736

Metastatic Lung Cancer: Emerging Therapeutic

Strategies
Sana Saif Ur Rehman, MD1 Suresh S. Ramalingam, MD2

1 Division of Oncology, Department of Medicine, Siteman Cancer Address for correspondence Suresh S. Ramalingam, Department of
Center, Washington University School of Medicine, St. Louis, Missouri Hematology and Medical Oncology, Emory University School of
2 Department of Hematology and Medical Oncology, Winship Cancer Medicine, 1365 Clifton Road NE, Ste 4014, Atlanta, GA 30322
Institute, Emory University School of Medicine, Atlanta, Georgia (e-mail: ssramal@emory.edu).

Semin Respir Crit Care Med 2016;37:736–749.

Abstract Advanced stage nonsmall cell lung cancer had been treated mainly with platinum-based
doublet chemotherapy, and other cytotoxic agents that offered significant survival
advantage over best supportive care, until recently. Modest improvements were
achieved with the addition of antibodies targeting the vascular endothelial growth
factor, and the introduction of maintenance chemotherapy. Improvements in our
knowledge of lung cancer biology have shifted the current treatment paradigm from
being based on histology to one based on molecular biomarkers. Identification of

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potentially targetable driver mutations in a subgroup of these patients, pertaining to
genes directing cell signaling pathways involved in proliferation and survival, has been
the single most influential development in the treatment of lung cancer in the last two
decades. Personalized medicine based on driver mutations offers enhanced efficacy at
Keywords the expense of relatively minimal toxicity burden. Targeting the epidermal growth
► lung cancer factor receptor pathway in patients with an activating mutation results in substantial
► NSCLC improvement in patient outcome. Similarly, targeting ALK (anaplastic lymphoma kinase)
► metastatic fusion gene with first- and second-generation inhibitors results in improved efficacy over
► chemotherapy chemotherapy. For certain other mutations such as MET exon 14 and BRAF, promising
► targeted therapy inhibitory strategies are being investigated. In addition, the recent emergence of
► EGFR immune checkpoint inhibitors to reverse exhaustion of T cells has been a major
► anaplastic lymphoma breakthrough in rapidly changing the therapeutic landscape for lung cancer. This article
kinase reviews the role of systemic therapy in advanced stage lung cancer.

Lung cancer is the most commonly diagnosed cancer world-
wide with an estimated incidence of 1.8 million cases (12.9%
of the total) in 2012.1 Unfortunately it is also responsible for
nearly one in five deaths attributed to cancer (19.4% of the
total).1 Nonsmall cell lung cancer (NSCLC) accounts for
approximately 80% of the newly diagnosed lung cancer cases
and more than half of these patients are diagnosed with
advanced stage disease.2
The use of platinum-based doublet therapy, maintenance
chemotherapy, and anti-angiogenic agents in combination
with chemotherapy have all contributed to improved patient
outcomes in advanced NSCLC. From the previous generation
of clinical trials that focused on improvements to systemic
chemotherapy, the present crop of studies are engaged in
personalizing treatment options. Identification of point
mutations (epidermal growth factor receptor [EGFR], BRAF)
and gene fusions (anaplastic lymphoma kinase [ALK], ROS1) as
oncogenic drivers in a small subset of patients with predomi-
nant adenocarcinoma histology has led to the new era of
personalized medicine, taking targeted therapy to the front-
line setting for these patients. Recently, therapies targeting
immune checkpoints have shown promising clinical activity

Issue Theme Lung Cancer: Evolving Copyright © 2016 by Thieme Medical DOI http://dx.doi.org/
Concepts in Management; Guest Editors: Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0036-1592111.
Doug Arenberg, MD, and Steven New York, NY 10001, USA. ISSN 1069-3424.
Dubinett, MD Tel: +1(212) 584-4662.

in advanced NSCLC and represent a significant leap forward in
lung cancer therapeutics. The objective response rates, how-
ever, are reported at roughly 20% in unselected patients,
although response rates appear to be higher in patients
with tumors expressing programmed death ligand 1 expres-
sion.3,4 In this article, we review the current treatment
approaches for advanced NSCLC with and without potential
actionable molecular alterations. Due to recent advances in
targeted therapy for advanced NSCLC, the College of American
Pathologists, the International Association for the Study of
Lung Cancer, and the Association for Molecular Pathology
issued new guidelines in 2013. They recommend testing for
EGFR mutations and ALK rearrangements in all patients with
advanced NSCLC with adenocarcinoma histology or compo-
nent, for patient selection, and therapy with targeted agents.5
Driver mutations beyond EGFR and ALK that could be amena-
ble to targeted therapy, including ROS1, BRAF, RET, HER2,
NTRK, and MET, have also been demonstrated. In these
molecularly selected patient populations, use of novel treat-
ment options has improved the outcomes dramatically.
Molecular testing is therefore considered the standard
approach for patients with advanced stage adenocarcinoma
of the lung. The presence of activating mutations in the EGFR
or gene rearrangement of ALK or ROS1 are considered to be
molecular drivers that can be treated with approved thera-
peutic agents. Therefore, NSCLC is broadly categorized as
either harboring a targetable driver mutation or not for
making therapeutic decisions.
Advanced NSCLC without Identifiable Driver
Mutations
First-Line Treatment/Platinum Doublet
Early evidence for the benefit of chemotherapy in palliative
setting for advanced NSCLC came from results of a clinical trial
showing superiority of platinum-based combination therapy
versus best supportive care (BSC) in terms of progression-free
survival (PFS) and overall survival (OS).6 The efficacy of plati-
num-based doublet chemotherapy has been established over
various systematic reviews and meta-analysis.7,8 A meta-analy-
sis including data from 65 trials (N ¼ 13,601) compared the
clinical efficacy of addition of another drug to single-agent
regimen or doublet regimen and demonstrated improvement
in tumor response and 1-year survival rate in the group receiving
doublet regimen. Although an increase in the tumor response
rate was observed in favor of the triplet regimen, no impact was
found on OS.9 Platinum-based doublet chemotherapy combina-
tions are associated with response rates of 25 to 35%, with
median (PFS) of 4 to 6 months and OS of 8 to 10 months.10,11
Trials comparing various platinum-based combinations have, in
general, showed comparable efficacy end points with differing
toxicity profiles (►Table 1).12–19
Both cisplatin and carboplatin are acceptable for the
treatment of advanced NSCLC. Two large meta-analyses20,21
suggested that the response rates were superior in patients
receiving cisplatin-based chemotherapy versus carboplatin;
however, no statistical difference was found in OS. Ardizzoni
et al21 found that carboplatin treatment was associated with a
Metastatic Lung Cancer Rehman, Ramalingam 737
nonstatistically significant increase in the hazard of mortality
relative to treatment with cisplatin (hazard ratio, HR ¼ 1.07;
95% confidence interval [CI] ¼ 0.99–1.15; p ¼ 0.1). Patients
with nonsquamous tumors as well as those treated with
third-generation chemotherapy (paclitaxel, docetaxel, gem-
citabine, vinorelbine, and irinotecan)22 had a statistically
significant increase in mortality (HR ¼ 1.12; 95% CI ¼ 1.01–
1.23 and HR ¼ 1.11; 95% CI ¼ 1.01–1.21, respectively) in the
carboplatin-based chemotherapy group. Toxicity profiles
were also different with more severe nausea, vomiting, and
nephrotoxicity in the cisplatin-based chemotherapy group
and thrombocytopenia with carboplatin-based chemothera-
py group. Since the overall goal for the treatment of advanced
NSCLC is palliation, the favorable tolerability of carboplatin-
based regimens provides a strong rationale to substitute
cisplatin with the former. Therefore, the choice of platinum
compound should be based on the specific patient situation.
The optimal number of platinum-based chemotherapy
cycles has also been an area of investigation with trials,
demonstrating comparable survival23–26 between a shorter
duration of platinum-based therapy (three to four cycles) and
a longer duration of therapy (six cycles or until disease
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progression). Toxicity burden is higher in patients receiving
longer duration of therapy, though there does not appear to
be any survival advantage. Based on the available evidence
and results from these trials, four cycles of platinum-based
doublet chemotherapy is generally recommended for the
treatment of advanced NSCLC.
Third-Generation Cytotoxic Agents
Taxanes (paclitaxel, docetaxel, and nab-paclitaxel), gemcitabine,
irinotecan, and vinorelbine have all demonstrated comparable
efficacy in combination with platinum. Pemetrexed, a folate
antimetabolite inhibiting thymidylate synthase, was studied in
combination with cisplatin versus gemcitabine and cisplatin
with a preplanned subgroup analysis by histology.27 Although
the trial met its primary endpoint of noninferiority for the two
regimens, the survival was superior with cisplatin/pemetrexed
in nonsquamous histology. Patients with adenocarcinoma
histology randomized to receive cisplatin/pemetrexed showed
a significant improvement in survival compared with those
receiving cisplatin/gemcitabine (12.6 vs. 10.9 months;
p ¼ 0.03). Conversely, patients with squamous histology treated
with cisplatin and gemcitabine had a better outcome relative to
cisplatin and pemetrexed (median survival 10.8 vs. 9.4 months;
p ¼ 0.05). Toxicity profile of the regimens showed that cisplatin
with pemetrexed was associated with less grade 3/4 neutrope-
nia, anemia, thrombocytopenia and febrile neutropenia, com-
pared to cisplatin with gemcitabine, however was associated
with more grade 3/4 nausea. This study led to the approval of
pemetrexed as treatment option with platinum for patients with
advanced nonsquamous histology.
The efficacy of pemetrexed was compared with that of
taxanes indirectly in a phase III trial that randomized patients
with stage IIIB or IV nonsquamous NSCLC in the first-line
setting to receive pemetrexed–carboplatin–bevacizumab or
paclitaxel–carboplatin–bevacizumab. There was no improve-
ment in survival with the use of pemetrexed compared with
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738 Metastatic Lung Cancer Rehman, Ramalingam

Table 1 Selected phase III trials in advanced NSCLC comparing various platinum containing regimens

Trials N Therapy Survival p-Value

12
ECOG 1594 1,207 Cis/Pac vs. Cis/Gem, Median OS: 8 mo Not significant
Cis/Doc, Carbo/Pac
SWOG 950913 408 Cis/Vin vs. Median OS: 8.1 vs. 8.6 mo p ¼ 0.87
Carbo/Pac
TAX 32614 1,218 Cis/Doc vs. Carb/Doc vs Median OS 11.3: vs. 9.4 vs. 10.1 p ¼ 0.44 for Cis/Doc vs.
Cis/Vin Cis/Vin
Scagliotti et al15 612 Cis/Gem vs. Median survival: 9.8 vs. Not significant
Carbo/Pac vs. Cis/Vin 9.9 vs. 9.5 mo
London Lung 422 Carbo/Gem vs. Cis/Mit/Ifos Median OS: 10 vs. 7.6 mo 0.008
Cancer Group16
Booton et al17 433 Carbo/Doc vs. Median OS: 9.5 vs. 8.7 mo 0.295
Cis/ Mit/Vb or Cis/Mit/Ifos
Belani et al18 369 Carbo/Pac vs. Cis/Etop Median survival: 9.1 vs. 7.8 mo 0.086
Ohe et al19 602 Carbo/Pac vs. Cis/Gem vs. Median survival: 12.3 vs. 14 vs. Not significant
Cis/Vin vs. Cis/Irin 11.4 vs. 13.9 mo

Abbreviations: Carbo, carboplatin; Cis, cisplatin; Doc, docetaxel; Etop, etoposide; Gem, gemcitabine; Ifos, ifosfamide; Irin, irinotecan; Mit, mitomycin;
N, number of patients; NSCLC, nonsmall cell lung cancer; OS, overall survival; Pac, paclitaxel; Vb, vinblastine; Vin, vinorelbine.

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the paclitaxel regimen.28 Thus, both pemetrexed- and pacli-
taxel-based regimens are considered appropriate for patients
with advanced nonsquamous NSCLC.
Another recently approved cytotoxic agent in NSCLC is
albumin-bound paclitaxel ( nab-paclitaxel). This agent does
not require the premedications necessary for standard pacli-
taxel formulation, is given as a shorter infusion, and is
associated with a lower risk of neuropathy. Nab-paclitaxel
with carboplatin was compared with solvent-based paclitaxel
(sb-PC) plus carboplatin in advanced NSCLC in a randomized
phase III trial. Patients in the nab-paclitaxel arm had a
significantly higher response rate than those in the sb-PC
arm (33 vs. 25%; p ¼ 0.005). The favorable response with nab-
paclitaxel was confined to squamous cell histology (41 vs.
24%; p < 0.001) and was comparable to the control arm with
nonsquamous histology. The increased response rate with
nab-paclitaxel did not translate into a survival advantage.
Nab-paclitaxel arm was associated with a lower incidence of
grade 3/4 neuropathy and neutropenia but higher rates of
thrombocytopenia and anemia.29 Based on this study, nab-
paclitaxel has emerged as another option for first-line treat-
ment of advanced NSCLC in combination with carboplatin.
Antiangiogenic Agents in the Treatment of Advanced
NSCLC
Vascular endothelial growth factor (VEGF) is an endothelial-
cell-specific mitogen acting as a significant regulator of
angiogenesis in normal and malignant tissue.30 Bevacizumab,
a humanized monoclonal antibody to VEGF-A, was studied in
combination with standard chemotherapy (carboplatin with
paclitaxel) in the first-line setting in a phase III trial. Com-
pared with chemotherapy alone, the addition of bevacizumab
resulted in improvements to both PFS and OS (6.2 vs. 4.5
months; p < 0.001 and 12.3 vs. 10.3 months; p ¼ 0.003,
respectively). This resulted in the approval of bevacizumab
for advanced nonsquamous NSCLC in combination with
carboplatin and paclitaxel for first-line therapy. The response
rate was also higher in the bevacizumab group (35 vs. 15%;
p < 0.001).31 An earlier phase II trial32 demonstrated signifi-
cant adverse events including six life-threatening pulmonary
hemorrhages (four being fatal) in patients with squamous cell
carcinoma with bevacizumab. Hence, bevacizumab should
not be administered to patients with squamous histology. The
adverse events associated with bevacizumab include hyper-
tension, proteinuria, and hemorrhage. A second phase III
study that studied bevacizumab in combination with cisplat-
in and gemcitabine failed to demonstrate survival benefit
over chemotherapy alone.33 Even though considerable efforts
were undertaken to identify biomarkers to select patients for
therapy, there is no proven biomarker. Taken together, while
the addition of bevacizumab to chemotherapy results in
modest efficacy benefit, the lack of a biomarker has resulted
in limited adoption of this agent in clinical practice.
More recently, ramucirumab, a human immunoglobulin G
(IgG1) monoclonal antibody targeting the extracellular
domain of VEGF receptor-2 (VEGFR-2), demonstrated survival
benefit in the second-line setting (salvage therapy) in combi-
nation with docetaxel.34 Compared with docetaxel alone, the
combination of ramucirumab with docetaxel was associated
with a favorable PFS and OS (median PFS 4.5 vs. 3.0 months
and 10.5 vs. 9.1 months, respectively). The incidence of grade
3 or higher bleeding was similar between the two groups.
These results led to the approval of ramucirumab in combi-
nation with docetaxel for salvage therapy of advanced NSCLC.
Multiple phase II and III clinical trials have used VEGFR
tyrosine kinase inhibitors (TKIs) in the treatment of advanced
NSCLC. Multitargeted TKIs with activity against VEGFR-2
including sorafenib,35–37 sunitinib,38–41 cediranib,42 motesa-
nib,43 pazopanib,44 axitinib,45 and vandetanib46–50 have all
been studied as single agents or in combination with erlotinib

Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 5/2016


or chemotherapy in both first-line setting and previously
treated NSCLC. Although these trials have shown improve-
ments in response rates and PFS in selected trials, none of
these have translated to gains in OS. Nintedanib (BIBF 1120) is
a triple angiokinase inhibitor that potently blocks the proan-
giogenic pathways mediated by VEGFRs, platelet-derived
growth factor receptors, and fibroblast growth factor recep-
tors.51 A phase 3 study of nintedanib in combination with
docetaxel demonstrated improved PFS over docetaxel alone
as salvage therapy in patients with advanced NSCLC.52 How-
ever, the improvement in efficacy was relatively modest (3.4
vs. 2.7 months; p ¼ 0.0019), and there was no benefit seen
survival for the overall study population. The subset of
patients with adenocarcinoma histology that progressed
within 9 months of starting first-line treatment experienced
a statistically significant improvement in survival with do-
cetaxel/nintedanib compared with docetaxel alone (10.9 vs.
7.9 months; p ¼ 0.073). This benefit persisted for all patients
with adenocarcinoma histology (12.6 vs. 10.3 months;
p ¼ 0.0359). Based on these results, nintedanib was approved
by the European Union in November 2014 for the treatment
of patients with advanced lung adenocarcinoma after the
failure of first-line chemotherapy.
Ramucirumab and nintedanib are the only agents that have
demonstrated improved outcomes in the salvage therapy
setting in combination with docetaxel. These options can be
considered for appropriate patients in the second-line setting.
Monoclonal Antibodies against Epidermal Growth
Factor Receptor
EGFR is overexpressed in approximately 85% of NSCLC, most
commonly in patients with squamous histology, and plays an
important role in cellular proliferation along with other
members of the ErbB family of transmembrane tyrosine
kinase receptors.53 Blockade of EGFR activity has been studied
as a therapeutic strategy in NSCLC. We will focus on the anti-
EGFR monoclonal antibodies in this section and discuss the
EGFR TKIs in a separate section dedicated to NSCLC harboring
potential targetable mutations.
Cetuximab, a monoclonal antibody against EGFR, was stud-
ied in combination with cisplatin and vinorelbine for first-line
therapy of advanced NSCLC. There was a modest improvement
in OS (11.3 vs. 10.2 months), with the addition of cetuximab to
chemotherapy, but the PFS was not improved.54 Cetuximab did
not gain regulatory approval in advanced NSCLC largely due to
the relatively modest clinical benefit and the lack of predictive
markers to optimize patient selection.
However, necitumumab, a second-generation, recombi-
nant human IgG1 EGFR antibody, was recently approved by
the U.S. Food and Drug Administration (FDA) for the treat-
ment of squamous NSCLC. It was evaluated in the SQUIRE trial
in combination with gemcitabine and in previously untreated
patients with stage IV squamous NSCLC.55 Compared with
chemotherapy alone, the addition of necitumumab resulted
in an improved OS (11.5 vs. 9.9 months; HR: 0.84; p ¼ 0.012),
though the PFS was not improved. The incidence of serious
adverse events was higher in the necitumumab arm (48 vs.
38%), with grade 3 and 4 toxicities including hypomagnese-
Metastatic Lung Cancer Rehman, Ramalingam 739
mia and rash. In contrast, a second study in nonsquamous
NSCLC failed to demonstrate benefit with the addition of
necitumumab to pemetrexed and cisplatin.56 Due to an
increased number of fatal thromboembolic events in patients
receiving necitumumab with cisplatin and pemetrexed, the
study was halted prematurely on the recommendation of an
independent data monitoring committee.
Necitumumab is now the first targeted drug to be approved
for the treatment of squamous cell NSCLC. Biomarkers for
patient selection for necitumumab therapy are urgently
needed. A recent report noted more favorable survival with
necitumumab in the SQUIRE trial for patients with tumors that
had a higher EGFR gene copy number. This observation, if
confirmed in prospective studies, will be an important step
forward for this novel agent.
Maintenance Therapy
Although most of the patients in first-line setting for advanced
NSCLC will receive platinum doublet chemotherapy, only two-
thirds will be able to receive a second-line treatment due to
significant clinical deterioration at the time of disease progres-
sion. Maintenance therapy, which is a relatively new paradigm in
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advanced NSCLC, allows for improving survival in patients who
achieve clinical benefit with first-line chemotherapy. The first
trial to show benefit of switch maintenance therapy using a
different (noncross resistant) chemotherapy agent after the
completion of platinum-doublet, randomized patients to doce-
taxel administered either immediately after gemcitabine plus
carboplatin (GC) or at the time of disease progression.57
Improved median PFS was observed for immediate docetaxel
compared with delayed docetaxel (5.7 vs. 2.7 months;
p ¼ 0.0001). But OS was not improved since nearly 40% of the
patients on the control arm did not receive docetaxel at
progression.
The first study to demonstrate survival benefit with main-
tenance therapy was by Ciuleanu et al58 who compared
maintenance pemetrexed versus placebo (BSC in both groups)
in patients with stable disease after initial platinum-based
chemotherapy. There was a statistically significant improve-
ment in OS (13.4 vs. 10.6 months; p ¼ 0.012) compared with
placebo. These resulted were further substantiated in another
study59 that randomized (2:1) patients without disease pro-
gression after completion of four cycles of cisplatin and
pemetrexed to receive maintenance pemetrexed versus place-
bo. This continuation maintenance strategy led to a statistically
significant 22% reduction in the risk of death (HR: 0.78;
p ¼ 0.0195) with an improvement in OS with pemetrexed
maintenance (13.9 vs. 11.0 months; HR: 0.78; p ¼ 0.0195).
Pemetrexed can be given safely and is well tolerated, as
evidenced by the fact that only 7% of patients on the mainte-
nance pemetrexed arm developed grade 3/4 neutropenia,
anemia, or fatigue. Pemetrexed is now approved in both the
switch and continuation maintenance therapy settings for
nonsquamous NSCLC.
The role of erlotinib, an EGFR TKI, was evaluated in the
SATURN trial, which randomized 889 patients to switch
maintenance with the EGFR inhibitor erlotinib or placebo
after four cycles of platinum-doublet chemotherapy.60 There
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 5/2016
740 Metastatic Lung Cancer Rehman, Ramalingam

was an improvement of median PFS with erlotinib (12.3 vs.
11.1 weeks; HR: 0.71; p < 0.0001). There was a modest
improvement in median survival (12.0 vs. 11.0 months;
HR: 0.81; p ¼ 0.0088). This study resulted in the approval
of erlotinib for maintenance therapy, though in clinical prac-
tice, this agent is used primarily for the treatment of EGFR-
mutated NSCLC.
Maintenance therapy ensures that patients who benefit
from first-line chemotherapy receive another active agent that
results in improved survival. It is likely that the improvement
in survival is mainly due to the ability to treat a greater number
of patients who otherwise would not been able to receive
additional lines of therapy due to toxicities or clinical deterio-
ration. Bevacizumab is also a reasonable option for mainte-
nance therapy in patients who received it with platinum-based
chemotherapy in the first-line setting since the pivotal studies
that led to its approval followed that paradigm. The role of
combination maintenance with pemetrexed and bevacizumab
will be addressed in the ongoing ECOG 5508 clinical trial.
Additional trials using maintenance therapy with other cyto-
toxic agents have shown improvements in PFS (but not OS);
selected trials are summarized in ►Table 2.28,58–65
6.7 weeks; p < 0.001) as well as improved median survival
(7.0 vs. 4.6 months; p ¼ 0.047) in favor of docetaxel.66 The 1-
year survival rate was reported as 37% for docetaxel versus
11% for BSC. The difference was even more significant in favor
of docetaxel given at 75 mg/m2 (7.5 vs. 4.6 months; p ¼ 0.010)
with lesser toxicity.
Pemetrexed was the next agent approved in this setting
based on results of a noninferiority trial comparing peme-
trexed versus docetaxel.67 Treatment with pemetrexed was
associated with statistically significant lower rates of neutro-
penia, febrile neutropenia, and neutropenia with infections,
and the efficacy profile was comparable to that of docetaxel. A
secondary retrospective analysis showed inferior OS of pe-
metrexed versus docetaxel in squamous histology and an
improved OS in patients with nonsquamous histology with a
statistically significant treatment by histology interaction
test (p ¼ 0.001).68 These data, along with the results from
the prospective frontline trial by Scagliotti et al,27 led to FDA
approval of pemetrexed restricted to patients with nonsqu-
amous histology. Erlotinib was approved in second- and
third-line setting for advanced NSCLC independent of the
EGFR mutational status (not routinely tested as standard of

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Second-Line Therapy
Historically, only 40 to 50% of the patients with advanced
NSCLC on frontline trials went on to received second-line
chemotherapy owing to the progressive and relentless nature
of this disease with rapid deterioration in performance status.
Docetaxel was the first agent approved for treatment in
second-line setting in patients after progression on first-
line platinum doublet therapy with advanced NSCLC. A phase
III clinical TAX 317 compared docetaxel (100 or 75 mg/m2)
versus BSC and showed longer time to progression (10.6 vs.
care at the time) based on superior PFS (2.2 vs. 1.8 months;
p < 0.001) as well as OS (6.7 vs. 4.7 months; p < 0.001)
against placebo in patients after progression on one or two
lines of therapy.69 Various subsequent trials70–74 have com-
pared single agent EGFR TKIs versus chemotherapy in second-
line setting. There was no difference in OS, though trends
indicated favorable outcome with chemotherapy in patients
with wild-type EGFR status.
Recently, a major breakthrough was achieved in the treat-
ment for advanced NSCLC in second-line setting from the
studies that documented favorable survival for immune

Table 2 Selected maintenance trials in advanced NSCLC

Trial Induction Maintenance PFS (maintenance) p-Value OS p-Value

JMEN58 Platinum doublet Pem vs. observation 4 vs. 2 mo; HR: 0.6 <0.001 13.4 vs. 10.6 mo; HR: 0.79 0.01
PARAMOUNT59 Cis/Pem Pem þ BSC vs. BSC 4.1 vs. 2.8 mo; HR: 0.60 <0.001 13.9 vs. 11 mo; HR: 0.78 0.0195
(0.5–0.73)
SATURN60 Platinum-based doublet Erlotinib vs. placebo 12.3 vs. 11.1 <0.001 12 vs. 11 mo; HR: 0.81 0.01
(67% of patients with
EGFR mutations
received TKI); HR: 0.71
ATLAS61 Platinum doublet þBev Bev þ Erlotinib vs. Bev 4.8 vs. 3.7; HR: 0.72 0.001 15.9 vs. 13.9 mo; HR: 0.9 0.53
PointBreak28 Carbo/Pac/Bev vs Bev 5.6 vs. 6 mo; HR: 0.83 0.012 13.4 vs. 12.6 mo 0.95
Carbo/Pem/Bev Pem/Bev
IFCT-GFPC 050262 Cis/Gem Gem or erlotinib 3.8 vs. 1.9 mo in Gem <0.001 12.1 vs. 10.8 mo 0.3867
vs. observation 11.4 vs. 10.8 mo
2.9 vs. 1.9 in Erlotinib ¼0.003 0.3043
PRONOUNCE63 Carbo/Pem vs Pem 4.4 vs. 5.4 mo; HR:1.06 0.61 10.5 vs. 11.7 mo 0.615
Carbo/Pac/Bev Bev
Belani et al64 Cis/Pac Pac vs. BSC 38 vs. 29 wk NR 75 vs. 60 wk NR
CECOG65 Cis/Gem Gemþ BSC vs. BSC 3.6 vs. 2 mo <0.001 13 vs. 11 mo 0.195

Abbreviations: Bev, bevacizumab; BSC, best supportive care; Carbo, carboplatin; Cis, cisplatin; EGFR, epidermal growth factor receptor; Gem,
gemcitabine; HR, hazard ratio; NSCLC, nonsmall cell lung cancer; OS, overall survival; Pac, paclitaxel; Pem, pemetrexed; PFS, progression free survival;
TKI, tyrosine kinase inhibitors; NR, not reported.

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 Metastatic Lung Cancer Rehman, Ramalingam 741

checkpoint inhibition over docetaxel. Nivolumab and pem-
brolizumab, inhibitors of the PD-1 receptor, have been ap-
proved by the FDA for salvage therapy of advanced NSCLC. The
details regarding these agents and the relevant clinical data
are discussed in a separate chapter in this issue of the journal.
As a result of these developments, docetaxel is now increas-
ingly being relegated to use after patients have received prior
therapy with a platinum-doublet and an immune checkpoint
inhibitor.
Advanced NSCLC with Identifiable Driver
Mutations
NSCLC with EGFR Mutation
Background
The identification and the ability to target the activating
mutations in the tyrosine kinase domain of the EGFR not
only changed the approach and outcomes of advanced NSCLC
in these patients, but also established the role for incorporat-
ing genomic testing of the tumor in mainstream clinical
practice. EGFR mutation is found in approximately 10 to
of patients in the chemotherapy group to receive EGFR TKI after
disease progression. Afatinib, an irreversible inhibitor, has a
greater affinity for the EGFR kinase domain as well as other
members of the EGFR family (human EGFRs HER2, HER3, and
HER4).84 Afatinib demonstrated superior PFS compared with
pemetrexed plus cisplatin (LUX-Lung 3)82 or gemcitabine plus
cisplatin (LUX-Lung 6)83 in the treatment of naive patients with
advanced NSCLC with activating EGFR mutations. In LUX-Lung 3
trial, patients with activating mutations in exon 19 and 21 were
found to have a median PFS of 13.6 months on a prespecified
subgroup analysis. OS did not differ significantly between the
control group and the afatinib group on either of these trials. A
meta-analysis that included data from 23 trials in front line,
second-line, and maintenance setting with 14,570 patients
reiterated the PFS advantage of using upfront EGFR TKI in
patients with activating EGFR mutations, though survival was
not impacted.85
Given the magnitude of the PFS benefit as well as a
relatively better tolerated side effect profile, testing for the
presence of a potentially targetable mutation in the EGFR
tyrosine kinase domain is recommended at the time of
diagnosis for patients with advanced NSCLC. Patients with

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15% of the Caucasian population with advanced nonsqua-
mous lung cancer.75 The mutations are located in two distinct
hotspots in exon 19 and 21 and are associated with exquisite
sensitivity to EGFR TKI therapy. Other uncommon mutations
are also sensitive to a lesser extent to EGFR inhibitors, with
the exception of exon 20 insertion mutations that do not
respond to this class of agents.
First-Line Treatment for EGFR-Mutated NSCLC
The first generation of EGFR TKIs was developed to bind revers-
ibly to the adenosine triphosphate binding sites and inhibit
activation of downstream signaling. Six randomized phase III
trials that compared first-generation TKIs such as erlotinib or
gefitinib to standard platinum-based chemotherapy have dem-
onstrated superior response rates and PFS with targeted therapy
in the frontline setting for patients with advanced NSCLC
harboring an EGFR mutation (►Table 3).76–83 However, survival
benefit was not demonstrated most likely as a result of crossover
EGFR activating mutations should receive treatment with an
EGFR targeted agent during the course of their disease,
preferably in the first-line setting.86 The use of empiric
treatment with an EGFR TKI in the first-line setting is strongly
discouraged based on the results of the IPASS study that noted
a detrimental effect for EGFR wild-type patients who received
first-line TKI therapy.76
While TKIs are the standard of care for patients with EGFR
mutations, it is still unclear which is the best TKI to be used
upfront out of the three (afatinib, erlotinib, and gefitinib)
approved agents. The LUX-Lung 7 is the first randomized
clinical trial (phase 2B) that compared afatinib to gefitinib in
the first-line setting for EGFR mutation positive NSCLC.87
There was improved median PFS with afatinib (11 vs. 10.9
months; HR: 0.73; p ¼ 0.017) compared with gefitinib, and
time to treatment failure was also prolonged (median 13.7 vs.
11.5 months; HR: 0.73; p ¼ 0.0073) with afatinib. The sur-
vival data are currently awaited. Afatinib was associated with

Table 3 Phase III trials comparing first-line EGFR TKI with platinum-based chemotherapy in advanced NSCLC with activating EGFR
mutations

Trials N Treatment PFS (mo) OS (mo)

76
IPASS 261 Gefitinib vs. Carbo/Pac 9.5 vs. 6.3; HR: 0.48; p < 0.001 21.6 vs. 21.9; HR: 1; p ¼ 0.99
77
First-SIGNAL 42 Gefitinib vs. Cis/Gem 8 vs. 6.3; HR: 0.54; p ¼ 0.086 27.2 vs. 25.6; HR: 1.04
WJTOG340578 177 Gefitinib vs. Cis/Doc 9.2 vs. 6.3; HR: 0.48; p < 0.001 35.5 vs. 38.8; HR: 1.18
NEJ00279 228 Gefitinib vs. Carbo/Pac 10.8 vs. 5.4; HR: 0.30; p < 0.001 27.7 vs. 26.6; HR: 0.887; p ¼ 0.483
80
OPTIMAL 154 Erlotinib vs. Cis/Gem 13.7 vs. 4.6; HR: 0.16; p < 0.001 22.6 vs. 28.8; HR: 1.06; p ¼ 0.685
EURTAC81 173 Erlotinib vs. Cis-Doc/Gem 9.7 vs. 5.2; HR: 0.37; p < 0.001 19.3 vs. 19.5; HR: 1.04; p ¼ 0.87
82
LUX-Lung 345 Afatinib vs. Cis/Pem 11.1 vs. 6.9; HR: 0.58; p ¼ 0.001
83
LUX-Lung 6 364 Afatinib vs. Cis/Gem 11 vs. 5.6; HR: 0.28; p < 0.0001 22.1 vs. 22.2; HR: 0.95; p ¼ 0.76

Abbreviations: Carbo, carboplatin; Cis, cisplatin; Doc, docetaxel; EGFR, epidermal growth factor receptor; Gem, gemcitabine; HR, hazard ratio; N,
number of patients; NSCLC, nonsmall cell lung cancer; OS, overall survival; Pac, paclitaxel; Pem, pemetrexed; PFS, progression free survival; TKI,
tyrosine kinase inhibitors.

Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 5/2016

742 Metastatic Lung Cancer Rehman, Ramalingam
a greater degree of toxicity relative to gefitinib, though
treatment discontinuation rates due to toxicity were similar
in the two groups. Results from another ongoing randomized
trial (ARCHER 1050, NCT0177472) that compares gefitinib
with dacomitinib will help answer the question of compara-
tive efficacy of second- versus first-generation EGFR TKIs.
Acquired EGFR TKI Resistance
Despite significant initial response and improvement in PFS,
the emergence of acquired resistance to EGFR TKI is inevitable
after a median of 9 to 13 months. The molecular mechanisms
for drug resistance include a secondary mutation in the
primary driver oncogene, thereby making the EGFR TKIs
ineffective or leading to the emergence of alternative activat-
ing cellular pathways.88 The most common mechanism of
resistance (50–60% of patients) is the acquisition of a T790M
mutation on exon 20,89,90 leading to resistance to competitive
inhibition by first- and second-generation EGFR TKIs.91
Osimertinib (AZD9291) is a potent irreversible EGFR TKI
selective for EGFR sensitizing mutations and the T790M
resistance mutation.92 Osimertinib was studied in a phase I
dose escalation study for patients with advanced EGFR-mu-
tated NSCLC after progression on first-generation of EGFR
TKIs. Although the dose escalation cohorts were not prese-
lected according to T790M status, for 239 patients evaluable
for response, the objective response rate was 51% (95% CI: 45–
58). Among 127 evaluable patients with EGFR T790M muta-
tion, the response rate was 67% (95% CI: 52–70). For patients
without EGFR T790M mutation, the response rate was lower
at 21% (95% CI: 12–34).93 Osimertinib was associated with a
median PFS in EGFR T790M-positive patients of 9.6 months
(95% CI: 8.3 to not reached). There were no dose-limiting
toxicities seen at any dose level and the most commonly seen
adverse effects were diarrhea, rash, nausea, and decreased
appetite. Updated data from the phase II extension cohort of
this trial further substantiated these promising early data. In
199 patients with a median follow of 8.2 months, the
response rate in the T790M-positive patients was 61%
(95%: CI 54–68) and the disease control rate was 91% (95%
CI: 85–94).94 Preliminary results from AURA 2, a phase II
single arm study assessing the efficacy of osimertinib at
80-mg dose in T790M-positive patients after progression on
standard EGFR TKI treatment, also demonstrated a response
rate of 71% (95% CI: 64–77).95 Based on the results of these
trials, the FDA granted accelerated approval for osimertinib
(TAGRISSO, AstraZeneca, Cambridge, United Kingdom) in
November 2015 for patients with EGFR T790M mutation-
positive NSCLC, as detected by an FDA-approved test, after
progression on an EGFR TKI therapy.
Rociletinib, another third-generation EGFR TKI, was initially
found be associated with high responses of 59% among evalu-
able patients with T790M-positive patients (95% CI: 45–73).96
However, further development of this agent was discontinued
recently due to concerns related to both efficacy and toxicity.
Several other novel third-generation EGFR TKIs are being
developed for the treatment of patients with T790M EGFR
resistance, including HM61713, ASP8273, EGF816, and PF-
06747775 (NCT02349633).97–100
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 5/2016
There have already been reports of a tertiary mutation in
the C797S domain of the EGFR that portends resistance to the
T790 inhibitors.101–104 Future directions will include develop-
ment of novel agents targeted against the C797S tertiary EGFR
mutation as well as exploration of combination therapies with
chemotherapy, immunotherapy, or various targeted agents
with hopes to improve outcomes in these patients. Third-
generation EGFR TKIs are now being studied in the first-line
setting for the treatment of patients with EGFR mutations.
Single-agent EGFR TKIs are considered a standard first-line
treatment for patients with activating EGFR mutations. Results
from phase III studies including The Cancer and Leukemia
Group B 30406 study,105 NEJ005/TCOG0902,106 and various
others107–109 have demonstrated no benefit to combining TKI
with chemotherapy in the first-line setting.
NSCLC with ALK Gene Rearrangement
Echinoderm microtubule-associated protein-like 4 (EML4)–
ALK fusion oncogene arises from inversion on the short arm of
chromosome 2. The EML4 fusion partner mediates ligand-
independent dimerization and/or oligomerization of ALK,
causing constitutive activation of the kinases.110 ALK-positive
Downloaded by: Cornell. Copyrighted material.
NSCLC represents almost 4 to 5% of patients with NSCLC with
rates as high as 22% in never/light smokers.111
Crizotinib is a small-molecule inhibitor of the receptor
tyrosine kinases (RTKs) c-MET (also known as hepatocyte
growth factor receptor) and ALK.112,113 Crizotinib was associ-
ated with response rate of approximately 60% in phase I/II
studies and in patients with ALK-positive NSCLC, and was
associated with median PFS of 7 to 10 months.114–116 In the
first-line setting, results from a randomized phase III trial
(PROFILE 1014) that compared crizotinib to platinum–peme-
trexed in patients with ALK þ NSCLC demonstrated significant
improvement in response rate and PFS with crizotinib.117 No
significant survival benefit was seen since almost 70% of
patients crossed over to crizotinib arm after progression on
chemotherapy. Crizotinib is now approved as first-line therapy
in ALK þ NSCLC patients with advanced stage disease.
The emergence of resistance is inevitable after a median of
8.9 to 10.5 months.118 Resistance mechanisms against crizo-
tinib can include ALK-dependent mechanisms such as amplifi-
cation/copy number gain and secondary mutations of the ALK
kinase domain preserving ALK signaling, including the most
commonly seen secondary mutation L1196M, similar to T790M
mutation in EGFRþ NSCLC.119,120 The ALK-independent mech-
anisms of resistance involve activation of bypass signaling
pathways such as the EGFR, HSP90, MET, KRAS, or KIT.
Ceritinib, a second-generation ALK inhibitor, was FDA-ap-
proved for the treatment of patients who develop disease
progression following crizotinib or experience intolerance to
crizotinib. In a cohort of patients with ALK-positive disease,
ceritinib was associated with a response rate of 72% (95% CI:
61–82) in ALK-inhibitor naive patients and 56% (49–64) in
patients previously treated with an ALK inhibitor. Median
PFS was 18.4 months (95% CI: 11.1 to not reached) in ALK-
inhibitor naive patients and 6.9 months (95% CI: 5.6–8.7) in ALK
inhibitor pretreated patients. Interestingly, this trial showed
promising activity of ceritinib for patients with brain metastasis,
 Metastatic Lung Cancer Rehman, Ramalingam 743

with an intracranial disease control in 79% (95% CI: 54–94) of the
ALK-inhibitor naive patients and in 65% (95% CI: 54–76) of ALK
inhibitor pretreated patients.121 Since central nervous system
(CNS) relapse is one of the main clinical problems in ALK-positive
patients, the promising CNS activity of ceritinib makes it a
valuable option in ALK-positive patients after progression on
crizotinib.122 There are ongoing clinical trials investigating
ceritinib against platinum doublet in treatment-naive ALK-posi-
tive NSCLC (NCT01828099) and against docetaxel in previously
treated patients (NCT01828112).
Alectinib is the most recently approved ALK inhibitor for
advanced NSCLC. It is a potent second-generation ALK inhibitor
that shows highly selective inhibition of ALK tyrosine kinase as
well as activity against L1196M, the most commonly seen
resistance mutations in ALK gene after exposure to crizoti-
nib.123 Alectinib showed a response rate of 94% (95% CI: 82–98)
in a single-arm phase ½ study conducted in Japan (AF-001JP) in
ALK-inhibitor naive patients with ALK-positive NSCLC.124 In
patients with ALK-positive NSCLC either resistant or intolerant
to crizotinib, alectinib was associated with a response rate of
55% (24 partial responses [PRs], one complete response [CR]) in
44 evaluable patients.125 Alectinib also showed impressive
alectinib arm and was 10.2 months (95% CI: 8.2–12.0) in
crizotinib arm.126 The response rate was nearly 90% for
patients treated with alectinib. Furthermore, the tolerability
profile favored alectinib over crizotinib. A similar study
conducted in the western patient population has completed
accrual and the results are awaited. If confirmed, it is likely
that alectinib will emerge as a first-line therapy option for
ALK-positive NSCLC.
Eventual choice of optimal ALK inhibitor therapy will still be
influenced by the pattern of disease progression, presence of
CNS disease, characterization of emerging resistance mutations,
and safety profile of each agent. Mechanisms of resistance to
ceritinib and alectinib are undergoing active investigation.
G1202R ALK mutation is pan-resistant to crizotinib, ceritinib,
and alectinib.127 Several ALK inhibitors currently in develop-
ment and are summarized in ►Table 4.128–133
ROS1
Chromosomal rearrangements involving the ROS1 RTK gene
have been described as potential driver mutations in NSCLC,
leading to constitutive kinase activity with an estimated preva-
lence of 1 to 2% in patients with NSCLC.134 Results from a phase 1

Downloaded by: Cornell. Copyrighted material.

CNS activity with response rate of 52% for the 21 patients with
baseline CNS metastasis, including five CRs.125
A phase III clinical trial comparing alectinib and crizotinib
in the first-line setting was stopped early as it met its primary
endpoint. Preliminary results from this Japanese study
(J-ALEX) demonstrated superior PFS for alectinib over crizo-
tinib (HR: 0.34; stratified log-rank p < 0.0001). The median
PFS was not reached (95% CI: 20.3 to not estimated) in the
expansion trial using crizotinib in ROS1-rearrangement-positive
NSCLC patients demonstrated impressive response rates of 72%,
including three CRs. The median duration of response was
17.6 months and median PFS was 19.2 months (95% CI: 14.4
to not reached).135 Crizotinib has recently been approved by the
FDA for the treatment of advanced NSCLC patients with ROS1
gene rearrangement. Similar to experience with other TKIs,
resistance to crizotinib develops with acquired mutations,

Table 4 Novel ALK and ROS1 inhibitors in clinical development

PFS Target Phase N RR Ongoing trials

AP26113 ALK, ROS1, EGFR I/II 78 74%, 100% in ALTA NCT02094573
(brigatinib)128 first-line setting
PFS 13.4 mo
in pretreated
Not reached in
first-line setting
PF-06463922 ALK, ROS1 I/II 52 50%a NCT01970865
(lorlatinib)129 (36 with CNS disease)
44% CNS responseb
X-396 ALK, c-MET I/II 11 55% NCT01625234
(Xcovery)130
TSR-011 ALK, TrkA, I/IIa 3 100% at 120 mg NCT02048488
(tersaro)131 TrkB, TrkC total daily dose
RXDX-101 ALK, ROS1, TrkA, I/II 7 57% STARTRK-1
(entrectinib)132,133 TrkB, TrkC NCT020\97810
80%
(at dose  400 mg/m2)
in ALKA-372–001
10 91% in first-line
(2 ALK, 6 ROS1 positive) setting in STARTRK-1

Abbreviations: ALK, anaplastic lymphoma kinase; c-MET, mesenchymal epithelial transition; CNS, central nervous system; N, number of patients; PFS,
progression free survival; ROS1, c-Ros oncogene 1; RR, response rates; Trk, tropomyosin receptor kinase.
a
Intracranial þ extracranial disease.
b
Target þ non target lesions.

Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 5/2016

744 Metastatic Lung Cancer Rehman, Ramalingam
such as G2032R and L2155S, in ROS1 kinase domain.136,137
Preclinical and early clinical studies with lorlatinib (PF-
06463922), a novel, CNS-penetrant, ATP-competitive small-
molecule inhibitor of ALK/ROS1, have demonstrated encouraging
results with activity against novel resistance mutations in both
ALK and ROS1.138 In an ongoing phase I/II trial, in patients with
advanced ALK þ NSCLC or ROS1 þ NSCLC with or without CNS
metastases, lorlatinib has demonstrated a well-tolerated safety
profile and clinical activity (►Table 4).129 Phase II evaluation of
lorlatinib is ongoing (NCT01970865).
BRAF
Oncogenic BRAF mutation is found in approximately 3 to 4%
of NSCLC with approximately 50% of these cases harboring
the characteristic V600E mutation. Unlike EGFR and ALK,
BRAF mutations commonly occur in smokers.139,140 Vemur-
afenib and dabrafenib are TKIs approved for BRAF-mutated
metastatic melanoma and have shown promising activity
against BRAF mutation positive NSCLC. A response rate of
42% was seen in 20 patients with advanced NSCLC carrying
BRAF mutations in a basket phase II trial using vemurafe-
nib.141 A two-stage phase II study evaluating the combina-
tion of the MEK inhibitor trametinib with dabrafenib in
patients with advanced NSCLC with progression after one
or more platinum-based chemotherapy is currently ongo-
ing. Updated results demonstrated a high response rate of
63% (95% CI: 49–75) with a median PFS of 9.7 months.142
We can stick to platinum based doublet therapy for
consistency.
MET Amplification or Exon 14 Skipping Mutation
The proto-oncogene MET (hepatocyte growth factor receptor)
exon 14 splice site alterations and other mutations have been
shown to result in MET activation. MET mutations are
observed in 3% of squamous cell lung cancers143 and 8% of
lung adenocarcinomas.144 A response rate of 33% was seen in
a phase I study using crizotinib in MET-amplified NSCLC.145
Anecdotal responses to both crizotinib and cabozantinib have
been reported in patients with MET exon 14 skipping muta-
tions.146 An ongoing phase I clinical trial with MET inhibitor
capmatinib (INC280) showed promising activity with PRs in
several patients (NCT02750215).
Though many of the driver mutations described in the
previous section are amenable to targeted therapies, it should
be noted that with the exception of EGFR, ALK, or ROS1 gene
abnormalities, chemotherapy should be the preferred first-
line option for advanced stage disease. The appropriate
targeted agents to the newer targets can be given in subse-
quent lines of therapy, until further evidence confirming their
superiority over chemotherapy is available.
Conclusion
The treatment landscape of advanced NSCLC has now evolved
from an empiric approach to a more personalized approach
based on an understanding of the molecular biology of the
tumor. There have been advancements in chemotherapeutics
using combination therapies with antibodies targeting the VEGF
Seminars in Respiratory and Critical Care Medicine Vol. 37 No. 5/2016
as well as demonstration of improved survival benefit of main-
tenance therapy. Promising activity of immune checkpoint
inhibitors has added immunotherapy as a major modality in
the treatment of advanced NSCLC, and identification of new
driver mutations offers a unique opportunity to personalize
therapy; however, it also comes with a challenge of inevitable
emergence of resistance. Novel strategies to delay or prevent
resistance to targeted therapies is the focus of several ongoing
studies. Approaches to combine immune checkpoint inhibitors
with chemotherapy, or targeted agents are also being studied to
improve outcomes in NSCLC. The outlook for patients with
metastatic NSCLC has improved considerably in the past decade
and it is hoped that long-term survival can be achieved for an
even higher proportion of patients.
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