Review doi:10.

1038/nature25183

The biology and management of

non-small cell lung cancer
Roy S. Herbst1, Daniel Morgensztern2 & Chris Boshoff1,3

Important advancements in the treatment of non-small cell lung cancer (NSCLC) have been achieved over the past two
decades, increasing our understanding of the disease biology and mechanisms of tumour progression, and advancing
early detection and multimodal care. The use of small molecule tyrosine kinase inhibitors and immunotherapy has led to
unprecedented survival benefits in selected patients. However, the overall cure and survival rates for NSCLC remain low,
particularly in metastatic disease. Therefore, continued research into new drugs and combination therapies is required
to expand the clinical benefit to a broader patient population and to improve outcomes in NSCLC.

L
ung cancer is the most common cause of cancer death worldwide,
with an estimated 1.6 million deaths each year1. Approximately 85%
of patients have a group of histological subtypes collectively known
as NSCLC, of which lung adenocarcinoma (LUAD) and lung squamous
cell carcinoma (LUSC) are the most common subtypes2. The most common
aetiology for lung cancer is tobacco smoking, accounting for more than
80% of cases in the United States and other countries where smoking
is common3. Although all major histological subtypes of NSCLC, as
well as small cell lung cancer (SCLC), are associated with smoking, the
association is stronger with LUSC and SCLC than LUAD, with the latter
being the most common histology in never smokers4. Lung cancer in
never smokers is more common in women and in East Asia, and has
been associated with environmental exposures including second-hand
smoking, pollution and occupational carcinogens, and with inherited genetic
susceptibility3,5,6.
Eradicating the use of all tobacco-related products is a key goal of
the global fight against cancer and requires a comprehensive approach.
Primary prevention efforts include targeting nicotine addiction by
­providing effective delivery of nicotine without the co-administration
of carcinogenic chemicals that are present in cigarettes, such as via
e-cigarettes7. Other strategies include the use of varenicline, a partial
agonist of the nicotinic acetylcholine receptor8, counselling and other
socio-economic methods including taxation, advertisement and legis-
lative measures, such as lowering the amount of nicotine in cigarettes to
non-addictive levels, a policy recently announced by the US Food and
Drug Administration (FDA) (https://www.fda.gov/tobaccoproducts/­
newsevents/ucm568425.htm). Despite best intentions, the use of
­e-cigarettes to facilitate smoking cessation remains unproven and
controversial given concerns that they might promote the initiation
of new ­individuals to use smoking devices with unknown long-term
consequences9.
Although a crucial component of the fight against lung cancer, tobacco
prevention strategies are not enough to win the war. Increasingly sophis-
ticated therapies are required to meaningfully improve clinical outcomes
for patients. Progress in this area has been substantial and promising over
the past 20 years with the advent of various targeted therapies and the
effective application of immunotherapy in some populations of patients
with advanced NSCLC. Yet, major challenges still remain, including the
identification of new driver gene alterations to expand the population that
benefit from targeted therapies, better understanding of mechanisms of
resistance to targeted therapy to allow them to be prevented or overcome,
and the need for better predictors of responses to immunotherapy,
new drugs and rationally designed drug combination therapies. In this
Review, we provide an overview of the recent progress made in lung
cancer b
­ iology and treatment, including the most promising strategies
that have already made a notable impact in outcomes for patients with
advanced stage NSCLC.
Biology of lung cancer
Lung cancer is a molecularly heterogeneous disease and understanding its
biology is crucial for the development of effective therapies. The treatment
of lung cancer has changed from the empirical use of cytotoxic therapy
based on a physician’s preference to a hallmark of personalized ­medicine,
with subsets of patients treated according to the genetic alterations of
their tumour and the status of programmed death ligand-1 (PD-L1),
which predict for benefit from targeted therapies or immune checkpoint
­blockers (ICBs), respectively.
Similar to most malignancies, lung cancer is composed of sub-populations
of cells, or clones, with distinct molecular features, resulting in intra-­
tumoral heterogeneity. A larger sub-clonal mutation fraction may be asso-
ciated with increased likelihood of postsurgical relapse in patients with
localized LUAD, implying that there is a greater propensity for metastases
early d
­ uring tumour development in those tumours with increased intra-­
tumoral ­heterogeneity10. The identification of clonal targetable genetic
alterations occurring early during cancer evolution has changed the
paradigm of treatment for oncogene-addicted cancers, although few
patients, if any, are cured owing to inherent and acquired resistance
mecha­nisms, with the latter occurring mostly through the selection of
resistant sub-clones, pre-existing before targeted drug exposure11,12.
The most common genetic alterations in LUAD and LUSC are shown
in Box 1. Variant allele frequencies for somatic mutations have shown
that mutations in the Kirsten rat sarcoma (KRAS) and epidermal growth
factor receptor (EGFR) genes, when detected, are usually present in the
founder clones, indicating their roles in tumour initiation and repre-
senting attractive targets for therapeutic intervention. KRAS and EGFR
mutations are usually mutually exclusive, but when they co-exist, KRAS
mutations may confer resistance to EGFR inhibitors13. Tumours that
harbour oncogenic drivers such as EGFR mutations14 and ROS1 and
anaplastic lymphoma kinase (ALK) rearrangements have a lower-than-­
average mutation load, mostly owing to occurrence in never or light
smokers, although the d ­ ominant driving properties of these oncogenes
may reduce the selection pressure for acquiring additional mutations.

1
Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut, USA. 2Washington University School of Medicine, St Louis, Missouri, USA. 3Pfizer, Inc. New York City, New York, USA.

4 4 6 | N A T U R E | V O L 5 5 3 | 2 5 j anuar y 2 0 1 8
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
 Review insight

Box 1
Alterations in targetable ­oncogenic pathways in LUAD and LUSC
Pathway diagram showing the percentage of NSCLC with alterations
involving key pathway components for receptor tyrosine kinase
signalling, mTOR signalling, oxidative stress response, proliferation
and cell cycle progression. The frequency of alterations is based
on the sum of somatic mutations, homozygous deletions, focal
amplifications, and by significant up- or downregulation of gene
expression (for example, AKT3, FGFR1, PTEN).
The most commonly mutated genes in LUAD include KRAS and
EGFR, and the tumour suppressor genes TP53, KEAP1, STK11 and
NF1. The frequency of EGFR-activating mutations varies greatly
by region and ethnicity. KEAP1 inactivation in the presence of
KRAS mutations confers sensitivity to inhibition of glutaminase in
preclinical lung cancer models, providing a potential therapeutic
strategy in dual KEAP1- and KRAS-mutant LUAD139.
Common mutated genes in LUSC include the tumour suppressors
TP53, which is present in more than 90% of tumours, and CDKN2A.
The latter, which encodes the p16INK4A and p14ARF proteins, is
inactivated in over 70% of LUSC through epigenetic silencing by
methylation (21%), inactivating mutation (18%), exon 1β​ skipping
(4%), or homozygous deletion (29%). Although EGFR amplification
occurs, unlike LUAD, actionable mutations in receptor tyrosine kinases
are rarely observed in LUSC. (Data compiled from refs 14, 17, 22, 45
and diagram adapted from refs 17, 22.)

.(<
EGFR ERBB2/3 MET FGFR1, 2, 3 ALK RET ROS
ROS
Activated 27% <9% 3% 2–4% 7% 7%, 3%, 2% <8% 1% 2% 2%

Inactivated

LUAD
LUSC PTEN KRAS NRAS RASA
3% 15% 32% 3% <1% <1% 4%
PI3CA
4% 16%
PIK3R1 HRAS RIT1 NF1
<1% <1% 3% 2% 11% 11%

STK11 AKT1 AKT2 AKT3

17% 2% 1% <1% 4% 16%
BRAF
7% 4%

TSC1/2
AMPK
3% 3%
MAP2K1
<1% <1%

MTOR
CDKN2A
43% 70%
Proliferation, cell survival, translation

KEAP1 CUL3 MDM2 ATM CCND1 CDK4 CCNE4

19% 12% <1% 7% 8% 9% 4% 7% 3%

NFE2L2 TP53 RB1

3% 19% 46% 90% 7% 7%

Oxidative stress response Proliferation, cell survival Cell cycle progression

Unlike LUAD, actionable mutations in receptor tyrosine kinases are
rarely detected in LUSC15.
Mutations in tumour protein p53 (TP53) are more commonly observed
with advancing grade, suggesting a role during tumour progression16.
By contrast, the frequency of KRAS mutations in LUAD seems constant
across tumour grades, suggesting a role in tumour initiation or early
tumorigenesis, and supporting the presence of KRAS alterations in
founder clones.
The genomic landscape of lung cancer is markedly distinct between
never smokers and smokers, with the latter containing a significantly
higher mutation frequency, predominantly cytosine to adenine (C>​A)
nucleotide transversions and non-actionable mutations such as those in
KRAS and TP53. By contrast, never smokers usually have a predomi-
nant transition of cytosine to thymine (C>​T), and a higher prevalence of
actionable driving gene alterations including activating EGFR mutations,
and ROS1 and ALK translocations14,17.
Tumour microenvironment
Genetic events that initiate and drive tumour evolution also shape the
tumour microenvironment (TME). Therefore, the genetic architecture of
a tumour determines not only the fitness of the cancer cells, but also the
composition of the TME. NSCLC has a particularly high somatic tumour
mutation burden (TMB), defined as the number of nonsynonymous
coding mutations per megabase, particularly in smokers, who represent

2 5 j anuar y 2 0 1 8 | V O L 5 5 3 | N A T U R E | 4 4 7
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
 insight Review

KEY Crizotinib (first ALK Crizotinib shown Osimertinib Osimertinib shown to

inhibitor) shown to to be superior to shown to be be superior to
Chemotherapy ALK or ROS1 effective in cytotoxic therapy in
be effective in cytotoxic therapy
EGFR Genomic analysis ALK-positive in 1L ALK-positive EGFR(T790M) previously treated
NSCLC NSCLC mutations EGFR(T790M)
Angiogenesis Immune therapy

Mutational burden
TCGA genomic associated with
Docetaxel Pemetrexed RET and ROS characterization responses to
benefit shown in ALK rearrangements shown activity fusions described of LUAD immune checkpoint
2L NSCLC identified in NSCLC in 1L LUAD in LUAD completed blockers

1997 2000 2004 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Discovery of EGFR Gefitinib shown TCGA genomic Crizotinib shown Pembrolizumab

mutations in LUAD better activity characterization to be effective in shown to be
sensitive to gefitinib than cytotoxic of LUSC ROS1-positive superior to
and erlotinib therapy in LUAD completed NSCLC cytotoxic therapy
in 1L PD-L1-high
NSCLC

EGFR Bevacizumab Nivolumab shown Immune checkpoint Alectinib shown

inhibitors shown activity with to be effective in blockers shown to to be superior to
enter clinical cytotoxic therapy NSCLC be superior to crizotinib in 1L
development in 1L NSCLC docetaxel in 2L ALK-positive
NSCLC NSCLC

Figure 1 | Timeline illustrating the development of targeted therapies have transformed the management of NSCLC over the past two decades.
and immunotherapies for the treatment of NSCLC over two decades. 1L, first line; 2L, second line; TCGA, The Cancer Genome Atlas.
Timeline highlights some of the pivotal discoveries and clinical studies that

the majority of patients. Overall, the number of mutations is significantly
higher in metastases than in primary lung lesions18.
Some mutations create neoantigens, which may be recognized by
tumour-infiltrating cytotoxic T cells. A high clonal neoantigen burden
in LUAD is associated with an inflamed TME, enriched with activated
effector T cells and the expression of proteins associated with antigen
presentation, T cell migration (CXCL-10 and CXCL-9), and effector T cell
function, as well as negative regulators of T-cell activity including PD-L1,
programmed death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3)19.
This phenotype may confer sensitivity to treatment with an ICB. Loss of
mismatch-repair function, which confers the microsatellite instability
phenotype, is an extreme example of cancer with a high TMB, with these
tumours demonstrating T cell infiltration and marked responses to ICBs,
independent of the tissue of origin20.
Genetic alterations may affect the TME in several ways. An example
is the inactivation of the tumour suppressor serine/threonine kinase 11
(STK11; also known as LKB1), occurring in one-third of KRAS-mutated
LUAD, which skews the TME towards the accumulation of immunosup-
pressive neutrophils and loss of PD-L1 expression, and is associated with
fewer tumour-infiltrating lymphocytes21. Large-scale studies to corre-
late the genomes of NSCLC to the cellular constituents of the TME are
required to understand how different genotypes determine the cellular
make-up of the TME.
Therapeutic advances during the past two decades
Over the past 20 years, treatment has evolved from the empiric use of cyto-
toxic therapies to effective and better tolerated regimens that are targeted
to specific molecular subtypes in LUAD, and therapies in d ­ evelopment to
target LUSC17,22 (Fig. 1). Platinum-based doublet therapy (for e­ xample,
cisplatin in combination with another cytotoxic therapy) has been the
standard therapy for patients with advanced stage NSCLC and good
performance status, with the option of maintenance therapy in patients
with non-LUSC histology who achieve tumour control after the initial
four to six cycles23. Overall, there have been no clinically meaningful
differences in outcome among the multiple cytotoxic regimens used
in patients with advanced stage NSCLC24, with the exception of
­pemetrexed, which is less effective in patients with LUSC25. The ­addition
of ­bevacizumab, a monoclonal antibody against vascular endothelial
growth factor (VEGF) or necitumumab, an antibody that targets EGFR,
­produced modest improvements in survival for patients with non-LUSC
and LUSC histological subtypes, respectively26,27. In the second-line
­setting, the standard of care has been docetaxel, with or without the anti-
VEGF receptor-2 antibody ramucirumab28.
Cytotoxic regimens have demonstrated their greatest effect on earlier
stage disease. Surgical resection is the most effective therapy for stages I
to II and selected cases of stage IIIA NSCLC29. However, despite its cura-
tive intent, a high percentage of tumours will recur, with 5-year overall
survival ranging from 83% for stage IA to 36% for stage IIIA disease30.
Adjuvant cytotoxic therapy with a cisplatin-based doublet is associated
with improved survival in patients with completely resected stage II and
IIIA NSCLC, with a likely benefit for stage IB disease measuring 4 cm
or more31. Morbidity and outcomes have also improved for early stage
lung cancer owing to advances in surgical and radiation technologies,
including robotic and video-assisted surgery32, as well as stereotactic and
hyper-fractionated approaches33. The standard therapy for patients with
unresectable locally advanced NSCLC is the combination of cytotoxic
therapy and thoracic radiation, with a survival advantage for concurrent
therapy over sequential approaches34,35.
The high lung cancer mortality is due to the presence of meta-
static disease at the time of diagnosis in most patients, indicating that
improvements in long-term survival will require more effective systemic
therapies36,37. Molecularly targeted therapies in patients with NSCLC
were initially used in the late 1990s with the introduction of gefitinib, an
oral EGFR tyrosine kinase inhibitor (TKI). In unselected populations,
the response rates were approximately 10%, with increased frequency
of responses noted in females, never smokers, and patients of Asian
descent38,39. Erlotinib, another TKI against EGFR, was associated with
improved survival compared to the best supportive care in patients with
previously treated advanced-stage NSCLC40. Retrospective studies sub-
sequently demonstrated that activating EGFR mutations were observed
in the vast majority of patients who benefited from EGFR TKIs41,42. Since
then, additional gene alterations, including ALK rearrangements, ROS1
fusions and BRAF mutations led to the development of effective targeted
therapies43.

4 4 8 | N A T U R E | V O L 5 5 3 | 2 5 j anuar y 2 0 1 8
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
 Review insight

An important advance in the management of advanced stage NSCLC updates on overall survival, may provide a guide to first-line therapy
occurred in 2015, when the US FDA approved the ICB nivolumab for in previously untreated patients with tumours harbouring an EGFR
the treatment of patients whose disease progressed during or after mutation.
platinum-based therapy, heralding a new era in the management of lung One of the mechanisms for acquired resistance to third-generation
cancer44. EGFR TKIs is the C797S mutation65 which in combination with the sensi-
tizing mutation and without T790M causes resistance to third-­generation
Targeted therapy EGFR TKIs, but not to gefitinib or afatinib. The presence of triple mutants
The identification of targetable gene alterations has transformed the (sensitizing mutation, T790M and C797S) however, leads to resistance
­management of lung cancer, with the incorporation of tumour genotyping to all three generations of EGFR TKIs66. Promising approaches to ­triple
to allow individualized therapy and leading to remarkable responses in mutants include the allosteric inhibitor EAI045 in tumours with ­original
selected patients treated with matched TKIs (Table 1). In the multicentre L858R-sensitizing mutation, and brigatinib, an ALK inhibitor with activity
Lung Cancer Mutation Consortium, targetable oncogenic drivers were against EGFR mutations, in tumours harbouring exon 19 d ­ eletion, both
observed in 64% of patients with LUAD, for whom the use of genotype-­ in combination with cetuximab, an anti-EGFR monoclonal antibody67,68.
directed therapy was associated with improved survival compared to
those treated without targeted therapies45. ALK
ALK encodes a transmembrane receptor tyrosine kinase with unclear
EGFR function in humans69. In ALK rearrangements, the most common partner
EGFR belongs to a receptor tyrosine kinase family that also includes is the echinoderm microtubule-associated protein-like 4 (EML4) gene
human epidermal growth factor receptor 2 (HER2, also known as ERBB2), (EML4-ALK)70. Crizotinib is an oral competitive ATP inhibitor of ALK,
HER3 (ERBB3) and HER4 (ERBB4). The receptor contains four extra­ MET and ROS1 tyrosine kinases with activity against ALK fusion-positive
cellular domains, a transmembrane domain, a tyrosine kinase domain, NSCLC71. Crizotinib is associated with improved ORRs and median PFS
and a carboxy tail46. Binding of activating ligands leads to EGFR dimeri- compared to cytotoxic therapy in both previously treated and untreated
zation and trans-phosphorylation of the tyrosine residues in the carboxy patients72,73. Most patients previously treated with crizotinib benefit
tail, with activation of downstream pathways involved in cell proliferation, from second-generation ALK inhibitors including ceritinib, alectinib
survival, invasion and angiogenesis47. Heterozygous mutations ­clustering and brigatinib74–76. Ceritinib also increased median PFS compared to
around the ATP-binding pocket of the tyrosine kinase domain may lead first-line cytotoxic therapy in patients with ALK-positive NSCLC77. Two
to constitutive EGFR activation and ligand independence41,42. The most randomized studies showed increased ORRs and median PFS for alectinib
common EGFR mutations associated with sensitivity to EGFR TKIs compared to crizotinib in patients with previously untreated ALK-positive
include exon 19 deletions and a missense mutation on exon 21 (L858R)48. NSCLC, establishing alectinib as a first-line treatment option78,79.
First-generation EGFR TKIs, including gefitinib and erlotinib, have Resistance to ALK inhibitors may occur owing to ALK alterations such
shown higher objective response rates (ORRs) and progression-free as mutations and amplification, or upregulation of bypass signalling path-
­survival (PFS) compared to cytotoxic therapy in previously untreated ways including EGFR and mitogen-activated protein kinase (MAPK).
patients with EGFR mutations49–54. In contrast to first-generation EGFR Secondary ALK mutations are the predominant mechanism of resistance
TKIs, which are reversible competitive ATP inhibitors that target only to second-generation TKIs80. The most common ALK resistance mutation
EGFR, second-generation inhibitors including afatinib and dacom- among patients treated with second-generation TKIs is G1202R, which is
itinib are irreversible inhibitors that also target HER2 and HER4. Both
­afatinib and dacomitinib showed improved PFS compared to gefitinib55,56. Table 1 | Selected randomized trials with first-line targeted
Afatinib also demonstrated a significant improvement in the median therapies
overall survival compared to platinum-based cytotoxic therapy in patients PFS
with an exon 19 deletion, but not in those with an L858R mutation57. Study Target Design ORR (%) (months)
Differences in outcomes between these two most common EGFR muta- IPASS49,50 EGFR Gefitinib vs 72.1 vs 47.3 9.5 vs 6.3
tions may occur owing to distinct conformational changes within the carboplatin plus
ATP-binding pocket and patterns of auto-phosphorylation induced by paclitaxel
NEJ00251 EGFR Gefitinib vs 73.7 vs 30.7 10.8 vs 5.4
each mutation58. carboplatin plus
The most common cause of acquired resistance to first-generation paclitaxel
TKIs is a second EGFR mutation in exon 20, with a threonine-to- WJTOG-340552 EGFR Gefitinib vs 62.1 vs 32.2 9.2 vs 6.3
methionine substitution on codon 790 (T790M)59,60. This mutation affects cisplatin plus
the initial EGFR TKI efficacy either from steric hindrance or by increased docetaxel
EURTAC54 EGFR Erlotinib vs 58 vs 15 9.7 vs 5.2
affinity of the tyrosine kinase domain for ATP. Other mechanisms of platinum doublet
resistance include amplifications in HER2 or mutations in MET, BRAF OPTIMAL53 EGFR Erlotinib vs 83 vs 36 13.1 vs 4.6
or phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha carboplatin plus
(PIK3CA), and SCLC transformation61, indicating that repeated mole­ gemcitabine
cular profiling at progression is needed to determine the next appropriate LUX-Lung-755 EGFR Afatinib vs 72.5 vs 56 11 vs 10.9
gefitinib
treatment. Third-generation EGFR TKIs are selective inhibitors of both ARCHER-105056 EGFR Dacomitinib vs 75 vs 72 14.7 vs 9.2
the original sensitizing and T790M mutations, while sparing wild-type gefitinib
EGFR. These drugs bind covalently to cysteine on codon 797, overcoming FLAURA 64
EGFR Osimertinib 80 vs 76 18.9 vs 10.2
the enhanced ATP affinity from the T790M mutation. Osimertinib, a vs gefitinib or
erlotinib
third-generation EGFR TKI, is effective in patients with NSCLC har-
PROFILE -101473 ALK Crizotinib vs 74 vs 45 10.9 vs 7
bouring EGFR(T790M) mutations following progression after first- cisplatin plus
generation EGFR TKI62, and showed increased ORRs and PFS ­compared pemetrexed
to platinum-based cytotoxic therapy63. In a randomized trial that ASCEND-477 ALK Ceritinib vs 72.5 vs 26.7 16.6 vs 8.1
­compared osimertinib to either erlotinib or gefitinib in previously platinum plus
pemetrexed
untreated patients with advanced stage NSCLC harbouring either EGFR
ALEX79 ALK Alectinib vs 82.9 vs 75.5 NR vs 11.1
exon 19 deletion or L858R mutation, osimertinib was associated with crizotinib
a significant improvement in PFS, establishing osimertinib as a first- The IPASS trial encompasses a subgroup of patients with EGFR mutation. NR, not reached; ORR,
line EGFR TKI option64. Additional follow-up from this trial, including objective response rate; PFS, progression-free survival.

2 5 j anuar y 2 0 1 8 | V O L 5 5 3 | N A T U R E | 4 4 9
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
 insight Review

Table 2 | Randomized phase 3 clinical trials comparing ICBs to Immunotherapy

cytotoxic therapy Harnessing the host immune response to treat cancer is not a new
ORR PFS OS concept102, and the introduction of ICBs such as monoclonal antibodies
Study Drug (%) (months) (months) that target cytotoxic T-lymphocyte antigen-4 (CTLA-4) and antibodies
Second-line against PD-1 or PD-L1 have signalled a new direction for lung cancer
CheckMate-017 Nivolumab 20 3.5 9.2 care. The first ICB approved by the US FDA was ipilimumab, a human
(squamous)110 3 mg kg−1 Q2W immunoglobulin G1 monoclonal antibody that blocks CTLA-4, for the
Checkmate-057 Nivolumab 19 2.3 12.2 treatment of metastatic melanoma103,104. During tumorigenesis, PD-1
(non-squamous)111 3 mg kg−1 Q2W
Keynote-010 (NSCLC Pembrolizumab 18 3.9 10.4
signalling, driven primarily by adaptive expression of PD-L1 within
PD-L1 positive)112 2 mg kg−1 Q3W the tumour, inactivates T cells that recognize tumour-specific antigens,
Oak (NSCLC)113 Atezolizumab 14 2.8 13.8 allowing tumour progression and metastasis105,106. Blocking the PD-1
1,200 mg Q3W and PD-L1 axis with antibodies offers an approach to restoring T cell-­
Combined docetaxel Docetaxel 9–13 2.8–4.2 6–9.6 mediated antitumour immunity107–109. ICBs have shown significant
results* (refs 110–113) 75 mg m−2 Q3W
First-line
­benefit in a broad population of patients with NSCLC (Table 2). Current
Keynote-024 Pembrolizumab 44.8 10.3 NR ICBs approved or in development for NSCLC include the anti-PD-1 anti-
(PD-L1 ≥​ 50%)114 200 mg Q3W bodies nivolumab (human IgG4) and pembrolizumab (humanized IgG4),
Checkmate-026 Nivolumab 26 4.2 14.4 as well as the anti-PD-L1 antibodies atezolizumab (human IgG1, with the
(PD-L1 ≥​ 5%)115 3 mg kg−1 Q2W Fc domain engineered to prevent antibody-directed cell cytotoxicity),
Combined Platinum-based 27–33 5.9–6 13.2
chemotherapy results† chemotherapy
durvalumab (human IgG1 engineered), and avelumab (human IgG1
(refs 114, 115) demonstrating preclinical antibody-directed cell cytotoxicity activity)29.
OS, overall survival; Q2W, every two weeks; Q3W, every three weeks. ICBs have been approved as a standard of care for patients with
*Combined control arm results from CheckMate trials 017 and 057, Keynote-010 and Oak. advanced NSCLC whose tumours progress on first-line cytotoxic t­ herapy.
†Combined control arm results from CheckMate-026 and Keynote-024.
Treatment with nivolumab was associated with significantly longer
median overall survival compared to treatment with docetaxel among
associated with in vitro resistance to all currently available ALK inhibitors patients with metastatic NSCLC who had disease progression during or
except for lorlatinib, a potent third-generation ALK inhibitor with activity after platinum-based cytotoxic therapy110,111. Subsequently, other ICBs
against most known ALK resistance mutations and efficacy in patients showed improvement in overall survival compared to treatment with
previously treated with up to three previous lines of ALK inhibitors81. docetaxel, including pembrolizumab112 and atezolizumab113.
In the first-line NSCLC setting, pembrolizumab was established as a
ROS1 new standard of care for patients with advanced or metastatic NSCLC
ROS1 encodes a receptor tyrosine kinase that becomes constitutively with tumour PD-L1 expression levels of 50% or more (by a companion
activated when a rearrangement leads to the fusion of its tyrosine kinase immunohistochemistry test), which is present in up to 30% of NSCLC. In
domain with a partner gene such as CD7482. Owing to the high h ­ omology these patients, pembrolizumab is associated with a significant improve-
between the kinase domains of ROS1 and ALK, drugs used to treat ALK- ment in ORRs, PFS and overall survival compared to platinum-based
positive tumours including crizotinib83, ceritinib84 and lorlatinib81 have cytotoxic therapy114. By contrast, among patients with PD-L1 expression
also shown marked activity in ROS1-positive tumours. Mechanisms levels of 5% or more, nivolumab was not associated with improvements in
of acquired resistance of ROS1 rearrangements to crizotinib include PFS or overall survival compared to cytotoxic therapy115. Among patients
secondary mutations, most commonly G2032R, wild-type EGFR in the nivolumab group with both PD-L1 expression levels above 50% and
­signalling activation, KRAS and KIT mutations85,86. high TMB, the ORR was 75%, confirming previous observations that both
TMB and PD-L1 expression may predict for benefit from ICB. The better
Other alterations toxicity profile with ICBs and equivalent survival outcome could support
Among patients with NSCLC and BRAF mutation, approximately half their selection as first-line therapy for patients with PD-L1-expressing
have a single transversion at exon 15, in which valine is replaced by advanced NSCLC, especially in those not eligible for cytotoxic therapy116.
­glutamate at residue 600 (V600E)87,88, predicting for sensitivity to the Cytotoxic therapy could synergize with ICBs by killing tumour cells,
BRAF inhibitors vemurafenib and dabrafenib as single agents89,90, or improving the T-cell-to-tumour ratio and restoring the ­metabolic restric-
dabrafenib in combination with the MEK inhibitor trametinib91. tions that result in T cell hyporesponsiveness in cancer117,118. Cytotoxic
Somatic mutations that affect MET exon 14, which contains the Y1003 ­therapy could also reduce immunosuppressive factors released by
residue required for the recruitment of CBL ubiquitin ligase that targets tumours or promote the release of antigens for presentation, b­ roadening
MET for ubiquitin-mediated degradation, lead to increased MET stability the antitumour T cell response. The combination of pembrolizumab, car-
and prolonged signalling from hepatocyte growth factor stimulation92. boplatin and pemetrexed resulted in improved ORRs and PFS ­compared
Patients with NSCLC harbouring MET exon 14 skipping may respond to to cytotoxic therapy alone, and this combination could be an effective
MET inhibitors including crizotinib or cabozantinib93,94. and tolerable first-line treatment option for patients with advanced non-
Other potential targetable gene alterations include mutations in HER2, LUSC119. Several randomized studies are evaluating the role of ICBs in
rearrangements in the proto-oncogene RET, which encodes a receptor combination with platinum-based cytotoxic regimens, with or without
tyrosine kinase, and fusions of the neurotrophic tyrosine receptor kinase bevacizumab, in first-line advanced or recurrent NSCLC. The magnitude
(NTRK) genes 1, 2 and 3, which code for tropomyosin receptor kinases of the overall survival benefit of such combinations will determine their
(TRK) A, B and C, respectively. Initial results from targeted treatment future use.
against HER2 and RET alterations have shown modest activity compared Combining anti-PD-(L)1 and anti-CTLA-4 monoclonal antibodies
to other oncogenic targets, which may reflect their roles as dominant may result in higher and more durable responses in NSCLC, as observed
clonal drivers95–99. By contrast, selective TRK TKIs have demonstrated in experimental models120, and suggested in a single-arm clinical study121.
histology-agnostic efficacy in patients with NTRK fusion-positive Randomized studies that combine nivolumab with ipilimumab, and
cancers, which occur in less than 1% of NSCLC. Although responses durvalumab with the anti-CTLA-4 human IgG4 antibody tremelimumab,
to TRK inhibition are notable and durable100, the duration of response are continuing and overall survival data from these studies are eagerly
may eventually be limited by resistance, and a next-generation TKI has awaited. It is expected that the safety profile for such combinations may
been identified to overcome acquired resistance to previous TRK kinase not be as favourable as those with ICB plus cytotoxic therapy combina-
inhibition101. tions, especially in terms of immune-related adverse events. Nevertheless,

4 5 0 | N A T U R E | V O L 5 5 3 | 2 5 j anuar y 2 0 1 8
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
 Review insight

0 6 12 18 24 30 36

EGFR 3rd gen TKI TKI/chemo/ICB

Low

15–17%
EGFR 1st gen T790M 3rd gen TKI TKI/chemo/ICB
Oncogene addiction
(incidence: 25%)

ALK 2nd gen TKI TKI/chemo/ICB

3–4%
ALK 1st gen TKI ALK 2nd gen TKI TKI/chemo/ICB
2–3% MET exon 14 TKI TKI/chemo/ICB

1% ROS1 1st gen TKI TKI/chemo/ICB

1% BRAF/MEK TKI Chemo/ICB

<1% NTRK TKI TKI/chemo/ICB

PD-L1 expression

Chemo PD-(L)1
(incidence: 50%)

Chemo PD-(L)1 Chemo/IT

Chemo + PD-(L)1 Chemo/IT

Other

PD-(L)1 + CTLA-4 Chemo/IT

PD-(L)1 + IDO1 Chemo/IT

KEY
CHEMO + PD-(L)1 + CTLA-4 Chemo/IT Indicates PFS range estimated
from ongoing study
(incidence: 25–30%)

Experimental or
MSI high PD-1 Chemo/IT
PD-L1 high+++

clinical trial option

PD-1 Chemo/IT Biopsy indicated or recommended
PD-(L)1 + chemo Approved treatment option
Investigational treatment
High

PD-(L)1 + CTLA-4 (ongoing phase II or III clinical study)

0 6 12
Figure 2 | Current and investigative treatment options for advanced
or metastatic NSCLC. Illustration of the current and future personalized
treatment options for NSCLC. Targetable oncogenic drivers account for
approximately 25% of NSCLC, of which EGFR mutations are the most
frequent45. Biopsies are indicated at the time of disease progression
to determine the best treatment option. For patients with tumours
expressing high levels of PD-L1 (>​50%) or high levels of microsatellite
instability (MSI), single agent ICB is indicated114. In general, median PFS
18 24 30 36
PFS (months)
is not the best indicator to capture the overall true benefit of ICBs, as a
proportion of patients remain alive or disease-free even after long-term
follow-up. In patients with tumours with high (>​50%) or low (>​1%)
expression levels of PD-L1, current studies are assessing the benefit of
anti-PD-(L)1 combinations with cytotoxic therapy, anti-CTLA-4, or other
immunotherapy (IT) approaches. PFS estimates illustrated for targeted
therapies from refs 52, 54, 64, 73, 79, 83, 100 and for ICBs from refs 114,
119, 121.

despite encouraging results with prolonged benefit in selected patients,
most lung tumours are either inherently resistant or will adapt to or
become resistant to current immunotherapies. The challenge is to develop
rational combinations that will increase responses, or delay the onset of
resistance122.
Whereas ICB monotherapy may be appropriate for tumours with high
expression levels of PD-L1 or a high nonsynonymous TMB, a d ­ ifferent
approach may be required for tumours with fewer T cells and a lower
TMB (Supplementary Table 1). The induction of immunogenic ­cancer
death with the use of cytotoxic therapy, epigenetic modifiers123 or
­oncolytic viruses124 appears promising in preclinical models or in early
phase 1 c­ linical studies. Another strategy includes combination with anti-­
angiogenic drugs, as VEGF contributes to an immunosuppressive TME by
recruiting suppressive immune cells, such as myeloid-derived suppressor
cells and regulatory T cells125. Furthermore, angiogenic ­inhibitors may
increase immune cell infiltration126.
In tumours with a low TMB, few T cells and low PD-L1 expression
(‘cold tumours’), the challenge for immunotherapeutic approaches is not
only to attract effector T cells into the TME, but also to present tumour
antigens to T cells. Possible approaches for such cold NSCLCs could
include the use of adoptive transfer of autologous tumour-infiltrating
lymphocytes or chimaeric antigen receptor T cell therapy. For the latter,
NSCLC-specific or unique cell-surface antigens will need to be identified.
Other approaches being developed for solid tumours, and in the future
for NSCLC, include the use of autologous vaccines that use genomic
information from a specific tumour to predict neo-epitopes that could be
presented to T cells, for the design and manufacture of a vaccine unique
for each patient127.
Most patients who achieve an initial benefit from an ICB eventually
develop resistance. Some of the mechanisms for acquired resistance to
ICBs include defects in interferon-γ​signalling or major histocompatibility
complex presentation128, and increased levels of the enzyme indoleamine
2,3-dioxygenase (IDO1), which catabolizes tryptophan, an amino acid
required for optimal T cell function129,130.
ICBs are poised to move to earlier stages of lung cancer therapy, in
an attempt to improve survival after surgery or radiotherapy, in which
the goal is curative. A randomized trial of durvalumab as a sequential
treatment in patients with locally advanced unresectable stage NSCLC
who had not progressed after standard concurrent platinum-based cyto-
toxic and radiation therapy showed a notable improvement in median
PFS compared to placebo131. The role of ICBs in patients with curable
non-metastatic disease will be further clarified with the results of many
continuing trials accruing in both the perioperative setting and in patients
with locally advanced disease treated with concurrent cytotoxic and
­radiation therapy.
The notable clinical success of cancer immunotherapy over a short
period of time suggests that it may form the foundation of future ­curative-
intent regimens for many malignancies, including NSCLC (Fig. 2).

2 5 j anuar y 2 0 1 8 | V O L 5 5 3 | N A T U R E | 4 5 1
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
 insight Review
Advancing personalized medicine and trial design
The rapid development of targeted therapies with newer and more
potent generations of drugs, and the characterization of the mecha-
nisms of acquired resistance, established the role for repeated genomic
­profiling at the time of tumour progression, particularly in patients with
EGFR mutations, in which the most common cause of resistance, the
T790M mutation, may be successfully treated with osimertinib. The
repeated genomic profile has traditionally been performed through
repeated biopsy, which may not always be feasible and carries risks for
complications. An ­emerging option is the use of plasma genotyping with
sequencing circulating tumour DNA (ctDNA). In a retrospective analysis
including 216 patients with both central tissue and plasma genotyping
available before treatment with osimertinib in a clinical trial, the sensi-
tivity of plasma genotyping for EGFR(T790M) was 70%132. Furthermore,
plasma EGFR(T790M) mutations were found in 31% of patients with
tissue-negative results. Because the outcomes with osimertinib t­ reatment,
including ORRs and PFS, were similar for T790M mutations detected
by tissue or plasma, a repeated biopsy could be avoided in those with
positive plasma results. By contrast, patients with negative plasma results
should undergo a repeated biopsy. Multianalytical ctDNA tests for
multiple molecular markers, including the detection of high TMB, are
being developed to support individualized lung cancer treatment.
Because many gene alterations are uncommon or rare, and h ­ undreds
of combination studies are being conducted in NSCLC, recruiting
patients to clinical trials is becoming more difficult. To adjust to this
current ­situation, innovative master protocols are being used in which
several questions can be answered in one study. Such master protocols are
designed to encompass a collection of trials that share key design features
and used to assess either multiple targeted therapies or immunotherapy
combinations for a single disease (umbrella trials) or a single targeted
therapy for multiple diseases (basket trials). The Biomarker-integrated
Approaches of Targeted Therapy for Lung cancer Elimination (BATTLE)
and Lung Cancer Master Protocol (Lung-MAP) trials are among the first
umbrella trials for patients with NSCLC, with the former showing the
feasibility of performing fresh biopsies to guide the next line of therapy, a
principle that has been often used in the most recent studies133,134.
Future perspectives
The treatment of NSCLC has undergone remarkable changes. A better
understanding of the tumour biology enabled the development of
targeted therapies that heralded the era of personalized medicine.
Furthermore, the introduction of ICBs has led to prolonged survival in
selected patients. Nevertheless, this unprecedented benefit from current
standard therapies is still observed in only a minority of patients, with
targeted therapies restricted to non-LUSC histological subtypes that contain
actionable driver mutations, and durable responses from immunotherapy
occurring uncommonly. One of the main concerns with targeted therapy
is the emergence of secondary clones that may not be effectively
targeted by the initial treatment directed at the founder clone. To improve
outcomes further, there is a need to understand better the mechanisms of
acquired resistance to allow their prevention or effective treatment at the
time of emergence. Therefore, focusing on both dominant and sub-clones
may be required for a more effective and durable benefit from targeted
therapies135.
The application of ctDNA to track the evolutionary dynamics of
early stage lung cancer should be expanded to detect both oncogenic
drivers and track resistant mutations, providing a future approach for
ctDNA-driven targeted therapeutics136. A systematic approach to collect
tissue samples not only at the time of diagnosis but also serially at the
times of relapse to evaluate the dynamic clonal evolution that occurs over
time and possibly at different metastatic sites will be crucial for further
therapeutic advances.
Better predictors for response to immunotherapy are critical for its
­optimal use. Although both PD-L1 and TMB may be used to select
patients for therapy137, most patients will not fit the ideal profile based
on these two biomarkers. Furthermore, correlating cancer genomic
4 5 2 | N A T U R E | V O L 5 5 3 | 2 5 j anuar y 2 0 1 8
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
information with the cellular components of the TME could allow the
use of rationally designed combination therapies138.
Over the past 20 years, there has been enormous progress in the
understanding of the biology and management of NSCLC, with targeted
and immunotherapies providing a new foundation towards rationally
designed therapeutic regimens with manageable toxicity profiles and
improvement in survival. Although the treatment of patients with met-
astatic NSCLC has long been considered palliative, continuing drug
development provides the hope for prolonged survival in an increasing
number of patients and, for the first time, raises the possibility of a cure
in those with metastatic disease. Furthermore, the use of new therapeutic
modalities including immunotherapy may have an even higher impact in
patients with earlier non-detectable metastatic disease, in whom treatment
is given with curative intent.
received 18 August; accepted 29 November 2017.
1. Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108
(2015).
2. Molina, J. R., Yang, P., Cassivi, S. D., Schild, S. E. & Adjei, A. A. Non-small cell
lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin.
Proc. 83, 584–594 (2008).
3. Alberg, A. J., Brock, M. V., Ford, J. G., Samet, J. M. & Spivack, S. D. Epidemiology
of lung cancer: diagnosis and management of lung cancer, 3rd ed.: American
College of Chest Physicians evidence-based clinical practice guidelines. Chest
143, e1S–e29S (2013).
4. Sun, S., Schiller, J. H. & Gazdar, A. F. Lung cancer in never smokers--a different
disease. Nat. Rev. Cancer 7, 778–790 (2007).
5. Vineis, P. et al. Environmental tobacco smoke and risk of respiratory cancer
and chronic obstructive pulmonary disease in former smokers and never
smokers in the EPIC prospective study. Br. Med. J. 330, 277 (2005).
6. Hackshaw, A. K., Law, M. R. & Wald, N. J. The accumulated evidence on lung
cancer and environmental tobacco smoke. Br. Med. J. 315, 980–988 (1997).
7. Shahab, L. et al. Nicotine, carcinogen, and toxin exposure in long-term
e-cigarette and nicotine replacement therapy users: a cross-sectional study.
Ann. Intern. Med. 166, 390–400 (2017).
8. Hays, J. T. & Ebbert, J. O. Varenicline for tobacco dependence. N. Engl. J. Med.
359, 2018–2024 (2008).
9. Brandon, T. H. et al. Electronic nicotine delivery systems: a policy statement
from the American Association for Cancer Research and the American Society
of Clinical Oncology. J. Clin. Oncol. 33, 952–963 (2015).
10. Zhang, J. et al. Intratumor heterogeneity in localized lung adenocarcinomas
delineated by multiregion sequencing. Science 346, 256–259 (2014).
11. Engelman, J. A. et al. MET amplification leads to gefitinib resistance in lung
cancer by activating ERBB3 signaling. Science 316, 1039–1043 (2007).
12. Turke, A. B. et al. Preexistence and clonal selection of MET amplification in
EGFR mutant NSCLC. Cancer Cell 17, 77–88 (2010).
13. Pao, W. et al. KRAS mutations and primary resistance of lung
adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2, e17 (2005).
14. Ding, L. et al. Somatic mutations affect key pathways in lung adenocarcinoma.
Nature 455, 1069–1075 (2008).
15. Reck, M. & Rabe, K. F. Precision diagnosis and treatment for advanced
non-small-cell lung cancer. N. Engl. J. Med. 377, 849–861 (2017).
16. Ahrendt, S. A. et al. p53 mutations and survival in stage I non-small-cell lung
cancer: results of a prospective study. J. Natl. Cancer Inst. 95, 961–970 (2003).
17. Cancer Genome Atlas Research Network. Comprehensive molecular profiling
of lung adenocarcinoma. Nature 511, 543–550 (2014).
18. Robinson, D. R. et al. Integrative clinical genomics of metastatic cancer. Nature
548, 297–303 (2017).
19. McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and
sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).
20. Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency.
N. Engl. J. Med. 372, 2509–2520 (2015).
21. Koyama, S. et al. STK11/LKB1 deficiency promotes neutrophil recruitment
and proinflammatory cytokine production to suppress T-cell activity in the
lung tumor microenvironment. Cancer Res. 76, 999–1008 (2016).
22. Cancer Genome Atlas Research Network. Comprehensive genomic
characterization of squamous cell lung cancers. Nature 489, 519–525 (2012).
References 17 and 22 are landmark genomics analyses that describe the
molecular landscapes of lung adenocarcinoma and squamous cell
carcinoma, respectively.
23. Hanna, N. et al. Systemic therapy for stage IV non-small-cell lung cancer:
american society of clinical oncology clinical practice guideline update. J. Clin.
Oncol. 35, 3484–3515 (2017).
24. Schiller, J. H. et al. Comparison of four chemotherapy regimens for advanced
non-small-cell lung cancer. N. Engl. J. Med. 346, 92–98 (2002).
25. Scagliotti, G. V. et al. Phase III study comparing cisplatin plus gemcitabine with
cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-
stage non-small-cell lung cancer. J. Clin. Oncol. 26, 3543–3551 (2008).
26. Sandler, A. et al. Paclitaxel-carboplatin alone or with bevacizumab for
non-small-cell lung cancer. N. Engl. J. Med. 355, 2542–2550 (2006).

27. Thatcher, N. et al. Necitumumab plus gemcitabine and cisplatin versus
gemcitabine and cisplatin alone as first-line therapy in patients with stage IV
squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised,
controlled phase 3 trial. Lancet Oncol. 16, 763–774 (2015).
28. Garon, E. B. et al. Ramucirumab plus docetaxel versus placebo plus docetaxel
for second-line treatment of stage IV non-small-cell lung cancer after disease
progression on platinum-based therapy (REVEL): a multicentre, double-blind,
randomised phase 3 trial. Lancet 384, 665–673 (2014).
29. Hirsch, F. R. et al. Lung cancer: current therapies and new targeted treatments.
Lancet 389, 299–311 (2017).
30. Goldstraw, P. et al. The IASLC Lung Cancer Staging Project: Proposals for
Revision of the TNM Stage Groupings in the Forthcoming (Eighth) Edition of
the TNM Classification for Lung Cancer. J. Thorac. Oncol. 11, 39–51 (2016).
31. Kris, M. G. et al. Adjuvant systemic therapy and adjuvant radiation therapy for
stage I to IIIA completely resected non-small-cell lung cancers: American
Society of Clinical Oncology/Cancer Care Ontario clinical practice guideline
update. J. Clin. Oncol. 35, 2960–2974 (2017).
32. Liang, H. et al. Robotic versus video-assisted lobectomy/segmentectomy for
lung cancer: a meta-analysis. Ann. Surg. https://doi.org/10.1097/
SLA.0000000000002346 (2017).
33. Chi, A., Chen, H., Wen, S., Yan, H. & Liao, Z. Comparison of particle beam
therapy and stereotactic body radiotherapy for early stage non-small cell lung
cancer: A systematic review and hypothesis-generating meta-analysis.
Radiother. Oncol. 123, 346–354 (2017).
34. Dillman, R. O. et al. A randomized trial of induction chemotherapy plus
high-dose radiation versus radiation alone in stage III non-small-cell lung
cancer. N. Engl. J. Med. 323, 940–945 (1990).
35. Curran, W. J., Jr et al. Sequential vs. concurrent chemoradiation for stage III
non-small cell lung cancer: randomized phase III trial RTOG 9410. J. Natl.
Cancer Inst. 103, 1452–1460 (2011).
36. Herbst, R. S., Heymach, J. V. & Lippman, S. M. Lung cancer. N. Engl. J. Med.
359, 1367–1380 (2008).
37. Morgensztern, D., Ng, S. H., Gao, F. & Govindan, R. Trends in stage distribution
for patients with non-small cell lung cancer: a National Cancer Database
survey. J. Thorac. Oncol. 5, 29–33 (2010).
38. Fukuoka, M. et al. Multi-institutional randomized phase II trial of gefitinib for
previously treated patients with advanced non-small-cell lung cancer
(The IDEAL 1 Trial) [corrected]. J. Clin. Oncol. 21, 2237–2246 (2003).
39. Kris, M. G. et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor
receptor tyrosine kinase, in symptomatic patients with non-small cell lung
cancer: a randomized trial. J. Am. Med. Assoc. 290, 2149–2158 (2003).
40. Shepherd, F. A. et al. Erlotinib in previously treated non-small-cell lung cancer.
N. Engl. J. Med. 353, 123–132 (2005).
41. 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).
42. Paez, J. G. et al. EGFR mutations in lung cancer: correlation with clinical
response to gefitinib therapy. Science 304, 1497–1500 (2004).
References 41 and 42 were among the first studies to demonstrate that
EGFR mutations in NSCLC confer sensitivity to anti-EGFR tyrosine kinase
inhibitors.
43. Rikova, K. et al. Global survey of phosphotyrosine signaling identifies
oncogenic kinases in lung cancer. Cell 131, 1190–1203 (2007).
44. Kazandjian, D. et al. FDA approval summary: nivolumab for the treatment of
metastatic non-small cell lung cancer with progression on or after platinum-
based chemotherapy. Oncologist 21, 634–642 (2016).
45. Kris, M. G. et al. Using multiplexed assays of oncogenic drivers in lung cancers
to select targeted drugs. J. Am. Med. Assoc. 311, 1998–2006 (2014).
46. Lemmon, M. A., Schlessinger, J. & Ferguson, K. M. The EGFR family: not so
prototypical receptor tyrosine kinases. Cold Spring Harb. Perspect. Biol. 6,
a020768 (2014).
47. Wheeler, D. L., Dunn, E. F. & Harari, P. M. Understanding resistance to EGFR
inhibitors-impact on future treatment strategies. Nat. Rev. Clin. Oncol. 7,
493–507 (2010).
48. Sharma, S. V., Bell, D. W., Settleman, J. & Haber, D. A. Epidermal growth factor
receptor mutations in lung cancer. Nat. Rev. Cancer 7, 169–181 (2007).
49. Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary
adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009).
This study relates to a change in the era of personalized therapy, and
demonstrates that an anti-EGFR tyrosine kinase inhibitor is superior to
cytotoxic therapy in patients with tumours that contain an activating EGFR
mutation.
50. 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).
51. Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer
with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010).
52. 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).
53. 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).
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Review insight
54. 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).
55. 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).
56. 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).
57. Yang, J. C. 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).
58. Okabe, T. et al. Differential constitutive activation of the epidermal growth
factor receptor in non-small cell lung cancer cells bearing EGFR gene
mutation and amplification. Cancer Res. 67, 2046–2053 (2007).
59. Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung
cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).
60. Sequist, L. V. et al. Genotypic and histological evolution of lung cancers
acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011).
61. Camidge, D. R., Pao, W. & Sequist, L. V. Acquired resistance to TKIs in solid
tumours: learning from lung cancer. Nat. Rev. Clin. Oncol. 11, 473–481
(2014).
62. Jänne, P. A. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung
cancer. N. Engl. J. Med. 372, 1689–1699 (2015).
63. Mok, T. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive
lung cancer. N. Engl. J. Med. 376, 629–640 (2017).
64. Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small
cell lung cancer. N. Engl. J. Med. http://doi.org/10.1056/NEJMoa1713137
(2017).
65. Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to
AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21,
560–562 (2015).
66. 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).
67. Jia, Y. et al. Overcoming EGFR(T790M) and EGFR(C797S) resistance with
mutant-selective allosteric inhibitors. Nature 534, 129–132 (2016).
68. 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).
69. Lin, J. J., Riely, G. J. & Shaw, A. T. Targeting ALK: precision medicine takes on
drug resistance. Cancer Discov. 7, 137–155 (2017).
70. Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in
non-small-cell lung cancer. Nature 448, 561–566 (2007).
This study describes the discovery of ALK rearrangements in NSCLC.
71. Kwak, E. L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung
cancer. N. Engl. J. Med. 363, 1693–1703 (2010).
This study is the first to report the activity of crizotinib in patients with ALK
rearrangements.
72. Shaw, A. T. et al. Crizotinib versus chemotherapy in advanced ALK-positive
lung cancer. N. Engl. J. Med. 368, 2385–2394 (2013).
73. Solomon, B. J. et al. First-line crizotinib versus chemotherapy in ALK-positive
lung cancer. N. Engl. J. Med. 371, 2167–2177 (2014).
74. Shaw, A. T. et al. Ceritinib in ALK-rearranged non-small-cell lung cancer.
N. Engl. J. Med. 370, 1189–1197 (2014).
75. Shaw, A. T. et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell
lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 17,
234–242 (2016).
76. 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).
77. 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).
78. 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).
79. Peters, S. et al. Alectinib versus crizotinib in untreated ALK-positive
non-small-cell lung cancer. N. Engl. J. Med. 377, 829–838 (2017).
80. 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).
81. 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).
82. Facchinetti, F. et al. Oncogene addiction in non-small cell lung cancer: focus on
ROS1 inhibition. Cancer Treat. Rev. 55, 83–95 (2017).
83. Shaw, A. T. et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer.
N. Engl. J. Med. 371, 1963–1971 (2014).
84. Lim, S. M. et al. Open-label, multicenter, phase II study of ceritinib in patients
with non-small-cell lung cancer harboring Ros1 rearrangement. J. Clin. Oncol.
35, 2613–2618 (2017).
85. Awad, M. M. et al. Acquired resistance to crizotinib from a mutation in
CD74-ROS1. N. Engl. J. Med. 368, 2395–2401 (2013).
2 5 j anuar y 2 0 1 8 | V O L 5 5 3 | N A T U R E | 4 5 3
 insight Review
86. Davies, K. D. et al. Resistance to ROS1 inhibition mediated by EGFR pathway
activation in non-small cell lung cancer. PLoS One 8, e82236 (2013).
87. Marchetti, A. et al. Clinical features and outcome of patients with non-small-cell
lung cancer harboring BRAF mutations. J. Clin. Oncol. 29, 3574–3579 (2011).
88. Cardarella, S. et al. Clinical, pathologic, and biologic features associated with
BRAF mutations in non-small cell lung cancer. Clin. Can. Res. 19, 4532–4540
(2013).
89. Hyman, D. M. et al. Vemurafenib in multiple nonmelanoma cancers with BRAF
V600 mutations. N. Engl. J. Med. 373, 726–736 (2015).
90. Planchard, D. et al. Dabrafenib in patients with BRAF(V600E)-positive
advanced non-small-cell lung cancer: a single-arm, multicentre, open-label,
phase 2 trial. Lancet Oncol. 17, 642–650 (2016).
91. Planchard, D. et al. Dabrafenib plus trametinib in patients with previously
treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an
open-label, multicentre phase 2 trial. Lancet Oncol. 17, 984–993 (2016).
92. Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations
occurs in multiple tumor types and confers clinical sensitivity to MET
inhibitors. Cancer Discov. 5, 850–859 (2015).
93. Paik, P. K. et al. Response to MET inhibitors in patients with stage IV lung
adenocarcinomas harboring MET mutations causing exon 14 skipping.
Cancer Discov. 5, 842–849 (2015).
94. Awad, M. M. et al. MET exon 14 mutations in non-small-cell lung cancer are
associated with advanced age and stage-dependent MET genomic
amplification and c-Met overexpression. J. Clin. Oncol. 34, 721–730 (2016).
95. Mazières, J. et al. Lung cancer that harbors an HER2 mutation: epidemiologic
characteristics and therapeutic perspectives. J. Clin. Oncol. 31, 1997–2003
(2013).
96. Mazières, J. et al. Lung cancer patients with HER2 mutations treated with
chemotherapy and HER2-targeted drugs: results from the European EUHER2
cohort. Ann. Oncol. 27, 281–286 (2016).
97. Kohno, T. et al. KIF5B-RET fusions in lung adenocarcinoma. Nat. Med. 18,
375–377 (2012).
98. Drilon, A. et al. Cabozantinib in patients with advanced RET-rearranged
non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm
trial. Lancet Oncol. 17, 1653–1660 (2016).
99. Gautschi, O. et al. Targeting RET in patients with RET-rearranged lung cancers:
results from the global, multicenter RET registry. J. Clin. Oncol. 35, 1403–1410
(2017).
100. Hyman, D. M. et al. The efficacy of larotrectinib (LOXO-101), a selective
tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion
cancers. J. Clin. Oncol. 35, LBA2501–LBA2501 (2017).
101. Drilon, A. et al. A next-generation TRK kinase inhibitor overcomes acquired
resistance to prior TRK kinase inhibition in patients with TRK fusion-positive
solid tumors. Cancer Discov. 7, 963–972 (2017).
102. Coley, W. B. The treatment of malignant tumors by repeated inoculations of
erysipelas. With a report of ten original cases. 1893. Clin. Orthop. Relat. Res.
(262):3–11 (1991).
103. Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor
immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).
104. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic
melanoma. N. Engl. J. Med. 363, 711–723 (2010).
105. Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential
mechanism of immune evasion. Nat. Med. 8, 793–800 (2002).
106. Iwai, Y. et al. Involvement of PD-L1 on tumor cells in the escape from host
immune system and tumor immunotherapy by PD-L1 blockade. Proc. Natl
Acad. Sci. USA 99, 12293–12297 (2002).
107. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1
antibody in cancer. N. Engl. J. Med. 366, 2443–2454 (2012).
108. Garon, E. B. et al. Pembrolizumab for the treatment of non-small-cell lung
cancer. N. Engl. J. Med. 372, 2018–2028 (2015).
109. Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody
MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
110. Brahmer, J. et al. Nivolumab versus docetaxel in advanced squamous-cell
non-small-cell lung cancer. N. Engl. J. Med. 373, 123–135 (2015).
111. Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous
non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015).
References 110 and 111 were the first phase 3 studies to show increased
survival for ICBs compared to cytotoxic therapy in patients with previously
treated advanced-stage NSCLC, heralding the era of immunotherapy for
NSCLC.
112. Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated,
PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a
randomised controlled trial. Lancet 387, 1540–1550 (2016).
113. Rittmeyer, A. et al. Atezolizumab versus docetaxel in patients with previously
treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre
randomised controlled trial. Lancet 389, 255–265 (2017).
114. Reck, M. et al. Pembrolizumab versus chemotherapy for PD-L1-positive
non-small-cell lung cancer. N. Engl. J. Med. 375, 1823–1833 (2016).
This study provides evidence that in selected patients with high tumour
expression of PD-L1, ICBs are more effective than cytotoxic therapy in the
first-line setting.
115. Carbone, D. P. et al. First-line nivolumab in stage IV or recurrent non-small-cell
lung cancer. N. Engl. J. Med. 376, 2415–2426 (2017).
4 5 4 | N A T U R E | V O L 5 5 3 | 2 5 j anuar y 2 0 1 8
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
116. Herbst, R. S. & Sznol, M. Diminished but not dead: chemotherapy for the
treatment of NSCLC. Lancet Oncol. 17, 1464–1465 (2016).
117. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a
driver of cancer progression. Cell 162, 1229–1241 (2015).
118. Zitvogel, L., Galluzzi, L., Smyth, M. J. & Kroemer, G. Mechanism of action of
conventional and targeted anticancer therapies: reinstating
immunosurveillance. Immunity 39, 74–88 (2013).
119. Langer, C. J. et al. Carboplatin and pemetrexed with or without pembrolizumab
for advanced, non-squamous non-small-cell lung cancer: a randomised,
phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 17,
1497–1508 (2016).
120. Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. PD-1 and CTLA-4
combination blockade expands infiltrating T cells and reduces regulatory
T and myeloid cells within B16 melanoma tumors. Proc. Natl Acad. Sci. USA
107, 4275–4280 (2010).
121. Hellmann, M. D. et al. Nivolumab plus ipilimumab as first-line treatment for
advanced non-small-cell lung cancer (CheckMate 012): results of an
open-label, phase 1, multicohort study. Lancet Oncol. 18, 31–41 (2017).
122. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, adaptive, and
acquired resistance to cancer immunotherapy. Nat. Med. 23, 1362–1368
(2017).
123. Bezu, L. et al. Combinatorial strategies for the induction of immunogenic cell
death. Front. Immunol. 6, 187 (2015).
124. Lawler, S. E., Speranza, M. C., Cho, C. F. & Chiocca, E. A. Oncolytic viruses in
cancer treatment: a review. JAMA Oncol. 3, 841–849 (2017).
125. Voron, T. et al. Control of the immune response by pro-angiogenic factors.
Front. Oncol. 4, 70 (2014).
126. Tian, L. et al. Mutual regulation of tumour vessel normalization and
immunostimulatory reprogramming. Nature 544, 250–254 (2017).
127. Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific
therapeutic immunity against cancer. Nature 547, 222–226 (2017).
128. Gettinger, S. et al. Impaired HLA class I antigen processing and presentation as
a mechanism of acquired resistance to immune checkpoint inhibitors in lung
cancer. Cancer Discov. 7, 1420–1435 (2017).
129. Zaretsky, J. M. et al. Mutations associated with acquired resistance to PD-1
blockade in melanoma. N. Engl. J. Med. 375, 819–829 (2016).
130. Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D. & Allison, J. P.
Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor
T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210, 1389–1402
(2013).
131. Antonia, S. J. et al. Durvalumab after chemoradiotherapy in stage III non-small-
cell lung cancer. N. Engl. J. Med. 377, 1919–1929 (2017).
132. Oxnard, G. R. et al. Association between plasma genotyping and outcomes of
treatment with osimertinib (AZD9291) in advanced non-small-cell lung
cancer. J. Clin. Oncol. 34, 3375–3382 (2016).
133. Kim, E. S. et al. The BATTLE trial: personalizing therapy for lung cancer.
Cancer Discov. 1, 44–53 (2011).
134. Herbst, R. S. et al. Lung Master Protocol (Lung-MAP)-A biomarker-driven
protocol for accelerating development of therapies for squamous cell lung
cancer: SWOG S1400. Clin. Cancer Res. 21, 1514–1524 (2015).
135. Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic
alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49,
1693–1704 (2017).
136. Abbosh, C. et al. Phylogenetic ctDNA analysis depicts early-stage lung cancer
evolution. Nature 545, 446–451 (2017).
This study introduces ctDNA profiling to track the subclonal nature of lung
cancer progression, providing an approach for ctDNA-driven therapeutic
studies.
137. Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines
sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348,
124–128 (2015).
This is a landmark study indicating that lung cancers with high non-
synonymous mutation burden are more responsive to ICB.
138. Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-
immune set point. Nature 541, 321–330 (2017).
139. Romero, R. et al. Keap1 loss promotes Kras-driven lung cancer and results in
dependence on glutaminolysis. Nat. Med. 23, 1362–1368 (2017).
Supplementary Information is available in the online version of the paper.
Acknowledgements We would like to thank L. Chen and A. M. Incassati for
editorial assistance. R. Herbst is supported by the Yale SPORE in Lung Cancer
(P50CA196530).
Author Contributions All authors contributed to the writing of this Review.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare competing financial interests:
details are available in the online version of the paper. Readers are welcome to
comment on the online version of the paper. Publisher’s note: Springer Nature
remains neutral with regard to jurisdictional claims in published maps and
institutional affiliations. Correspondence and requests for materials should be
addressed to R.S.H. (roy.herbst@yale.edu) or C.B. (chris.boshoff@pfizer.com).