Lung cancer treatment is evolving with smarter combination therapies  

Lauren Byers, M.D. Hi, I'm Dr. Lauren Byers, professor of Thoracic and Head Neck Medical Oncology at UT MD Anderson. I'm joined today by Dr. Ferdinandos Skoulidis, an associate professor in the department of Thoracic and Head and Neck Medical Oncology at UT MD Anderson. And this is the Cancerwise podcast. Dr. Skoulidis, thank you for being here today. 

Ferdinandos Skoulidis, M.D., Ph.D. Thank you for having me. There's a lot to talk about. 

Lauren Byers, M.D. Yeah, I think it's really exciting. In fact, I think I would actually say that it's a historical time right now, especially with some of the work that you're doing and the the advances that you and other colleagues are making are really changing what we can offer for patients. 

Ferdinandos Skoulidis, M.D., Ph.D. Absolutely. I think that this is an exciting and very consequential time in lung cancer research as a whole. Perhaps one area where this is most exemplified is in my favorite area of lung cancer research, which is aimed at targeting the KRAS oncogene. So, this is a very large population, subpopulation of patients with non-small cell lung cancer whose tumor is driven by mutations or faults in this particular gene, KRAS. We now have two FDA approved inhibitors for a specific mutant form of KRAS, called KRAS G12C, that is found in approximately 1-in-7 patients with non-squamous non-small cell lung cancer. But what we have seen over the past couple of years, and this is something that is particularly exciting, is an expansion in our ability to target both KRAS G12C more efficiently, but also importantly, expand our ability to target other forms of mutant KRAS, such as KRAS G12D, but also the entirety of KRAS through a new class of inhibitors called pan-RAS tri-complex inhibitors. This is perhaps, in my opinion, one of the biggest discoveries this year. We recently heard the positive topline results in pancreatic cancer, where for the first time, a direct pan-RAS inhibitor called daraxonrasib almost doubled the time that people were alive. Patients with advanced pancreatic cancer that had previously been treated with standard chemotherapy and their disease had progressed on chemotherapy when treated with this inhibitor, lived for an average of 13.2 months, compared to 6.7 months in the control arm. So, this is a historic achievement, a historic milestone in patients with pancreatic cancer. And I'm particularly excited because this drug is now being evaluated in the context of a Phase 3 clinical trial called the RAsolve 301 clinical trial. This is a trial that we've got open and running here at MD Anderson, as well as in multiple other places around the country and the world for patients with RAS mutant and non-small cell lung cancer. 

Lauren Byers, M.D. I think this is so exciting, and I can't really overemphasize how important these discoveries and breakthroughs have been. I remember when I was an early faculty member and it was, you know, really thought that KRAS would be undruggable and that it would not be something that, you know, there would be personalized treatment for. And so, this is a huge shift. And to see the activity that you and your research has shown for lung cancer patients, but also for pancreatic cancers, because that has definitely been a major challenge in terms of finding therapeutics that are personalized and beneficial for those patients. 

Ferdinandos Skoulidis, M.D., Ph.D. This was certainly the dogma drug that KRAS was indeed considered undruggable since its, you know, initial discovery and multiple efforts to target KRAS over the years, different approaches, had had failed. But perseverance pays off and innovation pays off, and this is why fundamental research in cancer is critical in order to improve outcomes for patients. We now have an expanding armamentarium and expanding a panoply, I would say, of novel RAS inhibitors with different mechanisms of action that are in different stages of clinical development. So, in addition to the first-generation inhibitors, which target the inactive state of KRAS, KRAS is a protein that toggles between two states. And it's really when it's locked in the active state or stays longer in the active state, that's when it causes cancer. So, we've got drugs that target both the inactive state of KRAS, but also now new classes of drugs that are able to importantly target KRAS, both in its inactive as well it's in active stage. And this is important because turning KRAS in its active state may be a mechanism through which cancer cells can eventually adapt or develop resistance to the first-generation KRAS inhibitors. So, this is particularly exciting. There are also novel drugs being developed continuously. I think a couple of weeks ago, we saw a major publication from the first drug that aims to degrade KRAS G12D rather than just inhibit it. So, this is another novel class of agents that holds promise for the future, trying to extinguish or degrade the protein rather than just inhibiting. And of course, there is tremendous enthusiasm about combining KRAS with other approaches to target tumor cells. 

Lauren Byers, M.D. Can you tell me, you know, a little bit about some of those combinations that you're studying currently and what you're excited about? 

Ferdinandos Skoulidis, M.D., Ph.D. I would be glad to. The backbone of first-line treatment for patients with advanced metastatic non-small cell lung cancer is a combination of chemotherapy. These are drugs that we have used for several decades as well as immune checkpoint inhibitors. So, these are drugs that aim to activate the immune system, the patient's immune system, to recognize and attack the tumor cells. So, in order for RAS inhibitors to make their biggest impact, they need to be combined effectively with immune checkpoint inhibitors. So, this is one area of active investigations where multiple novel RAS inhibitors are evaluated together with immune checkpoint inhibitors, PD1 or PD-L1 inhibitors, in patients who have previously been untreated. We have recently seen exciting data for multiple investigational RAS inhibitors in combination with immunotherapy. We have seen data from olomorasib, calderasib, adagrasib and at this year's ASCO annual meeting, I will be presenting novel data on the combination of divarasib with immune checkpoint blockade with pembrolizumab as part of the Krascendo-170 clinical trial. I'm particularly excited about this combination because previously, divarasib has proven to be one of the most effective investigational KRAS G12C inhibitors. So, so this will be important to evaluate. I think this has been one of the most consistent breakthroughs in lung cancer therapy is a continuously expanding array of targeted therapies for patients with different subsets of lung cancer. So, it's critical to recognize and this is something that we always discuss with patients when we see them in clinic, that lung cancer is not a singular disease. This disease is heterogeneous and there are multiple molecular subtypes of lung cancer. And what makes these subtypes different is different cancer-causing mutations. The way that I describe the mutation to my patients is in the same way that we have a spelling mistake in the, in the, in the words in, in the page of a book, and that creates a faulty word. A mutation is a spelling mistake in the DNA of the tumor cell, and that creates a faulty gene, and that faulty gene creates a faulty protein. And that faulty protein is frequently what causes cancer by pushing it to constantly proliferate and divide and avoid death. And so, today, we have genomic technologies that allow us to go deeply and analyze comprehensively both the DNA and the RNA of the tumor cell and find which mutation or which combination of mutations have conspired to cause that patient's cancer. Why is that important? That is important because for many of these faulty proteins, we now have targeted therapies, usually pills that are designed to specifically go and bind to that faulty protein that drives the cancer and shut it down effectively. And these have proven particularly effective therapies that have revolutionized care and have changed patient outcomes. We now have about 10 genomic, I would say, biomarkers, DNA or RNA changes that we routinely assess when we see a patient with non-small cell lung cancer. And for each one of these mutations, there are different approved targeted therapies, individualized specific therapies for each individual patient. And this spectrum of targetable or addressable or actionable, as we call them, mutations continues to expand. For example, at this year's ASCO meeting, we will see data from a drug called sunvozertenib, which is a specific and potent inhibitor of a particularly difficult to treat variant of EGFR-mutant lung cancer called EGFR exon insertion mutant lung cancer. We're looking forward to seeing the data, because this will likely establish a new standard of care for patients with this mutation that have not previously received systemic therapy. 

Lauren Byers, M.D. One thing when we think about all of these new personalized treatments and how to match each patient with the most effective therapy for them, we know that in addition to having effective, innovative medications that we can use for our patients, we also need to have the biomarkers. And I think that's something also that UT MD Anderson has really pioneered. And, you know, your work certainly has been transformational in terms of our understanding of how to use biomarkers, which are tests that we do on either the patient's tumor, you know, from a biopsy, for example, or now we can do, you know, many of them using a blood test. And this really is what the key is to then matching each patient with the most effective treatment or combination of treatments. 

Ferdinandos Skoulidis, M.D., Ph.D. It is imperative, I would say, that patients with with non-small cell lung cancer, certainly advanced non-small cell lung cancer, but also increasingly patients with earlier stage of disease undergo comprehensive genomic profiling that covers a whole array of potential biomarkers. Biomarkers are, as we mentioned, measurable entities, measurable parameters in the patient's tumor or in the, in the plasma that then give us an indication about how best to match individual patients, both with specific targeted therapies, but also how to assess before we start treatment the likelihood that a patient may respond or not to one of the standard approved treatments, such as combinations with chemotherapy and immunotherapy or immunotherapy on its own, as well as some of the novel drugs that are being developed. For example, the expanding and exciting field of antibody-drug conjugates. But I think the bottom line and the key message is that biomarker testing is imperative. And here at MD Anderson, we're very passionate about this. And we advocate that we should not be establishing a treatment plan, a definitive treatment plan for a patient without a comprehensive and complete assessment of the complete biomarker profile, be it DNA, RNA, or protein in their tumor. 

Lauren Byers, M.D. And, you know, I think one of the things by having very comprehensive biomarker testing here has let us do is we have patients where in the past, for example, you know, we were testing for KRAS mutations even before the drugs were available or in clinical trials because we expected that that was going to be an important target and it was going to just take some more time to have the the therapeutics to really act on it. And so, I remember being able to, you know, once those clinical trials started targeting KRAS, we were able to go back to the biomarkers that had been done on patients previously and then, you know, have new opportunities, new, new therapies that they could be potentially eligible for. 

Ferdinandos Skoulidis, M.D., Ph.D. Absolutely. Having that biomarker result available as early as possible in the patient journey is critical not only for deciding what is the optimal first-line treatment, upfront treatment, when the patient presents, but also how we stagger treatments, how we plan the whole therapeutic journey across multiple lines of treatment. And this is also another important point here, that we have here at MD Anderson, I think, tried to reinforce is that sometimes biomarkers can change or evolve. So, it's quite important at any point during the treatment when the tumor stops, for whatever reason, responding to our first line intervention to go and really try hard to re-analyze that tumor, to see what has changed in that tumor, to make it resistant to treatment, so that we can then most appropriately devise a salvage treatment plan for second and subsequent lines of therapy. 

Lauren Byers, M.D. Yeah, I think that's something we've been learning more and more about in terms of how cancers can change to try to escape from certain treatments. And so, you know, we need to be able to kind of get ahead of it. And a lot of the research that, that we and our colleagues are doing is to understand, you know, how did those cancers change? And can we anticipate that and use that to prevent resistance or to target cancers that have become resistant after previous treatments? 

Ferdinandos Skoulidis, M.D., Ph.D. This is where the novel combinations come in. There is an expansive array of combinations right now in the field of non-small cell lung cancer, including both two different targeted therapies on on their own. For example, there are clinical trials assessing two different RAS inhibitors, one that targets a specific variant version of KRAS, such as KRAS G12C, and then a pan-RAS inhibitor that targets the pathway more comprehensively. And the idea behind these combinations is exactly to prevent, to forestall or to overcome the clever ways that the tumor cell frequently finds to adapt and eventually develop resistance to our, to our therapies. 

Lauren Byers, M.D. Speaking of some of those newer therapeutics, you know, a lot of our research in the clinic and also in my research lab is focusing on a type of lung cancer called small cell lung cancer, which has been very challenging in the past in terms of finding effective therapies, especially in people who have, you know, maybe had traditional chemotherapy or immunotherapy, but then have developed resistance. And so, some of the very new data that will be presented at the ASCO conference will be sharing some of the results from these newer types of therapies. And these are called antibody-drug conjugates that you had mentioned before. We think of this somewhat as targeted chemotherapy. So, it's a type of therapy where there's an antibody that can identify and basically grab on to the cancer cells and bring in a very targeted approach, the chemotherapy molecules directly to where the cancer is and the activity of these, you know, have been shown in several different types of cancer. And we've presented last fall some of the very exciting results we were seeing from patients with small cell lung cancers and also with many other rare tumors, which historically have not been included in many of the clinical trials. And really being able to see that what we're learning from lung cancers can be beneficial and be applied to other patients with rare, rare tumors, including things like breast cancers, certain types of bladder cancers, you know, across many, many different types of of cancers. And so, I think that's something that, you know, we're really looking forward to, you know, sharing the most recent updates from, from those treatments. 

Ferdinandos Skoulidis, M.D., Ph.D. This is particularly exciting. And as you mentioned, Lauren, the small cell lung cancer has traditionally had a grave prognosis and had historically perhaps lagged in the development of novel treatments to improve patient outcomes until a couple of years ago, where essentially this notion was turned on its head. And now, small cell lung cancer represents one of the most dynamic and exciting areas where novel approaches are entering at a very rapid speed. And you have led several of these studies in your lab, and your team have led some of them foundational, both clinical as well as translational work in the field of small cell lung cancer, trying to understand both how best to target the disease as a whole, but also perhaps how to understand the heterogeneity of the disease at the molecular level better and perhaps in the future, develop targeted therapies for specific subsets of lung cancer that are more likely to respond to them. Do you want to share some of that research results or what you're excited about with us? 

Lauren Byers, M.D. Yeah, I would be happy to. For decades, small cell lung cancer was really treated as one-size-fits-all initially and again for many decades was treated with chemotherapy and then more recently combining chemotherapy and immunotherapy. But what we were observing was that there were some patients that responded extremely well with the addition of immunotherapy and had very good, you know, responses and very durable benefit from that. But still, you know, most of those other patients were not having that that long response, even with the immunotherapy. And so, together with our colleague Dr. Carl Gay, some of the work in our research at the lab and understanding from other patients being treated here, we really discovered that similar to the targeted therapies that we've been talking about for small cell lung cancer, that there are actually four major different types of small cell lung cancer. And further, we've been able to identify certain therapies, certain medications or drugs that seem to preferentially work well for each of those four types of small cell lung cancer. And so, again, kind of going back to biomarkers, you know, with this discovery, it was a huge breakthrough for the, for the field. But we also were able to partner with some of our collaborators to develop new biomarkers. And we actually are currently running new types of clinical trials where patients are being matched to specific therapies based on their biomarkers and which type of small cell lung cancer they have. 

Ferdinandos Skoulidis, M.D., Ph.D. This is hugely exciting. Personalizing treatment for small cell lung cancer is certainly something that one would not have thought would have been possible until a couple of years ago, and your work has truly been foundational and groundbreaking in making this a reality for patients. But for small cell lung cancer, the other, in my opinion, major recent discovery or breakthrough, has been developing innovative ways to engage the immune system against small cell lung cancer. Typically, small cell lung cancer historically has been considered immune cold tumor. A tumor where the immune system played, perhaps a minor role in, or at least we could not rejuvenate the immune system, in the appropriate way to tackle lung, small cell lung cancer. But recently, one of the biggest breakthroughs in this area has been novel ways to engage the immune system, such as T cell engagers and in the future, perhaps even additional approaches such as CAR T cells or T cell therapies. Do you want to tell us what are you most excited about in these areas? 

Lauren Byers, M.D. Yeah. So, there are a couple of things that I think are incredibly exciting for us right now. And this really goes back to, you know, something I'd mentioned earlier that, you know, we now have ways where we can target the surface of small cell lung cancers. And so, that's important because most small cell lung cancers do not have mutations or biomarkers that would respond to a pill therapy. But we have been mapping the surface of these small cell lung cancer, cancers and using new types of therapies where the drugs can bind onto the surface of the cancer cell and basically bring it to, you know, the immune cells and, and be able to really have the immune system to see and respond to these cancers as part of controlling it and treating the cancer. That has been incredibly effective and encouraging. I think it's still in early times with these new types of therapeutics, but I think what we're seeing is like none other that we've seen before. And also thinking about how to combine these and bring them earlier into patients' treatments. 

Ferdinandos Skoulidis, M.D., Ph.D. Absolutely. That is a very exciting notion. So, do you want to tell us maybe in a little bit more detail, how are we trying to bring these innovative treatments, such as T cell engagers, into earlier lines of treatment? What are the strategies that are being employed, and which ones do you consider to be the ones that are most likely to bear fruit? And what does the future hold? 

Lauren Byers, M.D. Yeah, a couple of things that are really changing. And this has, you know, happened across many different lung cancers is that, for example, with these T cell engagers where they can really engage with the cancer cell and bring the immune cells to where they need to be, and to recognize that there's a cancer present and that and that they can do their job of going after those cancer cells with the immune system. So, you know, we know from trials that have been done in the last couple of years that those can be effective for patients who have a recurrence of their small cell lung cancer. But now we're moving those into earlier lines of treatment. So, patients who have completed their, their chemotherapy and immunotherapy will now be getting those T cell engagers as what we'd call a maintenance therapy. So, bringing, you know, effective drugs earlier has been a successful recipe for a lot of cancers, not just lung cancer, but I think moving things earlier is really exciting. We also are able to use the type of therapy called CAR T therapy. This has traditionally been mostly used in leukemias or lymphomas, but I led the first clinical trial using CAR T therapy for small cell lung cancer. And it was an early study, but very exciting in terms of what was being seen. And so, that's another new approach with essentially a living drug, in a sense, where the patient's immune cells are re-engineered so that they can see the, the cancer cells and, and recognize that they're there, and then use the patient's engineered immune cells to then treat, treat their cancers. 

Ferdinandos Skoulidis, M.D., Ph.D. Very exciting. In addition to small cell lung cancer where we have seen an explosion of new therapeutics that you have outlined, there is also this spectrum of neuroendocrine cancers, cancers that are similar to small cell lung cancer, but not exactly like small cell lung cancer. But there are certain similarities, and we have not had effective treatments for them. We have treated them historically in a more-one-size-fits-all generic way. Can you tell us which particular types of lung cancer or other cancers that might benefit from these novel approaches, where small cell has led the way in clinical development, and what that might mean for patients? 

Lauren Byers, M.D. That's something that I'm really excited about and very passionate about. You know, when we have therapies that we think can benefit patients, we want to make sure that all of those patients who may benefit can have access to it. And so, one of the clinical trials that I've been leading is using these antibody-drug conjugates. And in that trial, we treated patients with small cell lung cancer, which is the more common form of neuroendocrine cancers. But for these other rare cancers that have very similar targets on the cancer cells and similar biology to small cell lung cancer, we really advocated to make sure that there would be these other patients included, that we thought would potentially benefit. We've been able to, you know, have clinical trials that are inclusive of these other rare cancers and those, you know, include patients who have cancers that are small cell cancers that occur or arise, you know, in the breast, in the GI tract, and the bladder, essentially every part of the body can potentially, you know, have a cancer that is similar to small cell lung cancer. And so, being able to really bring that, you know, to other patients that have these similar cancers and and can benefit from that is something that we think is incredibly important and something really unique to MD Anderson. 

Ferdinandos Skoulidis, M.D., Ph.D. This is a true triumph of cross-disciplinary collaboration and an example for how learnings in one area, in one field of oncology, can benefit a much larger population of patients. The other big area that is particularly close to my heart, as you know, is the concept of personalizing immunotherapy approaches for patients with non-small cell lung cancer in the same way that we are trying to identify which patients with small cell lung cancer might benefit mostly from distinct immunotherapies. There is a big effort to understand whether there are distinct types of engaging the immune system, or that might benefit distinct groups of patients with non-small cell lung cancer. At this year's ASCO, we will be presenting results from the TRITON study that I am particularly excited about. So, this was a Phase 2B clinical trial where two different standard of care, first-line combinations of chemotherapies and immunotherapies are being compared in patients with distinct mutations in their tumors. So, Dr. Byers, you mentioned, you highlighted antibody-drug conjugates as one of the major evolving fields in small cell lung cancer for our audience. Do you first want to explain what an antibody drug conjugate is and how those antibody-drug conjugates are being utilized in clinical trials in the context of small cell lung cancer and what the ultimate vision is for where will they find their place in the treatment landscape? 

Lauren Byers, M.D. You know, these antibody-drug conjugates are very exciting. And just to kind of go back to what those are, these are drugs where there's an antibody that can grab on to the surface of the cancer cell and bring with it chemotherapy molecules that then are deposited in a more directed, targeted chemotherapy of sorts. And one of the clinical trials that I'll be presenting at ASCO is looking at a specific target called SEZ6, SEZ6, which is on the surface of the majority of small cell lung cancers. And that becomes sort of a beacon to to lead the the drug to where it needs to be and then to directly deposit the chemotherapy molecules there. So, it's much more targeted. And again, you know, I think the data that we have already presented at some of the major international conferences, together with the data that will be presenting at ASCO, is very exciting and and really practice-changing, potentially, based on what's already been presented in terms of the activity of this antibody-drug conjugate. We have now had the opportunity to move forward with using it earlier for patients. And in fact, we have a clinical trial that has been opened to ask the question, could we replace traditional chemotherapy that we've been using for decades and decades? Could it be replaced with this targeted antibody-drug conjugate? 

Ferdinandos Skoulidis, M.D., Ph.D. Very interesting. And in addition to the obvious benefits from patients from a chemotherapy-free, or a more targeted chemotherapy, a more targeted approach, what is the current thinking regarding how antibody-drug conjugates are going to work together, perhaps with ways to engage the immune system, such as standard immune checkpoint inhibitors, but also potentially some of the novel ways to engage the immune system? 

Lauren Byers, M.D. One of the challenges with small cell lung cancer is that small cell lung cancers are very good at making themselves invisible to the immune system. So it's important that we, you know, leverage these newer therapeutics not just to target the cancer cells and damage and kill the cancer cells, but at the same time, how do we really enhance the immune system's ability to see the cancer cells and to more effectively get the patient's own immune system to really clear and treat the cancer cells. There's already clinical trials now going on looking at the combinations of these antibody-drug conjugates together with these newer types of immune therapies, the T cell engagers in particular, which are now approved as a standard treatment. In fact, we have probably treated possibly the largest number of patients to date with the approved T cell engager tarlatamab. And, you know, one of the things that we're really excited about that is not only seeing, you know, patients who are benefiting from this, but we're also learning from so much of our patients who are participating in our research programs so that we can use, you know, what we're learning from our patients to tailor treatment even more and to understand and anticipate if there's going to be resistance so that we can, you know, continue to make progress as quickly as possible. 

Ferdinandos Skoulidis, M.D., Ph.D. Your work has pioneered the identification and application of transcriptional subtypes as potential biomarkers. We're also looking at the expression of surface molecules as potential biomarkers. And then there's potentially additional biomarkers. How do you bring everything together? What do you, what do you believe the present and future of biomarker research in small cell lung cancer lies? 

Lauren Byers, M.D. Yeah. Well, I think it's very exciting. I think for small cell lung cancer with these four different types of small cell lung cancer, we often describe it as, you know, the genes that are turned on in each of these different small cell lung cancers. It's sort of like each one is playing different types of music. Maybe there's, you know, classical music being played by one of the subtypes, and then you've got country music and really have sort of different ways they behave and, and different, you know, therapies that they would respond to based on which genes are turned on and off. And, you know, this is something that's actually different than what we've done a lot in the past in terms of, you know, because these cancers don't have a mutation similar to KRAS that, that you talked about earlier, but with tools where we can really measure which of those genes are turned on or, you know, dialed down, we can understand which personalized treatment somebody might benefit the most from. So, I think it's, you know, it's a newer way of thinking about biomarkers. The other thing that I'm really excited about with this is because the way that we do the, the subtyping, the biomarker test for the different small cell lung cancer subtypes, it's based on looking at all of the genes that are expressed and how you know, to what extent they're turned on or turned off. And that means that, you know, when we complete these clinical trials and we have all of this information, you know, we can continue to learn from those patients' biomarker profiles. You know, there are, I think, certainly going to be new targets or new therapeutics that we'll be able to to leverage based on having these much more comprehensive biomarker approaches to patients with small cell lung cancer. Well, thank you so much, Dr. Skoulidis, for being here today. It was really a great discussion, and very happy to have the time together. 

Ferdinandos Skoulidis, M.D., Ph.D. Thank you for having me. 

Lauren Byers, M.D. And thank you for tuning in today. If you enjoyed this episode, don't forget to follow or subscribe on Apple Podcasts, Spotify, YouTube, or wherever you get your podcasts, and be sure to comment or review. For more information or to request an appointment at UT MD Anderson, call 1-877-632-6789 or visit MDAnderson.org. Thank you for listening to the Cancerwise podcast from UT MD Anderson.