Precision medicine in ALK-positive NSCLC: Results from the BFAST trial

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Published: 3 Oct 2019
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Prof Solange Peters and Prof Tony Mok

Prof Solange Peters (Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland) and Prof Tony Mok (Chinese University of Hong Kong, Hong Kong) discuss the latest developments presented at ESMO 2019 in ALK-positive non-small-cell lung cancer (NSCLC), including updates in precision medicine.

Prof Mok outlines the current landscape of ALK-positive NSCLC and discusses the BFAST study, which uses a blood-based assay to screen patients to detect patients with ALK fusions.

The experts discuss the clinical utility of this screening tool, which may be beneficial to patients with insufficient tissue for testing and may help oncologists understand the mechanisms of resistance to alectinib in these patients.

Prof Peters concludes by discussing the latest results from the CheckMate 227 trial and the role of ipilimumab plus nivolumab (I-O) combination in ALK-positive patients.

This programme has been supported by an unrestricted educational grant from Roche.

Current landscape of ALK-positive NSCLC
Background of the BFAST study
Screening for ALK-positive NSCLC
Molecular testing methods
Results from the BFAST study
Use of liquid biopsies
Understanding mechanisms of resistance
I-O as a treatment for ALK-positive NSCLC
PDL-1 expression and treatment choice


SP: Dear colleagues, it’s my pleasure to welcome you today at this ecancer discussion where we would like to focus on the advances presented at the ESMO 2019. First of all I need to introduce my discussant and my friend Tony Mok who is a Professor of Oncology and Medicine at the University of Hong Kong. My name is Solange Peters and I’m working in oncology in Lausanne in Switzerland.

TM: Solange, it’s a great pleasure to have a chat with you in lovely Barcelona.

SP: We tried to focus on one topic because there were many data we could cover, many things – immunotherapy, radiotherapy – many advances, but let’s focus on one very specific topic which moved a lot in the recent five years. It’s the molecular diagnostic and the treatment of ALK positive non-small cell lung cancer, a rare entity but something which, in terms of treatment paradigms, has changed like a revolution recently. So maybe to start the discussion and share the data presented here can you just remind us where we stand with the ALK treatment and the perspective of survival?

TM: Very briefly we started off knowing about this ALK translocation in 2007. Then the first recognition using crizotinib as the first line therapy and then the PROFILE 1014 study confirmed superiority of the chemotherapy in 2014. That was a median progression free survival of approximately 10 months. However, you and I collaborated on the ALEX study and we demonstrated on a second line TKI using alectinib in comparison with crizotinib in a randomised phase III study that the median progression free survival at both 34.8 months versus about 10 months and also with the benefit of CNS penetration. So the question is what next? In terms of the molecular diagnostic from the PROFILE 1014 we’ve moved on from FISH to IHC. So right now IHC is so-called one of the key standards for selection of patients. So what is new today is can we move it on the next step using plasma? That will come through the BFAST study.

Let me just explain a little bit, sorry for repeating. BFAST is actually a multi-cohort study. We used a plasma based NGS and then we identified patients with either a driver oncogene or with high TMB in the plasma. Then specifically we looked for ALK positive patients. Now we use an ALK positive based on plasma as a positive selection and then we just give them a single arm of alectinib. So those are the results that we presented in ESMO this year. We demonstrated a very high response rate.

SP: Is it different because we have these different ways to look for ALK? There’s one thing which might be important and I’d like you to discuss. We moved from FISH, which is a difficult test, it takes time and money, to immunohistochemistry which is ideal for large-scale screening because you can stain for ALK, many, many non-squamous tumours with not so much effort and it’s really not expensive. We go back to a test which might perform better in terms of having the correct positive and predictive ability of diagnosing ALK but also a little complex test in terms of screening methodology. So my question to you is is there any clinical benefit in terms of better selection of patients or where do you see this plasma test to come in the future, knowing that for screening it might be difficult but sometimes tissue is missing in our patients?

TM: I think there are a few levels to address your question. The first level is the fact that can we just provide a convenient diagnostic test in the patient with insufficient tissue. The answer is that would be great. However, IHC is relatively easy. Then the next question level is can we provide a more sensitive test than IHC? Now this will be a slightly tricky point in the way that we must have the so-called concordance test. Then we have to have both tissue and the plasma and then we’ll match the concordance. So that’s the next level. The third level is do we really need histology in the future if plasma is so accurate?

SP: It’s an interesting question because this reality of patients with insufficient tissue is more and more real at the time we prioritise other biomarkers before ALK. We have the era of immunotherapy so PD-L1 has to be tested, EGFR is still way more prevalent, so it might be in a certain number of patients that the cytological sample you have is not sufficient to go through many biomarkers, more than one most of the time, including the histological test for squamous or non-squamous. So maybe plasma is a way to move. The main question I have is how certain are you that if you prioritise the plasma, after your waiting time of, I don’t know, three, five, seven days to get the results, speaking about potentially absence of DNA circulating, the non-shedders which are observed, what is the risk, based on what you know, that you still need to do a biopsy afterwards?

TM: I think we should be looking at the whole thing – rather than a replacement can we do parallel? Now, you do make a good point is that it would take a few days but the question is when would you start doing it? For example, if you’ve already got a bone marrow CT scan before your biopsy you can already send your plasma sample. By the time you’ve got your histology back you may already get your genome sample but that is only on the assumption that the cost of the plasma test is an affordable cost. Right now it’s still relatively expensive but I think in the future the price may go even further down. So I think to provide the most proficient molecular testing for the patient I don’t think there’s one replacing the other but rather concurrently. You may have duplication of data but that is still helpful. If one is negative, the other positive, the specificity right now, actually, which I’m going to share with you the data from the BFAST is that we selected about 104 patients and 87 patients were able to be enrolled into the study. Then using alectinib 600 b.d. the response rate was extremely high, almost 75%. Also the efficacy in the CNS is also extremely high, close to 90%. So based on the data we are very encouraged in the fact that…

SP: It shows reliable tests.

TM: It’s a very reliable test. It’s correlated with a very positive clinical outcome.

SP: Absolutely. It was interesting, at the beginning of the year we had this hypothesis about liquid biopsy coming from the NILE trial which was trying to show that you can positively replace tissue biopsy in terms of getting all the mutations you need for the treatment decision making process in the vast majority of patients. So the challenge to me is it’s not something you will brew in the house, this liquid biopsy is not something that your pathologist will settle down as he did with PD-L1, right? So we need to implement, like you said, a whole strategy, system, pace and speed which probably we still don’t have in our centres, or not in place. So that’s a level of complexity which is probably worse but will take some time, don’t you think?

TM: Exactly. I agree with you entirely that it’s not an easy task and also we have to understand one gene at a time. It’s not one panel that each gene will have equal sensitivity and equal specificity. The meaning of each gene may also be quite different. For example, if you find KRAS in the plasma does it really come from the cancer or could it come from a white cell?

SP: Absolutely.

TM: But then on the other hand you find ALK translocation, then you know quite sure that it is coming from the cancer. So it’s very complex information and I don’t think we should take it lightly, just say NGS, no NGS, replacement, not replacement. We really have to have a very intricate system of how to utilise this information.

SP: So just let’s try to imagine waiting for that implementation of a nice system we might use liquid tests for resistance. Because you’re probably a little less under pressure of time, at the time of resistance you give alectinib, this is a long time PFS, after three years there’s a progression, usually systemic, not specifically in the brain, would potentially a blood test here help and do you perform this in your centre in order to understand the mechanism of resistance?  Because sometimes doing it a little bit, we’re a little frustrated not always to get the answer there.

TM: There is the research side and also the clinical application side. The research side of course I say yes to that – that’s the only way to learn. But on the other hand in the clinical side if the patient is already on alectinib as the first line treatment, as per the ALEX study, the question is which mutation makes the major difference in your treatment decision outcome? So obviously it’s ALK G1202R, if you have that positive then you’d probably go for a third generation drug lorlatinib. If you don’t have the others then you may just gamble on one second generation drug or go on chemotherapy. So in a way, yes, we want to know but actually right now, practically speaking, we only know the one gene.

SP: It doesn’t change your treatment.

TM: Only one gene that we look after. So right now we have to use a relatively expensive NGS but in the future maybe we can use the dual PCR.

SP: Absolutely. So the idea is when you have this progression on the alectinib you will never be wrong if you give a third generation and the one available is lorlatinib. So you will not be wrong in presence or in absence of a secondary mutation of the ALK gene, right? And then it’s going to be chemo or…?

TM: Lorlatinib may not be the only third generation drug, there are others coming up.

SP: No, there will be others.

TM: Whether they have higher sensitivity to the G1202R or ALK resistance, that remains to be debatable. But, of course, at the end of the day we always ask whether there was a role for IO. By the way, I just want to ask you, first of all congratulations on the very successful CM-227 trial.

SP: Thank you.

TM: I just want to shift a little bit. For ALK positive patients where would you put IO and then potentially what’s the IO/IO combination in the ALK positive patients?

SP: It’s a good question because it was part of my last question. The question is more for all these oncogene addicted situations where obviously the number of mutations, because most, if not all, of the patients are never smokers. They present with a tumour which is probably poorly immunogenic, not strongly immunogenic at least. So to try to position it that disease entity, this is immunotherapy first, like we do in unselected patients with chemo or without chemo, it’s probably not good idea. It’s certainly not a good idea when you see three years of PFS of alectinib. Who would start with something with eight months of duration of response? Nobody would do that. So chemo and IO have to enter the discussion when you have exhausted the TKIs. The TKIs combine not very well with immunotherapy and the results of combinations were never really promising and not really better than the TKI itself. So really if immunotherapy comes it’s really after you have exhausted the TKIs. That’s a good question – where and how to position immunotherapy. I’m quite sure it’s worth trying because in every long-term trial looking at five year survival you have these two EGFR mutated patients, this ALK patient, this massive brain metastatic patient. So we have these patients telling you that the truth is not in no way, the truth is we don’t know really how to select. So it’s worth exposing even the ALK patients. I would do it during a chemo combination, like in the IMpower150 because I like the idea that a little bit of neoantigen release is taking rise with the chemo of paclitaxel, carboplatin plus bevacizumab and the atezolizumab will expand somehow the T-cells. I like this idea. But you can also give the chemo and try to go later on with immuno but I would try immuno.

TM: For this decision does the PD-L1 expression affect your decision?

SP: It’s very difficult in ALK because my experience in my ALK patients is very variable. Many of them have a high PD-L1 and the predictive ability of PD-L1 in that specific disease has not been shown at all. We know there’s a low TMB so we know it’s not strongly immunogenic. PD-L1 can be driven by intrinsic regulation in the cell, it can be driven by the oncogenic pathways. So I’m not so sure that anyone has shown that PD-L1 is predictive there. For the IMpower150-like regimen, for all the chemotherapy combinations the PD-L1 loses a little bit its mandatory paradigm for selecting patients. So probably not. And you are late in the line, right, it’s five years you follow your patients. So I think you have to move with a lower level of evidence base, chemo for sure, because remember ALK positive disease is chemosensitive, and immunotherapy I would give it with the chemo. But what do you do?

TM: I agree entirely with you, this is exactly the way I practice. One thing that would be of interest, apart from the IO, after chemotherapy do you really rechallenge with the TKIs sometimes?

SP: I like to do that.

TM: And if you rechallenge do you also do another molecular profile to make sure it’s still ALK dependent before you rechallenge the patient?

SP: Yes, I do that. So I always try to rechallenge if you have the opportunity, sometimes you don’t. But I always do that because you very often find if you have a molecular profile before that the re-emergence of the wildtype clone or less mutated clones allows you to go for a certain range of TKIs. You maybe don’t have to go back to lorlatinib, you can maybe just go to alectinib again because the paradigm is that wildtype is probably fitter and comes across over time and under chemo. So that’s a good idea. The only problem you will have here if you use immunotherapy is to be sure that your TKI is not incompatible with the immunotherapy because this stays in your blood for 200-300 days. So you have to be just careful when you reintroduce the TKI after immunotherapy.

TM: I have to say that there’s a lot of similarity between us. I don’t know whether Switzerland and Hong Kong but just between you and me.

SP: Wonderful. I think we’ve covered it. Thanks a lot and thanks to all of you for your kind attention. Have a nice day.