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Medicine Matters oncology

Hello, everyone. I'm Ross Camidge, from the University of Colorado. And welcome to this expert panel discussion on ALK-positive non-small-cell lung cancer. I'm joined by two very special guests today. Rosario, could you introduce yourself?

Sure. Hi, Ross. Happy to be here with all of you. My name is Rosario Garcia Campelo, medical oncologist in the University Hospital of A Coruna in the northwest of Spain. It's a great pleasure.

Great. And Charlie, could you introduce yourself?

Yeah, definitely. OK, so my name is Yongchang Zhang. So you know, I'm from China. So, I focus on the targeting of receptors of lung cancer. And I have my own living tissue bank. So, just OK. Thank you, Ross.

All right, so let's start. So, here we are. So, we've got people from North America, people from Europe, people from Asia. And yet, we all represent our own individual centers. But I'm going to start with a question. And Rosario, I'm going to start with you. How do you do ALK testing? Who do you do it in? And when do you do it? And describe your own center, and perhaps your neighbors as well.

So we are doing ALK testing for all those advanced non-small-cell lung cancer carcinomas, overall those non-squamous population, and in other histologies with some clinical characteristics, like never-smokers, light smokers. We have moved from all these population. And we are doing now ALK testing in the earliest stages and locally advanced, since we have the monotherapy. And also, we have some clinical trials with targeted agents.

Regarding the methodology, we started with FISH. Then we moved to immunohistochemistry. And now, we are using NGS panels. I think it's pretty similar all around the country, not only the population we are testing, but also the methodology we are using in our daily clinical practice.

Great. Charlie?

OK, so the first is how. So in China, the NMPA has adjusted their approach. Ventana IHC and the RT-PCR are detecting ALK. So that's the methods. That's the how.

So, who? Who were tested with ALK? So, in our hospital, Hunan Cancer Hospital, every lung cancer patient excluded as a small-cell lung cancer will have receptor detection of ALK by IHC. And maybe other patients, including the adenocarcinoma and sarcoma carcinoma, will both receive the IHC.

Well, if the patient was adenocarcinoma, they will also be detected by a larger panel of NGS. So, I mean that that's the who. When to perform the-- I want to say that a patient first diagnosed with lung cancer, and then reveals relevant receptor detection for ALK. But if the patient progressed from the ALK TKIs, and we will perform the biopsy and the mixed rebiopsy and the next-generation sequence. So, this is all.

So, Charlie, do you-- so, Rosario mentioned that she would do all stages, because she's now doing PD-L1 testing in the adjuvant setting. Are you just doing advanced stage for the ALK testing, or other stages?

No, no. So, I want to say that all the patient-- maybe they received the surgery in stage I to III, they will also receive the detection of Ventana IHC. That's the screen. But if the patient will maybe diagnosed with stage IV, and they will also be detected by the NGS. So, I mean that.

All right, fantastic. So in the United States, because we have multiple different insurers, multiple different states, multiple different practitioners, it's a bit more varied. So, I would say next-generation sequencing is probably going on in more than 50% of patients now, but there are still some centers when I get second opinions, they've had FISH or they've had immunohistochemistry. And I always wonder whether that's, the pathologist and the medical oncologist haven't really spoken to each other.

Who do we test? Well, we are actually, a bit like Rosario, we are testing people pretty much from stage II onwards. And when? Well, we're testing them when they first come through the door.

So, let's move on to the second question. So, the second question is, you've got an ALK-positive patient. Let's assume that they have metastatic disease. Charlie, what is your first-line ALK inhibitor? And then what is going to be your second-line ALK inhibitor?

Well, so I will treat the patient clarified by the stages. If this patient was diagnosed with stage IV lung cancer, the first preferred treatment was alectinib. And we have another approved drug called ensartinib. It's an X-396. It's just made in China, used locally. So that's the first choice.

But if the patient progressed with alectinib or ensartinib, maybe the second line was clinical trials. We have lorlatinib and some local drugs. So, that's the second line. So, that's all.

So Charlie, let me just-- so, it sounds like you have alectinib and ensartinib equal in your mind. In your own practice, which one do you start a patient on?

No. So, I prefer to choose alectinib. We have the longest PFS. Yeah.

OK. And then Rosario, first- and second-line ALK inhibitor?

Yeah, that's the big question of the moment. Unfortunately, in Spain, we have just available the conventional first and second, crizotinib, sunitinib, and then alectinib and brigatinib. In my practice, I usually start with alectinib or brigatinib. I think it's basically the same all around the country, although I have to admit that probably alectinib has more penetrance in Spain. We don't have lorlatinib available, so we cannot use in the first-line setting. And we give this drug for those patients who progress after alectinib, or brigatinib in the first-line setting.

So let me-- do you think anyone is starting any patient on crizotinib or ceritinib now in your country, Rosario?

I don't think so, to tell you the truth. I think we have enough evidence today. And since we have the other drugs available, I don't think, in my country, crizotinib is an option, or ceritinib, because of the other drugs is not an option. I don't think it's a common practice at all.

OK. And then Charlie, is anyone starting on crizotinib as a first-line treatment in China anymore?

Maybe 2 or 3 years ago, we need to choose crizotinib. But now, we have more drugs. So, I just want to say, you lead the ALTA-1L study, just the brigatinib were just approved in China just maybe a few days ago. So now, we have a nice choice with brigatinib. But I do not have a lot of experience on these drugs, that's all.

In the United States, we have a lot of drugs. We don't have ensartinib licensed. But we have a lot of the other drugs licensed in the first-line setting. In general, in my experience, I still start people on alectinib, even though I did the brigatinib study and the alectinib study.

I actually keep brigatinib in reserve as a second-line agent off-label, because I think it's somewhat better tolerated than lorlatinib and has a really good spectrum of activity. I think alectinib is the dominant drug that most people are starting on in the United States. Second-line, a lot of people are using lorlatinib because that's actually on-label post-alectinib, although, as I said, I tend to see if I can put in a better tolerated agent in there, if possible.

Let's move on to a different question at this point. So at some point, we're going to use these ALK inhibitors. But at some point, we're going to get to chemotherapy. And so in that clinical scenario, when you get to chemotherapy, what do you do? Do you do chemotherapy on its own? Do you do chemotherapy with immunotherapy? If you do chemotherapy, do you keep the tyrosine kinase inhibitor going? So, I can't remember whose turn it is, but I think it's Charlie's turn to go on this one.

I just want to say that we do have a lot of patient receive the chemo plus bevacizumab or chemo plus immunotherapy. So, we're still-- we just missed the detection, how to clarify the patient who can benefit from the chemo plus immunotherapy. You know, if we treat a patient with a the PD-L1 inhibitor monotherapy, we can have some-- we cannot have the benefit.

But we have more than 70 patient, 70 ALK fusion non-small-cell lung cancer. When they feel the way is alectinib or other ALK TKI, they also chemo plus immunotherapy or chemo plus immunotherapy plus bevacizumab, just as the IMpower130. But we can say that in just some of the patient that can benefit, have maybe the minimum PFS was just 7 months. But now, we don't know how to choose the best patient for this or the best treatment of immunotherapy. So, I just wanted to say-- I want to hear some suggestions about this from Ross.

Well, so I get that. But I want to know what you do. So if the patient is in front of you and they get to chemotherapy, and they say, Dr. Zhang, do I go on chemo, chemo immunotherapy, or chemo keeping the TKI going, what do you say?

I just want to see some evidence. Professor Ou just published a paper, if the patient progressed from alectinib, they can just continue to the alectinib. But we have maybe six or five PFS. But we'll choose that. We have some, the more powerful data about the IMpower150 so I just, I will persuade my patient to receive the chemo plus immunotherapy. So I think that in the future, if you progress from the treatment, you can just switch to the former ALK TKI maybe you can have some benefit. I just want to suggest it for my patient.

All right, hold on. So, you're being a little squirrelly here. So let me just-- so you're saying, in your practice, you put people on chemo immunotherapy. That's your first choice. Is that what you're saying?

Yeah. Yeah.

OK. All right, Rosario?

OK, out of clinical trials, I try to avoid the immunotherapy monotherapy. So, the most regimen I use is a combination chemotherapy approach, platinum plus pemetrexed combination, without continuing the tyrosine kinase inhibitor. Regarding the role of schedules like IMpower150 I have some experience. But since we don't have such strong data, it's not a common regimen I use in my daily clinical practice. I hope I have answered--

You have.

--your question.

But, so I think what we have illustrated is that none of us know the right thing to do. And so, we just do whatever we feel like. And that's totally fine, because we don't have good data. In my own practice, first of all, I do believe that pemetrexed has exaggerated activity in ALK-positive lung cancer. So I tend to make it a pemetrexed-based regime.

And then my choice is carboplatin, pemetrexed, and pembrolizumab, or carboplatin, pemetrexed, and keeping the TKI going. And I don't have any better data than any of the rest of you. But I am not convinced that our PD-1 or PD-L1 agents are really having a lot of benefit in ALK-positive lung cancer. I do worry that in a disease that has a 50% lifetime risk of brain metastases, that removing the TKI leaves the brain vulnerable. So, I tend to do carboplatin, pemetrexed and keep the TKI going. But I can't prove it's the right thing. So, I think this diversity of action reflects our lack of data.

All right, so my last group of questions here relates to, so we all know that scientifically, there are different mechanisms of acquired resistance-- on target, ALK mutations, second drivers. But in routine practice, are you re-biopsying, reanalyzing, and acting on that? Rosario, let's start with you.

OK, yes. Definitely. If we can do a re-biopsy, we try to do it in all patients who progressed after whatever treatment they are receiving. And we know that sometimes, this information is just relevant from an academic point of view, because we cannot make decisions based on that information. But I think it's important to try to figure out what is going on in that person in that specific tumor. Is there is a histological transformation or whatever? So, we try to do it.

If we cannot because of the situation of the progression or the disease or because the clinical situation of the patient, we always try to do a liquid biopsy. Yes. I understand that the evidence we have to do so is limited, but in our daily clinical practice, we try to get this information.

It's not the same all around the country. That's true, also. We are a university center. We are a big center. We have clinical trials. So it's not the same. This is most-- it's controversial all around the country.

Got it. OK, Charlie?

If you ask me the question 2 years ago, I can tell you that less than 10% of patient who is resent for the biopsy when they progressed from their TKI. But now, I just want to tell you the new data. In our center, maybe almost 50% of the patient receives a biopsy for the resistant mechanism. So you know, not for-- not all the second- or third-generation ALK TKI can cover all the point mutations for resistance mechanisms But now, we have not all of the data.

But maybe sometimes, I can show data for those. We have a lot of patient-- yeah, we have a lot of patients who suffer from the complex resistance mechanisms, such as two- or three-point mutation. But we can't-- we don't know how to treat this patient.

OK, so that's good to know. So a couple of questions, though. One, this is because you're in a center that's interested in that. How much-- you're saying 50% of your patients are getting re-biopsied and reanalyzed. What do you think that is like across the country?

Honestly, I don't know.

OK, but I would imagine it would be less.

So, why do you think that would be less? Why do you think that?

Well, because they're not as cutting-edge and as interested in the analysis that you are. I suspect you're a local champion for getting this done. The other thing is, when we talked before about how you do the diagnostic testing, you talked about immunohistochemistry and FISH. And in order to make sense of these analyses, you really need to do next-generation sequencing.

So, I want to say in another cancer center, so for this patient, maybe-- I think maybe all the patient, all the adenocarcinoma, will receive the next-generation sequencing. But maybe when they progressed from the ALK TKI maybe the sample was unavailable. But I think that we can perform the liquid biopsy.

So when I face a patient, my suggestion is that I strongly suggest to the patient, you need to re-biopsy and detect the resistance mechanism. So if you can provide me more information, I can give you the better strategy of treatment. So, I just want to say all my patient.

Yeah, I mean, I totally agree with that, because I mean, Rosario had said this is not recommended because it's not like there's a drug that we're officially supposed to choose based on the results. And yet, for the patient in front of you, that information can be very useful. I'll give you an example.

So, Charlie, you've mentioned those compound mutations, more than one mutations occurring in cis. And in certain places around the world, there are trials of fourth-generation ALK inhibitors, so the Nuvalent drug and the Turning Point drug, that could work on those. If you found a patient with a compound mutation, I think it's important to give that information to them so they can seek out these trials, if it's feasible for them.

But if they don't, then sending them off to go to a fourth generation is a complete waste of their time. And I've had multiple second opinions where somebody had been re-biopsied. They clearly don't have an on-target ALK mutation. And yet, they're still sent to these trials. And they all blow through it. So, even though there isn't a licensed treatment, it's still important to the patient.

But I do think you can't just repeat your FISH test and say, that's enough. You really need to be looking, again, for ALK mutations and second drivers. All right, that was amazing. It was kind of quickfire. We've covered the entire world in about 20 minutes. Any last comments, any gems that you want to share about managing ALK-positive lung cancer? Charlie, we'll let you go first on this.

There was some unknown questions to be answered for the ALK treatment. But if the patient was suffer from ALK fusion, they were lucky. I think if we collaborated with each other, we can bring luck to all the patient. Thank you.

Oh, I like that. Rosario?

I think that despite all the success we have seen in the last year in this specific subset of non-small-cell lung cancer, we have seen in 20 minutes that there is a lot to do. So, I fully agree we need more trials. We need more real-world data. We need more collaborative efforts to offer the best for this kind of non-small-cell lung cancer population.

I agree. And then, if I'm going to sum up, if everybody could do what the three people on this call are doing, then the whole field will get better. I mean, the goal isn't to have ivory towers. The goal is to have everybody performing things at the cutting edge. And then you're always at the latest edge of research. What are the next mechanisms of resistance? How do we prolong control? Are there subgroups of ALK who do better or worse that we're going to need to manage separately? But that's all for the future. Thanks for listening.