GLYCOBIOLOGY Clinical impact and opportunities for drug discovery - Natural products in drug discovery - IQVIA
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March 2021 volume 20 no. 3 www.nature.com/nrd GLYCOBIOLOGY Natural products in Clinical impact and opportunities drug discovery for drug discovery Advances and opportunities
N E W S & A N A LY S I S
T R I A L WAT C H of 2014 or later (Supplementary Fig. 2).
We found that the older trials have progressed
Combinations take centre
to an ‘active, not recruiting’ phase, indicating
finished recruitment or a completed study,
whereas most trials starting from 2017 are
stage in PD1/PDL1 inhibitor in the ‘not yet recruiting’ or ‘recruiting’
phase. Notably, since 2017, the number of
clinical trials
trials in these two phases is greater than the
number of trials completed. This coincides
with the peak of new monotherapy trials in
2017 (197), whereas combination trials
Targeting the PD1 and PDL1 immune matched the 2-year growth between 2017 continue to increase every year, comprising
checkpoint axis has paved the way for a new and 2019 (1,539 trials, Supplementary Fig. 1). nearly 90% of all PD1/PDL1-targeted trials
era of clinical care in cancer. Of the existing Interestingly, the number of clinical (Fig. 2). Accordingly, the average planned
immuno-oncology (IO) agents in clinical trials assessing mAbs that are in clinical patient enrolment per monotherapy trial has
development, anti-PD1 and anti-PDL1 development but not yet FDA approved declined more than 500% in the past 7 years
monoclonal antibodies (mAbs) have achieved (Supplementary Fig. 1, Other PDx) shows from 854 in 2014 to 131 in 2020 (Fig. 2).
the most success. Indeed, there are ten the largest growth, notably in combination By contrast, the average planned patient
approved anti-PD1/PDL1 mAbs in the global with other therapies, indicating a robust enrolment per combination trial has
market, six of which are approved by the clinical development pipeline concentrated declined by only 40%, from 187 in 2014 to
FDA. To date, these mAbs have garnered a in anti-PD1/PDL1 combination treatment 111 in 2020. The overall decrease in planned
total of 67 FDA approvals across 17 different modalities. When we further analysed the enrolment may reflect a shift towards
cancer types and two tissue-agnostic landscape of anti-PD1/PDL1 therapies, increased biomarker-based patient selection,
conditions. This report summarizes the we found that 2,949 out of the 3,674 active which may slow recruitment and decrease
current landscape of anti-PD1/PDL1 mAb trials (80%) are testing combination trial size.
clinical trials and the challenges in patient regimens of anti-PD1/PDL1 mAbs with
recruitment. other cancer therapies, including IO Global trends in patient recruitment
therapies, targeted therapies, chemotherapies In our previous analyses, we calculated
Clinical trial growth doubled in 2020 and radiotherapies. Therefore, the growth the median patient recruitment rate (RR)
As of our current update in September 2020, in the number of combination trials has from clinical trial sites in the USA, China,
there are 4,400 clinical trials testing anti- outpaced the growth of trials assessing and major markets in Europe and the
PD1/PDL1 mAbs, 3,674 of which are active anti-PD1/PDL1 monotherapies in all stages Asia-Pacific area (Nat. Rev. Drug Discov. 19,
(Fig. 1). Compared with our first analysis of development. 163–164; 2020), and found that China had
conducted in September 2017, this represents the highest RR in both monotherapy and
a threefold increase in the total number Monotherapy trials are declining combination anti-PD1/PDL1 mAb clinical
of clinical trials testing anti-PD1/PDL1 To better understand the increased activity trials. To update the previous analysis
mAbs. Remarkably, the growth in the in anti-PD1/PDL1 mAb trials, we tracked (2019) and ascertain the current RR
past year, 2019–2020 (1,358 trials), has almost the status changes in trials with a start date globally, we acquired and analysed
1,200
1,199 Combination type
Immuno-oncology
1,078 Targeted therapy
258 1,030
Chemotherapy
1,000 Radiotherapy
396 156
Chemoradiotherapy
Multiway combo
Number of clinical trials
800 274 Others
Monotherapy 237
600 557 166
195
87 195
432 96 458
113 78 390
400 135
64
97 79 167 98
170 73 98
59 185 198
200 160 65
262 69 72 256
179 87 70 90
160 91 47
60 79 9
0
2017 2020 2017 2020 2017 2020 2017 2020 2017 2020 2017 2020 2017 2020
Pembrolizumab Nivolumab Durvalumab Atezolizumab Avelumab Cemiplimab Other PDx
Fig. 1 | The landscape of anti-PD1/PDL1 mAb clinical trials in 2017 and 2020. As of September 2020, there are 4,400 clinical trials assessing
anti-PD1/PDL1 mAbs, nearly tripling since September 2017. Other PDx includes any anti-PD1/PDL1 mAbs without FDA approvals.
168 | March 2021 | volume 20 www.nature.com/nrd
N E W S & A N A LY S I S
900 with VEGF/VEGFR-targeted therapies is
Average planned enrolment per trial per year
854.2 Therapy type
Number of PD1/PDL1 trials started per year
900
800 the top combination treatment modality
Combo
800 Mono (154 new trials), surpassing chemotherapy
700
700 (145 new trials) and anti-CTLA4 (64 new
600 trials) (Supplementary Fig. 5). Based on the
600
500
number of new trials started in the past year,
687 788
500 577 751 emerging therapies of interest for the future
395.9 400 may lie in combinations with approved
400
300
355 300 therapies such as PARP inhibitors, as well as
219.7 197.1 rising IO targets and agents such as TIGIT,
186.6 161.0 155.5
200 149.8 200
131.0 TGFβ/TGFR, TLRs, oncolytic viruses and
205
100 150.8 122.8 132.0 135.2 100 cancer vaccines.
69 111.5
0 41 74 141 197 184 135 91 0
2014 2015 2016 2017 2018 2019 2020* Conclusions
Year Our analyses of the anti-PD1/PDL1 clinical
trials landscape during the past 3 years have
Fig. 2 | Comparison of monotherapy and combination trials. Most new trials since 2014 have
revealed a continued interest and increased
been combination trials (bar graphs). The average planned patient enrolment (line graph) has
decreased since 2014 for monotherapy trials more than for combination trials. *Only data from the growth beyond monotherapy trials to
first three quarters of 2020 were used to generate the analysis. combination trials targeting more pathways.
Development outside of FDA-approved
agents has risen dramatically since our
patient recruitment data from New combination strategies first report in 2017 and is quickly joining
200 additional unique clinical sites As the landscape of anti-PD1/PDL1 clinical the hunt for promising new combinations.
and 11 additional IQVIA-run clinical trials. trials moves towards combination strategies, Consistent with findings from our previous
We found that, in the past year, RR which may be more efficacious, we examined analyses, combination trials have taken over
in anti-PD1/PDL1 monotherapy trials the targets pursued by such modalities. new clinical development, and the field
decreased globally, with China showing Our analysis revealed that 253 drug target has shifted from using chemotherapy and
the greatest drop (41%) (Supplementary groups (excluding PD1/PDL1) are being anti-CTLA4 combinations to other targeted
Fig. 3). By contrast, RR in anti-PD1/PDL1 tested, which represents an increase of approaches such as angiogenesis-targeted
combination trials in China saw an 129 new target groups in the past 3 years agents and novel IO–IO combinations to
increase of 18%, whereas RR largely (Supplementary Fig. 4). The trend in bypass resistance mechanisms that prevent
decreased or stayed the same in all other anti-PD1/PDL1 combination trials over greater anti-PD1/PDL1 efficacy. Although
regions. These RR trends are consistent the past decade showed VEGF/VEGFR- our datasets indicate a robust growth in
with a shift from monotherapy trials targeted therapy, chemotherapy and anti-PD1/PDL1 clinical trials, we did observe
to combination trials that may be CTLA4-targeted therapy as top combination a fall in patient recruitment rates globally
more patient selective. Overall, China strategies, where the former two showed and a stall in the completion of enrolment
still maintains the highest RR in both a continued steep upward trend in the for newer trials. The COVID-19 pandemic
monotherapy and combination trials, number of trials started per year (Fig. 3). has touched virtually all aspects of life and
and the global RR drop in most Indeed, a closer analysis of trials started its potential impact on the anti-PD1/PDL1
trials could be a result of the timing in the first three quarters of 2020 revealed clinical pipeline is yet to be fully realized.
of the COVID-19 pandemic. that combination of anti-PD1/PDL1 mAbs As such, it is reasonable to believe that
the pandemic could have played a part in the
Target decreased patient enrolment and stalls in
160 trials. Ongoing assessments of the landscape
Number of PD1/PDL1 trials started per year
VEGF/VEGFR
Chemotherapy will be crucial to identify future new trends in
140 CTLA4
Radiotherapy
the field and its effect on patients.
120 Chemoradio Samik Upadhaya1, Svetoslav T. Neftelino2,
PARP Jeffrey P. Hodge2, Cristina Oliva2, Jay R. Campbell1
100 Cancer vaccine
HER1/HER2/HER3 and Jia Xin Yu1 ✉
80 TIGIT 1
Cancer Research Institute, New York, NY, USA.
Oncolytic virus 2
IQVIA, Durham, NC, USA.
TGFβ/TGFβR
60
TLRs ✉e-mail: jyu@cancerresearch.org
EGFR https://doi.org/10.1038/d41573-020-00204-y
40 HDAC
LAG3 Competing interests
20 CDKs The authors declare no competing interests.
Neoantigens
0 IL-2/IL-2R Supplementary information
2011 2012 2013 2014 2015 2016 2017 2018 2019 2020* IL-15/IL-15R Supplementary information is available for this paper at
CD19 https://doi.org/10.1038/d41573-020-00204-y.
Year
Fig. 3 | Main targets assessed in combination with anti-PD1/PDL1 mAbs. The graph shows Related links
the number of combination trials starting each year since 2011. The main 20 targets assessed in CRI: PD-1/PD-L1 landscape: https://www.cancerresearch.
combination are shown in descending order according to the number of trials started in 2020. org/scientists/immuno-oncology-landscape/pd-1-pd-l1-
landscape
*Only data from the first three quarters of 2020 were used to generate the analysis.
Nature Reviews | Drug DisCovery volume 20 | March 2021 | 169
https://doi.org/10.1038/d41573-020-00204-y Supplementary information Combinations take centre stage in PD1/PDL1 inhibitor clinical trials In the format provided by the authors Nature Reviews Drug Discovery | www.nature.com/nrd
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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.
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