Treating elderly patients at the molecular level
Dr Christophe Massard - Institut Gustave Roussy, Paris, France
You’ve introduced a concept here at the Geriatric Oncology Conference of precision medicine, this is based on molecules. What is the big hope of looking at genetic analysis and looking for mutations? How much better can we treat cancer, especially in older patients, by looking for molecular signatures?
The basic idea of precision medicine, what we call personalised medicine or molecular medicine, is to define for each patient individually the molecular alteration that is implicated in the cancer progression. So the idea is to have a molecular portrait to define different molecular alterations and then to find the drug, the right drug for the right patient. The goal is to try to increase the clinical benefit to try to stabilise or to try to decrease the tumour burden. There are different examples where this kind of approach was a success, for example with crizotinib in ALK lung cancer or with immunotherapy in melanoma. There are some challenges because we need to perform a tumour biopsy in our patients, this is not an easy thing but we are convinced that during the time of cancer progression the biomarker is going to evolve so we need to re-biopsy patients, perform an analysis and then we need to find the drug.
So what would doctors now be doing with their patients? They presumably have to have some kind of biopsy and then get a full analysis of all the mutations.
Yes, until now this programme is only for clinical research because we do not demonstrate that this kind of approach is better compared to standard treatment. But I think it’s very good to discuss with our progress patients. Most of the time patients are very keen to participate with clinical programmes. They clearly understand that if we have a biopsy with a new analysis if we can understand better the cancer we will maybe be able to find better drugs.
You could have a new kind of phase I study, you’ve been saying, because some of these molecular alterations are obvious targets and they can lead to drugs which have a very big effect. How do you do these new studies? What’s been happening?
Exactly. During the last five years we have several examples of these mixed what we call phase I/II trials. So the goal of this trial is to have [?? 2:32] activity of a drug and this trial has been possible because we have very nice agents, very active agents. Most of the time the drug targets what we call oncogene addictions, so it is not always the case but a very nice example, like in cancer, we have been able to demonstrate that when you have a cancer with ALK translocation for example, which is a clear oncogene addiction, when you add a drug that targets that addiction you are able to have a huge clinical benefit. So in this case it’s very difficult to perform a phase III trial because there is no true comparator.
So do you have, or could you get, an algorithm that tells you which drugs to use when and when to give up the targeted approach and to use standard chemotherapy?
We are just at the beginning of this big adventure. There is some consensus about the targets but this is clearly at the beginning so during the next future we are going to make progress in the understanding of cancer biology and we are going to be able to define the good targets and, I would say, the bad targets.
Could you give me some examples? For instance lung cancer has changed quite a bit, hasn’t it?
Exactly, the management of lung cancer patients has been revolutionised by this approach. So now in Europe when you have a patient in your clinic with lung cancer you ask for different molecular alterations because each alteration could be targeted by drugs and you can individualise the treatment for each patient.
Individualising therapy has been the holy grail, how close do you think that is right now in many cancers?
In some cancers we can individualise treatment but the deception was we are not able to cure cancer this time because most of the time when you try to block cancer progression after several times the cancer is going to [?? 4:31]. So we cannot cure patients with this kind of approach but we are able to stabilise or prolong the life of patients. So we need to add something with this drug.
And you can alter the sequence of drugs because if you find a mutation you go in first with the drug that targets that mutation.
Exactly. So this precision medicine programme is very useful for, I would say, refractory patients but it’s also very useful for patients that progress after a first drug. So there are some programmes now which try to understand not the first molecular alteration but try to identify the resistance mechanism. So there is a future for precision medicine in this setting.
What messages would you give to doctors about getting on with this precision medicine? Clearly there’s a lot of studies still need to be done but what are the simple ways forward that you can describe to doctors and the hopes that they bring?
The major take home message is to consider that when you see patients in your clinic, when you see ten different patients in the clinic, probably these patients have ten different diseases even if it’s a lung cancer or prostate cancer. So the idea is to try to use a molecular portrait to individualise each tumour type and to try to find the best drug.
And the actual improvement could be huge?
It could be huge if there is what we call an oncogene addiction.
How many patients do have an oncogene addiction and something that really can be dramatically changed?
Probably at this time we consider between 20-30% of patients have this kind of cancer with a clear oncogene addiction and could benefit from this kind of approach.
Although we’re talking about individual mutations, collectively there’s a large number of patients with those relatively rare mutations.
Exactly. So this is the second lesson from this kind of programme, if you perform a [?? 6:25] you are going to create different often or rare disease. So there is no common cancer, this is a sum of different rare cancers.
And the final take home message for doctors is what?
The final take home message is to try to discuss this approach with patients and to refer patients to clinical trials for biopsy or for phase I [?? 6:48].