WHITE PAPER
—TRENDS AND CHALLENGES
IN IMMUNO-ONCOLOGY
TRIALS
by Beth Kiernan
Immuno-oncology (I/O) is changing the way that we approach cancer therapy.
As precision medicine comes to the forefront, clinical researchers are beginning
to home in on tumors with targeted therapies, focusing on those that have been
previously resistant to treatment. This has been accomplished with chemical
agents in small cancer subsets; however, immunotherapy seeks to harness the
mechanisms of our own immune system to target cancer and its pathways.
INTRODUCTION
Although a relatively new approach, I/O has
developers eager for the possibilities – monoclonal
antibodies, checkpoint inhibitors, therapeutic
cancer vaccines, cytokines, and other classes
of immunotherapy drug candidates are filling
the pipelines of biopharma at a rapid pace.
Uncharted territories, however, come with
challenges, and immuno-oncology is seeing its
fair share. Researchers are struggling to identify
biomarkers that can predict drug response, while
regulatory bodies scramble to keep up with the I/O
momentum.
Fig. 1. Active and
commercially relevant
immuno-oncology trials by
class. Cortellis Clinical Trials
Intelligence, February 2,
2016.
67+19+14
Looking at more than 2,500 active and
commercially relevant I/O trials in CortellisTM
Clinical Trials Intelligence (greater than 1/3 of the
current neoplasm trials), we can see that 33% of
the clinical space is comprised of two innovative
classes of immunotherapies: therapeutic
cancer vaccines and checkpoint inhibitors (Fig.
1). Although therapeutic cancer vaccine trials
have steadily trended downward in the past five
years, particularly in the noncommercial space,
checkpoint inhibitors experienced a twenty-fold
increase in the number of commercially relevant
trials started in 2015 as compared to 2010.
ACTIVE, COMMERCIAL IMMUNO-ONCOLOGY TRIALS
14%
19%
67%
Monoclonal Antibodies
Checkpoint Inhibitors
Therapeutic Cancer Vaccines
THERAPEUTIC CANCER VACCINES
While therapeutic vaccine candidates have been
on the clinical scene for decades, studies have
not always been rewarding. The goal of eliciting
an active immune response against malignant
cells is often thwarted by the complexity of the
immune system itself; a fact that may not reveal
itself until in-patient trials. Cancer cells, too, have
mechanisms in place to remain undetected by
T-cells, adding a layer of difficulty to the preclinical
process. Although there are currently three cancer
prevention vaccines that have been approved
by the FDA, only one cancer treatment vaccine,
Dendreon’s Provenge (sipuleucel-T) for prostate
cancer, has been approved thus far. However,
clinical researchers are identifying novel ways to
overcome previous roadblocks. Diverse vaccine
strategies and modalities are being employed
across clinical development to follow up on the
success of Provenge.
There are currently 347 active, commercial clinical
trials for therapeutic cancer vaccines. At an
average of 1.85 trials per sponsor, it is apparent
that vaccine development comes at a cost. But
small to medium specialized biotech companies
and research institutions are taking the risk (Fig. 2).
TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY TRIALS PAGE 3
Fig. 2. Top 10 sponsors for
active, commercially relevant
trials for therapeutic cancer
vaccines. Cortellis Clinical
Trials Intelligence, February 2,
2016.
TRIALS BY PHASE
33
3
21
32
1
10
+
Fig. 3. Active, commercially
relevant therapeutic cancer
vaccine trials by phase
(postmarketing studies and
unreported phases are not
shown). Cortellis Clinical
Trials Intelligence, February 2,
2016.
Phase 3
Phase 0
Phase 2/3
Phase 1
Phase 2
Phase 1/2
While most cancer therapy vaccine trials are still in
early development, indicating continued interest
by biopharma, approximately 10 percent have
progressed successfully to late stage trials (Fig. 3).
Despite the long-awaited success of a therapeutic
cancer vaccine with Provenge in 2010, developers
are still facing limitations in designing trials.
This is true especially when it comes to patient
selection. Since vaccines are an active form of
immunotherapy, they require a healthy immune
system to work. However, patients who have
previously been treated with chemotherapy and/
or other agents often lack the ability to produce
a strong immune response due to a suppressed
system. Adding to that, cancer cells themselves
inherently suppress the immune system – a
mechanism that ensures their survival. So how
are researchers working around this? Adjuvants
and delivery vehicles are being employed to both
boost and control the immune response to the
antigen. Silently introducing them into the system,
however, can be tricky. In the case of a study that
measured the response of mice injected with a
gp100 melanoma peptide, the popular water-in-oil
emulsion method for vaccination worked against
the intended cause, as T-cells were directed to the
injection site instead of the tumor.1
TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY TRIALS PAGE 4
CHECKPOINT INHIBITORS
Checkpoint inhibitors have been garnering muchearned attention in the I/O space. While cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4) has
been targeted for immunotherapies for some time,
two relatively new targets have developers upping
their enthusiasm for the class: programmed
cell death 1 (PD-1) and programmed cell death 1
ligand 1 (PD-L1). Like CTLA-4, PD-1 is a receptor
on T-cells. It binds ligands PD-L1 and PD-L2 to
downregulate the immune system by preventing
the activation of T-cells. In certain neoplasms,
these proteins are upregulated, thereby
suppressing an immune response to cancer cells.
Checkpoint inhibitors block this mechanism,
allowing the immune system to “see” cancer cells
and launch an attack.
Big pharma and specialized biotech companies
are active in the space, with Bristol-Myers Squibb
(BMS) leading the way (Fig. 4). Following the
success of both Yervoy (CTLA-4) and Opdivo
(PD-1), BMS is working to expand their approved
use for other cancer types. They are also studying
KIR and LAG3 inhibitors as part of their I/O
pipeline, with lirilumab (anti-KIR) in phase 1 trials
and BMS-986016 (LAG3) having begun a phase
1 study in 2013. Roche’s pipeline is made up by
PD-L1 and IDO inhibitors (RG-7446 and RG-6078,
respectively), while AstraZeneca focuses on CTLA4 and PD-1/PD-L1, as reported in a PharmaTimes
article by Charlotte Jago of Thomson Reuters.2
Looking at the 482 active, commercially relevant
checkpoint inhibitor trials, there are approximately
3.52 trials per sponsor – almost twice that of
therapeutic cancer vaccines. PD-1 trials are seeing
an upswing following the positive results of
Opdivo and Merck’s Keytruda and now comprise
approximately 52 percent of current checkpoint
inhibitor trials (Fig. 5).
In the PharmaTimes article, Jago shows that
survival and overall response rates with Yervoy,
Opdivo, and Keytruda were increased or high,
compared to standard treatments. In fact, the
author states that Merck’s Keytruda data was so
promising that the drug was approved based on
phase 1 results alone from the KEYNOTE-001
study for metastatic melanoma.2
Fig. 4. Active, commercially
relevant trials for cancer
checkpoint inhibitors by
sponsor. Cortellis Clinical
Trials Intelligence, February 2,
2016.
TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY TRIALS PAGE 5
Fig. 5. Active, commercially
relevant checkpoint inhibitor
trials by action. Cortellis
Clinical Trials Intelligence,
February 2, 2016.
52+23+25
ACTIVE, COMMERCIAL CHECKPOINT INHIBITOR TRIALS
25%
52%
PD-1
PD-L1
CTLA-4
23%
Checkpoint inhibitor trial phases are practically
split down the middle, with approximately 52
percent in early phase and 48 percent in phase
2 and 3, indicating both an ongoing interest by
biopharma and successful progression into later
stage trials (Fig. 6).
TRIALS BY PHASE
32
15
20
32
1
+
Fig. 6. Active, commercially
relevant checkpoint inhibitor
trials by phase (postmarketing
studies and unreported
phases are not shown).
Cortellis Clinical Trials
Intelligence, February 2, 2016.
Lung tumors have surpassed melanoma as the
top cancer type being studied for commercial drug
development of checkpoint inhibitors. Looking
at the top patient segments in lung tumors,
melanoma, and solid tumors, it is apparent that
developers in the space have identified an unmet
need – those with late-stage or treatmentresistant cancers, where other drugs have failed
(Fig. 7).
Phase 3
Phase 0
Phase 1
Phase 2
Phase 1/2
TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY TRIALS PAGE 6
Fig. 7. Most common
patient segments in top
three conditions of active,
commercially relevant
cancer checkpoint inhibitor
trials. Cortellis Clinical Trials
Intelligence, February 2,
2016.
One caveat that researchers have discovered in
bringing checkpoint inhibitor candidates to trial is
that predictive and prognostic biomarkers, which
are necessary for proving efficacy and identifying
patient populations, are difficult to measure in
terms of response. This is particularly seen in trials
where PD-L1 is being reported as a biomarker
(39 percent of all checkpoint inhibitor trials using
biomarkers). Although high PD-L1 staining often
does correlate with a high response rate, no
staining does not necessarily mean that there will
be no response rate. Physiological biomarkers,
too, may have equal correlations. Looking at the
current biomarkers used in checkpoint inhibitor
trials, there are 1.23 biomarkers per trial on
average. PD-L1 is the most common biomarker
used in the top three conditions of checkpoint
inhibitor studies. Of those lung tumor studies
that use biomarkers, PD-L1 is measured in 56
percent. Epidermal growth factor is measured in
44 percent, and ALK tyrosine kinase is measured in
31 percent (Fig. 8).
Another challenge Jago highlights in the immunooncology paradigm article is that guidance
on studying two unapproved drug candidates
in combination trials has only recently been
published by the FDA (in 2010 and 2013).2
TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY TRIALS PAGE 7
Fig. 8. Most common
biomarkers in top three
conditions of active,
commercially relevant cancer
checkpoint inhibitor trials
that use biomarkers. Cortellis
Clinical Trials Intelligence,
February 2, 2016.
CONCLUSION
As immuno-oncology draws biopharma in with
novel cancer therapies and staggeringly positive
results, it becomes crucial to find an unsaturated
niche within the space. Biotech companies have
carved out their place in therapeutic cancer
vaccines while big pharma invests heavily in
checkpoint inhibitors, but what comes next?
Immunotherapy and cross-class combinations are
proving to be successful, but I/O is a constantly
moving space. With the recent success of
Amgen’s melanoma candidate T-vec (Talimogene
laherparepvec), the first oncolytic virus to be
approved for marketing, it’s probable that the
next go-to class of immunotherapies will move
beyond T-cells. As we venture forth into immunooncology, it is becoming more of a reality that drug
developers will outsmart cancer cells. Exploiting
cancer pathways using our own immune system is
not a novel approach, but approaching it in a novel
way is key to staying one step ahead of both the
disease and the competition.
TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY TRIALS PAGE 8
AUTHOR
BETH KIERNAN
Beth Kiernan is a pharmaceutical research analyst – clinical trials at
Thomson Reuters. In this role, Beth is responsible for analyzing the
intelligence contained within Cortellis CTI, focusing on global clinical
trial developments. Prior to joining Thomson Reuters in 2013, Beth
worked as a research scientist and teaching assistant in the field of
molecular biology and genetics. She holds a degree in biology from
Rutgers University.
REFERENCES
1Hailemichael, Y. et al. Persistent antigen at vaccination sites induces tumor-specific CD8(+) T cell
sequestration, dysfunction and deletion. Nat. Med. 19, 465–472 (2013). http://www.nature.com/
nm/journal/v19/n4/full/nm.3105.html?WT.ec_id=NM-201304
2Jago, Charlotte. The Immuno-Oncology Paradigm. PharmaTimes (2015). http://edition.pagesuiteprofessional.co.uk//launch.aspx?eid=cd1122ab-5b80-428d-a3de-078a009af9c4
TRENDS AND CHALLENGES IN IMMUNO-ONCOLOGY TRIALS PAGE 9
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