Annals of Oncology 29: 84–91, 2018

doi:10.1093/annonc/mdx755
Published online 7 December 2017

REVIEW

Comprehensive analysis of the clinical

immuno-oncology landscape

J. Tang, A. Shalabi & V. M. Hubbard-Lucey*

The Anna-Maria Kellen Clinical Accelerator, Cancer Research Institute, New York, USA

*Correspondence to: Dr Vanessa M. Hubbard-Lucey, Anna-Maria Kellen Clinical Accelerator, Cancer Research Institute, 29 Broadway, 4th Floor, New York, NY 10006, USA.
Tel: þ1-212-6887515; E-mail: vlucey@cancerresearch.org

Advances from immuno-oncology (IO) are changing the standard of care of many types of cancer, and the paradigm of cancer
treatments and drug development is being rewritten on a regular basis. Moreover, an unprecedented number of new
investigational agents and companies are entering the field of IO. As such, it has become challenging for oncology physicians
conducting clinical trials, industry veterans developing IO drugs, and even regulators reviewing novel IO agents to keep track of
the rapidly evolving landscape. To help the key stake holders in the field understand the latest IO landscape, we sought to
present an unbiased, neutral, scientifically curated, and timely updated analysis of all the current IO agents in clinical
development and the clinical trials testing these agents. We based our analyses on information collected from numerous
trusted and publicly available sources. We have developed two databases. One database tracks 2004 IO agents (940 in clinical
stage and 1064 in preclinical stage) against 303 targets, from 864 companies; the other tracks 3042 active clinical trials of these
agents with a target enrollment of 577 076 patients. This report provides key analyses of these data. Furthermore, we will discuss
a number of important and actionable trends in the current IO landscape: a large number of companies developing agents
against the same IO targets; a rapid increase in the number of anti-PD-1/L1 combination studies, many of which are testing the
same combinations and following inefficient patterns; and a significant increase in the number of small, investigator-initiated
studies. For each of the findings, we speculate the causes and discuss a few initiatives that aim to address some of these
challenges. Finally, by making these landscape analyses available, we aspire to inform the cancer community as they seek to
strive for efficiencies and innovation while avoiding duplication.
Key words: immuno-oncology, cancer immunotherapy, landscape analysis, clinical trials, tumor immunology

Introduction CD3-targeted bispecific antibody (also targeting CD19) have

Advances in immuno-oncology (IO) are revolutionizing the
standard of care for many types of cancer. As of our data cut-off
date (September 2017), 26 immunotherapies have been
approved, and 17 types of cancer have at least one approved im-
munotherapy as a treatment option. The first approval of modern
cancer immunotherapy was interferon-a in 1986 for hairy cell
leukemia, and later for chronic myelogenous leukemia, follicular
non-Hodgkin lymphoma, melanoma, and AIDS-related Kaposi’s
sarcoma [1]. Several other agents have been approved since then,
but a transformation in the landscape of IO started with the ap-
proval of ipilimumab—a checkpoint inhibitor targeting CTLA-
4—for advanced melanoma in 2011 [2, 3]. In the past 3 years
alone, five new checkpoint inhibitors (targeting PD-1 or PD-L1),
two new cell therapies (targeting CD19), and one new
been approved [4–7]. These novel immunotherapies, in most
cases, are designed to treat advanced, refractory, or relapsed
cancers that did not respond to standard-of-care cancer treat-
ments (Table 1).
Since the approval of ipilimumab, the pipeline of IO agents in
clinical and preclinical development has become very crowded
[8]. As of September 2017, there were 940 IO agents in clinical de-
velopment, with another 1064 in preclinical phase. We also found
that 3042 interventional active clinical trials are evaluating these
clinical-stage immunotherapies with a target of enrolling 577 076
patients (supplementary Table S1, available at Annals of Oncology
online). These IO trials cover all common cancer types and the
majority of the less common ones, and promising results are
being reported on a daily basis in major conferences and clinical

C The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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Annals of Oncology Review
Table 1. The list of 26 approved immuno-oncology agents, company origins, and targets

Therapy type Therapy name Company Target

T-cell-targeted immunomodulatory (six in total) Ipilimumab Bristol-Myers Squibb Co. CTLA-4

Nivolumab Bristol-Myers Squibb Co. PD-1
Pembrolizumab Merck & Co Inc. PD-1
Atezolizumab Roche/Genentech Ltd PD-L1
Avelumab Merck KGaA PD-L1
Durvalumab AstraZeneca/MedImmune LLC PD-L1
Other immunomodulatory (eight in total) Aldesleukin Novartis AG IL2R
Imiquimod Valeant Pharmaceuticals Intl Inc. TLR7
Interferon alfa Sumitomo Dainippon Pharma Co Ltd IFNAR1; IFNAR2
Interferon alfa-1b Shenzhen Kexing Biotech Co Ltd IFNAR1
Interferon alfa-2a Cadila Healthcare Ltd IFNAR1; IFNAR2
Interferon alfa-2b Merck & Co Inc. IFNAR1; IFNAR2
Interferon beta Toray Industries Inc. IFNAR1
Interferon gamma-1a Otsuka Pharmaceutical Co Ltd IFNAR1
Cancer vaccine (seven in total) BCG Live Shire Plc TLR
ImmuCyst Sanofi TLR
Immuno BCG Ataulpho Paiva Foundation TLR
Mycidac-C Cadila Pharmaceuticals Ltd TLR2
Sipuleucel-T Dendreon Unspecified TAA
TICE BCG Merck & Co Inc. TLR
Uro-BCG Medac Inc. TLR
Cell therapy (two in total) Tisagenlecleucel Novartis AG CD19
Axicabtagene ciloleucel Gilead CD19
Oncolytic virus (two in total) Oncorine Shanghai Sunway Biotech Co Ltd CD40L
Talimogene laherparepvec Amgen Inc. GMCSFR
CD3-targeted bispecific ab Blinatumomab Amgen Inc. CD19 X CD3

journals. The large numbers of promising experimental therapies,
active clinical trials, and planned patient enrollment suggest that
we are entering a new era that could change the standard-of-care
in even more cancer types.
However, the fast-expanding and ever-changing IO field could
overwhelm even the most experienced clinical investigators as
they seek treatment options for their patients. To help the cancer
community stay informed of the current IO landscape, the Anna-
Maria Kellen Clinical Accelerator of the Cancer Research
Institute (CRI), the clinical research program of CRI, provides
herein an unbiased, neutral, comprehensive, and scientifically
curated landscape analysis that aims to inform the physician-
scientists, drug developers, regulators, and other stakeholders of
the latest trends in IO clinical development.
The landscape of clinical immuno-oncology
A large number of IO drugs in clinical development
with significant duplication
Overview of the Clinical Accelerator IO database. Our database
included 2004 IO agents as of September 2017, 940 of which are
in clinical development. On the basis of different mechanisms of
actions, we classified these agents into six categories: (i) T-cell-
targeted immunomodulators that act on inhibitory or activating
molecules expressed by T cells (e.g. agents targeting CTLA-4,
PD-1, CD40, and GITR); (ii) other immunomodulators that act
on other immune cells or the tumor immune microenvironment
to unleash antitumor immunity (e.g. agents modulating IFNAR,
CSF1R, IDO1, A2AR, and KIR); (iii) cancer vaccines that induce
antigen-specific antitumor immunity (e.g. sipuleucel-T); (iv) cell
therapies that engineer immune cells such as T cells to directly
attack cancer cells (e.g. anti-CD19 CAR-T); (v) oncolytic viruses
that rely on both direct tumor killing and activation of antitumor
immunity (e.g. T-VEC); and (vi) CD3-targeted bispecific anti-
bodies that bring T cell to the targeted tumor cells for direct kill-
ing (e.g. blinatumomab) (Figure 1).
Concentration of agents on a few targets. The 940 clinical-stage
IO agents are owned by 462 different companies or academic in-
stitutes (supplementary Table S2, available at Annals of Oncology
online), and these agents modulate 271 different targets.
Interestingly, a closer investigation of the 940 agents revealed that
almost half of them modulate only 40 targets (Figure 2). For ex-
ample, we found 164 agents targeting PD-1 or PD-L1 (PD-1/L1),
with 50 clinical-stage agents targeting PD-1/L1, 34 of which are
monoclonal antibodies (Figure 3). This confirms our assumption
of significant duplication, despite the fact that five anti-PD-1/L1
monoclonal antibodies have already been approved [9].
Although it is still unclear if targeting the PD-1 receptor or its lig-
and PD-L1 will result in any differences in efficacy and safety,
none of the agents or studies in our database show any head-to-
head evaluation in patients. In another example, agents targeting

Volume 29 | Issue 1 | 2018 doi:10.1093/annonc/mdx755 | 85

Review Annals of Oncology
Clinical
T-cell targeted immunomodulator agent count
99
Other immunomodulator
170
Cancer vaccine
344
Cell therapy Clinical stage
Approved 224
Oncolytic virus Phase III
Phase II 69
Phase I/II
CD3-targeted bispecific antibody Phase I
Preclinical & Discovery 34
350 300 250 200 150 100 50 0 50 100 150 200 250 300 350
Number of agents

Figure 1. The overview of 2004 immuno-oncology (IO) agents. Six classes of IO agents are identified on the basis of different mechanisms of
actions.

Target
Unspecified TAA
CD19
PD-1
HER2
NY-ESO-1
PD-L1
CD20
CD40
EGFR
CSF1R
GD2
WT1
IFNAR1
MUC1
PSMA
TERT
Survivin
HPV E6
Personalization
BCMA
CEA
LAG-3 Therapy type
OX40
TLR T-cell targeted immunomodulator
TLR7
CD123 Other immunomodulator
GITR
GPC3 Cancer vaccine
HPV E7
IDO1 Cell therapy
IL2
mesothelin Oncolytic virus
PSA CD3-targeted bispecific mAb
TLR9
CD22
CD30
CD47
MAGE-A3
ADORA2A
CD25
0 10 20 30 40 50 60 70 80 90 100 110 120
Number of clinical agents

Figure 2. The top 40 targets with the most clinical-stage immuno-oncology agents. Unspecified tumor-associated antigen is defined as the
target of unspecified antigens from either individual patients and cell lines. In this sense, therapies against this target mainly consist of cell
line-based vaccines, autologous tumor vaccines, autologous DC vaccines, and tumor-infiltrating T-cell therapies. Personalization is defined as
the targets discovered by algorithm-based approaches from, e.g. the individual patients’ tumor samples or blood circulating DNA.

unspecified tumor-associated antigens (unspecified TAA) rep-
resent the largest number of clinical IO agents. There are now
114 agents in the clinic, 98 of which are cancer vaccines. Of the
114 unspecific TAA-targeted IO agents, only sipuleucel-T (an au-
tologous dendritic cell vaccine) has been approved for prostate
cancer [10]. This number of agents raises questions on efficien-
cies of resources and, importantly, the patients who enroll into
clinical trials. The concentration of IO development and patient
resources on a few targets, some with already approved drugs,
could potentially be stalling future innovation. Rather, investing
these precious resources more efficiently could help accelerate
needed progress in finding cures to this deadly disease.
Rapid proliferation of CAR-T-cell therapy, especially in China.
CAR-T-cell therapy has delivered unprecedented results, with
two recent approvals of CD19-targeted CAR-T-cell therapies
[11, 12]. CD19 is also the most common CAR-T target, with
56 clinical-stage therapies against it (supplementary Table S3,
available at Annals of Oncology online). Surprisingly, by interrog-
ating our IO drug database, we found 291 different CAR-T thera-
pies, with 162 of them being tested clinically. These agents are
being developed by 136 different companies and academic cen-
ters. Interestingly, companies and academic centers from China
seem to lead the total number of clinical-stage CAR-T therapies,
with 98 clinical-stage agents owned by 46 companies from China

86 | Tang et al. Volume 29 | Issue 1 | 2018

Annals of Oncology Review
compared with 51 clinical agents owned by 22 companies from The landscape of anti-PD-1/L1 combination trials
the United States, with a much smaller number in other countries
combined (Figure 4 and supplementary Table S4, available at Trends in the landscape of 1105 PD-1/L1 combo therapy trials.
Annals of Oncology online). Despite the approval of five anti-PD-1/L1 antibody agents, our
database shows that there are numerous clinical trial programs
120 114
that are ongoing and actively recruiting patients. The clinical-stage
PD-1/PD-L1 agents are evaluating clinical questions across 1502
100 different studies. Of these, 1105 are combination trials that com-
Molecule type
bine anti-PD-1/L1 agents with other IO therapies, targeted thera-
Monoclonal antibody
Number of records

80
Bispecific antibody pies, chemotherapies, radiotherapies, or chemoradiotherapies. It is
Small molecule worth noting that 49 of the combination trials are testing agents
60 Other biologic that have not been approved, whereas the majority of combination
trials focus on the five approved agents (Figure 5).
40
30
20 Fragmentation and lack of coordination in PD-1/L1 combination
9 5 trial landscape. A deeper analysis of the 1105 trials reveals some
3 3
0 interesting observations. First, there has been a rapid increase in
Preclinical & Phase I Phase I/II Phase II Phase III Approved
Discovery new combination studies in the past 5 years. Analysis of our data-
base shows that in 2017 alone, 469 new studies were started, with a
Figure 3. The overview of 164 anti-PD-1/L1 agents. Of note, 164 target enrollment of 52 539 patients (Figure 6). Second, agents
agents are currently in development, 50 of whom are in clinical against 165 different targets are being combined with anti-PD-1/L1
stages. agents (supplementary Table S5, available at Annals of Oncology

China Clinical agent count

98

US
Clinical stage
51 Approved
Phase III
Other
Phase II
13 Phase I/II
Phase I
80 60 40 20 0 20 40 60 80 100 Preclinical & Discovery
Number of agents

Figure 4. The landscape of CAR-T-cell therapy. China leads the total number of clinical-stage CAR-T-cell therapies, whereas United States has
the largest number of preclinical agents.

399 Combination type

400
IO
Targeted
350 340
Chemotherapy
Radiotherapy
300 Chemoradiotherapy
Multi-way combo
Number of total trials

250

200
161
150
124

100

49
50 32

0
Pembrolizumab Nivolumab Durvalumab Atezolizumab Avelumab Others

Figure 5. Analysis of PD-1/L1 combination trial types. The majority of combination trials focus on the five approved agents. Combination
with other immuno-oncology agents, targeted therapies, and chemotherapies are the top common strategies.

Volume 29 | Issue 1 | 2018 doi:10.1093/annonc/mdx755 | 87

Review Annals of Oncology
Trial start year 2009 2010 2011 2012 2013 2014 2015 2016 2017
Clinical phase
Phase 4
Phase 3
Phase 2
Phase 1/2
Phase 1

Number
1 5 2 13 20 58 190 329 469
of new trials
Planned new
136 2473 582 4867 5031 11 276 39 821 46 153 52 539
enrollment
Planned
enrollment 136 495 291 374 252 194 210 140 112
per new trial

Figure 6. The rapid increase of new anti-PD-1/L1combination trials in the past 5 years. The size of the bubble correlates to the target enroll-
ment of patients. Multiple bubbles of the same color represent multiple cancer types that are being tested in these trials.

Numbers of trials using common combo strategies:

1. Anti-CTLA-4 agents: 251

2. Chemotherapies: 170

3. Radiotherapies: 64

4. Anti-VEGFA agents: 43

5. Chemoradiotherapy combos: 42

Figure 7. The landscape analysis of targets of anti-PD-1/L1 combination trials. The size of the bubble correlates to the number of trials.

online). Many of these studies we observed have significant over-
lap and duplication of the combination partner targets. For in-
stance, anti-CTLA-4 agents and chemotherapies are the two
most prevalent classes of therapies being combined with anti-
PD-1/L1 agents, with 251 and 170 studies, respectively (Figure
7). This could possibly be driven by the evidence of preclinical
synergy of the combination [13], or the recent approvals of anti-
PD-1/anti-CTLA-4 combination for advanced melanoma and
anti-PD-1/chemotherapy combination as the first-line treat-
ment of advanced non-small-cell lung cancer (NSCLC) [14, 15].
However, it should be questioned if 251 and 170 studies are
needed to answer clinically relevant questions. Other prevalent
combination partners are anti-VEGF agents (predominantly
with bevacizumab) and radiochemotherapy, with some having
already shown clinical benefits [16]. This wide coverage of dis-
tinct targets, in our opinion, reflects a fragmented and uncoor-
dinated approach to drug development across the anti-PD-1/L1
combination trial landscape.
New trial designs should be considered for IO
development
Breakthrough treatments sooner. The early activity observed with
anti-PD-1/L1 agents across multiple tumor types has accelerated
the use of novel trial designs, several of which have led to regula-
tory approvals. There are several examples of novel study designs
where drugs have leaped through the drug development phases:
from first-in-human, dose selection, safety, efficacy, biomarker
selection, all the way to regulatory approval, in one single study.
Particularly, the proliferation of agents has resulted in a competi-
tive drug development landscape with a need to answer clinical
questions faster within a shorter timeframe by using these novel
trial designs. One example is KEYNOTE-001, a phase I trial that
led to two FDA approvals, one in melanoma and the other in
advanced NSCLC [17]. Moreover, the PD-L1 biomarker was
evaluated and confirmed all within the same study. KEYNOTE-
001 is arguably the largest phase I trial, which finally recruited

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Annals of Oncology
1245 patients. Its adaptive design allowed the trial to seamlessly
transition from generating safety data to producing regulatory
submission-quality efficacy data rather than starting separate
studies for each clinical question [17]. Speed of development was
also demonstrated in this innovative trial design. In <4 years,
KEYNOTE-001 went from IND filing to the approval of pembro-
lizumab for ipilimumab-resistant metastatic melanoma [18].
One year after the first approval, results from this same trial led to
the second approval in advanced NSCLC [19].
Another example of novel study design involves biomarker-
based, histology-agnostic basket trial design. It was known that
tumors with high level of microsatellite instability (MSI-H) or
deficiency in mismatch DNA repair (dMMR) have very high level
of nonsynonymous mutations and high immunogenicity, which
associates with a high response rate to anti-PD-1 therapy [20,
21]. In KEYNOTE-059, a phase II basket trial, patients with solid
tumors tested positive with MSI-H or dMMR were enrolled, re-
gardless of their cancer types. Indeed, 149 enrolled patients with
MSI-H or dMMR tumors demonstrated a 39.6% objective re-
sponse rate, which led to the first histology-agnostic approval of a
cancer treatment in the United States [22]. Notably, most ap-
provals in IO today are based on unprecedented benefit–risk
ratios, with results from relatively small datasets. However, most
of these early approvals in the United States are accelerated
Number of trials
(1105 in total)
49 693
450
655
Sponsorship
Non-industry-sponsored trials
Industry-sponsored trials
Figure 8. Comparison of total trial numbers and target enrollment be-
tween industry-sponsored and non-industry-sponsored anti-PD-1/L1
combination trials.
Average target enrollment per new trial
400
300
200
100
0 0
2009
Figure 9. Comparison of average target enrollment between trials with different sponsorship.
Volume 29 | Issue 1 | 2018
Review
approvals (FDA sub-part H), which require confirmatory trials
to validate the results [23, 24]. These novel trial designs, coupled
with highly flexible and cooperative attitudes from regulators
globally have significantly accelerated the delivery of innovative
and clinically beneficial immunotherapies to patients with
cancer.
A notable shift in study sponsorship from
companies to investigators
Rapid increase of investigator-initiated trials in the early develop-
ment cycle. Traditionally, companies conduct most early- and
mid-stage development of a compound themselves—through
multicenter, industry-sponsored trials. Once the agent is closer to
regulatory approval, the companies would allow more ‘investiga-
tor-initiated’ exploratory studies to be conducted. However, for
IO agents, our analysis shows that this traditional development
paradigm is no longer followed. First, we found that of the 1105
anti-PD-1/L1 combo trials, 60% (655 out of 1105) are sponsored
by non-industry sources, such as individual academic centers,
government agencies, collaborative groups, or nonprofit entities
(Figure 8). Investigator-initiated studies are deemed more ex-
ploratory and have an enrollment target of 76 patients per trial on
average, compared with 257 patients per industry-sponsored trial
(Figure 9). Furthermore, as most of the investigator-initiated tri-
Planned enrollment als are being conducted at single centers, it is unrealistic that these
(1 65 215 in total)
655 non-industry trials will ever achieve the overall target enroll-
ment of 50 000 patients (Figure 8). This enormous recruitment
target, in our opinion, is also a challenging hurdle with many du-
plicate questions being addressed and limited patient resources.
1 15 522 Summary and discussion
In summary, the current clinical landscape of IO presents enor-
mous enthusiasm from academia and industry, which is exempli-
fied by 940 clinical-stage IO agents, 3042 immunotherapy trials,
and 1 105 anti-PD-1/L1 combination trials. The field is very
promising and has the potential to deliver many breakthroughs
to change the standard of care of many cancer types. However, it
is also very crowded, fragmented, and uncoordinated with
Industry-sponsored trials 700
Non-industry-sponsored trials
600
Number of new trials
500
400
300
200
100
2010 2011 2012 2013 2014 2015 2016 2017
doi:10.1093/annonc/mdx755 | 89
Review
significant duplication. Our research has identified and con-
firmed several opportunities and challenges: many IO agents
concentrate on a few targets such as PD-1; anti-PD-1/L1 combin-
ation trial space is very fragmented and uncoordinated; trad-
itional trial designs are not suited for the fast-changing landscape
of clinical IO development; and a significant proportion of the
increase in studies can be attributed to investigator initiated IO
trials—small, single-center trials that may fail to recruit enough
patients and produce high-quality results. We now discuss several
ongoing trends that could address these challenges.
There are clear limitations to traditional trial designs, namely
single-center studies and the pursuit of the same biological targets
by multiple companies. From our research of the IO landscape,
there is an urgent need to enhance efficiencies. In a recent publi-
cation led by the FDA, the authors provided an eloquent sum-
mary and examples of collaborative and novel trial designs,
which could allow more questions to be answered more effi-
ciently in a single multicenter trial [25]. These umbrella, basket,
or platform designs create a unique opportunity to drive collab-
oration, coordination, and accelerated innovation.
Although many biopharmaceutical companies are adopting
such study designs, they still tend to include drugs only from their
own portfolio. The nonprofit and public sectors can play an im-
portant role in facilitating and conducting these innovative trials
across multiple companies and research centers. There are now
several examples of nonprofit organizations leading these novel
study designs that have made significant contributions to the
field. Notably the I-SPY program for breast cancer [26] is a
unique nonprofit-led collaborative that has recruited over 1000
patients and has graduated multiple agents into pivotal develop-
ment. In another program, the LUNG-MAP for lung cancer [27]
was a multi-party collaboration between Friends of Cancer
Research, Foundation for NIH, National Cancer Institute, the
Southwest Oncology group, and multiple biopharmaceutical and
diagnostic companies. Despite a slow start and operational com-
plexities, the study is now open with multiple arms at hundreds
of sites. There is an opportunity to learn from these experiences
and apply them to future collaborative opportunities to help
avoid further fragmentation and duplication.
Public IO-focused information hubs would help coordinate ef-
forts, optimize research resources, and identify rising opportuni-
ties in the field. In basic research, the online cancer-immunity
cycle (https://cancer-immunity.nature.com/pages/map), which
evolved from a recent landmark review paper, serves as a central-
ized information hub for new IO targets and factors that affect
tumor immunology [28]. In clinical development, we realized the
urgent need of an updated, scientifically curated landscape for
the clinical IO community. Along with this publication, we will
make all related resources available on CRI’s website (www.can
cerresearch.org/IO-landscape). These analyses will be updated on
a quarterly basis. Working with the IO community, we aim to
build an unbiased, neutral, comprehensive information hub for
clinical IO.
Conclusion
It is probably the best time for progress in oncology in the past
decades. The historic opportunity would be maximally capital-
ized if people from academia, industry, regulatory agencies, and
90 | Tang et al.
Annals of Oncology
nonprofit organizations work together. This cross-sector collab-
oration, deep commitment to following the science, and adopting
novel study design would be the best ways to bring the true prom-
ise of cancer immunotherapies to patients, sooner than later.
Methods
All the information collected for these analyses came from publicly avail-
able sources, press releases, quarterly reports, web-based company pipe-
lines, news alerts, and GlobalData (London, UK). All data were manually
curated and analyzed using Tableau Software (v10.4).
Acknowledgement
The authors would like to thank the generous donors to the
Cancer Research Institute, particularly those who give philan-
thropically to the Anna-Maria Kellen Clinical Accelerator, espe-
cially Michael Kellen.
Funding
None declared.
Disclosure
JT and VHL have nothing to disclose. AS has an advisory role
with AstraZeneca.
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