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Medicine Matters oncology

Hello, everyone.

I am Luis Paz-Ares. I am a medical oncologist at the 12th of October University Hospital in Madrid. I really welcome you all to this panel discussion on ROS1-positive non-small-cell lung cancer. We have two excellent and expert panelists here today - Dr. Schneider from the Mass General Hospital and Dr. Besse from Gustave Roussy. And I'm just going to ask them to introduce themselves. So go ahead, please.

Yes. My name is Dr. Jaime Schneider, and I am a thoracic oncologist at the Massachusetts General Hospital Cancer Center in Boston, Massachusetts. And I'm also a research scientist, working at Harvard Medical School with a specific interest in oncogene-driven lung cancers and mechanisms of resistance.

I'm Benjamin Besse. I am a medical oncologist at Gustave Roussy near Paris, France. My field of interest is thoracic malignancy. And I'm also chair of the Scientific council at EORTC.

OK, wonderful. So we are here today to somehow discuss a bit about ROS1-positive non-small-cell lung cancer. So the first point would be maybe about the relevance. I mean, today I think it is our duty to have all our patients with non-small-cell lung cancer having the genomic profiling, so that we can really guide the treatment of those patients that are having genomic aberrations with-- that dictate oncogene addiction, so that we can then treat on a personalized fashion. So I find, let's say, in our population, in the very south of Europe, that some, I would say, 1.5% to 2% of the cases having ROS1-positive fusions. I understand this proportion maybe not the same everywhere.

So I would ask Dr. Schneider, for example, to start. What do you think about the relevance of this fusion? And secondly, what is the typical profile of the patient in the United States?

Yes, thank you for that. So native ROS1 is a receptor tyrosine kinase. And ROS1 fusions are, of course, oncogenic drivers detected in approximately, we say, 1% to 3% of non-small-cell lung cancers. The CD74 ROS1 fusion is the most common, but over 20 fusion partners have been reported. And what this ROS1 fusion does is it renders ROS1 constitutively active and ligand-independent, leading to unchecked downstream signaling and cell proliferation.

So ROS1-positive lung cancer is typically associated with younger age at diagnosis, minimal smoking history, and adenocarcinoma histology. However, I like to say that it's very important to remember that patients of any age and any smoking status can get lung cancer, including ROS1-positive lung cancer. So testing, of course, for ROS1 positivity is absolutely critical.

OK. I totally agree on that. And for example, let's say, in our practice nowadays, we tend to do an NGS panel in those patients that are diagnosed of non-small-cell lung cancer, So that we are, most of the time, getting information on all the relevant genes, particularly the 10, 12 genes that are more important in non-small-cell lung cancer, of course, ROS1 translocation are very important. In the past, we used to do FISH analysis. And even we were doing some screening with immunohistochemistry.

So Benjamin, what is your practice? How do you compare one method to the other? What would be your recommendation at the current stage?

Well, first of all, I agree. The current-- well, the old gold standard was FISH. But with the new, next-generation panel, fusions panel, it's clearly much more convenient, because you have all the information at one time, the mutation and the fusions. I think immunohistochemistry is still a weak biomarker, because the positive predictive value is not yet good on different clones. But overall, this is not a method that's been, let's say, approved and on which the clinical studies were done.

One thing that is clearly important, because nobody-- well, everybody has no access to NGS. Some centers still have to sequence the targets. I think it's important to remember that the main targets are mutually exclusive.

So if you have a light smoker, like Jaime said, adenocarcinoma, EGFR mutation is negative. ALK immunohistochemistry is negative. You really have to chase ROS1.

And I think this is the first population in which I will even rebiopsy the patients, to be sure it is not ROS1. But I agree with Jaime. All the populations can have that - heavy smoker, maybe more elderly, it will not be such a priority.

Second thing is that we have now access to liquid biopsy-- all the same, not in all the centers. But overall, for the fusions, the performance of the liquid biopsy has been shown to be a bit lower than tissue biopsy. So if it's positive by liquid, that's perfect. I think it's enough to treat. The negative by liquid-- again, in particular with this phenotype of, let's say, less than 15 pack-years, negative for EGFR and ALK, I would again rebiopsy the patients and analyze the tissue.

Yeah. I think that's crucial. Actually, for example, we tend not to do liquid biopsy as a standard of care-- that we typically do tumor biopsy first. Still it's very important that, for those patients that are never smokers, in our population, let's say, we found some genomic aberration, which are actionable in about some 70% of the cases. So still, on this patient population, if we are not able to find a genomic aberration, if we do liquid biopsy we typically in 10% to 12% of the cases are able to find these genomic aberrations.

So I don't know if you have similar data or what is the typical policy you're following. I think in the US maybe you're doing a bit more of liquid biopsy, though, to start with. Right, Dr. Schneider?

Yes, I'd say, our practice is to always perform a tissue biopsy when possible, when feasible. And we are starting to do more and more liquid biopsies or circulating tumor (ct) DNA at the time of diagnosis. Of course, we are using ctDNA mostly in the context of resistance or clinical relapse, to look for resistance mechanisms. But, yes, our practice is to increasingly use ctDNA at the time of diagnosis, to kind capture all possibilities.

OK. So I think he's very important, in that way, just to highlight the relevance of doing testing. Over the last few years, because of the increase in PD-L1 testing in some of the countries, in some of the publications, we have seen actually a decrease in the testing for some genomic aberrations. And ROS1 was one of the cases that I think that's particularly relevant, to be sure that we are doing, every time, appropriate testing for those genomic aberrations.

So then, if we go to the treatment of those patients, I remember the times when we started to do crizotinib treatment, that was really great news, looking at a treatment that was able to induce responses in maybe some 70% of the cases, particularly the PFS or in the initial studies was in the range of 19, 19.5 months. And then there were a number of other studies that maybe didn't mimic, all the time, all the results. I mean, what are your comments, in that sense? What is your typical treatment for those patients with ROS1-positive non-small-cell lung cancers? Are you doing crizotinib, are you doing any other TKI?

These recommendations are quite pragmatic. They recommend to test when you have a drug and crizotinib and entrectinib are approved by EMA. So, yes, ROS1 is a standard-of-care diagnosis.

And then you have the choice between crizotinib and entrectinib that are two ROS1 inhibitors. Historically, crizotinib was the first. I would say that crizotinib is probably a weak ALK inhibitor, but it's a very good and very strong ROS1 inhibitor. As you said, the initial PFS was very strong, 19 months. It was a bit lower in the Asian population.

And what we see, in fact, is that even if ROS1 positivity gives some kind of homogeneity, I mean, it's the same oncogene, so the same type of tumor, we know that there are factors that may affect the efficacy. For example, the presence of a TP53 mutation, co-mutation can affect. And also, the tumor burden seems to be something that is of poor prognosis. It has been shown, for example, when the treatment is given just on the fact that there is a positive liquid biopsy, the overall benefit is a bit lower.

And a lot of studies shows now that if you find in the blood the driver, it means that you have a lot of ctDNA in the blood, meaning bulky disease with probably poor diagnosis. So I think, by chance, the first study with crizotinib overselected the population. But we are all confident that we have the footprint of the addiction with more than 50% response rate and a PFS that is longer than 12 months.

Then, you have the choice now between crizotinib and entrectinib - two different side effect, maybe difference efficacy on brain mets. And I have to say that, in Europe, the access to the drug might be different across the countries. My country, France, we only have access to crizotinib. And the crazy thing is that we can only prescribe crizo plus chemo while this is not what I do in my routine practice. But the entrectinib it's only in second line, because there are no randomized data, which is completely unfair. But maybe, Jaime, you want to comment on the use of entrectinib and crizotinib?

Yes, absolutely. So I agree with everything you said. When I talk to patients about first-line therapies that are available for ROS1-positive lung cancer, we talk about the differences between crizotinib and entrectinib. So overall, by cross-trial comparison, the numbers that you all quoted are obviously correct. Both drugs show about a 70% to 80% response rate in those early trials, median PFS in the range of 19 months. And then, of course, now we have the updated long-term survival data for crizotinib, showing a median overall survival of about 51 months.

And so ultimately, in the US, both crizotinib and entrectinib were FDA approved for this indication. And so, as Dr. Besse had alluded to, while these agents are both approved for first-line treatments of ROS1-positive lung cancer, they have very different side effect profiles. The most common side effects really with crizotinib we think about are visual disturbances, edema, GI upset. And the more common side effects with entrectinib, which are really related to off-target inhibition of TRK are things like dizziness, dysgeusia, and weight gain. So managing those and deciding between which drug to use is certainly a conversation with the patient and their current comorbidities.

I mean, Benjamin alluded to the fact that in Europe even we may have approved both drugs by the EMA. At a country level, there is some reimbursement restrictions. For example, in my country it's quite the same that entrectinib is not covered by the NHS reimbursement. And so which this, I suppose, is somehow limiting this choice that really Dr. Schneider alluded to, because maybe there were some specific profiles of patients that maybe it would be really nice to have the two possibilities.

For example, for, let's say CNS metastasis, that would be a clear example where we know the limitation somehow of crizotinib at a time of getting enough CNS level. So that would be a convenient type of subset of patients that I really maybe would like to have the opportunity to use, particularly. The proportion of patients with CNS metastasis, of course, is not as high as ALK, but it's still quite high. And that is where we have some nice experience in clinical trials. So what is your preference for CNS metastasis patients in Boston?

Yeah, it's tough, because as you said, ROS1-positive lung cancer has a very high rate of CNS involvement, both at the time of diagnosis and then throughout the disease course. And so, despite pretty good systemic activity of these first-line agents, crizotinib and entrectinib, CNS relapse at disease progression is very common. So the CNS progression, I think, is really problematic for patients with baseline brain metastases.

So the pooled study that had initially led to the FDA approval of entrectinib in the US reported that CNS progression occurred in about almost half of patients with pretreatment brain metastases, compared with only 3% of patients without baseline brain metastases.

So our general practice in the US is to reach for entrectinib if possible with baseline brain metastases, as the data is a little bit stronger. But still problematic for both crizotinib and entrectinib, treating patients with baseline brain metastases. We always worry about CNS progression.

Yeah. That's really an issue. So what about, let's say, we are having patients treated first-line with crizo, entrectinib. So do you typically rebiopsy those patients at a time of progression as opposed to you are doing so? What is your preference?

Do you typically do liquid biopsy first? This is typically our preference. And if the result is not informative, we tend to do a tissue biopsy. Always, that is possible. Is that the policy at Gustave Roussy as well, Benjamin?

Yes, this is something that we do. I would say that, at a time of progression, we also like to dose the drug in the blood. This is not something we do so much, usually, with the TKI, although we've clearly shown that more than half of the patients treated chronically with TKI don't have the level of the drug that you expect in the blood.

And in particular you were referring, Jaime, to the difficulty of progressive brain metastases. We know that the brain is a sanctuary where a drug can be more, well, might have more difficulty to go in the brain mets. I think this is something that we should have more reflex. I think we all have, in our country, some centers that can dose. And it's not something difficult.

In terms of rebiopsy, I would say that, as we are a research center we rebiopsy the patients, always by liquid, sometimes solid. We don't have this urge that we have, sometime, with EGFR-mutated NSCLC, where we could suspect a transformation in small cell. This is something that is completely exceptional. So really, the biopsy, tissue biopsy, would be to catch some mutation.

It's a bit trendy to say, well, I rebiopsy all my patients. But the fact is that the only benefit of doing an exam in medicine is if it impacts your following steps. And I have to say that if my patients progress on crizotinib, I prescribe off-label lorlatinib or I offer a clinical trial. So, per se, it's interesting to understand and publish and research, but I think, for a community center with a ROS1-positive patient that progress, the next step will be to escalate to, I hope soon, the second generation if available, but if possible to lorlatinib, because we know that this drug, that it still has to be considered as a first-generation ROS1, probably has a better diffusion in the brain. And we know that about a third of the patients will experience a partial response with lorlatinib after failure of crizotinib.

OK, so I think you alluded to the way of treating those patients, which I think, I mean, in our setting as well, the very drug we have access to is lorlatinib, typically on expanded access programs. So there are some other new-generation drugs, in this setting, that also are giving us some hope. Maybe do have some experience Jaime, at the Mass General, with the new-generation ROS1 inhibitors? And what could be the place of those drugs, into the future?

Yeah, it's a great question. We spent some time talking about the first-line agents entrectinib and crizotinib, but important to also think about second-line agents that we have available. And so, when I think about second-line ROS1 TKIs and the landscape, certainly it's becoming increasingly complex, which is a good thing. And so I think about some considerations, when trying to select either something like lorlatinib or discussing clinical trials with a patient. So I think about, what do we know about duration of response? What do we know about CNS penetration? And what do we know about spectrum of activity against ROS1 resistance mutations. which we'll talk about more.

And so, in terms of the drugs that are currently in clinical trials, we think about things like repotrectinib and taletrectinib. So repotrectinib is a next-generation TKI with activity against ROS1, ALK, and NTRK, or TRK, with early data showing potency and selectivity against both treatment-naive populations and ROS1 G2032R resistance mutations.

And so the TRIDENT-1 is an open-label, multicenter phase 1, 2 study. And initial phase 1 data from the trident study was reported, I think, 2 years ago at World Lung and showed very impressive overall response rates, in the 90% of treatment-naive patients and pretty good activity in the response range of 30% to 40% in [pre-treated] patients. And so it's important to think about side-effect profiles, so, again, because it hits TRK, we're seeing some dizziness, dysgeusia, dyspnea, fatigue, constipation - kind of a variety of side effects, but seemingly manageable on repotrectinib.

And so actually in the US, based on early data from repotrectinib, it's actually been granted fast-track designation for TKI-treated patients and then breakthrough-therapy designation in treatment-naive patients. So it'll be interesting to see the final results of those studies.

And then I'd love to hear about your experience, as well, with taletrectinib. So that's another ROS1 TKI that has activity, looks like, in TKI-refractory disease, with, again, a response rate in the 30% to 40% in pretreated patients. So there's this ongoing TRUST-II. Study. I think it's a phase 2, global, single-arm, has multiple cohorts, looking at safety and efficacy of taletrectinib in ROS1-positive patients.

I agree that those agents are really promising, particularly activity on those difficult-to-treat mutations like the G2032R, right? And I could say we still need some time to really see if those agents are going to be able to, let's say, occupy the first-line setting.

So any other comment that you really, any other, let's say, comment you'd like to have on this patient population? Particularly, I would say, how do you treat those patients, in terms of - very often, like, one third of those do have a thrombosis-associated diagnosis. Would you typically treat those patients with prophylactic heparin, which is being kind of suggested by some people, or just only use that therapy in those one third of the cases with thrombosis or pulmonary embolism?

We typically do not offer prophylactic thromboembolic treatments. As Jaime said, the PFS of the drug are quite impressive, and it's a median PFS. So when we said the median PFS is 1 year and a half, it means that half of the patients will receive more than 1 year and a half of the treatment. And I think that if you start with prophylactic, it means duration of treatment that is very, very long - OS of almost 50 months, I think, it's - well,

we scan the patients very frequently. I personally see these patients each 3 months. So I think this close monitoring is enough to detect any sign of thrombosis. You can educate the patients. But I would say that the reflex shield to put some prophylaxis, for me, is a bit too much.

Yeah. We have reviewed a bit our experience. And in fact, most of the thromboses actually happen at the time of diagnosis. So only thromboses or rethromboses is happening in some less than 10% of the cases, during the rest of the disease not very common. So I fully agree that maybe it's not necessary to do antithrombotic therapy on a prophylactic way.

So just the final comments about the role of chemotherapy and chemo-IO in these patients. One thing that oncologists do, as compared to other specialists, that, where we incorporate in a new drug, we are not forgetting about the old drug. And so at the end of the day, very often our patients, even they have very fancy genomic aberrations in their tumors, we still use chemotherapy at some point.

And this is the fact for ROS1 tumors. They really respond pretty well to chemotherapy, particularly to, I mean, in my experience pemetrexed-based chemo doublets. And we use that most of the time.

More controversial issue would be here if chemotherapy alone or chemo-IO is serving better our patients. So in that sense, I would be happy to hear your comments on that. Are you doing chemo-IO or chemo alone, most of the time?

Our practice is typically to do chemo alone. As you mentioned, there is a lot of controversy around use of immunotherapy agents in patient populations like ROS1-positive lung cancer. And so what I'd say - there is good data in suggesting us not to use immune checkpoint blockade alone in this patient population. Multiple studies have demonstrated that single-agent immune checkpoint inhibitors have overall very little clinical activity in oncogene-driven lung cancers, such as those, of course, with sensitizing EGFR mutations and ALK rearrangements.

And so our group published a retrospective study last year in which we examined the immunophenotype of ROS1-positive non-small-cell lung cancer and the activity of immune checkpoint blockade monotherapy. And unsurprisingly, like all these other oncogene-driven lung cancers that have been studied, we also found that ROS1-positive lung cancers have very relatively low PD-L1 expression, low tumor mutational burden, and very, very modest activity of single-agent immune checkpoint blockade. So certainly, there's enough data to suggest we should not use monotherapy. So we do often use chemo, and we do have a discussion with the patient about whether to incorporate immunotherapy into that regimen.

OK, thank you. So what about in France? Do you use chemo-IO first or chemo alone, at the time of the TKI refractory?

I tend not to use chemo-IO, for two reasons. First of all, I think that bevacizumab might have a role, in particular when they are brain meds. So I tend to prefer chemo bev when there are no contraindication to that. That's the first point.

And the second point is that, given the outline of IO, it will be difficult to rechallenge any-- or at least crizotinib, because we know that there are interaction and because of the half-life during a few months after the end of the immunotherapy, it will be difficult to rechallenge. And, as you said, we might have good surprises with pem and long response. And I think that it's fair, when a patient's been on chemo for at least 1 year, to rechallenge even a first-generation TKI.

Another comment I would like to make is that, sometimes you face-- on nonsquamous patients, you stop because it is highly symptomatic for example. And you know that your molecular profile will take a lot of time. You start a platinum-based, well, a pem-platinum typically followed by pem. And then, after two or three cycles, you receive the information that the patient has ROS1.

I think we have to take a step back and say, well, if my patient has strong benefit to chemo, not too much toxicity, my management is to keep chemo, because I know that sometimes I will have a long PFS on chemo, and I know that the activity of crizo after that be as good as first line. And I think that rushing to changing to a TKI after two cycles of platinum-based chemotherapy, the risk is that you have learned the tumor to resist to platinum-based chemotherapy without taking all the advantage of chemo.

Yeah. I think that we have to squeeze any benefit from every single treatment. I mean, it is our practice that, after a patient had received the TKI that we have available, first of all, the ones that are already approved, then maybe sometimes you have a clinical trial and you try anything. Then when we started with chemo, we tend to do platinum-pemetrexed like carbo-pem. And a typical second-line chemo is beva-taxol I mean, actually I understand this is not maybe standard everywhere. We are, in that case, guide by the French phase 2 data comparing weekly carbo-taxol-- sorry, taxol - beva versus a taxotere. And in that population, particularly ALK translocated patients as well, we have seen really nice result in this setting. Of course, this is a local perception. So I think it's also a nice possibility here, let's say, at a later stage, I would say.

OK. So I don't know if there is any other issue that you like to comment that we didn't touch, over the last few minutes?

Well, maybe just to raise that we still don't understand why never-smoker or life-smoker are ill with this disease, while it's the same for EGFR, ALK. But ROS1, we don't know. And there are no family with ROS1-positive non-small-cell lung cancer. So it's very difficult when the patients ask you, why, why do I have this disease? And there are clearly no reason for that.

And I think we still need to understand why. And just to highlight that we have currently a large European study called BioRadon, where we find to match the radon exposure, which is the second cause of lung cancer, to the type of molecular abnormality that the patient has. So I really suggest, if a physician are listening, or even patients, to look at, there are a lot of sites in 17 countries for BioRadon to send your patients. Because if we can't understand why we will even be to prevent.

I think that's a nice, very nice suggestion, very important issue to tackle.

Maybe I'll just mention, additionally, we briefly talked about on-target ROS1-dependent resistance in the form of secondary ROS1 mutations, most commonly, G2032R. And so, of course, the profiling of these secondary acquired resistance mutations has kind of spawned newer, next-generation agents, like we've talked about-- taletrectinib, repotrectinib-- that are currently in trials. And then there's this newer agent - we recently opened a trial at MGH - the Nuvalent compound, Nuvalent 520-- I think is a very exciting, what looks like to be brain-penetrant, highly selective ROS1 inhibitor, with quite good preclinical activity against G2032R solvent-front mutations with really single-digit nanomolar or IC-50 values. So I'm very much looking forward to the - we have a long way to go - but looking forward to the results of that early phase trial.

Yeah, I think I'm on the non-- let's say, non-on-target kinase mutations. We have some I mean, we have have, this has been well-described, some cases of KRAS mutation, NRAS mutations. I don't know if you have any-- and you have the opportunity to treat any patient with KRAS inhibitors and have any success there.

The other thing that where we have some cases of responses actually was with cabozantinib in some patients with MET amplification, which I think is maybe not as frequent as in other diseases such as in EGFR-TKI refractory mutant cases. But here, I mean, those are pretty well described.

So at some point, I think we have access to the liquid biopsy or tissue biopsy is always a reasonable idea to have these done. That may guide or benefit some of the patients. And of course, it's also helping us and particularly to test novel drugs, knowing what we are treating. And you have given good examples for that.

Yeah, I think that's a great point and a great question. So, really important to think about off-target resistant mechanisms. And many of which have been described for TKI-refractory ROS1-positive disease. So things like MAP kinase activation, MET amplification, BRAF mutations, EGFR amplifications. And then very, very rarely, as Dr. Besse pointed out before, rarely you can see a histologic transformation to something like small cell. But that's incredibly rare.

And so there are early phase clinical trials looking at combination therapies for ROS1-positive disease. So at MGH in Boston, we have a phase 1-2 trial looking at lorlatinib combinations for patients with ALK-positive and ROS1-positive disease. This is in the form of lorlatinib plus either a SHIP2 inhibitor, lorlatinib plus a MEK inhibitor - binimetinib - or lorlatinib plus a MET inhibitor. As of right now, it's crizotinib.

So sometimes combination therapies can be tough, in terms of toxicities. If you're doing two TKIs, sometimes we see we have some trouble managing toxicities. But there have been some responses. And I think we'll be seeing a lot more of these combination trials trying to target off-target resistance mechanisms.

OK. Have you seen any response in patients having MEK mutations, as well? Because that would be, I suppose, quite a tough case to treat. And particularly, I mean, MEK inhibitors are not easy to combine with anything.

Yeah, exactly. So the swelling becomes an issue. Lorlatinib can cause edema. Binimetinib can cause edema. The SHIP2 inhibitor can cause edema. Crizotinib can...

So the toxicity has really become limiting. I'm not aware of any MEK-mutant patients who have been on the trial. I'm sure that data does exist somewhere, because they require biopsy. But it'll be interesting to see who the responders are and what their mutational profile looks like. Wonderful, ok, so thank you very much. I think we have very much covered some of the most relevant topics on ROS1 fusion-positive non-small-cell lung cancer. And I hope you enjoy the discussion. And we'll see you next time. Thank you very much.