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Cancer cell therapy

NK CELLS ‘Off-the-shelf’
An emerging addition to the allogeneic CAR T cells
cancer immunotherapy arsenal Development and challenges
 N E W S & A N A LY S I S

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From The an\\376\\377\\000alys\\376\\377\\000t’s cou\\376\\377\\000ch

Trends in clinical development

for PD-1/PD-L1 inhibitors
Jia Xin Yu, Jeffrey P. Hodge, Cristina Oliva, Svetoslav T. Neftelinov,
Vanessa M. Hubbard-Lucey and Jun Tang

PD-1/PD-L1-targeted monoclonal antibodies Compared with our first survey conducted in
(mAbs) are now the standard of care September 2017, there are 1,469 more active
for 16 different types of cancer and clinical trials, which cover most cancer types,
tissue-agnostic indication. Since our first and span across all lines of therapies (Fig. 1).
PD-1/PD-L1 trial landscape survey conducted At present, 76% of the active trials are
in September 2017 (Ann. Oncol. 24, testing combination regimens of PD-1/PD-L1
84–89; 2019), 23 additional approvals have mAbs with other cancer therapies, such
been granted to PD-1/PD-L1 mAbs by the as immuno-oncology therapies, targeted
FDA, and 4 new PD-1 mAbs have reached therapies, chemotherapies or radiotherapies.
the market, bringing the total on the global The shift from monotherapy to combination
market to 9. These achievements were therapy in the clinical trial space in
powered by some of the largest clinical trial recent years has resulted in 14 approvals
programmes ever in oncology. This report of combination therapies by the FDA.
analyses the current landscape of clinical Importantly, in the past two years, two new
trials evaluating mAbs against PD-1/PD-L1. combination strategies received approval —
the combination of a PD-1 mAb and targeted
PD-1/PD-L1 mAb clinical trial trends therapy for kidney cancer and endometrial
Since 2006, 3,362 trials have been launched cancer, and the combination of a PD-1 mAb,
to test PD-1/PD-L1 mAbs alone or in targeted therapy and chemotherapy for
combination with other agents, and 2,975 lung cancer.
of them are still active as of September 2019, We found that 295 other drug targets
planning to recruit over 500,000 patients. are being tested in combinations with
PD-1/PD-L1 inhibitors, an increase of
136 targets in 2 years (Supplementary Fig. 1).
The three most common combinations
in the past 2 years are with chemotherapy
(235 new trials), CTLA-4 mAbs (186 new
trials) and therapies that target the vascular
endothelial growth factor (VEGF) axis
(114 new trials) (Fig. 2). This combination
was the basis of four recent approvals
by the FDA: two for kidney cancer
(pembrolizumab plus axitinib, and avelumab
plus axitinib), one for endometrial carcinoma
(pembrolizumab plus lenvatinib) and
one for non-small-cell lung cancer
(atezolizumab, bevacizumab and
chemotherapy), suggesting a potential broad
utility of this combination strategy.
PD-1/PD-L1 trial size gets smaller
In terms of trial design, the average number
of planned patient enrolments per trial has
declined in the past 6 years from 429 patients

900 873
Immuno-oncology
807 Targeted therapy
800
180 Chemotherapy
700 Radiotherapy
299 Chemoradiotherapy
Number of active trials

600 175 Multi-way combo

558
Others
500 86 Monotherapy
147 432 121 * Approved in China only
114
400 383

62 169 65 323 82
300 92 32
100 270
55 57
35 36
53 51
200 124 187 63
38 45 161 158
71 54
71 38 30
100 217 29 67
159 142 75 40 70
45 38 46 14
92 32 16
45 46 58 29 45 10 3 2
0
2017 2019 2017 2019 2017 2019 2017 2019 2017 2019 2017 2019 2017 2019 2017 2019 2017 2019 2017 2019
ab

ab

ab

ab

ab

ab

x
ab

ab

ab

PD
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um

um

lim

im

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izu

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er
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izu
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al

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nt
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Fig. 1 | The landscape of PD-1/PD-L1 inhibitor clinical trials in 2017 and 2019. Four new PD-1 monoclonal antibodies (mAbs) have been approved
in the past 2 years (cemiplimab, sintilimab, toripalimab and camrelizumab), adding to the five mAbs targeting PD-1 or PD-L1 already on the market.
There were 2,975 active trials involving PD-1/PD-L1 mAbs in September 2019, compared with 1,506 in September 2017.

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N E W S & A N A LY S I S

4-1BB Chinese cancer patients do not receive

CD38
WT1 CD73 TLR9 PD-1/PD-L1 mAbs, which means the country
CD40 CD47
CD19 7 has the largest number of patients who are
TLR Neo- CDK4/
TIM-3 7 antigen Chemoradio CDK6 CSF1R eligible to join clinical trials.
Radiotherapy 48 Indeed, the clinical development of
TOP1 PI3K 9
MUC1 92
GITR 9 the three China-derived marketed PD-1
9
FGFR KIT PARP mAbs (sintilimab, toripalimab and
9 41 camrelizumab) by Chinese companies
CD20 was rapid (26–45 months) compared with
9
the rest of the approved PD-1/PD-L1
OV mAbs, which was aided by the fast patient
10 TAA
31 recruitment for these clinical trials. As China
Chemotherapy CTLA-4
235 186 recently joined the International Council for
MEK
11 Harmonisation of Technical Requirements
for Pharmaceuticals for Human Use (ICH),
IL2R IDO1 data generated from trials in China may
12 26 support market applications in other ICH
HDAC member countries. The global PD-1/PD-L1
HER2
12 19 FGFR1 trial community should make use of this
RTK EGFR
LAG-3 precious patient resource to accelerate
14 18 AMPK
IDH1 14 VEGFR-axis clinical development.
114 RAF
OX40 AXL ERK1/2 PSMA
BRAF
Vaccine Conclusion
BTK 15 The PD-1/PD-L1 mAb clinical trial
landscape continues its growth by adding
more trials, combination targets and cancer
Fig. 2 | Analysis of new combination trials with PD-1/PD-L1 inhibitors started in the past
types. The convergence of innovation
2 years. The number of clinical trials for the therapy types and targets with 7 or more trials is
indicated in the labelled circles. The most popular combination is with chemotherapy, followed by
across various disciplines in this space
CTLA-4 inhibitors, and then trials targeting either vascular endothelial growth factor (VEGF) or its has generated many practice-changing
receptor VEGFR. OV, oncolytic viruses; TAA, tumour-associated antigen. therapeutic regimens for patients. As the
field is shifting to combination therapies,
there is a need to develop an effective
per trial on average in 2014 to 129 patients Italy, Japan, Spain and the UK), and the biomarker for each combination strategy
per trial in 2019 (Supplementary Fig. 2). Asia-Pacific area (Australia, Hong Kong, to identify responding patients. In addition,
This decline in trial size is associated with Korea, New Zealand, Taiwan and Thailand) as most patients treated with the approved
a decrease in the number of new trials that by using the patient recruitment rate of PD-1/PD-L1 mAb regimens develop
target major cancer types such as melanoma, 629 clinical sites from 55 completed or resistance or relapse, the field should
breast cancer and kidney cancer, as well ongoing PD-1/PD-L1 clinical trials managed pay more attention to the development
as lung cancer. By contrast, more trials are by IQVIA. The USA has the lowest patient of novel combinations that address
targeting rare cancer types, which have a recruitment rate, probably owing to the PD-1/PD-L1 resistance. These novel
much smaller eligible patient population highest penetration of PD-1/PD-L1 mAbs biomarkers and therapies will need to
(Supplementary Fig. 3). as standard of care. By contrast, the patient be tested in clinical trials that require
recruitment rate in China is almost six times enrichment of sub-populations of patients.
China has the highest recruitment rate higher for monotherapy trials and about The large number of available patients in
We calculated the median patient recruitment four times higher for combination therapy emerging markets could support faster
rate per clinical site in the USA, China, than in the USA (Fig. 3). China has more than enrolment in trials, which would ultimately
six other major markets (France, Germany, 4 million new cancer cases per year and most bring more effective PD-1/PD-L1 therapies
to more patients worldwide.
Jia Xin Yu1, Jeffrey P. Hodge2,
1.50 Cristina Oliva2, Svetoslav T. Neftelinov2,
1.50
Median recruitment rate
(patients/site/month)

Vanessa M. Hubbard-Lucey1 and Jun Tang1*

1.02
1
Anna-Maria Kellen Clinical Accelerator, Cancer
1.00 Research Institute, New York, NY, USA.
2
IQVIA, Durham, NC, USA.
0.50 *e-mail: jtang@cancerresearch.org
0.30 0.23 0.36 Mono
0.22 0.21 0.24 https://doi.org/10.1038/d41573-019-00182-w
Combo
0.00 Competing interests
US China 6 major markets Asia-Pacific V.M.H.-L. is an unpaid scientific advisor and holds equity in
FX Biopharma. The other authors declare no competing
Fig. 3 | The median patient recruitment rate for trials of PD-1/PD-L1 inhibitors in interests.
different countries or regions. The six major markets are France, Germany, Italy, Japan,
Supplementary information
Spain and the UK. The Asia-Pacific area includes Australia, Hong Kong, Korea, New Zealand, Supplementary information is available for this paper at
Taiwan and Thailand. https://doi.org/10.1038/d41573-019-00182-w

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IQVIA Author Biographies

Cristina Oliva, MD, Vice President, Head of Oncology Center of Excellence, IQVIA
A board-certified medical oncologist licensed in UK and Italy, Cristina Oliva joined IQVIA
in 2016 with nearly 20 years of global pharmaceutical drug development experience from
first-in-human to Phase IV trials. In various oncology R&D roles in small to large biophar-
maceutical companies, Dr. Oliva led development of cytotoxics, targeted small molecules
and biologics. She has 12 years of clinical experience at major research institutes across
Europe and more than 100 publications in oncology.

Jeffrey P. Hodge, Vice President, Development Solutions, Oncology Center of Excellence, IQVIA
Jeff Hodge has more than 25 years of oncology drug development experience, with a
focus on early phase development. He joined IQVIA in 2010 after more than 15 years
at GlaxoSmithKline where he was involved in 10 INDs and 5 NDAs. Jeff holds MS and BS
degrees in Medical Microbiology and Bacteriology from Virginia Tech; he has published
more than 90 abstracts and peer-reviewed papers and presents at international oncology
meetings.

Svetoslav T. Neftelinov, Associate Director, Global Feasibility, IQVIA

Before joining IQVIA in 2008, Svetoslav Neftelinov earned a Doctor of Medicine degree
from Medical University – Sofia, Bulgaria. With roles in country feasibility and then global
feasibility, Dr. Neftelinov now manages the development of global clinical trial strategies,
applying data and advanced analytics to target countries, sites and patients.

03.2020.RDS