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Colorectal Cancer
Double EGFR and VEGF Inhibition effect between monoclonal antibodies against EGFR (panitumumab
Combining therapies that inhibit different signalling pathways has the or cetuximab) and bevacizumab in combination with oxaliplatin-
potential to be more effective than inhibition of a single pathway and based chemotherapy in first-line therapy of mCRC patients.
to overcome tumour resistance. Pre-clinical models suggest that at
least additive efficacy can be achieved blocking the EGFR and VEGF Conclusions
pathways.
34
Recently, Saltz et al. have reported the results of a In recent years the increased knowledge of human cancer biology
randomised phase II trial that compared the concurrent and the development of new targeted therapies have improved
administration of two monoclonal antibodies – cetuximab and outcomes for patients with CRC. So far, three targeted therapies
have been approved for the treatment of mCRC patients. The FDA
and the EMEA have approved bevacizumab in combination with
With the increasing number of new
fluoropyrimidine-based chemotherapy for the treatment of first- and
targeted agents that are being clinically
second-line mCRC patients. Cetuximab has been approved
in combination with chemotherapy in the first-line setting and in
evaluated, hopefully to be approved in the
combination with irinotecan in the refractory situation. Whereas the
near future, there is an ongoing need to
FDA’s approval is for the whole population, EMEA has restricted
the licence to K-Ras wild-type mCRC patients. Finally, the FDA has
identify predictive biomarkers of efficacy.
approved panitumumab as a single agent in mCRC patients
refractory to other chemotherapy regimens and the EMEA
exclusively for those patients with tumours that bear K-Ras wild type.
bevacizumab – with or without irinotecan in irinotecan-refractory
mCRC patients.
35
This study showed that the three-drug combination With the increasing number of new targeted agents that are being
produced better results than the two-drug combination with a higher clinically evaluated, hopefully to be approved in the near future, there
RR (37 versus 20%) and an increased median TTP (7.9 versus 5.6 is an ongoing need to identify predictive biomarkers of efficacy.
months). Although the combination of cetuximab and bevacizumab Successful development of these predictive biomarkers will translate
appeared to be effective in a refractory setting, these interesting into the concept of personalised medicine whereby we give ‘the right
results of double VEGF and EGFR inhibition were not confirmed in the drug to the right patient’. Thus, patients with mCRC would benefit
first-line setting in two recently reported phase III trials: the from the sequence of drugs that would more optimally control their
Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) and malignant disease yet avoid the potential toxicities of those drugs that
the CAIRO-2 studies. will not benefit them. Additionally, with new drug approvals pushing
up the cost of therapy, this tailored treatment approach would reduce
The first trial reported, the PACCE study, is a phase III trial evaluating the economic impact of treatment. Several molecular predictive
oxaliplatin- and irinotecan-based chemotherapy and bevacizumab biomarkers are under evaluation in pharmacodynamic, genomic and
with or without panitumumab in the first-line treatment of patients proteomic translational studies in order to achieve this aim. K-Ras
with mCRC.
36
The second study, the CAIRO-2 trial, is a phase III study mutation status analysis constitutes the first step in this process of
of capecitabine, oxaliplatin and bevacizumab with or without personalising targeted therapies in mCRC by defining the population
cetuximab in the first-line therapy of patients with mCRC.
37
Both that will benefit most from anti-EGFR monoclonal antibodies. As has
studies showed a detrimental effect in the arms that contained already occurred with K-Ras, these biomarkers will be integrated in
bevacizumab and the anti-EGFR monoclonal antibody. The results of the treatment decision algorithms, thus leading to an optimised
these two studies suggest that there is a lack of biological synergistic therapeutic strategy. n
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68 EUROPEAN GASTROENTEROLOGY & HEPATOLOGY REVIEW
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