How to Treat Metastatic NSCLC W/O Targeted Mutations – Treatment Algorithm with Dr. Christine Garcia

[MUSIC] We are at the oncology brothers. >> Hello and welcome back to the oncology brothers podcast. I'm Rohit Gossane, a practicing community medical oncologist, alongside my brother and co-host, Rahul Gossane. A mission from our oncology brothers podcast has been bridging the gap between academic research and everyday community practice. Today we'll be talking about our treatment algorithm series. The focus is going to be metastatic, non-small, so lung cancer without actionable driver mutation in frontline settings. >> Rohit, the few things have changed here since the last time we covered this. We now have the option of Telosovie in second line and beyond for that C-Met over expressing disease. Also, her two positive disease was here in this category as chemo-muneotherapy was a preferred option. But now we have the approval of zone girdinib in frontline settings. But a few dilemmas we often face in our clinical settings here are still who should get that dual checkpoint in the betters. Who is the right patient for single agent immunotherapy? And then what next at the time of progression? How do you pick one K-RAS in a bit or over another? To touch on all these nuances and data, we're excited to have Dr. Christine Garcia, a thoracic medical oncologist and the fellowship program director at the Will Cornell Medicine program. Christine, thanks for joining us. >> Thank you so much for inviting me today. >> Christine, welcome. Let's get started. What we are seeing is 50% of lung cancer patients who percent with metastatic disease. That is improving because of lung cancer screening guidelines. Talking about the treatment options here, where lung cancer has rather been the poster child for actual mutation in biomarker-driven treatment. As a result, first thing we do here is NGS testing. And if no underlying mutations are seen, then we rely on PDL1 score to decide our treatment options. If PDL1 is more than 50%, we tend to rely on immunotherapy. That is single or dual checkpoint inhibitor. For intermediate PDL1, that is 1 to 49%. We rely on chemotherapy with immunotherapy. Though there is certain patient populations, we will just use single agent immunotherapy particularly for elderly or patients with multiple comorbidities. For PDL1 negative disease, that is less than 1%, we tend to rely on chemo and immunotherapy. For chemotherapy, we use Platinum plus Pemetrexate for Edna carcinoma, Platinum plus Pactyl Taxi for Squamous cell carcinoma. And then with these combination, we will add the IO portion, whether that single agent or dual checkpoint inhibitor. Now, sticking with that story of single agent versus dual checkpoint inhibitor, how are you making that choice of single versus double? We have the data for Derva Tremie-Based-Off of Poseidon trial, Ippineval based off of checkmate 9L-L-A trial is TMB adding anything for you to decide one way or the other, or STK 11 or keep one from molecular testing helps you make that decision. This is a great question. And honestly, this is where I spend a lot of time in a lot of very nuanced conversations with my patients and colleagues. So my general approach is that dual checkpoint inhibition is reserved for a very select group. And I'm not using PDL1 as the only selector here. So as we all know, a high PDL1 alone wasn't pushed me towards double IO. What really moves the needle for me is the home and molecular context. We are focusing on the no-actual mutation in the frontline setting, but we need to know and confirm that there are no actual mutations first. So if I have a patient with an STK commutation, especially in a K-RAS mutant tumor, I'm much less enthusiastic about single agent IO and more inclined to either add a chemotherapy backbone or think about NIVO-IB combination. Because we know that STK 11 creates a cold and immunosuppressed microenvironment that single agent PD1 blockade just doesn't penetrate well. Keep one similarly gives me pause. Your question, TMB, hi. That's another story. I think it's an imperfect biomarker, but in a patient who is truly TMB I like 10 mutations per megabase. And especially if they're negative for STK 11, keep one commutations. They tend to track with poor IO response. So dual IO becomes more compelling of a conversation. So I'd say that I'm using dual checkpoint inhibition in a very small, but deliberate minority of my frontline patients. So I would say maybe 10 to 15% for two regimens that we can think about in this space. So either the Poseidon regimen or checkmate 9 LA. And I think you have to really factor in the immune-related adverse event risk profile because the toxicity ceiling increases when you are adding more checkpoint blockade. So I think it's really kind of putting in Poseidon and checkmate 9 LA. Kind of side by side. We can't compare them head to head, but at least trying to put them into context. Because we're asking really the same question in both regimens. Whether you throw on a CTLA inhibitor to P101 plus chemo, and will it give you a better benefit than just chemo IO alone? But I think that there is very different nuances to each one. Because they answer it in two different but very meaningful ways. Poseidon and checkmate 9 LA, they're both phase three trials. There were no EGFR-ELC patients included in these. And both had a limited course of chemo strategy, which was then layered on top of dual checkpoint blockade. So that's how I try to think about it. And they both showed sustained benefit versus chemotherapy at very long follow up. Regardless of PDO and expression histology, that's the common thread between. But the regimens look very different when you dig into it. Checkmate 9 LA uses chemotherapy and immunotherapy, so Mivo and Ibby with just two cycles of platinum doublet. So in this way, I think of the chemotherapy as like a bridge strategy. And the idea as the investigators have described it, is that you use the two cycles of chemo to get a rapid disease control. And then you carry through those patients through while the dual checkpoint blockade takes hold. And then you keep the Mivo Ibby as ongoing maintenance. And this is like continuous dual IO. So this is something that is important to think about. Because this is not a time limited course. This is you keep it going until there's unacceptable toxicity or up to two years. And most will just keep going. So I think that's a very big difference from what Poseidon was set up to look like. Poseidon structurally patients got tremolimumia or tremes. It's the easiest way to say it. Tremie plus chemo for four cycles. Then you have Durba maintenance with one additional priming or booster dose at week 16. By the time they get that extra tremidoes, are already on PDL monotherapy maintenance for Durba. So you're not getting the continuous Iblimimabic cloblin. You're using tremie as a time limited CTL, little booster shot and then stepping it down. So I think it has real implications for long-term immune toxicity management. And you know, out in the community, when we're treating GI malignancies, we actually have something similar to this in HCC, where you have this stride regimen, you get one cycle of Durba tremia, and then you continue with this Durba maintenance. And then we all continue to argue that, hey, if you're keeping ongoing CTLA for for longer, you're exposing your patients for longer side effects, immune related side effects. The way these clinical trials are designed are very different. But again, keeping that SDK 11, keep one in mind, maybe there is that right patient for this combination. And that is what the subgroup analysis for Poseidon also showed that these patients do better with this dual checkpoint and a better kind of strategy. Yeah, I think that's where Poseidon really distinguishes itself in their molecular subgroup analysis for these like difficult genomic profiles. Because they had very clear data on SDK 11, as well as they show data for for a key one. So I mean, I think that the checkmate, not only six year data had benefit across SDK 11, keep one, K-RST53. So it is reassuring. But I think the granularity of the Poseidon data is where it really stands out. Christine, so moving along outside this dual checkpoint and a bit when that PDL1 score is high, often we're talking about single agent immunotherapy. Is there any role of adding chemotherapy there for better overall response? Or is there a particular patient where even though that PDL1 score is high, you're tapping along chemotherapy outside the story of SDK 11 and keep one? Yeah, I think with PDL1 high, even though for a long time it seemed very clear that I don't think there's a very clean universal answer now. I think the sort of default narrative was, we had keynote O2Fore data, PDL1 monotherapy, PDL1 or 50% monotherapy with Pemoralism. It has great data, but I also think that it was in some ways we've sort of collectively oversimplified it. I think there are scenarios where I will absolutely reach for chemotherapy and IO even in the high expressors. I think if someone has really high disease burden symptoms, a younger patient, extensive liver meds, a beta cave syndrome, I'm not comfortable waiting to see when that single agent IO will kick in in eight to 12 weeks. I want rapid disease control. The patient needs that rapid disease control. So I think that that's a space where you definitely want to enter the chemo there. And we've seen this story play out well with the Empower 150 trial where we are using the ABCP regimen, where again, that responsiveness or survival benefit is there for that particular subgroup of liver meds and even tying in that SDK 11 and keep one. And these are the patients who had EGFR in alcohol tracians even in the front lines there. - Right, that's it. I'll jump on this for a second. I can't remember the last time I used this. - Regimen. - Sure. - I'm throwing the kitchen sink, even for EGFR, Alka. Again, if, yeah, there's hint of data, maybe immunotherapy, maybe no immunotherapy. I feel like every new study continues to go back and forth. But today, 2026, where we're recording this, I really don't think Alka positive or EGFR, immunotherapy is a good story, at least right this minute. - The one thing I also wanted to mention was, we say PDL-150% are higher, but there's also a subgroup of the super PDL-1 high, the 90%ers, and up. And there is good long-term benefit for temporalism, and or submiblimab for those really high PDL-1 patients. But again, that's thinking in the context of the patient in front of you, if they have a lot of disease burden, but it is a potential option for those who have really high PDL-1 and with continuing risk on this. - Christine, you mentioned submiblimab, which is again, you always more in squamous cell histology, just to dive into a bit more data does, histology changes your perspective here. That is for squamous cell, where we are still seeing about 25 to 30% of non-small cell lung cancer patient population, any role of single agent immunotherapy, whether that's submiplimab, or you are preferring one or the other immunotherapy. - I have started to lean towards using the submiplimab and squamous in this histology, especially. I think that the data is starting to really support that in squamous, especially. And I think that we have to be more nuanced here when you look directly at the histologies as well as the PDL-1. It's not like every immunotherapy work is exactly the same. - Absolutely. And again, bring back my general community, oncology experience here for chuteinous squamous. Again, submiplimab has very strong data as well. So maybe there is that hint that this particular immunotherapy is working better with this particular type of histology. - All right. What next if the disease was to progress where the option is dosy-taxol plus minus remuseremab c-mept over expression, where now we have the option of telosov and for K-RASG 12C mutation, we have two K-RAS inhibitors, that is edagraceb or sotoraceb. Chrissine diving in a bit more of the K-RAS story here, where we have these two options available, that is edagraceb, which is twice a day regimen. Sotoraceb is once a day regimen. Edagraceb has a bit more drug interactions, better c-N-S penetration, but also different side effect profile, where we tend to see GI side effects from both of them, but edagraceb QTC prolongation and creatinine elevation. How are you picking amongst the two agents here? - Yeah, thankfully we have more options in this K-RAS space. And because within K-RASG 12C, especially in lung cancer and non-sclaimous patients, you're seeing like 13, 14, I almost feel like closer to 20%, because it's the most common mutation outside of HGFR. So you have sotoraceb and edagraceb, and I think I actually have more cumulative experience with edagraceb at this point, although I have patients who are on both. And I think partly it's because of the intracranial data. There's a meaningful C-N-S response signal with edagraceb, and I think partly because of the combination data emerging with submittal madmen and other agents. So I think the choice between these two agents for me should factor in C-N-S involvement. I prefer it for my patients who have untreated or progressive previously treated brain meds. But I think that if you did not have C-N-S disease, either as reasonable, and code break 200 gave us head-to-head versus dose of tachylicsilidoranacid, which showed improved PFS. And response rates for both agents around 35, 40% in the second line, which is frankly better than dose of tachylicsilidoranacid. So my default does land with edagraceb, but may individualize based on prior therapy and patient specific factors. You mentioned the GI toxicity, nausea, degreea, hepatol toxicity. That's real, and it requires vigilance. And you need to make sure and counsel your patients extensively about the subfront, not to ignore it, and also to report it back to us, because especially with soda rings, it's a lot of pills. You could do a lot of those reducing there. And then the QTC prolongation with edagraceb is worth baseline EKG monitoring. And also something that you need to stop and look at what other comorbidities, especially cardiac ones, does my patient have? What medications are they taking? They taking any other QTC prolongating medications that may give you pause for edagraceb. I think that if you don't have a KerasG12C, dosy RAM still remains a solid backbone option. And I still use this regimen regularly. I don't abandon it because there's newer options. And sometimes that is your only option. Christine, actually, before we run away from Keras story, you touched on edagraceb having stronger data for CNS activity, cold-break 200 PFS, but no OS, edagraceb also ends up being my preferred option here. When you have that asymptomatic CNS lesion, you know, we all are very comfortable with our anti-EGFRs or alkenabiters saying, "Affront treatment is what we're going to rely on. What about these Keras inhibitors?" If there's asymptomatic CNS disease, do you lean into edagraceb and then repy brain MRI at a short interval? Or is your practice to reach into SRS and then continuing with Keras inhibitors? I feel very lucky because I practiced with a really great multidisciplinary group and we have a brain met tumor board on Thursdays. So that's become a discussion with some of our radiation oncologists or neuro-oncologists. But I do think it's a little bit different than edgFR. So with edgFR a lot of times, we say, "Okay, start your edgFR therapy. Let's wait and see how the responses and then treat." But I think more often because the response is not as robust very quickly, we will start the Keras inhibitor and then repeat a short interval scan depending on how the baseline was. So it is definitely a discussion that we get to have as a group. Christine, I know this was for Keras-specific patient population. How about that denoval metastatic patient who presented in front line option where we do not have any actionable mutations at hand and now we have limited brain meds where patient is rather asymptomatic and we are seeing some hint of response even with systemic therapy, chemo plus hydro combination. Is that good enough or you do partner up with your radiation oncology colleagues in this setting as well? - I think it would depend on what you see on the scans. I do feel like we rely more on our radiation oncologists because the field of radiation oncology has significant events and we are doing a lot more SRS and more brain preserving treatments for radiation oncology. So I do think we rely on combining some of our treatments more with brain radiation. - Okay. And again, Roy, do you have more data of CNS penetration with immunotherapy? We see this with melanoma, but when there's no actionable mutation, yes, there is CNS penetration with immunotherapy. A lot of times we're leaning into SRS and then continuing with that systemic treatment. - And a multidisciplinary tumor board always trumps that for sure. All right, moving along Christine, with regards to the approval of TILISOE which was based off of luminosity trial. Could you talk about what is the prevalence of C-MET or expression and data around TILISOE here? - Yeah, you know, I didn't know this until recently, really that C-MET isn't actually very high. It can affect like, in non-screen response also lung cancer, probably affects somewhere in the range of 25 to 30% of patients. And like EGF-Armure tumors, post-OC, it can be even higher given the development of metamplification as a resistant mechanism. So it's really exciting to see a targeted therapy in this space because I think one, not a lot of people are looking for C-MET and now there's an option that could be, you know, it's quite prevalent for our patients. So first of all, the first thing we should cover is that how you check it. So C-MET needs to be on, it's based on IHC high positivity. It has to be high positivity to be like a really high age score, 150 or more. And it needs to be, in my opinion, ordered reflexively at progression. Luminosity did have some data to show that if you've got it at initial diagnosis, that it did correspond with progression, but at progression you should be doing this. It's not part of your standard NGS and you have to get it separately on IHC. And for us, we send it out. We don't have that in house. So I think this is a common gap that we see is that it's something that's not regularly being checked. As far as the data for, in my experience with Tolisofi, it's, I haven't had very many patients, despite the 25 to 30% I'm always looking for it, but the data still is very encouraging. And you see patients with, I have meaningful responses who've already gone through I/O and Platinum Dublin. This is an ADC toxicity profile, mostly with peripheral neuropathy and macular events, but it's manageable, but it does require proactive monitoring. So I've started routinely checking baseline visual but acuity, which I shouldn't say I'm checking it, sending them to a lot of the models. At the baseline and also at their first hint of a complaint, too. But for the right patient, like IHC, 3 plus Hscore, over 150, non-scway mis, post-IO, this is a real option for patients. Can I just add a few things here? This approval of Tolisofi is based off face-to-study. So we definitely need more mature data here. Also on it. And in CCN, telosovie is listed for that HGF receptor, which is hepatocyte growth factor, which is indeed our C-MET overexpression. And this approval is for non-EGFR mutated C-MET overexpression, because, Chris, you also mentioned, we also have that as a resistant mechanism to EGFR disease, where at times we can lean into M-Eventa-Map, because you have that bi-specific antibody of EGFR and MAP. You know answers to keep in mind when we're leaning into telosovie. Lastly, Christine, you were just talking about this, dosataxyl and ramissarumap story. The benefit from ramissarumap is very small at its best. In your practice, who gets ramissarumap versus dosataxyl alone? I think it's really tough to get it approved. I mean, the revel data holds up, but to your point, it's a very small benefit that you get with the ramissarumap. So I find more and more that insurance companies won't allow the ramissarumap portion. So many and more of my patients are on dosataxyl and, you know, other reasons for holding off on a V-JF, like patients who have uncontrolled hypertension, blood clots. I think that's a real consideration, but unfortunately, I feel like some of this has been dictated by insurance, too. Right. I'll have to add to that benefit. What we are looking at is roughly about four weeks, and that has been my practice where I will be relying on single agent dosataxyl. And if it's that very particular fit patient where we can talk about additional of that tying in the side effect profile, I'll add ramissarumap. Well, we've covered quite a bit here, Christine. Thank you so much for walking us through where we stand today from treatment standpoint of lung cancer without actionable mutation in frontline settings. Or listeners, let us go over a quick recap from today's discussion. In today's episode with Dr. Christine Garcia, we walk through the treatment algorithm for metastatic non-small cell lung cancer without actionable driver mutations in frontline settings. A front biomarker testing and broad NGS panel has been now the standard of care here for several years. PDL1 and histology still dictates first line chemo plus IO for PDL1 negative or intermediate disease, whereas single immune checkpoint inhibitor or dual checkpoint inhibitor for that high PDL1 positive disease is a viable option. Lastly, we touched on the role of SDK 11 and keep on in deciding who gets dual checkpoint inhibitors. Rohe, your key takeaways? Rohe, we have to remember that treatment here is with palliative intent. As a result from the get go, we have to keep in mind what if the disease was to progress? With on progression, if Keras G12C mutation is present, we have the choice of a dagrosyb or Cetorysyb. For Cmit over expression, we have Tlisovv based off of accelerated approval from luminosity trial. And then dosey taxa plus minus remusirumab if we do not have any underlying mutation present. Thanks for tuning in. Make sure to check out our other treatment algorithm episodes. See you at annual ask. Go soon. We are the oncology brothers.