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10
Wrapping Up
Given the complexity of cancer and the mounting evidence that tar-
geted cancer treatments and cancer immunotherapies are likely to have
stronger and more long-lasting effects when combined makes it impera -
tive to develop greater collaborations among industry, academia, and
government in the development of combination investigational cancer
therapies. During the course of the workshop, participants offered numer-
ous suggestions for how to facilitate such collaboration.
In the preclinical arena, participants suggested more effort and fund-
ing to develop animal models in which to test investigational drug combi-
nations and their mechanisms of action and pharmacokinetics, as well as
resistance mechanisms. These animal models could entail tumor explants
or be genetically engineered to develop tumors with the molecular defects
commonly seen in human tumors. Surrogate efficacy models can be used
to assess the effects of combinations of immunotherapies, which cannot
be tested in standard explant models. Alternatively, researchers could
create animal versions of the immunotherapies that have been devel-
oped, and test them in animals with intact immune systems. Tumor cell
lines could also be grown in different microenvironments to see how
they affect agents and their targets, and more effort should be made to
grow tumor cell lines in three-dimensional culture situations. “There are
multiple models, and we still don’t know what is the best model to use
to determine which combinations to go forward with,” summarized Dr.
Hohneker.
There could be more interplay between the bench and the bedside,
73
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74 COLLABORATIONS TO DEVELOP COMBINATION CANCER THERAPIES
participants suggested. Researchers could use animal models to suggest
which combinations of agents would be most effective at countering the
specific molecular defects in patients’ tumors. If clinical testing of such
combinations cause toxicity or resistance, the same combinations could
be retested in animal models to assess better dosing, scheduling, or the
molecular resistance mechanisms and what other agents might counter
them. Studies of biopsies collected from patients with tumor progression
could also point toward more effective combinations of agents.
Several participants pointed out the need for higher standards for
both preclinical and clinical effectiveness. Tumor shrinkage is likely to
be a better endpoint in laboratory studies than blocking tumors from
forming or from growing, whereas overall survival is likely to be a better
endpoint than time to progression in clinical studies, they argued.
Given the numerous possible combinations and limited number of
patients and other resources, there has to be some prioritization of what
combinations should be tested clinically. Suggestions for prioritizing
included testing only those combinations that:
• erform well and consistently in several xenograft models;
P
• Have a biological mechanism for which there is an assay;
• ave demonstrated adequate pharmacokinetics and some evi-
H
dence of activity or target engagement at clinically relevant doses
and exposures;
• re composed of the best in each class of agents that are pharma-
A
cologically compatible; and
• ave validated biomarkers for patient selection and pharmacodynamics.
H
Some participants cautioned that effective combinations should not
be judged on the basis of the single-agent activity of their components,
as many combinations have been found to be effective even though stud-
ies of the single agents did not show significant effects. There also was
concern about the additive, synergistic, or unexpected toxicities that
can result from combinations, particularly those that target the same
pathways. Researchers need to explore more creative innovations in the
approach to dosing and scheduling to avoid toxicity and improve efficacy,
several participants suggested. Agents could be used intermittently or
sequenced in a manner that makes sense from a biological, mechanistic
perspective.
To aid both preclinical and clinical investigations, more basic informa-
tion could be gathered on genetic expression, and feedback and network
responses to signaling perturbations and DNA damage. Some participants
stressed that information is also needed on the non-genetic effects that
influence treatment, including the microenvironment of the tumor, the
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75
WRAPPING UP
host immune response, and proteins made by the tumor and surround -
ing cells.
In the clinical arena, there was enthusiasm for using adaptive trial
designs to determine the best combinations and dosing strategies, and to
assess patient selection biomarkers as the trial progresses. “Adaptive trial
designs may really facilitate the ability to screen for drugs,” Dr. Hohneker
summed up. Several participants suggested repeat biopsies of patient
tumors to assess effectiveness and confirm mechanism of action of inves -
tigational agents. Assessing the maximum tolerated doses of all the drugs
used in combination may not be meaningful or appropriate, especially
for combinations that employ immunotherapies. But researchers should
have enough sampling points so they can model the dose–response curve.
Several participants suggested that different cancer patient advocate
groups join together to encourage the same specific goals, particularly
because such advocacy proved highly valuable in fostering rapid devel-
opment of effective treatments for HIV infection. Patient advocates could
be helpful in putting pressure on companies and institutions to work
more collaboratively, have quicker IRB reviews, and share patient speci-
mens. Advocates can also work with investigators to assess and promote
the clinical testing of priority combinations. Mutual education between
advocates and scientists can be helpful in furthering progress.
Companies could communicate more about their compounds in pre -
clinical development and join forces when they do not individually have
all the agents needed for an effective combination in their portfolios, and
other companies can supply the missing agents. Compelling those col-
laborations will be the “good science” underlying them, Dr. Hohneker
said. “If the data are there, people will work together. I don’t think you’ll
find much resistance to good science.”
More efforts should be made to collect patient specimens during clini-
cal trials, and store and make these tissues available for future research on
biomarkers, several participants noted. The development, validation, and
use of biomarkers for patient selection and treatment effectiveness will be
key to the success of cancer combination therapies. Easier access to study
drugs would also be helpful. Safe harbors for companies and institutions,
such as FNIH and the CEO Roundtable on Cancer Life Sciences Consor-
tium, have proven helpful in negotiating collaborations and managing
the patents and other intellectual property rights that result from such
collaborations. A safe harbor to distribute study drugs to investigators,
or to do preliminary clinical testing of combinations, might substantially
further development of combination cancer therapies, many participants
stressed.
Within the regulatory arena, FDA recognizes the importance of com-
bination therapies for cancers and is currently revising its guidelines
on the combination of investigational therapies and codevelopment of
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76 COLLABORATIONS TO DEVELOP COMBINATION CANCER THERAPIES
a diagnostic with a therapeutic. The agency has indicated that it wants
to be flexible in what is required of sponsors, and will sometimes accept
preclinical data instead of extensive clinical testing of drug combinations.
FDA welcomes pre-IND consultations, especially for innovative study
designs. “We still will have to show the contribution of the agents, but
the encouraging part is that how we do that is something that can be
discussed,” as Dr. Hohneker pointed out. More effort should be made to
make FDA regulations compatible with EMA regulations so as to foster
global drug development, some participants suggested.
To help tackle some of the other complex legal issues linked to devel -
oping combination therapies, such as IP and indemnification, there could
be more reliance on NERFs and the development of standard clauses and
core principles to make legal negotiations more expedient. Identifying
key decision makers, who are knowledgeable about the legal issues, can
also be helpful in legal negotiations. Antitrust issues are not likely to pose
barriers to collaborations among companies, particularly if they will not
limit competition; if the collaborators do not already have entrenched
products; if the collaboration is limited to core research efforts; and if it
is possible to show benefits that the collaboration will achieve that could
not be achieved as easily on an independent basis. It is possible to obtain
prior guidance with the FTC or the DOJ about antitrust issues. Antitrust
lawyers can also advise research and development efforts.
There are several examples of collaborations in the early development
as well as the clinical testing of combination cancer therapies. These col -
laborations show that barriers are not insurmountable and provide exam-
ples for others to follow. Particularly notable innovative clinical testing
examples are the I-SPY 2 TRIAL and the BATTLE 2 trial. Several scientific
tools to aid cancer combination therapy development are available in the
public domain, including GSK’s epigenetic toolbox and preclinical data,
NCI’s mechanism-of-action assays and preclinical models for combina-
tions, as well as the investigational agents that NCI makes available for
preclinical testing.
Several participants stressed the importance of doing whatever it
takes to facilitate collaboration in the development of combination investi -
gational cancer therapies. “There is really an urgency to identify solutions
for the barriers because we have patients at stake,” said Dr. Hohneker.
Dr. Mendelsohn agreed with the urgency to speed up combination drug
development, given that “one-third of our patients will not live 5 years—
that’s a half-million people a year.” Dr. Hohneker concluded the confer-
ence by stating, “The takeaway is that for success and learning, it takes
a team of people who are very committed and passionate, and willing to
work together to come up with the solutions, as well as strong collabora -
tions, persistence, good science, and the willingness to learn.”
