How to Treat Metastatic Non-Small Cell Lung Cancer (NSCLC) Without Targeted Mutations

Intro Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Ghossein and I'm here with my Co host and brother, Rohit Ghossein. We're here to keep our community oncologist up to date as we continue to strive to provide the best care close to home. Today with our treatment algorithm series, we're diving into metastatic non small cell lung cancer where we do not have any actionable mutation upfront in frontline settings. For this, we're thrilled to have a world renowned thoracic medical oncologist, Doctor Mark Awad from the Memorial Sloan Kettering. Mark, thank you so much for joining us. Speaker 2 Thank you so much for having me. Thanks for all the work you're doing. Speaker 3 Welcome, Mark. Over the next few minutes we are hoping to touch on the current treatment landscape for metastatic non small cell lung cancer with no actionable mutations in frontline settings. Following that we will touch a little on KRAS G12C and her two disease in second line settings. Any of this discussion does not negate the importance of NGS testing. This discussion is valid once we have ruled out that there are no targetable mutations on liquid and solid tissue NGS. And here our treatment options are chemotherapy with IO, single agent IO or dual checkpoint inhibitors. If there is true contraindication to immunotherapy, then chemotherapy alone should be considered. Mark, can you start us off here? Treatment Algorithm for Metastatic Non-Small Cell Lung Cancer with No Actionable Mutation How do you make your treatment decision in frontline settings and what data do we have to support this? Speaker 2 I think as you said, the list of actionable mutations is growing year after year. So it isn't very important that we have broad and comprehensive next generation sequencing covering a growing number of actionable genomic alterations in lung cancer. Liquid biopsy has been revolutionary at providing rapid diagnostic testing, but it's important to know that many cancers do not release enough DNA into the circulation be negative. Liquid biopsy test does not necessarily mean there are no targetable mutations that we really should make sure we have a good tissue sample for tissue based NGS. Many genomic alterations now for which we have targeted therapies approved in the first line setting. For others, we don't yet have first line approvals, but there is ongoing clinical trials incorporating these targeted therapies which are approved in later lines. As some of which you have here are TRSG 12C inhibitors are approved in second line setting, are her two AD CS approved in the second line setting. There are ongoing trials incorporating these into the first line, but for now there are still a large fraction of lung cancers for which there are no known actionable alterations in the frontline setting. This is a huge population given that almost 50% of patients diagnosed with lung cancer now have advanced or metastatic disease at initial diagnosis. So this is a large problem, large population as you have here. There are a large number of options for our patients and we do think about our treatment decisions based on the PDL 1 tumor proportion score. For most lung cancer trials, we're talking about the TPS rather than immune cell sustaining of PDL one or the combined proportion score. So for the TPS, we for practical purposes divided into these three buckets or categories, PDL one negative, this low positive group which is 1 to 49% tumor portion score and then the high group of 50% or above. It is important to know that you know PDL 1 staining is on this continuous scale from zero to 100%. And we do know that even among that 50% or greater group, the higher the PDL one level, the better patients do with immune checkpoint inhibition, especially as the PDL one level gets above 90%. Many patients can do very well with PD1 monotherapy. The caveat to that statement is that is not necessarily true in certain molecular subsets of lung cancer like EGFR, Al Ross One, and others. They might still have high PDL one expression. But we know by and large, in general those molecular subsets of lung cancer do not respond to immunotherapy. Sometimes if you're still waiting genomic information to come back might feel like you can't hold off on starting systemic therapy. We may use the first cycle of just chemotherapy alone until genomic information comes back. Then if they have a target, we might switch to targeted therapy. If they don't have a target, we may add immunotherapy once we have all the genomic information back. If we have all the information back in the PDL one score, we have a lot of options. So how do we choose? In many cases, we don't have randomized perspective phase three clinical data to guide these decisions. But in general, if a patient has a very high PDL one level good performance status and and you feel like you have the ability to try a single agent PD1 inhibitor to see if by the 1st scan they'll respond as a very good option for patients to use PD1 alone for the PDL one score 50% or above that spares patients from added toxicities that may come with platinum doublet, chemotherapy or other immune checkpoints. CTA 4 inhibitor toxicity. We know that there was the randomized clinical trial of PD1 plus or minus CTLA 4. In this high PDL one group of 50% or above, there was no survival benefit and there were added toxicities. So for the high PDL 1 expressors, we tend not to use dual immunotherapy in most circumstances. Now, if somebody has a high PDL one level 50% or above, but if you have certain worries or concerns that if they progress on first line PD1 alone to a point where they might not be well enough to try second line therapy. There are certain circumstances where despite a high PD one level, you may choose to use chemo plus immunotherapy. For example, if they have a large burden of disease or the central nervous system, it has to seize where we have some evidence for immunotherapy being effective, but you may want to combine with chemotherapy. Some of our systemic chemotherapies do have some CNS activity like Pametrexit for example. There are certain circumstances where you would want to discuss using chemotherapy plus immunotherapy in the very high PO1 expressing groups in the one to 49% category as you have here. We have an approval for single agent immunotherapy for example, based on the keynote O42 study which was pembrolizumab versus chemotherapy where in the population of PDL one 1% or above there was an overall survival benefit with pembrolizumab over chemotherapy. We think that OS benefit was driven or pulled up by the high PDL 1 expressors. There are some data that have come come out of pooled analysis from the FDA suggesting that chemo and immunotherapy is better than immunotherapy alone in this one to 49% population. So in the lung cancers with APDL 1 less than 50% including the negatives, we do tend to use chemotherapy plus immunotherapy and that's based on a number of clinical trials such as Keynote 189 for non squamous lung cancer, Keynote four O 7 for squamous lung cancer and and many other clinical trials as well. I think the big question for our community and the topic of a lot of debate is about dual immunotherapy, namely where do you use CTLA 4. If you ask a group of oncologists, you'll hear many different opinions on this. It speaks to the unmet need where we would love to have a randomized controlled clinical trial looking at chemotherapy plus PD1 alone versus chemotherapy plus PD1 and CTLA 4. As of today, we don't have that a trial to draw experience from. The challenge is doing these cross trial comparisons and looking at chemo plus ibenevo or chemo plus sturvalumab and tribulumumab and to try to infer based on tails of curves that one regimen is superior than the other. Or looking at specific molecular subsets in a retrospective fashion to infer whether there are some forms of lung cancer that may benefit from dual immune checkpoint inhibition. There are some people that feel differently about the data strongly one way or the other. And I think we really need these kind of gold standard trials to help guide our treatment decisions. There are some retrospective data, for example, looking at patients with lung cancer and keep one mutations or STK 11 mutations. We know that those mutations in general and especially for KRS lung cancers confer worse outcomes, too many therapies including immunotherapy. There are some preclinical and small subgroup analysis from clinical trials suggesting that there may be more benefit to C2A4 based combination regimens compared to PD one alone. But I think really we we don't have that perspective data to know that for sure. Specifically in those molecular subtypes of lung cancer, there have been some pieces of data looking at various subgroups, for example, squamous lung cancer or PD one negative lung cancers where you know, looking at across these trials that tails of the curve seem to suggest that dual immunotherapy or CTA4PD1 may, you know, if you follow the these trials out long enough that the tail of the curve may be higher than PD 1 based immunotherapy alone. Again, the the challenge is that these trials have been done in different times in different regions of the world and we don't really understand who is comprising the tail of these curves. So it's a big challenge in a field that we could really benefit from perspective data to answer these questions more definitively. Speaker 1 Wow. Different Immunotherapies for Lung Cancer There's a lot to unpack here, Mark. We have a few different immunotherapies that are available, doesn't matter for us out in the community, doesn't matter which immunotherapy we pick from, be it simplimab, pembrolizumab or other options that are available. Speaker 2 Yeah. For many of our cancer types, not just lung cancer, we haven't had trials comparing one to the other. So we're drawing from various clinical trials to understand. It's always been a curiosity why embrylizumab established more of a foothold in the first line setting for lung cancer than nivolumab. Somebody early first line of olimab trials were not as successful for various reasons leading to questions about differences between the PD1 therapies, difference between PD1 and PDL 1 inhibitors. We don't necessarily think there are strong differences between these therapies and there are multiple regimens approved for the same indication. For example, enbrelizumab or simiblamib or otezilizumab for the PD1 high lung cancers. I think any of those is a reasonable option. I think there are number of forces at play. But biologically, medically, we don't necessarily think there are striking differences in efficacy between the various PD1 and PDL 1 inhibitor. Speaker 3 Tagging along with the same theme of the comparison here we have dual checkpoint inhibitors, we have Neevo API and Durva Tremi. Dual checkpoint inhibitors Are these just me too? There is no real difference. And also going back to your point about high risk mutation that is STK 11 keep one, do you tend to rely here in this particular population on dual checkpoint inhibitors? Speaker 2 Yeah, we definitely know that the addition of CTLA 4 to PD1 adds immune related adverse event risk and and toxicity in our patients with metastatic lung cancer. We want to achieve the dual goals of extending life and also maintaining and preserving high quality of life. And so we don't want patients to be suffering with things like colitis or pneumonitis or other toxicities or arthritis, aches and pains that can limit quality of life. I think it's a discussion and it's a good question and one where there is no clear answer. To your first point about ipilimab and nivolumab versus trimilimab and durvalumab don't have a lot of comparative data to know which regimen may or may not be better than the other. We have the Poseidon regimen of Durva tremi chemo versus chemo alone and that did better than chemotherapy in terms of overall survival. Although interestingly on that trial, the chemo Durva arm did not seem to perform that well compared to chemotherapy versus regimens like Checkmate 9 LA which is chemo plus epinevo versus chemo alone. There may be some other factors to consider between the Poseidon and the Checkmate 9 LA regimens. Checkmate 9 LA is chemotherapy plus Ippinevo, but the chemotherapy is limited to two cycles that stops versus the Poseidon regimen of chemotherapy plus Durva Tremi did did not limit the chemotherapy to those two cycles and was more traditional with extending the chemotherapy to the four cycles and considering maintenance therapy chemotherapy as well in the non squamous cancers. And so that may come into consideration when choosing between those two approved dual immunotherapy regimens in terms of how much chemotherapy is part of the regimen and whether the patient needs and to tolerate more than two cycles of chemotherapy. So I think the those are more of the consideration as to choosing between 9:00 LA and and Poseidon. Oncologists fall into different camps here depending on the patient's performance status and other features. There are some patients with high burden of disease and or some potentially worrisome molecular features commutations where some people might say there are certain aspects of this patient's cancer that I'm concerned about. I might try to throw the book at the cancer with many therapies at once with platinum, double chemotherapy and dual immune checkpoint inhibitors. And I think that's reasonable in the right setting if you have a patient who has a good performance status. There are other examples where you might say in the absence of data showing the specific benefit of CTLA 4 in a perspective fashion, I want to offer the best therapy to my patients but also minimize toxicity and side effects. I'll give chemo plus PD1 alone. I think looking at the usage and trends of regimens are used in the US and globally at most oncologists, most patients are receiving regimens that do not contain the CTA 4 therapy. I think it just speaks to the importance of biomarker discovery and development in this space. We've had CTA 4 approved for many years in lung cancer and other tumor types, but we just don't know the right patient population that benefits from CTA 4 today. Speaker 1 Absolutely. When we're talking about all this, this is with palliative intent. So there has to be this fine balance of how much time we're buying for our patients with the side effects that come along. All right, for the last few minutes, let's switch gears to our second line treatment. Second-Line Treatment Options The disease was to progress options here are more chemotherapy or if you have K res G12C then K res G12C inhibitors and anti her two therapy. Mark, you alluded to some of these options. Can you walk us through your treatment options in second line and beyond here? Speaker 2 In general, a patient has a targetable alteration, we'll want to use targeted therapy if we don't have a specific clinical trial to consider. With regards to QSG 12 C, we'd have the two options currently approved with aggressive and soda acid. 1 consideration is what the last line of therapy was. Much of the time it's an immunotherapy containing regimen. There have been concerns about the interaction between PD1 therapy and Sodor acid, especially when combined together, and those trials have not been able to move forward due to high rates of high grade hepatotoxicity and by extension because immune checkpoint inhibitors have a long half life. When transitioning from immunotherapy to sotorasib or AD aggressive, there seems to be more concern about hepatotoxicity to sotorasib coming right on the heels of prior immunotherapy. AD aggressive could be a good consideration in that context. Speaker 1 Well, Adagrasib ends up being my go to KRSG 12C inhibitor as well, just given the data that we've covered. Speaker 2 In cases where there isn't targetable alteration, we are using dosataxel with or without ramiseramab. There are different opinions and camps here. We know that remiseramab statistically speaking did improve overall survival, but that improving in median OS. In the rebel study done in the pre immunotherapy era, it was a matter of weeks. There are added financial costs and toxicities as well as clinical side effects that come with VEGF inhibition. It's a discussion and a lot of health systems and pathways have made a decision about whether to recommend dosatexil monotherapy or dosatexil plus ramiserumab. And so I think that's that's part of discussion within, you know, a clinic or healthcare system and also with a patient. Many of our systems and guidelines do not necessarily recommend the addition of framisir metadositaxel this. Speaker 3 Is a dire unmet need and the clinical trials are very important in every aspect, but here they're very, very important with regards to NGS testing. I've tried doing that on progression, but I have not had much luck finding new mutations in the second line on progression with TDXD. We've covered in our prior episode of tox check for antibody drug conjugates some of the important side effects of nausea, fatigue, alopecia and importantly ILD because there's mortality associated with it. Mark, about KRAS G12C inhibitors, we have the option as you stated, sotorasib and edagrasib. Any important side effects and clinical problems to keep in mind with those two drugs? Speaker 2 Like with all small molecules, there can be risk of hepatitis, risk of pneumonitis. Be mindful of moving from immunotherapy to other small molecules. Adagrasive has a little bit more prospectively collected data on CNS efficacy. I think if a patient has progressive brain Mets, there's a little bit more data supporting the use of Adagrasive there. As you mentioned with the trustees, we have drugs to can, we need to be very mindful of the pneumonitis or ILD risks when patients progress on any of these second line therapies that we typically move from single agent chemotherapies such as gemcitabine, venerelpine or others. So it's definitely need improved options for our patients. Speaker 1 Mark, we've covered a lot here in this short time. Outro Thank you so much for walking us through your treatment algorithm for metastatic non small cell lung cancer with no actionable mutation in frontline. For our listeners, let us go over a quick recap. Speaker 3 In today's discussion, we had a chance to focus on metastatic non small cell lung cancer with no actionable mutations in frontline settings with Doctor Markoward from Memorial Sloan Kettering. Upfront NGS testing and PDL 1 levels are key indicating how we select our frontline treatment option. With no actionable mutation and high PDL one single agent immunotherapy is the preferred approach in most patients for low or intermediate. PDL one score chemotherapy with immunotherapy or rather dual checkpoint inhibitors for selected patient is a way to. Speaker 1 Go. Even though we've titled this discussion as no actionable mutation in frontline settings, we still need to keep TRS G12C, her 2 positive disease, on our radar as these are actionable mutations, but the current approval is in second line settings. Speaker 3 Yes, absolutely. That is where NGS is still extremely important. Speaker 1 Yes, during this discussion we touched on atagrasib, which ends up being my preferred as G12C inhibitor and then Trustez Map Dirks decant for her two mutated disease. If none of these mutations are available, then relying on chemotherapy is the current standard of care. Thanks for joining us. Make sure to check out our other conference highlights treatment algorithms and recent FDA approval discussions. We also look forward to seeing you in person at ASCO. We are the oncology brothers.