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Lung cancer review - October 2014



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® • October2014 • Vol.39No.10
Lung cancer treatment has evolved in the past decade,
leading to remarkable growth in the number and variety of
therapeutic options. Clinicians and patients have witnessed
a shift from a relatively small arsenal of mostly chemothera-
peutic therapies to an expanding array of targeted treatments
(Table 1) and treatment combinations. This
change reflects, in part, a significant refinement
in the molecular categorization of lung cancer
and the increasingly successful exploitation of
the molecular diversity of lung tumors.
“We clearly can no longer think of lung
cancer as a monolithic entity,” says Corey
Langer, MD, Director of Thoracic Oncology
and Professor of Medicine at the University
of Pennsylvania. “With the identification of a
significant number of actionable or potentially
actionable molecular drivers—including not
just mutations but translocations and other
molecular aberrations, most of which we
weren’t aware of even 10 years ago—lung
cancers really break down into distinct entities, each of which
should be recognized as having separate cancer behaviors.”
“As lung cancers are further subdivided and characterized
according to histology and molecular fingerprints,” Dr. Langer
adds, “we may see an increasingly specific and beneficial
impact on treatment, as we have already begun to see in our
patients with adenocarcinoma, about 25% of whom have some
molecular abnormality that directs their treatment.”
As breakthroughs in identifying oncogenic drivers of lung
cancer continue, researchers should be in an increasingly
better position to revisit persistent problems, such as the
dearth of treatments for patients with squamous non–small-
cell lung cancer (NSCLC) and small-cell lung cancer (SCLC);
intransigent overall survival rates among patients with all types
of lung cancer; and the need to assess potential
new treatments more rapidly and efficiently.
Featured presentations at the 2014 meeting
of the American Society of Clinical Oncology
(ASCO) reflected progress in some of these
areas, primarily in the NSCLC realm: Trials
of novel targeted therapies for advanced lung
cancers, including squamous NSCLC; agents
designed to overcome resistance to approved
targeted therapies; and promising new immu-
notherapies were among the highlights.
In June 2014, shortly after the ASCO meeting
concluded, a study likely to address several
unmet needs in the field was launched. While
initially testing new targeted treatments and
an immunotherapeutic agent in the second-line treatment
of patients with squamous NSCLC, the Lung-MAP study is
expected to match lung cancer patients more quickly and
efficiently with investigational treatments.
Despite recent advances in NSCLC treatment (Figure 1),
options for patients with SCLCs remain limited. SCLC, which
represents about 15% to 20% of lung cancers and occurs mostly
in patients who have a significant smoking history, has the
most aggressive clinical course of any type of lung cancer,
Susan Worley
Disclosure: The author reports that she has no commercial or financial
relationships in regard to this article.
Susan Worley is a freelance medical writer who resides in Pennsyl-
Corey Langer, MD
MechanismofAction/Indication 30-DayCost*
Erlotinib (Tarceva) Roche
Metastatic NSCLC tumors with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations
Genentech Vascular endothelial growth factor-specific inhibitor of angiogenesis for unresectable, locally
advanced, recurrent, or metastatic nonsquamous NSCLC (with carboplatin and paclitaxel)
Gefitinib (Iressa) AstraZeneca Selective inhibitor of EGFR tyrosine kinase domain for locally advanced or metastatic NSCLC $2,042
Afatinib (Gilotrif) Boehringer
Tyrosine kinase inhibitor for metastatic NSCLC tumors with EGFR exon 19 deletions or exon
21 (L858R) substitution mutations
Certinib (Zykadia) Novartis
Kinase inhibitor for patients with ALK-positive metastatic NSCLC tumors who have progressed
on or are intolerant to crizotinib
Crizotinib (Xalkori) Pfizer Kinase inhibitor for ALK-positive metastatic NSCLC tumors $14,383
ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; NSCLC = non–small-cell lung cancer
* Based on average wholesale prices from Red Book and regimens in prescribing information for each medication
Based on intravenous administration of 15 mg/kg to an 85-kg patient every 21 days, extrapolated to a 30-day cost of bevacizumab alone
Vol.39No.10 • October2014 •
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with a median survival from diagnosis of less than five months.
“Unfortunately,” says Dr. Langer, “in 25 years we have made
virtually no progress with regard to small-cell lung cancer.
Although it often responds well to treatment initially, small-cell
cancer quickly becomes resistant to treatment, and we have
not figured out how to tackle it other than with
the use of standard chemotherapeutic agents.
It’s the chemo-resistant population of cancer
cells that determines patient survival.”
Dr. Langer and other experts trace treatment
difficulties in part to multiple genetic mutations
in small-cell cancers, which are still poorly
understood but are due in part to damage
caused by smoking. These multiple mutations
increase the likelihood that SCLC will become
resistant to treatment. New SCLC research
effor ts have focused primarily on the use of
prophylactic cranial irradiation to reduce brain
metastases1 and some moderately successful
effor ts to develop new platinum-based combina-
tion treatments. Lung cancer experts are cautiously optimistic
that this type of cancer may eventually benefit from advances
in molecular research,
a better understanding of SCLC tumori-
genesis,3 and recent innovations in clinical trials.
Among the most widely discussed lung cancer presentations
at ASCO 2014 was a retrospective analysis of phase 3 trial data
for afatinib (Gilotrif, Boehringer Ingelheim), an FDA-approved
treatment for patients with activating epidermal growth factor
receptor (EGFR) mutations.
Afatinib is an
irreversible tyrosine kinase inhibitor (TKI) of
the human epithelial receptor (HER) family,
which includes EGFR, and was approved based
on data from the LUX Lung 3 study. LUX Lung 3
demonstrated significant response rates and
superior progression-free survival (PFS) among
patients who received afatanib compared
with those who received chemotherapy. The
Boehringer Ingelheim analysis of LUX Lung 3
and LUX Lung 6 data presented at ASCO was
notable for showing that afatinib significantly
improves overall survival (OS) compared with
chemotherapy, particularly for patients whose
tumors harbor exon 19 deletions. While this
survival benefit was encouraging, some experts have ques-
tioned whether, in the molecular era, new EGFR TKIs should
continue to be compared with chemotherapy.5
“The most important question we face when treating patients
Howard West, MD
Figure 1 Treatment Algorithm for Patients with Non–Small-Cell Lung Cancer (NSCLC)
Source: Courtesy of Anne Tsao, MD, MD Anderson Cancer Center, Houston; and Howard West, MD, Swedish Cancer Institute, Seattle
Nonsquamous Squamous *†‡
Neuroendocrine Adenocarcinoma
* Avoid pemetrexed or bevacizumab
Consider second-line EGFR TKI or maintenance erlotinib (BR.21, SATURN)
Docetaxel, pemetrexed, or erlotinib as second-line therapy (based on what has not been previously administered)
EGFR mutation EGFR wild-type
EML 4 ALK or ROS 1
Front-line chemotherapy
Not FDA/EMEA-approved:
Platinum-doublet + cetuximab
(FLEX, BMS-099)
Platinum-doublet + necitumumab
Platinum doublet +/- bevacizumab x 4–6 cycles
Consider continuation maintenance therapy with
pemetrexed +/- bevacizumab if given first-line
Consider switch maintenance with pemetrexed or erlotinib
(E4599, AVAiL, Pointbreak, SATURN, JMEN)
First- or second-line
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with advanced lung adenocarcinoma and an activating EGFR
mutation is whether a new EGFR TKI provides incremental
value over the agent or agents it would replace,” says Howard
(Jack) West, MD, Medical Director of the Thoracic Oncology
Program at the Swedish Cancer Institute in Seattle, Washington.
According to Dr. West, the most relevant comparison in the
U.S. today should be between afatinib and erlotinib (Tarceva,
Genentech). He points to the LUX Lung 7 trial, which random-
ized patients to first-line treatment with afatinib or gefitinib
(Iressa, AstraZeneca), as the first trial that has
attempted a direct comparison.
“The question of whether there is a signifi-
cant difference between EGFR TKIs will likely
be answered when we begin to see the results
of the LUX Lung 7 trial,” says Dr. West. “This
trial already has been completed, and we should
expect to see results in 2015.”
Dr. West points to another study involving
an EGFR TKI, presented at ASCO by Kato and
which was noteworthy for establish-
ing the value of adding bevacizumab (Avastin,
Genentech) to erlotinib for the first-line treat-
ment of patients with advanced EGFR muta-
tion–positive nonsquamous NSCLC.
“Although this study is still in the early stages and hasn’t
yet reported on sur vival, the dif ference in PFS is more than
six months, and I would say that’s a very clinically significant
difference,” says Dr. West.
Presentations of early data from studies of several novel
targeted treatments were also featured at ASCO. These
included necitumumab (Eli Lilly),7 a human immunoglobulin
G1 anti-EGFR monoclonal antibody being tested for the treat-
ment of patients with stage 4 squamous NSCLC; onartuzumab
(MetMab),8 a humanized monovalent antibody to the MET
receptor, used in conjunction with erlotinib to treat patients
with stage 3b or 4 NSCLC; and ramucirumab (Cyramza, Eli
a monoclonal antibody that targets the extracellular
domain of VEGFR-2, used with docetaxel in the second-line
treatment of patients with stage 4 NSCLC.
While targeted treatments approved in recent years,
including erlotinib and crizotinib (Xalkori, Pfizer), for tumors
with anaplastic lymphoma kinase (ALK) protein mutations,
have been associated with remarkable response rates, most
patients who respond to these treatments will eventually
develop resistance to them. Research geared toward identify-
ing and targeting mechanisms of resistance in these patients
has begun to yield promising potential treatments.
At ASCO 2014,” Dr. West says, “among the most impor tant
presentations in this area were those that featured novel agents
for patients whose tumors harbor the T790 mutation, which is
seen in about 60% of patients who develop acquired resistance.”
Two of these, AZD9291 (AstraZeneca) and rociletinib (for-
merly CO-1686, Clovis), are third-generation TKIs that show
activity against T790 in vitro and have earned breakthrough
status from the FDA. Phase 3 clinical trials are under way for
both drugs.
“In clinical studies conducted to date, there have been
response rates in the range of 50% to 60% with these agents, with
many of the other patients participating in these trials showing
at least minor responses or stable disease,” Dr. West says. “So
there are very striking benefits in patients, many of whom are
experiencing prolonged responses. We don’t really know yet
how prolonged these responses will be, because the studies
are still in the early stages. The encouraging results with both
of these agents suggest we are in the midst of breaking that
impasse of not having anything constructive to of fer patients
with acquired resistance. And, although in
the past there has not been a good answer to
the question of whether to do a repeat biopsy,
these drugs of fer a clear reason to repeat
molecular testing.”
Also reported at ASCO were clinical trial
results for ceritinib (Zykadia, Novartis), which
targets crizotinib-resistant tumors with ALK
mutations and received FDA approval earlier
this year.10
Discouraging early effor ts to develop
effective immunotherapeutic treatments for
lung cancer, with agents such as interferon,
interleukin 2, Bascillus Calmett-Guérin, and various cancer
vaccines, caused many experts until recently to regard lung
cancer tumors as nonimmunogenic.11 However, a deeper
investigation of the methods by which lung tumors are able
to escape destruction by the immune system has led to the
development of a new generation of immunotherapeutic agents
called immune checkpoint inhibitors.12,13 This class of drugs
comprises monoclonal antibodies that suppress inhibitory
signaling in the immune system and allow T cells to recognize
and destroy tumor cells.
Preliminary clinical trial results for several new immuno-
therapies, including nivolumab (Bristol-Myers Squibb) and
pembrolizumab (Merck), both of which target the T-cell protein
programmed death-1 (PD-1), as well as for combinations of
agents in this class, were reported at ASCO. Although these
agents act in slightly different ways, patients have generally
experienced early and durable responses with them, and they
have been shown to have tolerable safety profiles. Bristol-Myers
Squibb and Merck are conducting phase 3 trials of these agents.
Selected investigational treatments are listed in Table 2.
Lung cancer experts have been par ticularly impressed by
sustained responses among patients who respond to these
drugs; many patients who benefit continue to do so for prolonged
periods, in some cases even after treatment is discontinued
following a single dose. Investigators hypothesize that these
responses occur as T cells essentially become memory cells
and some resetting of the immune system occurs. Interestingly,
these agents have proven to be effective for some patients who
are not PD-L1 positive, an unexpected development that suggests
uncertainty regarding which patients are most likely to benefit.
“I think some of these inconsistencies can be explained by the
variability among all of the tests being used to screen patients
for these biomarkers,” says Julie Brahmer, MD, Associate
Professor of Oncology and Interim Director of the Thoracic
Oncology Program at the Sidney Kimmel Comprehensive
Julie Brahmer, MD
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Cancer Center at Johns Hopkins University, who anticipates
that approximately 20% of lung cancer patients will be able
to benefit from immunotherapies. “We also know that PD-L1
expression can change over time, and that PD-L1 expression
can be heterogenous within a tumor. Expression does seem
to concentrate where the tumor interacts with the surround-
ing tissue, so it is possible to biopsy the wrong spot; there are
many variables that must be taken into account when you are
drawing information from one small tumor sample. It is also
possible that we’ll discover other factors that come into play
for particular patients, which may af fect their responses to
these agents.”
Some experts have expressed concer n that
enthusiasm over the new immunotherapeutic
treatments may contribute to a public misper-
ception that these agents lack side effects.
“No drug is without side ef fects,” says
Dr. Brahmer. “While it is refreshing for patients
and clinicians that these agents are not associated
with those we typically see with chemotherapy,
they are associated with other side effects, such
as inflammatory reactions that may range from
arthritis to thyroiditis. So the use of these dr ugs
will require rethinking, and patient and provider
education will play a key role in determining
how best to monitor and manage side effects of
immunotherapies. It is important to note that if you compare,
for example, just grade 3 and 4 side effects of nivolumab with
the same grade of side effects for chemotherapies, the rates of
these categories of side effects are much lower with nivolumab.”
The pace and sophistication with which new oncological
drivers of lung cancer are currently identified, par ticularly for
and the speed with which corresponding
investigational treatments are subsequently developed, are
steadily outgrowing the inflexible machinery of traditional clini-
cal trials. The Lung-MAP study, a model of clinical testing that
launched in June 2014, is designed to address this problem by
simultaneously testing large numbers of patients for a range of
molecular aberrations and efficiently matching these patients
with appropriate experimental treatments.
“Traditional clinical trials, which have long been limited
by challenges related to start-up time, recruitment, accrual,
expense, and the need to identify particular subpopulations
of patients, often result in frustratingly slow
results,” says Roy Herbst, MD, PhD, Chief of
Medical Oncology at the Yale Cancer Center
and co-chair of the Lung-MAP study.
“Let’s say a particular mutation is present in
approximately 10% of patients with lung cancer.
It would be necessary to screen at least 100
patients to find 10 who qualify for a trial, 400
patients to conduct a trial with 40 patients—and
that’s assuming that everyone who tests posi-
tive is otherwise healthy enough to participate.
Screening that many patients for a single trial
can require an enormous investment of time
and resources, even when multiple sites are
involved, and many patients who test negative
will be frustrated if they are left without the oppor tunity to try a
new drug. With the master protocol, which follows an umbrella
design, many patients are tested at once and subsequently
assigned to an appropriate treatment, and no one receives
a placebo. Everyone is assigned to a treatment.” (Figure 2)
Dr. Herbst is one of the lead organizers of the Lung-MAP
study, which has been made possible by a unique collaboration
among government, industr y, private foundations, and advocacy
Roy Herbst, MD, PhD
Table 2 Investigational Lung Cancer Drugs
Agent Manufacturer MechanismofAction/Indication StageofDevelopment
Nivolumab Bristol-Myers Squibb Anti-PD-1; MAb Phase 3
Pembrolizumab Merck Anti-PD-1 checkpoint inhibitor; MAb Phase 3
AZD9291 AstraZeneca EGFR mutation-positive acquired resistance Phase 2
Rociletinib Clovis Oncology EGFR mutation-positive acquired resistance Phase 2/3
Selumetinib AstraZeneca KRAS mutation-positive NSCLC Phase 3
MEDI4736 Medimmune Anti-PD-L1 immune checkpoint inhibitor; MAb Phase 1/2
MPDL3280A Roche/Genentech Anti-PD-L1 immune checkpoint inhibitor; MAb Phase 3
Nintedanib Boehringer Ingelheim VEGFR2 inhibitor Phase 3
Ganetespib Synta HSP90 inhibitor Phase 3
Veliparib AbbVie PARP inhibitor Phase 3
Bavituximab Pelegrine Phosphatidylserine inhibitor; MAb Phase 3
Necitumumab Lilly EGFR; MAb Phase 3 (completed)
Ramucirumab Lilly VEGFR; MAb Phase 3 (completed)
EGFR = epidermal growth factor receptor; HSP = heat shock protein; MAb = monoclonal antibody; NSCLC = non–small-cell lung cancer;
PARP = poly ADP ribose polymerase; PD-1 = programmed death-1; PD-L1 = programmed death ligand-1; VEGFR = vascular endothelial growth
factor receptor
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groups.16 The first five pharmaceutical companies to enter into
this pre-competitive partnership are Amgen, Genentech, Pfizer,
AstraZeneca, and AstraZeneca’s global biologics research and
development arm, MedImmune.
The trial will initially test five experimental drugs, including
an anti–PD-L1 immunotherapy in the second-line treatment of
squamous NSCLC. Foundation Medicine will provide next-
generation sequencing to identify more than 200 cancer-related
genomic alterations. Approximately 500 to 1,000 patients will
be screened per year, and patients in each treatment sub-
group will be randomly assigned to a targeted treatment or
to chemotherapy.
“Patients are currently being enrolled,” says Dr. Herbst,
“and each trial is a phase 2/3 trial, so we will await meaning-
ful results in each subgroup to see if we can move forward to
phase 3. The phase 2 endpoint, an improvement in PFS of at
least twofold, is determined after 56 events. This protocol is
not only an efficient mechanism for getting new drugs to lung
cancer patients quickly, it will also tell us when to discontinue
the investigation of drugs that aren’t going to work.”
Most experts agree that the single greatest obstacle to sig-
nificantly improving OS rates for all types of lung cancer lies in
the fact that most patients have locally advanced or metastatic
disease at the time of diagnosis (Figure 3). Prognosis is strongly
After genomic evaluation, patients will be assigned to one of these five substudies, depending on their
biomarker status:
•MEDI4736 (immunotherapy) versus docetaxel—Patients whose tumors do not harbor any of the targeted
alterations will be randomized to receive either MEDI4736, a monoclonal antibody directed against the
programmed death ligand-1 (PD-L1), or standard chemotherapy (docetaxel).
•GDC-0032 versus docetaxel—Patients whose tumors test positive for the PI3KCA mutation will receive
either GDC-0032 or docetaxel. GDC-0032, a beta-isoform-sparing PI3K inhibitor, is an oral agent from
•Palbociclib versus docetaxel—Patients whose tumors test positive for CDK4/6 or CCDN1/2/3 amplification
will be randomized for treatment with either palbociclib or docetaxel. Palbociclib is a small molecule from
Pfizer that has gained breakthrough status in breast cancer.
•AZD4547 versus docetaxel—Patients whose tumors harbor FGFR1/2/3 alterations will be randomized to
receive either AZD4547 or docetaxel. AZD4547 is a tyrosine kinase inhibitor from AstraZeneca.
•Rilotumumab plus erlotinib versus erlotinib—Patients whose tumors have HGF/c-MET mutations will receive
rilotumumab intravenously on day 1 and erlotinib daily, or erlotinib daily. Rilotumumab is a monoclonal anti-
body from Amgen that inhibits hepatocyte growth factor activity. Erlotinib (Tarceva) is an EGFR inhibitor
already approved for the treatment of lung cancer.
Figure 2 The Lung-MAP Study:
Squamous Cell Lung Cancer, Second-Line Therapy
CT = chemotherapy (docetaxel or gemcitabine), E = erlotinib; NGS = next-generation sequencing; OS = overall
survival; PFS = progression-free survival
profiling (NGS/CLIA)
Multiple phase 2 and 3 arms with “rolling” opening and closure
PiK3CA mutation CCND1 amplification or
CDKN2 loss + RB WT
FGFR amplification,
mutation, fusion
MET expression
Source: Roy Herbst, MD, PhD, Chief of Medical Oncology, Yale Cancer Center; co-chair of the Lung-MAP study
Vol.39No.10 • October2014 •
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tied to the stage of disease at diagnosis, and only about 15% of
patients are diagnosed with localized disease.
Although the U.S. Preventive Services Task Force recom-
mends low-dose computed tomography (CT) screening in high-
risk patients,17 based largely on findings that such screening
reduces mortality by approximately 20% among patients at high
risk, several aspects of screening for this disease are a source
of controversy.
In the U.S. a fully effective national program
of screening for lung cancer remains a major unmet need.20
“Lung cancer is the primary cause of cancer mortality for
both men and women in the U.S.,” says Michael Unger, MD,
Professor of Medicine at the Sidney Kimmel Medical College of
Thomas Jefferson University, who is among a growing number
of researchers dedicated to improving screening techniques.
“Deaths from this cancer exceed those from colon, breast, and
prostate cancers combined—cancers for which we already
have established screening programs.” Echoing the sentiments
of all clinicians and researchers interviewed for this article,
Dr. Unger adds, “The screening and detection of this disease
at earlier stages will provide opportunities to reduce overall
mortality and, in some patients, potentially cure the disease.”
Research effor ts in this realm are focused on addressing the
markedly high rates of false-positive results associated with
current screening practices.
A primary aim is to develop
noninvasive techniques for detecting biomarkers in biological
specimens—such as blood, breath, or sputum—that can assist
in resolving the status of indeterminate pulmonar y nodules.
Detecting lung cancer at its earliest stages, perhaps prior to
CT screening, is a longer-term goal. Despite occasional media
reports of success in this area,22 most investigational studies
still require extensive validation. Furthest along in development
are so-called breathalyzer tests,23 which involve the analysis
of volatile organic compounds in exhaled air, and blood tests,
including one that exploits signals by which the presence of
a tumor is communicated to the immune system.24
According to Pierre Massion, MD, Professor of Cancer
Research at Vanderbilt University, it is unlikely that any single
novel screening method will provide sufficient information on its
own. “Currently,” says Dr. Massion, “CT screening is the only
modality that has been proven to work. Although imaging will
likely become more sophisticated, indeterminate pulmonar y
nodules and indolent tumors will continue to present chal-
lenges. Ultimately it may be necessary to combine methods to
develop a successful multidisciplinary model of screening—one
that brings the strength of clinical data, or molecular markers,
to the time-tested value of imaging data.”
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Confined to
primary site
Spread to regional
lymph nodes
Cancer has
Surveillance, Epidemiology, and End Results Program, SEER 18,
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continued on page 714
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Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
LBA8006^ Background: RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The REVEL study evaluated the efficacy and safety of RAM+DOC vs. PL+DOC (DOC) in patients (pts) with stage IV nonsquamous (NSQ) and squamous (SQ) NSCLC after platinum-based therapy. Methods: Pts with NSQ and SQ stage IV NSCLC were randomized 1:1 (stratified by sex, region, ECOG PS, and prior maintenance therapy) to receive DOC 75 mg/m ² in combination with either RAM 10 mg/kg or PL on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS), and objective response rate (ORR). Results: Between Dec 2010 and Feb 2013, 1,253 pts (26.2% SQ) were randomized (RAM+DOC: 628; DOC: 625). Pt characteristics were balanced between arms. ORR was 22.9% for RAM+DOC and 13.6% for DOC (P<0.001). The hazard ratio (HR) for PFS was 0.762 (P<0.0001); median PFS was 4.5 months (m) for RAM+DOC vs. 3.0m for DOC. REVEL met its primary endpoint; the OS HR was 0.857 (95% CI 0.751, 0.98; P=0.0235); median OS was 10.5m for RAM+DOC vs. 9.1m for DOC. OS was longer for RAM+DOC in most pt subgroups, including SQ and NSQ histology. Grade ≥3 adverse events (AEs) occurring in >5% of pts on RAM+DOC were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all pts: 2.1% vs. 1.6%; SQ pts: 3.8% vs. 2.4%). Conclusions: REVEL demonstrated a statistically significant improvement in ORR, PFS, and OS for RAM+DOC vs DOC in NSCLC pts with stage IV NSCLC as second-line treatment after platinum-based therapy. Benefits were similar in NSQ and SQ pts, and no unexpected AEs were identified. Clinical trial information: NCT01168973.