2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Opportunities and Pitfalls of Targeted
Therapeutic Combinations in Solid Tumors
By Joaquin Mateo, MD, MSc, Michael Ong, BSc, MD,
Timothy A. Yap, BSc, MBBS, MRCP, and Johann S. de Bono, MB ChB, MSc, PhD
Overview: Recent advances in cancer biology have led to the
discovery and development of chemical compounds and drugs
that target specific cellular receptors, mediators, or effectors
that are central to oncogenic survival, growth, and invasion.
However, the complexity of tumor biology makes it is unrealistic
to expect an antitumor therapeutic to be successful
based on the inhibition of a single target or even a lone
signaling pathway. Therefore, the potential success of such
“targeted therapies” is likely to require the development of
multiagent combinations. Combination strategies have a
greater likelihood of addressing issues with genetically complex
tumors, potentially avoiding drug resistance mechanisms
NOVEL DRUGS aim to selectively inhibit mechanisms
essential to cancer pathogenesis, while limiting “offtarget
effects” and undesired toxicities. Despite the hype,
only a limited number of targeted agents have been successful;
this includes the inhibition of ABL and c-KIT by imatinib
for chronic myeloid leukemia and in gastrointestinal
stromal tumors (GIST). 1 However, primary and secondary
resistance to therapy is common because of mechanisms
such as novel mutations that decrease imatinib binding, or
mutations in downstream proteins involved in the phosphatidylinositol
3-kinase (PI3K) pathway that are c-KIT independent.
2,3 Ultimately, the application of a single targeted
agent even in these successful models has not abrogated
the development of resistance, nor has it led to increased
rates of cure. 4,5
Opportunities with Targeted Combinations
Numerous well-established examples exist in oncology
where combination regimens of anticancer drugs are more
successful than single agents. An example of a successful
antitumor combination is 5-fluorouracil, leucovorin, and
irinotecan (FOLFIRI) with bevacizumab in colorectal cancer.
6 In addition, it is well known that diseases such as
Hodgkin lymphoma require multiagent chemotherapy to
achieve cure. This and our increased understanding of
disease biology indicate that in order to increase the odds of
successful anticancer strategies, specific targeted agents
should be combined with either other selective inhibitors or
chemotherapy.
The development of combination regimens involving targeted
therapies versus chemotherapy combinations may
differ in that chemotherapy was traditionally studied in
combination only once a single agent was approved and
demonstrated clinical activity benefit. Conversely, targeted
drugs may and probably should be tested in hypothesistesting
rational combinations earlier in the drug development
journey if tolerability data are available, assuming
there is a strong biologic rationale to combine two drugs.
Even if these agents demonstrate modest anticancer activity
as single agents, with substantial pharmacodynamic inhibition
of target and pathway, satisfactory pharmacokinetics
and tolerability, combination studies may be warranted. We
envision that earlier testing of such combinations in early-
670
through the inhibition of escape signaling pathways and
slowing the development of newly resistant tumor cells. Combination
regimes also have the potential of enhancing target
inhibition through synergistic antitumor effects and minimizing
drug-related toxicities to patients. However, numerous
challenges to developing these combinations exist. This review
will focus on the opportunities and pitfalls of developing
novel targeted drug combinations, with a particular focus on
early-phase drug development, where the greatest challenges
exist, analyzing key points for the design and development of
clinical trials for combinations of targeted agents.
phase trials to be increasingly desirable and an important
opportunity to accelerate drug development.
Before the clinical testing of a combination regimen, it is
critical to understand the underlying biologic rationale and
to have some preclinical evidence demonstrating synergistic
or additive antitumor effects for the anticancer drugs being
evaluated. Because targeted agents have been developed
as potent inhibitors of select biologic targets, combination
targeted therapy strategies can also seize the opportunity to
selectively titrate effects on multiple targets using potent
inhibitors. In this manner, combination dosages and schedules
can be altered to optimize antitumor efficacy and
minimize the toxicity profile (Table 1).
Examples of Strategies to Combine Targeted Agents
Superinhibition of a single target. This strategy maximizes
the inhibition of a single target, enhancing the “on
target” effect. Examples include strategies of dual HER2
blockade (e.g., trastuzumab with lapatinib or pertuzumab in
combination). Several studies have demonstrated these
strategies to be tolerable, with evidence of clinical benefit,
in various stages of breast cancer. 7,8 This strategy may be
best utilized in tumors that are highly dependent on a single
gene or target, without significant resistance mechanisms
that bypass the target. This strategy also has the disadvantage
of possibly enhancing overlapping drug-related
toxicities.
Inhibition of several targets within a single pathway. This
strategy takes an approach to inhibiting multiple substrates
to maximize pathway inhibition while minimizing resistance
mechanisms that may occur because of regulatory
feedback loops. For example, there is evidence of upregulation
of AKT phosphorylation after mTOR inhibition in several
cell lines and human tumor types, 9 suggesting a role for
From the Drug Development Unit, Royal Marsden NHS Foundation Trust, The Institute
of Cancer Research, Downs Road, Sutton, Surrey, United Kingdom.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Professor Johann S. de Bono, MB ChB, MSc, PhD, Division
of Cancer Therapeutics and Division of Clinical Sciences, The Institute of Cancer Research/
Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, United
Kingdom; email: johann.de-bono@icr.ac.uk
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10