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abstracts
a paradigm shift in early drug
development: individualizing
to more patient benefit
27IN THE IMPORTANCE OF PATIENT SELECTION IN TREATMENT
EFFICACY
S. Aamdal
Dept of Oncology, Oslo University Hospital, Oslo, NORWAY
The importance of patient selection in treatment efficacy Cohorts of patients selected
according to biomarkers are shifting the cancer treatment paradigm from population
based to personalized medicine introducing a new area termed theragnostics in
which the combination of diagnostics and therapeutics identifies patients most likely
to benefit or not from a treatment regimen. Apart from safety and toxicity
assessment phase I trials now also test hypothesis, determine target engagement,
biologic response, identify the appropriate patient population, proof-of-concept, and
identify potential predictive biomarkers in Phase II and Phase III trials. There are
several strategies to select patients on molecular bases for early drug development. 1)
The molecular alterations are sufficient frequent in a tumor type that without
pre-selection retrospective analysis of the mutation can be carried out. A
retrospective analysis on fixed tissue can confirm the drug activity in presence of the
molecular alteration. Selection is then based on tumor type, not on molecular
analysis. Such selection would put a number of patients at risk of exposure to a study
drug despite not presenting the target of interest. 2) Prescreening patients by sending
tumor tissue to a central laboratory for analysis just before inclusion in a trial. This
ensures state-of the art central laboratory analyses. Amount of tumor tissue may
become an issue if several labs are involved. Turnaround time between molecular
analyses and trial initiation may become too lengthy for patients with advanced
disease. 3) Local prescreening of patients while still on standard treatment. Less
tumor material is needed and no delay from progression on standard therapy to
recruitment in a clinical trial. Multiple patient consent forms are not necessary.
However patients will be screened for participating, but never will enter trial due to
early disease progression. Intra-tumor heterogeneity, presence of more than one
clone in the tumor and inter-tumor heterogeneity, the presence of different genetic
alterations in different metastases from a single patient is a major challenge to patient
selection. Single cor biopsy may lead to underestimation of the mutations in the
tumor and could influence the efficacy of molecular targeted therapies even in
carefully selected patients.
Disclosure: The author has declared no conflicts of interest.
28IN THE ROLE OF TUMOR/MOLECULAR TARGET SELECTION
IN THE SUCCESS OF A NEW AGENT
C. Dittrich
3rd Med. Dept.-Centre for Oncology and Haematology, Kaiser Franz
Josef-spital, Vienna, Austria, LBI-ACR VIEnna & ACR-ITR Vienna, Vienna,
AUSTRIA
Rational drug discovery/development is targeted at structures and pathways, which
cause, permit, or maintain malignancy. This let restrain from the histopathologically
characterized organ entities and substitute them for merely molecularly characterized
entities, such as EGFR, HER2, KRAS, BRAF driven entities. The presence of a target
and its therapeutic consequence in one organ cannot be extrapolated to another. As
an example, a BRAF mutation positive (m+) status in melanoma, which is highly
predictive for response to the anti-BRAF directed TKI vemurafenib (Flathery 2010),
cannot be extrapolated to the situation in BRAFm+ CRC (Kopetz 2010). A further
difficulty in switching from tumor entity to target entity lies in the experience that
clinical effectiveness does not only depend on whether a functional axis is hit by a
drug or a class of drugs anyhow and anywhere, but moreover in a much more
defined context; TKIs like erlotinib (Zhou 2011; Rosell 2012) yielded increased OS
and PFS, respectively, in EGFRm+ tumors. But, the interference of the same axis at a
different site and via the anti-EGFR MoAb cetuximab (in combination with standard
therapy) led to an OS advantage independent of the EGFR mutational status of
NSCLC (O’Byrne 2011). This touches upon the necessity to discover, identify,
develop, and finally validate the most relevant biomarker(s) for the purpose of drug
development, notably with high predictive accuracy early in the developmental
process. In NSCLC, it took almost a decade of trial and error to better define the
position/clinical usefulness of various biomarkers and methodologies, respectively, to
Annals of Oncology 23 (Supplement 9): ix32–ix33, 2012
doi:10.1093/annonc/mds374
characterize/measure the probability to benefit clinically in form of EGFR expression/
gene amplification/copy number and mutations on the one side, and ORR, PFS, and
OS, respectively, on the other side. A shortcoming derived from the earlier
developmental process is the lack of fixing the right time point to preselect/enrich the
relevant patient population. This is of utmost importance, especially if patient
segments are small. In addition, it has to be found out whether a new targeting
substance is not only reaching /modulating the target, but has also enough impact on
the relevant biology of the tumor to gain clinical effectiveness.
Disclosure: C. Dittrich: Unrestricted research grants to the research institutes
Honoraria for consulting services by several companies
29IN WHAT IS THE FEATURE OF AN OPTIMAL NEW AGENT:
SELECTIVE TARGET VERSUS MULTI-TARGETED VERSUS
COMBINATION DRUGS
J.H.M. Schellens, S. Marchetti
Department of Clinical Pharmacology, The Netherlands Cancer Institute,
Amsterdam, NETHERLANDS
There are in principle two pharmacological ways to address the question whether
selective targeted or multitargeted drugs are to be preferred as single agent and/or in
combination. One approach is to focus on benefit and the other is to focus on safety.
The modern era of development of targeted agents started with the launch of two
key molecules: one monoclonal antibody (MoAb) rituxumab and one so-called small
molecule imatinib. Rituximab was registered in the EU in 1998 and since then about
seven other MoAbs have been registered. All MoAbs tend to have a selective
mechanism of action and target on average one key protein, for example CD-20
(rituximab), or Her2 (trastuzumab). The benefit of these drugs has been clearly
demonstrated and the safety of these MoAbs is on average good. Possible exception is
where they target the same proteins in normal tissues such as the skin (cetuximab,
panitumumab), or the heart (trastuzumab) resulting in sometimes poorly predictable
but on average manageable side-effects. The small molecule imatinib was registered
in the EU in 2001 and since then more than 13 other targeted small molecules have
been registered. Some of these drugs are rather selective, such as erlotinib (mainly
EGFR) and vemurafenib (mainly BRAF V600) whereas others are less selective and
certainly less selective than the MoAbs, for example sorafenib, pazopanib and
sunitinib. This translates into sometimes significant normal tissue toxicity (sunitinib).
From the safety perspective one would prefer selective drugs targeting unique tumor
expressed proteins or deranged pathways, which would result in a wide therapeutic
window. From a benefit perspective at first glance one might prefer multi targeted
drugs as tumors show a multitude of mutations and amplifications and a double- or
even multi-barreled shotgun approach might hit one or more of these targets at the
same time. The disadvantage however is that the mutational profile may not fit to
the activity spectrum of the “targeted” drug and that this approach will probably
increase normal tissue toxicity. In view of increasing insight in the molecular
derangements of tumors one would prefer to have many selective anticancer drugs
that can safely be combined on the basis of a patient’s individual tumor genetic
profile. This would fit into the concept of a “personalized treatment”.
Disclosure: J.H.M. Schellens: Research grants have been received from: Roche, Eisai,
GSK and Astrazeneca.S. Marchetti: No conflicts of interest to declare
30IN BIOMARKERS OF RESISTANCE TO TARGETED AGENTS
R. Bernards, S. Huang
Molecular Carinogenesis, The Netherlands Cancer Institute, Amsterdam,
NETHERLANDS
Unresponsiveness to therapy remains a significant problem in the treatment of
cancer, also with the new classes of cancer drugs. In my laboratory, we use functional
genetic approaches to identify biomarkers that can predict responsiveness to targeted
cancer therapeutics; drugs that specifically inhibit molecules or pathways that are
often activated in cancer. Nevertheless, it remains poorly explained why a significant
number of tumors do not respond to these therapies. We aim to elucidate the
molecular pathways that contribute to unresponsiveness to targeted cancer
therapeutics using a functional genetic approach. This will yield biomarkers that may
be useful to predict how individual patients will respond to these drugs.
Furthermore, this work may allow the development of drugs that act in synergy with
the established drug to prevent or overcome drug resistance. To identify biomarkers
that control tumor cell responsiveness to cancer therapeutics, we use multiple
complementary approaches. First, we use genome wide loss-of-function genetic
screens (with shRNA interference libraries) in cancer cells that are sensitive to the
drug-of-interest to search for genes whose down-regulation confers resistance to the
© European Society for Medical Oncology 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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