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PeerView Heart, Lung & Blood CME/CNE/CPE Video Podcast
Natasha B. Leighl, MD, MMSc, FRCPC, FASCO - Refining Biomarker Testing and Targeted Treatment of NSCLC With Common and Uncommon EGFR Mutations

PeerView Heart, Lung & Blood CME/CNE/CPE Video Podcast

Play Episode Listen Later Nov 8, 2022 59:37


Go online to PeerView.com/RJV860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The term "EGFR-positive lung cancer” is no longer adequate or specific enough to characterize this complex molecular subtype of lung cancer. Increased granularity is needed both in biomarker testing and targeted treatment selection for patients with different types of EGFR mutations. A growing number of new agents and combinations have become available for patients with common (eg, exon 19 deletion, exon 21 L858R) and uncommon (eg, exon 20 insertions) EGFR mutations, and more are on the horizon, requiring a precision approach. Watch PeerView's latest educational video, based on a recent live symposium, and learn to better navigate biomarker-driven, individualized therapy for patients with EGFR-mutated NSCLC. Experts analyze the expanding evidence base and provide actionable, case-based guidance for improving testing, interpretation of results, and therapeutic decision-making for patients with NSCLC across a variety of EGFR mutations. Upon completion of this activity, participants should be better able to: Review the different types of EGFR mutations and their role as therapeutic targets in NSCLC, including in earlier disease stages; Collaborate with the multidisciplinary team to promote widespread biomarker testing in patients with NSCLC, select appropriate tests to detect common and less common EGFR mutations, and ensure accurate interpretation of results to guide targeted therapy selection; Apply current evidence and guidelines to individualize targeted therapy for patients with EGFR-mutated NSCLC based on EGFR mutation type and patient needs, values, and preferences; and Communicate with the multidisciplinary team and with patients to promote rapid detection and management of treatment-related adverse events in patients receiving EGFR-targeted therapies for NSCLC.

PeerView Clinical Pharmacology CME/CNE/CPE Audio Podcast
Natasha B. Leighl, MD, MMSc, FRCPC, FASCO - Refining Biomarker Testing and Targeted Treatment of NSCLC With Common and Uncommon EGFR Mutations

PeerView Clinical Pharmacology CME/CNE/CPE Audio Podcast

Play Episode Listen Later Nov 8, 2022 59:37


Go online to PeerView.com/RJV860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The term "EGFR-positive lung cancer” is no longer adequate or specific enough to characterize this complex molecular subtype of lung cancer. Increased granularity is needed both in biomarker testing and targeted treatment selection for patients with different types of EGFR mutations. A growing number of new agents and combinations have become available for patients with common (eg, exon 19 deletion, exon 21 L858R) and uncommon (eg, exon 20 insertions) EGFR mutations, and more are on the horizon, requiring a precision approach. Watch PeerView's latest educational video, based on a recent live symposium, and learn to better navigate biomarker-driven, individualized therapy for patients with EGFR-mutated NSCLC. Experts analyze the expanding evidence base and provide actionable, case-based guidance for improving testing, interpretation of results, and therapeutic decision-making for patients with NSCLC across a variety of EGFR mutations. Upon completion of this activity, participants should be better able to: Review the different types of EGFR mutations and their role as therapeutic targets in NSCLC, including in earlier disease stages; Collaborate with the multidisciplinary team to promote widespread biomarker testing in patients with NSCLC, select appropriate tests to detect common and less common EGFR mutations, and ensure accurate interpretation of results to guide targeted therapy selection; Apply current evidence and guidelines to individualize targeted therapy for patients with EGFR-mutated NSCLC based on EGFR mutation type and patient needs, values, and preferences; and Communicate with the multidisciplinary team and with patients to promote rapid detection and management of treatment-related adverse events in patients receiving EGFR-targeted therapies for NSCLC.

Think BIG Bodybuilding
Drugs N Stuff 159 Steroids QA

Think BIG Bodybuilding

Play Episode Listen Later Nov 7, 2022 72:46


Drugs n Stuff 159 Dave Crosland & Scott McNally - Navy Seals on Steroids? Persiflage & Steroid QA TIME STAMPS BELOW

ASCO Daily News
Novel Therapies Targeting KRAS in Lung Cancer & RAS-altered Tumors

ASCO Daily News

Play Episode Listen Later Nov 3, 2022 28:33


Dr. Vamsi Velcheti and Dr. Benjamin Neel, of the NYU Langone Perlmutter Cancer Center, and Dr. John Heymach, of MD Anderson Cancer Center, discuss new therapeutic approaches for KRAS-mutant lung cancers and therapy options for RAS-altered tumors.   TRANSCRIPT Dr. Vamsidhar Velcheti: Hello, I'm Dr. Vamsidhar Velcheti, your guest host for the ASCO Daily News podcast today. I'm the medical director of the Thoracic Oncology Program at Perlmutter Cancer Center at NYU Langone Health. I'm delighted to welcome two internationally renowned physician-scientists, Dr. John Heymach, the chair of Thoracic-Head & Neck Medical Oncology at the MD Anderson Cancer Center, and my colleague, Dr. Benjamin Neel, the director of the Perlmutter Cancer Center at NYU Langone Health, and professor of Medicine at NYU Grossman School of Medicine. So, we'll be discussing new therapeutic approaches today for KRAS-mutant lung cancers, and we will talk about emerging new targeted therapy options for RAS-altered tumors. Our full disclosures are available in the show notes, and the disclosures of all the guests of the podcast can be found on our transcript at: asco.org/podcast. Dr. Heymach and Dr. Neel, it's such a great pleasure to have you here for the podcast today. Dr. John Heymach: My pleasure to be here. Dr. Benjamin Neel: Same here. Dr. Vamsidhar Velcheti: Dr. Neel, let's start off with you. As you know, RAS oncogenes were first discovered nearly four decades ago. Why is RAS such a challenging therapeutic target? Why has it taken so long to develop therapeutic options for these patients? Dr. Benjamin Neel: Well, I think a good analogy is the difference between kinase inhibitors and RAS inhibitors. So, kinase inhibitors basically took advantage of an ATP-binding pocket that's present in all kinases, but is different from kinase to kinase, and can be accessed by small molecule inhibitors. So, the standard approach that one would've thought of taking, would be to go after the GTP-binding pocket. The only problem is that the affinity for binding GTP by KRAS is three to four orders of magnitude higher. So, actually getting inhibitors that are GTP-binding inhibitors is pretty much very difficult. And then, until recently, it was felt that RAS was a very flat molecule and there weren't any surfaces that you could stick a small molecule inhibitor in. So, from a variety of biochemical and medicinal-pharmacological reasons, RAS was thought to be impervious to small molecule development. But as is often the case, a singular and seminal insight from a scientist, Kevan Shokat, really broke the field open, and now there's a whole host of new approaches to trying to drug RAS. Dr. Vamsidhar Velcheti: So, Dr. Neel, can you describe those recent advances in drug design that have enabled these noble new treatments for KRAS-targeted therapies? Dr. Benjamin Neel: So, it starts actually with the recognition that for many years, people were going after the wrong RAS. And by the wrong RAS, the overwhelming majority of the earlier studies on the structure, and for that matter, the function of RAS centered on HRAS or Harvey RAS. We just mutated in some cancers, most prominently, bladder cancer, and head & neck cancer, but not on KRAS, which is the really major player in terms of oncogenes in human cancer. So, first of all, we were studying the wrong RAS. The second thing is that we were sort of thinking that all RAS mutants were the same. And even from the earliest days, back in the late eighties, it was pretty clear that there were different biochemical properties in all different RAS mutants. But this sort of got lost in the cause and in the intervening time, and as a result, people thought all RASes were the same and they were just studying mainly G12V and G12D, which are more difficult to drug. And then, the third and most fundamental insight was the idea of trying to take advantage of a particular mutation in KRAS, which is present in a large fraction of lung cancer patients, which is, KRAS G12C. So, that's a mutation of glycine 12 to cysteine and Kevan's really seminal study was to use a library of covalently adducting drugs, and try to find ways to tether a small molecule in close enough so that it could hit the cysteine. And what was really surprising was when they actually found the earliest hits with this strategy, which was actually based on some early work by Jim Wells at Sunesis in the early part of this century, they found that it was actually occupying the G12C state or the inactive state of RAS. And this actually hearkens back to what I said earlier about all RASes being the same. And in fact, what's been recently re-appreciated is that some RAS mutants, most notably, G12C, although they're impervious to the gap which converts the active form into the inactive form, they still have a certain amount of intrinsic ability to convert from the inactive form. And so, they always cycle into the inactive form at some slow rate, and that allows them to be accessed by these small molecules in the so-called Switch-II Pocket, and that enables them to position a warhead close enough to the cysteine residue to make a covalent adduct and inactivate the protein irreversibly. Scientists at a large number of pharmaceutical companies and also academic labs began to understand how to access various other pockets in RAS, and also even new strategies, taking advantage of presenting molecules to RAS on a chaperone protein. So, there's now a whole host of strategies; you have a sort of an embarrassment of riches from an impoverished environment that we started with prior to 2012. Dr. Vamsidhar Velcheti: Thank you, Dr. Neel. So, Dr. Heymach, lung cancer has been a poster child for personalized therapy, and we've had like a lot of FDA-approved agents for several molecularly-defined subsets of lung cancer. How clinically impactful is a recent approval of Sotoracib for patients with metastatic lung cancer? Dr. John Heymach: Yeah. Well, I don't think it's an exaggeration to say this is the biggest advance for targeted therapies for lung cancer since the initial discovery of EGFR inhibitors. And let me talk about that in a little more detail. You know, the way that lung cancer therapy, like a lot of other cancer therapies, has advanced is by targeting specific driver oncogenes. And as Dr. Neel mentioned before, tyrosine kinases are a large percentage of those oncogenes and we've gotten very good at targeting tyrosine kinases developing inhibitors. They all sort of fit into the same ATP pocket, or at least the vast majority of them now. There are some variations on that idea now like allosteric inhibitors. And so, the field has just got better and better. And so, for lung cancer, the field evolved from EGFR to ALK, to ROS1 RET fusions, MEK, and so forth. What they all have in common is, they're all tyrosine kinases. But the biggest oncogene, and it's about twice as big as EGFR mutation, are KRAS mutations. And as you mentioned, this isn't a tyrosine kinase. We never had an inhibitor. And the first one to show that it's targetable, to have the first drug that does this, is really such an important breakthrough. Because once the big breakthrough and the concept is there, the pharmaceutical companies in the field can be really good at improving and modulating that. And that's exactly what we see. So, from that original insight that led to the design of the first G12C inhibitors, now there's dozens, literally dozens of G12C inhibitors and all these other inhibitors based on similar concepts. So, the first one now to go into the clinic and be FDA-approved is Sotoracib. So, this again, as you've heard, is inhibitor G12C, and it's what we call an irreversible inhibitor. So, it fits into this pocket, and it covalently links with G12C. So, when it's linked, it's linked, it's not coming off. Now, the study that led to its FDA approval was called the CodeBreak 100 study. And this was led in part, by my colleague Ferdinandos Skoulidis, and was published in The New England Journal in the past year. And, you know, there they studied 126 patients, and I'll keep just a brief summary, these were all refractory lung cancer patients. They either had first-line therapy, most had both chemo and immunotherapy. The primary endpoint was objective response rate. And for the study, the objective response rate was 37%, the progression-free survival was 6.8 months, the overall survival was 12.5 months. Now you might say, well, 37%, that's not as good as an EGFR inhibitor or the others. Well, this is a much harder thing to inhibit. And you have to remember in this setting, the standard of care was docetaxel chemotherapy. And docetaxel usually has a response rate of about 10 to 13%, progression-free survival of about 3 months. So, to more than double that with a targeted drug and have a longer PFS really is a major advance. But it's clear, we've got to improve on this and I think combinations are going to be incredibly important now. There's a huge number of combination regimens now in testing. Dr. Vamsidhar Velcheti: Thank you, Dr. Heymach. So, Dr. Neel, just following up on that, unlike other targeted therapies in lung cancer, like EGFR, ALK, ROS, and RET, the G12C inhibitors appear to have somewhat modest, I mean, though, certainly better than docetaxel that Dr. Heymach was just talking about; why is it so hard to have more effective inhibitor of KRAS here? Is it due to the complex nature of RAS-mutant tumors? Or is it our approach for targeting RAS? Is it a drug-related problem, or is it the disease? Dr. Benjamin Neel: Well, the short answer is I think that's a theoretical discussion at this point and there isn't really good data to tell you, but I suspect it's a combination of those things. We'll see with the new RAS(ON) inhibitors, which seem to have deeper responses, even in animal models, if those actually work better in the clinic, then we'll know at least part of it was that we weren't hitting RAS hard enough, at least with the single agents. But I also think that it's highly likely that since KRAS-mutant tumors are enriched in smokers, and smokers have lots of mutations, that they are much more complex tumours, and therefore there's many more ways for them to escape. Dr. Vamsidhar Velcheti: Dr. Heymach, you want to weigh in on that? Dr. John Heymach: Yeah, I think that's right. I guess a couple of different ways to view it is the problem that the current inhibitors are not inhibiting the target well enough, you know, in which case we say we get better and better inhibitors will inhibit it more effectively, or maybe we're inhibiting it, but we're not shutting down all the downstream pathways or the feedback pathways that get turned on in response, in which case the path forward is going to be better combinations. Right now, I think the jury is still out, but I think the data supports that we can do better with better inhibitors, there's room to grow. But it is also going to be really important hitting these compensatory pathways that get turned on. I think it's going to be both, and it seems like KRAS may turn on more compensatory pathways earlier than things like EGFR or ALK2, you know, and I think it's going to be a great scientific question to figure out why that is. Dr. Vamsidhar Velcheti: Right. And just following up on that, Dr. Heymach, so, what do we know so far about primary and acquired resistance to KRAS G12C inhibitors? Dr. John Heymach: Yeah. Well, it's a great question, and we're still very early in understanding this. And here, if we decide to call it primary resistance - meaning you never respond in the first place, and acquired - meaning you respond and then become resistant, we're not sure why some tumors do respond and don't respond initially. Now, it's been known for a long time, tumors differ in what we call their KRAS-dependence. And in cell lines and in mouse models, when you study this in the lab, there are some models where if you block KRAS, those cells will die immediately. They are fully dependent. And there's other ones that become sort of independent and they don't really seem to care if you turn down KRAS, they've sort of moved on to other things they're dependent on. One way this can happen is with undergoing EMT where the cell sort of changes its dependencies. And EMT is probably a reason some of these tumors are resistant, to start with. It may also matter what else is mutated along with KRAS, what we call the co-mutations, the additional mutations that occur along with it. For example, it seems like if this gene KEAP1 is mutated, tumors don't respond as well, to begin with. Now, acquired resistance is something we are gaining some experience with. I can say in the beginning, we all knew there'd be resistance, we were all waiting to see it, and what we were really hoping for was the case like with first-generation inhibitors with EGFR, where there was one dominant mechanism. In the first-generation EGFR, we had one mutation; T790M, that was more than half the resistance. And then we could develop drugs for that. But unfortunately, that's not the case. It looks like the resistance mechanisms are very diverse, and lots of different pathways can get turned on. So, for acquired resistance, you can have additional KRAS mutations, like you can have a KRAS G12D or V, or some other allele, or G13, I didn't even realize were commonly mutated, like H95 or Y96 can get mutated as well. So, we might be able to inhibit with better inhibitors. But the more pressing problem is what we call bypass; when these other pathways get turned on. And for bypass, we know that the tumor can turn on MET with MET amplification, NRAS, BRAF, MAP kinase, and we just see a wide variety. So, it's clear to us there isn't going to be a single easy to target solution like there was for EGFR. This is going to be a long-term problem, and we're going to have to work on a lot of different solutions and get smarter about what we're doing. Dr. Vamsidhar Velcheti: Yeah. Thank you very much, Dr. Heymach. And Dr. Neel, just following up on that, so, what do you think our strategies should be or should look like while targeting KRAS-mutant tumors? Like, do we focus on better ways to inhibit RAS, or do we focus on personalized combination approaches based on various alterations or other biomarkers? Dr. Benjamin Neel: Yeah. Well, I'd like to step back a second and be provocative, and say that we've been doing targeted therapies, so to speak, for a long time, and it's absolutely clear that targeted therapies never cure. And so, I think we should ask the bigger question, "Why is it that targeted therapies never cure?" And I would start to conceive of an answer to that question by asking which therapies do cure. And the therapies that we know do cure are immune therapies, or it's therapies that generate durable immune response against the tumor. And the other therapies that we know that are therapies in some cases against some tumors, and radiation therapy in some cases against some tumors. Probably the only way that those actually converge on the first mechanism I said that cures tumors, which is generating a durable immune response. And so, the only way, in my view, it is to durably cure an evolving disease, like a cancer, is to have an army that can fight an evolving disease. And the only army I know of is the immune system. So, I think ultimately, what we need to do is understand in detail, how all of these different mutations that lead to cancer affect immune response and create targetable lesions in the immune response, and then how the drugs we'd give affect that. So, in the big picture, the 50,000-foot picture, that what we really need to spend more attention on, is understanding how the drugs we give and the mutations that are there in the first place affect immune response against the tumor, and ultimately try to develop strategies that somehow pick up an immune response against the tumor. Now in the short run, I think there's also lots of combination strategies that we can think of, John, you know, alluded to some of them earlier. I mean one way for the G12C inhibitors, getting better occupancy of the drug, and also blocking this so-called phenomenon of adaptive resistance, where you derepress the expression of receptor tyrosine kinases, and their ligands, and therefore bypass through normal RAS or upregulate G12C into the GTP state more, that can be attacked by combining, for example, with the SHIP2 inhibitor or a SOS inhibitor. Again, the issue there will be therapeutic index. Can we achieve that with a reasonable therapeutic index? Also in some cases, like not so much in lung cancer, but in colon cancer, it appears as if a single dominant receptor tyrosine kinase pathway, the EGF receptor pathway, is often the mechanism of adaptive resistance to RAS inhibitors, and so, combining a RAS inhibitor with an EGF receptor inhibitor is a reasonable strategy. And then of course, some of the strategies they're already getting at, what I just mentioned before, which is to try to combine RAS inhibitors with checkpoint inhibitors. I think that's an expected and understandable approach, but I think we need to get a lot more sophisticated about the tumor microenvironment, and how that's affecting the immune response. And it's not just going to be, you know, in most cases combining with a checkpoint inhibitor. I think we ought to stop using the term immunotherapy to refer to checkpoint inhibitors. Checkpoint inhibitors are one type of immunotherapy. We don't refer to antibiotics when we mean penicillin. Dr. Vamsidhar Velcheti: Dr. Heymach, as you know, like, there's a lot of discussion about the role of KRAS G12C inhibitors in the frontline setting. Do you envision these drugs are going to be positioning themselves in the frontline setting as a combination, or like as a single agent? Are there like a subset of patients perhaps where you would consider like a single agent up front? Dr. John Heymach: So, I think there's no question G12C inhibitors are moving to the first-line question. And the question is just how you get there. Now, the simplest and most straightforward approach is to say, “Well, we'll take our standard and one standard might be immunotherapy alone, a PD-1 inhibitor alone, or chemo with the PD-1 inhibitor, and just take the G12C inhibitor and put it right on top.” And that's a classic strategy that's followed. That may not be that simple. It's not obvious that these drugs will always work well together or will be tolerated together. So, I think that's still being worked out. Now, an alternative strategy is you could say, “Well, let's get a foot in a door in the first-line setting by finding where chemotherapy and immunotherapy don't work well, and pick that little subgroup.” There are some studies there using STK11-mutant tumors, and they don't respond well to immunotherapy and chemotherapy and say, “Well, let's pick that first.” And that's another strategy, but that's not to get it for everybody in the first-line setting. That's just to pick a little subgroup. Or we may develop KRAS G12C inhibitor combinations by themselves that are so effective they can beat the standard. So, what I think is going to happen is a couple things; I think they'll first be some little niches where it gets in there first. I think eventually, we'll figure out how to combine them with chemotherapy and immunotherapy so it goes on top. And then I think over time, we'll eventually develop just more effective, targeted combos where we can phase out the chemo, where the chemo goes to the back of the line, and this goes to the front of the line. Dr. Vamsidhar Velcheti: And Dr. Heymach, any thoughts on the perioperative setting and the adjuvant/neoadjuvant setting, do you think there's any role for these inhibitors in the future? Dr. John Heymach: Yeah, this is a really exciting space right now. And so that makes this a really challenging question because of how quickly things are moving. I'll just briefly recap for everybody. Until recently, adjuvant therapy was just chemotherapy after you resected a lung cancer. That was it. And it provided about a 5% benefit in terms of five-year disease-free survival. Well, then we had adjuvant immunotherapy, like atezolizumab, approved, then we had neoadjuvant chemo plus immunotherapy approved; that's a CheckMate 816. And just recently, the AEGEAN study, which I'm involved with, was announced to be a positive study. That's neoadjuvant plus adjuvant chemo plus immunotherapy. So now, if you say, well, how are you going to bring a G12C inhibitor in there? Well, you can envision a few different ways; if you can combine with chemo and immunotherapy, you could bring it up front and bring it afterwards, or you could just tack it in on the back, either with immunotherapy or by itself, if you gave neoadjuvant chemo plus immunotherapy first, what we call the CheckMate 816 regimen. So, it could fit in a variety of ways. I'll just say neoadjuvant is more appealing because you can measure the response and see how well it's working, and we in fact have a neoadjuvant study going. But the long-term benefit may really come from keeping the drug going afterwards to suppress microscopic metastatic disease. And that's what I believe is going to happen. I think you're going to need to stay on these drugs for a long while to keep that microscopic disease down. Dr. Vamsidhar Velcheti: Dr. Neel, any thoughts on novel agents in development beyond KRAS G12C inhibitors? Are there any agents or combinations that you'd be excited about? Dr. Benjamin Neel: Well, I think that the YAP/TAZ pathway inhibitors, the TEAD inhibitors in particular, are potentially promising. I mean, it seems as if the MAP kinase pathway and the GAPT pathway act in parallel. There's been multiple phases which suggest that YAP/TAZ reactivation can be a mechanism of sort of state-switching resistance. And so, I think those inhibitors are different than the standard PI3 kinase pathway inhibitor, PI3 kinase mTOR inhibitor, rapamycin. I also think as we've alluded to a couple of times, the jury's still out in the clinic, of course, but it'll be very exciting to see how this new set of RAS inhibitors works. The sort of Pan-RAS inhibitors, especially the ones that hit the GTP ON state. So, the G12C inhibitors and the initial preclinical G12D inhibitors that have been recorded, they all work by targeting the inactive state of RAS, the RAS-GDP state. And so, they can only work on mutants that cycle, at least somewhat, and they also don't seem to be as potent as targeting the GTP or active state of RAS. And so, at least the Rev meds compounds, which basically use cyclophilin, they basically adapt the mechanism that cyclosporine uses to inhibit calcineurin. They basically use the same kind of a strategy and build new drugs then that bind cyclophilin and present the drug in a way that can inhibit multiple forms of RAS. So, it'll be interesting to see if they are much more efficacious in a clinic as they appear to be in the lab, whether they can be tolerated. So, I think those are things to look out for. Dr. Vamsidhar Velcheti: Dr. Heymach? Dr. John Heymach: Yeah, I agree with that. I'm excited to see that set of compounds coming along. One of the interesting observations is that when you inhibit one KRAS allele like G12C, you get these other KRAS alleles commonly popping up. And it's a little -- I just want to pause for a second to comment on this, because this is a little different than EGFR. If you inhibit a classic mutation, you don't get multiple other separate EGFR alleles popping up. You may get a secondary mutation in cyst on the same protein, but you don't get other alleles. So, this is a little different biology, but I think the frequency that we're seeing all these other KRAS alleles pop up tells us, I think we're going to need some pan-KRAS type strategy as a partner for targeting the primary driver. So for example, a G12C inhibitor plus a pan-KRAS strategy to head off these other alleles that can be popping up. So, I think that's going to be probably a minimum building block that you start putting other things around. And by partnering an allele-specific inhibitor where you might be able to inhibit it a little more potently and irreversibly with a pan-KRAS, you may solve some of these problems at the therapeutic window. You can imagine KRAS is so important for so many different cells in your body that if you potently inhibit all KRAS in your body, bad things are likely to happen somewhere. But if you can potently inhibit the mutant allele and then dampen the other KRAS signaling that's popping up, it's more hopeful. Dr. Benjamin Neel: There is a mouse model study from Mariano Barbacid's lab, which suggests that postnatal, KRAS at least, complete inhibition is doable. So, you could take out KRAS postnatally and the mice are okay. Whether that translates to human of course, is not at all clear. And you still have the other RAS alleles, the HRAS, the NRAS that you'd still have to contend with. Dr. John Heymach: Yeah, it's an interesting lesson. We've shied away from a lot of targets we thought weren't feasible. I did a lot of my training with Judah Folkman who pioneered targeting angiogenesis. And I remember hearing this idea of blocking new blood vessels. I said, "Well, everyone is just going to have a heart attack and die." And it turns out you can do it. You have to do it carefully, and in the right way but you can separate malignant or oncogenic signaling from normal signaling in an adult, pretty reasonably in a lot of cases where you don't think you could. Dr. Vamsidhar Velcheti: All right. So, Dr. Neel, and Dr. Heymach, any final closing comments on the field of RAS-targeted therapies, you know, what can we hope for? What can patients hope for, let's say five years from now, what are we looking at? Dr. John Heymach: Well, I'll give my thoughts I guess first, from a clinical perspective, I think we're already seeing the outlines of an absolute explosion in targeting KRAS over the next five years. And I think there's a really good likelihood that this is going to be the major place where we see progress, at least in lung cancer, over these next five years. It's an example of a problem that just seemed insolvable for so long, and here I really want to acknowledge the sustained support for clinical research and laboratory research focused around RAS. You know, the NCI had specific RAS initiatives and we've had big team grants for KRAS, and it shows you it's worth these large-scale efforts because you never know when that breakthrough is going to happen. But sometimes it just takes, you know, opening that door a little bit and everybody can start rushing through. Well, I think for KRAS, the door has been opened and everybody is rushing through at a frantic rate right now. So, it's really exciting, and stay tuned. I think the landscape of RAS-targeting is going to look completely different five years from now. Dr. Benjamin Neel: So, I agree that the landscape will definitely look different five years from now, because it's reflective of stuff that's been in process for the last five years. And it takes about that long to come through. I want to make two comments; one of which is to slightly disagree with my friend, John, about these big initiatives. And I would point out that this RAS breakthrough did not come from a big initiative, it came from one scientist thinking about a problem uniquely in a different way. We need a basic science breakthrough, it almost always comes from a single lab person, thinking about a problem, often in isolation, in his own group. What big initiatives can help with is engineering problems. Once you've opened the door, and you want to know what the best way is to get around the house, then maybe big initiatives help. But I do think that there's been too much focus on the big team initiative and not enough on the individual scientists who often promote the breakthrough. And then in terms of where I see the field going, what I'd really like to see, and I think in some pharmaceutical companies and biotechs, you're seeing this now, and also in academia, but maybe not enough, is that sort of breaking down of the silos between immunotherapy and targeting therapy. Because I agree with what John said, is that targeted therapy, is just sophisticated debulking. If we want to really make progress-- and on the other hand, immunotherapy people don't seem to, you know, often recognize that these oncogenic mutations in the tumor actually affect the immune system. So, I think what we need is a unification of these two semi-disparate areas of therapeutics in a more fulsome haul and that will advance things much quicker. Dr. Vamsidhar Velcheti: Thank you both, Dr. Neel and Dr. Heymach, for sharing all your valuable insights with us today on the ASCO Daily News podcast. We really appreciate it. Thank you so much. Dr. John Heymach: Thanks for asking us. Dr. Benjamin Neel: It's been great having us. Dr. Vamsidhar Velcheti: And thank you all to our listeners, and thanks for joining us today. If you value our insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement. Follow today's speakers: Dr. Vamsi Velcheti @VamsiVelcheti Dr. Benjamin Neel @DrBenNeel Dr. John Heymach Want more related content? Listen to our podcast on novel therapies in lung cancer.    Advances in Lung Cancer at ASCO 2022 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Vamsi Velcheti: Honoraria: Honoraria Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline Dr. Benjamin Neel: None disclosed Dr. John Heymach: None disclosed    

Research To Practice | Oncology Videos
Non-Small Cell Lung Cancer | Meet The Professor: Current and Future Management of Non-Small Cell Lung Cancer with an EGFR Mutation — Part 3

Research To Practice | Oncology Videos

Play Episode Listen Later Oct 31, 2022 62:15


Featuring perspectives from Dr Pasi Jänne, including the following topics: Introduction: Journal Club with Pasi A Jänne, MD, PhD — Part 1 (0:00) Case: An Asian man in his late 60s with adenocarcinoma of the lung and pleural effusion with EGFR amplification (PD-L1 20%) — Jennifer L Dallas, MD (12:33) Case: A man in his late 50s with metastatic adenocarcinoma of the lung with discordant EGFR testing results and a new mediastinal lesion after therapy with osimertinib — Rohit Gosain, MD (16:10) Case: A man in his late 40s with metastatic adenocarcinoma of the lung and a brain metastasis with an EGFR exon 19 mutation and disease progression after stereotactic body radiation therapy (SBRT) and osimertinib, now with an ALK mutation by RNA testing (PD-L1 0) — Namrata I Peswani, MD (18:44) Case: A man in his early 50s with Stage III unresectable adenocarcinoma of the lung with an EGFR mutation who receives chemoradiation therapy and consolidation durvalumab, now with metastatic recurrence — Ferdy Santiago, MD (21:51) Case: A man in his early 70s with Stage IIIC large cell neuroendocrine carcinoma of the lung and an EGFR S768I mutation (PD-L1 1%) — Jarushka Naidoo, MB BCH, MHS (28:17) Case: A man in his early 80s with metastatic adenocarcinoma of the lung with an EGFR exon 20 insertion mutation and disease progression on mobocertinib — Jiaxin (Jason) Niu, MD, PhD (32:15) Case: A woman in her mid 70s with adenocarcinoma of the lung and an EGFR exon 20 insertion mutation with new bone and brain metastases after therapy with osimertinib — Dr Niu (37:11) Journal Club with Dr Jänne — Part 2 (43:02) Case: A woman in her mid 80s with metastatic adenocarcinoma of the lung with an EGFR exon 21 mutation who switched to erlotinib due to osimertinib-related toxicities, now with recurrence at the primary site (PD-L1 10%) — John Yang, MD (55:18) Case: An Asian man in his early 70s with metastatic adenocarcinoma of the lung with an EGFR exon 19 deletion and brain metastases who receives SBRT and osimertinib but develops extracranial biopsy-proven small cell lung cancer progression — Dr Niu (58:35) CME information and select publications

Lung Cancer Update
Meet The Professor: Current and Future Management of Non-Small Cell Lung Cancer with an EGFR Mutation — Part 3 of a 3-Part Series

Lung Cancer Update

Play Episode Listen Later Oct 31, 2022 62:14


Featuring a discussion on the treatment of non-small cell lung cancer with Dr Pasi Jänne, moderated by Dr Neil Love.

PeerView Heart, Lung & Blood CME/CNE/CPE Video Podcast
Brendon M. Stiles, MD - Precision Decisions in Multimodal Management of Early-Stage NSCLC: Integrating EGFR-Targeted Therapy in Perioperative Settings

PeerView Heart, Lung & Blood CME/CNE/CPE Video Podcast

Play Episode Listen Later Oct 28, 2022 41:23


Go online to PeerView.com/WRG860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Approximately 40% of patients with early-stage lung cancer experience disease recurrence within 1 year of receiving curative-intent surgery, representing a significant unmet medical need. Management of patients with NSCLC should be individualized based on a number of factors, including the molecular profile of the patient's tumor and the benefits and limitations of therapeutic options in the context of the latest evidence. Continued advances with targeted therapies have prompted strong interest in expanding their use into earlier disease settings, and adjuvant EGFR-targeted therapy has demonstrated remarkable efficacy in early-stage NSCLC, leading to the first regulatory approval of osimertinib as adjuvant therapy after resection in patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. Early findings from studies in the neoadjuvant setting are beginning to emerge now as well, as perioperative use of EGFR-targeted therapy continues to demonstrate improved outcomes. As part of the multidisciplinary team, thoracic surgeons play an essential role in collaborating and coordinating with other specialists to determine the best treatment plan, including incorporating EGFR-targeted therapy into multimodal management strategies. This PeerView educational video, based on a recent live symposium, provides an essential overview of the latest clinical evidence supporting the use of EGFR-targeted therapy in perioperative settings, as well as practical advice for optimal integration of targeted therapies in practice or as part of a clinical trial. Multidisciplinary discussions on the new practice-changing data highlight important implications for the surgeon–oncologist partnership, utilizing EGFR-targeted therapy as part of multimodal management of patients with resectable NSCLC with the goal of improving outcomes and quality of life. Upon completion of this activity, participants should be better able to: Review the role of EGFR mutations in NSCLC, advances in EGFR-targeted therapy in earlier disease settings, and importance of identifying patients who might benefit from these therapies in perioperative settings; Apply the latest evidence and guidelines to identify patients with early-stage resectable NSCLC who are candidates for adjuvant EGFR-targeted therapy or investigational targeted approaches; Collaborate with the multidisciplinary team to integrate EGFR-targeted therapy into multimodal treatment plans for eligible patients with early-stage resectable NSCLC

PeerView Clinical Pharmacology CME/CNE/CPE Audio Podcast
Brendon M. Stiles, MD - Precision Decisions in Multimodal Management of Early-Stage NSCLC: Integrating EGFR-Targeted Therapy in Perioperative Settings

PeerView Clinical Pharmacology CME/CNE/CPE Audio Podcast

Play Episode Listen Later Oct 28, 2022 41:17


Go online to PeerView.com/WRG860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Approximately 40% of patients with early-stage lung cancer experience disease recurrence within 1 year of receiving curative-intent surgery, representing a significant unmet medical need. Management of patients with NSCLC should be individualized based on a number of factors, including the molecular profile of the patient's tumor and the benefits and limitations of therapeutic options in the context of the latest evidence. Continued advances with targeted therapies have prompted strong interest in expanding their use into earlier disease settings, and adjuvant EGFR-targeted therapy has demonstrated remarkable efficacy in early-stage NSCLC, leading to the first regulatory approval of osimertinib as adjuvant therapy after resection in patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. Early findings from studies in the neoadjuvant setting are beginning to emerge now as well, as perioperative use of EGFR-targeted therapy continues to demonstrate improved outcomes. As part of the multidisciplinary team, thoracic surgeons play an essential role in collaborating and coordinating with other specialists to determine the best treatment plan, including incorporating EGFR-targeted therapy into multimodal management strategies. This PeerView educational video, based on a recent live symposium, provides an essential overview of the latest clinical evidence supporting the use of EGFR-targeted therapy in perioperative settings, as well as practical advice for optimal integration of targeted therapies in practice or as part of a clinical trial. Multidisciplinary discussions on the new practice-changing data highlight important implications for the surgeon–oncologist partnership, utilizing EGFR-targeted therapy as part of multimodal management of patients with resectable NSCLC with the goal of improving outcomes and quality of life. Upon completion of this activity, participants should be better able to: Review the role of EGFR mutations in NSCLC, advances in EGFR-targeted therapy in earlier disease settings, and importance of identifying patients who might benefit from these therapies in perioperative settings; Apply the latest evidence and guidelines to identify patients with early-stage resectable NSCLC who are candidates for adjuvant EGFR-targeted therapy or investigational targeted approaches; Collaborate with the multidisciplinary team to integrate EGFR-targeted therapy into multimodal treatment plans for eligible patients with early-stage resectable NSCLC

The Fellow on Call
Episode 035: Lung Cancer Series, Pt. 12: NSCLC Capstone with Dr. Jack West (Con't)

The Fellow on Call

Play Episode Listen Later Oct 26, 2022


We strongly recommend you listen to our previous episodes metastatic lung cancer (Episodes 0032 and 0033) to better be able to follow along with this conversation. Key trials mentioned in this episode include:CHECKMATE 227KEYNOTE 024Q:Do you send molecular testing (PDL1 and NGS) on the biopsy, peripheral blood or both?* Yield is highest from the tissue sample* Peripheral blood (circulating DNA) samples are dependent on the burden of disease and so often the yield is lower ** One of the benefits is that it can be sent quickly and having a fast turn-around; Tissue samples are dependent on being able to schedule a biopsy* Dr. West says he definitely sends this on a non-smoker with non-squamous lung cancer, as they are more likely to have molecular targets* Dr. West has not personally adopted the idea of sending peripheral and tissue samples for NGS testing for everyoneQ: Do you ever use Ipi/Nivo in patients with PDL1

Oncotarget
Press Release: PDGF Cross-Signaling Indicates Bypassed Signaling in Colorectal Cancer

Oncotarget

Play Episode Listen Later Oct 20, 2022 4:02


A new research paper was published in Oncotarget's Volume 13 on October 19, 2022, entitled, “Platelet-derived growth factor (PDGF) cross-signaling via non-corresponding receptors indicates bypassed signaling in colorectal cancer.” Platelet-derived growth factor (PDGF) signaling, besides other growth factor-mediated signaling pathways like vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF), seems to play a crucial role in tumor development and progression. Previously, researchers Romana Moench, Martin Gasser, Karol Nawalaniec, Tanja Grimmig, Amrendra K. Ajay, Larissa Camila Ribeiro de Souza, Minghua Cao, Yueming Luo, Petra Hoegger, Carmen M. Ribas, Jurandir M. Ribas-Filho, Osvaldo Malafaia, Reinhard Lissner, Li-Li Hsiao, and Ana Maria Waaga-Gasser, from Harvard Medical School, Shenzhen Traditional Chinese Medicine Hospital, University of Wuerzburg, and Mackenzie Evangelical Faculty of Paraná, recently provided evidence for upregulation of PDGF expression in UICC stage I–IV primary colorectal cancer (CRC) and demonstrated PDGF-mediated induction of PI3K/Akt/mTOR signaling in CRC cell lines. In their new study, the researchers sought to follow up on our previous findings and explore the alternative receptor cross-binding potential of PDGF in CRC. “Our analysis of primary human colon tumor samples demonstrated upregulation of the PDGFRβ, VEGFR1, and VEGFR2 genes in UICC stage I-III tumors.” Immunohistological analysis revealed co-expression of PDGF and its putative cross-binding partners, VEGFR2 and EGFR. The team then analyzed several CRC cell lines for PDGFRα, PDGFRβ, VEGFR1, and VEGFR2 protein expression. They found these receptors to be variably expressed amongst the investigated cell lines. Interestingly, whereas Caco-2 and SW480 cells showed expression of all analyzed receptors, HT29 cells expressed only VEGFR1 and VEGFR2. However, stimulation of HT29 cells with PDGF resulted in upregulation of VEGFR1 and VEGFR2 expression despite the absence of PDGFR expression and mimicked the effect of VEGF stimulation. Moreover, PDGF recovered HT29 cell proliferation under simultaneous treatment with a VEGFR or EGFR inhibitor. “Our results provide some of the first evidence for PDGF cross-signaling through alternative receptors in colorectal cancer and support anti-PDGF therapy as a combination strategy alongside VEGF and EGF targeting even in tumors lacking PDGFR expression.” DOI: https://doi.org/10.18632/oncotarget.28281 Correspondence to: Ana Maria Waaga-Gasser - awaaga@bwh.harvard.edu Keywords: PDGF, VEGFR, EGFR, bypassed signaling, colorectal cancer About Oncotarget: Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, visit Oncotarget.com and connect with us on social media: Twitter - https://twitter.com/Oncotarget Facebook - https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram - https://www.instagram.com/oncotargetjrnl/ LinkedIn - https://www.linkedin.com/company/oncotarget/ Pinterest - https://www.pinterest.com/oncotarget/ LabTube - https://www.labtube.tv/channel/MTY5OA SoundCloud - https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com. Oncotarget Journal Office 6666 East Quaker Str., Suite 1A Orchard Park, NY 14127 Phone: 1-800-922-0957 (option 2)

CURE Talks Cancer
S5 Ep6: Patient With Lung Cancer ‘Stays One Step Ahead' of His Rare Mutation

CURE Talks Cancer

Play Episode Listen Later Oct 20, 2022 26:27


Jeffery Battles, a 53-year-old with stage 4 lung cancer, says that he feels lucky for having a rare genetic mutation. The father of three from Connie Lake, Pennsylvania, wasn't expecting lung cancer to become part of his life. Even when he started experiencing chest pains in February 2021, Battles originally dismissed the pains as lingering symptoms from an earlier case of COVID-19. Once he finally saw his doctor, he was diagnosed with non-small cell lung cancer, the most common type of lung cancer. He then immediately underwent genetic testing, which revealed that Battles had an EGFR exon 20 insertion mutation — information his doctors used to modify his cancer treatment.  EGFR exon 20 insertion mutation is a mutation in the cells that increases the growth of the epidermal growth factor receptor (EGFR), a protein on cells that helps cancer cells grow. Of note, cancers with an EGFR exon 20 insertion mutation doesn't respond to tyrosine kinase inhibitors (TKIs), the typical treatment for EGFR-positive lung cancer. In today's episode of “Cancer Horizons,” Battles describes how he feels fortunate to know the status of his mutation, and how it helped him be proactive with his cancer treatment, finding support from his family and online communities.

The Fellow on Call
Episode 034: Lung Cancer Series, Pt. 11: NSCLC Capstone with Dr. Jack West

The Fellow on Call

Play Episode Listen Later Oct 20, 2022


Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we begin to round out our NSCLC series with the first of two episodes where we interview Dr. Jack West from City of Hope!We strongly recommend you listen to our previous episodes on early stage lung cancer (Episodes 026 and 029) to follow along in this discussion. Key trials mentioned in this episode include:ADAURA Trial IMPOWER010CHECKMATE816Q: We've previously discussed that adjuvant cisplatin doublet chemotherapy is used for tumors > 4cm and/or nodal involvement. Given that PD-L1 status and EGFR status can also potentially change adjuvant therapy choices, how do you employ these tests in your practice?* Different approaches at every center/with different thoracic oncologists. * Dr. West does NOT recommend sending broad NGS testing on everyone if it is not going to change management. * It it may influence management, at the very least, PDL1 and EGFR should be performed because of implications on adjuvant treatment options (See Episode 026 for treatment discussions): ** ADAURA Trial: Adjuvant Osimertinib x3 years for EGFR+ patients** IMPOWER010: In patients with PDL1 >50%, patients did better with 1 year of immunotherapy (atezolizumab) after adjuvant therapy* In patients with higher risk disease, can consider sending broad NGS, particularly looking for ALK and other mutations; remember that EGFR and ALK+ patients do NOT respond to immunotherapy well. This is important because we don't want to give someone side effects that they would not otherwise had (these patients are getting treatment adjuvantly AKA after their disease is already resected!)Q: What are limitations of the ADUARA Trial? * The ADUARA suggested disease-free survival advantage with use of osimertinib, but we don't know final overall survival data yet.*Limitations:** Three years of therapy** Very expensive drug** More data presented at ESMO 2022 on efficacy; Dr. West stated that there appears to be drop off in survival after stopping drug. Overall survival data not yet available * Just because patients can get osimertinib does NOT mean that they are not eligible for chemotherapy**Adjuvant chemotherapy for patients provides long-term benefit** JBR.10 Trial: Older trial, but showed that patients who got adjuvant treatment (in this case vinorelbine plus cisplatin) had prolonged disease-free and overall survival in early-stage non–small-cell lung cancer.** Follow up study suggested that EGFR+ patients trended towards longer survival Q: What are your thoughts on Checkmate 816 with the use of neoadjuvant nivolumab in addition to the platinum doublet? Do you think pathologic CR was an appropriate surrogate endpoint for the trial?* Complete path CR is a new end-point, but it does correlate with PFS. We cannot always for traditional endpoints, such as overall survival data, to mature because doing so may result in us withholding therapy that may be very beneficial. * Biggest benefit to neoadjuvant treatment is that more patients are able to get the full regimen. Many have complications after surgery and never are able to then get/benefit from chemotherapy. Supported by data from NATCH trial Q: What are your thoughts on induction chemoradiation vs. chemotherapy alone?* Dr. West prefers to not use radiation pre-operatively, with some exception (for instance, pancoast tumor) Tune in next week for part 2 of this discussion!About our guest:Dr. Jack West is an internationally-renowned Thoracic Oncologist. Associate Professor in the Department of Medical Oncology & Therapeutics Research at City of Hope Comprehensive Cancer Center. He is also the Clinical Executive Director of AccessHope. He completed his medical education at Harvard Medical School, and then trained at Brigham and Women's Hospital before heading to Fred Hutchinson at the University of Washington. Twitter: @JackWestMD References:https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02098-5/fulltext - IMPOWER 010 Trial https://www.nejm.org/doi/full/10.1056/NEJMoa2027071- ADAURA Trial https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032958/ - NATCH Trial https://www.nejm.org/doi/pdf/10.1056/NEJMoa043623 - JBR.10 Trialhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3033998/ - Follow up to JBR.10 Trial looking at influence of EGFR status on chemotherapy responsehttps://www.nejm.org/doi/10.1056/NEJMoa2202170 - CHECKMATE 816 https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s - Episode 026https://www.thefellowoncall.com/tfocpodcast/episode-001disclaimer-wfhgf-ml3b6-9m66a-8rrc4-k8w87-x7xdd-wrzye-4xg8x-t73gt-cxc5s-nmg8f-cfyd6-hgs35-5pcwx-tf6dh-trggt-xzkt7-923gg-rpjzx-6s36p-hk27n-bbpgx-jymml-9lfam-76m4s-6xae9-ws6nt-ntn8g - Episode 029Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google PodcastLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!

ASCO Guidelines Podcast Series
Treatment of Metastatic Colorectal Cancer Guideline

ASCO Guidelines Podcast Series

Play Episode Listen Later Oct 17, 2022 21:12


An interview with Dr. Van Morris from The University of Texas MD Anderson Cancer Center in Houston, TX and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, TN, co-chairs on "Treatment of Metastatic Colorectal Cancer: ASCO Guideline." Dr. Morris and Dr. Eng review the evidence-based recommendations from the guideline, focusing on areas of uncertainty in the treatment of metastatic colorectal cancer, and highlighting the importance of multidisciplinary collaboration and shared decision-making between patients and clinicians. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Van Morris, from The University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee - co-chairs on, 'Treatment of Metastatic Colorectal Cancer, ASCO Guideline.' Thank you for being here, Dr. Morris, and Dr. Eng. Dr. Cathy Eng: Thank you. Dr. Van Morris: Thank you. Brittany Harvey: First. I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Morris, do you have any relevant disclosures that are directly related to the guideline topic? Dr. Van Morris: Not personally, but I do have research support to my institution from Pfizer and Bristol Myers Squibb who have products that I'll be discussing on this podcast. Brittany Harvey: Thank you, Dr. Morris. And Dr. Eng, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Cathy Eng: Also, not personally associated with any honorarium specific to this topic. Brittany Harvey: Great. Thank you both. So then, let's talk about the content of this guideline. So first, Dr. Morris, can you provide an overview of the scope of this guideline? Dr. Van Morris: Sure. So colorectal cancer is the second-leading cause of cancer-related death in the United States. And especially in the time of the recent COVID-19 pandemic with people less likely to go for screening colonoscopies, there's great concern that more and more patients will be presenting at the time of their initial diagnosis with later-stage, more advanced colorectal cancer. So with that said, research is moving very quickly for the benefit of patients with colorectal cancer, and we were interested in assembling a multidisciplinary team that consisted of medical oncologists, surgical oncologists, radiation oncologists, pathologists, and radiologists as well, to help us make guidelines that really summarize the most relevant up-to-date practices, based on rigorous literature review for treatment recommendations for advanced metastatic colorectal cancer. Brittany Harvey: Great. And then as you just mentioned, this guideline provides recommendations, and a lot of those focus on areas of uncertainty in the treatment of metastatic colorectal cancer. And I'd like to review those key recommendations that you mentioned for our listeners. So, Dr. Eng, starting with - for patients with previously untreated, initially unresectable metastatic colorectal cancer, who are candidates for chemotherapy plus bevacizumab, is doublet or triplet cytotoxic chemotherapy recommended? Dr. Cathy Eng: For treatment-naive patients, bevacizumab has been approved, and we do agree that it's a very reasonable treatment option with doublet or triplet therapy for our patient population. Obviously, these are guidelines, and it's extremely important to keep in mind that as a provider, you need to discuss the potential side effects with the patient. With bevacizumab, you know, standard concerns must be discussed with the patient, especially in regards to wound healing, if they've had recent surgery or any potential risk factors for a recent cardiac event from a recent thrombosis. So, those things obviously, would preclude the patient from initiating treatment with bevacizumab. But currently, doublet therapy or triplet therapy could be a potential option for patients. Brittany Harvey: Great. And yes, as you mentioned, shared decision-making is paramount to these decisions. So then following that recommendation, Dr. Morris, which patients should be offered pembrolizumab in the first-line setting? Dr. Van Morris: Yeah. So, I think that this represents really one of the exciting advances in the treatment of metastatic colorectal cancer over the past several years. We have great data now that suggests for patients with microsatellite instability-high metastatic colorectal cancer, especially who have not had any prior treatment, we would recommend use of immune checkpoint blockade therapies, really coming from the seminal KEYNOTE-177 trial. This was a phase III international trial that looked at patients with advanced unresectable or metastatic colorectal cancer. And patients were either randomized to pembrolizumab monotherapy, or cytotoxic chemotherapy with FOLFOX, with or without bevacizumab. And this trial did meet its primary endpoint and showed an improvement in progression-free survival, with use of pembrolizumab as a single agent relative to cytotoxic chemotherapy. And based on this trial and the clear benefit that we see in patients with pembrolizumab, the FDA has approved this as an option for patients with MSI-high untreated metastatic colorectal cancer. There are other trials which have looked at use of immunotherapy; the CheckMate 142 trial looked at combination PD-1 CTLA-4 therapy as a single-arm study. And, you know, there's another trial, the CheckMate 8HW, which is looking at one versus two immunotherapy agents in this setting as well. But really, as it stands for now, patients with MSI-high untreated metastatic colorectal cancer are the ones who benefit from the use of immunotherapy. One of the questions that we often get in talking with other clinical oncologists is the FDA approval for pembrolizumab in any cancer type for a TMB, tumor mutation burden, greater than 10. And, we talked about this with our panel in this context, and we don't see that patients with microsatellite-stable metastatic colorectal cancer, who have a tumor mutation burden over 10 benefit from use of immunotherapy. There is one exception to this for patients who harbor pathogenic POLE or POLD1 mutations, these patients oftentimes do experience sustained clinical benefit with immunotherapy. But in general, patients with microsatellite-stable metastatic colorectal cancer, who don't have POLE/POLD1 mutations, we don't favor use of immunotherapy in that context at this point in time. Brittany Harvey: Great. Thank you for reviewing that recommendation and the data behind who benefits and who doesn't benefit from immunotherapy in this setting. So then following that, the next question that this guideline addressed is for treatment-naive RAS-wild type metastatic colorectal cancer. So, for these patients, Dr. Eng, is anti-EGFR therapy recommended for patients with right or left sided primary tumors? Dr. Cathy Eng: That is such an important question, and thank you for asking this. We know based upon pivotal data from CALGB/SWOG 80405, that right-sided tumors treatment-naive, even if they're RAS-wild type, these patients should not receive anti-EGFR therapy. But also, we've learned from 80405, FIRE-3, and PEAK, which was a phase two study, that there appeared to be some benefit versus anti-VEGF therapy for left-sided tumors based upon studies that have been conducted. So, at this year's ASCO, actually, the PARADIGM trial was specifically a phase III trial, more focused on left-sided tumors. It was amended twice before it decided to focus on the left-sided patient population. And it was a phase III study where patients were randomized to FOLFOX plus panitumumab versus FOLFOX and bevacizumab. And the primary endpoint was overall survival. And we added this data to our guidelines. This data just came out, hot off the presses in June, at this year's ASCO. And the primary endpoint was fulfilled. And basically, it prospectively demonstrated that the data from the other three trials, based upon a pooled analysis, suggested left-sided tumors fare better with anti-EGFR therapy. And in fact, the PARADIGM trial basically validated those findings. Obviously, the PARADIGM trial just recently presented, we have not seen the final publication, we do not know much about the maintenance setting, but specifically, when thinking about anti-EGFR therapy, it is very reasonable to consider it in a left-sided tumor, all RAS-wild type patient population. I would like to mention though, and we do highlight this also in the guidelines, which is critically important, is that there was another study, which is a phase III trial called, TRIPLETE, that was presented as well, looking at FOLFOXIRI plus panitumumab versus basically, standard treatment. And what it noted is that there is no additional benefit for FOLFOXIRI plus panitumumab in left-sided tumors in regards to response or progression-free survival, there was no additional benefit. So, FOLFOX plus panitumumab seems very reasonable, FOLFOXIRI plus panitumumab is not necessarily needed in left-sided tumors. Brittany Harvey: Great. Thank you for that explanation, and also for the work of the panel to rapidly include this new information recently presented at ASCO. So then following those recommendations, Dr. Morris, what recommendation did the panel make for patients with previously-treated metastatic colorectal cancer with a BRAF V600E mutation? Dr. Van Morris: Yeah. So, this recommendation was made essentially based on one randomized phase III clinical trial, which reported out about three years ago now, the BEACON trial. This is looking at patients with BRAF V600E mutated metastatic colorectal cancer, which we know accounts for probably eight to 10% of all patients with advanced colorectal cancer, and when found, really harbors a poor prognosis relative to BRAF-wild type counterparts. So, the BEACON trial was a trial that looked at patients with previously-treated metastatic colorectal cancer, who have BRAF mutations, either kind of standard of care cytotoxic chemotherapy, or a BRAF/EGFR combination with encorafenib and cetuximab or alternatively, a BRAF/EGFR/MEK combination. That trial showed that improvement in survival outcomes with a BRAF/EGFR-targeted approach, as well as the BRAF/MEK/EGFR. However, because there was no difference in survival with the addition of the MEK inhibitor, the FDA subsequently approved encorafenib and cetuximab as the recommended treatment for patients with BRAF V600E previously-treated metastatic colorectal cancer. Because the MEK combination with binimetinib was not recommended by the FDA, you know, we did not include that analysis in our guidelines for ASCO. But as it stands right now, we do strongly encourage all clinicians to check for their BRAF V600E mutation status in their patients with metastatic colorectal cancer, with the goal of getting them to a targeted therapy approach over their treatment course. Brittany Harvey: Great. Thank you for providing that information. So, following that, Dr. Eng, what are the recommendations for patients with colorectal peritoneal metastases? Dr. Cathy Eng: The current recommendations for colorectal cancer with peritoneal disease, really, there's no strong evidence to support the role of heated intraperitoneal chemotherapy. We now know based upon the literature from one of the largest studies to date, the PRODIGE data, demonstrating that there may be some potential benefit from cytoreductive surgery for the patients in regards to overall survival. But these patients are at high risk for bowel obstruction, potentially for perforation, and obviously, quality of life is an issue. So, these patients should always be discussed in a multidisciplinary tumor board whenever possible, and hopefully, to meet with a surgeon that is more experienced, specifically, in treating peritoneal disease, because these patients do require a lot of multidisciplinary care and discussion. So currently, based upon the existing data, we don't recommend heated intraperitoneal chemotherapy, but there may be a role for cytoreductive surgery. Brittany Harvey: Thank you, Dr. Eng for going over those recommendations. So then following that, Dr. Morris, for patients with unresectable liver-limited metastatic colorectal cancer, which liver-directed therapies are recommended? Dr. Van Morris: So, this is I think a really good question and one that just like the prior question with regards to peritoneal surgery, is one that we felt was a challenging one, but a common one that we wanted to address. And specifically, I think this is an example of where level of evidence comes into the strength of recommendation. So, for patients with unresectable liver-limited metastatic colorectal cancer, we looked at the questions of, "What is the role of SBRT - stereotactic body radiotherapy, and what is the role of SIRT, which is selective internal radiotherapy?" And for both of these, we felt that the level of evidence was weak, and I think that it's very important to make note of that in assessing the recommendations. But to start with, for SBRT, we looked at one meta-analysis for patients with oligometastatic colorectal cancer, and also analyzed 18 non-randomized control trials in this setting. Most of the patients in these studies had one to five liver metastases, with the majority having one or two liver metastases. From the meta-analysis, we saw kind of a one-year local control rate of around 67%, a two-year control rate of 59%. So, based on those and recognizing the limitations of non-randomized trials and making recommendations, the panel did feel that it was reasonable to consider use of SBRT for oligometastatic colorectal cancer. The SABR-COMET trial is one that had looked at the role of radiotherapy for treatment of oligometastatic colorectal cancer, and I just want to make the point as well, that we did not include that in our analysis or recommendations at this point in time, because this really didn't include a lot of patients with colorectal cancer that we felt warranted inclusion. Now, with regards to SIRT, we looked at kind of one meta-analysis and three randomized control trials for patients with mostly liver-limited metastatic colorectal cancer. All patients had liver disease, but there were about 40% of the patients we looked at in the meta-analysis, had extra hepatic disease as well. In the frontline setting, there really was no difference in progression-free survival or overall survival with the use of SIRT. And more recently, we've seen in a second-line trial, it was called the EPOCH trial, reported several years ago, this looked at patients with previously-treated metastatic colorectal cancer in the second-line setting. Patients were randomized to either chemotherapy with, or without transarterial radioembolization with Y90. While there was an improvement in overall response rate, there was no meaningful improvement in overall survival with the use of SIRT. But there were significant increases in grade 3 or grade 4 toxicities when SIRT was added to chemotherapy. So, kind of given this, we didn't feel at this point in time that SIRT should be recommended for patients with metastatic colorectal cancer. Although, again, I do want to highlight that really these discussions should be happening at high-volume centers, kind of with a multidisciplinary group of clinicians. Brittany Harvey: Definitely. And thank you for highlighting that multidisciplinary collaboration. And the last section of recommendations, Dr. Eng, what is recommended for patients with metastatic colorectal cancer, and potentially-curable oligometastatic liver metastases? Dr. Cathy Eng: So, another controversial topic. And once again, this is why we decided to include this as part of the guidelines, because this is a common scenario where patients are potentially curable, following liver resection for oligometastatic disease. We cannot highlight enough the importance of multidisciplinary discussion. Prior data has not been strong regarding specific guidelines following liver resection. We do recommend that based upon the existing data, there is no level one evidence to say, you should go one way or another following metastatic resection, and whether or not adjuvant therapy is warranted in that setting. But we do recommend multidisciplinary management and engagement and discussion. So, although it's not definitive, it basically suggests that there is a role for resection. It does provide improved five year survival relative to systemic chemotherapy, if the patient is potentially resectable, but does require multidisciplinary discussion. And it is a shared decision-making process. Brittany Harvey: Great. Thank you. And I appreciate you highlighting the importance of shared decision-making throughout this guideline. So then, Dr. Morris, what is the importance of this guideline in your opinion, and how will it impact clinical practice? Dr. Van Morris: Yeah. So, I think that we understand that management of metastatic colorectal cancer is extremely complex given the various molecular annotations and the multimodality therapies which are possible for our patients. So, we tried to limit the guidelines here to include what we feel are the most recent updates, but also kind of the most clinically-relevant multidisciplinary questions that get asked for treatment of metastatic colorectal cancer. We also recognize that things are changing quickly. And for example, we didn't decide to include at this point in time, management of HER2 neu amplified metastatic colorectal cancer, although we are seeing more and more data coming out, suggesting targeted therapies. So, I think it's important for clinicians to realize that these are guidelines which are ever-changing, given the updates with new therapies available for our patients. And the other thing I think that's very good about these guidelines is that, even though we may be making recommendations about controversial topics in the management of metastatic colorectal cancer - specifically, I think the use of HIPEC with cytoreductive surgery, locally-directed therapies to the liver, and the role of perioperative chemotherapy and metastasectomy - I think it's important for oncologists to realize that these recommendations come with varying strengths of level of evidence and that we as oncologists should be considering the level of evidence that's out there when making recommendations that affect our patients as well. So, we really wanted to support these guidelines and recommendations and empower clinicians to know and understand the quality of evidence that exists in the management of patients with metastatic colorectal cancer. Brittany Harvey: Excellent. And yes, those are key points on the level of evidence and the strength of recommendations throughout the guideline. And then finally, Dr. Eng, you've talked a bit about shared decision-making and the importance of this guideline for patients. So, how will these guideline recommendations affect patients with metastatic colorectal cancer? Dr. Cathy Eng: The reason that we created these guidelines is to help patients, their caregivers, and providers, learn of the most recent developments in colorectal cancer, and the best approach based upon the information that we have personally reviewed with our multidisciplinary team of faculty members that participated in this exercise. We really just want to make sure that patients do get optimal care. And we hope that these guidelines also will help provide a foundation for some of the clinical trials that may be under development, or for other clinical trials that are being considered. So, we really just want to provide the most up-to-date information to all individuals that are interested in colorectal cancer so we can help guide their care better. Brittany Harvey: So, I want to thank you both so much for your work on these guidelines, and all of the time it's spent developing these recommendations, and thank you for your time today, Dr. Morris, and Dr. Eng. Dr. Van Morris: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to: www.asco.org/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

Rio Bravo qWeek
Episode 114: Diabetes Care Update

Rio Bravo qWeek

Play Episode Listen Later Oct 14, 2022 14:32


Episode 114: Diabetes care updateYvette presents updates from ADA on diabetes care regarding SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone. Written by Yvette Singh, MSIV, American University of the Caribbean. Comments and text edition by Hector Arreaza, MD. You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.The American Diabetes Association (ADA) released revisions in May 2022; specifically regarding sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and finerenone for cardiovascular and renal comorbidities. What are SGLT2 inhibitors and GLP-1 receptor agonists?SGLT2 inhibitor class of oral antidiabetic drugs, including empagliflozin, canagliflozin, dapagliflozin, and more. They increase the excretion of glucose and sodium in the urine by inhibiting SGLT2 in the kidney, thus lowering blood glucose levels. In other words, it has a glucoretic effect. GLP-1 receptor agonists are a class of non-insulin drugs, including exenatide, liraglutide, semaglutide, and more. They mimic the intestinal hormone incretin and bind to its receptor, which slows the rate at which foods leave the stomach, controls appetite, and regulates insulin and glucagon secretion.What is the NEW use of SGLT-2 Inhibitors and GLP-1 RA in treatment?Traditional glucocentric approaches recommend initial medications such as metformin for most adults with type 2 diabetes, leaving SGLT-2 inhibitors and GLP-1 receptor agonists as alternative options mainly for patients with high risk for atherosclerotic cardiovascular disease in whom additional glucose lowering was needed after metformin treatment. Current guidelines now recommend these agents (SGLT-2 inhibitors and GLP-1 RA) for any T2DM patient with current or high-risk for ASCVD, chronic kidney disease (CKD), or heart failure (HF). This guideline stands regardless of the need for additional glucose lowering and/or metformin use. This has now changed through trials, demonstrating that cardiovascular disease and chronic kidney disease benefits independent of a medication's glucose-lowering potential.HbA1c has long been used to guide clinical decision-making about type 2 diabetes. However, systematic reviews have revealed minimal benefits in the normalization of HbA1c.Moreover, the cardiovascular and kidney protection of SGLT-2 inhibitors and GLP-1 receptor agonists are unrelated to their impact on HbA1c. Double-blinded randomized clinical trials showed that SGLT-2 inhibitors reduced the risk of cardiovascular death and hospitalization for heart failure in patients with or without diabetes. Therefore, cardiovascular and kidney risk, rather than HbA1c, constitutes a possible indication for the two medication classes. If patients with ASCVD remain above goal A1C despite the addition of an SGLT-2 inhibitor or GLP-1 RA, then adding the agent the patient is not currently on out of the two is recommended before dipeptidyl peptidase-4 aka (DPP-4) inhibitors, basal insulin, or sulfonylureas because the combined use of an SGLT-2 inhibitor and GLP-1 RA can produce an additive risk reduction for cardiovascular and renal adverse events.What is Finerenone, and how does it help with diabetes? Finerenone (Kerendia®) selectively blocks sodium reabsorption and overactivation of mineralocorticoid receptors within epithelial and non-epithelial tissues. This, in turn, reduces fibrosis and inflammation of both the kidneys and blood vasculature.Finerenone use for patients with advanced CKD, i.e., moderately elevated albuminuria, eGFR of 25- 60 mL/min, and diabetic retinopathy, is encouraged for nephroprotection. However, Patients with less-advanced CKD, i.e., stages 1-2, do not receive any benefit. Regardless of the severity of CKD, SGLT-2 inhibitors remain first-line therapy.Although Finerenone improves cardiovascular outcomes and reduces CKD progression for patients, it is still unknown if there are any additive cardioprotective effects if used with SGLT2 inhibitors and/or GLP-1 receptor agonists.Some Closing Pearls: The use of SGLT2 inhibitors in patients with eGFR > 25 decreased from 30 previously.If the A1c goal is not being met, combination therapy of insulin with a GLP receptor agonist can be considered, as this combination treatment has been shown to increase the efficacy and duration of insulin.Overall, this new change could be very beneficial if accepted internationally. Though understandably, there could be some limitations to this guideline given the availability and cost of these medications, as well as their contraindication of use in specific populations such as pregnancy, ages >65 with concurrent risk factors for hypoglycemia or dehydration, and those with history of acute pancreatitis. ____________________________Conclusion: Now we conclude our episode number 114 “Diabetes care update.” Yvette explained that the ADA now recommends the use of SGLT2 inhibitors and GLP-1 agonists in any patient with type 2 diabetes with current or at high risk for cardiovascular disease, chronic kidney disease, or heart failure. Primary care physicians should become familiar with the dosing, cautions, side effects, and contraindications of these meds. Also, a newer medication for CKD in diabetes was mentioned: Finerenone. Diabetes treatment continues to evolve, and we hope this information is useful for you. This week we thank Hector Arreaza, Yvette Singh, and Fiona Axelsson. Audio edition by Adrianne Silva.Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week! _____________________________Lacanlale, Jana K et al. “Notable Revisions in Diabetes Treatment According to ADA Guidelines.” Pharmacy Times, 26 Mar. 2021, https://www.pharmacytimes.com/view/notable-revisions-in-diabetes-treatment-according-to-ada-guidelines.Li, Sheyu, et al. “SGLT-2 inhibitors or GLP-1 receptor agonists for adults with type 2 diabetes: a clinical practice guideline.” British Medical Journal 2021; 373:n1091. doi:10.1136/BMJ.n1091Royalty-free music used for this episode: BUrn Flow by Gushito, downloaded on September 22, 2022, from https://www.videvo.net/royalty-free-music-track/burn-flow/1008877/ 

ReachMD CME
Reducing Morbidity and Mortality in Patients with CKD in T2D: New Late-Breaking Data

ReachMD CME

Play Episode Listen Later Oct 14, 2022


CME credits: 0.50 Valid until: 14-10-2023 Claim your CME credit at https://reachmd.com/programs/cme/reducing-morbidity-and-mortality-in-patients-with-ckd-in-t2d-new-late-breaking-data/14165/ The FIDELITY pooled analysis findings demonstrated benefits in cardiovascular and kidney outcomes when nonsteroidal mineralocorticoid receptor antagonists (MRAs) were added to the mix. Tune in to hear Drs. Pam Taub, Gerasimos Filippatos, and George Bakris discuss the risk factors of chronic kidney disease, the importance of measuring eGFR and UACR, and how finerenone improves outcomes.

GeriPal - A Geriatrics and Palliative Care Podcast
Updates in ID and Nephrology: Lona Mody, Rasheeda Hall, Devika Nair, Sonali Advani

GeriPal - A Geriatrics and Palliative Care Podcast

Play Episode Listen Later Oct 13, 2022 48:01 Very Popular


When I'm on service these days there is inevitably a moment when a resident says “Patient so-and-so is on X” - and I have absolutely no idea what X is.  Modern subspecialist practice advances at such a remarkably rapid pace, it can be hard to keep up. In this context, we're excited to hear from infectious disease experts and nephrologists about updates in the care of older adults.  Sonali Advani and Lona Mody talk about their recent JAGS article highlighting three recent articles that every clinician caring for older adults should be aware of in the treatment of infectious diseases (hint: I've never finished a course of antibiotics, and maybe your patients don't need that full course either).  Devika Nair and Rasheeda Hall talk about their JAGS article highlighting updates from nephrology in the care of older adults, including a link to this new eGFR calculator that does NOT include race.  We have a discussion about the decision to remove race, a social construct, from clinical risk calculators (though I'm not 100% sold that race should always be removed - if removal is likely to worsen disparities for example - at least until a superior race-blind calculator can be developed). These articles are part of a new series called Clin-Star Corner, a new series in JAGS that reviews practice changing articles in the care of older adults.  And yeah, they made me sing a Miley Cyrus song…(but not this hilarious parody about UTIs). Enjoy! -@AlexSmithMD

The Fellow on Call
Episode 033: Lung Cancer Series, Pt. 10: Metastatic NSCLC with driver mutations

The Fellow on Call

Play Episode Listen Later Oct 12, 2022


Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we continue our discussion on metastatic non-small cell lung cancer, focusing on NSCLC with driver mutations. * The approach to treatment of a patient with widespread metastatic NSCLC (mNSCLC) is very different than a patient without distant disease, which highlights why we do what we do:- Important to complete staging (discussed in prior episodes) to determine the extent of disease- Important to check molecular testing (looking for mutations in the cancer cells) and IHC for tumor proportion score (TPS) helps determine treatment options - If your molecular testing is identified in a driver mutation gene, there are targeted options for this! *Driver mutations are predictive of response to an oral therapy and a LACK of response to immune therapy (particularly in EGFR and ALK mutated patients) * EGFR Mutation:- Pay attention to the types of mutation in EGFR (not all are the same):-- Exon 19 deletion -- Exon 19 L858R-- Exon 21 T790M-- Exon 20 Insertion (Osimertinib [see below] cannot be used for this mutation)- Osimertinib is first-line standard of care for patients with EGFR-- Used to be a second-line agent. Many patients with EGFR mutations receiving earlier generation TKIs would develop resistance and when these tumors were sequenced, they would have Exon 21 T790M mutations. Osimertinib was effective even with this mutation and had superior overall survival data compared to chemotherapy (AURA3 Trial)--Now it is used in first-line setting for patients with EGFR mutation based on the FLAURA trial --- In this study, patients received osimertinib as first line vs. older generation EGFR-targeting TKIs (erlotinib or gefitib) and Osimertinib had better outcomes: ---- Showed that the median OS was 38.6 months with Osi vs. 31.8 months; also improved brain penetration! ---- Also effective in patients with metastatic disease to the brain: ----- Only 6% of patients had CNS progression with Osi vs. 15% with others- What if a patient is on Osi and later develops new brain mets?-- If there is progression within just the brain (and good control in other sites of the body) you can refer patient to Radiation Oncology for SRS-- Remember, based on discussion with Dr. Osmundson in our RadOnc lectures (Episode 028), it is important to HOLD Osimertinib if patient is going to get radiation to minimize the side effects- What is patient had progression of disease in several sites throughout the body?-- Management is less straightforward. -- In many of these cases, you can consider:--- Consolidative radiation - If small amounts of disease--- Changing therapy - If there has been widespread progression; likely would change to chemotherapy (without IO, since lower predictive response to IO with EGFR mutation)---- No clear guidelines if you should continue the TKI---- Remember that IO + TKIs can cause increased risk of side effects, such as pneumonitis and hepatitis. DO NOT DO THIS!* ALK Mutation:- There are many options for ALK mutations-- The first generation drug is crizotinib--- Lots of side effects —> “It is crazy to start with crizotinib”--- Studies for later generation TKIs were compared to crizotinib -- Many people today will use third generation ALK-inhibitor alectinib (Important trials: ALEX Trial and J-ALEX Trial)--- With alectinib, PFS 34.8 months, RR 83%, less CNS progression (12% vs 45%)--- 5 year OS rate 62.5%- What to do with disease progression while on ALK inhibitor?-- In ALK, you can actually switch to another ALK inhibitor and many will respond well--- Of course, with each change, you may expect not as great of a response * Lots of other mutations!- TFOC recommends just looking these up!-- Link to NCCN Guidelines on NSCLC; Page 41 has full list!- Another way to think about this, when do we NOT do TKIs as first line: -- KRAS G12C-- EGFR Exon 20 Insertion-- HER2- How do you counsel a patient when considering/starting a TKI? -- Patients with highest chance of having a targeted mutation are younger non-smokers with adenocarcinoma-- Set expectations: great outcomes overall, but still not a cure. -- Remembering the drugs: All TKIs usually end in “-nib” -- In general, the way we recommend remembering this: “Fatigue, GI, Derm (skin/nail changes)”; rarely pneumonitis References:* AURA3 Trial - https://www.nejm.org/doi/full/10.1056/NEJMoa1612674Established osimertinib was better than chemo for patients with EGFR mutation and acquired Exon 21 T790M resistance mutation* FLAURA Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1713137 Established osimertinib as first-line agent for patients with EGFR mutation * ALEX Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1704795Helped establish alectinib as superior for ALK mutations compared to crizotinib * J-ALEX Trial - https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30565-2/fulltextHelped establish alectinib as superior for ALK mutations compared to crizotinib * NCCN Guidelines on NSCLC - https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450 Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google PodcastLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!

GRACEcast - Discussions with the Global Resource for Advancing Cancer Education
Advancements of Targeted Therapy for EGFR Mutations in NSCLC

GRACEcast - Discussions with the Global Resource for Advancing Cancer Education

Play Episode Listen Later Oct 12, 2022 3:14


Dr. Chul Kim gives a brief history of targeted therapies, and discusses EGFR-TKIs.

Research To Practice | Oncology Videos
Small Cell Lung Cancer | Oncology Today with Dr Neil Love: Management of Patients with Small Cell Lung Cancer

Research To Practice | Oncology Videos

Play Episode Listen Later Oct 6, 2022 47:24


Featuring perspectives from Dr Benjamin Levy, including the following topics: Disease biology of and therapeutic strategies for small cell lung cancer (SCLC) (0:00) Current and future management of limited-stage SCLC (3:32) Case: A man in his mid 70s with newly diagnosed SCLC and isolated brain metastases (5:51) Novel therapies for SCLC (21:51) Future directions for lurbinectedin in the treatment of SCLC (25:54) Case: A man in his late 40s with no smoking history diagnosed with adenocarcinoma of the lung with EGFR exon 19, TP53 and RB1 mutations and small cell transformation apparent on repeat biopsy (29:54) Case: A man in his mid 50s with a heavy smoking history diagnosed with SCLC and disease progression after anti-PD-L1 monotherapy (36:25) Expanding immunotherapy options for the treatment of SCLC (41:07) Palliative and supportive services for patients with SCLC (44:21) CME information and select publications

The Fellow on Call
Episode 032: Lung Cancer Series, Pt. 9: Metastatic NSCLC without driver mutations

The Fellow on Call

Play Episode Listen Later Oct 5, 2022


Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we start our discussion on metastatic non-small cell lung cancer, focusing on NSCLC without driver mutations. * The approach to treatment of a patient with widespread metastatic NSCLC (mNSCLC) is very different than a patient without distant disease, which highlights why we do what we do:- Important to complete staging (discussed in prior episodes) to determine the extent of disease- Important to check molecular testing (looking for mutations in the cancer cells) and IHC for tumor proportion score (TPS) helps determine treatment options * Choosing a treatment is based on:- Histology - cannot use pemetrexed or bevacizumab in squamous cell - Platinum - Carboplatin is usually used (as opposed to our prior discussions about using Cisplatin because of LACE pooled analysis data)-- Why is Cisplatin not a great idea? Cisplatin should not be used if patients have (***high yield to know cisplatin eligibility criteria!!***): --- Poor performance status--- Patients with eGFR 50% can get IO monotherapy (spared chemotherapy)---- KEYNOTE 024: approval for pembrolizumab monotherapy in patient with PDL1>50%----- Study compared pembro to platinum doublet----- OS 70% vs. 50% at one year---- IMPOWER110: approval for atezolizumab monotherapy----- Study compared atezo to chemotherapy----- OS 64.9% vs 50% at 12 months--- Patients with score 50% WITHOUT SYMPTOMS: IO alone- In PDL1 >50% WITH SYMPTOMS: Chemo + IO- In PDL1

Physician's Weekly Podcast
Biomarkers for NSCLC: What You Need to Know – Part 2

Physician's Weekly Podcast

Play Episode Listen Later Sep 28, 2022 16:46


The evolution of biomarkers informing therapy decisions began in 2004, when the FDA approved a medicine to treat EGFR mutated non-small cell lung cancer (NSCLC). Since then, researchers have identified more than 20 distinct mutations in driver genes that are specific to lung cancer, nine of which are treatable through FDA-approved therapy drugs: epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, BRAF V600E, NTRK, MET, RET, and histological expression of programmed death ligand 1 (PD-L1).Confirming a patient's biomarker status can open the door to precision medicine. The molecular characterization of lung cancer has considerably changed the classification and treatment of these tumors, becoming an essential component of pathologic diagnosis and oncologic therapy decisions. The success of targeted anticancer therapies and new immunotherapy approaches has created a new paradigm of personalized therapy and has also led to accelerated development of new drugs for lung cancer treatment. Additional research is needed to identify and help treat the approximately one-third of lung cancer patients for whom biomarkers have yet to be identified.This podcast focuses on clinically relevant cancer biomarkers as targets for therapy, as well as potential new targets for drug development. We spoke in our first episode with Dr. David M. Waterhouse, who just moved to the Dana Farber Cancer Institute at Harvard Medical School, and until last month was the former Director of Clinical Research at Oncology-Hematology Care, in Cincinnati. We also talk about how these biomarkers are used in academic versus community hospitals. In this second episode, we talk with Dr. Sinchita Roy Chowdhuri, a molecular pathologist from University of Texas MD Anderson Cancer Center, about what you didn't know about actionable biomarkers for NSCLC.

CCO Oncology Podcast
Managing EGFR-Mutated Non-Small-Cell Lung Cancer in Today's Clinic: Expert Answers to Frequently Asked Questions

CCO Oncology Podcast

Play Episode Listen Later Sep 28, 2022 29:48


In this episode, Ryan D. Gentzler, MD, MS, and Jonathan Riess, MD, MS, answer audience questions on managing EGFR-mutated non-small-cell lung cancer (NSCLC) from a live meeting series. The episode includes expert insights on:• Identifying patients who may benefit the most from adjuvant osimertinib  • Testing for EGFR mutations in early-stage NSCLC• Critical importance of getting molecular test results before starting immunotherapy• Monitoring cardiac toxicity in patients receiving osimertinib• Key ongoing trials in EGFR-mutated NSCLC for patients with newly diagnosed disease and following progression on osimertinibPresenters:Ryan D. Gentzler, MD, MSAssociate ProfessorDivision of Hematology/OncologyDepartment of MedicineUniversity of VirginiaThoracic Medical OncologistUniversity of Virginia Comprehensive Cancer CenterCharlottesville, VirginiaJonathan Riess, MD, MSAssociate ProfessorDepartment of Internal Medicine/Hematology-OncologyUniversity of California, DavisMedical Director, Thoracic OncologyUniversity of California, Davis Comprehensive Cancer CenterSacramento, CaliforniaLink to full program: https://bit.ly/3DZGzSO  

Research To Practice | Oncology Videos
Non-Small Cell Lung Cancer | Oncology Today with Dr Neil Love: Management of Localized Non-Small Cell Lung Cancer

Research To Practice | Oncology Videos

Play Episode Listen Later Sep 26, 2022 39:49


Featuring an interview with Dr Heather Wakelee, including the following topics: Similarities and differences in the efficacy of neoadjuvant and adjuvant immunotherapies for localized non-small cell lung cancer (NSCLC) (0:00) Available data on the treatment of patients whose disease relapses on or after adjuvant immunotherapy (6:15) Activity of immunotherapy in patients whose tumors are EGFR mutated (10:29) Case: A woman in her mid 70s with EGFR-mutated NSCLC in her right lung (14:49) Case: A woman in her early 60s with a smoking history and a 4-cm right lower lobe lesion (24:17) Case: A man in his mid 50s with a smoking history and a left upper lobe mass with high PD-L1 expression (28:04) Optimal treatment of localized NSCLC in patients who have alterations in RET, BRAF and ALK (33:08) Importance of primary care doctors screening their patients for lung cancer (37:03) CME information and select publications

Neuro-Oncology: The Podcast
EGFR: the lazarus target in glioblastom

Neuro-Oncology: The Podcast

Play Episode Listen Later Sep 23, 2022 37:20


Dr. Maya Graham interviews Drs. Benjamin Lin, David Nathanson, Frank Furnari and Ryan Miller about their recent manuscript entitled: "EGFR, the Lazarus target for precision oncology in glioblastoma", published online in Neuro-Oncology in September 2022.

Hope With Answers: Living With Lung Cancer
What is my biomarker? THE question to ask

Hope With Answers: Living With Lung Cancer

Play Episode Listen Later Sep 22, 2022 35:15


What is my biomarker? A newly diagnosed lung cancer patient should ask this question before starting treatment. Why? Because the answer to this question can change the odds and the choices for your personalized treatment plan, especially for Black or African American patients. Black and African Americans must ask their doctors, “What is my biomarker?” to ensure they receive the latest targeted therapy treatment that is applicable. Hear from Dr. Sydney Barned and Brandi Bryant in this episode as they discuss their care and what a difference it made in knowing their biomarkers. And maybe even more importantly, they are advocating that every black or African American should ask that question, “What is my biomarker?”  There are more options for treating lung cancer and they want to make sure every black or African American patient, like everybody, else gains access to that full range of options. Why do Biomarkers matter in lung cancer treatment? Minority and underserved communities must advocate for themselves to get the best treatments, especially treatment that can increase the quality of their lives. Guest Dr. Osarogiagbon dives into not only the importance of asking, “what is my biomarker?”, but why it is essential that Black and African Americans make this question a priority. Thanks to lung cancer research, he's really excited that lots of biomarkers have been discovered to help doctors split what used to be a single disease, into a disease of many different bits and of different sizes.  Understanding biomarkers now allows doctors to predict how the cancer is going to behave. And then determine what treatment is most likely to benefit the patient, in terms of surviving lung cancer - and the quality of life, in response to cancer treatment.  “So, you go from 4% to 6% five-year survival, to up to 60%, if you get the right treatment for right cancer. As with ALK mutated lung cancer, so with some of the other subsets, the EGFR mutated lung cancers, the ROS1 mutated lung cancers, the BRAFF mutated lung cancers, the MET exon 14 mutated lung cancer, all... There are at least nine subsets of biomarker-driven lung cancers, and that continues to change all the time. So, that's why it's vital that we get tested, so we know which treatment would benefit us.” - Dr. Raymond Osarogiagbon Guests: Dr. Sydney Barned, a hospitalist at Ann Arundel Medical Center in Annapolis, Maryland, a lung cancer patient, and a member of the LCFA Speakers Bureau Brandi Bryant, a lung cancer patient, and a member of the LCFA Speakers Bureau Dr. Raymond Osarogiagbon, Chief Scientist for Baptist Memorial Health Care, Director of Baptist Cancer Center's Multidisciplinary Thoracic Oncology Program and Thoracic Oncology Research Group, and Principal Investigator of Baptist's Mid-South Minority-Underserved Consortium initiative, NCORP, in Memphis, Tennessee Show Notes | Transcript | Watch the video Resources: What Do I Need to Know About Biomarker Testing? National Comprehensive Cancer Network (NCCN) Guidelines for Non-Small Cell Lung Cancer What is a Liquid Biopsy for Lung Cancer? 7 Signs of Lung Cancer You Should Know

Lung Cancer Update
Meet The Professor: Current and Future Management of Non-Small Cell Lung Cancer with an EGFR Mutation — Part 2 of a 3-Part Series

Lung Cancer Update

Play Episode Listen Later Sep 20, 2022 64:53


Featuring a discussion on the treatment of non-small cell lung cancer with Dr Lecia Sequist, moderated by Dr Neil Love.

Research To Practice | Oncology Videos
Non-Small Cell Lung Cancer | Meet The Professor: Current and Future Management of Non-Small Cell Lung Cancer with an EGFR Mutation — Part 2

Research To Practice | Oncology Videos

Play Episode Listen Later Sep 20, 2022 64:55


Featuring perspectives from Dr Lecia Sequist, including the following topics: Introduction: Journal Club with Lecia V Sequist, MD, MPH (0:00) Case: A woman in her early 70s with Stage IIB adenocarcinoma of the lung and an EGFR exon 19 mutation— Adam R Miller, MD (19:26) Case: A man in his late 70s with metastatic adenocarcinoma of the lung and an EGFR L858R mutation develops hemoptysis from an “escape lesion” on osimertinib — Priya Rudolph, MD, PhD (24:59) Case: A man in his early 70s with metastatic adenocarcinoma of the lung (PD-L1 high) and an EGFR L858R mutation experiences disease progression on pembrolizumab — Sandip Patel, MD (28:45) Case: A woman in her mid 60s with metastatic adenocarcinoma of the lung with an EGFR exon 20 insertion with multiple brain and bone metastases (PD-L1

Clinical Papers Podcast
#116 - ADAURA - Osimertinibe adjuvante em pacientes com câncer de pulmão não pequenas células EGFR mutados, operados (IB-IIIA) – Dados atualizados – ESMO 2022

Clinical Papers Podcast

Play Episode Listen Later Sep 16, 2022 27:15


Em 2020 o estudo ADAURA avaliou o osimertinibe como tratamento adjuvante, após a cirurgia, para pacientes com câncer de pulmão não pequenas células EGFR mutados. Esse grande e importante Estudo mostrou, em sua primeira análise, que o osimertinib adjuvante obteve um benefício significativo de sobrevida livre de doença (SLD) quando comparado com o placebo em pacientes com câncer de pulmão EGFRm completamente ressecado, ± quimioterapia adjuvante (QT). O estudo incluiu pacientes estágio II-IIIA com Hazard Ratio (HR) pra SLD de 0,17 (p

Cancer.Net Podcasts
2022 Research Round Up: Lung Cancer, Lymphoma, and Childhood Cancers

Cancer.Net Podcasts

Play Episode Listen Later Sep 15, 2022 30:09


ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In the Research Round Up series, ASCO experts and members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, our guests will discuss new research in lung cancer, lymphoma, and childhood cancer that was presented at the 2022 ASCO Annual Meeting, held June 3-7 in Chicago, Illinois. First, Dr. Charu Aggarwal will discuss 3 studies looking at treatment options for people with non-small cell lung cancer. Dr. Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine in Philadelphia, Pennsylvania. She is also the Cancer.Net Associate Editor for Lung Cancer. You can view Dr. Aggarwal's disclosures at Cancer.Net. Dr. Aggarwal: Hello and welcome to this Cancer.Net podcast. I'm bringing you updates from the Annual Meeting of the American Society of Clinical Oncology, held in Chicago in 2022. I'm Dr. Charu Aggarwal. I'm the Leslye Heisler Associate Professor for Lung Cancer Excellence at the University of Pennsylvania's Abramson Cancer Center. I will be discussing updates on 3 studies today that offer insights and new advances in the management of patients with non-small cell lung cancer. I don't have any direct relationship with any of these companies or studies, and you can view a list of my disclosures on the Cancer.Net website. First off, I would like to talk a little bit about advances in the management of patients with EGFR exon 20 mutations. We know that a lot of advances have been made in the management of patients with non-small cell lung cancer, and much of that has been attributed to the fact that we are now able to deliver targeted therapy for a subset of patients. EGFR mutations form one such subset where we have a lot of oral drugs that are available, and we can offer these that improve survival, and patients can avoid chemotherapy, immunotherapy, and other IV infusional therapies. Within the subset of EGFR mutations lies this unique subset of EGFR exon 20 insertion mutations, which have been historically harder to target with currently available EGFR inhibitors. And over the last 5 years, we have seen tremendous growth of opportunities, targets, and new drugs for this subset of patients. The mutations in this subset forms about 2% to 5% of all non-small cell lung cancers. But now we have 2 FDA-approved drugs in this space, one being intravenously administered, amivantamab, and another that is orally available, mobocertinib. We covered this in a podcast as well as a blog, so please check those out on our Cancer.Net website. But building upon that progress, there is now another drug that was reported at ASCO. This drug is called CLN-081. And we saw preliminary activity in a phase 1 and 2 study of this molecule or this drug in patients with EGFR exon 20 insertion mutations. It's an orally available drug. The top line data is that it is safe, it is effective, it was tested in different doses. It was tested at less than 65 milligrams, 100 milligrams, and 150 milligrams, again, as I mentioned, administered orally, and we saw responses and patients that had previously received other therapies and may have progressed on other therapies. And what we found was that this drug also tends to have activity against brain metastases, which I think is this huge unmet need in the management of such patients. So I think more to come, but again, I think offers us an insight into what may be in the future, an attractive drug for our patients with EGFR exon 20 insertion mutations. So stay tuned, more on that in the future. Shifting gears, I would like to now talk about one of the common mutations. So we talked about EGFR exon 20, which is about only 2% to 5%, but the largest subset of mutations in non-small cell lung cancer really revolves around KRAS mutations, and these form about 30% to 35% of all mutations in non-squamous, non-small cell lung cancer. And amongst this group there is another subset which is KRAS G12C non-small cell lung cancer, that forms about 13% of all lung cancers. We have 1 approved drug already in this space by the name of sotorasib that is FDA approved for the management of patients with this particular mutation after having received 1 prior therapy, be it chemo-immunotherapy or immunotherapy. At this year's ASCO meeting, we heard data from a study called KRYSTAL-1, which looked at the activity and safety of another molecule called adagrasib, which is an orally available drug targeting KRAS G12C, again, in a similar population of patients with advanced and metastatic non-small cell lung cancer harboring a mutation. We found that this drug is again effective, the overall response rate was about 43%, the majority of the patients had stabilization of disease, about 80%, and many patients were able to remain on treatment with stabilization of disease. We found that this drug does have side effects and adverse events and most commonly of this were diarrhea, nausea, vomiting, and fatigue. Many patients did require dose reductions, but the activity of the drug remained despite dose reductions. Now, what would be the advantage of this drug against the currently available sotorasib? In another smaller study reported at ASCO, there seemed to be activity in the brain, including intracranial penetration with the use of this molecule, adagrasib, which has not been demonstrated before with other KRAS G12C inhibitors, so I think that makes it a potentially attractive option. Again, I will say that the report of this intracranial activity was in a very small subgroup of patients, so I think needs to be further corroborated in a larger study. Shifting gears again and talking about our last study, so I would like to highlight what do we do if, in case, patients don't have a targetable mutation. I want to highlight that we do have a lot of available options, and we are continuing to improve upon available options. The way we treat such patients is by using immunotherapy, either alone or in combination with chemotherapy. But what do we do after this treatment stops working? Researchers from the Southwestern Oncology Group, or SWOG, launched a massive national effort called Lung-MAP, which is basically a clinical trial that evaluates several different strategies all at once, either for patients with targetable mutations or for patients without a targetable alteration. And they reported results from a study that evaluated the combination of pembrolizumab with ramucirumab in patients that may have progressed after frontline immunotherapy. Now, pembrolizumab is immunotherapy, so the concept was, can we continue immunotherapy beyond progression and perhaps get some synergistic activity by using ramucirumab, which is a drug that prevents blood vessels from forming in the tumor itself. It's an anti-angiogenic agent, meaning that it is a targeted molecule that prevents blood vessel formation and promotes tumor death. What they found was that patients that received pembrolizumab and ramucirumab were more likely to live longer, so overall survival was longer for patients with this combination compared to a physician investigator discretion choice, such as chemotherapy in combination with ramucirumab or other chemotherapies that are otherwise used in the second line setting. And interestingly, we did not find a significant improvement in shrinkage with this combination of pembrolizumab and ramucirumab or a significant reduction in the time of progression-- or, sorry, prolongation of the time of progression of disease. But the overall survival findings are interesting, and I think that's why we are including them in this podcast because that's one of the approaches that is leading to an improvement in survival and improvement in outcomes. I will point out that this is a phase 2 study. These results would need to be validated in a large prospective phase 3 trial so that we can account for certain confounding factors that may have led to these results. Having said that, I think there's a tremendous excitement, there's tremendous excitement in this field. I gave you examples of, or highlighted, 3 studies: one in patients with EGFR exon 20 insertion mutations, another in KRAS G12C mutations, and the third in patients who may have already received either immunotherapy or chemoimmunotherapy. We will continue to update our Cancer.Net website with updates as they come through, new advances, new studies, so thanks for following, thanks for listening, and more to come. Stay tuned. Thank you. ASCO: Thank you, Dr. Aggarwal. Next, Dr. Christopher Flowers will discuss new research in treating people with different subtypes of lymphoma, including mantle cell lymphoma and diffuse large B-cell lymphoma. Dr. Flowers is the Chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center and was appointed Division Head ad interim of Cancer Medicine in August 2020. He is also the 2022 Cancer.Net Associate Editor for Lymphoma.   You can view Dr. Flowers' disclosures at Cancer.Net. Dr. Flowers: Hello and welcome to this podcast that is a review of late breaking abstracts from the ASCO Meeting and recent updates in lymphoma. I'm Dr. Christopher Flowers, professor and chair of the Department of Lymphoma and Myeloma and Interim Division Head for Cancer Medicine at The University of Texas MD Anderson. And it's my great pleasure to discuss with you some of these late breaking abstracts. I do have some disclosures that are related to the content that I will present from this year's ASCO Meeting and recent studies in lymphomas. Those are available at Cancer.Net. Those relate to my role as a consultant for the development of clinical trials in lymphomas and research funding that MD Anderson has received from companies related to my role in clinical trials in lymphoma and clinical trials across cancers. So, the ASCO Meeting had a host of new information that was presented. Some of that information centers around key clinical trials. One that was a pivotal clinical trial, the SHINE clinical trial, looked at patients with mantle cell lymphoma, a rarer lymphoma subtype, that looked at the combination of bendamustine and rituximab, a standard chemoimmunotherapy combination, compared to that same chemoimmunotherapy combination, bendamustine, rituximab, plus the Bruton's tyrosine kinase inhibitor ibrutinib. Ibrutinib, as some of you may know, is a kind of therapy that is typically used in the relapse setting for patients with mantle cell lymphoma when they have their disease come back. And the SHINE clinical trial was looking at adding it to frontline therapy. What this randomized, controlled trial in the phase 3 setting found was that patients who received the combination of bendamustine, rituximab, plus ibrutinib had improvement in their progression-free survival, meaning that the time that it took for their disease to come back or them to have deaths related to the lymphoma was longer for patients who received this combination. About 2.3 years longer than the group that received bendamustine, rituximab, plus placebo. And in total, that led to a median progression-free survival of 6.7 years. That study has now been published in the New England Journal of Medicine and was led by my colleague Dr. Michael Wong from MD Anderson. Dr. Wong also led another study that was presented at the ASCO Meeting looking at CAR T-cell therapy for patients with mantle cell lymphoma. That study has now been published in the Journal of Clinical Oncology, and it looks at brexucabtagene autoleucel, a kind of CAR T-cell therapy, where that-- the CAR T-cell therapy was successfully manufactured for 71 of the 74 patients in the trial. 68 of those patients received an infusion and the median progression-free survival, so the average amount of time that it took for patients to have progression of their disease, was about 25 months. And so a marked benefit for those patients who were receiving CAR T-cell therapy when their mantle cell lymphoma came back. There also were major breaking abstracts at the ASCO Meeting in the area of diffuse large B-cell lymphoma. As many of you may know, diffuse large B-cell lymphoma is the most common type of lymphoma that occurs in the United States. And there was a breaking trial that was presented in December at the American Society of Hematology Meeting describing polatuzumab, a CD79b antibody drug conjugate, as a new drug in the substitution of frontline therapy for patients with diffuse large B-cell lymphoma in combinations with rituximab, cyclophosphamide, adriamycin, and prednisone, or the pola-R-CHP arm, that compared favorably to rituximab and CHOP chemotherapy, which has been the standard of care for patients with diffuse large B-cell lymphoma. And that trial showed an improvement in progression-free survival. At this year's ASCO Meeting, Franck Morschhauser presented results from looking at subsets of that patient population. Those patients who had BCL2 by immunohistochemistry that was positive or MYC expression by immunohistochemistry that was positive, or both of those, what we call double-expressor lymphomas, those who have poorer risk than standard groups. And those double-expressor lymphomas, treated with pola-R-CHP, had improvement in progression-free survival compared to R-CHOP with a hazard ratio of 0.64 in that group. We also saw in a multitude of analysis that that supported the benefit of pola-R-CHP in patients with both BCL2-positive and MYC-positive diffuse large B-cell lymphoma. Another area that has been very hot in diffuse large B-cell lymphoma clinical trials is the role of bispecific antibodies. Bispecific antibodies are antibodies that bind both to CD20, a marker on the diffuse large B-cell or the lymphoma cells, and to the marker CD3, which is a marker on T-cells which brings the normal T-cells of the immune system in close proximity to the lymphoma cells and then leads to immune-directed killing of lymphoma cells. The agent glofitamab is an agent that was presented by Michael Dickinson at this year's ASCO Meeting in an abstract. And in this study, 107 patients who received more than 1 dose of steady treatment went on to have complete responses in about 35% of patients. And this showed that glofitamab induced durable complete responses and had a very favorable safety profile in patients with relapsed and refractory diffuse large B-cell lymphoma. And in this trial, they compared that also for patients who had prior exposure to CAR T-cells and showed that responses were also good in those patients. Another set of studies has also looked at bispecific antibodies and a whole host of other areas with multitude of other agents. Another study that was presented at this year's ASCO Meeting explored the use of bispecific antibodies in the frontline setting in combination with the R-CHOP regimen that I just discussed. In that study, Lorenzo Falchi presented results of the subcutaneous bispecific antibody epcoritamab in combination with R-CHOP. This was a relatively small study of 33 patients that showed that the combination of epcoritamab plus R-CHOP was something that was safe and tolerable. There were no new treatment emergent adverse events that led to discontinuation of epcoritamab in the study. And there are some adverse events that are of special interest that we see with the bispecific antibodies, and those include the kind of immune-mediated adverse events that we can also see with CAR T-cells, like cytokine release syndrome, or CRS, or neurologic toxicities that we can see there that are also called ICANS. What we've seen in this trial, that about 42% of patients had some form of cytokine release syndrome, but that most severe form of cytokine release syndrome, those that were greater than grade 3 in severity, was only in 3% of patients. And likewise, the neurologic toxicities, or ICANS, that were grade 2 was in only 3% of patients. Relatively few patients completed all therapy by the time that this was presented. Only 10 patients had completed 6 cycles of therapy, but that showed an overall response rate that was quite high in that patient population. There were a whole host of other trials that were presented at this year's ASCO Meeting, and those portend improved kinds of outcomes on the horizon for patients with lymphomas across the spectrum. And I think it's an exciting time moving forward for clinical trials in lymphoma and hopefully, to see new therapies that emerge for the management of this disease. One of those new therapies that happened outside of the ASCO Meeting was the recent FDA approval of CAR T-cell therapy in the relapse setting for follicular lymphoma. And this was based on the ELARA clinical trial. And I think the future is quite bright for therapies and for patients with lymphomas broadly. ASCO: Thank you, Dr. Flowers. Finally, Dr. Daniel Mulrooney will discuss new research in childhood cancers, including a study comparing treatment options for Ewing sarcoma, and several studies on neuroblastoma. Dr. Mulrooney is an Associate Member in the Division of Cancer Survivorship at St. Jude Children's Research Hospital. He is also the Cancer.Net Associate Editor for Pediatric Cancers. You can view Dr. Mulrooney's disclosures at Cancer.Net. Dr. Mulrooney: My name is Dr. Dan Mulrooney from St. Jude Children's Research Hospital. I'm the Deputy Director of the After Completion of Therapy Clinic at St. Jude and primary care for survivors of pediatric solid tumors. The annual ASCO Meeting is typically quite busy and full of research presentations sharing knowledge and advances in cancer treatment and care. Today, I'd like to highlight some of the exciting presentations in pediatric cancer. Please note, I do not have any relationships to disclose related to any of these studies. At this year's meeting, one of the highlights was a European study in patients with relapsed or refractory Ewing sarcoma. Ewing sarcoma is a rare bone cancer that typically occurs in adolescents or young adults. While challenging to treat, it is difficult to cure in patients who have relapsed, and studies are needed to improve the care of these patients. Investigators from 13 European countries and Australia and New Zealand studied the most common relapsed therapies, which include irinotecan and temozolomide, gemcitabine and docetaxel, topotecan and cyclophosphamide, or high-dose ifosfamide. The study enrolled 451 patients between 2014 and 2021 and randomly assigned them to one of these four treatments. Based on response rates, the first 2 arms were dropped and the study was largely a comparison between topotecan cyclophosphamide and high-dose ifosfamide. The main outcome was event-free survival. Event-free survival is a common way in a clinical trial to see how well a treatment works. It measures the time from treatment that the patient remains free of complications, such as return or progression of the cancer. But investigators also looked at overall survival, toxicity, and quality of life. The 6-month event-free survival was better for high-dose ifosfamide at 47% compared to 37% for topotecan cyclophosphamide. The median overall survival was also better for high-dose ifosfamide compared to topotecan cyclophosphamide. The results were best for children younger than 14 years old versus those 14 or greater. Toxicities included fever and neutropenia, nausea, vomiting, and diarrhea. Patients receiving high-dose ifosfamide had more neurologic and kidney toxicities, which might be expected since ifosfamide is known to affect these organ systems, while only descriptive measurements of quality of life appeared higher for those children treated with high-dose ifosfamide compared to topotecan and cyclophosphamide. The strength of this trial is its large size, particularly for a rare cancer, and the fact that it randomized patients to the most commonly used treatment regimens for relapsed Ewing sarcoma. Importantly, data did not previously exist comparing these different treatments. While the results of this study are promising, clearly more needs to be done, and there was a lot of discussion at the ASCO Meeting about how to further improve survival in these patients. This study provides some information for doctors and patients, but importantly, provides data to advance future trials, which will concentrate on incorporating new targeted drugs with high-dose ifosfamide. This study is ongoing and is adding additional arms to continue to improve the outcomes for patients with relapsed or refractory Ewing sarcoma. In addition to this study in Ewing sarcoma, several studies investigating neuroblastoma were presented. Neuroblastoma is the most common extracranial solid tumor in children and for children with high-risk disease requires intensive and prolonged treatment, including chemotherapy, surgery, radiation therapy, and stem cell transplantation. Treatment for these patients has improved since the introduction of immunotherapy, particularly an antibody directed at a particular antigen named GD2 on the neuroblastoma cells. One study showed improvement in outcomes using this antibody for children with relapsed or refractory neuroblastoma, and another study demonstrated feasibility of using this antibody earlier in treatment, which was not previously known to be safe and tolerable. In what is called the BEACON study, investigators tested whether the antibody, called dinutuximab, would be effective when combined with chemotherapy for relapsed or refractory neuroblastoma. They enrolled 65 patients from 2019 to 2021 and randomized these patients to either chemotherapy alone or chemotherapy plus dinutuximab. The median age of these children was 4 years. The overall response rate, which means either a complete or partial response, was 18% for the chemotherapy-only arm but improved to nearly 35% for those treated with chemotherapy and dinutuximab. The progression-free survival was 27% for chemotherapy only and improved to 57% for those treated with chemotherapy and the antibody. There was no change in overall survival, though investigators think this may have been due to some patients who had progressive disease and crossed over to the antibody arm of the study. This presentation was followed by a study from the Children's Oncology Group, which investigated the feasibility of adding antibody treatment earlier in the treatment regimen for neuroblastoma. Prior studies had used antibody later in treatment when the tumor burden is thought to be lower. The endpoint of this study was tolerability measured by toxic deaths or unacceptable toxicities, such as adverse reactions to the medication. For example, sustained low blood pressure requiring a ventilator or breathing machine, or severe neuropathy. 42 high-risk neuroblastoma patients were enrolled from 8 different children's hospitals between 2019 and 2021. 41 of the 42 were able to complete the induction chemotherapy plus the antibody. There were no toxic deaths or unacceptable toxicities. Importantly, 85% were able to complete the next phase of treatment, called the consolidation phase, and 79% were able to complete the following phase after consolidation, called post-consolidation. One-year event-free survival was 83%, and 1-year overall survival was 95%. Now, it's important to know these are still early results, and the trial recently closed, and some of the patients have only completed therapy within the last year. Both of these studies add to the knowledge of chemoimmunotherapy for children with high-risk neuroblastoma. These studies provide a foundation for larger randomized trials that will further advance the care of these children. And finally, another study looked at race, ethnic, and socioeconomic disparities among children treated for high-risk neuroblastoma on Children's Oncology Group studies. There were no differences in event-free survival, but there were differences in overall survival based on ethnicity. The 5-year survival was lowest for Hispanic patients at 47%, 50% for non-Hispanic other ethnicities, which included Asian, Native American, Native Hawaiian, or Pacific Islanders, and 62% for non-Hispanic Black and non-Hispanic White children. Importantly, these investigators also studied household and neighborhood poverty. Overall, survival was lower for children living in poverty, though some of these differences went away when accounting for other factors, such as stage of disease or high-risk features. This study is important because it highlights the increasing need to collect data on clinical trials that may contribute to inequities in outcomes. While most studies collect data on the race and ethnicity of participants, other factors known as social determinants of health, such as income, neighborhood, education, access to health care, and insurance coverage, may also contribute to outcomes in pediatric cancer patients. Overall, the studies highlighted here and presented at this year's ASCO Annual Meeting focused on difficult-to-treat cancers, such as relapse or refractory disease, and they have laid the groundwork for future investigations to continue to improve survival rates for all children diagnosed with a malignancy through improved therapies and by addressing potential social barriers. Thank you for listening to this brief summary of the new research in pediatric oncology presented at the 2022 ASCO Annual Meeting. ASCO: Thank you, Dr. Mulrooney. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

ASCO Daily News
How Primary Tumor Sidedness Impacts Treatment and Other Advances in Colorectal Cancer

ASCO Daily News

Play Episode Listen Later Sep 15, 2022 18:51


Gastrointestinal cancer experts Dr. Aparna Parikh and Dr. Kristin Ciombor discuss the treatment implications of the phase 3 PARADIGM trial and other advances in colorectal cancer with guest host and ASCO Daily News Associate Editor, Dr. Shaalan Beg.   TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the ASCO Daily News Podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Center and vice president of Oncology at Science 37. I'm delighted to welcome Dr. Aparna Parikh, and Dr. Kristen Ciombor to the podcast today. Dr. Parikh is an assistant professor of Medicine at Harvard University and a GI medical oncologist at the Mass General Hospital Cancer Center. Dr. Ciombor is an associate professor of Medicine and GI medical oncologist at the Vanderbilt University Medical Center. Today, we'll be discussing exciting new approaches using EGFR inhibitors as frontline therapy in colorectal cancer, and promising advances with immune therapy in the treatment of rectal cancer. Our full disclosures are available in the show notes, and disclosures of all guests on the podcast can be found in our transcripts at: asco.org/podcasts. Dr. Parikh, and Dr. Ciombor, it's great to have you on the podcast today. Dr. Aparna Parikh: Thanks so much. Dr. Kristen Ciombor: Thanks so much for having us. Dr. Shaalan Beg: We've seen some exciting advances in GI oncology this year. Let's start with colorectal cancer. Dr. Parikh, there have been many trials looking to compare EGFR and VEGF inhibitors in colorectal cancer. We've heard about the IDEA studies, the FIRE trials, and CALGB 80405. At the 2022 ASCO Annual Meeting, we heard the results of the PARADIGM trial. Have we finally answered the question of when to use EGFR inhibitors as frontline therapy for colorectal cancer? Dr. Aparna Parikh: Thanks so much, Dr. Beg, for this great question. It has been a really exciting year for colorectal cancer across the board. So, the anti-EGFR story is really interesting and has evolved. And maybe just for a little bit of background, we know that colorectal cancer originating from both the right and left side of the colon differ. So, they differ embryologically, and epidemiologically; there are different genetic and molecular aspects to right and left sides of colon cancers. And we have learned over time that in the era of targeted therapy, the primary tumor location has been found to play a very important role, not only in the prognosis of patients but to predict treatment response. We know that patients that have left-sided colon cancers-- and when we think about left-sided colon cancers, we think about cancers that originate from the splenic flexure and descending colon, sigmoid colon, rectosigmoid junction, and sometimes include the rectum in this as well. The rectals have slightly different molecular features than distal colons. And we know that these left-sided patients, overall, have better survival benefits than patients that have right-sided CRC. And that includes again, cecum, ascending colon, hepatic flexure, and transverse colon. So, we know that that had prognostic implications, but what about the predictive implications? And with ASCO, we saw some really exciting data with the PARADIGM study, as Dr. Beg highlighted. We have seen many examples in the past showing the predictive power of anti-EGFR therapy, and anti-EGFR therapy showing a detriment for patients on the right side of the colon. But all these results historically have been obtained by retrospective analysis. So, retrospective analysis of the pivotal CALGB 80405 study, which is the first-line biologic trial. FIRE-3, which is a similar study, but done out of Europe, and KRYSTAL. So all these studies show the same finding but were all obtained basically by retrospective analysis. And what we saw with PARADIGM this year, which is exciting to see, is that this was the first prospective trial to test the superiority of an anti-EGFR inhibitor panitumumab versus bevacizumab in combination with standard doublet first-line chemotherapy for patients that were RAS-wild type. I guess I forgot to mention that again, anti-EGFR therapies are only eligible for patients that are RAS-wild type. We know that RAS-mutant patients and RAS, KRAS HRAS patients don't respond to anti-EGFR therapy. So, the study was looking at RAS-wild type patients, and again, asking the question “was panitumumab better than bevacizumab in combination with chemotherapy for these RAS-wild type patients and for left-sided tumors?” It was a multicenter trial done in Japan-- and I always commend the Japanese on their work and their designs and ability to do these studies that ask really important questions. And, overall survival was the primary endpoint of the study in patients with left-sided tumors, but they also did a full set analysis including patients that didn't have left-sided tumors. They had 823 randomized patients. Many patients, a handful did not receive per-protocol treatment, and some were excluded for other reasons relating to inclusion criteria. And they had 400 patients that ultimately received panitumumab and 402 patients that received bevacizumab in the full set analysis. And of those patients, there were 312 and 292 respectively had left-sided tumors. And although the PFS was comparable between the treatment group, we saw that panitumumab in the left-sided patients actually did improve the OS in both patient populations. But when you looked at the left-sided tumors, the difference was 37.9 versus 34.3 months meeting statistical significance. So, this was an exciting study because it confirmed prospectively what we have seen time and time again, and really behooves us to do early biomarker testing and know RAS status early for these patients with right-sided tumors, as they do derive benefit from anti-EGFR. Maybe I'll just pause there and open it up for more questions or comments from Dr. Ciombor as well. Dr. Kristen Ciombor: Yeah, Dr. Parikh, I thought these data were encouraging. And as you mentioned, the first prospective data that we have in this setting now that we know this primary tumor sidedness matters. Just on a practical note, what do you do in practice? Do you give a lot of anti-EGFR in the first-line? I find that the toxicity can be challenging sometimes and patients may not want to do that. So, it leaves us in a quandary sometimes. Dr. Aparna Parikh: Yeah. So, what's interesting and I don't think we have this data clearly answered yet is, I had, especially for kind of a fit patient-- with the previous data that we've seen with TRIBE and others showing a survival benefit with triplet chemotherapy for first-line therapy, my inclination had actually been to prefer triplet-- and we know that triplet and anti-EGFR toxicity-wise is really, really tough to manage, and really no benefit there that we've seen with OS or PFS, even though you maybe do get a little bit of a better response rate with that. And so where I have sort of struggled is triplet versus just doing first-line doublet plus anti-EGFR. You know, we are not having a discussion about triplet today, but we also saw some data at ASCO showing that perhaps the benefit of the triplet, with the triplet study, is not as much as we had hoped it would've been too. So, it's a good question. I do tend to prefer triplet, I guess, overall, for the healthy, good performance status patient. And then, if not, then doublet. And we, unfortunately, don't have kind of rapid EGFR testing, we're pushing for that. In practice, I think having RAS/RAF status up front would be entirely helpful. It's lumped into our pan-tumor profiling, comprehensive genomic panels. We get microsatellite instability (MSI) status, which I know we'll talk about here next right away. But I think another reason that oftentimes we don't add it right away, is because we don't have the RAS status right away. So, you just start with a doublet and you may end up sneaking it on later. And then, I'd love to, maybe in another podcast, where we can discuss second-line anti-EGFR therapies and what people do in practice for those right-sided patients should they never get anti-EGFR and later-lines of therapy too. And I would argue, perhaps not, because we do see some patients that do benefit, but it can be challenging sometimes with a fresh new patient to make these decisions. But at least, feel encouraged that we're doing the right thing by adding anti-EGFR therapy if they can tolerate it for the left-sided RAS-wild type patient. How about you? What do you do? Dr. Kristen Ciombor: Yeah. Largely, it's a great question. And I don't love giving anti-EGFR therapy. We have an additional issue where I am geographically in that we don't ever give cetuximab because of the high rates of an infusion reaction. So, we pretty much stick to panitumumab and are glad to have that option. But I have started to talk to patients about toxicity and I'm really upfront with the survival data. And it's interesting how people choose differently in terms of what's important to them. And whereas a few extra months in the overall survival may be overshadowed by the toxicity that they have to go through to accomplish that. So, it's good to have many options though, and that's the important thing, and I think the takeaway, as well. Dr. Shaalan Beg: So, kind of brings it back to the fundamentals of practicing medicine, right? Bringing our patients and giving them the options that are most available to them. But I'm going to ask both of you one by one: So, if we have our patient with left-sided colorectal cancer, known as KRAS RAS-wild type, do you recommend EGFR therapy and VEGF therapy and allow the patients to decide, or do you feel that we decide if their profile is such that we should continue with VEGF therapy instead? Dr. Ciombor, do you want to go first? Dr. Kristen Ciombor: Yeah, I think both are good options. I don't only do bevacizumab in the first-line by any means because we do have that survival data. It mostly comes down to a discussion with the patient in terms of toxicities and survival and how well those balance out. Dr. Aparna Parikh: Yeah, very similar. I think we have also gotten a little bit more adept at managing toxicity. I'm pretty aggressive about prophylaxis with even doxy and topicals for managing the rash. And so, for some of my younger patients who are wanting to be "aggressive" and want the exposure to anti-EGFR early but are still very mindful of how it's impacting their day-to-day semblance of self, especially for the younger patients, try to be very proactive about side effect management. And then, of course, we have the patients that have the electrolyte wasting and things too that sometimes if it's bad, we are stuck with infusions frequently and you may end up dropping for those patients. But I think the rash at least I feel like for most patients we can manage if you're aggressive about it too. And I think we have gotten better at that than we were many years ago. Dr. Kristen Ciombor: Never thought we'd be dermatologists, did we? In training, that was definitely not a path I was good at. Dr. Shaalan Beg: Dermato-Oncology, rapidly growing field. So, Dr. Ciombor, the rectal cancer space has evolved very rapidly in recent years, especially when we hear about total neoadjuvant therapy, short-course radiation, watch-and-wait, for those with complete clinical responses. So at ASCO this year, we heard results on immune therapy and rectal cancer. Can you summarize where we are with immune therapy and rectal cancer? Dr. Kristen Ciombor: So, yes. We heard a lot this year at ASCO; both at ASCO GI and ASCO, from the Memorial group and Dr. Cercek's group. And this has been a really exciting advance that we're starting to see and potentially paradigm-shifting data. So, we know-- as you mentioned, that our treatment of rectal cancer, specifically, locally advanced rectal cancer has changed a lot in the last few years with a shift to more Total Neoadjuvant Therapy. And what the Memorial data showed was that for the patients who have microsatellite instability or mismatch repair deficiency, which admittedly, is a small group, but certainly ones that we see in clinic, those patients, on their trial were treated with six months of dostarlimab as neoadjuvant therapy prior to any other treatment; before radiation, surgery, et cetera, and no chemotherapy. And what they found was that actually, six months of dostarlimab in the first 14 evaluable patients actually induced a 100% clinical complete response rate. So, it's really unheard of in most of our trials to see 100%. And I think that caught everyone's attention for sure. I think we have to keep in mind who these patients were and are because they are currently being followed. So, for instance, these were patients that had pretty bulky node-positive disease, almost all these patients did. These were not really early-stage tumors. We did see that 100% were BRAF-wild type, so it does tell us maybe this is not completely the population that we're all seeing when we do see microsatellite instability since we see a lot of sporadic tumors with BRAF mutations. But on the whole, I mean, these were all MSI-high patients and treated with dostarlimab; the six months, that was the total amount of treatment that they received, though a few patients achieved that clinical complete response earlier at about three months, at the three-month reassessment. And what the clinical complete response rate was, was looking both radiographically, as well as endoscopically, and not seeing any sign of residual tumor. I think the important thing here is that median follow-up is still pretty short. There are a few patients who are approaching now two years past that dostarlimab therapy and have not had tumor recurrence, but overall, the median follow-up is still quite short. So, I think we do need to continue to follow these patients. We don't have overall survival data yet either. I think we still have a lot to learn, but this is a very encouraging start and certainly, something that could be really treatment-changing for these patients, which again, as Dr. Parikh was saying, we need this molecular profiling early to make treatment decisions right off the bat, not even only for metastatic now, but even for these locally-advanced rectal cancer patients. Because if you think about it, we've all taken care of patients who have to go through chemoradiation, and chemo, and surgery, and have a lot of morbidity from those treatments so that even if you cure them, they're left with a lot of toxicity. So, if we could avoid some of that, even potentially, surgery, that would be wonderful. But I do caution that this is not the standard of care yet. This is only based on 14 patients with short follow-ups at the current time. But the trial is ongoing, and there are other trials open in this space for patients who don't live in New York or can't get to New York. And for instance, ECOG-ACRIN study 2201 is treating these same patients with nivo and ipi, as opposed to dostarlimab. And that trial is open in about 80 sites now across the US. So hopefully, geographically near all of these patients. Dr. Shaalan Beg: I think a lot of us and a lot of our listeners, that Monday after the results were announced on ASCO had our phone lines and our patient secure messaging lines blowing up. Dr. Kristen Ciombor: We should have warned our nurses and our treatment teams that they would be fielding these questions, yes. On one hand, it's wonderful that our data and the science is getting out to patients. But I think we also have to be really careful as to what is reaching them because many of them didn't realize it was for this subset of patient populations. But great that they're asking those questions and wondering-- being advocates for themselves too. Dr. Shaalan Beg: You use the term clinical complete response. Can you talk about how we determine someone has a complete clinical response and what their follow-up looks like? Dr. Kristen Ciombor: Yeah. In the context of this study, it was actually, as I mentioned, it was both radiographic complete response, as well as endoscopic. So that's one thing that is a little bit tricky when you think about surveillance of these patients. So, it requires a lot, both in frequent surveillance, MRIs, FLEX SIGs often, digital rectal exams, sometimes doing PET scans or CTs, and patients who-- not only on this kind of study but also in non-operative management; watch-and-wait - really have to commit to very close, very frequent follow-up because if the cancer recurs, we don't want to miss that and lose our chance to cure them. So I think that's a little bit different everywhere, how that watch-and-wait approach really manifests, but I think we're learning how to do that, and working in a multidisciplinary group to make sure that patients get the surveillance that they need. Dr. Aparna Parikh: Yeah. I totally agree. If we offer, for the MSI-high patients, if we ultimately end up offering neoadjuvant immunotherapy-- and actually, I'm looking forward to your study, Dr. Ciombor, too, I think the monotherapy versus doublet, too, is going to come up for these patients. But I had a patient just a week or two ago that was starting on this approach with neoadjuvant immunotherapy, but for now, as a group, if we're proceeding down that and they do get a clinical complete response, we're deciding to forego even the radiation and surgery. We're following what they did in the OPRA study, which was pretty aggressive surveillance on the backend, both with direct visualization and MRIs, and you're seeing these patients every three months or so. Dr. Shaalan Beg: Well, thank you Dr. Ciombor and Dr. Parikh for sharing some valuable insights with us on the podcast today. Dr. Aparna Parikh: Thanks so much for having us. It was a lot of fun. Dr. Kristen Ciombor: Thanks for having us on. Dr. Shaalan Beg: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe, wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Follow today's speakers: Dr. Kristen Ciombor @KristenCiombor Dr. Aparna Parikh @aparna1024   Dr. Shaalan Beg @ShaalanBeg Listen to additional episodes on advances in GI oncology: Novel Therapies in GI Oncology at ASCO22 ASCO22: Key Posters on Advances in GI Oncology Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals Dr. Kristen Ciombor: Consulting or Advisory Role: Merck, Pfizer, Lilly, Seagen, Replimune, Personalis Research Funding (Inst.): Pfizer, Boston Biomedical, MedImmune, Onyx, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Incyte, Amgen, Sanofi Recipient, Bristol-Myers Squibb, Array BioPharma, Incyte, Daiichi Sankyo, Nucana, Abbvie, Merck, Pfizer/Calithera, Genentech, Seagen Travel, Accommodations, Expenses Company: Array Dr. Aparna Parikh: Stock and Ownership Interests: C2i genomics Consulting or Advisory Role: Eli Lilly, Natera, Checkmate Pharmaceuticals, Pfizer, Roche/Genentech, Inivata, Biofidelity, Guardant Health Research Funding(Inst.): PMV Pharma, Plexxikon, Bristol-Myers Squibb, Genentech, Guardant Health, Array, Eli Lilly, Novartis Pharmaceuticals UK Ltd., PureTech, Mirati Therapeutics, Daiichi Sankyo

OncLive® On Air
S7 Ep29: Elamin Elaborates on Poziotinib in EGFR Exon 20–Mutant NSCLC

OncLive® On Air

Play Episode Listen Later Sep 12, 2022 10:45


Dr Elamin discusses results from a phase 2 study of poziotinib efficacy in EGFR exon 20–mutant non–small cell lung cancer and highlights the agent's sensitivity in relation to insertion location.

Oncotarget
Press Release: Imaging With Polypeptide Fusion Protein Targets Bladder Cancer

Oncotarget

Play Episode Listen Later Sep 8, 2022 4:44


Listen to a press release about a new research paper published by Oncotarget, entitled, “Targeted elastin-like polypeptide fusion protein for near-infrared imaging of human and canine urothelial carcinoma.” _______________________________ A new research paper was published in Oncotarget on September 6, 2022, entitled, “Targeted elastin-like polypeptide fusion protein for near-infrared imaging of human and canine urothelial carcinoma.” Bladder cancer (BC) is the 10th most common malignancy, affecting more than half a million people worldwide each year, and accounts for 4.6% of the total new cancer cases in the United States. With urothelial carcinoma (UC), the most common form of BC, the 5-year BC recurrence rate is nearly 78%, necessitating life-long surveillance, making it one of the costliest cancers to treat and manage. Cystoscopic visualization of bladder cancer is an essential method for initial bladder cancer detection and diagnosis, transurethral resection, and monitoring for recurrence. Researchers Aayush Aayush, Saloni Darji, Deepika Dhawan, Alexander Enstrom, Meaghan M. Broman, Muhammad T. Idrees, Hristos Kaimakliotis, Timothy Ratliff, Deborah Knapp, and David Thompson from Purdue University and Indiana University sought to develop a new intravesical imaging agent that is more specific and sensitive using a polypeptide based NIR (near-infrared) probe designed to detect cells bearing epidermal growth factor receptors (EGFR) that are overexpressed in 80% of urothelial carcinoma (UC) cases. The NIR imaging agent consisted of an elastin like polypeptide (ELP) fused with epidermal growth factor (EGF) and conjugated to Cy5.5 to give Cy5.5-N24-EGF as a NIR contrast agent. In addition to evaluation in human cells and tissues, the agent was tested in canine cell lines and tissue samples with naturally occurring invasive UC. “Dogs with naturally-occuring UC are an emerging option for a suitable large animal model of BC, where the cancer displays similar microscopic anatomy, histological appearance, biological behavior, heterogeneity, and molecular subtypes and markers to human invasive BC.” Full press release - https://www.oncotarget.com/news/pr/oncotarget-targeted-elastin-like-polypeptide-fusion-protein-for-near-infrared-imaging-of-human-and-canine-urothelial-carcinoma/ DOI: https://doi.org/10.18632/oncotarget.28271 Correspondence to: David Thompson – davethom@purdue.edu Keywords: bladder cancer, elastin-like polypeptide, NIR imaging, epidermal growth factor receptor (EGFR), translational studies About Oncotarget: Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. To learn more about Oncotarget, visit Oncotarget.com and connect with us: Twitter – https://twitter.com/Oncotarget Facebook – https://www.facebook.com/Oncotarget YouTube – www.youtube.com/c/OncotargetYouTube Instagram – https://www.instagram.com/oncotargetjrnl/ LinkedIn – https://www.linkedin.com/company/oncotarget/ Pinterest – https://www.pinterest.com/oncotarget/ LabTube – https://www.labtube.tv/channel/MTY5OA SoundCloud – https://soundcloud.com/oncotarget For media inquiries, please contact: media@impactjournals.com

Oncology Today with Dr Neil Love
Ocular Toxicities in Patients Receiving Anticancer Therapy with Dr Asim Farooq

Oncology Today with Dr Neil Love

Play Episode Listen Later Sep 6, 2022 28:15


Dr Asim Farooq from The University of Chicago Medical Center in Chicago, Illinois, discusses common ocular toxicities associated with anticancer agents, including antibody-drug conjugates and EGFR, ALK, MEK and BRAF inhibitors. CME information and select publications here (http://www.researchtopractice.com/OncologyToday22OcularToxicities).

Lung Cancer Update
Meet The Professor: Current and Future Management of Non-Small Cell Lung Cancer with an Actionable Target Beyond EGFR — Part 4 of a 4-Part Series

Lung Cancer Update

Play Episode Listen Later Sep 2, 2022 62:06


Featuring a discussion on the treatment of non-small cell lung cancer with Dr Stephen Liu, moderated by Dr Neil Love.

Research To Practice | Oncology Videos
Non-Small Cell Lung Cancer | Meet The Professor: Non-Small Cell Lung Cancer with an Actionable Target Beyond EGFR — Part 4

Research To Practice | Oncology Videos

Play Episode Listen Later Sep 2, 2022 62:07


Featuring perspectives from Dr Stephen Liu, including the following topics: Introduction: Journal Club with Stephen V Liu, MD (0:00) Case: A woman in her mid 40s with metastatic lung adenocarcinoma with a ROS1 fusion — Minesh Dinubhai Patel, MD (10:54) Case: A woman in her late 70s with metastatic lung adenocarcinoma with a HER2 mutation — Adam R Miller, MD (17:40) Case: A woman in her early 60s with RET-fusion-driven lung adenocarcinoma — Kapisthalam (KS) Kumar, MD (22:30) Case: A woman in her early 70s with metastatic adenocarcinoma of the lung with a MET exon 14 mutation — Dr Kumar (31:02) Case: A woman in her early 70s with recurrent lung adenocarcinoma with a MET T263M mutation — Priya Rudolph, MD, PhD (34:15) Case: A woman in her late 70s with metastatic adenocarcinoma with a MET exon 14 mutation — Gigi Chen, MD (39:53) Case: A woman in her late 70s with ALK fusion-driven lung adenocarcinoma — Rajni Sinha, MD, MRCP (45:52) Case: A woman in her late 60s with metastatic lung adenocarcinoma and a KRAS G12C mutation — Dr Miller (52:08) Case: A woman in her early 60s with metastatic lung adenocarcinoma and an NRG1 fusion — Jiaxin (Jason) Niu, MD, PhD (57:06) CME information and select publications

Clinician's Roundtable