2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

COMBINING TARGETED AGENTS IN CLINICAL TRIALS
the doses for combination can occur in many permutations.
Dose-escalation rules for combination therapy must take into
consideration preclinical data for the single agent and the
combination. Depending on the stage of development of each
agent, their mechanism of action and the potential overlapping
toxicities, different scenarios are envisioned: dose escalation
is probably best pursued sequentially, increasing the
dose of one compound in every step; dose escalation of both
drugs at the same time is not recommended; and to optimize
antitumor cell kill there is also merit in fixing the drug
targeting the driver pathway (e.g., BRAF/MEK inhibitor for
BRAF mutation in melanoma) at the highest tolerable dose
while dose escalating the combination drug (e.g., PI3K/AKT/
TOR inhibitor). When combining two drugs with no pharmacokinetic
interactions and nonoverlapping mechanisms
of action and toxicity, and when we already have extensive
experience regarding the tolerability profile of each drug,
fewer dose-escalation steps may be necessary to accelerate
combination development, as recently reported in a trial
exploring the combination of sunitinib and everolimus in
metastatic renal cell carcinoma (mRCC). 24
Novel combinatory designs have also been suggested as
potential improvements over algorithmic approaches. These
strategies try to pursue fewer levels of dose escalation,
thereby reducing the rate of patients exposed to biologically
inactive doses without exposing them to more toxicities, in
contrast to more classical drug development designs. 25
Novel models of multiple parallel cohorts permit escalating
two or more drugs in a sequential/parallel manner based on
mechanism-related toxicities. 26 Bayesian model-based designs
are based on continual reassessment of risk of toxicities
and have been applied to dose escalation of combination
targeted agents. 27
Flexible dose escalation and de-escalation rules and intense
knowledge about the mechanisms of toxicity of each
drug in the combination are required to maximize outcomes
without compromising a potentially or already known active
dose of a single agent. Despite the availability of these novel
trial designs, they are not commonly used.
Furthermore, although the rationale for the combination
should consider which pathway is the main driver of the
disease and therefore which drug is administered at a dose
level closer to its single-agent MTD, investigators may have
to be prepared to decrease the dose of the main drug if the
biologic rationale of a trial suggests a likelihood that synergism
and full-dose combination is not tolerable.
Biomarker-Guided Selection of Patients
Although the selection of patients in early-phase trials
based on biomarkers may make trial recruitment more difficult,
combinations of targeted agents based on hypotheses of
synergistic biologic effect will ultimately require patient selection
using biomarkers that identify populations that may
benefit. Unfortunately, often the development of valid biomarkers
that predict for benefit are often slow to develop
in both clinical and preclinical models, making patient selection
in early-phase trials difficult. The development of predictive
biomarkers for patient selection is crucial to the success of
targeted agents as well as combinations of targeted agents.
Assessment of Tolerability in Combination Studies
Since chronic dosing is usually indicated for these drug
combinations, delayed and cumulative toxicities should be
carefully considered when selecting the recommended dose
for further development. As an example, a phase I trial of
the combination of bevacizumab and everolimus 28 escalated
doses up to 10 mg/kg fortnightly and 10 mg/d po respectively,
without observing dose-limiting toxicities during the
first cycles of treatment. In a phase II trial in mRCC, 29 up to
a quarter of the patients had grade 3 or 4 proteinuria with
the combination, while grade 3 or 4 proteinuria with bevacizumab
alone at the same dose in mRCC was below 8%. 30
Trial designs that integrate information from late onset
toxicities for deciding regarding dose selection may be warranted.
31 In addition, clinical trials should aim to assess
mechanistic data to define causal relationships with drug
and observed toxicities to make better informed decisions
regarding choices of combination targeted agents. Uncertainty
regarding the mechanisms behind targeted agent
toxicity and off-target drug effects may negatively affect
promising combinations.
Regulatory Concerns and Legal Barriers
The evaluation of different combinations of several targeted
agents from multiple companies may sometimes be
challenging because of competing interests, and may be
further complicated if multiple sponsors are not fully committed
to the trial. A clear example may be combining an
established drug or chemotherapy regimen with a novel
agent, as the outcome of the trial may not be equally
profitable for both sponsors. Apart from intellectual property
issues and the requirement of financial support, the
risk of novel toxicities and adverse outcomes with concomitant
administration might be considered a risky commercial
decision for sponsors whose antitumor compound is already
at a more advanced stage of development. Academic institutions,
patient lobbies, and regulatory authorities may
need to assume a championing role for some combinations
with a strong biologic rationale that are perhaps less commercially
attractive.
Conclusion
The advent of targeted therapies has shifted the emphasis
in drug development from cytotoxic chemotherapy combinations
to selective and potent molecular therapeutics. Such
specific inhibitors may not result in significant or durable
antitumor activity as single agents, and should therefore be
given in combination with one or more drugs to molecularly
defined populations of patients. We should now be focusing
more efforts on combinatorial drug development strategies,
perhaps even from the outset of first-in-human trials to
maximize the likelihood of benefit to patients dying of
advanced cancer. Such an approach may be able to further
accelerate the delivery of anticancer treatment to benefit
and improve the lives of our patients with cancer.
ACKNOWLEDGMENTS
The Drug Development Unit of the Royal Marsden NHS
Foundation Trust and The Institute of Cancer Research is
supported in part by a program grant from Cancer Research
United Kingdom. Support was also provided by the Experimental
Cancer Medicine Centre (to The Institute of Cancer
Research) and the National Institute for Health Research Biomedical
Research Centre (jointly to the Royal Marsden NHS
Foundation Trust and The Institute of Cancer Research).
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