How to Treat Metastatic NSCLC with Targetable Mutations – Treatment Algorithm with Dr. Eric Singhi

[MUSIC] We are at the oncology brothers. >> Hello, and welcome back to the oncology brothers podcast. I'm Rohit Gossane, alongside my two younger brothers. One, a community medical oncologist, Rahul Gossane, and Dr. Eric Singey from MD Anderson Cancer Center, our panelists, the RASIG Medical Enclogist. I must say it makes me look much older here, but we'll get going. So the topic at hand is metastatic non-small cell lung cancer, where we are focusing on targeted mutation in frontline setting. This subset is getting more and more exciting with more treatment options available. The most recent one has been in her two space. There's quite a bit to cover today. Eric, let's dive right in, sir. It's always so good to have you here. >> Likewise, and I need to grow my beard so that I can match you both. >> [LAUGH] >> So that will take much luck. >> All right, Eric, let's get started. Let's start with common easier front mutations. Exxon 19 deletions and RL858R. You know, we here have improved overall survival. Back with the Fattenib, our second generation TKI's overall survival was roughly two to 1/2 years. Then with also Mertonib alone, close to three years. But now with combination like Amulaz, we're looking at more than four years. Do we need to do better? Absolutely, but thankfully, we are headed in the right direction. Here, we now have three options. Single Agent Olsen Mertonib, still potential option, but now for a very small subset. And then Amulaz based off Mariposa or Aussie chemo based off Florida too. We also have to keep CNS activity in mind here as roughly 30% of the patients can have CNS involvement. And for this, NCCN leads towards Amulaz combination. Patient centered and patient informed decision is always the key. With all this in mind, Eric, how do you pick that one option over another, and what data do we have to support that? Yeah, well, I think you summarize the data really well. So for most of my patients that are presenting with a classical EGFR mutation, X on 19 deletion, L.A. 5-odd, my default option for most patients is a combination therapy. That's not to say there isn't still a role for single Agent Olsen Mertonib, particularly if the patient has multiple comorbidities, they have an advanced age, or we're really factoring their quality of life. But for most patients, it's combination therapy. And that's because these combination therapies have really shown superior progression for your survival and overall survival compared to Osen Mertonib. Right? I'm really thinking about it particularly for patients that have a high risk feature. So CNS metastasis, like you highlighted, but also liver disease, baseline CTDNA. That's positive. The L.A. 5-odd commutations, mutation specifically in even TP53. Really leaning in, I think, on the unique profiles, the side effects, the toxicity, the administration schedule, the time toxicity, the cost. I think a lot of that is really important. So what I say to patients is, really, this is an opportunity to lean in on those patient preferences where we can make a decision together. Right? But for most patients, the default option is one of the combination therapies. How do you choose which combination therapy? Honestly, if you asked different medical oncologists, you'll get different answers. So as of right now, we don't have the perfect biomarker to guide us, but we have some of the subgroup data. Right? So if you look at some of the subgroups, for example, one of the convincing subgroups is liver metastasis or liver disease. There seems to be a good signal there, with amythamab and lizard nibb and that strategy. So I am thinking about for my patients with visceral disease, liver disease, reaching for the maraposta strategy. We now have every four weeks dosing with subcutaneous for amythamab. And so that's a nice sort of time toxicity consideration that's new. And then we're also thinking about technically a chemotherapy-free regimen, right? And a lot of patients and their families have this stigma with chemotherapy. Chemotherapy-free doesn't mean it comes without toxicity. It doesn't come without compromising sometimes safety of a patient. But that is a real consideration, a real world consideration that happens quite often. Eric, you summarized it very well. What we are talking about here is that each EFR mutation matters, and also CNS involvement matters. And the reason for that is because we are seeing more CNS metastasis with EFR mutation. As a result, what we saw from maraposta trial was serial MRIs. For all patients was rather mandated. With amylaz combination, what we saw was intracranial PFS benefit was essentially doubled when compared to Aussie Mertnib. With amyvantamab-lesertnib, initially we were hesitant from community standpoint, but now we are much more comfortable, especially now we have subcutaneous version available, which is decreasing the infusion-related reaction, cocoon data to guidance from dermatological toxicity, nail management, and also VTE management for use of anti-quagulation for first or months is rather critical. On the other hand, we have Aussie chemo combination, where from community standpoint we have a bit of comfort from chemotherapy aspect of it. At the end of the day, there is data to support that a lot of these patients are not even making it to second or third-line therapy. As a result, combination should be utilized up front. One has to balance the side effect profile and co-morbidities when deciding amongst the two regimen. As a result, if you have not checked it out, we have a podcast focusing on EGFR inhibitor side effect management, so please give that a listen. All right, moving along into disease progression space. If the disease was to progress here, one has to repeat the biopsy. To check for that small cell conversion or rather resiston mutation that is rather critical. And if one was started on amyvantamab-lesertnib combination, disease progresses here, choice is platinum-based chemotherapy or data-DXD. Or if you got patients started on osymertinib disease progresses, the choice is adding chemotherapy here or switching to amyvantamab-les chemotherapy. Now, moving along into EGFR X1-20 insertion here, we have choice of amyvantamab-les chemotherapy, a front-based on papillon study. If the disease was to progress here, one could again use data-DXD in second line as this was approved for all EGFR mutation. Eric, this is a good segue for other uncommon EGFR mutation. What's your go-to therapy here? Yes, this is a great question. Several of these uncommon mutations in EGFR refer to as pack mutations. And so the first thing I would say is if you can get your patient onto a clinical trial, there seems to be some promising agents in this space. It's not the majority of patients that have EGFR disease, but it's still a meaningful subset and there are trial options. That being said, for many of these patients with pack mutations, my preference tends to be a standard of care, a fatnib. But we also have some data that's come out about amyvantamab, with these patients. And there is a subset of patients who can derive a benefit from an end-of-the-vant-map plus a certain of even in the subset. So I'm thinking about those options as standard of care. You know, in the past, this is where I was using a fatnib a lot more, but we also have unicorn study that, yes, small number granted. Here, I do lean towards also my retinib for those compound mutations. Again, as you highlighted, we also have data for amyvantamab and lizard-tinib, especially if there's CNS involvement. A fatnib has none. There are so these are the things that at least I'm keeping in mind moving forward. All right, now let's shift to out-positive disease. Here, we have electinib, lorlatinib, and brigatinib. Lorlatinib data from crown trial looks phenomenal. But again, we have to keep side effects in mind. Electinib is also approved in adjuvant settings based off Alina trial, so there is that comfort around that. Eric, what's your frontline approach here? And how do you sequence these options at the time of progression? It's a great problem to have, right? We've got really exciting and effective agents in this space for patients with Alifesion positive disease. And so once I saw the data, you guys from ASCO a couple years ago, the updated data from the crown study, the five-year data, that's really when lorlatinib became my preferred frontline option for most patients. Not all patients, but for most patients. The median progression for these survival as a reminder was not reached. Five-year progression for these survival was 60%. This was unheard of in stage 4 lung cancer. And so that really solidified my opinion there with reaching for lorlatinib in the frontline for most of my patients. That being said, Electinib we're seeing more data. Seven-year overall survival rates of just shy of 50% is incredible. The toxicity profile is pretty manageable. The top three that I teach my fellows in clinic, anemia constipation and fatigue. We know how to manage those while we can counsel our patients on how to do it. With lorlatinib it's really about optimizing toxicity management for the long run, right? You're in it for the long haul, hopefully for patients. So focusing on dyslipidemia, focusing on the weight gain, focusing on the CNS and neuropathy. I think those are the big ones that a lot of people have trouble with. But I feel like with the data that's come out, you owe it to your patients to talk about both options and to really tell them about that progression for your survival data that we have now. Absolutely. And then at the time of progression, are you leading into prorlatinib? Yes, this is a good question. My strategy for patients is trying to get them on a trial. As you know, Nell Adalcib is a drug of four-generation TKI that's particularly useful for compound alt mutations on target resistance. It's not the most common form of resistance. I'll tell you that. But it is a drug to be thinking about and considering they're even going to be studying it in the front line of the phase three Alkazar study, Nell Adalcib versus electinib actually. But yes, prorlatinib is an option based on the resistance profile that emerges, for example, thinking about adding in chemotherapy as well, too, as an option and thinking about really just trial options in general for these patients. Yeah, can I just reiterate that for a second? That once we've exhausted our Alk inhibitors, let's not forget that Pemetrexid is relatively active here. So, carbopem can provide us some meaningful responses for that Alk positive disease. Okay, Ben on to Rosswan, direct your preferred option. We've seen TEL tractinib also get approved last year here. Yep. So, thankfully, we've moved away from the good old days of chrysanid. And now we have a lot more exciting agents. So, TEL tractinib, repo tractinib, those are more recent agents. My preference at this time, given the efficacy and given the safety profile is TEL tractinib as my standard of care. We saw a meeting progression fee survival exceeding 40 months. We saw the safety profile, you know, LFTs you have to watch for diarrhea, nausea, fatigue. But it's a lot more manageable, unfortunately, than And it's sort of competitor right now in the standard care space and that's repo trectinib. There's a lot of dizziness, even grade one dizziness. If you're having it frequently, it can be really tough, right, for patients. And so that's my preference as of now. I do want to put on your radar that there is a newer drug in this space that seems to be making waves and that's did a santiment. And so objective response rates are 89% for treatment naive patients, which is really high. Yep. And very low dose reductions, very low treatment discontinuation rates. So a lot more to come in the space, trying to do better on CNS activity, trying to increase systemic activity and trying to work after exposure to prior TKI some more to come. Let's see how this new drug plays out. But again, as you stated, Eric, the common side effects here are dysnia and dizziness and fatigue. One has to keep those in mind. Now, moving along into B-Raff V600 e space. Now, I know that we are moving through this rather fast, but there is quite a bit to cover. For this particular mutation, these do respond to IO or IO chemo therapy combination. We will take a deeper dive into this particular space in another episode. However, before we even move there, Eric, your take here, how are you deciding amongst B-Raff mech combinations that are approved here or IO or IO chemo combination? I think it's highly clinically relevant. And it's important to emphasize that not all mutations or fusions in non-small cell and cancer act the same way. So the majority of them won't respond well to immunotherapy, but there is a subset that can. So K-Raff, B-Raff, MeticS on 14. So how do you make that decision? So there is some data. It's retrospective, not prospective to help guide us. So there was data from last year's ASCO. It was the front B-Raff study. And it looked to see what's more effective for patients as it's starting off with immunotherapy plus or minus chemo or leaning towards targeted therapy. What they interestingly found was that the median overall survival was actually significantly improved for patients if they were on immunotherapy, but really for a subset of patients. So if they had a history of smoking, if they had a pd-o on TPS that was at least greater than 1%, ideally even higher into the 50s or above, if they did not have brain metastases. So those are maybe the patients where I'm thinking, maybe I should reach for immunotherapy first. And out of the B-Raff mech combination, do you favor one or the other by any chance? I do. It has to do with some updated data that we have and just the manageable safety profile. So for me, EnkoBinney is really my preference for these patients. We do have updated data from the pharaoh study and that included patients that were treating a naive objective response rates were 75% median progression for the survival over 30 months, median overall survival almost 48 months, which is pretty incredible to be able to tell patients that. And so my preference is that you have more GI side effects with EnkoBinney than you do with Dubraffinib Tremetinib, but the Pyrexia, thankfully, is a lot more manageable. You have actually no great three Pyrexia to my knowledge in that trial. And so lower discontinuation rates as well. Yeah, I have to agree. My preferred option here also ends up being EnkoBinney, just because I think that the side effect profiles better and you have better overall response rate. I was just struggling with what you just brought up saying who gets chemo, chemo, I/O, I/O alone, or B-Raff Mech and the bitters. And if you think to keep in mind, you have you can extrapolate few things from melanoma trials as well. If you're looking for a quick response rate, B-Raff Mech and the bitters are going to do it. But if you have someone with extensive tobacco exposure, maybe immunotherapies the way to go. If it's liver or CNS mats, again, B-Raff Mech and the bitters is what you would rely on. All right, then on to Intrek and Met abnormalities. When we're talking about met abnormalities, this also looks different. Met overexpression, particularly C-MAT. With that, we have Telosovie, an ADC in second line. But here, let's talk about met exonskipping mutation. Eric, your approach here for these two mutations. Yeah, so you've got to look to find that Intrek fusion. But if you find it, you got to go with it, right? A very small subset, a meaningful subset of options, right, for patients like this. So we have Leroy Trectinib and Intrekinib for Intrek fusions that's approved. My preference, I slightly favor Leroy Trectinib a little bit more. Not only from the efficacy standpoint, but also the safety profile. So you may see my alias, dizziness, you have to watch the LFTs. But overall, pretty manageable. So that's my standard of care option. I will say we should also put Repotrectinib on here as well. That is an option. But objective response rates were just shy of 60%. If I remember, of course, you can't do cross-trial comparisons. And then we've already talked about that safety profile, just being a little bit more difficult to handle in the real world. So for most patients, standard of care, outside of clinical trial, I would say they're retractinib. Absolutely. And again, we're talking about Intrek. We're looking at needle and hei-stack. Yeah. So moving on to Met, when we say Met altered non-small cell lung cancer can mean a few different things. So if we say Met X on 14, skipping mutation, that's really important to emphasize. Because now there's approvals for Met protein over expression. There's also approvals for Met amplification. So there's a lot of just terminology to understand. So we focus just on the NGS results, Met X on 14. We do have a few options. We've got Kate Matnib, we have Tepotnib. Objective response rates are pretty similar between the two, I think, close to 60 to 68% respectively. Big problem with these is the edema to manage clinically. And so that is really hard to overcome unless you make changes with the doses. I don't have a strong preference one way over the other. There are slight differences in Numenitis, incidence as well, too associated with these agents. And so I'm paying a little bit more attention to patients. If maybe I'm worried that they've got a higher Numenitis risk, then maybe I'll reach for Tepotnib. Right, I want to go back to Intrek here. This is a rare entity, but it is important to check for this because we have bucket approval for all solid malignancies here. All right, moving along into Rhett and her two space. Eric, can you start us off with Rhett mutation and then after this we'll dive into her two options. What is your go-to regimen for Rhett mutation? Yep. So Rhett is well not as common but still meaningful. So we do have a couple of approved options here that I favor, self-recognitive and pralceptive. Not really reaching for as much cabosantinib to be honest. Treatment response rates for patients that are treated in naive with self-recognitive pralceptinib are almost 70 to 80 plus percent. Again the edema can be an issue with these drugs, but also you've got to watch for LFT abnormalities. You can maybe see a little bit more diarrhea with self-recognitive, so I'm watching for those things. What's exciting is there are some next generation Rhett TK highs that are being studied. One agent that I'm watching is EP0031. So we'll see what these next generation Rhett target therapies will bring for us. Right, this list is only going to get more crowded, but again that's exciting times itself. All right, and for her to initially we had TDXD, but then we got zone-gurtinib and sever-burtinib in second line settings. More recently what we've seen is zone-gurtinib with great activity and rather favorable side-effect profile as well. Eric, at the time of progression where one got started on zone-gurtinib, utility off sever-burtinib or TDXD here or you're going to switch that patient to chemotherapy. Yeah, so this is a really new approval, right? We just got this approval for the frontline for zone-gurtinib. So I think we are actively as a community learning about acquired mechanisms of resistance about how to best sequence for patients. So just as a quick reminder, to be able to qualify for zone-gurtinib, you have to have a her to mutation, not only just a her to mutation, but it has to be within the tiresome kinase domain. The good news is that if you're going to have a her to mutation that's activating the majority of them are in the tiresome kinase domain. So if you had to put your money down, you're more likely to qualify than you're not. So I think that's good news. Now what to do after progression on zone-gurtinib, I would advocate for another biopsy. And there's actually been case reports that have already been coming out. Patients were started on zone-gurtinib. They developed disease progression. The biopsy helped because what they did was they checked for ERB2 amplification. They checked for her to protein overexpression. They saw that that was what was driving the resistance and you were able to salvage your response with TDXD, right? So I think really understanding why the resistance is happening is becoming even more important. Absolutely. And again, be it her to and try these are rare subtypes, but we have to keep looking out for them. You know, we've covered a lot here. Eric, any final thoughts before we wrap up? Yeah, no, it's an exciting time to be a thoracic oncologist and unpack all of this data. I think one, just the nomenclature of some of these biomarkers is really confusing. The met story with having different ways to really say that disease is met altered. And with her to same situation, so trying to understand the biomarker results and then translate into clinical practice are two separate things, but they need to be together and they need to be meaningful for patients. And then also we're adding more and more to this list. So even some emerging biomarkers to watch out for, we haven't even talked about M-TAP loss. It's something to be looking for for patients with actual genomic alterations. It can qualify patients for clinical trials with drugs like PRMT5 inhibitors. And then understanding acquired mechanisms of resistance so we can continue to offer precision medicine for these patients at time of progression. So I have a starter pack for new patients that meet with not small cell lung cancer. The starter pack abscle includes NGS. It's got to be comprehensive DNA and RNA, right? That's a non-negotiable. What I'm also doing is IHC testing up front as well. So I'm doing it not only for PDL1, but I'm also looking at C-MET, HER2, and now even M-TAP loss because I do feel like that opens options for clinical trials for a good subset of patients. If a patient has been exposed to targeted therapy as their front-line therapy, I would encourage you at time of progression on a targeted therapy to repeat better. Wow, I feel like I've learned a lot. So I hope anyone tuning in is walking away with the same enthusiasm. Again, NGS testing is absolutely critical here. Eric, thank you so much for walking us through your treatment algorithm for a metastatic non-small cell lung cancer with actionable mutations in frontline settings. For you tuning in, let's go over a quick recap. Today with Dr. Eric Sengi, we covered metastatic non-small cell lung cancer with actionable mutations in frontline settings. NGS affront. and in select cases, retesting at the time of progression to appreciate resistant mutations or small cell transformation is critical. For common EGFR mutations, we have strong data around combination options over a single agent, Osomar Teneb. In Mariposa, with amylaz, median overall survival has not reached and is projected to be more than four years. Then for out positive disease, we often rely on electoneb or lular latineb in frontline settings and then go for brigatinneb or chemotherapy thereafter. Roha, we've covered a lot here. What else do you wanna add? - Right, Roha, besides EGFR and ALC, we had a chance to touch on mutations like Ross one. Here, we have the treatment choice of tel-trekneb and repo-trekneb. Then we also touched on her two as on-gurtneb just got recently approved in frontline settings. And what do you do at the time of progression after zone-gurtneb? Juries out, but re-biopsy is extremely important and checking for her two status. Also, what is your preferred B-Raff Mechenebitter or do you rather lean on IO-based treatment for B-Raff V600E mutation that was also touched on? This discussion was packed with clinically relevant scenarios. We see in our day-to-day clinical practice. Thanks for joining us. We'll see you in another discussion. We are the oncology brothers.