourth line (7.3%)
17.4 mo • 46%
• 9.6 mo (whole cohort), 13.5 mo (second line),
and 9.2 mo (third line and beyond)
• NA
66,81
• I I
• ORR
• Lorlatinib (n = 228)
• First line (13.1%), second line or beyond, prior treatment
with crizotinib only (11.8%), crizotinib + chemotherapy
(14.1%), non- crizotinib ALK TKI (12.3%), any two ALK TKIs
(28.5%), or any three ALK TKIs (20.2%)
NA • 90%, 69%, 33% or 39%
• NR , NR , 5.5 mo after treatment with ALK
inhibitor other than crizotinib, and 6.9 mo
after ≥2 lines of ALK TKIs
• NA
66,81
DLT, dose- limiting toxicity ; DOR , duration of response; mo, months; MTD, maximum tolerated dose; NA , not available; NE, not estimable; NR , not reported; ORR ,
overall response rate; OS, overall survival; PFS, progression- free survival; TKI, tyrosine- kinase inhibitor ; TTR , time to treatment recurrence. aLine of treatment stated
for second- generation and third- generation inhibitors; all the first- generation inhibitors were tested in the first- line setting. bUpdated presented data from the
original publication. c90 mg daily for 7 days and then 180 mg daily.
Table 2 (cont.) | Clinical trials testing ALK TKIs in sequential strategy

Nature reviews
|
CliniCal OnCOlOgy
Reviews
TKIs mediated by off-target mechanisms23,27. On the
basis of these observations, bypass mechanisms involv-
ing robust oncogenic pathways, such as MAP2K1, SRC,
EGFR, or PI3K, that are activated upon treatment with
second-generation ALK TKIs have been proposed to
also drive resistance to third-generation ALK TKIs23.
A series of laboratory studies have focused on
the brain penetration of both EGFR and ALK TKIs.
Erlotinib Dacomitinib Osimertinib
Osimertinib
Gefitinib Icotinib
First-line treatment for ALK-rearranged NSCLC
L1196M
S1206C/Y
E1210K
G1269A
I1151Tins
L1152P
C1156Y
F1174L/C/V
I1171T/N/S
G1202R
Brigatinib
Resistant mutations in ALK KD with crizotinib
Resistance mutations in ALK KD with next-generation ALK TKIs
Lorlatinib
Off-target
mechanisms
Unknown or
not studied
Off-target
mechanisms
Unknown or
not studied
Second-generation
ALK inhibitors
Local
treatment
b
Oligoprogressive
disease
Oligoprogressive
disease
Afatinib
Crizotinib
Crizotinib
EGFR T790M status
Loss of EGFR
T790M mutation
Local treatment
PositiveNegative
Activation of
bypass resistance
mechanism
• Clinical trial
• Chemotherapy
• Clinical trial
• Chemotherapy
Small-cell
transformation
Platinum +
etoposide
Tertiary kinase
mutations Yes
No
Unknown
resistance
mechanism
• Clinical trial
• Chemotherapy
• Clinical trial
• Chemotherapy
Off-target mechanism
of resistance?
First-line treatment for EGFR-mutant NSCLC
a
EGFR C797S
allelic distribution
TransCis
Erlotinib or
gefitinib
+ osimertinib
Alectinib
Alectinib
Alectinib
Alectinib
V1180L
I1171T/N/S
F1174L/C/V
C1156Y
C1156Y +
L1198F
E1210K + S1203N
E1210K + S1206C G1202R
Ceritinib
Ceritinib
Ceritinib
Ceritinib
Brigatinib
Brigatinib Brigatinib
Any second-
generation
Lorlatinib
Lorlatinib
Lorlatinib Lorlatinib
Lorlatinib Lorlatinib
Clinical trial
Molecular biology
and hypothesis
First-generation
TKI
Second-generation
TKI
Third-generation
TKI
Treatments
Fig. 1 | Biomarker integration in the management of patients with NSCLC. This chart depicts the optimal sequencing
strategies for the selection of frontline tyrosine- kinase inhibitors (TKIs; either first generation or next generation), adapted
to the occurrence of secondary mechanisms of resistance in patients with non- small-cell lung carcinoma (NSCLC)
harbouring EGFR mutations (part a) or ALK rearrangements (part b). KD, kinase domain.

www.nature.com/nrclinonc
Reviews
In studies using mouse models, alectinib was superior to
crizotinib in controlling metastatic disease in the CNS111;
moreover, responses to lorlatinib were observed even in
mice with disease progression after alectinib treatment27.
Importantly, evidence from several of these preclinical
studies suggests that next-generation TKIs provide
optimal long-term outcomes when used as frontline
treatments19,26,27.
Other preclinical studies were aimed at provid-
ing a biological rationale to explain systematic relapse
in patients treated with TKIs despite major initial
responses. Several studies have shown that a small sub-
population of tumour cells (<5%) cultured in the pres-
ence of a TKI remain alive and are reprogrammed into
a drug-tolerant state112–117. These cells, with limited or no
growth during months of TKI treatment, are referred to
as ‘persister’ cells and provide a reservoir of cells from
which drug-resistance mechanisms could emerge. Initial
studies have suggested that epigenetic reprogramming
of TKI-persister cells involves the histone demethylase
KDM5A and thus could be selectively targeted by his-
tone deacetylase inhibitors112. The results of preclinical
studies indicate that persister cells can later cause tumour
regrowth through the denovo acquisition of diverse
genetically driven resistance mechanisms, such as sec-
ondary mutations or activation of bypass signalling113,115.
Eradicating persister cancer cells early during the course
of treatment might therefore block or drastically post-
pone the onset of resistance. Persister cells display an
impaired apoptotic response to TKI (as assessed by
annexin V staining)115, and, thus, treatment with inhib-
itors of the BCL-2 family anti-apoptotic proteins has
been proposed to be a potentially effective therapeutic
strategy; the combination of osimertinib and navitoclax
is currently being tested in patients with NSCLC har-
bouring the EGFR T790M mutation (NCT02520778)115.
Two studies with results published in 2017 revealed a
common persister-cell-specific dependency on the lipid
hydroperoxidase GPX4, targeting of which prevented
tumour relapse in mice116,117.
Finally, tumour heterogeneity occurs early in the
course of cancer progression: in patients with resect-
able NSCLC, a median of 30% of the somatic muta-
tions detected are subclonal118. Tumour heterogeneity
is an important factor contributing to the develop-
ment of therapeutic resistance because it contributes
to both the selective expansion of pre-existing resist-
ant clones and the adaptive resistance of persister
tumour cells115. In patients with NSCLC harbouring
EGFR mutations and with disease progression after a
first-generation or second-generation TKI, the allelic
fraction of T790M mutations can, for instance, affect
the therapeutic response to third-generation EGFR
TKIs119. Observations in patients treated with osim-
ertinib95 or lorlatinib109 indicate that clones resistant
to third-generation TKIs can emerge upon sequential
treatment with first-generation and second-generation
EGFR or ALK TKIs, affecting the choice of the next
optimal treatment strategy. In line with these observa-
tions, preclinical and clinical studies performed dur-
ing first-line treatment with third-generation ALK and
EGFR TKIs revealed that the emergence of resistance
driven by on-target mutations can be delayed19,27,120.
Mice bearing EGFR19 and ALK27 TKI-sensitive tumours
treated with first-generation and third-generation
inhibitors showed prolonged tumour responses and
delay of resistance with third-generation TKIs. In two
cohorts of patients with EGFR-mutated NSCLC treated
with upfront osimertinib in the phase I AURA study,
none of the evaluable patients had disease progression
owing to T790M mutation120. Overall, in addition to
enabling the interpretation of the outcomes of clini-
cal studies, the studies discussed herein highlight the
importance of characterizing the molecular mecha-
nisms of resistance to TKIs during or after each line
of treatment using blood or tissue sampling to inform
clinical decision-making.
Paradigm shift for first-line therapy
The historical trend in the management of patients with
cancer has been to move more-potent, more-specific, and
possibly less-toxic drugs to the first-line treatment setting.
Similarly to chemotherapy, the magnitude of efficacy of
next-generation TKIs generally increases in accordance
with an earlier administration during the course of treat-
ment with targeted therapies21,28,29,71,72,77. Indeed, several
single-arm early phase trials in patients with NSCLC who
had not received any previous TKI showed prolonged dis-
ease control upon first-line treatment with osimertinib120,
ceritinib70, or alectinib74 (in comparison with data avail-
able for first-generation and second-generation TKIs).
In 2017, additional evidence of major PFS benefits
emerged from three phase III trials, supporting the
upfront use of next-generation TKIs over the standard
first-line EGFR TKIs and crizotinib (TABLE3).
EGFR TKIs. In the randomized phase III FLAURA
study28, osimertinib was compared as a frontline ther-
apy with the standard choice of gefitinib or erlotinib
in patients with NSCLC harbouring EGFR exon 19
deletions or L858R point mutation28. As expected,
the median PFS was significantly prolonged by
almost 9 months with osimertinib compared with
first-generation TKIs (HR 0.46; P < 0.001), although
the ORRs were similar between trial arms (TABLE3).
The median time to second-line treatment or death was
23.5 months with osimertinib and 13.8 months with
first-line EGFR TKI, and the median time to third-line
treatment was not reached and 25.9 months, respec-
tively. Brain imaging was mandatory at study entry, as
well as during the course of the study for patients with
brain metastases; at study entry, 19% of patients in the
osimertinib arm and 23% in the control arm had brain
metastases. Fewer patients treated with osimertinib
had disease progression in the CNS (6% versus15%)
or extracranial disease progression (38% versus 54%),
compared with the control arm28. The benefit in PFS
was maintained for patients with brain metastases
(15.2 months with osimertinib versus 9.6months
with first-generation TKIs; HR 0.47; P < 0.001).
Osimertinib was better tolerated than first-line TKIs
(34% versus 45% of patients had grade 3 adverse
events). Accordingly, the rate of treatment discontinu-
ation was 13% in the osimertinib arm compared with

Nature reviews
|
CliniCal OnCOlOgy
Reviews
18% in the control arm. Of note, QT interval prolon-
gations were more frequent with osimertinib than with
first-line TKIs (10% versus 4%). In this trial, crosso-
ver to subsequent treatment with osimertinib was
permitted in patients in whom the T790M mutation
was detected after progression upon treatment with
first-generation EGFR TKIs. Among the 129 patients
who received treatment after disease progression in the
control arm, 48 patients (37%) crossed over to receive
treatment with osimertinib; data on the overall sur-
vival of patients who received treatment after disease
progression are eagerly awaited.
ALK TKIs. Ceritinib was the first second-generation
TKI approved as a first-line treatment option for
patients with ALK-rearranged NSCLC on the basis of
the superior efficacy over platinum-based chemother-
apy observed in the ASCEND-4 study71 (TABLE2). In
this study, the incidence of grade 3–4 adverse events
was higher with ceritinib than with chemotherapy
(65%versus 40%), but treatment discontinuations
owing to toxicity occurred in 5% of patients treated with
ceritinib versus 11% in the control arm. This study was
designed before crizotinib was established as standard
first-line therapy in this disease setting; taking toxicities
into consideration, ceritinib remains a valid option for
first-line treatment. Encouraging results from a phase
I/II trial of brigatinib (NCT01970865) include a median
PFS of 34.2 months in 8 patients treated upfront with
this agent78. In another phase II trial, the ORR was 90%
in a cohort of 30 patients receiving frontline lorlatinib
and the median PFS had not been reached at the time of
reporting; mature results of this ongoing study will pro-
vide further insight into the clinical outcomes derived
from lorlatinib treatment81.
Alectinib is the first ALK inhibitor that was com-
pared against crizotinib in the first-line setting in two
randomized studies: the phase III trials J-ALEX30, con-
ducted in Japan, and the international ALEX trial29
(TABLE3). None of the patients enrolled in J-ALEX had
been previously treated with an ALK TKI, but 36% of
them had received chemotherapy. Alectinib was associ-
ated with a significant PFS benefit (TABLE3), as well as a
more favourable toxicity profile than crizotinib: grade 3
adverse events were reported in 26% of patients receiv-
ing alectinib versus 52% of those receiving crizotinib,
and fewer patients required dose interruptions (29%
versus 74%) or toxicity-related treatment suspensions
(9% versus 20%).
All the patients enrolled in the ALEX trial29 received
alectinib in the frontline setting. The median PFS dura-
tion and ORR were higher with alectinib than with cri-
zotinib; according to the last update121, median PFS was
34.8 months with alectinib and 10.9 months with crizo-
tinib (HR 0.43; 95% CI 0.32–0.58 months). Crossover
was not permitted in the study protocol, hampering the
direct comparison of outcomes obtained by administer-
ing alectinib using sequential or upfront strategies. One
strength of this study29, however, was the evaluation of
CNS activity through mandatory brain MRI at study
entry and every 8 weeks during treatment. Baseline brain
metastases were detected in 42% of patients allocated to
receive alectinib and in 38% of patients in the crizotinib
group. Patients with measurable CNS metastases had an
intracranial response rate of 81% (45% of them being
complete responses) with alectinib and 50% (9% com-
plete responses) with crizotinib. The median duration
of CNS responses was 17.3 months with alectinib and
5.5 months with crizotinib, and the 12-month cumu-
lative incidence of brain metastases was significantly
Table 3 | Clinical trials comparing first- generation and next- generation TKIs in the frontline setting
Trial Trial design (phase, primary
end point and treatment arms,
including number of patients and
dosing schedule when relevant)
Median follow- up
duration
Outcomes (ORR, median investigator- assessed PFS,
median IRC- assessed PFS, OS and grade ≥3 AEs)
Refs
ALK TKIs
ALEX • III
• Investigator- assessed PFS
• Alectinib (n = 152; 600 mg b.i.d.)
versus crizotinib (n = 151)
22.8 mo (alectinib arm)
and 27.8 mo (crizotinib
arm)a
• 82.9%a versus 75.5%
• 25.7 mo (95% CI 19.9 mo–NE) versus 10.4 mo (95% CI 7.7–14.6
mo; HR 0.50; P < 0.001); 34.8 moa versus 10.9 mo (HR 0.43; 95%
CI 0.32–0.58)
• 1-year OS 84.3% versus 82.5% (HR 0.76; P = 0.24)
• 44.7%a versus 51%
29,121
J- ALEX • III
• IRC- assessed PFS
• Alectinib (n = 103; 300 mg b.i.d.)
versus crizotinib (n = 104)
12 mo (alectinib arm)
and 12.2 mo (crizotinib
arm)
• 92% versus 79%
• NA ; HR 0.34 (95% CI 0.21–0.55)
• Not reached (95% CI 20.3 mo–NE) versus 10.2 mo (95% CI
8.2–12.0 mo; HR 0.34; P < 0.0001)
• NA (immature data)
• 26% versus 52%
30
EGFR TKIs
FL AURA • III
• Investigator- assessed PFS
• Osimertinib (n = 279) versus
gefitinib or erlotinib (n = 277)
15 mo (osimertinib
arm) and 9.7 mo (first-
generation TKI arm)
• 80% versus 76%
• 18.9 mo versus 10.2 mo (HR 0.46; P < 0.001)
• 17.7 mo versus 9.7 mo (HR 0.45; P < 0.001)
• 18 mo OS 83% versus 71% (HR 0.63; P = 0.007 , nonsignificant
owing to immature data)
• 34% versus 45%
28
AE, adverse event; b.i.d., twice daily ; mo, months; IRC, independent review committee; NA , not available; NE, not estimable; ORR , overall response rate;
OS, overall survival; PFS, progression- free survival; TKI, tyrosine- kinase inhibitor.a Updated data.

www.nature.com/nrclinonc
Reviews
lower with alectinib than with crizotinib (9.4% versus
41.4%), showing that alectinib provides superior con-
trol against the development of brain metastases com-
pared with crizotinib. Interestingly, the difference in PFS
between arms can be mainly attributed to the higher
rates of CNS-related disease progression with crizotinib,
because no significant differences in extra-CNS progres-
sion rates were observed between arms (24% and 22%
with alectinib and crizotinib, respectively). Comparative
trials of crizotinib with brigatinib (NCT02737501),
lorlatinib (NCT03052608), or ensartinib (NCT02767804)
will provide further information on the efficacy of all
next-generation ALK TKIs in the first-line setting.
Choice of upfront treatment strategy
With the management of patients with advanced-stage
EGFR-driven and ALK-driven NSCLC on the verge of
a paradigm change, the risk–benefit balance of choos-
ing between sequential treatment or next-generation
upfront strategies needs to be taken into consideration
when optimizing treatment strategies. Several argu-
ments favour each strategy, and, thus, the choice remains
complex (BOX1).
Traditional sequential approach. This approach has
been in place for a longer time than the next-generation
upfront strategy, and, thus, sufficient data support an
impressive long-term survival with therapies involv-
ing sequencing TKIs. The long-term benefit of pro-
viding sequential therapies is based on the response
rates and the duration of PFS that can be achieved
with next-generation inhibitors upon resistance to
first-generation TKIs. In patients with NSCLC harbour-
ing mutations in EGFRT790M, a pooled analysis update
of the AURA 2 and AURA extension studies59 revealed
a median global overall survival of 26.8 months. The
2-year overall survival was 56% for the entire cohort.
The mature survival outcomes of the AURA 3 study21 and
data on treatment outcomes from the ASTRIS study122
have not yet been published; these results should provide
insight into the clinical benefits derived from osimertinib
treatment in patients with EGFRT790M-mutated NSCLC.
In patients with ALK-rearranged NSCLC, results
from the PROFILE 1014 trial showed, at a median
follow-up duration of 46 months, that median survival
was not reached (95% CI 45.8 months–not reached) and
that 4-year overall survival was 56.6% in patients treated
with crizotinib, of whom 33% received subsequent
next-generation TKIs65. The French national IFCT-1302
retrospective study123 analysed the survival outcomes of
318 patients with ALK-rearranged NSCLC involved in
an expanded crizotinib access programme123. In this
study, 31.9% of patients received the second-generation
ALK inhibitors ceritinib or alectinib after disease pro-
gression on frontline crizotinib. The median over-
all survival duration from the first dose of crizotinib
was not reached for patients who received sequential
treatment, and 3-year survival was 59.2% (both cer-
itinib and alectinib analysed together). Impressively,
the median overall survival from the time of diagnosis
of metastatic NSCLC was 89.6 months. This duration
is highly superior to that observed in patients with
NSCLC not driven by alterations in EGFR or ALK and
treated with chemotherapy in ‘real-world’ settings
(~10 months)124.
The studies discussed support the notion that effec-
tive sequential strategies with upfront first-generation
inhibitors can lead to impressive overall survival in some
patients with NSCLC in which the driver alterations have
been characterized; whether upfront next-generation
inhibitors could provide a similar long-term bene-
fit remains to be established. The available preclinical
and clinical evidence suggests that no clinical benefit is
derived from treatment with first-generation TKIs after
disease progression on next-generation TKI treatment,
with the exception of ALK L1198F108, MET amplifica-
tion125, and EGFR C797S mutation in trans95, thus limit-
ing the availability of targeted therapeutic options when
next-generation inhibitors are used upfront.
Next-generation ALK and EGFR TKIs upfront. This
therapeutic option is associated with prolonged PFS
durations, improved disease control in the CNS, and
a more favourable toxicity profile than treatment with
first-generation TKIs — providing a major argument
in favour of upfront treatment with next-generation
TKIs. In the ALEX29 and FLAURA28 studies, the dif-
ference in the incidence of grade 3 adverse events with
first-generation versus next-generation TKIs was ~10%,
favouring the latter. With the upfront administration of
next-generation TKIs, T790M or secondary ALK muta-
tional screening does not need to be performed on a
continuous basis, an approach that is convenient in cen-
tres where repeated molecular diagnosis is not available.
Indeed, the medical practice environment needs to be
considered in decisions of the best therapeutic strat-
egy for patients. Close monitoring and timely access
to molecular diagnostics and treatment options are
essential to providing optimal care.
In the ALEX29 and FLAURA28 studies, alectinib and
osimertinib showed greater efficacy in the treatment of
brain metastases than first-generation TKIs; thus, these
agents should be considered for patients in this set-
ting126–128. The prevention or delay of the onset of brain
metastases is key to controlling morbidity and reduc-
ing the needs and costs for localized CNS therapies129.
In this context, the results of the ongoing evaluation of
Box 1 | Arguments supporting different frontline treatment strategies
Arguments in favour of using first- generation tyrosine- kinase inhibitors
(TKIs) upfront
•Maturefollow-updataavailablesupportinglongsurvivalforpatientstreated
withsequentialTKIs
•Multiplesubsequenttreatmentoptionsavailableintheeventofresistance
Arguments in favour of using next- generation TKIs upfront derived from
studies comparing with first- generation TKIs
•Inpreclinicalstudies:longerdiseasecontrolinmice
•Reducedtoxicityinmostcases
•Enhancedtherapeuticactivityinthecentralnervoussystem
•Prolongedprogression-freesurvival
•Reducedneedforsubsequentmoleculardiagnostic

Nature reviews
|
CliniCal OnCOlOgy
Reviews
responses to frontline lorlatinib are awaited81. Indeed,
results from studies in mouse models suggest that front-
line lorlatinib could dramatically delay the emergence
of resistance, including those with brain metastases27.
Despite having superior potency and the widest spec-
trum of activity against secondary mutations, lorlatinib
might not replace alectinib as the standard-of-care ALK
TKI in the first-line setting because of its association
with an increased incidence of neurological adverse
effects; lorlatinib, however, might represent the ideal
second-line treatment option after disease progression
on alectinib.
An important argument in favour of using
next-generation upfront originates from the emerging
evidence from studies of persister cells. An intuitive
hypothesis is that a ‘hitting hard first’ strategy would
help to limit the number of drug-tolerant cells that
would later lead to disease progression; however, to
our knowledge, direct comparisons of the persistence
capacities of cancer cells treated with first-generation
or next-generation TKIs have not been performed.
Understanding the molecular mechanisms supporting
the viability of these cells and how they can be targeted
therapeutically are key questions that have not yet
beensolved.
Another key aspect that remains to be elucidated
is whether frontline treatment with next-generation
TKIs can decrease the emergence of subclonal hetero-
geneity involving TKI resistance mechanisms, either
with a mutational or non-mutational component.
Importantly, the existence of intratumour hetero-
geneity is evidenced by simultaneous oncogenic alter-
ations that can mediate resistance to EGFR or ALK
TKIs, including the co-occurrence of EGFR with
ALK alterations or ALK with KRAS alterations, which
present a challenge for treatment selection23,130–134.
To address this issue, multiple combinations of ALK
or EGFR TKIs with other kinase inhibitors target-
ing MET (NCT02143466), MEK (NCT03392246,
NCT03087448, NCT03202940, and NCT02143466),
JAK (NCT02917993 andNCT03450330), mTOR
(NCT02503722 and NCT02321501), SRC
(NCT02954523), AXL (NCT03255083) or CDK4/6
inhibitors (NCT03455829 and NCT02292550), or apop-
totic modulators, such as navitoclax (NCT02520778),
are ongoing. The aim of these strategies is to revert, delay
or prevent the onset of off-target resistance. In addition,
several studies have intended to modulate the antitu-
mour immune response by combining an EGFR or ALK
TKI with anti-programmed cell death 1 (PD-1) and/or
anti-programmed cell death 1 ligand 1 (PD-L1) mono-
clonal antibodies, which generally lack efficacy as single
agents in patients with oncogene-addicted NSCLC135.
Nevertheless, toxicity issues have already hampered the
development of combinations of osimertinib with dur-
valumab and of crizotinib with nivolumab. In the phase
Ib TATTON study, recruitment into the combination
arm (osimertinib plus durvalumab) was closed owing
to the occurrence of interstitial lung disease in 38% of
patients136. In the multicohort phase I/II CheckMate 370
trial, the combination of nivolumab and crizotinib was
associated with severe hepatic toxicity in 38% of patients,
with two adverse-event-related deaths137. By contrast,
preliminary data of the combination of crizotinib or lor-
latinib with avelumab and of alectinib with atezolizumab
have shown an acceptable safety profile138,139.
Integrative strategy. In the absence of survival data after
disease progression from head-to-head comparative tri-
als, investigators rely on the sum of PFS from studies
held in different therapy lines to establish comparisons.
This provocative approach is not supported statisti-
cally140 but can provide an estimation, in the absence
of valid surrogates, of the theoretical benefit of sequen-
tial targeted therapies in patients with advanced-stage
NSCLC (FIG.2).
Relying on the results from clinical trials22,69,72,77,80,
patients with ALK-translocated NSCLC would derive a
median PFS of 16–25 months from frontline crizotinib
followed by a next-generation ALK TKI, compared with
34.8 months with alectinib121. Likewise, patients
with EGFR-mutated NSCLC would derive a PFS bene-
fit ranging from 21–27 months21,36,41,47,53 with sequential
treatment, a value close to the 18.9 months reported for
frontline osimertinib in the FLAURA study28. Of note,
chemotherapy is the standard treatment for patients
with T790M-negative NSCLC with disease progression
after receiving first-generation EGFR TKIs. For these
patients, the median PFS with cisplatin-based chemo-
therapy after progression upon treatment with first-line
EGFR TKIs was reported to be 5.4 months141; thus,
frontline treatment with a first-generation TKI would
provide a slightly inferior sum of PFS than frontline
osimertinib.
In addition, a subset of patients treated with TKIs
can develop oligoprogressive disease. In this scenario,
and especially in the setting of brain metastasis, patients
can benefit from a 6-month gain in PFS when local
ablative treatments (such as surgery or radiotherapy)
are applied142. These local ablative treatments are cru-
cial because they enable the continuation of previously
administered systemic therapies, delaying the switch
to the next treatment line and prolonging systemic
diseasecontrol.
The economic burden of novel drugs can also influ-
ence the choice of upfront TKIs — for example, osime-
rtinib is more expensive than afatinib143. In the absence
of definitive evidence of meaningful overall survival
benefits, the prolonged administration of costly thera-
peutic agents might not be easily accepted by regulatory
authorities.
In this new era, a growing need exists for the develop-
ment of clinical trials to enable further understand-
ing of the best sequential therapeutic strategy in the
setting of advanced-stage NSCLC. Monitoring resist-
ance onset using sequencing of circulating cell-free
DNA can provide new insights into the effect of early
treatment of subclinical resistance144. In the setting of
EGFR-mutated NSCLC, the ongoing phase II APPLE
trial145 will shed light on this matter, evaluating the
overall survival outcomes of patients treated sequen-
tially with a first-line EGFR TKI and switching to osi-
mertinib upon progression, compared with treatment
with osimertinib upfront.

www.nature.com/nrclinonc
Reviews
Conclusions
At present, the optimal approach for the selection
of a frontline EGFR or ALK TKI for patients with
advanced-stage NSCLC remains a matter of debate,
while results and post-progression survival analysis at
longer follow-up durations from ongoing comparative
trials are awaited. Both strategies have advantages and
disadvantages that need to be carefully weighed (BOX1).
The currently available evidence suggests that patients
with EGFR-mutated NSCLC could benefit from frontline
18.9 mo
11.2 mo
11 mo
11.1 mo
9.7 mo
10.8 mo
10.2 mo
9.2 mo
7. 9 mo
10.9 mo
6.9 mo
5.2 mo
5.4 mo
FLAURA
ARCHER-1050
CONVINCE
LUX-Lung 7
LUX-Lung 3
EURTAC
NEJ002 Chemotherapy
Chemotherapy
Chemotherapy
Gefitinib
Erlotinib
Afatinib
Afatinib
Gefitinib
Dacomitinib
Gefitinib
Gefitinib or erlotinib
Osimertinib
AURA 3
T790M+
T790M–
Chemotherapy
Chemotherapy
Osimertinib
Chemotherapy 5.4 mo
4.4 mo
10.1 mo
?
a EGFR
Sequential strategy
Next-generation upfront
Chemotherapy
Icotinib
IMPRESS
25.7 mo
16.6 mo
10.9 mo
10.4
8.1 mo
7 mo
NCT01970865
ALEX
ASCEND-4
PROFILE 1014
Crizotinib
Chemotherapy
Ceritinib
Alectinib
ASCEND-5
ALUR
ALTA
NCT01970865
Lorlatinib
Chemotherapy
Crizotinib
NR (95% CI 11.4–NR)
Lorlatinib
9.6 mo
5.4 mo
1.6 mo
1.4 mo
Ceritinib
Alectinib
Brigatinib
NR (95% CI 12.5–NR)
b ALK
Sequential strategy
Next-generation upfront
Lorlatinib
NCT01970865
6.9 mo
Lorlatinib
5.5 mo
NCT01970865
Lorlatinib 5.5 moNCT01970865
14.7 mo
12.9 mo
Chemotherapy
Chemotherapy
Fig. 2 | Comparison of PFS results in selected clinical trials testing TKI sequencing in NSCLC. Sum of progression- free
survival (PFS) durations in different trials of frontline tyrosine- kinase inhibitors (TKIs) in patients with non- small-cell lung
carcinoma (NSCLC) harbouring EGFR mutations (with first- generation, second- generation and next- generation TKIs)
(part a) or ALK rearrangements (with first- generation and next- generation TKIs) (part b). mo, months; NR , not reported;
T790M−/T790M+, negative/positive for the T790M mutation in EGFR.

osimertinib over first-generation EGFR TKIs in terms
of tolerability and efficacy, especially patients without
targetable T790M mutations. Similarly, patients with
ALK-rearranged NSCLC would derive a greater benefit
from frontline alectinib than with first-line ALK TKIs
in terms of tolerability, activity in the CNS, and PFS. For
these patients, lorlatinib might be a favourable option
for second-line treatment upon regulatory approval.
Nonetheless, analysis of long-term survival outcomes
of ongoing and future randomized trials, including the
effect of post-progression treatments, will be key to settle
what the most beneficial treatment strategy for patients
with NSCLC according to the molecular profile of their
tumours in order to adapt therapies to tumour dynamics.
Published online xx xx xxxx
1. Das, M. etal. Specific radiolabeling of a cell surface
receptor for epidermal growth factor. Proc. Natl Acad.
Sci. USA 74, 2790–2794 (1977).
2. Ward, W. H. etal. Epidermal growth factor receptor
tyrosine kinase. Investigation of catalytic mechanism,
structure-based searching and discovery of a potent
inhibitor. Biochem. Pharmacol. 48, 659–666
(1994).
3. Li, T., Kung, H.-J., Mack, P. C. & Gandara, D. R.
Genotyping and genomic profiling of non-small-cell
lung cancer: implications for current and future
therapies. J. Clin. Oncol. 31, 1039–1049
(2013).
4. Fitzmaurice, C. etal. Global, regional, and national
cancer incidence, mortality, years of life lost, years
lived with disability, and disability-adjusted life-years
for 32 cancer groups, 1990 to 2015: a systematic
analysis for the global burden of disease study.
JAMAOncol. 3, 524–548 (2017).
5. Shi, Y. etal. A prospective, molecular epidemiology
study of EGFR mutations in Asian patients with
advanced non-small-cell lung cancer of adenocarcinoma
histology (PIONEER). J. Thorac. Oncol. 9, 154–162
(2014).
6. Barlesi, F. etal. Routine molecular profiling of
patientswith advanced non-small-cell lung cancer:
results of a 1-year nationwide programme of the
French Cooperative Thoracic Intergroup (IFCT).
Lancet387, 1415–1426 (2016).
7. Rosell, R. etal. Screening for epidermal growth factor
receptor mutations in lung cancer. N. Engl. J. Med.
361, 958–967 (2009).
8. Murray, S. etal. Somatic mutations of the tyrosine
kinase domain of epidermal growth factor receptor
and tyrosine kinase inhibitor response to TKIs in
non-small cell lung cancer: an analytical database.
J.Thorac. Oncol. 3, 832–839 (2008).
9. Dearden, S., Stevens, J., Wu, Y.-L. & Blowers, D.
Mutation incidence and coincidence in non small-cell
lung cancer: meta-analyses by ethnicity and histology
(mutMap). Ann. Oncol. 24, 2371–2376 (2013).
10. Koivunen, J. P. etal. EML4-ALK fusion gene and
efficacy of an ALK kinase inhibitor in lung cancer.
Clin.Cancer Res. 14, 4275–4283 (2008).
11. Novello, S. etal. Metastatic non-small-cell lung
cancer: ESMO Clinical Practice Guidelines for
diagnosis, treatment and follow-up. Ann. Oncol. 27,
v1–v27 (2016).
12. Yu, H. A. etal. Analysis of tumor specimens at the
time of acquired resistance to EGFR-TKI therapy in
155 patients with EGFR-mutant lung cancers.
Clin.Cancer Res. 19, 2240–2247 (2013).
13. Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity
and resistance to cancer therapies. Nat. Rev. Clin.
Oncol. 15, 81–94 (2018).
14. Sequist, L. V. etal. Genotypic and histological
evolution of lung cancers acquiring resistance to
EGFRinhibitors. Sci. Transl. Med. 3, 75ra26 (2011).
15. Yun, C.-H. etal. The T790M mutation in EGFR kinase
causes drug resistance by increasing the affinity for
ATP. Proc. Natl Acad. Sci. USA 105, 2070–2075
(2008).
16. Michalczyk, A. etal. Structural insights into how
irreversible inhibitors can overcome drug resistance in
EGFR. Bioorg. Med. Chem. 16, 3482–3488 (2008).
17. Sos, M. L. etal. Chemogenomic profiling provides
insights into the limited activity of irreversible EGFR
Inhibitors in tumor cells expressing the T790M EGFR
resistance mutation. Cancer Res. 70, 868–874
(2010).
18. Janne, P. A. etal. AZD9291 in EGFR inhibitor-resistant
non-small-cell lung cancer. N. Engl. J. Med. 372,
1689–1699 (2015).
19. Cross, D. A. E. etal. AZD9291, an irreversible EGFR
TKI, overcomes T790M-mediated resistance to
EGFRinhibitors in lung cancer. Cancer Discov. 4,
1046–1061 (2014).
20. Nanjo, S. etal. High efficacy of third generation
EGFRinhibitor AZD9291 in a leptomeningeal
carcinomatosis model with EGFR-mutant lung cancer
cells. Oncotarget 7, 3847–3856 (2016).
21. Mok, T. S. etal. Osimertinib or platinum-pemetrexed
in EGFR T790M-positive lung cancer. N. Engl. J. Med.
376, 629–640 (2017).
22. Solomon, B. J. etal. First-line crizotinib versus
chemotherapy in ALK-positive lung cancer. N. Engl.
J.Med. 371, 2167–2177 (2014).
23. Gainor, J. F. etal. Molecular mechanisms of resistance
to first- and second-generation ALK inhibitors in
ALK-rearranged lung cancer. Cancer Discov. 6,
1118–1133 (2016).
24. Friboulet, L. etal. The ALK inhibitor ceritinib
overcomes crizotinib resistance in non-small cell lung
cancer. Cancer Discov. 4, 662–673 (2014).
25. Sakamoto, H. etal. CH5424802, a selective ALK
inhibitor capable of blocking the resistant gatekeeper
mutant. Cancer Cell 19, 679–690 (2011).
26. Zhang, S. etal. The potent ALK inhibitor brigatinib
(AP26113) overcomes mechanisms of resistance to
first- and second-generation ALK inhibitors in preclinical
models. Clin. Cancer Res. 22, 5527–5538 (2016).
27. Zou, H. Y. etal. PF-06463922, an ALK/ROS1
inhibitor, overcomes resistance to first and second
generation ALK inhibitors in preclinical models.
Cancer Cell 28, 70–81 (2015).
28. Soria, J.-C. etal. Osimertinib in untreated
EGFR-mutated advanced non–small-cell lung cancer.
N. Engl. J. Med. 378, 113–125 (2018).
29. Peters, S. etal. Alectinib versus crizotinib in untreated
ALK-positive non-small-cell lung cancer. N. Engl.
J.Med. 377, 829–838 (2017).
30. Hida, T. etal. Alectinib versus crizotinib in patients
with ALK-positive non-small-cell lung cancer (J-ALEX):
an open-label, randomised phase 3 trial. Lancet 390,
29–39 (2017).
31. Lynch, T. J. etal. Activating mutations in the epidermal
growth factor receptor underlying responsiveness of
non-small-cell lung cancer to gefitinib. N. Engl. J. Med.
350, 2129–2139 (2004).
32. Paez, J. G. etal. EGFR mutations in lung cancer:
correlation with clinical response to gefitinib therapy.
Science 304, 1497–1500 (2004).
33. Mok, T. S. etal. Gefitinib or carboplatin-paclitaxel in
pulmonary adenocarcinoma. N. Engl. J. Med. 361,
947–957 (2009).
34. Fukuoka, M. etal. Biomarker analyses and final
overall survival results from a phase III, randomized,
open-label, first-line study of gefitinib versus
carboplatin/paclitaxel in clinically selected patients
with advanced non–small-cell lung cancer in Asia
(IPASS). J. Clin. Oncol. 29, 2866–2874 (2011).
35. Han, J.-Y. etal. First-SIGNAL: first-line single-agent
iressa versus gemcitabine and cisplatin trial in
never-smokers with adenocarcinoma of the lung.
J.Clin. Oncol. 30, 1122–1128 (2012).
36. Mitsudomi, T. etal. Gefitinib versus cisplatin plus
docetaxel in patients with non-small-cell lung cancer
harbouring mutations of the epidermal growth factor
receptor (WJTOG3405): an open label, randomised
phase 3 trial. Lancet Oncol. 11, 121–128 (2010).
37. Yoshioka, H. etal. Final overall survival results of
WJTOG 3405, a randomized phase 3 trial comparing
gefitinib (G) with cisplatin plus docetaxel (CD) as the
first-line treatment for patients with non-small cell
lung cancer (NSCLC) harboring mutations of the
epidermal growt. J. Clin. Oncol. 32, 8117 (2014).
38. Maemondo, M. etal. Gefitinib or chemotherapy for
non-small-cell lung cancer with mutated EGFR.
N.Engl. J. Med. 362, 2380–2388 (2010).
39. Inoue, A. etal. Updated overall survival results from a
randomized phase III trial comparing gefitinib with
carboplatin-paclitaxel for chemo-naive non-small cell
lung cancer with sensitive EGFR gene mutations
(NEJ002). Ann. Oncol. 24, 54–59 (2013).
40. Zhou, C. etal. Erlotinib versus chemotherapy as
first-line treatment for patients with advanced
EGFRmutation-positive non-small-cell lung cancer
(OPTIMAL, CTONG-0802): a multicentre, open-label,
randomised, phase 3 study. Lancet Oncol. 12,
735–742 (2011).
41. Zhou, C. etal. Final overall survival results from a
randomised, phase III study of erlotinib versus
chemotherapy as first-line treatment of EGFR
mutation-positive advanced non-small-cell lung cancer
(OPTIMAL. CTONG-0802). Ann. Oncol. 26,
1877–1883 (2015).
42. Wu, Y.-L. etal. First-line erlotinib versus gemcitabine/
cisplatin in patients with advanced EGFR mutation-
positive non-small-cell lung cancer: analyses from the
phase III, randomized, open-label, ENSURE study.
Ann.Oncol. 26, 1883–1889 (2015).
43. Rosell, R. etal. Erlotinib versus standard
chemotherapy as first-line treatment for European
patients with advanced EGFR mutation-positive
non-small-cell lung cancer (EURTAC): a multicentre,
open-label, randomised phase 3 trial. Lancet Oncol.
13, 239–246 (2012).
44. Shi, Y. K. etal. First-line icotinib versus cisplatin/
pemetrexed plus pemetrexed maintenance therapy for
patients with advanced EGFR mutation-positive lung
adenocarcinoma (CONVINCE): a phase 3, open-label,
randomized study. Ann. Oncol. 28, 2443–2450
(2017).
45. Shi, Y. etal. Icotinib versus gefitinib in previously
treated advanced non-small-cell lung cancer (ICOGEN):
a randomised, double-blind phase 3 non-inferiority
trial. Lancet Oncol. 14, 953–961 (2013).
46. Rosell, R. etal. Erlotinib and bevacizumab in patients
with advanced non-small-cell lung cancer and
activating EGFR mutations (BELIEF): an international,
multicentre, single-arm, phase 2 trial. Lancet Respir.
Med. 5, 435–444 (2017).
47. Seto, T. etal. Erlotinib alone or with bevacizumab
asfirst-line therapy in patients with advanced
non-squamous non-small-cell lung cancer harbouring
EGFR mutations (JO25567): an open-label,
randomised, multicentre, phase 2 study. Lancet
Oncol. 15, 1236–1244 (2014).
48. Sequist, L. V. etal. Phase III study of afatinib or
cisplatin plus pemetrexed in patients with metastatic
lung adenocarcinoma with EGFR mutations. J. Clin.
Oncol. 31, 3327–3334 (2013).
49. Wu, Y.-L. etal. Afatinib versus cisplatin plus
gemcitabine for first-line treatment of Asian patients
with advanced non-small-cell lung cancer harbouring
EGFR mutations (LUX-Lung 6): an open-label,
randomised phase 3 trial. Lancet Oncol. 15,
213–222 (2014).
50. Yang, J. C.-H. etal. Afatinib versus cisplatin-based
chemotherapy for EGFR mutation-positive lung
adenocarcinoma (LUX-Lung 3 and LUX-Lung 6):
analysis of overall survival data from two randomised,
phase 3 trials. Lancet Oncol. 16, 141–151 (2015).
51. Laporte, S. etal. Prediction of survival benefits from
progression-free survival benefits in advanced
non-small-cell lung cancer: evidence from a
meta-analysis of 2334 patients from 5 randomised
trials. BMJ Open 3, e001802 (2013).
52. Yang, J. J. etal. A phase III randomised controlled trial
of erlotinib versus gefitinib in advanced non-small cell
lung cancer with EGFR mutations. Br. J. Cancer 11 6,
568–574 (2017).
53. Paz-Ares, L. etal. Afatinib versus gefitinib in patients
with EGFR mutation-positive advanced non-small-cell
lung cancer: overall survival data from the phase IIb
LUX-Lung 7 trial. Ann. Oncol. 28, 270–277 (2017).
54. Park, K. etal. Afatinib versus gefitinib as first-line
treatment of patients with EGFR mutation-positive
non-small-cell lung cancer (LUX-Lung 7): a phase 2B,
open-label, randomised controlled trial. Lancet Oncol.
17, 577–589 (2016).
Nature reviews
|
CliniCal OnCOlOgy
Reviews

www.nature.com/nrclinonc
Reviews
55. Wu, Y.-L. etal. Dacomitinib versus gefitinib as first-line
treatment for patients with EGFR-mutation-positive
non-small-cell lung cancer (ARCHER 1050): a
randomised, open-label, phase 3 trial. Lancet Oncol.
18, 1454–1466 (2017).
56. Mok, T. S. etal. Improvement in overall survival in a
randomized study that compared dacomitinib with
gefitinib in patients with advanced non-small-cell lung
cancer and EGFR-activating mutations. J. Clin. Oncol.
https://doi.org/10.1200/JCO.2018.78.7994 (2018).
57. Yang, J. C.-H. etal. Osimertinib in pretreated
T790M-positive advanced non-small-cell lung cancer:
AURA study phase II extension component. J. Clin.
Oncol. 35, 1288–1296 (2017).
58. Goss, G. etal. Osimertinib for pretreated EGFR
Thr790Met-positive advanced non-small-cell lung
cancer (AURA2): a multicentre, open-label, single-arm,
phase 2 study. Lancet Oncol. 17, 1643–1652 (2016).
59. Mitsudomi, T. etal. Overall survival (OS) in patients
(pts) with EGFR T790M-positive advanced non-small
cell lung cancer (NSCLC) treated with osimertinib:
results from two phase II studies. Ann. Oncol.
28(Suppl. 5), mdx380.050 (2017).
60. Cui, J. J. etal. Structure based drug design of
crizotinib (PF-02341066), a potent and selective dual
inhibitor of mesenchymal-epithelial transition factor
(c-MET) kinase and anaplastic lymphoma kinase (ALK).
J. Med. Chem. 54, 6342–6363 (2011).
61. Camidge, D. R. etal. Activity and safety of crizotinib in
patients with ALK-positive non-small-cell lung cancer:
updated results from a phase 1 study. Lancet Oncol.
13, 1011–1019 (2012).
62. Kwak, E. L. etal. Anaplastic lymphoma kinase inhibition
in non-small-cell lung cancer. N. Engl. J. Med. 363,
1693–1703 (2010).
63. Blackhall, F. etal. Final results of the large-scale
multinational trial PROFILE 1005: efficacy and safety
of crizotinib in previously treated patients with
advanced/metastatic ALK-positive non-small-cell lung
cancer. ESMO Open 2, e000219 (2017).
64. Shaw, A. T. etal. Crizotinib versus chemotherapy in
advanced ALK-positive lung cancer. N. Engl. J. Med.
368, 2385–2394 (2013).
65. Solomon, B. J. etal. Final overall survival analysis from a
study comparing first-line crizotinib with chemotherapy:
results from PROFILE 1014. J. Clin. Oncol. https://
doi.org/10.1200/JCO.2017.77.4794 (2018).
66. Shaw, A. T. etal. Lorlatinib in non-small-cell lung
cancer with ALK or ROS1 rearrangement: an
international, multicentre, open-label, single-arm
first-in-man phase 1 trial. Lancet Oncol. 18,
1590–1599 (2017).
67. Shaw, A. T. etal. Ceritinib in ALK-rearranged
non-small-cell lung cancer. N. Engl. J. Med. 370,
1189–1197 (2014).
68. Kim, D.-W. etal. Activity and safety of ceritinib in
patients with ALK-rearranged non-small-cell lung
cancer (ASCEND-1): updated results from the
multicentre, open-label, phase 1 trial. Lancet Oncol.
17, 452–463 (2016).
69. Crinò, L. etal. Multicenter phase II study of
whole-body and intracranial activity with ceritinib in
patients with ALK-rearranged non–small-cell lung
cancer previously treated with chemotherapy and
crizotinib: results from ASCEND-2. J. Clin. Oncol. 34,
2866–2873 (2016).
70. Felip, E. etal. ASCEND-3: A single-arm, open-label,
multicenter phase II study of ceritinib in ALKi-naïve
adult patients (pts) with ALK-rearranged (ALK+)
non-small cell lung cancer (NSCLC). J. Clin. Oncol. 33,
8060 (2015).
71. Soria, J.-C. etal. First-line ceritinib versus
platinum-based chemotherapy in advanced
ALK-rearranged non-small-cell lung cancer
(ASCEND-4): a randomised, open-label, phase 3 study.
Lancet 389, 917–929 (2017).
72. Shaw, A. T. etal. Ceritinib versus chemotherapy in
patients with ALK-rearranged non-small-cell lung
cancer previously given chemotherapy and crizotinib
(ASCEND-5): a randomised, controlled, open-label,
phase 3 trial. Lancet Oncol. 18, 874–886 (2017).
73. Seto, T. etal. CH5424802 (RO5424802) for patients
with ALK-rearranged advanced non-small-cell lung
cancer (AF-001JP study): a single-arm, open-label,
phase 1–2 study. Lancet Oncol. 14, 590–598 (2013).
74. Tamura, T. etal. Three-year follow-up of an alectinib
phase I/II study in ALK-positive non-small-cell lung
cancer: AF-001JP. J. Clin. Oncol. 35, 1515–1521
(2017).
75. Gadgeel, S. M. etal. Safety and activity of alectinib
against systemic disease and brain metastases in
patients with crizotinib-resistant ALK-rearranged
non-small-cell lung cancer (AF-002JG): results from
the dose-finding portion of a phase 1/2 study.
LancetOncol. 15, 1119–1128 (2014).
76. Yang, J. C.-H. etal. Pooled systemic efficacy and safety
data from the pivotal phase II studies (NP28673 and
NP28761) of alectinib in ALK-positive non-small cell
lung cancer. J. Thorac. Oncol. 12, 1552–1560
(2017).
77. Novello, S. etal. Alectinib versus chemotherapy in
crizotinib-pretreated anaplastic lymphoma kinase
(ALK)-positive non-small-cell lung cancer: results
fromthe phase III ALUR study. Ann. Oncol. 29,
1409–1416 (2018).
78. Bazhenova, L. A. etal. Brigatinib (BRG) in anaplastic
lymphoma kinase (ALK)-positive non-small cell lung
cancer (NSCLC): long-term efficacy and safety results
from a phase 1/2 trial. Ann. Oncol. 28 (Suppl. 5),
mdx380.046 (2017).
79. Gettinger, S. N. etal. Activity and safety of brigatinib
in ALK-rearranged non-small-cell lung cancer and
other malignancies: a single-arm, open-label, phase
1/2 trial. Lancet Oncol. 17, 1683–1696 (2017).
80. Kim, D.-W. etal. Brigatinib in patients with
crizotinib-refractory anaplastic lymphoma
kinase-positive non-small-cell lung cancer: a
randomized, multicenter phase II trial. J. Clin. Oncol.
35, 2490–2498 (2017).
81. Solomon, B. etal. OA 05.06 phase 2 study of
lorlatinib in patients with advanced ALK+/ROS1+
non-small-cell lung cancer. J. Thorac. Oncol. 12,
S1756 (2017).
82. Costa, D. B. etal. Clinical experience with crizotinib in
patients with advanced ALK-rearranged non–small-cell
lung cancer and brain metastases. J. Clin. Oncol. 33,
1881–1888 (2015).
83. Gadgeel, S. M. etal. Pooled analysis of CNS response
to alectinib in two studies of pretreated patients with
ALK-positive non-small-cell lung cancer. J. Clin. Oncol.
34, 4079–4085 (2016).
84. Camidge, D. R. etal. Exploratory analysis of brigatinib
activity in patients with anaplastic lymphoma
kinase-positive non-small-cell lung cancer and brain
metastases in two clinical trials. J. Clin. Oncol. https://
doi.org/10.1200/JCO.2017.77.5841 (2018).
85. Kobayashi, S. etal. EGFR mutation and resistance of
non-small-cell lung cancer to gefitinib. N. Engl. J. Med.
352, 786–792 (2005).
86. Pao, W. etal. Acquired resistance of lung
adenocarcinomas to gefitinib or erlotinib is associated
with a second mutation in the EGFR kinase domain.
PLOS Med. 2, e73 (2005).
87. Engelman, J. A. etal. MET amplification leads to
gefitinib resistance in lung cancer by activating ERBB3
signaling. Science 316, 1039–1043 (2007).
88. Zhang, Z. etal. Activation of the AXL kinase causes
resistance to EGFR-targeted therapy in lung cancer.
Nat. Genet. 44, 852–860 (2012).
89. Morgillo, F., Woo, J. K., Kim, E. S., Hong, W. K. &
Lee, H.-Y. Heterodimerization of insulin-like growth
factor receptor/epidermal growth factor receptor
andinduction of survivin expression counteract the
antitumor action of erlotinib. Cancer Res. 66,
10100–10111 (2006).
90. Takezawa, K. etal. HER2 amplification: a potential
mechanism of acquired resistance to EGFR inhibition
in EGFR-mutant lung cancers that lack the second-site
EGFRT790M mutation. Cancer Discov. 2, 922–933
(2012).
91. Ricordel, C., Friboulet, L., Facchinetti, F. & Soria, J.-C.
Molecular mechanisms of acquired resistance to
third-generation EGFR-TKIs in EGFR T790M-mutant
lung cancer. Ann. Oncol. 29, i28–i37 (2018).
92. Yu, H. A. etal. Acquired resistance of EGFR-mutant
lung cancer to a T790M-specific EGFR inhibitor:
emergence of a third mutation (C797S) in the EGFR
Tyrosine kinase domain. JAMA Oncol. 1, 982–984
(2015).
93. Thress, K. S. etal. Acquired EGFR C797S mediates
resistance to AZD9291 in advanced non-small cell
lung cancer harboring EGFR T790M. Nat. Med. 21,
560–562 (2015).
94. Yang, Z. etal. Investigating novel resistance
mechanisms to third-generation EGFR tyrosine kinase
inhibitor osimertinib in non-small cell lung cancer
patients. Clin. Cancer Res. 24, 3097–3107 (2018).
95. Niederst, M. J. etal. The allelic context of the C797S
mutation acquired upon treatment with third-generation
EGFR inhibitors impacts sensitivity to subsequent
treatment strategies. Clin. Cancer Res. 21 , 3924–3933
(2015).
96. Uchibori, K. etal. Brigatinib combined with anti-EGFR
antibody overcomes osimertinib resistance in
EGFR-mutated non-small-cell lung cancer.
Nat.Commun. 8, 14768 (2017).
97. Jia, Y. etal. Overcoming EGFR(T790M) and
EGFR(C797S) resistance with mutant-selective
allosteric inhibitors. Nature 534, 129–132 (2016).
98. Wang, Z. etal. Lung adenocarcinoma harboring EGFR
T790M and in trans C797S responds to combination
therapy of first- and third-generation EGFR TKIs and
shifts allelic configuration at resistance. J. Thorac.
Oncol. 12, 1723–1727 (2017).
99. Arulananda, S. etal. Combination osimertinib and
gefitinib in C797S and T790M EGFR-mutated
non-small cell lung cancer. J. Thorac. Oncol. 12,
1728–1732 (2017).
100. Choi, Y. L. etal. EML4-ALK mutations in lung cancer
that confer resistance to ALK inhibitors. N. Engl.
J.Med. 363, 1734–1739 (2010).
101. Doebele, R. C. etal. Mechanisms of resistance to
crizotinib in patients with ALK gene rearranged
non-small cell lung cancer. Clin. Cancer Res. 18,
1472–1482 (2012).
102. Katayama, R. etal. Mechanisms of acquired crizotinib
resistance in ALK-rearranged lung cancers. Sci. Transl
Med. 8, 120ra117 (2012).
103. Sasaki, T. etal. A novel ALK secondary mutation and
EGFR signaling cause resistance to ALK kinase
inhibitors. Cancer Res. 71, 6051–6060 (2011).
104. Sasaki, T. etal. The neuroblastoma-associated F1174L
ALK mutation causes resistance to an ALK kinase
inhibitor in ALK-translocated cancers. Cancer Res. 70,
10038–10043 (2010).
105. Katayama, R. etal. Two novel ALK mutations mediate
acquired resistance to the next-generation ALK
inhibitor alectinib. Clin. Cancer Res. 20, 5686–5696
(2014).
106. Johnson, T. W. etal. Discovery of (10R)-7-amino-12-
fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-
tetrahydro-2H-8,4-(m etheno)pyrazolo[4,3-h]
[2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile
(PF-06463922), a macrocyclic inhibitor of anaplastic
lymphoma kinase (ALK) and c-ros. J. Med. Chem. 57,
4720–4744 (2014).
107. Lin, J. J. etal. Impact of EML4-ALK variant on resistance
mechanisms and clinical outcomes in ALK-positive lung
cancer. J. Clin. Oncol. JCO2017762294 https://doi.org/
10.1200/JCO.2017.76.2294 (2018).
108. Shaw, A. T. etal. Resensitization to crizotinib by the
lorlatinib ALK resistance mutation L1198F. N. Engl.
J.Med. 374, 54–61 (2015).
109. Yoda, S. etal. Sequential ALK inhibitors can select
forlorlatinib-resistant compound ALK mutations in
ALK-positive lung cancer. Cancer Discov. https://doi.org/
10.1158/2159-8290.CD-17-1256 (2018).
110 . Crystal, A. S. etal. Patient-derived models of acquired
resistance can identify effective drug combinations for
cancer. Science 346, 1480–1486 (2014).
111. Kodama, T. etal. Antitumor activity of the selective
ALK inhibitor alectinib in models of intracranial
metastases. Cancer Chemother. Pharmacol. 74,
1023–1028 (2014).
112 . Sharma, S. V. etal. A chromatin-mediated reversible
drug-tolerant state in cancer cell subpopulations.
Cell141, 69–80 (2010).
113 . Ramirez, M. etal. Diverse drug-resistance mechanisms
can emerge from drug-tolerant cancer persister cells.
Nat. Commun. 7, 10690 (2016).
114 . Blakely, C. M. etal. NF-kappaB-activating complex
engaged in response to EGFR oncogene inhibition
drives tumor cell survival and residual disease in lung
cancer. Cell Rep. 11, 98–110 (2015).
115 . Hata, A. N. etal. Tumor cells can follow distinct
evolutionary paths to become resistant to epidermal
growth factor receptor inhibition. Nat. Med. 22,
262–269 (2016).
116 . Viswanathan, V. S. etal. Dependency of a
therapy-resistant state of cancer cells on a lipid
peroxidase pathway. Nature 547, 453–457 (2017).
117 . Hangauer, M. J. etal. Drug-tolerant persister cancer
cells are vulnerable to GPX4 inhibition. Nature 5 51,
247–250 (2017).
118 . Jamal-Hanjani, M. etal. Tracking the evolution of
non-small-cell lung cancer. N. Engl. J. Med. 376,
2109–2121 (2017).
119 . Piotrowska, Z. etal. Heterogeneity underlies the
emergence of EGFRT790 wild-type clones following
treatment of T790M-positive cancers with a
third-generation EGFR inhibitor. Cancer Discov. 5,
713–722 (2015).
120. Ramalingam, S. S. etal. Osimertinib as first-line
treatment of EGFR mutation-positive advanced
non-small-cell lung cancer. J. Clin. Oncol. 36,
841–849 (2018).

Nature reviews
|
CliniCal OnCOlOgy
Reviews
121. Camidge, D. R. etal. Updated efficacy and safety data
from the global phase III ALEX study of alectinib (ALC)
versus crizotinib (CZ) in untreated advanced ALK+
NSCLC. J. Clin. Oncol. 36 (Suppl.), Abstr. 9043
(2018).
122. De Marinis, F. etal. ASTRIS: a real world treatment
study of osimertinib in patients (pts) with EGFR
T790M positive non-small cell lung cancer (NSCLC).
J.Clin. Oncol. 35, 9036 (2017).
123. Duruisseaux, M. etal. Overall survival with crizotinib
and next-generation ALK inhibitors in ALK-positive
non-small-cell lung cancer (IFCT-1302 CLINALK):
aFrench nationwide cohort retrospective study.
Oncotarget 8, 21903–21917 (2017).
124. Abernethy, A. P. etal. Real-world first-line treatment
and overall survival in non-small cell lung cancer
without known EGFR mutations or ALK rearrangements
in US community oncology setting. PLOS One 12,
e0178420 (2017).
125. Li, Y. Q., Song, S. S., Jiang, S. H. & Zhang, X. Y.
Combination therapy of erlotinib/crizotinib in a lung
adenocarcinoma patient with primary EGFR mutation
plus secondary MET amplification and a novel
acquired crizotinib-resistant mutation MET G1108C.
Ann. Oncol. 28, 2622–2624 (2017).
126. Ballard, P. etal. Preclinical comparison of osimertinib
with other EGFR-TKIs in EGFR-mutant NSCLC brain
metastases models, and early evidence of clinical brain
metastases activity. Clin. Cancer Res. 22, 5130–5140
(2016).
127. Yang, J. C.-H. etal. Osimertinib for patients (pts) with
leptomeningeal metastases (LM) from EGFR-mutant
non-small cell lung cancer (NSCLC): updated results
from the BLOOM study. J. Clin. Oncol. 35, 2020
(2017).
128. Goss, G. etal. CNS response to osimertinib in patients
with T790M-positive advanced NSCLC: pooled data
from two phase II trials. Ann. Oncol. 29, 687–693
(2017).
129. Peters, S., Bexelius, C., Munk, V. & Leighl, N. The
impact of brain metastasis on quality of life, resource
utilization and survival in patients with non-small-cell
lung cancer. Cancer Treat. Rev. 45, 139–162 (2016).
130. Toyokawa, G. & Seto, T. Updated evidence on the
mechanisms of resistance to ALK inhibitors and
strategies to overcome such resistance: Clinical and
preclinical data. Oncol. Res. Treat. 38, 291–298
(2015).
131. Cai, W. etal. Intratumoral heterogeneity of
ALK-rearranged and ALK/EGFR coaltered lung
adenocarcinoma. J. Clin. Oncol. 33, 3701–3709
(2015).
132. Schmid, S. etal. Clinical outcome of ALK-positive
non-small cell lung cancer (NSCLC) patients with
denovo EGFR or KRAS co-mutations receiving
tyrosine kinase inhibitors (TKIs). J. Thorac. Oncol. 12,
681–688 (2017).
133. Oxnard, G. R., Hu, Y., M. K. Osimertinib resistance
mediated by loss of EGFR T790M is associated
withearly resistance and competing resistance
mechanisms. J. Thorac. Oncol. 12, S1767–S1768
(2017).
134. Dardaei, L. etal. SHP2 inhibition restores sensitivity
in ALK-rearranged non-small-cell lung cancer resistant
to ALK inhibitors. Nat. Med. 24, 512–517 (2018).
135. Lee, C. K. etal. Checkpoint inhibitors in metastatic
EGFR-mutated non-small cell lung cancer-a meta-analysis.
J. Thorac. Oncol. 12, 403–407 (2017).
136. Ahn, M.-J. etal. 136O: Osimertinib combined with
durvalumab in EGFR-mutant non-small cell lung cancer:
results from the TATTON phase Ib trial. J. Thorac.
Oncol. 11, S115 (2016).
137. Spigel, D. R. etal. Phase 1/2 study of the safety and
tolerability of nivolumab plus crizotinib for the first-line
treatment of ALK Translocation-positive advanced
non-small cell lung cancer (CheckMate 370). J. Thorac.
Oncol. 13, 682–688 (2018).
138. Shaw, A. T. etal. Avelumab (anti–PD-L1) in
combination with crizotinib or lorlatinib in patients
with previously treated advanced NSCLC: phase 1b
results from JAVELIN Lung 101. J.Clin. Oncol. 36
(Suppl.), Abstr. 9008 (2018).
139. Kim, D. -W etal. Safety and clinical activity results
from a phase Ib study of alectinib plus atezolizumab in
ALK+ advanced NSCLC (aNSCLC). J.Clin. Oncol. 36
(Suppl.), Abstr. 9009 (2018).
140. Broglio, K. R. & Berry, D. A. Detecting an overall
survival benefit that is derived from progression-free
survival. J. Natl Cancer Inst. 101, 1642–1649
(2009).
141. Mok, T. S. K. etal. Gefitinib plus chemotherapy versus
chemotherapy in epidermal growth factor receptor
mutation–positive non–small-cell lung cancer resistant
to first-line gefitinib (IMPRESS): overall survival and
biomarker analyses. J. Clin. Oncol. 35, 4027–4034
(2017).
142. Weickhardt, A. J. etal. Local ablative therapy of
oligoprogressive disease prolongs disease control
bytyrosine kinase inhibitors in oncogene-addicted
non-small-cell lung cancer. J. Thorac. Oncol. 7,
1807–1814 (2012).
143. Aguiar, P. N. J. etal. Cost-effectiveness of osimertinib
in the first-line treatment of patients with
EGFR-mutated advanced non-small cell lung cancer.
JAMA Oncol. https://doi.org/10.1001/jamaoncol.
2018.1395 (2018).
144. McCoach, C. E. etal. Clinical utility of cell-free
DNA for the detection of ALK fusions and genomic
mechanisms of ALK inhibitor resistance in non-small
cell lung cancer. Clin. Cancer Res. 24, 2758–2770
(2018).
145. Remon, J. etal. The APPLE Trial: feasibility and
activity of AZD9291 (Osimertinib) treatment on
positive plasma T790M in EGFR-mutant NSCLC
patients. EORTC 1613. Clin. Lung Cancer 18,
583–588 (2017).
146. Ou, S. -H. I. etal. Pooled overall survival and safety
data from the pivotal phase II studies (NP28673 and
NP28761) of alectinib in ALK-positive non-small cell
lung cancer (NSCLC). J. Clin. Oncol. 36 (Suppl.), Abstr.
9072 (2018).
147. Huber, M. etal. Brigatinib (BRG) in crizotinib (CRZ)-
refractory ALK+ non–small cell lung cancer (NSCLC):
efficacy updates and exploratory analysis of CNS ORR
and overall ORR by baseline (BL) brain lesion status.
J.Clin. Oncol. 36 (Suppl.), Abstr. 9061 (2018).
Acknowledgements
The authors would like to thank T. Sourisseau for fruitful dis-
cussions and critical reading of the manuscript. The work of
G.R. is supported by a grant from the Nelia & Amadeo
Barletta Foundation. The work of L.F. is supported by a
European Research Council (ERC) starting grant (agreement
number 717034).
Author contributions
All authors made substantial contributions to all aspects of
manuscript preparation.
Competing interests
B.B. has received institutional grants for clinical and transla-
tional research from AstraZeneca, Boehringer-ingelheim,
Bristol-Myers Squibb (BMS), Inivata, Lilly, Loxo, OncoMed,
Onxeo, Pfizer, Roche-Genentech, Sanofi-Aventis, Servier,
and OSE Pharma. All other authors declare no competing
interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
RELATED LINKS
US National Institutes of Health ClinicalTrials.gov database:
https://www.clinicaltrials.gov