WHITEPAPER

Addressing Key Challenges in the

Clinical Development of Combination
Immuno-Oncology Therapies:
A CRO’s perspective

Jai Balkissoon, M.D., FACS

Vice President, Immuno-Oncology, Global Product Development

Dirk Reitsma, M.D.

Vice President, Oncology, Global Product Development

Ryan Hardy, B.A.

Senior Director, Commercial Strategy, Hematology/Oncology

Veronica Vlad, M.D.

Director, Global Project Management, Hematology/Oncology

Joseph Dudash, Jr., Ph.D., PMP

Director, Operations Strategy Lead, Project Management

HELPING DELIVER LIFE-CHANGING THERAPIES www.ppdi.com

Driven by a greater understanding of the immune system and the complexities of the tumor
microenvironment, the oncology field is moving toward a broader treatment paradigm. With the
approval of high dose interleukin (IL)-2 in advanced renal cell carcinoma (RCC) in 1991, followed by
metastatic melanoma in 1998, the scientific community began to gain a deeper understanding and
appreciation of the relationship between host factors, immune surveillance, immune suppression,
the tumor microenvironment and tumor killing/evading recognition by the immune system1,2,3.
Today, immuno-oncology (I-O) has emerged as one of the most promising areas of cancer research.
Though we have only begun to tap its potential, new immunotherapies have dramatically benefited
thousands of patients across the United States and Europe in many indications, demonstrating
more durable responses along with improved median overall survival and a more acceptable
toxicity profile.

2 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION

IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE
Rapid-fire Development Meanwhile, patients are clamoring to get new drugs faster, and
patient advocacy groups and nonprofits are working to raise
A confluence of shared—and sometimes competing—interests
awareness for important I-O research, riding an unprecedented
are driving extraordinarily fast and significant progress in
swell of donations.
immuno-oncology. As venture capital flows into I-O, and startups
and pharmaceuticals compete to gain a foothold, more than
Regulatory approval timelines frequently are shortened by priority
240 I-O treatments are now in development. Cross-industry
reviews, breakthrough designations, orphan designations and the
collaborations between global pharmaceuticals, biotechnology
support of innovative trial designs. As a result, whereas one I-O
companies, academic centers and community-based oncologists
agent was approved in 2010, more than 30 agents/indications have
are being announced almost weekly. A prominent example is
been approved so far between 2015-2017 in the United States and
Gilead’s acquisition of Kite Pharma, a developer of CAR T-cell
Europe in increasingly diverse indications. (See Figure 1.)
therapies, in a deal estimated to be valued at $11.9 billion.

Figure 1. I-O approvals in the United States and Europe

2010 2011 2013 2014 2015 2016 2017

Avelumab
Provenge Ipilimumab Provenge Nivolumab Ipilimumab Nivolumab/ipi Relapsed Advanced Merkel cell
Advanced PC (US) 1L melanoma (US) Advanced PC (EMA) Relapsed melanoma (US) Adjuvant melanoma (US) 1L melanoma (EMA) (US/EMA)
Ipilimumab Pembrolizumab Blinatumomab Pembrolizumab Pembrolizumab Nivolumab
2L melanoma (EMA) Relapsed melanoma (US) Ph-B-cell ALL (US) 1L melanoma (US/EMA) 2L HNSCC (US) 2L HNSCC (EMA)
Pembrolizumab
Ipilimumab Nivolumab/Ipilimumab Nivolumab 3L Gastric & GEJ cancer (PD-L1+)
1L melanoma (EMA) 1L melanoma (US) 2L HNSCC (US) (US)
Nivolumab Elotuzumab Tisagenlecleucel
1L melanoma (EMA) 2L+ MM (EMA) 3L B-ALL (US)
Elotuzumab Nivolumab Pembrolizumab
2L+ MM (US) Classical HL 3L (US/EMA) Classical HL- 3L (US)
Nivolumab Pembrolizumab Axicabtagene ciloleucel (CAR-T) 3L
2L NSCLC Squamous (US/EMA) 2L NSCLC (PD-L1+) (EMA) B-ALL (US)
Pembrolizumab Atezolizumab Pembrolizumab
2L NSCLC (US) 2L NSCLC (US) 1L NSCLC (PD-L1+≥50%) (EU)
Pembrolizumab Pembrolizumab/carbo/pem
Nivolumab 2L RCC (US) 1L NSCLC (PD-L1+ ≥50%) (US) 1L NSQ NSCLC (US)
Atezolizumab Pembrolizumab
2L UBC (US) 2L UBC (US/EMA)
Avelumab
2L UBC (US)
Pembrolizumab
1L UBC Cisplatin-ineligible
(US/EMA)
Durvalumab
2L UBC (US)
Nivolumab
2L UBC (US)
Atezolizumab
1L UBC Cisplatin-ineligible (US)
Nivolumab
2L HCC US
Legend of Indications Pembrolizumab
MMRD/MSI-H Tumors-2L
Heme MMRD/ endometrial and CRC (US)
Gastric and
Prostate Skin Cancer (MM,HL, NSCLC RCC HNSCC UBC HCC MSI-H
GEJ Nivolumab
ALL) Tumors
MMRD/MSI-H relapsed CRC (US)

3 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION

IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE
Moving Toward Combination Strategies in concert with checkpoint receptor blockade in clinical trials.
Immunotherapy is delivered in multiple therapeutic formats, but
Just as the application of chemotherapy evolved from being used
checkpoint inhibitors (CPI), which release the “brakes” on the
as monotherapy to frequently being applied in combination
immune system, have emerged as the “backbone” therapy.
strategies, immunotherapies have begun to make this leap forward
to improve the potential for developing efficacious treatments. In
The field is becoming very crowded. We also are seeing older
combination strategies, one agent is used to increase, sustain or
therapies being combined with the current generation of active
complement the response of the other. This may involve a novel
immunotherapies with hopes of increased somatic mutations,
agent designed to inhibit immune suppression combined with a
neoantigens and better clinical activity. Intratumoral vaccines and
backbone checkpoint inhibitor that increases T-cell activation
oncolytic viruses have emerged again in combination with CPIs
within the tumor.
with the anticipation of both local and abscopal (distant) effects
with increased clinical activity, which we did not observe in older
I-O agents may be integrated with standard chemotherapy or
clinical trials. Other areas of innovative immunotherapy including
radiation, molecularly targeted therapies, antiangiogenic therapies,
chimeric antigen receptors (CAR) T-cells, bispecific antibodies
vaccines or other I-O agents. Novel immunotherapy agents that
and other platforms to target tumor specific antigens with T-cell
increase tumor associated antigens, activate toll-like receptors
activation are expected to be combined with the current
(TLR), increase dendritic cell antigen presentation, inhibit
generation of checkpoint receptor therapies.
immune suppression and increase the number and activity of
tumor-infiltrating lymphocytes (TIL) are being clinically evaluated

Figure 2 Some examples of classes of immuno-oncology agents (includes agents targeting checkpoint receptors)

PD-1 PD-L1
Nivolumab (Opdivo®) BMS
Atezolizumab Tecentriq® Roche
Pembrolizumab (Keytruda) PD-1
Merck
MEDI0680 (AMP-514) MedImmune PD-L1 Bavencio® Pfizer
Avelumab
Nivolumab (Opdivo®) BMS Durvalumab
REGN2810 Regeneron AtezolizumabImfinzi® MedImmune/AZ
Tecentriq® Roche
Pembrolizumab (Keytruda) Merck BMS-936559 (MDX-1105) (BMS)
BGB-A317 Beigene Avelumab Bavencio® Pfizer
MEDI0680 (AMP-514) MedImmune
PidilizumabREGN2810
Medivation/Curetech Durvalumab Imfinzi® MedImmune/AZ
Regeneron
PDR-001 Novartis BMS-936559 (MDX-1105) (BMS)
BGB-A317 Beigene
Pidilizumab Medivation/Curetech
PDR-001 Novartis IDO
Epacadostat (INCB024360) Incyte
IDO
Indoximod (NLG919) NewLink/GNE
CTLA-4 Epacadostat (INCB024360) Incyte
Ipilimumab (Yervoy®) BMS Indoximod (NLG919) NewLink/GNE
CTLA-4
Tremelimumab AZ LAG3
Ipilimumab (Yervoy®) BMS BMS-986016 BMS
TIM3
Tremelimumab AZ LAG3 (Prima biomed)
IMP-321
Tesaro-preclinical Tesaro-preclinical
BMS-986016 BMS
TIM3 IMP-321 (Prima biomed)
Tesaro-preclinical Tesaro-preclinical

CAR T- cell
Tisagenlecleucel Kymriah® Novartis
Axicabtagene CiloleucelCAR T- cell
Yescarta® Kite GMO/oncolytic virus
Juno
Tisagenlecleucel Kymriah® Novartis CRS-207 ADURO
Cellular Biomedicine Group
Axicabtagene Ciloleucel Yescarta® Kite GMO/oncolytic
Pexa-Vec SillaJen virus
Bluebird
Juno Talimogene laherparepvec (TVec)
CRS-207 ADURO
Cellular Biomedicine Group (Imlygic®) Amgen
Pexa-Vec SillaJen
Bluebird Talimogene laherparepvec (TVec)
(Imlygic®) Amgen

Phosphytidyl serine inhibitor (aPS)

Bavituximab (Peregrine)
TLR agonists
Phosphytidyl serine inhibitor (aPS) TLR9 agonist Dynavax TLR9
Bavituximab (Peregrine)
OX40 TLR agonists
Agonist (MGN1703) Mologen AG
TLR9 agonist Dynavax TLR9
MOXR-0916 Roche/GNE
Agonist (MGN1703) Mologen AG
OX40
MEDI-6469 MedImmune
MOXR-0916 Roche/GNE TIGIT
Adenosine-2A receptor
MEDI-6469 MedImmune MTIG7192A-Genentech
Corvus TIGIT
BMS-986207-BMS
Adenosine-2A receptor ASP8374- Astellas
MTIG7192A-Genentech
Corvus BMS-986207-BMS
ASP8374- Astellas

4 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION

IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE
Figure 3. Where we want to be with our Precision medicines targeting genomic aberrations in tumor cells, immunotherapies
next generation of I-O treatments
targeting the antitumor immune response and the intersection of these approaches used in
concert all can be optimized by the development of companion diagnostics that identify
patients most likely to benefit from them. The goal is to turn “immune deserts” or “cold
immune areas” into hot or inflamed areas that have large amounts of intratumoral T-cells
that can lead to improved response, thus raising the tail of the survival curve.
Survival

(See Figure 3.)

It is not surprising that many sponsors are cross-examining their pipelines for novel
agents that can inhibit immune suppression and/or increase immune-activating properties
to combine with checkpoint receptor therapy. Sponsors are developing both checkpoint
receptor agonists and antagonists and studying them in a wide variety of tumor types,
mostly in combination with other types of immunotherapy or targeted therapies.
Figure 4 shows examples of the current checkpoint receptors on T-cells that are targets
Time
Control for immunotherapy4.
Targeted therapies
Immune checkpoint blockade
Combinations/sequencing/
biomarker selection Challenges in Clinical Development
Salvati M, 3rd Intl Symp in Lung Ca, 2014; Ribas A,
WCM, 2013; Ribas A, et all, Clin Cancer Res 2012; With the expectation that combination strategies hold more potential than monotherapy
Drake CG, Ann Oncol 2012 in many cases, sponsors are setting up combination trials as early as possible in clinical
development. From the early phases through to approval, clinical development of I-O
Figure 4. T-cell immune checkpoints as combination agents poses significant complexities that can be challenging to address.
targets for immunotherapy In this paper, we explore approaches we have applied to four challenges in I-O
combination trials:
Activating Inhibitory
receptors receptors
CTLA-4 1. Planning for programs that are typically large, complex, multi-national,
CD28
PD-1 resource-intensive, competitive and highly specialized
OX40
B7-1
2. Designing innovative modernized trials
G1TR T-cell TIM-3
CD137 3. Activating sites and enrolling patients in a competitive landscape
BTLA
CD27 4. Managing pseudoprogression, immune-related responses and immune-related adverse
VISTA
HVEM
LAG-3 events to avoid premature stoppage of treatment

Agonistic
antibodies
Blocking
antibodies
KEY CHALLENGES AND APPLIED APPROACHES
Mellman I, Coukos G, Dranoff G. December 21, 2011. Challenge 1: Planning for programs that are typically large, complex,
Cancer immunotherapy comes of age, Nature, multi-national, resource-intensive, competitive and highly specialized
21;480(7378):480-9.
Given the groundswell of support and demand for new I-O therapies, it is a common
and serious mistake to underestimate the required effort to successfully execute an I-O
combination program. These programs push the boundaries of clinical development.
Comprehensive planning and risk management strategies steeped in a deep understanding
of the trial environment are essential for successful I-O protocols.

Protocol and trial optimization, along with identification of the most experienced
and capable sites, must address all specific challenges presented by the I-O clinical
trial landscape. Successful strategy development of a clinical trial must analyze many
facets including disease prevalence, the competitive environment, patient pathways,
site experience and capabilities, shifting standards of care, regulatory landscape,
biomarkers and specific protocol demands. Thus, a robust and comprehensive
feasibility study is essential.

5 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION

IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE
Only a minority of patients achieve durable responses to most
I-O therapies. One component necessary to drive the development
of more effective I-O therapies is in-depth biomarker analysis to
identify patients who are most likely to respond to specific
therapies. Often this requires complex and demanding protocols
which may require multiple tissue biopsies and blood assessments.
It is critical to identify the sites that have these capabilities and
assess whether complex protocol assessments will challenge
milestones and timelines.
As more combination trials are started and planned around the
globe, feasibility studies also can identify regions outside North
America and Europe that have successfully operationalized I-O
clinical trials and are appropriate based on the phase of clinical
development, patient population and protocol complexities.
Given the inevitability of shifts in regulatory requirements,
regional and national standards of care and priorities over the
course of a long, complex trial, programs should plan and
budget for ongoing assessments.
CHALLENGE 2: Designing innovative
modernized trials
Combination I-O strategies entering clinical trials have the
potential for much-needed therapeutic benefits, but they also
bring a higher risk of enhanced and unexpected toxicities.
Considering that only 7 percent of all oncology agents that enter
Phase I clinical trials are likely to gain U.S. FDA approval5,
combination I-O trials with their additional questions about
toxicity and sequencing require nimble decision-making to
increase their odds of success. Study teams need to be ready to flex
midstream, for example, by altering control arms or expanding the
number of arms, in response to early findings. I-O studies require
modernized trial designs that can take advantage of ongoing
advancements in innovative approaches in data collection and
statistical assessments. While traditional designs contribute to high
failure rates and escalating costs because answers to pivotal
research questions are obtained only at the end of the trial,
adaptive designs, in contrast, leverage accumulating data so early
findings can inform the next phase in a flexible process. Modifying
trials as they progress can accelerate timelines, reduce costs,
generate more knowledge from a smaller number of patients and
improve the overall quality of decision-making to identify the
right dose for the right disease in the right patient.
Adaptive designs may address multiple research questions
simultaneously. A single trial can evaluate multiple dose regimens,
indications and drug combinations. For example, a trial might
include adaptive approaches to stop early for futility, assess dose
response, drop or add arms, change the proportion of patients
6 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION
IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE
Figure 5. Seamless Phase II-III trial
Adaptively randomize
Adaptively randomize
Drug A
Equaly randomize
Drug B
Drug B
Drug B
Combination
Combination Control
Control
Control
Start Drop Drop End
Drug A Combination
Interim Analyses Confirmatory stage
Source: The National Academy of Sciences
randomized to each arm and enrich the patient population with
subjects most likely to respond based on biomarker driven
randomization. (See Figure 5.)
Traditionally, the clinical drug development paradigm for
oncology drugs has used sequential trials, with an escalating
number of patients exposed to a drug in each phase.6 It’s becoming
increasingly common, however, to see first-in-human (FIH)
Phase I clinical trials introduce expansion cohorts to explore
emerging clinical hypotheses.7 For example, trials may test
different doses and schedules, more sophisticated PK and PD
parameters, alternative product formulation or administration
strategies, various predictive biomarkers and assessment of clinical
activity in different populations. The addition of new expansion
cohorts to FIH trials to explore hypotheses in real time can help
expedite the development of new therapies and start to shift the
traditional sequential ordering of trials (e.g., a Phase I might lead
into Phase III).
Basket trial designs enroll patients based not on the type or
location of the cancer, but on whether tumors have molecular
alterations that can be targeted by approved or investigational
therapies. These trials can efficiently address multiple questions
under the auspice of one protocol. For example, The National
Cancer Institute-Molecular Analysis for Therapy Chose (NCI-
MATCH) trial matches patients based on their molecular
aberration profile (e.g., BRAF). Basket trials are useful for finding
signals related to the functionality of the aberration and treatment
response irrespective of histology. For example, the FDA approval
of pembrolizumab for cancers that share mismatch repair
deficiency (MMR), a genetic abnormality, represents the first time
a drug has been approved on the basis of a specific genetic profile
rather than where the cancer originated. The basket trial enrolled
patients with a dozen different cancer types. Results demonstrated
that the potential for a response to immunotherapy was not
unique to MMR-deficient colorectal cancer, but held true for all
the MMR-deficient cancers, regardless of tissue of origin.
A key to successful use of innovative design is to seek and respond
to early data to modify a trial as it progresses. Biomarkers, for
example, are critical in adaptive design to provide early measures
of efficacy. In this model, the traditional long-term oncology
endpoints of survival and progression-free survival are less crucial.
Useful markers might include early clinical outcomes such as
imaging, response, progression, serum markers or molecular
markers from tumors via biopsies.
As part of the quest to incorporate data into trial designs as early
as possible, we anticipate that real-world outcomes will be used to
inform study designs. Real-world evidence can be generated on a
disease, treatment patterns and treatment outcomes. This deeper
understanding of how treatments are being used in the
community will help design studies that optimize outcomes.
Challenge 3: Activating sites and enrolling patients
in a competitive landscape
As additional I-O targets are identified and combined with
existing and nascent therapies, the volume of clinical trials will
The following case study illustrates real-world challenges and subsequent key learnings in a
global I-O combination program.
CASE STUDY
BACKGROUND
A large pharmaceutical company sought a CRO for pivotal
Phase III studies of a checkpoint inhibitor in lung cancer patients.
The program was enormous, encompassing seven studies each
with its own protocol.
Four of the studies were combination studies, two were being
studied as monotherapy and one was adjuvant. The program—
which would span the globe across about 30 countries–would
require 20 percent of the lung cancer patients available for clinical
trials in North America alone in 2016.
7 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION
IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE
continue to grow, generating increased demands for specific
patient populations in an already crowded field. In many cases, we
are seeing that established I-O sites, and even some relatively
inexperienced sites, are inundated with competing studies. When
entering this landscape, it can be difficult to find sufficient sites
with I-O experience and access to treatment-naïve patents,
especially sites experienced in adoptive T-cell therapies capable of
running CAR T-cell studies.
New approaches are coming to market to accelerate identification
of patients available for I-O trials. For example, PPD’s Optimal
Research, a US-based site community, features a unique site
activation model called Just In Time (JiT) that connects to
patients within their own local communities. By expanding the
pre-screening physician population to almost 1,000 oncologists in
a myriad of indications, studies can expedite First Patient In (FPI),
Last Patient In (LPI), or even boost lagging cohorts in early
development studies.
CLIENT OBJECTIVES
• Seeking first-line market leadership, the client wanted a single
CRO with the global resources to drive the full program to gain
cross-efficiencies, for example, leveraging PI relationships
and competitive data across trials
• Activate sites as quickly as possible across all seven
studies simultaneously
CHALLENGES AND STRATEGIES
PPD established a program structure that provided each study
with its own dedicated study team along with centralized directors
positioned to see the big picture, collate learnings, oversee the
sharing of experiences lessons learned and findings to address
challenges and replicate best practices across all studies and align
plans, procedures, logistics and efficiencies implementation.
Figure 6. Global reach of lung This structure proved its value as the program immediately faced many challenges
cancer program
impacting enrollment:

Region Country 1. A surge of increased competition with other checkpoint inhibitors, by multiple
sponsors, in a similar patient population put additional pressure on an already burdened
APAC Australia target patient population. Deep analysis at the country level for the patient population
APAC Japan showed near saturation rates in some countries.
APAC Singapore
2. The complexity of the protocol, compared to the emerging alternative options, bore a
APAC Taiwan
high burden for sites to understand and administer the study therapies and for patients
EMEA Austria
to commit to (e.g., mandatory multiple tumor biopsies were not attractive to patients).
EMEA Belgium
EMEA Bulgaria Moreover, attempts to reduce complexity through amendments placed additional
EMEA France burdens on the study/sites, diverting efforts from enrolling patients.
EMEA Germany 3. PIs were managing, on average, four or five competing lung cancer trials. They often
EMEA Israel did not have a clear understanding of our study’s key scientific rationales, such as the
EMEA Italy benefits of post-progression biopsies or the value of some of the combination therapies
EMEA Latvia
that were being investigated.
EMEA Lithuania
EMEA Netherlands
EMEA Portugal HIGH-LEVEL CONSIDERATIONS
EMEA Russia • Internal review of data, protocol optimization and reducing complexity and site burden
EMEA Slovakia
EMEA Spain • Less restrictive biomarker requirements
EMEA Switzerland • Timelines aligning with other competing studies
EMEA Ukraine
LA Argentina
• Managing complexities in:
LA Brazil –– Labs, including logistics and timely test results
LA Chile
–– Biomarker+patients
LA Mexico
LA Peru –– Multiple vendors
NA Canada
• Proactive, continuous and constant collaboration with client to strategize:
NA United States
–– Recruitment workshops
–– M.D. to M.D. discussions with PIs regarding scientific rationale and merits
of the study
–– Medical strategy meetings with client/Medical Science Liaison/PPD medical
team (monthly)
–– Benefits of program face-to-face investigator meeting with study-specific
breakout sessions
• Therapeutic and study-specific training for team and site staff

PPD developed strategies to address the identified challenges. To lay a foundation for
consistent communications that could cut through the noise, we spearheaded the
development of high-level and differentiating messaging for each study to articulate the
value proposition and clarify the scientific rationale for PIs, study coordinators and other
site staff. Patient-friendly education materials further helped illustrate the benefits of
the investigational drug combination versus competing agents.

8 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION

IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE

Highlights
• Four of the six studies (two studies
were merged) have achieved LPI,
enrolling 4,000+ patients and
activating 1,300+ sites in about
30 countries.
• Developed strategies to address a
complex set of challenges brought
about by new competition in a rapidly
evolving environment.
• Effective communication and
clear, simplified processes had a
significant impact.
The messaging, in turn, was strategically rolled out over a series of meetings. Multiday
kickoff meetings helped foster understanding, engagement and buy-in. In addition to
formal training, meetings incorporated time for study teams to brainstorm with us about
how to address the complexities of the protocol and manage challenging processes, such as
mandatory tumor biopsies. After a few months, the sites were invited to participate in
smaller half-day recruitment workshops. Importantly, the meetings and face-to-face time
helped strengthen site-CRO and site-client relationships. Given the complexity and the
intense competition, open lines of communication between the client’s medical science
liaisons across the world and the sites proved to be an important component. Success
demanded that all stakeholders worked collaboratively to proactively respond to issues as
they surfaced.
Because of the volume of patients needed, studies were enrolling sites that had, in many
cases, investigators with relatively limited I-O experience. These sites required guidance
and education. CRAs involved in the program were retrained to offer sites the necessary
enhanced support.

Challenge 4: Managing pseudoprogression, immune-related

responses and immune-related adverse events to avoid premature
stoppage of treatment
As oncologists choose from an expanding array of I-O therapies, we believe tolerability will
emerge as the key differentiator. I-O treatment can cause unique autoimmune reactions in
any tissue or organ system. (See Figure 7.)

Figure 7. A broad range of potential autoimmune reactions

Neurologic
Neuropathy
Meningitis
Guillane-Barre Syndome

Endocrine
Thyroiditis
Ocular
Hypothyroidsim
Iritis
Hyperthyroidism
Uveitis
Hypophysitis
Conjunctivitis
Hypopituitarism
Adrenal Insufficiency

Pulmonary
Pneumonitis Cardiac
Respiratory Failure Pericarditis

Gastrointestinal
Nausea, Emesis Diarrhea, Dermatologic
Colitis, Perforation; Mucositis
Pancreatitis Rash, Vitaligo

Renal Hepatic
Nephritis Transaminitis
Renal Insufficiency Hepatitis

9 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION

IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE
Treatment with both CTLA-4 and PD-1/PD-L1 blockade has Figure 8. RECIST v1.1 vs. iRECIST
been associated with immune-related adverse events (IrAE).8
PD-1/PD-L1 blockade is associated with fewer IrAEs as compared iRECIST
to CTLA-4 blockade 8. Although significant clinical benefits are • Derived from RECIST v1.1 conventions
• RECIST v1.1 should remain the primary response criteria in
apparent, increased toxicity with the combination of nivolumab
late-stage clinical trials
and ipilimumab has been seen in patients with advanced • iRECIST can be used as secondary endpoint in late-stage
melanoma resulting in the investigation of lower doses of trials and primary in early phase trials
ipilimumab and longer dosing intervals in other tumor types. • Used for assessing disease progression and response to
immunotherapy in solid tumors
Other important toxicities include Cytokine release syndrome
(CRS) commonly seen with CAR T-cell therapy. This syndrome
RECIST v1.1 iRECIST
can be fatal if not anticipated and managed properly. Recent CAR
T-cell approvals have required treating institutions to be properly New lesion Defines progression iUPD and if more new
after baseline lesions present at
trained in the identification and management of CRS, to educate
next assessment or
patients about CRS, and to have the IL-6 inhibitor, tocilizumab, increase size (>5mm)
available on site for patients treated with CAR T-cell therapies. then ICPD

CR, PR or SD Cannot have PD Can have had

before CR, PR or SD iUPD (one or more
Occasionally, unusual kinetics of tumor instances) but not
iCPD before iCR, iPR
response with delayed responses, possible or iSD
progression, and mixed responses also can
Confirmation Only required for As per RECIST 1.1
be seen.9 of CR, PR or SD non-randaomized
trials
Confirmation Not required (unless Required
of progression equivocal)
Pseudoprogression, an increase in tumor size because of a
Radiographic First instance of Unconfirmed PD
treatment effect rather than true disease progression, occasionally
progression > 20% increase in (iUPD) needs to be
can be seen in a minority of patients receiving checkpoint the sum of diameters confirmed at next
blockade, most commonly in patients with metastatic melanoma, or unequivocal tumor assessment.
but the frequency is less than 10 percent.10 Pseudoprogression may progression in Continue treatment if
precede a durable response to the immunotherapy.10 Therefore, if non-target disease clinically stable

a patient is doing well clinically, the strategy may be to continue Consideration Not included in Clinical stability
treatment beyond what would appear to be a RECIST 1.1 of clinical assessment needed to continue
status treatment after iUPD
progression. If the patient continues to show evidence of
RECIST 1.1 progression at the next scheduled tumor assessment, Independent Recommended in Collection of scans
blinded review some circumstances (but not independent
then treatment should be discontinued. Using immune-related and central (PFS trials planned review) recommended
response criteria (IrRC) in a patient who is doing well clinically collection for marketing for all trials
can prevent early discontinuation of treatment to capture the of scans approval)
benefits of the therapy. I-O trials are routinely using iRECIST for
Seymour L, Bogaerts J, Perrone A, et al. iRECIST: guidelines for response criteria for
treatment decisions, however, RECIST 1.1 is still the gold use in trials testing immunotherapeutics Lancet Oncol. 2017 Mar;18(3):e143-e15211.

standard for assessing response and progression endpoints

necessary for regulatory approval.11
Given the unique nature of the immune-related response, the
potential for pseudoprogression, and the possibility of IrAEs,
site staff must be properly trained in iRECIST to respond
appropriately to avoid premature stoppage of treatment.
It’s also important to educate patients to report symptoms
early so appropriate management can occur without
discontinuing treatment.
New technologies can help facilitate instant reporting of adverse
events. For example, the integration of electronic patient-reported
outcomes into the routine care of patients with metastatic cancer
was associated with increased survival compared with usual care,
according to a study published by JAMA.12 Early diagnosis and
appropriate management of toxicities may prevent more serious
complications and discontinuation of effective treatment.
Awareness of the timing of IrAEs during treatment with
checkpoint inhibitors can also help prevent serious complications
and premature discontinuation of therapy. (See Figure 9.)

10 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION

IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE
Figure 9. Kinetics of IRAEs with checkpoint blockade
Toxicity Grade
0 2 4 6 8 10 12 14
Weeks
Rash, pruritus
Liver toxicity
Diarrhea, colitis
Hypophysitis
• Data from pts receiving anti-PD-1 antibodies q2w
for > three years show most irAEs occure by
week 24 (6 months)
• Toxicities with PD-1/PD-L1 agents may take longer
to resolve than with ipilimumab, so long-term
surveillance is recommended
Weber J, Kähler K, Hauschild A. Management of immune-related adverse events and
kinetics of response with ipilimumab. J Clin Oncol. 2012 Jul 20;30(21):2691-7.13
Conclusion
The I-O field has advanced to better elucidate the tumor/immune
microenvironment, which is unlocking new and expanding
therapies, indications and combinations, while transforming
cancer care. With patients and clinicians clamoring to gain access
to new I-O regimens faster, the race is on to identify effective and
tolerable immunotherapies in both solid tumors and hematologic
malignancies, generate high-quality data, accelerate approvals and
ensure patient safety.
We expect that the pace of the development of I-O therapies,
including investigation of CAR T-cell therapy and other cellular
therapies in different tumor types—both as monotherapy and in
combination—will only continue to accelerate. This pace is driven
in large part by cross-industry collaborations between global
pharmaceuticals, biotechnology companies, academic centers,
CROs and community-based oncologists, with strong support
from regulatory authorities. We also expect to continue to see a
surge of innovations that will help propel the development of the
I-O landscape. This innovation will come on a diverse range of
fronts. To name a few, we anticipate a deepening understanding
11 ADDRESSING KEY CHALLENGES IN THE CLINICAL DEVELOPMENT OF COMBINATION
IMMUNO-ONCOLOGY THERAPIES: A CRO’S PERSPECTIVE
and application of biomarkers, the adoption of JiT activation
models that connect studies to patients within their own local
communities, more patient centric studies that leverage unique
trial designs and new approaches to address the important issues of
financial toxicity and patient access. The I-O space is pushing the
limitations of scientific, technological and operational advances,
and we are happy to continue to share our learnings in this
ever-evolving landscape.
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