Pharmaceutical Commerce - May/June 2017 - 16

Market Access
combine I/O therapies with traditional
chemotherapies and newer biolog ic
oncology agents. As there are dozens of
new drugs in development to modulate
the immune environment in a variety of
ways, this leads to an exponentially high
number of combinations and sequencing
"This surge in treatment candidates
calls for novel and adaptive clinical trial
designs-including studies that use serial
tumor biopsy sampling and selection of
enriched patient populations for immune
targets-to help guide the effort," says
Cowey of Texas Oncology. "The staggering
cost of drug development makes
appropriate trial design and drug utilization
a high priority, especially in markets that
are increasingly competitive and crowded."
To wit: According to 2015 data from
IMS Institute for Healthcare Informatics
(Parsippany, NJ), the annual growth rate
in cancer drug costs has risen from 3.8% in
2011 to 11.5% in 2015, at constant exchange
rates. In the US, cancer drugs now make up
11.5% of total drug costs, up from 10.5%
in 2011.
"Drug makers must think through how
to position their novel I/O therapies (frontline, relapse, maintenance, or all of these),"

says Chadi Nabhan, MD, VP and chief
medical officer, Cardinal Health Specialty
Solutions (Dublin, OH).
Similarly, perhaps unlike other oncology
therapy approaches, "the key thing is
to know when and how to apply I/O
therapies for best effect," adds Dr. Robert
Rifkin, oncologist with Rocky Mountain
Cancer Centers (Denver), a practice in The
US Oncology Network. "I/O approaches
will likely work best with patients with
some immune system that can still be
reprogrammed. Similarly, if the patient's
immune system is too damaged, they
will not be as effective and the cost of the
approach may not be justified."
The two most well-known commercial
I / O p r o d u c t s - M e r c k 's Ke y t r u d a
(pembrolizumab), approved for melanoma,
NSCLC ,and some head and neck cancers,
and Br istol-Myers Squibb's Opdivo
(nivolumab), approved for NSCLC-both
use humanized antibodies that block PD-1
(a protective mechanism on cancer cells
that help them evade detection by the
immune system). In essence, these therapies
rip the proverbial 'cloak of invisibility'
off the cancer cells, allowing the body's T
cells to actively attack them. Both rely on
companion diagnostic testing to identify

Data from a national survey by Cancer Treatment Centers of America
16 Visit our website at May | June 2017

the most receptive patients in each of the
approved indications.
M e a n w h i l e , G e n e n t e c h / R o c h e 's
Tecentriq (atezolizumab), approved last
October, was the first FDA-approved
checkpoint inhibitor that is focused on the
anti-PD-L1 pathway instead of PD-1, and
is approved for use with bladder cancer and
metastatic NSCLC.
The ligand PD-L1 is a protein that is
expressed on cancer cells and immune
cells; anti-PD-L1 antibodies bind to the
PD-L1 ligand and undermine the ability
of tumor cells to use PD-L1 for protection
against white blood cells, such as human
T-cells from the immune system -
thereby allowing the immune system to
take the tumor cells out more effectively.
In a nutshell, in the words of the National
Cancer Institute (NCI): "Immunotherapies
either stimulate the activities of specific
components of the immune system, or
counteract signals produced by cancer cells
that suppress immune responses."
In March, the latest human PD-L1
antibody-Bavencio (avelumab) from
EMD Serono (the US biopharmaceutical
business of Merck KGaA) and Pfizer-
won FDA approval for the treatment of
metastatic Merkel cell carcinoma (mMCC),
a rare and aggressive skin cancer with fewer
than half of patients surviving more than
one year and fewer than 20% surviving
beyond five years. The companies reported
that Bavencio produces durable tumor
responses in mMCC patients, with 86%
of responses lasting at least six months
(n=25), and 45% of responses lasting
at least 12 months (n=13). Duration of
response ranged from 2.8 to 23.3 months.
"With the approval of Bavencio for the
treatment of mMCC, we now have seven
approved oncology indications for PD-1
and PD-L1 checkpoint inhibitors, and we
expect to see another five to eight different
oncology indications being addressed in
the next round of checkpoint inhibitor
approvals," says Herman Sanchez, partner,
Trinity Consultants (Princeton, NJ).
"Both categories of checkpoint
inhibitors (the anti-PD-1 and anti-PD-L1
therapies) rely on the same pathway-
checkpoint inhibition-but are coming at
it from a different direction," says Evans
of Genentech. "Developers are targeting
the right pathway, but the companion
diagnostics are just not precise enough
to effectively target the right patient right
"There are currently five molecules
under development that appear to offer
relatively similar efficacy and safety
tradeoffs," says Kaman of ZS Associates. As
of this past summer, there were more than
700 ongoing trials for the main PD-1 and
PD-L1 checkpoint inhibitors (nivolumab,
pembrolizumab, atezolizumab, avelumab
and durvalumab). Of these trials, more
than 200 were for Phase I or II programs
involving 100 or more patients. "This
signifies a big shift in the way we think
about bringing these drugs to market. It

also denotes a massive arms race to be firstin-class in new indications."
Later entrants to the space will
face greater challenges to differentiate
themselves to physicians and providers.
"If a par ticular I/O w ill be third or
later launching in a given tumor type,
manufacturers must pass a higher bar
and find meaningful ways to gain payer
cove r a g e ," s ay s Ka m a n . " T h e t re n d
is toward faster, more efficient trials,
followed by RWE to prove it's working.
The key is to break the cycle of adversarial
negotiations that can prevent faster and
more meaningful progress on this topic."
Hidden danger
Since the aim of immunotherapy
is to "exaggerate" the immune response
against cancer, it can, unfortunately, also
elicit unwelcomed inflammatory and
autoimmune side effects, so managing
these risks will be an important issue as I/O
therapies become more widely used," notes
Shields of Xcenda. For instance, among
the warnings and precautions stated for
EMD Serono/Pfizer I/O therapy Bavencio
are such immune-mediated adverse
reactions as pneumonitis, hepatitis, colitis,
endocrinopathies, nephritis and renal
dysfunction. Many of these are associated
with other checkpoint inhibitors as well.
"Interestingly and not surprisingly,
there is a growing interest among patients
who want to know more about the ability
to train the body's immune system to
fight the disease, but unfortunately their
oncologists are not talking about it with
them," says Crilley of CTCA. In general,
patients and other stakeholders may not be
fully aware of how immunotherapy works,
or be aware of the early- and late-term side
effects. Patients, caregivers and providers
need to be educated on immunotherapy
treatment in order to facilitate patientprovider discussions. Manufacturers can
play a leading role in this initiative.
Specifically, according to a study
re l e a s e d by C TC A i n Fe br u a r y, t h e
2017 Cancer Experience,* "More than
two-thirds of cancer patients and their
caregivers have limited knowledge of
the latest treatments to help inform
their treatment decisions; 74% of cancer
patients expressed interest in learning
more about immunotherapy, yet only
32% say their oncologist has discussed
immunotherapy with them," says Crilley.
"Patients and caregivers frequently don't
know what questions to ask, especially
after an initial diagnosis, and they typically
default to the Internet to obtain additional
information," said Maurie Markman,
MD, president of medicine and science at
CTCA, at the time of the announcement.
"Much of this is difficult for them to
interpret, however, so an increasingly

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