2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

COMBINING TARGETED AGENTS IN CLINICAL TRIALS
the rational combination of mTOR inhibitors with either AKT
or PIK3CA inhibitors or the development of TOR kinase
inhibitors. This strategy may be best utilized in tumors driven
mainly by one pathway but which may fail if alternative
pathways are prominent as a mechanism of resistance. This
strategy also has the disadvantage of possible overlapping
drug-related toxicities via inhibiting the same pathway.
Targeting parallel or unrelated pathways. This strategy
maximizes the likelihood of avoiding resistance mechanisms,
especially those caused by the upregulation of parallel
pathways, and also minimizes overlapping toxicities. The
concomitant inhibition of two pathways may also result in
selective tumor cell cytotoxicity, whereas each agent alone
may not be active as a single agent.
An example of this approach is the dual targeting of the
PI3K and Ras/Raf/Mek/ERK pathways. Deregulation of the
Ras/Raf/Mek/ERK pathway has been identified as a determinant
of resistance to PI3K-Akt inhibitors. 10 There is also
strong preclinical evidence that ERK-independent mechanisms
of resistance to B-RAF and MEK inhibitors are
mediated by the upregulation of the PIK3CA/Akt/mTOR
pathway. 11 In murine models, double inhibition of PIK3CA
and MEK shows synergistic antitumor activity for K-RAS
mutant tumors, 12 and PI3K-Akt activation leads to MEKinhibitor
resistance in K-RAS mutants, which is reversible
when blocking both pathways. 13 Moreover, mutations in
both pathways tend to coexist. 14
Clinical trials are currently being conducted to evaluate
this strategy of targeting parallel pathways. Recently, a
first-in-human trial of the pan-AKT inhibitor MK-2206 has
been reported; although strong pharmacodynamics evidence
of AKT signaling blockade was demonstrated, minimal evidence
of single-agent antitumor activity was observed. 15 A
combination trial of MK-2206 with the MEK inhibitor
AZD6244 is currently being evaluated (NCT01021748) and
is demonstrating antitumor activity in KRAS-mutant cancers.
Other similar early-phase trials of combinations based
on this approach include drugs targeting MEK and mTOR
(NCT01378377), or MEK and PIK3CA/mTOR inhibition
KEY POINTS
● The biology of cancer cells involves complex signaling
networks, so anticancer strategies may not be successful
if blocking single targets.
● A combination of targeted agents will be necessary to
maximize antitumor activity, counteracting primary
and secondary resistance.
● The rationale for evaluating combinations of drugs
must rely on biology-driven hypothesis and smart
screening strategies.
● Different strategies include using two or more drugs
against the same target, targeting different points
upstream and downstream of one pathway, or targeting
several pathways simultaneously on which the
cancer cell is dependent.
● Design of clinical trials with combinations of targeted
agents should consider how to deal with the challenges
pertaining to such studies.
Table 1. Opportunities and Pitfalls of Combining
Targeted Agents
Opportunities Pitfalls
1. Validate novel biologic hypotheses
2. Synergize antitumor effect without
synergizing toxicity: increasing the
therapeutic window
3. Further develop single agents that do
not have activity as monotherapy:
synthetic lethality
4. Counteract primary and secondary
resistance
5. Develop novel indications for existing
and/or approved drugs
(NCT01390818). These data allow us to envision the testing
of biology-driven hypotheses with multiple combinations;
these may eventually require more drugs for optimal blockade
of cancer growth. Combinations for the treatment of
advanced prostate cancer that we propose include abiraterone
acetate and MDV3100; either of these agents with
PI3K/AKT/TOR inhibitors; or possibly triple therapy with
abiraterone, MDV3100, and a PI3K/TOR inhibitor.
Choosing the Right Combination Therapy
1. Unreliable preclinical models
2. Optimal selection of drugs and
targets to combine
3. Optimal sequence and dosage of
the combination
4. Risk of overlapping toxicities
5. Lack of standardized design for
phase I/II trials for combination
targeted therapies
6. Competing interests of different
researchers, corporations, and/or
institutions to combine therapies
When combining two (or more) targeted therapies for the
first time, each must be tested at various doses and dosing
schedules in a phase I study. However, the process of dose
finding, or defining the recommended phase II trial dose,
can take 1 year or longer to complete depending on the
complexity of the trial and compatibility of the agents, all at
significant cost. Therefore, it is critical to utilize strategies
that identify the best therapeutic combinations, and furthermore
identify targets that cancer cells are reliant on so that
when blocked, there is a lethal or at least cytostatic effect.
This type of approach is based on concepts of oncogene
addition, nononcogene addiction, and synthetic lethality
that attack the “hallmarks” of cancer. 16
Adopting systems-based approaches may help to address
this complexity, such as utilizing information from deep
transcriptomic, genomic, proteomic, and/or metabolic analyses.
17 Although this “personalized” approach is attractive,
it may often yield information on targets for which there is
no active drug, for which there are only “passenger” mutations
rather than drivers of oncogenesis, or for genes for
which we have incomplete functional information. It has
been suggested that systems-based approaches can be used
to select targeted combinations 17 ; however, further development
and application of bioinformatics is clearly necessary
to process the high amounts of data derived from massive
screening strategies.
Another strategy is to identify potential drug combinations
using RNA interference (RNAi) to simulate models of
pharmacologic inhibition. In this method, wild-type cell lines
or cell lines with induced loss of function for a particular
target are exposed to RNAi libraries with or without exposure
to a particular drug to look for antitumoral synergism
or drug sensitization. These RNAi screens can therefore
select potential combination of targets to be tested further
18,19 and ideally identify potential synthetic lethality
effects when inhibiting two a priori nonlethal targets. How-
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