ECC 2015

Biomarker driven access to crizotinib in ALK, MET

Prof Gilles Vassal - University Paris-Sud, Orsay, France

Crizotinib has a problem in France to do with access because it’s an interesting drug, it could be used on a lot of cancers but it isn’t being. What is it that you have been investigating?

You are absolutely right. Crizotinib is a targeted drug with several targets and beyond non-small cell lung cancer it can be very active in other disease. So this programme is not only tackling an issue in France, it’s tackling an issue over the globe and we do have a proposal in France that could be interesting for the other countries as well.

So ALK positive lung cancer is the obvious application for crizotinib but it could be used elsewhere, like what?

Exactly. The indication is non-small cell lung cancer with high but these alterations can be found in lymphoma, in paediatric tumours, in sarcomas, in colon cancer we do have amplification of MET. So we have fifteen malignancies which we know exhibit alteration of one of the three targets of crizotinib, fifteen. And those malignancies there is no indication. If your patient has a MET amplification in his tumour, for example in colon cancer, then the physician has no way but to prescribe the drug off label. The programme tackles this issue, access to biomarkers for those patients who could benefit from crizotinib and access to the drug within a clinical trial, so it’s safe, secured, and not off-label use by many doctors.

Now, you established this by the work done reported in your abstract here in Vienna. Tell me about that work, what did you do to establish these facts?

The programme set up, this is a programme from the French National Cancer Institute operated by UNICANCER and the programme said once diagnosis. So over the last two years 5,500 patients with a disease which potentially could have alteration of one crizotinib target have got a test. 5,000 and more than 12,000 tests have been done for these 5,000 patients in the 28 genetic platforms working in France. This is an academic programme, a fully academic programme, and out of these patients with a positive we could propose them to participate in a clinical trial. And 130 patients participated to a clinical trial, different disease, different target, treated by crizotinib, which is looking at the activity of the drug in those patients with a disease expressing a target of crizotinib.

Now, how are you going to apply this knowledge in the real world because doctors need to have tests for the biomarkers that are readily available and then those need to be accepted and become routine, don’t they?

Absolutely and you know that the tests are usually companion tests being approved with the drug that is targeted and targeting the indication. More and more it’s not one test, one biomarker; more and more we have the next generation sequencing. So patients will have a full analysis of 70 or 100 mutations in their tumours and then it will be reimbursed in some countries, it should be paid by the patient in other countries, but then we will have information on the tumour of these patients with several targets and the point is how can we match the drug.

What are the main targets in the case of crizotinib? Of course ALK positive is one of them, MET is another, isn’t it? What are the targets?

So there are three targets – ALK, MET and ROS and they can be either mutated, translocated or amplified. We are looking for oncogenic drivers, the Achilles heel of the tumour that could be one of these alterations.

How much of an improvement in cancer care for some of the other malignancies, not just non-small cell lung cancer, could you get potentially by using crizotinib when the biomarker target is there?

What you need to understand is that it is a phase II trial, we are exploratory. We are asking the question is crizotinib active in patients with colorectal cancer and a MET amplification? If yes, then additional data should be generated. We are searching for a signal and we are giving patients access to innovation when they have a disease which is advanced and likely to kill them.

Right. What’s the message then, the practical message, for cancer doctors right now about this whole area?

Clearly the message to the doctor is about what the message is in France because the programme is open in 168 centres which means that many, many oncologists and physicians taking care of patients with a cancer, when they do have an advanced malignancy they can participate into the programme, and tell their patients we will see whether or not your disease has the target of this drug and if your disease has a target of this drug then you can participate to this programme.

Of course, as a broader issue it’s all part of a movement to get better individualisation by searching for particular biomarkers in a whole range of cancers and a whole range of drugs, isn’t it?

Absolutely. And this programme is tackling the issue of information for a patient, drugs, and I cannot have the right to prescribe the drug. So we need to think, based on this programme, how to set up a registry, how to collect information to be sure that the patient receives a drug he could benefit from in a safe environment and that’s the key point. This programme tackles the issue of off-label use and addresses the topic of patient advanced disease, molecular biomarker, access to the drug.

But you have other drugs, it’s not just crizotinib is it?

Absolutely because it’s only one project, it’s a programme, access to innovation for patients. So access crizotinib is open but we do have also access vemurafenib. So patients with a BRAF mutation, not just melanoma, and there are plenty of patients, plenty of diseases with a BRAF mutation, can have access to BRAF testing and the drug. And we are preparing another, a third programme to give access to paediatric patients to a large number of drugs. So it’s really an initiative, not only a single test or single example, to really test the concept of access to biomarkers, access to drugs, generating evidence and providing patients with a chance to benefit from the drug.