Professor Tony Mok – Chinese University of Hong Kong, Hong Kong

ALK positive lung cancer was discovered only in 2007 and since then the first agent was approved, it was crizotinib, back in 2014. Since then there are actually a number of second generation drugs become available, including ceritinib, alectinib and also, lately, brigatinib. So right now in the majority of countries, including in the EU and United States and most of the Asian countries, now we have four drugs to choose from. Now, with that being available then we’re to say which one is better. But obviously there are comparative studies of brigatinib versus the crizotinib, which is the ALTA first line study, as well as the ALEX study that compared alectinib with the crizotinib. So with these two comparative studies the second generation drugs are definitely better than crizotinib. So now there’s a tendency for people to choose either alectinib or brigatinib as the first line treatment.

Then for ceritinib there’s a little bit of an issue with the GI toxicity, so I think there will be some challenges to using it because there’s no direct comparison with the crizotinib. So in that way they lose an angle for it being selected as a first line therapy.

When the ALK was first discovered, since it’s a translocation the most logical way to look for it is by FISH. In other words, we look for the translocation of the gene and then you will see the signal in the FISH. However, the FISH process is actually laborious and also a little bit expensive so it moved on to use the IHC. Now, ALK is a protein that does not usually get expressed in normal cells so when you have expression that’s usually an indication that there is an abnormality, meaning the presence of the translocation. So, in the first study that we have done, the PROFILE 1014, the so-called randomised crizotinib versus the chemotherapy, we used the FISH. However, in the ALEX study we actually made the specific point to use IHC for the convenience and also therefore it had subsequently also become one of the standard testing. So, right now, IHC is actually more commonly used as a standardised test for selection of patients with ALK translocation and fusion.

What are the current challenges surrounding the diagnosis and treatment of ALK NSCLC?

Focussing first on the diagnosis, is simply the fact that the patient may not have sufficient tumour tissue for either IHC or FISH. Those are the patients that we asked the question, can we test it from the plasma? So in that regard actually there will be a new study that’s coming up, it’s called the BFAR study, that we use a liquid biopsy looking for patients with ALK and this is NGS based. Certainly the data is not available yet but in the future, once that study becomes positive, it will help us to use plasma, or liquid biopsy, to look for patients with ALK translocation as well. So this is one issue.

The other issue regarding the management of ALK positive patients would be the brain mets and also the resistance. Now, brain mets are a key issue because about 40-50% of ALK positive patients will eventually develop brain metastases. So now we have some effective agents, such as alectinib or brigatinib, so now the question is should we use radiation or should we use systemic therapy? What is the sequence, what is the combination? What are the patients that we should consider radiation and what are the patients we should consider systemic therapy? I think we probably have to delineate that a little bit further.

Coming to the second problem is the resistance because the gatekeeper resistance is quite diverse in ALK positive patients. Unlike EGFR mutations the majority may have a T-cell line mutation; there are a number of different mutations and they may behave quite differently. So I think the future development is whether we are going to select our therapy according to the resistant pattern. Now, in particular there is the G1202R resistance which is actually right now only sensitive to lorlatinib for the first generation drug. So how do we place lorlatinib in the future paradigm, that will be another challenge.

Can you describe the ALEX study and how that has influenced our understanding of ALK NSCLC?

There are actually three trials that are under the name of ALEX: there is the J-ALEX, which is from Japan, and there is the global ALEX as well as it’s called ALESIA which is the Asia ALEX trial. So let me just focus on the global ALEX trial. This is actually a large randomised phase III study selecting, as I say, IHC positive ALK positive patients to either alectinib 600mg versus the patients with crizotinib at 250mg twice a day.

Now, the primary endpoint is progression free survival and the most updated data we were able to demonstrate a median progression free survival of 34.8 months versus about 10 months. Now, 34.8 months is a long time – for any kind of therapy for lung cancer this is probably one of the record highs of the progression free survival. But more interestingly it will be what will be the survival data going to be, which I will address a little bit more in a moment. But one other important aspect in the so-called secondary endpoint of ALEX is the time to CNS progression. We actually have taken meticulous effort monitoring the patients in terms of the CNS progression with the MRI on a regular basis. With that we’re able to demonstrate at a one year time point approximately 40% of patients on crizotinib may have a progression in the brain, that is a CNS event, as compared to only 9% of the patients in the alectinib arm will have a CNS progression. So that pretty well is the first study that confirms this efficacy in the brain.

Moving on, it’s the overall survival. Even up to this moment we don’t have mature overall survival data and we still have to monitor very closely. I can tell you the events are coming in very slowly. So are we going to achieve a quote-unquote ‘extraordinary overall survival outcome’? It’s hard to say. Remember, in the [?] 51014 the median overall survival in the control arm, which are the patients who got chemo and then crizotinib, is approximately four years. I certainly hope to look into even a longer median overall survival in the patients in the ALEX trial.

In lung cancer we always have to promote a concept – can we convert this fatal disease into a chronic illness? I think the ALK positive lung cancer will be the prime example that we can actually put the patient on a relatively non-toxic pill and then the patient can live months, years, of normal life, just like patients with diabetes and hypertension. So this will be a good demonstration of the possibility of conversion of lung cancer into a chronic illness.

What other ALK inhibitors are currently in use for treating ALK NSCLC?

With the second generation drugs, apart from alectinib and brigatinib, there’s ensartinib which is also undergoing a phase III study with collaboration with China and hopefully the data will become available soon. The other study that’s catching up fast is a comparative study of lorlatinib with crizotinib, which is called the CROWN study. That specific drug had actually even more potent penetration to the brain, so are we going to observe even more or better control of the CNS situation? We’ll have to wait and see. But all these are very promising drugs and I’m quite sure that these two other drugs, ensartinib and lorlatinib, will eventually come to the market and become available. By that time how do we choose is the big question.

When might these drugs become used in the clinic?

I don’t think it will be that long. Ensartinib, I’m hoping, may be 2020; lorlatinib is a little bit harder to predict, it really depends on their accrual rate. But then they really involve a lot of centres so I think the outcome will come relatively quickly.

For ensartinib, given the fact that it is a collaboration with a pharmaceutical company called Beta Pharma in China, so there’s a good chance that ensartinib may come to even China earlier before some other parts of the world. As compared to lorlatinib which is a global study run by Pfizer, more likely it will be America that would be the first country to get registration.

Is there use for alectinib in combination with other types of therapy in these patients?

There are a number of small size phase I/II studies on the combination of alectinib because with EGFR mutations we asked the same questions – can we combine it with chemotherapy? Can we combine it with anti-angiogenesis or even combine it with immunotherapy? So all those have been explored. I think it is potentially feasible, it’s scientifically interesting. To me, taking the pill alone with little toxicity is also important for the patient. You can combine with chemotherapy but I think it will be very difficult, given the fact that they already get median progression free survival with a single drug alone to be 34.8 months, adding chemotherapy may even say longer but it’s going to take a very large trial to show that in fact. So, personally, I’m not too optimistic that the combination is going to so-called take over the current use of the single agent drug.