Pharmacodynamic endpoints need to be included in GI trials

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Published: 17 Jul 2012
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Prof Fortunato Ciardiello – Seconda Università degli Studi di Napoli, Italy

Prof Ciardello talks to ecancertv at the ESMO 14th World Congress on Gastrointestinal Cancer in Barcelona.


Disease-free survival, response rate and overall survival are all important clinical endpoints commonly used in trials, but which is the best measure of outcome for use in gastrointestinal cancer (GI) studies?


This was the topic for discussion during a session on clinical trials and endpoints. Prof Ciardello gives an overview of the session and highlights the importance of using pharmacodymanic endpoints in clinical trials of new, molecularly-targeted agents.


Prof Ciardello also discuses highlights of the ESMO consensus conference in relation to colorectal cancer guidelines and optimal management for patients.


This programme was supported by BAYER.

Pharmacodynamic endpoints need to be included in GI trials

Professor Fortunato Ciardiello – Seconda Università degli Studi di Napoli, Italy

You were part of a session on clinical trials and endpoints in GI cancer, could you give us an overview of what was discussed by Dr Marc Buyse?

This was a very interesting session I participated in, it was an educational session. Marc Buyse was giving a very important, nice talk on the differences between the classical clinical endpoints and pitfalls of having a single endpoint such as either progression free survival or response rate or biomarkers or survival, but introducing the concept of having multiple endpoints that could better help us, especially now that we have multiple lines of treatment in metastatic colorectal cancer with very effective drugs and drug combinations. The concept of maintenance breaks and re-challenge has started and so to use the classical clinical endpoints, sometimes it’s very difficult and sometimes it’s meaningless. So if we can use all of them in a multi-variant analysis this could be good for the future, at least for the randomised phase II part of the studies before going to randomised phase III trials.

Prof Alberto Sobrero also spoke at the session, what did he discuss?

Alberto Sobrero gave a few examples on why we should carefully evaluate which is the delta, the increase in effectiveness we are looking for, in new drugs or new drug combinations in metastatic colorectal cancer. How can we do this both by statistical evaluation and in clinical evaluation because sometimes both seem statistically relevant as hazard ratio, as improvement, as median gain, it’s not clinically relevant or vice versa. This should be put in the context of the line of treatment, the type of patient – chemo-naive or chemo-refractory, and what are the expectations in that part of the disease for the patient. It is very important, also because it brings again the problem of interpretation in an evidence-based medicine approach of the results.

What about the use of pharmacodynamics endpoints?

My presentation was on pharmacodynamic endpoints and after defining that pharmacodynamic endpoints we measure the mechanism of action without defining which is the real target in-vivo in the patient, both in the tumour and in normal tissues. And so it will give us more information on the drug dose to use and the side effects. This will be very important for any novel drug to be developed in early clinical development in colorectal cancer but also to guide the development of biomarkers that could be used for later stage disease evaluation like phase III trials or eventually fully for clinical practice. I gave a few examples and a clinical trial we performed with cetuximab, the anti-EGFR monoclonal antibody in this sense in the phase I study.

What are some of the challenges with using pharmacodynamics endpoints?

The major problem with pharmacodynamic endpoints is the source of patient material; that is plasma or serum, it’s much easier to get, and need for biopsies. So if biopsies are mandatory in a clinical trial, we should carefully evaluate aspects of it, especially if repeated biopsies are required. I was also presenting the data of a recent overview published in the Annals of Oncology from researchers at Villejuif, Gustave Roussy Institut in Paris, in which was shown a very good acceptance of patients in a phase I clinical trial programme to have repeated skin and chemo biopsies.

How do you take this information and put it into practice?

This is very important because all early stage development from first phase I trials to more late-stage phase I and randomised phase II trials should mandatorily use pharmacodynamic endpoints. And the objective is that after this early phase development, when we want to go to real comparative trials in phase III randomised trials, we have developed some of the biomarkers coming up from the pharmacodynamics studies to be used to select and guide the use of the drugs in a prospective way in the randomised phase III studies. Only in this way we can get in account the points of colorectal cancer that is not a single disease but is a miscellaneous of different diseases with biological and genetic differences. More and more we learn about this, more and more we learn about the fact that any drug in metastatic colorectal cancer works only in a subgroup of patients. So pharmacodynamics endpoints should help us to define predictive biomarkers for the right selection for the right patient.

On a broader level, what are some of the important developments discussed at this meeting?

In terms of colorectal cancer, this meeting we will have very important educational events, one of these is the first report in congress of the ESMO Consensus Conference on the treatment of colorectal cancer from early disease to metastatic disease. This has been a big effort that ESMO started in September 2010 when a group of more than forty experts from Europe and the rest of the world gathered in Lugano and we had a two-day conference to discuss all the aspects. Since September 2010 to today, this group of experts led by Andrés Cervantes, Hans-Joachim Schmoll and Eric Van Cutsem, has worked on a full paper that will be published soon in the Annals of Oncology, and Andrés Cervantes and Hans-Joachim Schmoll, in this meeting tomorrow morning, will present the main data of the consensus conference. This is very important because this is the evolution of the ESMO guidelines that we do in more than fifty aspects of cancer treatment to a very important aspect such as management of colorectal cancer from early disease stages to later stages of metastatic chemo-refractory disease.

What were some of the main points to come out of the ESMO consensus conference for colorectal cancer?

The main points will be a truly multidisciplinary approach in the early stage of the disease in colon cancer, in rectal cancer, in which the radiotherapy is very important, imaging is very important, and in metastatic disease in which, especially for a subgroup of patients, I think about the limited metastatic disease in colorectal cancer, the possibility for cure exists for these patients but only after careful evaluation on a multidisciplinary team in which radiologist, gastroenterologist, pathologist, surgeon and medical oncologist are part of the team for the better outcome of patients. So the conclusion from the consensus, also the general thing coming up from this congress, is that the best approach to a metastatic colorectal cancer patient, I would say to a colorectal cancer patient in general, is if a dedicated multidisciplinary team will take care of the patient since the diagnosis. Because this is the only way to approach in a meaningful way all the therapeutic steps that will allow the patient to live longer or even to get cured of cancer.

What is your take home message from the ESMO 14th WCGC for the audience?

We are making improvements in colorectal cancer management, these improvements are small steps every day, I would say, but they are all in the same direction to make the disease, of course, a deadly disease for most patients especially in the metastatic setting, a disease that is curable in most of patients in early stage such as stage 1, stage 2 and stage 3, and as an improved survival in stage 4 metastatic disease. As I said, we have new options for prolonging survival, now it’s approaching a median of two years for most of the patients with metastatic disease and it’s much longer, even with the hope for a cure, in groups of patients that are not so few, between 10-30% of metastatic colorectal cancer patients in which disease, as metastatic disease, is limited to the liver. There we have a lot of improvements with drugs that employ the reduction such as chemotherapy and biologic agents such as cetuximab in KRAS wild-type patients. We’ve had a lot of improvements with the use of surgical techniques in removing the metastatic disease in the liver by expert liver surgeons, that’s why I said before that a multidisciplinary approach is crucial for the outcome of patients in this setting.