Mechanism of action and toxicity of amivantamab in patients with MET-driven non-small cell lung cancer (NSCLC)

DR LOVE: Welcome to Oncology Today: Management of MET-Altered Non-Small Cell Lung Cancer; this is medical oncologist Dr Neil Love. For this program, I met with Dr Rebecca Heist from the Massachusetts General Hospital in Boston. In addition to this interview, there is also a corresponding program featuring Dr Heist’s slide presentations. In our conversation, Dr Heist presented patients who received MET-targeted TKIs. But to begin our conversation, we talked about another potential future strategy: the use of bispecific antibodies that target MET, including an agent approved for exon-20 insertion, amivantamab.

DR HEIST: It’s a bispecific antibody, so it’s 1 antibody and then it recognizes both EGFR and MET, and I think some of the activity comes from the fact that it’s a bispecific.

There are, frankly, a host of different antibody and antibody drug conjugate. There’s a lot of science behind them, and I think that that is actually spurring some of the progress that we’re seeing here. So that bispecific antibody is one mechanism. Some of the antibody-drug conjugates that we see are really interesting. So that is — the antibody part recognizes, for example, MET or another antigen.

DR LOVE: Sure.

DR HEIST: There’s a linker, and then it’s attached to a payload, which is usually some kind of chemotherapy drug. And so that kind of entity is a way of targeting a specific cancer cell a little bit more accurately. It’s targeted therapy but chemotherapy targeted therapy. So I think there’s a lot of development being done in terms of kind of optimizing the way the antibodies are created, how they recognize the antigen, and then in the case of the ADCs, optimizing the different components of the ADC. But much of that research and science, I think, is spurring some of the activity we’re seeing with some of the newer drugs that we have now.

DR LOVE: And then also in terms of amivantamab I’ve heard that you also see edema, which you were describing for the MET-TKIs. To what extent — is it a similar amount of edema that you see with amivantamab?

DR HEIST: We do see edema. In my opinion it’s a little bit less than what we see with the MET-TKIs, but we definitely do see edema. And I think to the extent that drugs inhibit MET in that pathway we’re going to see edema because it does seem to be a class effect.

Potential role of MET inhibitors as pan-tumor treatment for MET-altered cancer

DR LOVE: So a couple of general questions before we get back to your cases. Do you see any potential role — I was really interested by the pan tumor approval for dabrafenib/trametinib that came out fairly recently. I kind of wonder whether that’s going to lead to other targeted pan tumor approvals. Is there any potential for that happening with MET?

DR HEIST: I think so. We know that, for example, MET amplification occurs in other tumor types. MET exon 14 skipping actually is relatively rare to see in other tumor types. There have been big kind of case series looked at, and other than lung cancer it’s actually a relatively rare event. But we know that MET amplification occurs in many other tumor types, for example gastric cancer, it’s actually relatively one of the more common alterations. And I think there’s a real need in that setting to have effective drugs, and so I would hope that some of these drugs that have activity in lung cancer in that setting could be used in that — in these other tumor types as well. And certainly there are cases that I know of of people with other tumor types who have had benefit from some of these MET-directed therapies that we’re talking about.

The other alterations, there are fusions involving MET that we see that also occur. They’re very, very rare. They probably — they may occur, frankly, the most commonly in some primary CNS tumors like glioblastoma, and that’s another area where you could potentially see that some of these treatments that we’re talking about may be able to have activity.

But I think you’re getting to a good point, which is that for some of these oncogenic drivers they act as a driver in many different kinds of tumors, and so the ability of some of these drugs that we have to have benefit to people regardless of the tumor type if they are driven by this pathway is something that I think is really important to look into and make sure that we have available for everybody.

DR LOVE: One other thing about amivantamab. Is the activity enough that investigators want to use it or are using it off label in MET exon 14?

DR HEIST: So it’s not approved yet in MET exon 14. Would I use it off label? I think that’s hard to say. If you look at the reported results, if people have had a prior MET-TKI the response rates aren’t that high. And I would say many people are getting a MET-TKI in some line of therapy, including in first line because there are approved drugs. Would I use it instead of a MET-TKI in the first-line setting where the response rate was the highest in that study? The number there was so small that I think I wouldn’t yet, but I think the jury’s still out in terms of kind of getting more data and understanding more about the drug.

Selection and sequencing of targeted therapy for patients with MET-altered NSCLC

DR LOVE: So of course I’ve got to ask you about choice of approved agent. Any preference one way or the other, or is it a 100% coinflip, letrozole/anastrozole, you can’t tell the difference, or are there anything different?

DR HEIST: So among the approved agents for MET exon 14 skipping, we have 2 Type I inhibitors, that’s tepotinib and capmatinib. Tepotinib has once-daily dosing, capmatinib has twice-daily dosing. They’re both oral. If the frequency of the dosing is an issue that’s just something worth knowing.

They both have some reported CNS activity, so I think they’re probably relatively similar in terms of CNS activity, although they both are being studied in ongoing studies, so eventually we’ll have some more data about that.

If I’m treating somebody in the first-line setting the capmatinib data for first line had the highest response rate at 68%, and so I tend to go to that if I am treating somebody who has never received any prior treatment for metastatic lung cancer and they’ve got MET 14 skipping based on that first-line data. But other than that, in subsequent settings the response rates look quite similar.

So I think those are the considerations. I think the edema is quite similar across all the MET-TKIs. And those are the considerations I think about when I think about what drug to use.

DR LOVE: So there’s a bunch of issues that tend to come up every time we talk about targeted therapy of lung cancer, and I just want to kind of focus down on those issues as it relates to MET, and the first is a question of whether you use targeted therapy up front or not in metastatic disease. What you see is a lot of times if the response rate’s like over 50% or 60% people just use it whether there’s a randomized trial or not. What about first-line TKI for MET exon 14? Is that something you and other investigators generally do, or do you hold it for second line?

DR HEIST: I do. If I know somebody has a MET 14 skipping alteration I will use it in the first-line setting. I do think that it’s got very good activity. It has side effects, these MET-TKIs have side effects, but in general I find that they tend to be milder than chemotherapy and immunotherapy for example. And so I will use it in the first-line setting.

Managing MET-altered NSCLC in patients with brain metastases

DR LOVE: So another targeted issue that comes up all the time, and you were kind of referring to it there, is brain mets and whether or not — the typical scenario, if somebody presents with brain mets, they have no symptoms, neurologic symptoms, and of course the classic ALK and EGFR, to use targeted therapy, hold off on radiation. Does that paradigm, from your point of view, apply here?

DR HEIST: Yeah. So in relatively small numbers of people both capmatinib and tepotinib have shown CNS activity, and so I would do that. Of course it always depends on the type of brain mets. If there are, for example, multiple mets but they’re all relatively small and they’re not causing a lot of symptoms, then I think starting with an oral drug like capmatinib or tepotinib makes a lot of sense. If there’s a really big mass that’s causing mass effect, then I don’t rely on these drugs to do everything I need to get done to deal with the metastasis. And frankly, even in the EGFR-ALK setting I might not. And sometimes we’re doing things like resecting a really big symptomatic mass or doing focal radiation to something if we’re worried about 1 specific area in particular.

So it kind of depends on the nature of the CNS mets in terms of how we address it, but I do think these drugs do have CNS activity and so would use them to address many of the cases where we are dealing with CNS mets.

Immune checkpoint inhibitors and MET-targeted therapy for patients with NSCLC and MET alterations

DR LOVE: So another pan-targeted issue is the use of IOs, and for ALK in particular, even EGFR, we hear a lot of hesitancy, including from your colleague, Dr Sequist. But then I start thinking — hearing about BRAF and MET, and I’m not so sure. So what do we know about response to checkpoint inhibitors in patients with these MET alterations?

DR HEIST: Yeah. We don’t know that much. There have certainly been case series showing that people with MET exon 14 alterations actually don’t seem to respond as well to PD-1 or PD-L1 inhibition as you would hope for, even if they have high PD-L1 status. And so that has affected, I think, the way we think about things. We’re a little bit worried when we see patients with MET exon 14 of whether they will benefit in the same way that we think kind of the non-small cell population at large will benefit.

But when you look at kind of the big studies that looked at PD-1 inhibition, chemo/IO combinations compared to chemo, it’s really hard to tease out who are the patients who had MET 14 skipping and probably the numbers are so small that it’s really hard to know. But certainly from some of the case series data we worry a bit about will patients with exon 14 skipping have the same benefit from immunotherapy that we hope for for others.

DR LOVE: So another immunotherapy-related issue with targeted therapy is the scenario of the patient who’s had a recent IO, like for example maybe durvalumab, with locally-advanced disease, and now you want to give them targeted therapy. And coming out I think mainly EGFR there’s been a lot of concern about toxicity, but then oncologists are asking what about other targeted therapy. I think I saw a couple papers on — you were on looking at IO plus MET-TKI, so I assume it’s safe to use it after an IO. Is that the case?

DR HEIST: So there are some studies ongoing or that have been ongoing of MET-TKI and IO. I think we need to see how those read out. I don’t believe those have been reported fully yet.

We do know from some of the other data that’s been generated that that concern of going from IO to a TKI is a real one. Crizotinib, not in this space, but in the ALK space when it was studied with IO had heightened toxicities, and so that’s a real concern that we have. And part of actually why, to your prior question of do I use a MET inhibitor in the first-line setting, I say yes. It’s because in general I do think the paradigm of doing from a TKI to an IO is my mind safer than going from immunotherapy to a TKI.

And that has to do with the half-life of how long these drugs are going to stay around after you stop them. And immunotherapy tends to hang around for much longer than a TKI, where after a set number of half-lives it’s kind of washing out of your system in a way that IO does not.

DR LOVE: Right. That’s a really going point. So again, continuing along with these general questions, another dose related to locally advanced and nonresectable, the durvalumab space, for EGFR and ALK, and I’m starting to hear about other things, ? should you use targeted therapy, not use durvalumab. I don’t know how often you see this with MET, probably — I assume not that often, but if and when you do see it do you generally want to go with durva or targeted therapy or neither?

DR HEIST: Yeah. It’s a great question. We don’t know. We don’t know what the right answer is, and the study has not been done where we look at patients with unresectable disease who had chemorads and say should they get durva, for example, as per PACIFIC study or if they get a MET-TKI. We don’t know the answer to that.

I think my general practice right now is in the absence of data that suggests that people with MET alterations don’t benefit, I think if you have Stage III disease, and you’re giving chemoradiation I’m going to give you then afterwards the durvalumab as per PACIFIC, which has been shown to have benefit. So in the absence of data to tell me otherwise, I think it’s worth treating kind of the stage of disease that you’re dealing with at the time in the best way possible.

DR LOVE: So kind of a related question is we have osimertinib in the adjuvant space. I’m always asking people if they could, putting aside reimbursement, whether or not they would ever — if you have a patient maybe who is an oncologist or something who’s got — is in the adjuvant situation, Stage II or III, and they have another kind of alteration, ALK, and I’m going to say exon 14, if you — if somebody was interested in that would you be okay using it in the adjuvant setting? Or do you think we ought to wait for more data?

DR HEIST: I think we need to wait for more data. I think we don’t know yet that it has benefit. And side effects are real. And so without data I would be hard pressed to really give a MET inhibitor in the adjuvant setting right now.

Case: A woman in her mid 60s with no smoking history and newly diagnosed NSCLC with a MET exon 14 skipping mutation

DR LOVE: All right. Let’s talk a little bit about your cases. These are actually patients you took care of?

DR HEIST: Yes.

DR LOVE: Okay. 66-year-old lady. What happened with her?

DR HEIST: So this is a woman. She was a never smoker. She presented, at this point several years ago, with a cough, chest pressure, and shortness of breath. She had a CT that showed a lung mass. There was extensive lymphadenopathy involving the hilum, the supraclavicular area, and the mediastinum. She actually had a pericardial effusion, and she presented actually a few days after I met her with tamponade physiology and got admitted to the hospital, and she was actually in the CCU for several days.

She had a pericardiocentesis, as we do for tamponade. The cytology on that confirmed adenocarcinoma. And I actually will never forget going back to her CCU room after the pericardiocentesis, and she was stabilizing out when I had the NGS data, and it showed that it had MET exon 14 skipping.

And she recovered well from the procedures in the hospital. She was discharged from the hospital, and then she stabilized quickly after that, and we actually started her on capmatinib on a clinical trial that we had open at the time.

This is her baseline and first restaging scan, and you can see she had this big mass in the upper lobe of the lung that you can see there, and when you look, this was at the first restaging, she had a PR at that time. And she has had an ongoing PR. I’m still seeing her. She’s been on treatment for about 4-plus years, and she’s tolerated it well. She’s living a full life. She’s traveling and doing a lot of things. She does have some adverse events, the most prominent of which is peripheral edema, and she manages that mostly with compression stockings.

DR LOVE: It’s interesting you mention the compression stockings and local therapy because I’ve been asking people about that because I know that the diuretics don’t work that well. Anything else you want to say, kind of clinical pearls about how to manage the edema? Anything beyond support stockings? Do you have them elevate their legs? Any kind of exercise? Anything that you find helpful?

DR HEIST: Yeah. So what this patient actually told me, she said tell all of your other patients who are dealing with edema, she puts on her compression stockings in bed. So she said don’t even let your legs swing down to the ground. You need to have your compression stockings at your bedside table and put them on before you even get up for the day. And I think she’s found that to be the best kind of preventative measure for the edema.

The other thing that has helped some people is some lymphedema massage, and really there we’re borrowing a bit from the breast cancer world where they’ve dealt with lymphedema for much longer. But lymphedema massage does seem to help, and so that’s something that I will add on if people are finding that even with elevation and compression stockings that they’re not actually getting as much symptomatic relief as they would like.

DR LOVE: So I assume this is some kind of capillary leak or something local and not excess volume.

DR HEIST: It seems that way to me. Nobody has really kind of definitively described why this happens or the mechanism by which inhibition of MET causes this, but to me it seems like it’s a capillary leak type of syndrome.

DR LOVE: And the fact that she has this pericardial effusion and was in the ICU brings up another important issue that we’ve talked a lot about, which — and I don’t know that she necessarily fit into this because I guess she might have gotten a window, so maybe they stabilized her, but there are situations when people really are in deep trouble in the ICU, respiratory failure, and the doc feels they just really can’t wait, they want to treat. And they have a patient who’s a nonsmoker, they don’t have back the NGS or anything else, and they want to give chemo, and then the question is would you add an IO.

And we’ve been talking about that scenario in our programs for a long time. Only recently did I start asking people would you approach that situation differently if it was a smoker, betting on the odds so to speak. And interestingly there are a few people who do it differently. I’m curious, first of all, what this lady — was that a consideration? Once she had the window she was okay, or she was still — you felt like she really needed to be treated? And how do you handle that situation when you’re waiting for targeted workup, your assays? The patient’s really sick. Do you add the IO or do you wait?

DR HEIST: It’s a great series of questions, and it’s really complicated. First of all, if somebody is sick enough that they’re in the ICU they are very often too sick to get chemotherapy or chemotherapy/immunotherapy. Many systems are not working as well as they should, and they’re critically ill, and more often than not I find that giving a non-targeted therapy like chemo or IO is actually not going to be very helpful.

In the situation where you really have a high suspicion for there being a target, frankly what we have done is really tried to expedite getting the answer because I think it makes such a difference. And there’s a huge difference between starting chemotherapy on somebody who’s in the ICU versus starting a small molecule inhibitor simply because the side effects that we give to the body has a whole are just so different.

And so for me in my practice we’ve really focused on trying to get the answer in a day or 2, and we’re lucky enough that we are in a system where we can do that. So if we are meeting a new patient, and for example they’re a never smoker and they seem to have metastatic disease, when we’re getting the biopsy we have pathways in place where we can really try to get that NGS done within a day or 2 and know that answer because we think it is critically important.

But I find that more often than not if somebody is sick enough to require ICU-level care adding chemo or systemic treatment to the fire is often not the thing to do because the response rates aren’t high enough to really warrant that, and the toxicities are high.

The other exception other than in the setting where we know we have a target, I’ll say that we do, is small cell, really, because small cell lung cancer the response rates to chemotherapy are so high. And so if that is all happening because of the disease burden we think that’s a situation where we kind of would consider using chemotherapy even in an ICU setting.

DR LOVE: That’s such an interesting point. Amazing. Nobody’s ever made that point. We’ve talked about this a hundred times in our program. It makes so much sense — why never anybody bring it up.

A related question, you said you get NGS in a day or 2?

DR HEIST: Yeah. So we get —

DR LOVE: Or a liquid biopsy?

DR HEIST: So from tumor we’ve worked very closely with our molecular pathologist to be able to get — actually it’s not like the huge panel we usually want to get —

DR LOVE: Right.

DR HEIST: — but for our kind of list of — it’s an ever-growing list, but maybe 9 to 10 that we really want to know, we get that answer. We can get that answer in a day or 2.

DR LOVE: That’s interesting. For the community-based oncologist who I guess often can get a liquid biopsy before NGS how comfortable are you if there’s nothing on the liquid biopsy? How often are you missing something you’re going to pick up on NGS?

DR HEIST: Yeah. You can definitely miss stuff on liquid. So the liquid biopsy’s a great tool. It does usually come back much faster than most tumor NGS, and so we use it quite a bit, and I think it’s a great tool to have. If it is negative, though, I do think we really need the tumor because it does miss some things. And there are some — for example, the tumor has to be shedding. There’s some where, particularly if it’s CNS-prominent disease or the disease is confined to the chest, where we think there’s a more likely chance of there being a false negative. So we certainly would go with a positive result if one were found, but if it is showing nothing at all then we think it’s important to follow that up with tumor.

DR LOVE: Another thing that you mentioned that I thought was interesting was that if this is found in patients with squamous cell. Do you general run the same assay on people with squamous that you do in nonsquamous?

DR HEIST: I do. And I know that that’s not something that’s across the board, but in all honesty, if we don’t look we’re never going to find it. And we know, for example, for things like MET exon 14 skipping, that it is found in people with squamous histology. It’s certainly found in people with sarcomatoid histology. And so I do do the full NGS on all my patients who have non-small cell lung cancer.

DR LOVE: All right. Let’s talk about your other case.

Case: A woman in her mid 70s with MET-amplified relapsed NSCLC with an EGFR L858R mutation

DR HEIST: Yeah. This is a 77-year-old woman. I treated her for many, many years. I initially met her back in 2013. She had presented with a cough. It was treated with antibiotics, but the cough persisted. Ultimately she had a chest CT that showed bilateral lung nodules and a left pleural effusion. She had a thoracentesis that showed malignant adenocarcinoma, and molecular testing on that showed an EGFR L858R mutation.

She was started on erlotinib, which at that point was one of the first-line TKIs that we were using for EGFR. And she had a very nice response to that, tolerated it well, and the response lasted for about 2 years, when she had progression. And at that point we did a repeat biopsy to try to figure out why she was resistant, and that showed the original EGFR L858R mutation, as well as a T790M.

And as you know, T790M was at that time one of the most common resistance mechanisms, seen about half of the time when people were becoming resistant to the first- and second-generation EGFR inhibitors.

And so she started on a clinical trial. This was when osimertinib was still in a clinical trial. At that point it was called AZD9291. She started on that study and had good response for a little bit over a year. And then when she progressed on that, on osimertinib, she had another biopsy that at that point showed the EGFR L858R mutation, the T790M had regressed, but she had MET amplification with really high-level MET amplification, the MET:CEP7 ratio was greater than 25:1. And so she started on another study, this was looking at the combination of osimertinib with savolitinib, and had another response for about a year.

Ultimately she progressed on that. She then went onto another study of erlotinib with ABBV-399, which is a MET ADC, and had a good response with that combination actually for about 9 months but then ultimately progressed. And at that point her performance status was declining, and she declined further therapy, and she did pass away.

DR LOVE: Where if anywhere is savolitinib heading?

DR HEIST: Yeah. I don’t know, to be honest with you. I’m not exactly privy to the determinations at the level of the company. Certainly it has been studied. It is in multiple ongoing studies, for example the SAVANNAH study and the ORCHARD study both have savolitinib in it, and you saw data earlier about savolitinib in MET exon 14 skipping. So it’s a MET-TKI that has activity, and I don’t exactly know where the deliberations are with the company and/or the FDA about where it’s heading.

DR LOVE: From what you’ve seen, though, does it seem to overlap the 2 approved agents, or does it look less effective or more toxic?

DR HEIST: I mean to me it seems like it’s similar to the 2 approved agents. I think when we think about the drugs that this patient was exposed to, the ABBV-399 is a different class of drug. The savolitinib is a Type I MET inhibitor. The ABBV-399 is a MET ADC, and I think the antibodies, or ADCs against MET, are things where there are many being studied, and frankly I think it would be good as the years go on to really fully understand kind of their place in therapy and what kind of activity they have.

DR LOVE: Yeah. The ADCs seem to be starting to heat up a little bit in lung cancer, finally. What do we know about the ADCs, like this one and others, targeting MET both in terms of activity, I see here it was combined with erlotinib, I don’t know if it’s used by itself, and also what do you see in terms of tolerability issues? I guess it depends on the payload, but any experience with these ADCs?

DR HEIST: Yeah. So with the MET ADCs they do have activity. Some of that activity seems to be a little bit dependent on the level of expression or overexpression. And as you said the toxicities do seem dependent on the payload, so different ADCs use different payloads, and we see kind of the spectrum of AEs kind of reflecting what the payload is.

There are other ADCs that are in development where the level of expression of the target antigen actually hasn’t seemed to correlate with response. So I think there’s still a lot that we don’t fully understand about how best to use these and how they work and how they work against the different antigens, but I think as a class of drug it’s certainly a very interesting class of drug and one where we’re going to see more and more of these in the lung cancer world, as well as in cancer in general.

DR LOVE: This space, the post-response to osimertinib space that has — of course everybody’s so interested in it, when you look at the types of mutations that you see in that situation, at least that are partially targetable, what — you mentioned MET, can you kind of paint a little bit of a picture of globally what kind of alterations you see, how frequently they are, and to what extent, if at all, you think they’re targetable?

DR HEIST: Yeah. So there are a host of different resistance alterations to osimertinib, and frankly the kind of range or frequency seems to be a little bit different depending on whether osi was used first line or in second- or third-line therapies. But in any event, we see in general there can be on-target secondary mutations.

So similar to a T790M developed to the EGFR-TKIs that were first or second generation you see, for example, the C797S secondary mutations happening, and that seems to affect a place where osi binds to EGFR, and so there are some secondary mutations within EGFR that we see that occur as a resistance mechanism. But it’s not only on-target mechanisms of resistance, there are off-target mechanisms of resistance, and we see activation of other pathways. So this a theme among the targeted agents where we see activation of alternative pathways to kind of signal and cause cancer cell proliferation.

And that can be MET. MET is one of the more common ones that we see, but we’ve also seen alterations in — with BRAF fusions, with RET fusions, and so many of the different oncogenic driver pathways that we think of as targets in and of themselves have shown up as resistance mechanisms to a drug like osi.

And then of course there’s histologic transformation, and there’s transformation from the adenocarcinoma histology to small cell or sometimes even squamous cell histologic differentiation.

And so those are kind of, when I think about the major mechanisms of resistance the 3 different categories that we see happening. And then there’s the fourth category of unknown. It’s none of the above, and we don’t really fully understand yet why it’s resistant.

DR LOVE: But I mean globally for patients in that situation what fraction do you think would respond to further targeted therapy of some type?

DR HEIST: Yeah. So I guess probably less than half. I mean the rates of MET amplification to EGFR, for example, have ranged anywhere from 5-15%, I think, is a ballpark figure. And so in that setting if we see it I would think combining with a MET inhibitor of some sort would make a lot of sense. But in the vast majority of the time where we’re not seeing it, it wouldn’t make sense to me to combine with a MET inhibitor, and that’s why I think re-evaluating and re-biopsying is really important so that we can understand and figure out what the best next steps are going to be for somebody.

Novel agents and strategies for the management of MET-altered NSCLC

DR LOVE: Assuming the patient does have a biopsy and there’s no small cell, from your point of view what’s the most exciting clinical trial strategy or agent out there in that situation? I mean we know kind of what you can do with chemotherapy/IO, whatever, but what about research avenues? From your point of view what looks most promising? And I’ve got to say it’s only been in the last couple weeks I started to really understand what patritumab is, and HER3, and I’m curious.

DR HEIST: Yeah.

DR LOVE: We did a program with Dr Jänne, and I finally — I think I got it, but I was like woah, that seems pretty effective. So anyhow, I’m curious what you think right now is the most promising avenue in this type of patient like case 2.

DR HEIST: Yeah. So I think one thing would be getting the biopsy to understand, and there are some studies that are structured to really kind of encompass, for example, both the biomarker-driven strategy and a non-biomarker-driven strategy. So some of the umbrella studies, for example ORCHARD or SAVANNAH, have multiple different kinds of arms or cohorts where if your acquired resistance is MET amplification then you get EGFR-TKI with a MET inhibitor. It’s a BRAF mutation you get the correct combination for that, on and on down the line. And then if there is no specific biomarker then you get various different chemotherapies or chemotherapy-type agents or new agents that make sense in kind of a non-directed population. And so I think a clinical study like that is definitely worthwhile to think about.

You mentioned This is an antibody-drug conjugate. It was reported by Dr Jänne recently at one of the major meetings. And in a study in patients with EGFR mutations who were becoming resistant to EGFR-TKI it had really nice activity in the, I want to say about 39% range, for a response rate. I think one of the interesting things about that, it’s an antibody-drug conjugate where it attaches to HER3, and then it’s linked to the payload, which is deruxtecan.

One of the interesting things about that study is that regardless of the mechanism or resistance it seemed to have activity, which is a really nice feature because it kind of makes you a little bit less kind of dependent on knowing exactly what the mechanism is.

There have been other studies. For example, there have been some CHRYSALIS studies of looking at amivantamab, the EGFR bispecific MET antibody, with lazertinib, for example, and they’ve reported activity in the post osi or post osi with chemotherapy space. And there is some suggestion based on some of those studies that maybe if you have a MET or EGFR-directed mechanism of resistance that the activity’s going to be higher.

But all of those are kind of really interesting clinical trial novel agents that we look at. And so I really would say that if somebody is becoming resistant in a situation like this I’m always really looking for is there a clinical trial that really makes sense for this patient, and what are the newest or newer agents that we can really think about, because there is so much research being done in this space that it makes sense to try to kind of look for that and move in that direction.

DR LOVE: Incidentally, one of the things I’m hearing more people talk about, I’m not exactly sure why this is happening, is continuing the osimertinib. Now of course I guess lazertinib is a lot like osimertinib, but in general when you switch, when somebody’s progressing on osimertinib, and you’re switching, whether it’s to chemo or other therapies, do you continue the osimertinib? And if so, for how long? And is it different if they have brain mets?

DR HEIST: So this is I think a hotly debated topic. There was a study that looked at continuing the EGFR-TKI when you made the switch to chemotherapy, and it didn’t seem to show a benefit to that. I think many of us for many years have worried about flare when you come off of an EGFR-TKI.

And so I think there are kind of nuances of each individual person that make a difference in what I decide to do. And so the cases where I decide to continue the osimertinib for example would be, for example, if somebody had a burden of CNS metastatic disease, where I really want to have everything onboard to try to get as good CNS penetration as possible, and that includes using the osi in that setting.

I think other scenarios are if there’s a really big burden of disease, and I’m worried about kind of any kind of foot being let off the gas I tend to think about using them together with chemotherapy rather than just switching entirely. But I think it’s a case-by-case decision, and then also you ultimately have to see what the tolerability is when you use things together. And I would say, frankly, I’ve run more into issues with platelets with combinations with osi and chemo than almost anything else.

DR LOVE: Platelets.

DR HEIST: Yeah. I mean osi can cause low platelets. It does a little bit —

DR LOVE: Really?

DR HEIST: — and then with chemotherapy. Yeah. It does have an effect on platelets.

DR LOVE: I’ve never heard that. Really?

DR HEIST: So when you look at people’s platelet counts on osi many will kind of dip a little bit, and occasionally you’ll have somebody who it actually dips quite significantly.

DR LOVE: I didn’t know that. So you have 1 more slide that summarizes I guess your thoughts. Maybe you can go through that.

DR HEIST: Oh, sure. So in summary, MET exon 14 is a targetable alteration. We think MET amplification is a target. How much of a target it is, frankly, I think depends on the level of amplification that we’re seeing. And we talked about resistance, and it encompasses both on-target and off-target mechanisms.

There are many clinical options to think about here in the MET-altered space. Capmatinib and tepotinib are both Type I inhibitors that have FDA approvals for MET exon 14 skipping non-small cell lung cancer. There are other Type I inhibitors that have also shown activity. Among these include drugs like crizotinib and savolitinib. And then the Type II inhibitors, which are more of the multitargeted inhibitors that also inhibit MET, examples of this might be something like cabozantinib. These do have a role, as well, in some of the secondary mutations that we see as resistance, we think that there might be some activity of these drugs in that setting, whereas the Type Is don’t retain activity.

There are many MET antibodies and ADCs that are in development. I think it will be exciting classes of drugs. And we recently also saw activity of amivantamab, the bispecific MET-EGFR antibody, in MET exon 14-altered non-small cell lung cancer. So overall a really exciting time to be dealing with targeted therapy and really exciting to see that MET is targetable and the kind of wealth of agents that we have against it.

DR LOVE: This concludes our program. Special thanks to Dr Heist and thank you for listening. This is Dr Neil Love for Oncology Today.