Hello, I’m Riyaz Shah, I’m a medical oncologist in Kent in the United Kingdom and we’re here today to talk about the best treatments in the first line setting for ALK positive lung cancer patients.

Hello, I’m Maurice Perol, I’m responsible for thoracic oncology in the Cancer Centre of Lyon in France and I’m happy to discuss with Dr Shah the first line treatment of ALK positive patients. I think there are some probably discrepancies between the UK and France. I would like first to ask how you detect ALK positive lung cancer patients in the UK, what is the method of testing you use?

With the recent data that has evolved reflex testing is becoming more and more standard so it’s probably fair to say that most of the UK will reflex test non-squamous non-small cell lung cancer for EGFR, ALK, ROS1, PD-L1. Those are the fundamental things that we use to judge first line treatment decisions. Most of the UK, to my understanding, will test non-squamous tumours, not squamous which some people may have an issue with, and we tend to do a confirmatory FISH, so it’s IHC testing, confirmatory FISH but most clinicians will start therapy with the IHC result and not wait for the FISH because that could potentially be a significant delay. Occasionally you do meet patients who based on their clinical features it may be a squamous cancer but actually when you meet the patient you realise they’ve never smoked, you can then request that an ALK and an EGFR test be done. So that’s generally the standard practice although there are regional variations in the UK.

OK. I think we have a similar situation in France, we use reflex testing for the non-squamous patients, we use mainly immunohistochemistry to detect ALK positive patients. So we have the results very fast, faster than for EGFR mutations, so there is no issue to start very early the treatment, the specific treatment. So it’s a good thing, comparatively, to EGFR mutations because many platforms in France have moved to NGS so it requires more time, it takes more time to get the results for EGFR mutations. But for ALK we used to start the treatment on the basis of immunohistochemistry but many centres also prefer to confirm the ALK rearrangement by FISH or by NGS, it depends on the platform. But immunohistochemistry has changed clearly the picture to detect ALK positive patients. Probably we are not missing so many ALK positive patients at this time in France, I think it is the same in the UK.

I would agree with that. In my practice it’s very rare for me to see a patient without an ALK result; because it’s immunohistochemistry we usually have enough tissue. I think our diagnosticians, because in the UK, different from perhaps France, is that pulmonologists are very much involved in the work up and diagnosis of patients but the systemic treatment is purely done by oncologists. But we have regular MDM meetings, we meet, discuss, and so the diagnosticians have become very acutely aware of our need for enough tissue. So now we’re finding I do generally get results in most of the patients, be it EBUS or CT guided biopsies. That has been a work in progress because I think that is something that has changed over the last 2-3 years. People have become more and more attuned to the issues of getting enough tissue. We do occasionally miss cases so there are cases where the ALK has been reported as negative and a subsequent biopsy further down the line, because I think it’s important particularly with patients who have been on treatment for a long time at some point to consider re-biopsying them and re-genotyping them and you do sometimes pick up ALK translocations.  So it sounds to me like we’re doing more or less the same things. I understand the French system is much more organised and nationalised.

Yes, it is organised on the basis of regional platforms so every patient in every centre can have access to molecular testing. So it’s well organised and most of the pathologists are locally using ALK immunohistochemistry without referring the sample to the platform for ALK, it’s just referring for the molecular testing for EGFR mutations and other mutations.
So we have seen with the ALK TKI that we have changed the natural history of this disease and the patients can enjoy now longer survival. What are the available drugs in the UK and what is the drug you will use preferably in first line at this point?

Crizotinib has been on label for some time. In the UK the health service, which is a nationalised health service, does have regional differences. So each individual devolved nation runs its health service separately so there are some regional differences, perhaps, between England and Scotland and Northern Ireland. I personally work in England so I can only with confidence speak about England. But in England crizotinib is still available but alectinib is also available through something called the Cancer Drugs Fund. Generally, based on the data that we’ve got, that is probably the most favoured agent in use in the UK right now.

Yes, we have the same available drugs in France. Alectinib has been approved by the EMA a long time ago but alectinib is available and reimbursed in France only since August 2018 so it’s recent. But there is a shift between crizotinib and alectinib in first line due to the ALEX trial results which were very interesting because of the prolongation of PFS first and prevention of brain metastasis which is very important in ALK positive patients. At the end a lot of patients will die of CNS disease so it’s very important to prevent as long as possible the occurrence of brain metastasis in this particular disease. So what do you perform as a follow up? Do you change your practice by replacing crizotinib with alectinib in terms of patient follow up, especially for brain MRI or brain scans? Did you change your practice about that?

I very much changed my practice. Over the last few years I’ve become increasingly aware that brain metastasis management is one of the key issues if you really want to obtain the kind of survival that the French have demonstrated from their ALK database. We know from audits done in the UK that we’re not achieving that; the management of brain mets is a critical part of that. So that is a multi-factorial issue; one of the debates is around should you be up front scanning the brain to determine whether there are brain metastasis or not. Many people in the UK don’t do that, we haven’t got a culture of doing that, and there is a change in culture going on. My own personal practice is to definitely discuss that with all patients; there are implications because if we detect brain metastases in patients they’re banned from driving for at least a year so I have had some patients who are carrying on working and have requested that I don’t scan the brain but I would say that’s the minority now. I think the majority of patients when they see the data, when they appreciate the potential advantages of knowing, will agree to have brain imaging and by brain imaging I mean an MRI, not a CT scan.

Then the important thing that we’re evolving in the UK is our understanding of what to do once you see the brain metastases because it’s not entirely clear because brain metastases can be symptomatic, they can be asymptomatic, they can be oligometastatic, there can be lots of little lesions, there’s a whole different spectrum of patterns. Then the question is what do you do, does neurosurgery have a role, does SRS have a role, does the TKI have a role because the TKI gets into the brain very well? So I think we are, as a country, still learning about how we want to do this. If I can talk about what I do, in general in my practice these TKIs, particularly alectinib, has excellent CNS penetration. The brain met data from ALEX was really very powerful, very strong, both active against brain mets and neuroprotective in preventing brain mets from forming in patients who don’t have them to start with. So I now regularly survey patients with brain MR, not that often, once every six months perhaps. If we demonstrate brain metastases early on at baseline we usually let the inhibitor work first before making further decisions. But once you’ve established there are brain mets and you can monitor the effect of the inhibitor if things start changing, if a lesion starts progressing or something starts evolving, you can entertain a discussion with your radiotherapy specialists or surgeons and make a plan to manage that particular problem.

Also we change our practice – when we used crizotinib as a first line treatment we used to perform brain MRI at each tumour assessment, every three months. Now with alectinib we can probably perform brain imaging probably every six months because it’s more reasonable. Also the patient with ALK positive disease can have a very long survival so it is very important that the physicians are aware of that and we should avoid whole brain radiotherapy as much as possible because they can have the connective detrimental effect of whole brain radiotherapy during their lives. So it is very important not to have the reflex of whole brain radiotherapy if you see brain mets at baseline. Alectinib is working very well in cases, the response rate is very high, so it’s really possible to use the inhibitor first and to see what will happen. The stereotactic radiotherapy is very big progress, a very big advance in this field. It doesn’t resolve all the problems we have, some issues with radiation necrosis which is very difficult to make the distinction with a tumour progression, sometimes difficult. But it is one of the major advances that alectinib has brought in this field, the prevention of brain disease progression and disease progression in the brain which is very important.

What is your opinion about the ALTA-1 trial which has been released three weeks ago in Toronto? What space do you see for brigatinib in first line or maybe after alectinib?

I think that’s a very interesting question. Obviously the ALTA-1 trial has compared brigatinib to crizotinib, the results look very good. They’re still preliminary so obviously the ALEX study we’ve got longer follow up, we’ve got an idea of the median progression free survival – 34.8 months or something of that sort – and I think it will take some time before we get a sense from brigatinib as to what the actual outcomes are going to be. Ostensibly, from what we’ve seen, there doesn’t seem to be much difference. My personal experience of using this drug in expanded access programmes is it’s a well-tolerated drug; there were some concerns about pneumonitis but actually I don’t think that has panned out to be a big problem. The question is is there a difference and at the end of the day until there’s a head to head study we’re not going to know. So I think it will be a bit like EGFR TKIs where we have three approved on label first generation inhibitors and now osimertinib, there will be a choice and I suspect that’s what is going to happen in this space. It will be interesting to see how clinicians change their practice or stick with what they’re doing.

Maybe the different patterns of resistance mechanisms should play a role by selecting one TKI instead of another one because the main issue will be how to manage the patients after acquired resistance to alectinib – should we rebiopsy the patient, should we detect resistance mutations in the blood? So there is a big space now to see how to manage the patient after acquired resistance to alectinib. Do you perform routine liquid biopsies and ctDNA in the UK or not necessarily?

Not for ALK.

Not for ALK?

No, not for ALK fusions and that level of technology is not really deployed. T790M and EGFR yes but outside of that it’s very patchy.

We have some experience, of course, in research programmes to perform NGS on ctDNA for ALK resistance mutations and it works rather well. It was possible to detect some resistance mutations and maybe in the future, because it’s not very easy sometimes to rebiopsy a patient, so maybe it will play a role because we have stronger inhibitors so probably more frequent resistance mutations. So maybe it will be an interesting tool to use to detect resistance mutations.

So we’re going to wrap this conversation up now. I hope that’s been helpful. This has been a very exciting meeting here in Munich. This is obviously a very exciting field that’s rapidly developing and watch this space.