Introduction: Actionable Genomic Alterations

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice, and welcome back to Year in Review, as today we talk about therapeutic targets beyond EGFR in non-small cell lung cancer.

We have a great faculty today: Dr Jessica Lin from the Massachusetts General Hospital in Boston and Dr Joel Neal from Stanford Medicine Cancer Center in Stanford, California.

As in all of our activities, we will be discussing the use of nonapproved agents and regimens, so check out the relevant package inserts for more information.

As we do in all of our Year in Review programs, I’ve met individually with each faculty member over the last week recording presentations that go through some of the top papers of the past year in targeted treatment of non-small cell beyond EGFR. There are tons of papers they go through. These are really terrific presentations for you to really get into depth about what’s going on in the field. I kind of reviewed all of these, and as I typically do I came up with a bunch of questions that’s going to really form the focus of what we’re going to talk about tonight. We’ll chat a little bit referring back to these papers, but really if you check out the presentation you’ll get a lot more.

Here's where we’re heading. We’re going to talk not just about these specific alterations and targeted treatment, but also try to get a little bit of a macro view of these tumor types globally. And so here’s where we’re heading. We’ll talk about all kinds of alterations and targeted therapy and some new strategies.

I want to just take a step back before we start going through the specifics. And Jessica, I was thinking about the fact that in terms of subsets of common cancers that we deal with and how we subset it out. For example, lymphomas, a lot of it’s histology based: Hodgkin lymphoma, follicular, diffuse large B-cell, mantle cell. Breast cancer, it’s more — at this point more biomarker driven. So we’ll do a whole symposium just on triple-negative breast cancer; ER-positive, HER2-positive disease.

Lung cancer, to me, started out with kind of a histology-driven approach, but it’s quickly evolved into a real biomarker approach. And I wanted to just start out with a term, Jessica, that we’ve been hearing a lot about recently, which I think applies to all these alterations, which is “actionable genomic alterations.” Can you talk a little bit about your vision about this broad classification, Jessica?

DR LIN: Right. Thanks, Neil. So actionable genomic alterations, or AGAs, we refer to specific gene alterations present in a patient’s tumor that predicts some sort of benefit from an existing therapy, whether that’s already available or emerging in clinical trials. And so it’s important to remember there are not only mutations, like EGFR mutations or KRAS mutations, but also gene rearrangements, like ALK, ROS1, RET rearrangements, and then other types of mutations, like MET exon 14 skipping as well.

But I think something that all of us have been discussing recently with the latest emerging therapies is whether AGAs alone are at this point sufficient to describe older biomarkers in lung cancer that we consider before initiating therapy. And I think the consensus that’s emerging is no, because there are starting to be protein biomarkers as well.

DR LOVE: So I want to start out with some global questions about these alterations and kind of get a little bit more of a feel. Just like we know HER2-positive breast cancer, brain mets, certain phenotypes, therapies, et cetera, how these break out a little bit.

And Joel, yesterday I was doing a video; we’re getting ready for our big ASCO meetings, with Dr Warren Brenner, a general medical oncologist nearby here, who’s in Boca Raton, Florida. And was telling him that we were doing this thing, this webinar tomorrow night, and he say ask them about this patient I just saw with pancreatic cancer who’s got a — presents with metastatic disease, not that symptomatic, not that much but metastatic, and I want to — and he’s got an EML4-ALK in his NGS. And he said I wanted to give him an ALK inhibitor, but he went for second opinion at a tertiary center, and they’re going to give him chemotherapy.

But I’m just kind of curious. Thinking back to this list of — a lot of them we have pan-tumor approvals on already, T-DXd for example, and RET, et cetera, but what about the other ones? I hear cases where you see — it looks like EGFR mutations. Warren has this ALK. What do we know about, for example, EGFR and ALK outside of lung cancer, Joel? Do they respond?

DR NEAL: Yeah. I think that’s a great question. Being a thoracic medical oncologist I see few of those patients, but we occasionally get those questions from our institution. In addition, a lot of the targeted therapy trials that we’ve run, oftentimes when they’re cohort based they’ll have cohorts of other types of malignancies beyond lung cancer. So I can think of HER2 mutation trials. HER2 mutation is very distinct from what we see in breast cancer, but certainly they’re described in other malignancies. And I’ve done a search to look for other malignancies that have those within Stanford; have found 3 or 4.

I’ve seen ALK-positive other malignancies. It’d be interesting to know what happens if they try an ALK inhibitor for that patient. I also wonder if it’s actually pancreatic cancer or maybe a lung cancer that actually just metastasized to the pancreas, because that’d be so unusual.

Other things. We haven’t really seen MET exon 14 skipping mutations. NTRK is pan-tumor approval, so of course that’s across everything. And then the KRAS mutations happen across multiple different malignancies, the inhibitors and the new targets that we’re finding for KRAS G12C, pan-RAS and KRAS G12D. I think we’re seeing emerging evidence that they might work in lung cancer and also other malignancies.

So I’d be very interested, but a lot of these actionable genomic alterations are fairly unique to lung cancer, so I always have to second guess, was it a lung cancer that just happened to be occult and then went somewhere else.

DR LOVE: That’s a really great point about the possibility of being a met. I’d be curious if anybody in the chat room has treated a patient, for example, with ALK in a case like this.

So Jessica, another global question I have relates to you have a situation where you have an actionable genomic alteration, you have a targeted therapy, but how do you decide whether or not use targeted therapy up front or, for example, chemotherapy, chemo/IO. And a related question is where does checkpoint inhibitors fit inhibitors because, of course, in a number of these it appears that checkpoint inhibitors are rarely useful.

So again, kind of thinking back to our list of alterations, what situations here — I mean, even if you think about exon 20, KRAS G12C, in what situations would you not use targeted therapy up front? And what about PD-1? Do you avoid PD-1 completely? Do you avoid it relatively? How do you portray these tumors from that point of view, Jessica?

DR LIN: Such an important question. And I would break that down into 2 parts. So the first part is which are the targets where there are targeted therapies that are approved for first-line use. And so for that part I would say all of these except for the NRG1 fusion, which is later-line use of zenocutuzumab, KRAS G12C mutation, where right now the approvals of the KRAS G12C inhibitors are for later-line use, and then currently for HER2 mutations as well. The trastuzumab deruxtecan approval is for later, second-line use also. And so the rest of them have first-line approvals of targeted therapies, including with — together with chemotherapy for EGFR exon 20 with amivantamab.

The second part to that question that you just asked, Neil, is even if let’s say a genomic alteration has a targeted therapy that’s approved for first-line use is that always universally the recommended path to pursue or should we consider immunotherapy or immunotherapy plus chemotherapy. So for that question it’s a little bit more complex. I would say even for AGAs certainly there is some diversity in terms of disease biology and behavior. For example, with BRAF mutations, BRAF V600E mutations. MET exon 14 skipping, for example. Those alterations can be present recurrently in patients who have had a smoking history.

They’re felt to be different in terms of biology compared to other alterations, like EGFR classical mutations, ALK, ROS1, RET fusions. For the latter, the classical EGFR mutations, ALK, ROS1, RET fusions and so forth, we would be really careful about considering immunotherapy. In fact, we would not recommend thinking about immunotherapy for first-line use. But for patients who have EMT exon 14 skipping or BRAF V600E mutation, perhaps with a heavy smoking history and high-level PD-L1, it would not be wrong to consider immunotherapy or with chemotherapy. I think it’s a consideration.

ALK

DR LOVE: So I want to move on. We’re going to get back to some of these general considerations in a few minutes, but I want to get into some of the developments that have been occurring in these specific areas and a lot going on in terms of ALK. I was telling the — we did a program on myeloma last week, and I said you’re in the fourth generation of ALK inhibitors already. They were all jealous about that.

But anyhow, this is a — Jessica went through in her talk the evolution of first-, second-, third- and now going to be fourth-generation inhibitors, of course lorlatinib now really revolutionizing first-line therapy of metastatic disease. We also saw a new ALK inhibitor, ensartinib, I’ll ask a couple questions about that, that was approved. I’m not sure it’s going to be able to bump lorlatinib away, but we’ll hear a little bit. It kind of looks similar to what we’ve seen with some of the other agents like alectinib.

We also, Jessica, updated the lorlatinib data that looks amazing. And Jessica, I was telling you that your colleague in GU Oncology at MGH, Matt Smith, developed what we call the pelican curve. And when I saw that curve on the right with lorlatinib — this is Matt’s view of what a pelican curve is. It looks like you guys have one as well. There was a curve in prostate cancer that I saw him put on that.

So really amazing data now with lorlatinib. A lot of issues about tolerability that Jessica goes through in her talk, particularly CNS, and we’ll get into that a little bit, but also this new agent. Here we go, fourth generation. So Jessica, what about NVL-655? Why is it different than the prior ALK inhibitors? I know in a weird way it reminds me of pirtobrutinib with BTK that you see responses in people who’ve already had resistance to earlier treatment. But what’s the secret sauce here, Jessica?

DR LIN: Thank you. So NVL-655, also called neladalkib, it was designed specifically to meet some of the needs in metastatic ALK-positive lung cancer and other ALK fusion-driven solid tumors. There were several goals that NVL-655 was developed to meet, one of which was that with the existing excellent next-generation ALK inhibitors there are still disease relapses, progression events. And that can occur because of acquired secondary site mutations in ALK, whether those are single ALK mutations or in the case of lorlatinib, compound ALK mutations. So NVL-655 was developed to be potent against a very diverse array of single and compound ALK mutations. That was the first need.

The second need was that brain metastases are very common in patients with metastatic ALK-positive lung cancer, especially now that people are living longer and longer with this disease. And so this fourth-generation ALK inhibitor was developed to be brain penetrant and active against brain metastases.

And then finally the third need was to really develop an agent that was not only highly efficacious, hopefully, but also well tolerated. So it was developed as an ALK-selective inhibitor that could spare other kinases, such as TRK kinases, as much as possible, with the knowledge that in the clinic, when TKIs also block TRK kinases, we can see undesirable neurological toxicities.

And so those were goals that were kept in mind when NVL-655 was developed, and the preliminary data emerging from the ALKOVE-1 trial that had been presented, really attests to the success of that design.

DR LOVE: So Joel, right now how are you approaching patients with disease progression after lorlatinib? Pretty uncommon event, it seems like, at least in the first few years. But when you do see progression how do you approach it? Do you ever look for resistance mutations? What do you think about NVL, or nela — we’re going to have to work — we need a nickname for this one too. But anyhow, how are you approaching it now, and what do you think about this agent?

DR NEAL: Yeah. I don’t think I’ve said neladalkib before, and I’ll have to practice that with Jessica and around ASCO.

DR LOVE: Yeah. You’ve got to say that a hundred times.

DR NEAL: We’ve been calling it NVL-655. We did have the program open, and I would say generally our experience is consistent with it seems to be a little easier than lorlatinib at least. But it may or may not overcome some of those resistance mutations or bypass tracks that lorlatinib can’t hit either, so I think the spectrum of activity is likely similar between the two.

That’s another way of saying that I doubt other ALK inhibitors are going to work potently after lorlatinib. There may be isolated cases where there’s a particular mutation, which lorlatinib doesn’t hit. There were some case reports a long time ago about that. But I think for most patients we’re probably looking at a situation where we should add chemotherapy, which we know is highly active.

We do have data that says you can add chemotherapy together with drugs like lorlatinib, and that’s a strategy we’ll sometimes use for patients with brain metastases, much like we have an approval for osimertinib plus chemotherapy for EGFR-mutant lung cancer.

So I’d say out in the community adding chemotherapy or moving to chemotherapy, carboplatin/pemetrexed, not very enthusiastic about immunotherapy for the rearranged non-small cell lung cancers in general, especially without a smoking history, plus or minus maybe antiangiogenic like bevacizumab. That would be my general approach, but also repeat biopsy, liquid biopsy, tissue biopsy, see what you can find.

DR LOVE: So on the left there are patients with prior lorlatinib. That waterfall plot looks pretty decent, the one to the right there, in purple, is lorlatinib naïve. We’ll see where it comes in, whether it’s useful clinically in the recurrent situation or maybe even the first-line situation if it has great efficacy with better tolerability.

I’m going to get back to these in a second, but I just want to continue on in terms of ALK, in terms of the use of ALK in localized disease. Jessica reviewed the ALINA trial, where alectinib was compared to chemotherapy and now is a standard part of treatment.

What I really want to do is get into some questions that came up in my mind as I was hearing about all this. So the first thing, Jessica, is we mentioned this newly approved, just from December, ALK inhibitor, ensartinib, and yet it kind of doesn’t look indirectly as good as lorlatinib. It also ties into — I think you said to me that there’s still a lot of alectinib being used first line, which kind of was surprising. I figured most people switched over. But anyhow, what about alectinib and also this newly approved ensartinib right now, Jessica? What role do they have in your practice, if any?

DR LIN: I would say ensartinib I really think of as a second-generation ALK inhibitor in the same class as other second-generation ALK inhibitors, like alectinib and brigatinib. The approval was based on the data from the eXalt3 Phase III trial, and the PFS data, the systemic efficacy data that we’ve seen did not look that different from what we’ve seen with other second-gen TKIs like alectinib and brigatinib, especially since the updated analysis from the CROWN trial, where we’re really seeing very prolonged PFS achieved with the third-generation TKI lorlatinib. My own practice has been for preferred use of lorlatinib as initial therapy as opposed to using second-generation agents like alectinib or ensartinib.

DR LOVE: So a couple questions about lorlatinib. I think a lot of people are kind of nervous about the CNS effects of lorlatinib. I’m curious if patients have pre-existing neurologic issues or psychiatric issues do you not use lorlatinib? Joel, any comments?

DR NEAL: Yeah. I think the neuropsychiatric effects of lorlatinib are tough, sometimes also leg swelling, muscle cramps, generalized fatigue. And patients also note that it’s sometimes hard to speak words, so word-forming difficulty, and a few have reported that seeing speech therapists can help with that to just practice talking.

I don’t think of patients pre-existing conditions as a contraindication to starting lorlatinib, but oftentimes I think about starting with a relative dose reduction, maybe not coming in with the full 100 mg daily, which is a single pill, but instead using the 25-mg pills maybe at 75 mg. Now for a patient with brain metastases, large burden of disease, a lot of symptoms, I probably wouldn’t dose reduce, but I don’t hesitate to go down to make it more tolerable.

DR LOVE: So Jessica, you’re getting on the elevator, and you’re going down, and there’s a doc next to you who says hey, I’ve got a quick case for you. This is from the chat room from Dr Rudolph: 58-year-old professional athlete with ALK lung cancer, now on lorlatinib first line. Limited brain mets, 2 lesions, bone mets, lymphadenopathy. He’s curious to know his projected overall survival, his progression-free survival. Also, his trainer also had ALK-positive lung cancer a few years ago. Any known environmental exposures?

DR LIN: Right. So a lot packed in there. In terms of overall survival I would say let’s sit tight and wait for the overall survival data to be presented from the CROWN trial at some point. All of the overall survival data from the randomized Phase III trials of next-generation ALK inhibitors are still immature, which is good news. It means patients are living longer, doing well. PFS. We still don’t have a median progression-free survival with first-line lorlatinib therapy from the CROWN trial either. So again, we’ll have to sit tight for that data. What we do have is the landmark data of 5-year progression-free survival, so we do have that piece of statistics.

The second part of the question was the trainer with ALK-positive lung cancer, environmental exposures. So much interesting research happening in that area, but we have yet to deeply understand what leads to ALK fusions in tumors, including in lung cancer, as opposed to what we know about smoker-related lung cancer or certain pollutants with EGFR-related lung cancers. I think we still have a lot to learn there, but exciting research going on.

DR LOVE: So I didn’t think I was going to get through all my questions, and I’m definitely not going to, but I’ve got to ask 1 question that’s really on my mind, I was going to even ask before when we were talking about these different mutations, Joel, which is why is lorlatinib so effective. I mean, you look at this list of alterations, and 5-years PFS of 60% is kind of amazing, go me. What is it about lorlatinib or ALK? Do you think all these potentially, if you find the right agents, could have this kind of activity, or is there something different about ALK?

DR NEAL: Yeah. I’ve wondered that, too, Neil, and I think if we look to the CML folks they’d probably say, “Only 5 years progression-free survival? With BCR/ABL we can do a lot better than that.” So I think part of it has to do with rearrangements or really strong oncogenic drivers, and the tumor is very, very addicted to them. It’s hard to overcome resistance. We saw these point mutations, which just happen to be holes in the spectrum of TKIs, and lorlatinib has effectively covered most of those point mutations of resistance. So then we’re looking at resistance being from tumor heterogeneity, which happens in all tumors, but ALK being a relatively mutation-low tumor, TMB is almost always very, very low, I think there’s less tumor heterogeneity to kind of have a base for resistance. So may it’s a simpler cancer, like CML.

I see the same thing in ROS. We’re still developing better ROS1 inhibitors, but I’ve had patients on crizotinib for 10 years who had metastatic disease.

DR LOVE: Wow.

DR NEAL: So some of those tumors are incredibly slow to grow also or just very sensitive.

ROS1

DR LOVE: So interesting. So speaking of ROS1, again, Jessica went through, of course we have several agents available, but more importantly, I think, some coming down the line. We have repotrectdinib now that looks like maybe it has more effectiveness and excellent outcomes with that. But also this agent, again, zidesamtinib, or NVL-520. Jessica, can you comment a little bit about this agent? It looks like it has pretty encouraging-looking waterfall plots. Its safety profile, where you see things heading?

DR LIN: That’s right. So NVL-520, or zidesamtinib, was developed as a next-generation ROS1 inhibitor that is highly selective for ROS1, again, developed to spare the TRK kinases and related neurologic toxicities, hopefully, in patients; also designed to be brain penetrant. And in the ARROS-1 trial we’ve already seen excellent activity against brain metastasis.

The data that have been presented were mostly for heavily pretreated patients with metastatic ROS1 fusion-positive lung cancer, so it’s amazing that we’re seeing activity in that patient population. The ongoing Phase II trial is actually evaluating zidesamtinib now, not only in pretreated patients but also treatment-naïve patients with metastatic ROS1 lung cancer. So I think it’ll be interesting to see how the durations of response and progression-free survival play out in that treatment-naïve population as well.

DR LOVE: So Jessica also talks about taletrectinib, another ROS1 agent with encouraging-looking outcomes/results, and she summarizes it, but I want to kind of come back to some broader questions. So Joel, right now how do you select first-line therapy for ROS1 metastatic disease?

DR NEAL: Yeah. Right now I think the drug that’s emerged as probably the most potent in terms of CNS penetration and overcoming resistance is repotrectdinib. We’ve used historically crizotinib, and entrectinib also has an approval. So I look for a reason not to give repotrectdinib, but I do in cognizant of the side effects of it. So patients, again, have all these TRK-related side effects. Most notably for this one, I think dizziness is one of the side effects that is tough for patients to overcome. So again, similar to lorlatinib, I think about dose reductions. Lorlatinib has some activity in ROS1, but I think repotrectdinib is better overall.

But I’m really intrigued by not only the efficacy data of the newer agents but also the safety data of the newer agents. They look a little bit more tolerable than cross-trial comparisons, at least, than repotrectdinib. So I think we’ll have some emerging options here that are exciting.

DR LOVE: So Jessica, how are you currently approaching second-line therapy with patients who get first-line repotrectdinib? And also, can you talk a little bit more about these TRK-related side effects that hopefully these newer agents are going to avoid? What specifically are they?

DR LIN: Sure. Let’s start with the latter question, TRK inhibitors. So TRK kinases are really important for our central nervous system, both essential and peripheral, actually. And so we have TRKA, TRKB and TRKC proteins, and when they’re inhibited we can see side effects like dizziness, motor neuron effects, dysgeusia, paresthesia and so forth, as well as appetite changes and weight gain in patients. So with potent ROS1-NRK dual inhibitors like repotrectdinib, like entrectinib, we can see the neurologic side effects that are associated with the TRK inhibition portion of therapy. Therefore, by avoiding that TRK inhibition part of the TKI therapy we can hopefully mitigate the occurrence of the neurologic toxicities.

In terms of the next-line therapy after progression on first-line ROS1 inhibitor, I would say my approach here really echoes what Joel outlined earlier for patients post lorlatinib therapy in ALK-positive lung cancer, right? So currently the standard of care next-line therapy would be chemotherapy with a histology-specific agent, but I always try to do rebiopsy to understand the mechanism of resistance so that if there happens to be something that’s actionable we can work on that approach.

DR LOVE: So Joel, this — we’re going to talk a little bit about HER2 as a target in different ways. I always hesitate to show a slide like this because it’s totally over my head, but I’m hoping the audience will have a better understanding. I get very clueless when I start looking at ERBB2, and then I see exon 19, exon 20, et cetera. But would you like to give kind of a brief primer on ERBB2 mutations, Joel?

DR NEAL: Absolutely. I prefer the nomenclature HER2. I think we’ve been using it in breast cancer for a long time, but ERBB2 is the gene, so we’ll use those interchangeably. Most of the mutations that we see are very analogous to EGFR and the exon 20 insertion mutations. So if you look, the main point of the slide is the 33.9% of that 1 duplication YVMA, up above the red box of exon 20, and there’s some other insertion mutations in exon 20 as well.

The other notably point mutation, over on the far left, is S310F. And I think as we look for tyrosine kinases the exon 20 insertions analogous to EGFR have been very difficult to inhibit. It was just a stroke of luck back in the day that EGFR exon 19 deletions bound so strongly to the TKIs that we had and inhibited them, but the exon 20 insertion mutations are a little bit tougher to drug.

DR LOVE: So and of course now we’re getting into therapy, which is what everybody wants to know about. It’s like what do you do about patients with the mutations, but also HER2 overexpression. We know at this point there’s a pan-tumor approval for IHC 3+ for trastuzumab deruxtecan, but actually what’s really exciting, at least in lung, in particular, a little bit in other tumors, is HER2-mutant disease, Jessica.

And of course Joel went through the data shown here that you get good benefit and maybe less toxicity with a lower dose of 5.4 mg, but a lot of efficacy. A lot of efficacy also with HER2 overexpression on immunochemistry, as seen in the DESTINY-Lung trial. You can see the waterfall plot down there below, but also pretty good activity and pretty good tolerability, although a number of issues that do come up that I want to ask you about in terms of overexpression. And of course the huge issue that everybody thinks about, which is interstitial lung disease. All these things I want to kind of get some feedback.

But I’d also like to hear your thoughts in terms of HER2 TKIs, which of course in breast cancer we have tucatinib, as an example, neratinib also used, I think, in lung cancer. We have zongertinib for HER2-mutant disease, a TKI that Joel went through in his talk, and this agent that doesn’t also have a name, I don’t think, but also a TKI with excellent activity, and it seems like pretty good tolerability for both of these approaches. But also this new agent, NVL-330, another HER2 TKI. Joel, what’s the difference between this and the others, and what’s the hope in terms of where this might be heading?

DR NEAL: So like we’ve discussed for other second- and third-generation drugs, and I’ll argue that zongertinib and the BAY drug were arguably probably second- or third-generation drugs themselves because this has been such a hard target to hit, especially for the exon 20s. This drug was designed for excellent CNS penetration, good PKs, and perhaps overcoming some of the potential mechanisms of acquired resistance too. So it’s just in the very early Phase I at this point, and we’ll look forward to seeing some data on it, as you’ve highlighted, at ASCO.

DR LOVE: Right. So yeah, we’ll see what’s seen in this Phase IA study, Phase IA/IB.

HER2

DR LOVE: Alright. Let’s get into some practical questions about HER2. So Jessica, you have a patient with metastatic disease and is HER2-mutant, and you have a second patient who’s HER2-overexpressed. You have another patient that’s HER2 low. You have patients who have HER2 amplified, but they’re HER2 maybe low. How do you think through sequencing or use in these various situations in metastatic disease, Jessica?

DR LIN: Starting with the HER2-mutated non-small cell lung cancer, my approach is to use trastuzumab deruxtecan as second-line therapy after first line, following the FDA label. However, I am really eagerly awaiting the data from the DESTINY-Lung04 trial that’s evaluating trastuzumab deruxtecan in the front-line setting for this patient population.

For HER2-overexpressed disease in lung it’s really IHC 3+, as you alluded to earlier, where the FDA approval is. And so I will have our pathologists perform HER2 IHC for all patients with a metastatic lung cancer diagnosis at this point, and if they have 3+ scoring, then we’ll consider trastuzumab deruxtecan as a later-line therapy. I do not currently use trastuzumab deruxtecan for HER2-low non-small cell lung cancer or for HER2-amplified disease without overexpression.

DR LOVE: So second opinion from you, Joel, and particularly about HER2-mutant. I’ve heard a lot of people say they like to use it first line. I don’t even know if it’s easy to access, but any differences in your approach for these scenarios, Joel?

DR NEAL: Yeah. I think on the question of what’s the ideal therapy for HER2-mutant disease it technically is approved in the second-line setting, but I know that it’s chemotherapy plus a targeted therapy, so there’s a lot of appeal in trying it first, and I and at least other colleagues in Northern California have tried it in that setting off label and have seen good responses.

I do want to note, though, that the numbers we saw on zongertinib look better than what we’ve seen for trastuzumab deruxtecan, at least in the previously treated patients. And so I think it’s exciting to think about maybe we can move TKIs into that front-line setting too.

The development strategy looks like it’s going to be with chemotherapy most likely, as opposed to single agent. I can’t comment. I don’t have any other knowledge on that. But there is a certain appeal to a drug that works for PFS of 9 to 11 months, and it’s 12.4, right? That’s better than we saw from gefitinib, erlotinib back in the day. And response rates of 71%. I think zongertinib looks like a targeted therapy, so does trastuzumab deruxtecan, and there might even be a way to combine these therapies together.

DR LOVE: Interesting. So of course nowadays we talk to all types of disciplines about HER2-positive disease. We were just at the Society of Gynecologic Oncology Meeting and did an entire program on HER2-positive gynecologic cancers, and of course a lot of that is precipitated because of T-DXd. And it’s interesting to hear how people deal with tolerability with T-DXd outside of breast cancer because we’ve been hearing from the breast cancer people for years about how they deal with it.

And Jessica, one of the things that I’ve seen evolve a lot in breast cancer has been attention to acute GI toxicity with T-DXd. I don’t know that that was appreciated as much originally. We started hearing it more and more, and now it’s something that really requires a lot of attention.

How do you approach it, Jessica, and what have you seen with patients with lung cancer in terms of these acute toxicities?

DR LIN: For us it’s really been vigilant monitoring and the use of appropriate supportive antidiarrheals and antiemetics as needed. We don’t routinely automatically prescribe prophylactic antidiarrheals, for example. Joel, I would love to hear what your practice is in the clinic.

DR NEAL: I’ve given this, and I haven’t found that diarrhea or nausea/vomiting are particularly bothersome side effects, certainly not as much as we see with some of the TKIs, for example. Nausea/vomiting are side effects from the chemotherapy payload, probably, and things that oncologists are very used to managing. So it hasn’t been really a limiting side effect in my experience.

DR LOVE: The breast cancer people talk a lot about the use of olanzapine. They use it pretty frequently with these patients.

Of course the other huge issue here is interstitial lung disease, of particular concern here in lung cancer because a lot of the patients have coexisting comorbidities: COPD, coronary artery disease, et cetera. And I’m curious, Jessica, in that setting of lung cancer, maybe with comorbidities, how you approach the issue of screening for interstitial lung disease. Of course, these patients are getting CT scans anyhow, but the breast people are every 8 weeks, every 10 weeks. They want to pick it up on imaging before the patient gets symptomatic, because at least in breast cancer if you have Grade 1, asymptomatic, just on imaging, they can stop, give steroids and hopefully retreat, whereas at least in breast cancer once they have symptoms they don’t use it again.

So with that in mind, Jessica, how are you thinking through screening? What do you do if they do develop Grade 1 or Grade 2?

DR LIN: We also like to catch interstitial lung disease before it causes symptoms or problems. We are “fortunate,” I guess, in the sense that we do, as you refer to, regular CT scans so much for patients with lung cancer, so we do have a chance to catch it early. It’s really a radiologic and clinical diagnosis, right, so unless patients are having symptoms, respiratory symptoms, we’re not necessarily going to be doing CT scans every 3, 4 weeks, right? Our usual interval is every 2-3 months, but certainly if someone’s reporting symptoms that are concerning for possible pneumonitis we’ll do imaging earlier, and that’s what we use for our main diagnostic method.

If it’s Grade 1, patients are not really symptomatic. I have very low threshold to hold and treat, as you were talking about for breast cancer. Certainly, if they were having multilobar involvement or symptoms due to pneumonitis, even after resolution I would not typically rechallenge.

DR LOVE: And Joel, how do you deal with people with already existing pulmonary densities or comorbidities, even symptoms? Do you hold off using the drug? If you do use it, how do you follow them?

DR NEAL: Yeah. This is a good question of what are the comorbidities where we really worry about therapies. And thinking about that previous term, interstitial lung disease, I’ve seen it tossed around in a number of different settings. So I like to distinguish kind of interstitial lung disease called by a radiologist, where it’s really underlying idiopathic pulmonary fibrosis, which is a longstanding thing from before the diagnosis of the cancer and can cause the cancer versus drug pneumonitis, right?

So a comorbidity. If somebody has “IPF” as an ILD finding before we even start therapy I’m really worried about any treatment we give them. COPD, if their DLCO is low, if their FEV-1 is low, I’m a little worried, but I have to weigh that against the risk of the lung cancer growing, and when we’re dealing with metastatic lung cancer usually that outweighs the risk of anything else. So I don’t worry about heart failure. We do do echoes as we’re giving these drugs, every few months at least, and if somebody has acute breathing problems we suspect drug pneumonitis above all else.

RET

DR LOVE: Alright. Well, let’s talk about some other AGAs and their management and get an update on that. And Jessica, you reviewed RET. Of course, we have 2 approved agents. You went through some of the data for each one and comparing them. But I am kind of curious right now, bottom line, how you pick first-line therapy between these 2 agents, Jessica, whether you see any difference in toxicity. I know one of them causes lymphatic obstruction. I think it’s selpercatinib. Maybe you can correct me. I think your colleague, Justin Gainor, was telling me about that. But how do you decide on first-line therapy?

DR LIN: Yeah. Pralsetinib and selpercatinib were really developed in parallel along the same timelines, and I think of both as comparable efficacy. There are some differences when it comes to side effects, actually, even though both are called RET-selective inhibitors. For example, with selpercatinib we can see commonly dry mouth, which can be bothersome for patients. We can see chylous effusions, both chylous pleural effusions, as well as ascites, which is an interesting toxicity that our group and the group out of Memorial Sloan Kettering have reported. We really haven’t seen that much of chylous effusions with pralsetinib. The mechanism of this is not well understood.

On the other hand, with pralsetinib more so than with selpercatinib, we can see cytopenias, including lymphopenia and leukopenia, so there are some distinctions there. With both agents we can see some hypertension.

In terms of deciding between the 2 TKIs, like I said, I think both are comparable in terms of efficacy. Which one have I used more? I guess I’ve used selpercatinib more since the development of pralsetinib has been discontinued, and I’m more familiar with selpercatinib, but I think both are good drugs.

DR LOVE: So Joel, I want to use this as an opportunity to ask a more global question, including RET, which is we talked before about all these different alterations and all these different targeted therapies, but I’m curious in what situations you’re comfortable using targeted therapy without radiation in patients with brain mets. We first saw this strategy, I think, in EGFR, quickly we started to see it in ALK, and now we’re seeing it with other — RET, for example. But thinking about all of these different alterations, we’ve seen in breast really good activity in the brain of T-DXd. I don’t know whether that would be a consideration. But where would you be okay starting out with targeted therapy with brain mets, Joel?

DR NEAL: Yeah. It’s a complex question because I think we have to factor in what are the first-line therapies that are approved, and I generally start with just the first-line therapies that are already approved as opposed to the ones that are in second-line therapy. We know that most of these patients will have nonsquamous non-small cell lung cancer. Carboplatin and pemetrexed has decent efficacy in the brain. From older data immunotherapy can have good efficacy in the brain, too, so let’s start with the ones that are just first-line approved. Out of those, most of our current generations of the first-line approved drugs have decency and have penetration, so I would say that’s generally but not exclusively true. But we want to see drugs that have CNS penetration and activity.

And then third, and I think most important is what are we talking about for brain mets? Are we talking 2 little asymptomatic things that are less than a centimeter? Are we talking about 15 large, cystic metastases with edema around, like a patient that I saw yesterday in clinic that came in, and I still don’t know what the molecular alteration is, and they’re buying their time on dexamethasone? I’m smelling EGFR in a woman never smoker, but I don’t know until the circulating tumor DNA comes back in a few days, right?

What I know for sure, though, is I really want to avoid whole-brain radiation. So as we’re seeing patients live longer and longer — like if we have an ALK patient that’s going to have progression-free survival over 5 years we can probably control those brain metastases with a pill, and we can avoid whole-brain radiation and not give them those long-term cognitive side effects that are inevitable if we do it on the sooner side.

So radiation, targeted radiation is fine to a few mets, giving chemotherapy is fine if we don’t know what the alteration is, but let’s avoid whole-brain radiation so long that we may never use it. That’s okay.

DR LOVE: So Jessica, I don’t know whether Joel’s thinking about SRS on 15 lesions. I’m curious what the limit is for SRS and how often you end up giving whole brain even if you don’t want to.

DR LIN: I rarely give whole brain these days for these patients with AGAs, where we have CNS-penetrant targeted therapies available. Most of the time we’re actually able to get by with a brain-active systemic therapy.

In terms of patients where focal SRS may be necessary, when you ask about the limit, Neil, that answer is going to be different depending on where the clinician practices, depending on the institution center.

DR LOVE: Right.

DR LIN: Some centers will radiate as many as 20 lesions. Some centers will limit it to under 5. I would say at our center it tends to be less, in the less than 5 range, because really when it’s multifocal our view is that you need systemic therapy to not only address the existing visible lesions but also microscopic disease also.

DR LOVE: So incidentally, Joel, your patient, if he turns out to have EGFR what are you going to do? What are you going to treat her with, or him?

DR NEAL: So for sure first-line TKI, most likely osimertinib plus chemotherapy, and try to wean off the steroids. I am referring this patient to our SRS group plus a neurosurgeon plus our neuro-oncology group just to stand by and manage side effects. But I’m hoping that with the combination of chemo plus TKI that we can control the brain mets, which were too numerous and too large. Some were over 3 cm. Too numerous and too large to consider radiosurgery alone.

DR LOVE: Right. Well, hopefully, yeah. That is a situation where I hear everybody thinking about adding chemo to osimertinib in a patient with brain mets.

NTRK

DR LOVE: We talked a little bit about NTRK in terms of tolerability issues that come up with agents targeted, such as entrectinib, larotrectinib, that Jessica reviewed, repotrectdinib that we already talked about with ROS1. What I want to just find out, ask you, Jessica, is how do you determine first-line therapy nowadays?

DR LIN: It’s really good to have these various targeted therapies for a very rare oncogene driver in lung cancer. I would say in terms of TRK inhibitors we are not seeing great distinguishing factors in terms of the level of efficacy so far when comparing efficacy data from separate trials. Side effects, there may be subtle differences, but all of them are TRK inhibitors. I still have used larotrectinib. I think whether repotrectdinib as a next-generation TRK inhibitor that can overcome some of the TRK resistance mutations is going to be better in the first-line setting that remains to be determined.

MET

DR LOVE: So Joel, Eva in the chat room is already getting ahead of us. She said, “Question for the MET section. Exciting news regarding the FDA approval of teliso-V. For other oncogenic drivers, such as ALK, does this approval open up the use of this agent in patients who develop MET as a mechanism of resistance?” Kind of interesting thought there. We’ll go into the more likely scenario, just patients who have MET, but before we get there what do you think about this question from Eva in terms of MET as a mechanism of resistance, teliso-V there?

DR NEAL: Yeah. That’s a very interesting question. So I think MET is certainly an acquired mechanism of resistance for all of the oncogenic drivers that we’ve talked about. One of the important reasons to repeat biopsy is to look for MET. I’m not sure if IHC matters in that setting, some people are doing it, but certainly MET FISH or DNA sequencing can identify MET amplification, which is common.

So I think of acquired resistance a little bit different than I think of primary MET drivers, and then with this new approval of teliso-V it’s a question of is it a primary-driven MET-positive tumor or are we basically saying there’s enough of a target to bring chemotherapy to these cells that happen to have MET. MET itself, the biology of it, it’s a nasty protein. And MET exon 14 is just basically overexpression of the protein, is what its mechanism is. There’s no mutation, mutation in exon 14, but it’s overexpression of a wild-type protein.

So suffice it to say teliso-V, yes, we’ve tested it. There’s older data with erlotinib plus teliso-V to try and overcome acquired resistance from Becca Heist, and there are other trials that have been ongoing to try and overcome MET-directed resistance with savolitinib. We’ve used some of the MET TKIs in this setting too. So I think this may be an option if I find MET-acquired resistance for other than EGFR. In EGFR I’d prefer amivantamab because it’s already hitting EGFR plus MET. But here’s another tool, and so I think it’s interesting. Longwinded answer, I’m sorry, for the question.

DR LOVE: It’s okay. So Jessica, what about tolerability issues? We have the last name of vedotin that in other situations we see peripheral neuropathy, but what do you see with teliso-V?

DR LIN: I would say peripheral neuropathy is really the main common side effect to watch out for this agent outside of the usual kind of chemo-associated side effects.

Novel Targeted Strategies

DR LOVE: So I want to bring up a couple of new strategies that I’m curious to hear what your thoughts are in terms of these patients who have actionable genomic alterations, potentially new approaches. We’ll get back to some of the other first, but I wanted to hear your thoughts first about datopotamab deruxtecan, Joel, of course currently approved in ER-positive breast cancer, but also a lot of data that’s been out there in non-small cell lung cancer, including this study that I think was originally reported at ESMO and then published just in the JCO earlier this year looking at dato in recurrent disease with actionable, not just EGFR, which was most of the patients, but they had a bunch of other actionable genomic alterations. Again, a pretty good-looking waterfall plot.

Any thoughts, Joel, about where this is heading? Is this enough activity to get you to want to use it?

DR NEAL: Well, certainly that’s the development program, and there’s plans for FDA review of the joint data between this study, which was for the actionable genomic alterations, as well as the patients who had EGFR-mutant lung cancer from TROPION-Lung01, the current plan is for an approval in prior-treated setting for EGFR-mutant lung cancer for dato-DXd.

I did eye that approval in breast cancer in January with a little bit of anticipation and wonder if this agent is better than the currently approved therapies in the N^th-line setting that we have, such as docetaxel, docetaxel plus ramucirumab, gemcitabine. For EGFR, for all the exciting drugs we have, there are patients that progress through all of these, and then we’re back to boring old chemotherapy, sometimes with TKI, sometimes not. So I think I’m eagerly anticipating this approval, and it may work in other AGAs too.

DR LOVE: So Jessica, have you or would you at this point attempt access dato in a patient who already had a bunch of other therapies with EGFR-mutant disease? Is there enough efficacy here that you would like to use it in that situation now, or have you actually? I mean, it is approved in breast. Maybe theoretically you could access it, maybe.

DR LIN: I would love to be able to access this for patients with EGFR-mutated lung cancer. I’ve certainly had patients, my patients with EGFR-mutated lung cancer, access this in clinical trials. I have not used it off label yet, but I, just like Joel said, am eagerly awaiting FDA decision on this.

DR LOVE: So of course I always ask faculty in our Year in Review series what are we going to be covering next year, what are some of the new things that you’re looking forward to seeing. And Joel, you brought up this question. Of course there’s a lot of excitement. This is a bispecific targeting PD-1 and VEGF that it seems like forever, but I guess it was last year that it was first presented in an Asian study that it looked better than pembro.

But you pointed out there’s this study looking at this bispecific with chemotherapy in progressive — EGFR-mutant progressive disease, patients who progressed on an EGFR TKI, usually osimertinib, so they’re going to look at whether by adding this bispecific to chemotherapy you get greater efficacy. Of course, I would wonder whether the control arm should have been amivantamab plus chemotherapy. But any thoughts, Joel, about where this molecule is heading, both in this situation and others?

DR NEAL: Yeah. I think the really interesting thing about this particular clinical trial is with all of the exciting things in EGFR-mutant lung cancer we’ve kind of left immunotherapy by the wayside, and we’ve also left VEGF inhibition by the wayside. There’s strong data that bevacizumab can be added to chemotherapy and improve the efficacy, especially in EGFR-mutant lung cancer, probably other targetable-alteration lung cancers too.

And immunotherapy may work in some. I think Jessica did a great job at the beginning of pointing out who it might work in and who it might not work in, but we don’t really know how to use it in the vast majority of patients. So I think this anti-PD-1 plus VEGF bispecific antibody tested in EGFR might open up a whole new mechanism of action and realm, so I’m excited to see how the study pans out.

DR LOVE: Again, Jessica, any thoughts about this, and particularly where it’s being studied? Also, we haven’t talked about patritumab, the antibody-drug conjugate targeting HER3. Is that something that you see in the future here in this setting also, as well?

DR LIN: Absolutely. I think it’s just overall an exciting space to watch. So much evolution going on in the treatment paradigm for EGFR-mutant lung cancer, with emerging ADCs and bispecific antibodies, and we’re all looking forward to seeing more mature data from different trials emerge.

BRAF

DR LOVE: So I want to finish out with a couple words about BRAF, Joel, and you went through the different mutations in a great review of therapy, including this new entry from the PHAROS study, encorafenib and binimetinib, which of course now is being used a lot in melanoma. And I’m just kind of curious, having had experience with dabrafenib/trametinib, I heard all those stories about fevers that patients have at home, et cetera, but I’m curious about your experience with enco/bini so to speak, Joel.

DR NEAL: Yeah. I had tried it on a couple of patients, I remember, 2 or 3 years ago. I saw that they got the approval in melanoma and asked my colleagues there should I be thinking about this in lung cancer, and then I think David Spigel presented the data at ASCO, and it was approved not long after.

So I think given the slightly more favorable toxicity profile there is compelling reason to think about starting with this combination as opposed to dabrafenib/trametinib. Some of my patients on dabrafenib/trametinib have had to have dose reductions, especially for the fevers and other side effects like that. I would say in general I’ve been able to have patients tolerate full doses of encorafenib and binimetinib, for what it’s worth.

KRAS G12C

DR LOVE: So we can finish out with some thoughts about KRAS G12C, Jessica. Here’s, again, a slide that Joel presented looking at the various KRAS mutations that we see in non-small cell lung cancer, and of course the fact that we now have 2 approved agents. He talked in his presentation about a number of ones that are coming along, including zoldonrasib that’s going to target KRAS G12D.

But the main thing I wanted to ask you, Jessica, is what’s your clinical experience with these agents? Do you really see use — I know the response rates are not as high as what you see, for example, with ALK and EGFR, but do you see clinically meaningful responses with these agents? Do tumors shrink? Do people feel better? And how’s the tolerability?

DR LIN: I do see clinical benefit in patients, and I have with both sotorasib and adagrasib that are FDA approved. Even though not everyone responds there have certainly been patients where I’ve seen objective tumor shrinkage and improvement in disease-related symptoms. Tolerability is not always easy. The GI side effects can be really tough for patients, so there’s certainly room for improvement there.

DR LOVE: Joel, this is such a common alteration. We’d hope that we could find something that’s going to be effective. Any thoughts about whether these newer agents are going to have great efficacy?

DR NEAL: Well, I think one comment, too, about the current agents, the sotorasib and the adagrasib, is we’re still seeing modest CNS efficacy, and I think there’s more opportunity for better CNS penetration because so commonly these tumors go to the brain.

There’s a whole new class, and we talked about a couple of the G12C inhibitors, but there’s also the RAS (ON) inhibitors that form tricomplexes. They’re really a bizarre mechanism of action. They bind to a third protein called cyclophilin and bring the KRAS on form together with that and really mess up the downstream signaling. So it’s a beautiful story of rational drug development, and there are RAS (ON) inhibitors for pan-RAS, as well as the G12D inhibitor that we talked about, and G12C RAS (ON) inhibitors.

Preliminary, and we’re seeing very, very small water plots for all of these so far, and presented data of monotherapy. But preliminarily they look effective, and we’ll see about tolerability and CNS penetration.

DR LOVE: So Jessica and Joel, thank you so much for joining us today. We all learned so much. Audience, thank you for attending.

Be safe, stay well and have a great night. Thanks so much, Jessica. Thanks, Joel.

DR LIN: Thank you for having us.

DR NEAL: Thanks.