How to Treat Metastatic Non-Small Cell Lung Cancer w/o Targeted Mut in Front-line - Dr. Preeshagul

Intro Hello again and welcome back to the Oncology Brothers Podcast. I'm Rahul Ghasain, and I'm here with my brother and Co host, Rohit Ghasain. We hope you're ready for an exciting discussion. Today we're diving back into non small cell lung cancer, but this time our focus is metastatic non small cell lung cancer with no actionable mutations in first line settings. To cover this, we're joined by none other than Doctor Isabel Prichogal from Memorial Sloan Kettering Cancer Center. Isabel, welcome. Speaker 2 Thank you both so much for having me. It's an honor to be on this world renowned podcast that I turn into to learn myself and stay up to date. So thank you both for having me. Speaker 3 Today that's very kind of usable. Thanks for joining us. To kick things off, imagine you're at a community oncology center and you have a patient in front of you with newly diagnosed metastatic non small cell lung cancer. First step in treating metastatic non-small cell lung cancer with no actionable mutations NGS testing on tissue and liquid was done. Unfortunately, no actionable mutations were found in frontline settings. What is your first move from the treatment options standpoint and how does PDL 1 impacts your decision making here? Speaker 2 Sure. So I think first of all, probably the most common patient that we see, right, We know that patients have driver alterations and we always need to make sure that we obtain next generation sequencing regardless of Histology. But the first thing that I look into is what is their PDL one status, meaning what is the percent expression of PDL one on their tissue? And this can be done at your institution, some via IC, some via other panels. So we need to sort of stratify these patients, 1st 50% or greater. And if it's 50% or greater, they go into sort of the high PDL 1 expressors cohort and I can talk about that. Or you look into patients with PDL one 1% to 49 percent or no expression of PDL 1. And it can get very, you know, talking about tumor heterogeneity and, and biopsy technique. But I think really we need to just sort of determine PDL 1 positive versus PDL one negative. In addition to that, it's really important to look at tissue Histology. Are we looking at somebody with adenocarcinoma? Are we looking at someone with squamous cell Histology? Because the treatment algorithms and the options available differ based on your Histology. So let's start with the, I guess the easiest one, right? So let's say someone has a high PDL one, it's greater than 50% expression. You have the most common, the most common option that we have here is based on Keynote 024, which looked at patients that had, you know, high PDL one expression greater than 50%. They enjoyed a benefit with single agent pembrolizumab over standard of care chemotherapy. So if you're seeing a patient in your clinic that has a high PDL 1 / 50%, enbrelizumab might be a great option for them. However, I would like to make sure that you make sure that your patient does not have any underlying rheumatologic issue, whether that be lupus, glaroderma, rheumatoid arthritis, any inflammatory bowel disease, ulcerative colitis, you know, some other kind of rheumatologic issue. You know, dyscoid lupus, also psoriatic arthritis. Because immunotherapy in patients that harbor these underlying rheumatologic issues can really exacerbate these issues and it can become life threatening. So it's always important to take a very thorough history before you subject your patient to any immunotherapy. But if you have somebody that has no underlying autoimmune issues, a high PDL 1 stage 4 non small cell lung cancer, frontline treatment with pembrolizumab based on Keynote 024 is a very fine option. I do say that it's important to scan the patient after two cycles. So that would be six weeks of therapy, one dose every three weeks. And the reason for that is because you wanted time to take a peek and make sure that this is working right. You don't want to just treat them and send them out to pasture. You really want to make sure that what you're giving them is, you know, is the bang worth the buck. So you want to make sure that, number one, I always say this scan is not to make sure you're having a miraculous response, but to make sure that, one, there aren't any new spots, right? And two, that the spots that we see have not gotten bigger. If we see a response after six weeks or two cycles, that's a huge win. But I just want to make sure this is not progressing. So I always tell my patients that. And if that scan looks good, then we can kind of plan for your next scan per NCCN guidelines, which would be in about 3 months time. Speaker 1 And a few things to reiterate, you brought up underlying autoimmune disorders. I just want to make sure that is not a complete true contraindication. A well controlled autoimmune disorder is something that again, having that patient centered discussion, of course this is very different if they have a transplant, liver transplant, heart transplant, Those are times when you are taking a pause and saying I cannot use immunotherapy. Isabel, in this particular scenario, we're all getting very comfortable using single agent immunotherapy. Combining immunotherapy with chemotherapy If there's high tumor burden. Are you combining immunotherapy with chemotherapy in even with high PDL 1 score for looking for a quick response or you feel comfortable because you are in this scenario looking for a repeat scan in six weeks? Speaker 2 Thank you for that question. You led me right into my next thought. So you have someone that has a high disease burden. Sometimes you think you need to pack a little more punch than immunotherapy alone. And in this case, I tend to have sort of a risk versus benefit discussion with my patients, patients that are really symptomatic, really feeling rousy, otherwise fit and I think that they could tolerate concurrent chemotherapy and immunotherapy. We talked about this. So there's a couple different options in this space. You could go with the Keynote 189 regimen, which is carboplatin, pemotrexid and pembrolizumab. Or you could go with the Keynote four O 7 regimen if you have squamous cell Histology, which is carboplatin, Abraxane or Taxol plus pembrolizumab. Or you could go with what we affectionately known as the quad, which is carboplatin, paclitaxel, bevacizumab and atezolizumab. And, and there's other options and other ways to, you know, there's also carboplatin, paclitaxel, Negro it be as well, which we can get into. But that wouldn't be my first choice here. I would say if you have someone with a large disease burden, my first choices would be if it's adenocarcinoma, it will be carboplatin, amitrexit, pembrolizumab. Based on Keynote 189 and if they have squamous cell Histology, it would be carboplatin, paclitaxel or Abraxane plus pembrolizumab. If you really have someone with maybe poorly differentiated carcinoma, which we do see sometimes sarcomatoid, you know, very angry features, sometimes these patients benefit from the addition of bevacizumab. So sometimes these patients, we talk about the EMPOWER 150 regimen, which is carboplatin, paclitaxel, bevacizumab and atezalazumab. It is by no means a free lunch. All of these have toxicities which I'm sure we will get into, but you know, big disease burden. Sometimes we give them a little bit of a punch with the chemo and the immunotherapy upfront and then we can always, you know, curtail it a little bit back based on that response after six weeks. Speaker 3 Thanks for covering that. Covering that, Isabel. In Community, we are very comfortable utilizing single agent immunotherapy. What is the ideal patient for nivolumab plus ibulumab? With chemotherapy particularly the confusion comes in when we have these dual checkpoint inhibitors, AP Nebo or Derba tremie and now you combine that with with or without chemo. So what is your ideal patient when you are pulling off these tools, dual checkpoint inhibitors and even on top of that adding that with chemotherapy here? Speaker 2 So you know, when you're adding novolumab plus ibulumumab to chemotherapy, you are adding as you had said more toxicity. And there we, I don't think in full transparency, we know the perfect patient, you know, that would enjoy a response from this. But if you're looking back at the data and the subset analysis, it does seem that patients, you know, perhaps regardless of their PDL 1 exposure, but maybe patients that have a higher tumor mutation burden may benefit from the addition of nivolumab plus icalumumab to their regimen. And what do I mean by a high tumor mutation burden? So we look at, you know, when you're looking at someone's next generation sequencing report, you need to have the next generation sequencing report to understand what someone's tumor mutation burden is. It's a calculated score that is based on MB MEGA base pairs. So if you have 10 MEGA base pairs or higher that are mutated, that is considered a high tumor mutation burden. So let's say you have someone with a high disease burden, right, a tumor mutation burden of 26 APDL, one of 1%, maybe Carbotaxol, NEVO, if they might be a good regimen for that. But I can't say that I would choose that per SE over carboplatin, pemetraxate pembrolizumab or carboplatin packet Taxol or Braxane pembrolizumab. It's just yet another option. And if you want to get into the weeds about things, if you have ATMB, that may be an option for you. Speaker 1 Isabel, can I push a little further on this topic because again, this whole dual checkpoint with chemotherapy seems so elusive with higher toxicities, but now you have NGS, you have higher TMB, the PDL 1 score is low, SDK 11, keep one TP 53. Dual checkpoint chemotherapy Are you using some of that information as well to lean towards this dual checkpoint in a better combination? Speaker 2 So in some cases we know. So let's backtrack a little bit. We know that patients have that have these Co mutations STK 11 and keep one are bad players, right. We know these patients typically don't enjoy a response to immunotherapy and sometimes we see them, you know, in combination with K Ras alterations and some of the K Ras alteration, unfortunately at this time still gets treated with chemotherapy and immunotherapy upfront or immunotherapy only upfront. There is no targeted therapy in the frontline setting for patients with AK Ras G12C alteration or K Ras alphabet soup, whatever it may be afterwards. So I think sometimes I use this as a way to to kind of guide how I expect patients, how I set expectations about how I think patients will respond to treatment. And I may say, you know, in addition to, you know in addition to your KRS alteration or on your next generation sequencing report, we didn't notice anything actionable. However, I did note that you have two commutations keep one in STK 11. And unfortunately we know patients that harbor these alterations tend to have a worse prognosis and tend to not enjoy as much of a response to treatment. So sometimes for these patients, I think we need to give them a little more upfront then then less, but it needs to be a case by case discussion. You have someone that's older, you have someone that's frail, you have someone lots of medical comorbidities, you know, throwing everything but the kitchen sink at them may not be the best thing for them. And you never know. Sometimes these patients that get combination therapy with female therapy and immunotherapy, you never really know, which is really driving the response here sometimes, right? So I think it's it's a risk versus benefit discussion with each patient. Speaker 1 Now the same patient, unfortunately the disease was to progress in second line as if now we have Kira's G12C is about, you've alluded to this already. EGFR Exxon 20 The other targeted option is EGFR Exxon 20 likely to move in frontline settings. And then you have Part 2 mutation starting with Kira's G12C story. Here is about your thoughts. This is finally a targeted mutation, but by no means this has been a home run when we're comparing it to Dosataxel. Speaker 2 Yeah, correct. And I do want to just backpedal a little bit that anytime you have a patient in your clinic regardless of the stage of their disease, you need to think about clinical trials in the oppressed setting, right. So we are, we are talking about a patient that is not eligible for a clinical trial. Sure. So I think if you have a patient with AK Res G12C alteration that's progressed on frontline treatment, I first want to know, are they having oligo progression, meaning progression in one site while everything else is quiet or are they having progression diffusely, right? So if it's oligo progression, then my gut is always to offer local therapy options, whether that be radiation, whether that be IO ablation, cryo ablation or even a reception, if that's possible. So if that's possible, that's the road that I go and I continue the same line. Frontline therapy. However, if it's diffuse progression and you don't want to go play whack a mole, then you need to think about what other systemic therapy options we have. So there's two FDA approved agents for patients with K res G12C alterations that have progressed on frontline therapy and one is sodorasive and one is adagrasive. Both of these are pills that target your cancer cells that have the K res G12C alteration. So between these two, I think if you really go through with a fine tooth comb, there is some finite data that patients that have CNS metastases may benefit slightly more from adagrasive. Though someone that has brain metastases or progressive brain metastases, I might consider leaning more towards adagrasive. But if there are no brain metastases, I think it's really just what can you get for this patient? I don't think there's never been a head to head trial and I don't think there's ever going to be. You need to look into it insurance authorization and also thinking about, you know, patients and dosing Sotorasib is quite a lot of pills that you need to take per day as opposed to add aggressive. So maybe you have someone that's not as compliant that that has, you know, a very high pill burden at aggressive might be a better option for you. But if you have somebody that has, you know, maybe maybe their insurance doesn't approve at aggressive or maybe they are really, they had a family member that was on sotorasib and they really want that. I I don't see I don't have any problem between the two and I would not switch from one to the other. If someone progresses on sotorasib, I wouldn't then give them adagrasib and vice versa. Speaker 3 Isabel, thank you so much for touching on that. Agreed. This certainly provides our patient with an oral option, but again, we've not seen dramatic overall survival benefit here. Another actionable mutation is e.g. Actionable mutations F RX120AS Rahul mentioned, currently we have an event map here, but based off of the Papillon study where amivantamab with chemotherapy in frontline setting is showing better outcomes. This is likely to be moving in our first line settings. And then her two mutation where we have TDXD approved. TDXD recently got bucket approval for all solid tumors with R2 IHC 3 plus in refractory settings. Isabel, your experience here and are you likely going to be using this upfront or save it rather for second line space? Speaker 2 So we can talk about e.g. FRX on 20 insertion alterations first. So initially, these patients did not have a targeted therapy in the frontline setting. They had to receive chemotherapy and edantemab and robocertinib. And edantemab is an infusion therapy and robocertinib is an e.g. FRX on 20 alteration targeted therapy pill. Both of them were only approved in the second line setting. And now mobocertinib is coming off market and edantemab is the only option now. But in order to, you know, now we are have amivantamab plus chemo that's getting moved out to the frontline setting. So my experience with this in full transparency is that it amivantamab is tough in itself. You have the risk of the infusion reaction that typically happens on day one, which is why we split the first dose into day one and day 2. And it can be very scary for the patients. And despite giving them Singulair, you know, three days leading up to prevent this infusion reaction, it can still be quite frightening. And typically if patients have grade 3 or grade 4 infusion reactions to amivantamab, we don't reach challenge them with it. And then we're kind of stuck with looking at, well, what's the next best thing for them. So I would say, I think it's I think amivantamab plus chemotherapy is reasonable to try with a very clear expectation that if they can't tolerate it, I would pull back the chemo and save that for a later line and just proceed with single agent amivantomab. Speaker 3 So we are hoping that this paradigm would change with subcutaneous formulation being available. But again, some of those side effects are still real, but mainly infusion related reactions are rather being minimized with that. Speaker 1 Can I actually jump on that bandwagon for a second? I think that we all need to start to get used to a little more about Amivantab and be more cognizant about the side effects because we'll see this in more common EGFR space. So these side effects are real and it's not easy. We're not even touching on the idea of increased risk of VTE that we saw with other studies with Mariposa and Mariposa too. So these side effects for our patients are still very real and in the community. We need to be cognizant and we need to get used to these side effects and set the right expectations for our patients. Speaker 2 Absolutely. I often just tell my patients right off the bat, you're most likely going to have a reaction on day one. It's going to feel like XY and Z. This is what's going to happen. And if it becomes this severe, we won't give it to you anymore. And if it's this severe or less, we will consider re challenging on day 2. But you have to set the stage. Speaker 1 Thank you for touching on that. Coming back to the idea of her two mutation, right now this is approved in second line is about if you see a patient with her two mutation. TDXD in second line for patients with HER2 mutation This is a very small subset of our non small cell lung cancer patients. Would you rather use TDXD upfront? Are you still using it in second line after chemo immunotherapy? What's your current practice? Speaker 2 So we happen to have a trial looking at TDXD in the front line setting. So I, I, I had tended to really push for that for our patients. There are other studies looking at other targeted therapies in this space that may or may not be better than TDXD, We don't know yet. But I tend to favor if you have a target and you have a drug that you're able to offer that can address this target, I I would push for that first. Speaker 1 Whenever we're talking about TDXD, we have to acknowledge some of the side effects around this agent as well, fatigue, nausea, alopecia, but it's ILD that's associated with mortality and in patients with lung cancer that potentially have compromised lung function or might have been exposed to radiation or immunotherapy is about, is the incidence a lot higher for ILD in these patients? Speaker 2 So fortunately I have not seen it, but I think that's just because I've been, you know, sub cognizant of it and so aware of it that I'm and counseling my patients about it. But I think, I think in regards to TDXD toxicity, the one that I'm seeing more frequently than ILD is actually nausea. And I think it's under treated and under prevented. These patients I feel like should be, you know, TDXD really should be up there with like grade 5 anti metagenic, like same with cisplatin and carboplatin. It is rough. I often give these patients dexamethasone on days two and three following each infusion. And some patients I've even had to have olanzapine 5 milligrams or 2.5 milligrams at night to help just right around each cycle. So the nausea is something that I really want to emphasize that you know, it's under treated and a big problem. In addition to that, the cardiac toxicity, you want to make sure you get a baseline echo in an echo every three months for these patients to make sure that you don't have any changes in your ejection fraction. And in regards to the ILD, it can happen. I can't say that giving a patient immunotherapy or chemotherapy and immunotherapy before getting a TDXD is going to potentiate your risk of it. But same with radiation. I don't think we have that data, but I am very, I'm very forthcoming with my patients saying that ILD is a risk. This can happen and you are in a way getting agents whether it be radiation or immunotherapy that could set you up or you developing. Speaker 3 This and again important to stress the importance of these side effects because again it impacts the quality of life and especially when talking about ILD which has been related to mortality here Isabel. Now this particular patient has progressed where the disease now in second line settings we if we have a targetable mutation, we utilize that. Second-Line Therapy for KRAS Mutations What are you utilizing after that? And if they do not have targetable mutation, again, what is your second or third line? We have Dositaxel with or without Remuceramab, but again, not the most robust option either. Speaker 2 Correct. So obviously you know what I'm going to say, I'm going to say look into a clinical trial for patients with KRS alterations with learning that just targeting the KRS on the surface is not really enough. We need to look into, you know, combination therapy, right? Do we need to hit RAF, do we need to hit MEC, Do we need to hit or do we need to hit all of these downstream pathways to prevent resistance because resistance is what we're worried about. So I would always look into a clinical trial for those patients with K res alterations, patients that progress on TDXD. There is some data that you can try TDM one or Adotras tuzumab for these patients on a clinical trial and that is something that I've done before. And there are other her two altered clinical trials that are available. But let's say these patients are not eligible for clinical trials and we're looking at standard of care options. So yeah, we are looking at dose of Taxol plus or minus ramoserumab or gemcitabine plus or minus Venerel beam, in which case you need to make sure you have a metaport because venerel beam is a vesicant and you want, you don't want that to cause any issues with extravasation. Speaker 1 And talking about clinical trials, this is going back ASCO 2022, there was a phase two study looking at ramiserumab with combination of pembrolizumab at the time of progressive disease, even once they've been exposed to pembrolizumab. Do you re challenge your patients with immunotherapy after progression? There's ongoing phase three study for this. But in your practice is about outside clinical trials, do you re challenge your patients with immunotherapy again if they've actually progressed on immunotherapy? Speaker 2 Upfront. So I think it depends. That's a very loaded question. So let me give you a patient scenario. Let's say you have someone that was treated with upfront carboplatin pametrexit, pembrolizumab, received 4 cycles of three drugs and then progressed on single agent immunotherapy maybe 6 or 12 months after their carboplatin Pametrexit exposure. At that point I might consider re challenging adding the chemotherapy back to the immunotherapy and then getting a short interval scan and if they have a response then obviously dropping the chemotherapy portion and keeping going on the immunotherapy to kind of re agitate the tumor again maybe. Speaker 1 Yeah, because the argument that we're making here is there is ongoing synergy between all these three agents. Speaker 2 Right. And I would look into clinical trials for these patients. I know I'm a broken record with that. But there's, you know, there's cancer vaccines that are out there that there's lots of exciting stuff in the IO space. There's tumor infiltrating lymphocytes, there's a lot of stuff. So you know, just 'cause you progress on immunotherapy does not mean that there aren't other options in the IO space. Speaker 1 Absolutely. It's about we've covered a lot here in such a short time. Thank you so much for joining us and sharing your insights for our listeners. Stay with us for a quick recap for today's discussion. Speaker 2 Thank you. Speaker 3 Today with Doctor Prishable we have covered the latest in metastatic non small cell lung cancer treatment without actionable mutations in frontline settings. Key take away include the importance of comprehensive testing, the strategies for using immunotherapy and chemotherapy combinations and emerging second line treatment options. We've. Speaker 1 Also discussed the impact of new data on clinical practice, particularly with agents targeting KR SG12C, her two mutation with TDXD and the anticipation around combination of ramiserumab with pembrolizumab. Thanks for tuning in. Make sure to check out our other discussions in this lung cancer series. We are the oncology brothers.