the emergence of immuno-oncology in clinical cancer

An Article from PAREXEL's IMMUNO-ONCOLOGY STRATEGIC WORKING GROUP
THE EMERGENCE OF
IMMUNO-ONCOLOGY IN
CLINICAL CANCER RESEARCH
Denis R. Miller, M.D., Vice President,
Global Head of Oncology/Hematology
Immuno-oncology has become one of the most
promising and fastest growing areas of cancer
research. Immuno-oncology clinical trials are emerging
as an increasingly important activity within a rapidly
expanding field of precision-oriented cancer drug
development. Immuno-oncologic therapeutics offer the
ability to harness and activate the patient’s immune
system to attack and destroy tumor cells, potentially
transforming the treatment landscape. Additional
important advantages beyond enhanced efficacy include
reduced toxicity and an increased tolerability, which
can further improve the chances of therapeutic success
across a broad range of potential cancer indications.
Unlike specific targeted therapies directed against a
driver mutation, immuno-therapy is not restricted by
the expression of genomic abnormalities that are the
targets of precision medicine. And as with many other
successful approaches in cancer therapy, combinations
of immuno-therapy and other targeted therapies may
increase efficacy even further.
The cell-mediated immune system in cancer patients
is suppressed for a number of cogent reasons. Cancer
itself suppresses T-cell function as does prior anticancer therapy, especially chemotherapy and radiation
therapy. Immune function decreases with age as the
incidence of cancer increases with this demographic.
Finally, upregulation and increased expression of
specific immune checkpoints that suppress anticancer T-cell function and the increased suppressive
activity of other cells and cytokines in the tumor
microenvironment all conspire to blunt or put brakes
on an effective immune-mediated anticancer response.
Our expanded understanding of these suppressors and
activators in the past decade and the application of this
new knowledge has created a renaissance in cancer
therapy.
Immunologically-based therapy has been part of the
anticancer armamentarium since the late 1990’s with
the approval of rituximab for the treatment of relapsed
follicular lymphoma. Since then, other monoclonal
antibodies have been synthesized to inhibit virtually
every known receptor or growth factor that drives the
oncogenic process in solid tumors and hematologic
malignancies as well as benign hematologic disorders.
area as new pathways, combinations, and suppressors
are being discovered, targeted, and investigated. Over
the past three years, PAREXEL has managed over 600
clinical trials in oncology, of which nearly 20% are in
the field of immuno-oncology (Figure 1).
PAREXEL has extensive experience with most of the
different classes of immunotherapeutic anti-cancer
drugs as shown in Figure 2. Monoclonal antibodies were
evaluated in 72% of the studies we managed.
Immune checkpoint inhibitors (ICIs) are directed towards
receptors and ligands that suppress the host’s immune
Figure 1. Proportion of Immuno-Oncology Trials
within PAREXEL’s Oncology Portfolio 2016 (nonimmuno-oncology=83%, immuno-oncology=17%)
Figure 2. PAREXEL's Immuno-Oncology studies
by class of immunotherapy
Classes of Immunotherapy
ICI
12%
Vaccine
8%
moAb Excl. ICIs
68%
Immunomod
12%
Today in laboratory and clinical cancer research,
immuno-oncology is clearly the most rapidly advancing
YOUR JOURNEY. OUR MISSION.®
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response against tumor antigens. These include
monoclonal antibodies directed against CTLA-4, PD-1,
and PD-L1 but other ICIs are under development and
include small molecules directed against adenosine
2A receptors and monoclonals directed against LAG3,
TIM3, OX40, and others.
Monoclonal antibodies include unarmed (e.g. rituximab,
cetuximab, etc.) and antibody-drug conjugates or armed
monoclonals (e.g. TDM-1), radiolabeled monoclonals
(e.g. 90Yt-labelled anti-CD20), bispecific T-cell engagers
(BiTE) so-called duo antibodies or full bispecific
antibodies directed against antigens on B-cells
and T-cells. (e.g. CD20xCD3), and chimeric antigen
receptor T-cells or CART. Other monoclonal antibodies
like bevacizumab are directed against the vascular
endothelial growth factor (VEGF, which acts by blocking
the binding of VEGF to its cognate receptor.
Immunomodulatory therapy agents like lenalidomide or
pomalidomide were evaluated in 12%. Vaccines including
autologous dendritic cell or combined autologous
tumor cell/autologous dendritic cell immunotherapy
and polypeptides were evaluated in 8%. We have also
conducted studies with cytokines like interleukin-2 (IL-2)
and interferons (IFN).
EMERGING TRENDS
The distribution of immuno-oncology studies by Phase
is illustrated in Figure 3. The proportions of early phase
studies (Phase I and II) and later phase studies (Phase
III and IV) are nearly equal but the numbers of early
phase studies in oncology is increasing rapidly. Studies
classified as Phase I include Phase Ia, Phase Ib, and
Phase Ib/IIa (when the Phase IIa stage was a dose
expansion in a specific indication after the recommended
Phase II dose was determined in Phase Ib).
A second rapidly emerging trend is the evaluation of
combinations of immunotherapy (with two ICIs, an ICI
and a small molecule targeted therapy, or an ICI with
either chemotherapy, radiation therapy, or peptide
vaccines). These combination studies are now being
conducted as Phase I dose escalation again followed
by dose expansion in enriched patient populations or
those identified by specific indication (e.g. triple negative
breast cancer) or by expression of a specific biomarker
(e.g. T790M in NSCLC (NSCLC) or BRAF V600E mutation in
malignant melanoma.
Figure 3. PAREXEL's Immuno-Oncology Studies
by Phase
Immuno-Oncology Phase Chart
IV
7%
III
47%
I
16%
II
30%
However, unlike each of the above classes of
immunotherapeutic agents all directed against specific
targets on tumor cells, or endothelial cells supplying
developing tumors with their required nutrition in
the form of angiogenesis, ICIs target the immune
system, including cytotoxic T-cells and dendritic or
antigen presenting cells that are suppressed by the
malignancy itself. Immune checkpoint inhibitors (ICI)
activate cytotoxic T-cells by unleashing or unbraking
their suppressed state. To date, monoclonal antibodies
directed against CTLA4 (ipilimumab) and PD-1
(pembrolizumab, nivolumab) have been approved for
the treatment of malignant melanoma, metastatic
renal cell carcinoma, and NSCLC. PD-1 inhibitors are
also extraordinarily active in patients not only with
solid tumors, but also with refractory or recurrent
hematologic malignancies including Hodgkin disease
and non-Hodgkin lymphoma (NHL). More recently,
combinations of ICIs (ipilimumab plus nivolumab) have
been shown to be superior to monotherapy with one or
the other in metastatic melanoma. The safety profile
of this combination has been acceptable but a new and
major adverse event, financial toxicity, is a realistic and
impactful challenge that will stress the stability of even
the most economically privileged health care systems
and may obviate less-well-off countries from being able
to afford these costly new agents.
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Not unexpectedly, PAREXEL’s global footprint is clearly
illustrated by the regional distribution of trials we have
managed. The proportion of our immuno-oncology
trials conducted in North America and Europe are
nearly identical. Studies in the Asia/Pacific (APAC)
region make up 20% but activity there is increasing
rapidly. Latin America and the rest of the world make
up the remaining 25% of our activities. These data are
summarized in Figure 4.
Immunotherapy in cancer is rapidly expanding and has
become the most exciting area in clinical research and
translational medicine. Second and third generation
monoclonal antibodies directed against growth factors
(e.g. VEGF) or growth factor receptors (e.g. EGFR,
VEGFR. IGFR), and in hematologic malignancies, and
various clusters of differentiation or CDs (e.g. CD20 in
B-cell malignancies) are demonstrating superiority
in some cases when compared to their originator
ancestors. (e.g. obinutuzumab vs. rituximab in chronic
lymphocytic leukemia [CLL]). Arming monoclonal
antibodies with cytotoxic agents is showing great
potential.
PD-L1 is another target of this new class of
immunostimulatory agents or ICI. A number of antiPD-L1s (e.g. durvalumab or Medi4736, atezolizumab,
Figure 4. Regional Distribution of PAREXEL’s Studies
in Immuno-Oncology
Immuno-Oncology Studies by Region
Rest of Asia
16%
Africa
4%
Europe
25%
North
America
25%
India
5%
Japan
6%
Middle East
10%
Latin America
9%
avelumab) are in early and later phase development in
an increasingly broadening group of malignancies. More
and more of these studies are evaluating combinations
of ICI, ICIs with small molecule tyrosine kinase
inhibitors (e.g. inhibitors of Bruton tyrosine kinase,
PARP inhibitors), anti-angiogenic agents (bevacizumab,
cedirinub), other immunostimulant vaccines (e.g. gp100
oligopeptides and toll like receptor agonists), cytokines
(e.g. interferon α), and even chemotherapeutic agents
or hypofractionated radiation therapy. The PD-1 and
PD-L1 inhibitors engage and interact with tumor cells,
dendritic cells, T-cells, and other components of the
microenvironment including Tregs, myeloid derived
suppressor cells, macrophages, tumor infiltrating
lymphocytes (TIL), and inflammatory cytokines.
THE COMPETITIVE ENVIRONMENT
The three approved immune checkpoint inhibitors are
the two PD-1 inhibitors, nivolumab and pembrolizumab,
and ipilimumab, an inhibitor of CTLA4. The 2015 market
share of each is shown in Figure 5.
Reviewing the marketing success of approved and soonto-be-approved immune checkpoint inhibitors since
2013 and projecting to 2020, Figure 6 illustrates major
market sales estimates for the following major markets:
(USA, UK, France, Germany, Italy, Spain, and Japan of
inhibitors of CTLA-4, PD-1, and PD-L1 in cancer patients
in millions of US$. (Figure 6)
Despite the hype regarding response rates, durability
of response, and an acceptable safety profile, most
patients don’t respond to immune checkpoints and
only 20-25% of patients reach the plateaued curve of
survival three years or more after therapy has been
completed. The huge cost of these compounds is also
a negative that will undoubtedly limit their availability
and affordability globally. Some strategies to improve
the efficacy of immune checkpoint inhibitors will include
1) improving outcomes using innovative combinations;
2) identifying active agents to deal with patients who
do not respond initially or progress after treatment
with the available immune checkpoint inhibitors;
3) demonstrating that anti-PD-1 inhibitors are more
efficacious than the available immune checkpoint
inhibitors as monotherapy or in combination;
4) expanding the indications beyond the current
tumors; and 5) furthering development of other ICIs
with different mechanisms of action including
YOUR JOURNEY. OUR MISSION.®
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pembrolizumab, and ipilimumab, an inhibitor of CTLA4. Their market share of eac
shown in Figure 5.
Figure 5. Leaders
Immuno-Oncology
2015
Figurein5.
Leaders in Immuno-Oncology
2015
,
Source: BMS.com, JP Morgan Healthcare Conference, presented by Giovanni Caforio, January 2016, page 7,
http://s2.q4cdn.com/139948097/files/doc_presentations/2016/BMY-Presentation-JPM-Caforio-Final.pdf
Reviewing the marketing success of approved and soon-to-be approved immune
inhibitors since 2013 and projecting to 2020, the following figure estimates major ma
•Priming and T-cell activation via anti-CTlA4
Figureand
6. Sales
Estimates
for Anti-PD-1,ofPD-L1,
(USA, UK, France, Germany, Italy, Spain,
Japan
of inhibitors
CTLA-4, PD-1
and CTLA4, 2013-2020
•T-cell activation
via anti-OX,
anti-GITR,
anti-LAG3, of US$..(Figure 6)
in cancer
patients
in millions
anti-CD137 or urelumab)
Figure
6. Sales
Estimates
for Anti-PD-1,
•NK activation
via anti-KIR
or lirilumab
or elastuzmab
PD-L1, and CTLA4, 2013-203[‘\\\\\\\\\\\\\\\\\
•Inhibition of inhibitory components of the
microenvironment including anti-CSF1R, IDO,
anti-CD73, and adenosine receptor 2A. Some
microenvironmental targets still awaiting a new
inhibitor agent include myeloid-derived suppressor
cells and Treg cells.
We recognize that PD-1, PD-L1, and CTLA-4 are
important components of the microenvironment
and immuno-suppression in cancer patients. More
recently the complexity and heterogeneity of the
tumor microenvironment has revealed its secrets.
Somewhat analogous to driver mutations in other
cancers, the differentiation of four types of the tumor
Source: 'The immune checkpoint inhibitors: where are we
Despite
the hype
regarding
response
durability of response
now?' by Rachel
M. Webster,
Nature
Reviews rates,
Drug Discovery
profile,
most(2014)
patients don’t respond to immune checkpoints and on
13, 883–884
the plateaued curve of survival three years or more after therapy
huge cost of these compounds is also a negative that will undoubte
affordability globally. Some strategies to improve the efficacy of im
®
will include 1) improving
outcomes
using
innovative
2
YOUR
JOURNEY.
OUR
MISSION.combinations;
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deal with patients who do not respond initially or progress after
immune checkpoint inhibitors; 3) demonstration that anti-PD-1 inh
microenvironment based on PD-L1 expression and the
presence or absence of tumor infiltrating lymphocytes
(TILs) will lead to much more specific immunotherapy
(Table 1).
A more granular view of the cellular and humoral
components of each subtype or node are shown in
Figure 7.
Other components of activating the immune system
and directing it against a malignancy for which targeted
therapy is awaited include T-cell trafficking and
infiltration, antigen release, and antigen presentation
to dendritic cells. Interferon may have such a role
as might agents like toll-like receptor agonists that
stimulate interferon and IL12 production which in
turn increase the response to anti-PD1 agents.
Intratumor injection of these agents may increase
both local and abscopal tumor responses. When using
combinations of ICIs with other agents, the exact
timing of administration may have a profound effect on
efficacy and still require considerable investigation. The
components of the immunostimulatory pathway that can
be directed against cancer are shown in Figure 8 with
approved therapies and those in clinical or preclinical
development.
In 2016 regulatory approval of anti-PD1 ICIs in a number
of additional indications and lines of therapy are shown
in Table 2.
On May 16, 2016 US FDA approved Genentech’s antiPD-L1 atezoliz umab or Tactentriq for advanced
urothelial cancer. The other major companies deeply
involved in development of immune checkpoint inhibitors
are BMS, Merck, Astra Zeneca/Medimmune. Without
any attempt to commercialize the activities of one
pharmaceutical company over another, the following
tables are presented to provide an example of the
immunotherapeutic program of one major player in this
highly competitive field. Merck has a very ambitious
development program for ICIs as shown in Figure 9.
Not to be surpassed by its competitors in New Jersey
(BMS in Princeton, Merck in Kenilworth) Roche/
Genentech (South San Francisco) has a large and
growing developmental program for immunotherapy as
shown in Figure 10. An increasing number of smaller
Table 1.
Subtype or
Node of Tumor
Microenvironment
Mechanism
•I. (node 1: PD-L1
positive with TILs
driving adaptive
immune resistance
•Elimination of immune
suppression
•II (node 2): PD-L1
negative with no TILs
indicating immune
ignorance
•Enhanced APC
function/adjuvanticity
•III (node 3): PD0-L1
positive with no TILs
indicating intrinsic
induction
•Immunogenic cancer
cell death
•Enhance
T/Macrophage Effector
Activity
•I V (node 4): PD-L1
negative with TILs
indicating role of other
suppressor pathways
Source: 'Combination cancer immunotherapies tailored to
the tumour microenvironment', by Mark J. Smyth, Shin Foong
Ngiow, Antoni Ribas & Michele W. L. Teng, Nature Reviews Clinical
Oncology 13, 143–158 (2016).
Table 2. Approval of Anti PD-L1 ICIs in 2016
Tumor
Study Design
Hodgkin Lymphoma
CheckMate-205
Monotherapy single arm
study in second line
Head and Neck
CheckMate-141
Monotherapy vs. standard
care in second line
Non-Hodgkin
Lymphoma
CheckMate-139
Monotherapy single-arm
study in relapsed/refractory
diffuse large B-cell
lymphoma
Bladder
CheckMate-275
Monotherapy single arm
study in second line bladder
Glioblastoma
CheckMate-143
Monotherapy vs. standard
of care in recurrent
glioblastoma
1L NSCLC
CheckMate-026
Monotherapy vs. chemo in
first-line PD-L1 expressers
Source: BMS for Barclay's Healthcare Conference,
http://s2.q4cdn.com/139948097/files/doc_presentations/2016/
mar/BMY-Barclays-Boerner-FINAL.pdf
YOUR JOURNEY. OUR MISSION.®
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shown
shown in the Figures
7: in the Figures 7:
Figure
7.
A, Type
1 Elimination
of immune
B. TypeCancer
2. Immunogenic
A, Type 1 Elimination
of immune
Suppression
B.Suppression
Type 2. Immunogenic
Cell DeathCancer Cell Death
A. Type 1. Elimination of Immune Suppression
B. Type 2. Immunogenic Cancer Cell Death
C. Type 3. Enhanced APC Function
D. Type 4. Enhance T/Macrophage Effector Activity
C. Type 3. Enhanced
APC
Function APC Function
D. Type 4. Enhance
T/Macrophage
Effector ActivityEffector Activity
C. Type
3. Enhanced
D. Type
4. Enhance
T/Macrophage
C. Type 3. Enhanced
APC Function
D. Type
4. Enhance
T/Macrophage Effector Activity
From Smyth MJ, et al. Nat Rev Clin Oncol 2013; 13: 143-158.
Other components of activating the immune system and directing it against a malignancy for
which targeted therapy is awaited include T-cell trafficking and infiltration, antigen release, and
antigen presentation to dendritic cells. Interferon may have such a role as might agents like tolllike receptor agonists that stimulate interferonα and IL12 production which in turn increase the
response to anti-PD1 agents. Intratumor injection of these agents may increase both local and
abscopal tumor responses. When using combinations of ICIs with other agents, the exact
timing of administration may have a profound effect on efficacy and still require considerable
investigation. The components of the immunostimulatory pathway that can be directed against
From
Smyth
MJ, et MJ,
al. Nat
Rev
Clin
Oncol
2013; Oncol
13: 143-158.
From
Smyth
et
al.
Nat
Rev
Clin
2013;
13:Oncol
143-158.
cancer
shown
in Figure
8 with
approved
therapies and those in clinical or preclinical
From Smyth
MJ,are
et al.
Nat Rev
Clin
2013;
13: 143-158.
development.
Other components
activating the
and directing
against
a malignancy
Otherofcomponents
of immune
activatingsystem
the immune
system itand
directing
it against for
a malignancy for
Figure
8. Compartments
ofisthe
Anti-Cancer
Immune
Response
and
Status ofantigen
Immuno-Therapy
which
targetedwhich
therapy
awaited
include
T-cell
trafficking
and
infiltration,
release,
and of
Figure 8.
Compartments
the Anti-Cancer
Immuneand
Response
and antigen
Status
Immuno-Therapy.
targeted
therapy
is awaitedofinclude
T-cell trafficking
infiltration,
release,
and
antigen presentation
to
dendritic
cells.
Interferon
may
have
such
a
role
as
might
agents
like
tollantigen presentation to dendritic cells. Interferon may have such a role as might agents like tolllike receptor agonists
that stimulate
andinterferonα
IL12 production
which
in turn increase
like receptor
agonists interferonα
that stimulate
and IL12
production
which inthe
turn increase the
response to anti-PD1
agents.
Intratumor
injection
of
these
agents
may
increase
both
and both local and
response to anti-PD1 agents. Intratumor injection of these agents may local
increase
abscopal tumorabscopal
responses.
using combinations
ICIs with other
agents,
the exact
tumorWhen
responses.
When using of
combinations
of ICIs
with other
agents, the exact
timing of administration
may
have
a
profound
effect
on
efficacy
and
still
require
considerable
timing of administration may have a profound effect on efficacy and still require considerable
investigation. The
components
the immunostimulatory
pathway that can
be directed
against
investigation.
Theofcomponents
of the immunostimulatory
pathway
that can
be directed against
cancer are shown
in
Figure
8
with
approved
therapies
and
those
in
clinical
or
preclinical
cancer are shown in Figure 8 with approved therapies and those in clinical or preclinical
development. development.
Figure 8. Compartments
of the Anti-Cancer
Immune
Response
and Response
Status of Immuno-Therapy.
Figure 8. Compartments
of the
Anti-Cancer
Immune
and Status of Immuno-Therapy.
Modified from Sznol et al, Clin Can
Research
2013;Sznol
19: 1021-34.
Modified
from
et al,
Clin Can Research 2013; 19: 1021-34
YOUR JOURNEY. OUR MISSION.®
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Figure 9. Clinical Development Program for Immunotherapy at Merck
Source: http://www.pharmalive.com/annual-report-top-10-pipelines/
Not to be surpassed by its competitors In New Jersey (BMS in Princeton, Merck in Kenilworth)
Roche/Genentech (South San Francisco) has a large and growing developmental program for
immunotherapy
as companies,
shown inparticularly
Figure 10. An increasing
number
of smaller
growing
but growing
biotechnology
COMPANION
DIAGNOSTICS
ANDbut
PREDICTIVE/
biotechnology
companies,
particularly
in
Asia,
are
in
the
earlier
stages
of
developing
ICIs as
in Asia, are in the earlier stages of developing ICIs as
PROGNOSTIC BIOMARKERS
monotherapy
in combination
for both
solid tumors and hematologic malignancies.
monotherapy
and in and
combination
for both solid
tumors
Biomarkers and pharmacogenomics studies are
increasingly used to identify patients most likely to
Considering the ever-increasing number of
benefit from an investigational drug in order to maximize
immunotherapeutic agents, the broad array of
potential benefits (increased response, prolonged
indications from glioblastoma to acral melanoma of
progression-free and overall survival, and decreased
the hallux, the various lines of therapy, and finally the
toxicity). The expression of PD-L1 on tumor cells,
infinitesimal number of potential combinations with
as determined by immunohistochemistry, has been
other iCIs, small molecule TKIs and other enzyme
proposed as a prognostic biomarker of PFS and OS
inhibitors, peptide vaccines, chemotherapy, cytokines,
in patients with advanced NSCLC treated with the PD-1
and radiation therapy, clinical research in the field of
inhibitor, pembrolizumab. As noted in Figure 11a, PD-L1
immuno-oncology is really just beginning to extend
expression is a continuous variable. Three broad
below the surface and should be a fruitful and
subgroups of expression (<1%, 1%-49%, and ≥50%
productive and profitable area for the next decade.
(Garon et al, NEJM 2015). Expression of ≥50% was
associated with a significant improvement in both PFS
Figure 10. Full Immunotherapy Clinical Development
Program
of c).aOfMajor
and OS
(Figure 11b,
note is Pharmaceutical
that PD-L1 expression
Company
was not prognostic in another study in NSCLC treated
and hematologic malignancies.
YOUR JOURNEY. OUR MISSION.®
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Figure 10. Full Immunotherapy Clinical Development Program
Status as of Jan 28, 2016; Outcome studies are event-driven: timelines may change.
Source: http://www.pharmalive.com/annual-report-top-10-pipelines/
Considering the ever-increasing number of immunotherapeutic agents, the broad array of
indications from glioblastoma to acral melanoma of the hallux, the various lines of therapy, and
with nivolumab but in this study, a different method and
FUTUREwith
PERSPECTIVES:
finally the infinitesimal number of potential combinations
other iCIs, small molecule TKIs
definition of PD-L1 positivity was used. The definitive
WHERE ARE WE HEADED?
and other enzyme inhibitors, peptide vaccines, chemotherapy, cytokines, and radiation therapy,
final word on the value of PD-L1 expression is awaited
Huge
advances
been made
the pastbelow
five years.
clinicala research
in the
field
of immuno-oncology
is
really
just have
beginning
to in
extend
the
because
number issues
remain
unresolved.
These
What
can
we
expect
in
2016?
Figure
12
summarizes
surface
a fruitful
and
productive and profitable area for the next decade.
include
theand
exactshould
method be
used,
the tissue
evaluated
the major areas of activity and likely approval of
(fresh, archival, initial diagnosis, recurrent disease), and
immunotherapeutics
Companion
Diagnostics and
Predictive/Prognostic
Biomarkers in new or expanded indications
the
definition of negativity/positivity,
to mention
a few.
and combinations.
We
anticipate the
further
refinements of companion
Biomarkers
and
pharmacogenomics
studies are increasingly
used to identify patients most likely
PAREXEL’s Immuno-Oncology Strategic Working
diagnostics will be discovered, evaluated, and validated,
to benefit from an investigational drug in order Group
to maximize
potential
(I-O SWG) was
created tobenefits
keep pace(increased
with these
becoming useful tools in evaluating candidates for
response,
prolonged
progression-free
and
overall
survival,
and
decreased
tocicity).
The
extraordinary
and
exciting
new
advances.
The
Strategic
therapy with ICI and serving as key predictive and
Workingby
Group
is comprised of our leadinghas
experts
expression
of PD-L1
on tumor
cells,
as determined
immunohistochemistry,
been
prognostic
biomarkers.
Considering
the large
number
in
immuno-oncology
across
a
number
of
functions,
a toprognostic
biomarker
of PFS
ofproposed
ICI and the as
need
identify companion
diagnostics
for and OS in patients with advanced NSCLC treated
including medical oncology, immunology, medical
them,
be an ongoing
area pembrolizumab.
of research. PD-L1 As noted
with this
thewillPD-1
inhibitor,
in Figure 9a, PD-L1 expression is a
imaging, biostatistics, regulatory affairs, translational
expression
as
measured
by
immunohistochemistry
is
continuous variable. Three broad subgroups of expression
(<1%, 1%-49%, and >50% (Garon
research biomarkers, and business development. The
shown in Figure 11a.
et al, NEJM 2015). Expression of >50% was associated with a significant improvement in both
PFS and OS (Figure 9b, c). Of note is that PD-L1 expression was not prognostic in another
YOUR JOURNEY.
MISSION.® of
study in NSCLC treated with nivolumab but in this study, a different method
andOUR
definition
|9
PD-L1 positivity was used.
The definitive final word on the value of PD-L1 expression is
awaited because a number issues remain unresolved. These include the exact method used,
We anticipate the further refinements of companion diagnostics will be discovered, evaluated,
to identify
to identify
companion
companion
diagnostics
diagnostics
for them,
for them,
this will
this be
willan
beongoing
an ongoing
area area
of research.
of research.
PD-L1
PD-L1
and validated, becoming useful tools in evaluating candidates for therapy with ICI and serving
experssion
experssion
as measured
as measured
by immunohistochemistry
by immunohistochemistry
is shown
is shown
in Figure
in Figure
11a. 11a.
as key predictive and prognostic bioarkers. Considering the large number of ICI and the need
to
identify
diagnostics
for
them, this will be an ongoing area of research. PD-L1
Figure
Figure
11a.companion
11a.
PD-L1
PD-L1
expression
expression
in NSCLC.
in NSCLC.
Figure
11.
experssion
as measured by immunohistochemistry is shown in Figure 11a.
Figure 11a.
expression
in NSCLC
Figure
11a.PD-L1
PD-L1
expression
in NSCLC.
<1% <1%
1-50%
1-50%
Figure
Figure
11b (PFS)
11b (PFS)
<1%
1-50%
Figure 11b (PFS)
Figure 11b. PFS vs. PD-L1 Positivity
>50%>50%
>50%
Figure
Figure
11c (OS)
11c (OS)
Figure 11c (OS)
Figure 11c. Overall Survival vs. PD-L1 Positivity
Source: Garon EB et al., New England Journal of Medicine, 2015, 372:2006-2017.
fromfrom
Garon
Garon
EB etEB
al.etNal.
Engl
N Engl
J Med
J Med
2015.2015.
372: 372:
2006-2017.
2006-2017.
members of the SWG have participated in trials for
lung cancer, breast cancer, hematologic malignancies,
many
different
classes
of cancer
therapeutic
including
Future
Future
Perspectives:
Perspectives:
Where
Where
Are We
Are
Headed?
We Headed? and Early Product Development. Members of the
from Garon EB et al. N Engl J Med 2015. 372: 2006-2017.
extensive work in cytotoxics, biologics, targeted
PAREXEL I-O SWG are the core team that will interface
therapeutics,
cancer vaccines,
immunotherapy,
with our immuno-oncology counterparts and colleagues
Future Perspectives:
Where
Are We Headed?
and supportive-care products. The I-O SWG meets
in pharmaceutical and biotechnology companies
regularly to review recent advances in the field from
developing novel immunotherapeutic agents.
the medical literature and recent scientific meetings,
current immuno-oncology projects, recent RFP/RFIs,
recent regulatory approvals/rejections, the competitive
environment, and future perspectives. Considering
the fact that immunotherapy is being utilized in other
disease specific indications, the Immuno-Oncology SWG
interacts with other disease-oriented SWGs, including:
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Figure 12. Perspectives for Immunotherapeutics in 2016
Source: American Association for Cancer Research
PAREXEL’s Immuno-Oncology Strategic Working Group (I-O SWG) was cr
with these extraordinary and exciting new advances. The Strategic
comprised of our leading experts in immuno-oncology
a number of
Visit our website across
to learn more
about our immuno-oncology
medical oncology, immunology, medical imaging,
biostatistics, regulatory a
and other therapeutic area
Our regional leads are always available for a conversation.
research biomarkers, and business development. The members of the SWG
experience.
in trials for many different classes of cancer therapeutic including extensive
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biologics,
targeted
therapeutics,
cancer
vaccines, immunotherapy, an
Fred LeMoine
+1 919 294 5125 products. .The I-O SWG meets regularly to review recent advances in the fie
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literature and recent scientific meetings, current immuno-oncology projects
recent regulatory approvals/rejections, the competitive environment, and f
EUROPE
Considering the fact that immunotherapy is being utilized in other disease
Graham Sanders
the Immuno-Oncology SWG interacts with other disease-oriented SWGs, inc
+44 (0) 1895 614319
breast cancer, hematologic malignancies, and Early Product Developmen
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PAREXEL I-O SWG are the core team that will interface with our
ASIA PACIFIC
counterparts and colleagues in pharmaceutical and biotechnology companie
Brian Yang
‘immunotherapeutic agents.
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