ASCO Daily News

American Society of Clinical Oncology (ASCO)

The ASCO Daily News Podcast features oncologists discussing the latest research and therapies in their areas of expertise.

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Dec 7, 2023 • 26min

Navigating the Complexities of Next-Generation Endocrine Therapy in HR+ Breast Cancer

Drs. Hope Rugo and Nancy Davidson discuss the next generation of endocrine therapy in hormone receptor-positive breast cancer – SERDs, SERMs, CERANs, and PROTACs – and challenges relating to the optimal sequence of therapeutic options. TRANSCRIPT Dr. Hope Rugo: Hello, I'm Dr. Hope Rugo, your guest host of the ASCO Daily News Podcast today. I'm a professor of medicine and director of breast oncology and clinical trials education at the University of California San Francisco's Comprehensive Cancer Center. Hormone receptor-positive (HR+) breast cancer is the most common subset of this disease and breast cancer is the most common cancer diagnosed in women worldwide. Endocrine therapy (ET) is the cornerstone of management in hormone receptor-positive breast cancer and may involve suppressing estrogen production with aromatase inhibitors in the cancer cell itself, or directly blocking the estrogen receptor pathway through selective estrogen receptor modulators, such as tamoxifen, or the injectable selective estrogen receptor degrader, fulvestrant. However, despite the availability of these therapies, the largest unmet need lies in treatment of HR-positive HER-negative disease lies after progression on endocrine therapy. On today's episode, we'll be discussing the emerging generation of endocrine therapies in breast cancer, some of which were designed to overcome common mechanisms of endocrine resistance, and the challenges relating to the optimal sequence of therapeutic options. Today, I'm delighted to welcome the world-renowned breast cancer researcher, Dr. Nancy Davidson, to the podcast. She's a professor and the executive vice president for clinical affairs at the Fred Hutchinson Cancer Center and professor of medicine at the University of Washington as well as past president of ASCO and AACR. You'll find our full disclosures in the transcript of this episode and disclosures of all guests on the podcast can be found in our transcripts at asco.org/DNpod. Nancy, it's great to have you on the podcast today. Thanks so much for being here. Dr. Nancy Davidson: Thank you so much, Hope, for the opportunity. Dr. Hope Rugo: You've done incredible work in the area of treating HR+ disease, but also in understanding some of the agents and pathways that are most important to our understanding of how we treat and really think about developing new drugs for HR+ breast cancer. The first generation of anti-estrogen drugs really included selective estrogen receptor modulators, but now we have a new generation of these anti-estrogen drugs. And there's also orally administered selective estrogen receptor degraders, so-called SERDs, that we hope someday will be an alternative with already one approved for the injectable SERD, fulvestrant. But there's a whole additional class of drugs, complete estrogen receptor antagonists, referred to as CERANs, and proteolysis targeting chimerics, PROTACs. These agents are all at various stages of development in both early and metastatic settings and really represent, I think, a confusing array of different treatments that are being studied, some of which of course are approved. Nancy, it would be great if you could tell us some about these exciting new agents, starting with our approved drugs and moving on to the agents that we're studying in clinical trials. Dr. Nancy Davidson: Hope, this is a terrific example of how basic science has really begun to inform clinical practice. For us as breast cancer practitioners, it was really easy for a long time because we only had tamoxifen. And then things like the aromatase inhibitors as a means of decreasing the estrogen ligand came into practice, as did fulvestrant, as you mentioned, a selective estrogen receptor degrader. Thanks though to a lot of understanding about estrogen receptor biology, and specifically, the discovery about a decade ago of estrogen receptor mutations, something that we didn't think exist ed for a long time, but which we now know exists in maybe a third to a half of breast cancers after exposure to aromatase inhibitors, that's led to really an explosion, this alphabet soup of possibilities that you talked about. SERMs, selective estrogen receptor modulators, tamoxifen is the classic one—something that acts as an agonist and as an antagonist, depending on the tissue. The SERDs, the selective estrogen receptor degraders, lead to estrogen receptor destruction. Fulvestrant is the classic example of this right now. But we're very excited that a second one has been FDA approved. That's elacestrant that was approved earlier this year, and it has specifically been developed to try to target those estrogen receptor mutant breast cancers because those are the ones that are particularly resistant. So that's the first of this new generation of SERDs that's coming on the market, has come on the market. As you say, a key advantage there is that it's oral, unlike fulvestrant, which requires 2 monthly injections and is very, very inconvenient and uncomfortable for patients. Other SERDs are coming along. I think another one that is well along in clinical development is giredestrant, which is in the same family and being tested in clinical trials of the classic varieties. It's been tested in a window trial, looking at its ability to down-regulate Ki67. It's being tested against standard of care in first-line metastatic breast cancer. And there are some studies that are going to begin looking at it in the adjuvant setting as well. There are other members of this particular family, but I think that elacestrant is the one that we have at our fingertips right now, and giredestrant is one that's certainly coming along in clinical trials, and we should look forward to those results. For those who are interested in the giredestrant, the trials in question right now that are going on are persevERA, which is in stage 4 breast cancer, and lidERA, which is in the adjuvant setting. Now that's one new category, or it's an old category with a new twist. A second is these agents that are called complete estrogen receptor antagonists, CERANs, as you talked about them. The key here is that what they do is, the estrogen receptor has a couple of domains, and in particular, it has 2 different activation domains, AFT1 and AFT2. And these CERANs are complete estrogen receptor antagonists, so they block both of those domains. And the hope would be that they might end up being more effective than the other agents that we have available to us right now. So those are also in clinical trial at the present time, and we're waiting to see whether or not there's going be any value in that particular area that's going to able to go forward for us. Another area that I think we want to talk about is the PROTACs, as you mentioned. These are proteolysis targeting chimeric entities. So, this is a kind of a complicated situation where you have a kind of bivalent situation where you have something that binds both to the estrogen receptor and then also to E3 ubiquinase. So, it leads to degradation again of the agents; that's another area for us to be watching. And then finally the SERCAs. So those are the selective estrogen receptor covalent antagonists, and what they do is they bind very specifically to a cysteine 530 that exists in the estrogen receptor but not in other steroid receptors. So that's where the selective part of this comes along. Now these are all in various stages of clinical investigation. Some of them are pretty early at this point, but I think the ones that are well established are elacestrant, giredestrant is coming along as we just talked about. Camizestrant is also coming along through the SERENA series of trials, and imlunestrant is also coming on through the EMBER series of trials. Hope, I would also be remiss if I didn't go back to an old drug that's a new drug, and that's lasofoxifene, which is also in the SERM family. Those who have been in our field for a while will remember that lasofoxifene was actually originally kind of tested in the prevention setting, where it seemed to have some activity. It came back into our interest because it has really strong activity against estrogen receptor mutant breast cancer models in the laboratory. And as a consequence of that, it's coming back into the clinic through a series of trials that are called the ELAINE trials, where we're looking to see whether or not it might also be better than fulvestrant. It too is an oral agent, so that's a real plus for us, and the first set of ELAINE trials would suggest that there's some nice activity without a lot of toxicity. So, lots going on in this field. You know, I think for all of these things, obviously, we're also working very hard to think about the toxicities. All of these, as I recall, are oral agents. So that gets rid of 1 huge toxicity, which is you don't have the need for some sort of injection. But they all do have some side effects. Frequently, [the toxicities] are like GI side effects or fatigue. In a couple of cases, there might be some concern about cardiac arrhythmias, but I think GI turns out to be one of the most important things that we have seen in some of these trials. Generally, it's very well tolerated, though. I think another important question, which I'm sure is in your head and is in mine, is that how are we going to integrate these into what we already have? And so, I think a lot of the work right now is looking at patients who have already received an aromatase inhibitor plus a CDK4/6 inhibitor and are now going on to one of these new agents. But you might wonder, if they turn out to be effective and well-tolerated, whether they too should be perhaps combined with CDK4/6 inhibitors in place of the aromatase inhibitors or the fulvestrant that we use now. So, I think that we can imagine that those clinical trials are either in progress in some cases or will be coming on as we try to think about how to integrate these new approaches into our existing standard of care, which is already quite complicated, right? We've gone far from tamoxifen, which was good for everybody, to now a really complex algorithm about how we think about hormone therapy, both in early breast cancer and in metastatic breast cancer. Dr. Hope Rugo: Well, that was a fabulous discussion about the new agents and our existing agents and both the exciting aspects, as well as the challenges. One question that comes up, I think a lot, and this is of course a huge question in many ways, but for ER-positive metastatic breast cancer, where these drugs are first being tested, maybe we'll talk about that first. There's one trial at SERENA-6, looking at camizestrant in patients who have developed evidence of an ESR1 mutation in circulating tumor DNA, who are on first-line therapy with an AI and a CDK4/6 inhibitor. What do you think about that study and where do you think that progress might go? Of course, that's based on data from another trial, which wasn't definitive, but suggested, had sort of a suggestion, you know, without studying the sequencing in detail that maybe you would have improved progression-free survival with that approach. Dr. Nancy Davidson: Yeah, by which you mean the idea of monitoring pre-ESR1 mutations and circulating DNA and then making therapy changes based on that? Is that what you're talking about? Dr. Hope Rugo: The PADA-1 trial, yes, and that led to this huge SERENA-6 trial, which of course is now accruing. Dr. Nancy Davidson: So, you know, we would love that, right? I think that obviously breast cancer for many years has been interested in trying to have circulating markers that we could use to help to guide our therapy in a more meaningful way than we have in the past. And I think that the trial that you've talked about is certainly one that's trying to make that see whether that's a possibility for us based on information like the PADA trial. I'm hopeful it's going to work out. I would say, let's see what that looks like, whether it's going to be useful or not. It seems to me in some cases, some of these trials have not been quite what we hoped for, but I don't think we necessarily had the molecular techniques or the sensitivity, nor did we necessarily have other things to move to because, you know, those two approaches require both a really good test, but also the ability to use the test to define a new therapy that's going to lead to improved patient outcomes. And I think that these are ingredients that we now have available to us at our fingertips more than we did, say, a decade or 2 decades ago. Exciting approach. Dr. Hope Rugo: I do think there's a lot of challenges inherent in this process, monitoring blood on a regular basis and following up and then randomizing based on results. But I think [SERENA-6] is an incredibly important trial, as you have mentioned, to try and think about moving past using circulating tumor cells, which didn't work, to just change blindly to the next therapy, but more have a rational reason to change to a drug that may be more effective before the disease itself progresses. And just for our listeners, the unique aspect of trials like this in SERENA-6 is that you change therapy before you have evidence of disease progression, but only this molecular evidence of a mutation that is associated with resistance to the therapy you're on. So, it's a really important question. We'll see what happens, as you mentioned, sometimes we're not clever enough to really get around the fact that there are multiple mutations driving resistance in this setting, so we'll see how straightforward this is. The question also comes up, and I think that's a question with many of these trials now, is they're randomizing patients after a progression on an AI and CDK4/6 inhibitor to receive the novel endocrine therapy or fulvestrant. One of, I think, the concerns of treating oncologists is that then you're sort of eliminating the possibility of a targeted agent in that setting. And of course, we have new targeted agents we're studying as well, AKT inhibitors and new inhibitors of the PI3 kinase pathway. So, the newer trials are now combining, as you mentioned. There's a lot of concerns about drug-drug interactions here and how you might really combine them. And then there are triplet studies looking at CDK4/6 inhibitors, oral SERDs primarily, and pi3-kinase and CDK4/6 inhibitors. What's your thought on these and will they really help to move the needle forward? Dr. Nancy Davidson: I think that's a really interesting question, Hope, is whether or not we're going to find that combination therapies from the get-go are the way to go, or whether we're going to end up having to use maybe more serial therapies. Because not only is it a question about whether or not you can tackle all of these different resistance mechanisms simultaneously, but I think the other question is, as you say, are there negative drug-drug interactions, and are there toxicities that are intolerable? Although these are targeted in all cases and they're relatively benign in terms of side effects from the breast cancer perspective, they're not devoid of toxicity. And so, I think that's going to be another issue for us – whether they're well tolerated during the time that patients are taking them. I guess the other thing I always think about, Hope, is that it's hard to know about value of cancer care, but you know, we are talking about agents that are not inexpensive. You know, when you think about the financial toxicity, in addition to the side effect toxicity that you and I just talked about, trying to think about what that value is going to look like is going to be very important for us. Also, as somebody who worked for a long time in the lab and in the clinic, you know, there are an infinite number of combinations that you and I could think about that are rational. And so, the question is, how are we going to pick the ones that are the most rational, if you will, the ones that seem to be the most promising, and take them forward into clinical trials? Because patients are our most precious resource. And so, we want to make sure that we are bringing forward only those things that really seem to have a very strong foundation and the opportunity to improve outcomes over time. Tough, tough question for us to try to think about, as you've talked about. The other thing is that, you know, these trials are not only for postmenopausal women, who are the majority of patients, but we also want to target them to premenopausal women. So, in those women, we're also looking at using an LHRH agonist on top of this, right, because many of these things are really at least so far designed for the postmenopausal state. So stay tuned. Lots of work going on. I think one of the interesting things will be making the leap from using these in metastatic disease at time of progression to taking them forward into the early breast cancer space. And several of the agents are now beginning to do that because of very strong preclinical and clinical data to date. Dr. Hope Rugo: So, we have new agents that we're studying in the metastatic setting, and we've seen a trend to move fairly rapidly from phase 1B trials directly into phase 3 trials, because as you pointed out so clearly, there are a number of drugs in this setting, and we don't really know not only which agent is better, but even what class of agents is better. So, as we move more quickly from phase 1B to phase 3, the question comes up about how we're going to study these agents optimally in the early-stage setting. They, I think we all thought that maybe changing based on ctDNA evidence of a mutation might be an approach, but that's complicated. A big question for you is whether or not you think that's ready for prime time as it's being marketed as such. And then the second question is really, are we better changing our whole approach upfront in high-risk disease or should we wait until after patients are exposed to their endocrine therapy and then switch as we go along; the EMBER-4 trial is looking at that switching approach? Dr. Nancy Davidson: Yeah, I think that this is obviously the billion-dollar question for many companies and for many of us as investigators. I don't know that I have a crystal ball into what the best approach might be. We know that already some of these have been abandoned. For example, amcenestrant. So, I don't even have to learn how to say it because it has been abandoned. It did go to phase 3, as you pointed out, in the advanced setting, looking at it with palbo vs letrozole plus palbo, and it didn't really show a whole lot that the company wanted to pursue. So, I think that sometimes these things are going to be abandoned based on the metastatic setting, which is a large trial, and that's a trial where obviously it might be a little easier to the circulating markers, as you talked about, than maybe in the early-stage breast cancer setting. I think that probably these early-stage trials are going to end up being big; they're going to have be clean. I'm guessing that most companies and most investigators will want to target them towards high-risk individuals, as you talked about, for 2 reasons. One is that ethically, I think we feel more comfortable with that. These are individuals where standard therapies are maybe not serving them as well as we would like and where we have information to think that we can at least have equipoise about a new approach. And the second is that from a trial design point of view, the event rate is likely to be higher, and therefore you might get answers earlier and with a smaller clinical trial. So that's where I suspect we're going to go. But it's a challenging question, and I think that many investigators and many companies are really trying to struggle with that right now because we do have so many options. And we're not quite sure how to, first, develop these new drugs, but then really importantly, put them in the context of our existing drugs. And as you say, we're also simultaneously trying to develop superior molecular or circulating markers to guide us. So, there's so many variables that are going on right now in this field that, from my point of view, itmakes it really exciting, but it also makes it pretty complicated, both for investigators and for pharma as we try to think about how to position these going forward. But what a great problem to have, Hope, because remember when you and I started in breast cancer, pretty much all you needed to know was tamoxifen. And I think you and I also probably started at the tail end of the time when we were using androgens and progestins and agents that now have basically completely fallen out of favor. Dr. Hope Rugo: Estrogen Dr. Nancy Davidson: Estrogen, yeah, and your side effect profiles were not as good. So, it's a good problem to have. It's a nice situation when science can inform our clinical investigation, our clinical practice. Dr. Hope Rugo: Yes, I think it'll be fascinating to see where we end up at the end, but of course, the complexities of this include the fact that sometimes just the clinical trial design leads to a less than positive result because of the way the trial itself has been designed, which I think is the nice part about moving these earlier into treatment of high-risk disease, but also brings up the question of all sorts of areas we're not really a place to discuss today, like how the statistical design is made, et cetera, that can sometimes result in poor evaluation of excellent agents. One of the questions that comes up, and you brought this up earlier, which I think is really important, is that we are in the era of combining our endocrine agents with targeted agents, and, oral agents, in a fascinating way, really bring up drug-drug interactions in a way that the injectable fulvestrant hasn't, and aromatase inhibitors were kind of quiet on the impacting metabolism, unlike tamoxifen. But we are seeing some drug-drug interactions and certainly the discussions about using these agents may include the question about whether or not you're having more diarrhea or nausea or fatigue or one drug causes photopsia, flashing lights, things like that. Keratitis is becoming a new toxicity to follow. How are we going to figure out how to sequence these drugs and are they only going to work better all of them as a class in patients with ESR1 mutations in their tumors? Dr. Nancy Davidson: I think we don't know the answer to the second question yet. That's something that really needs to be sorted out. Even if they do, that's still a really important subset of patients, assuming that we continue to start with the aromatase inhibitors, right? That's where those things really seem to emerge right now. I don't know how we're going to figure those things out. I guess that I'm hoping that maybe a couple of agents in these classes will become kind of the lead agents. And so, we'll be able to do this work with a handful of things as opposed to a whole array of things. But we'll see. I think that even within classes, obviously, these agents are going be slightly different, probably. And so it may be that one member of a class may be slightly better from a, maybe not from an efficacy point of view, but from a toxicity point of view. And we'll just have to see how it goes. I don't think I have any magic answers about that. Dr. Hope Rugo: Yes, it'll be interesting to see whether or not the agents work in sequence too. You know, could you use a PROTAC after an oral SERD, for example, or a CERAN? That'll be fascinating to see. Dr. Nancy Davidson: I'm hoping that preclinical modeling may help with that a little bit, though of course we all know that there are plenty of things that do well in preclinical models, GEMS and rodent models and PDXs, and sometimes those things translate nicely into clinical practice, but sometimes they don't. Dr. Hope Rugo: You mentioned, Nancy, that when we started out, that it was a fairly simple decision about what endocrine therapies, and we ran out very quickly. We're seeing some of those old classes come up with new agents. And you mentioned lasofoxifene, the oral SERM that seems to have some benefits and works in the later-line setting and also can be combined with a CDK4/6 inhibitor; [and also] has data with abemaciclib. There's also a new androgen receptor agonist, enobosarm, that's being tested as well. Do you think that these older mechanisms have a future as well? Dr. Nancy Davidson: I do. I think that because we'll be able to understand the biology better than we did in the past. A lot of our hormone therapy was pretty empiric several decades ago. But I think with better understanding of mechanisms and better understanding of what the patterns of resistance might be for a particular tumor, that we might be able to think about those things. You're right that there's a whole parallel universe right now in androgen receptor targeted therapies that we're not talking about today, both in perhaps in hormone-responsive breast cancers, but also in triple-negative breast cancers in a certain subset. And so that's an area where we probably need to be watching what our prostate cancer colleagues are doing as they develop these agents and thinking about where they might mechanistically make sense to apply in the breast cancer field. It won't be the first time that we've received insights from them because remember, prostate cancer people knew about androgen receptor mutations a really long time before we figured out that they existed in estrogen receptor as well. So, there's a nice cross talk, I think, between the prostate cancer field and the breast cancer field in that regard. Dr. Hope Rugo: That's an excellent point. And we learn a lot from our colleagues studying other malignancies, and prostate cancer has been a big area there for us and hopefully will help us with studying these agents because there's different toxicity profiles, of course, as well. And then you mentioned the approval of elacestrant, the first oral SERD to have regulatory approval, and it's approved in patients who have ESR1 mutations in their tumors. We're also studying it in the ELEVATE trial in combination with all of the different targeted agents, the CDK4/6 inhibitors, mTOR inhibitor, everolimus, and the PI3 kinase inhibitor, alpelisib, to really try and understand how these can be optimally combined. Would you check for ESR1 mutations at diagnosis of metastatic disease, or would you do this more after progression or start of progression of disease on an aromatase inhibitor? Dr. Nancy Davidson: I tend to be a conservative, Hope, and so unless there's a clinical trial that might be able to be considered, I would tend to check it only after progression on the aromatase inhibitor. But I think some people are earlier adopters, and I suppose it's possible that they might want to know from the get-go. Having said that, I do think elacestrant has an approval after aromatase inhibitor, as I recall. So, presumably the patient would have to have that exposure before you would be able to act on the ESR1 mutation by administering the oral SERD. This is also a new area that may well change with time, right? You know, as we develop different agents, as the agents have different requirements or different indications, and as we perhaps have better tests, it may be things that we don't do routinely now will become very routine in the future. And perhaps in series like you talked about in a serial fashion. Dr. Hope Rugo: Absolutely. I think that's a really important comment about how we're going to think about treating hormone receptor positive disease and potentially, you know, we have new chemo options, of course, not part of our talk discussion today and antibody drug conjugates. So, the future is certainly challenging in terms of understanding this appropriate sequencing. We need data, but it's exciting to have these options. As you pointed out, this is this is a great problem to have, you know, too many drugs with efficacy to try and understand how to use these in the most appropriate way. And as you also pointed out, the use in young women is particularly important. Whether or not you need to suppress the ovaries with all of these new agents is going to be important to understand as well as a next step. I don't know if you have specific thoughts on that area as well. I mean, that may reduce toxicity for younger women. Dr. Nancy Davidson: I guess our approach right now has been to suppress them, but I agree with you; you wonder if you look at some of the mechanisms of action, whether that's really a requirement biologically and medically, or whether it's something that's kind of a leftover from the approval process. You know, that for the drug approval, these women were suppressed. I think we need to work that out because that's another area where certainly women could have ovaries removed. That's pretty straightforward, although it requires a surgical procedure. But otherwise use of LHRH agonists continues to be injections, right? And so, if we're trying to minimize convenience or maximize convenience and minimize toxicity for women with any stage of breast cancer, anything we can do, it seems to me to eliminate an injection is going to be a good thing. So important for us to be able to work that out as well, even though numerically it's a smaller number of women, it's obviously a very important number. population of women. Dr. Hope Rugo: Last question for you. One question that comes up and sent to me and panels all the time is, if you have done your next generation sequencing and you see an ESR1 mutation and a P13CA mutation, what do you prioritize in terms of your choice of treatment, because we have the choice of either using elacestrant or a fulvestrant in combination with an agent targeting the PI3 kinase pathway? Dr. Nancy Davidson: I don't know that there's a right answer to that medically right now. So, when I talk about it with patients, I suggest to them that it's probably not one or the other. It's kind of the question of which one to use first. So, we talk a little bit about side effect profiles. We talk a little bit about patient preference and neither of these drugs is devoid of problems, but sometimes patients have pretty strong feelings about which set of side effects seems the least unattractive to them or the possibility of having those side effects. And I know that if one isn't well tolerated, you can swap over to the other. Dr. Hope Rugo: Absolutely. I think that's a very important way to think about next therapies in our era of not really knowing what's right. And this idea of shared decision-making is so incredibly important. Nancy, thank you so much for sharing your insights and knowledge with us today. I could talk to you for hours about this. Dr. Nancy Davidson: Hope, thank you so much for the opportunity. It is an exciting area and I really enjoyed talking with you about what we know and the many things that we don't yet know, but we're working on. Dr. Hope Rugo: Indeed, it's certainly an exciting time. Thank you to our listeners for joining us today. And thanks to the ASCO Daily News Podcast for highlighting this important area. You'll find a link to all of the studies discussed today in the transcript of this episode. Finally, 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. Thanks so much. 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. Hope Rugo @hoperugo Dr. Nancy Davidson Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Hope Rugo: Consulting or Advisory Role: Napo Pharmaceuticals, Puma Biotechnology, Mylan, Eisai, Daiichi Sankyo Research Funding (Inst.): OBI Pharma, Pfizer, Novartis, Lilly, Genentech, Merck, Daiichi Sankyo, Sermonix Pharmaceuticals, AstraZeneca, Gilead Sciences, Astellas Pharma, Talho Oncology, Veru, GlaxoSmithKline, Hoffmann-LaRoche AG/Genentech, Inc Travel, Accommodations, Expenses: Merck, AstraZeneca Dr. Nancy Davidson: No Relationships to Disclose

Aug 17, 2023 • 20min

ASCO Breakthrough: Scientific Innovations and Emerging Technologies in Cancer Care

Drs. Lillian Siu and Melvin Chua discuss scientific innovations, disruptive technologies, and novel ways to practice oncology that were featured at the 2023 ASCO Breakthrough meeting in Yokohama, Japan, including CRISPR and gene editing, CAR T-cell and adoptive cell therapies, as well as emerging AI applications that are poised to revolutionize cancer care. TRANSCRIPT Dr. Melvin Chua: Hello, I'm Dr. Melvin Chua, your guest host of the ASCO Daily News Podcast today. I'm a radiation oncologist and I currently practice in the Division of Radiation Oncology at the National Cancer Center in Singapore. I also served as the chair-elect of the ASCO Breakthrough Program Committee, and, on today's episode, we'll be discussing key takeaways from this year's Breakthrough meeting. The global meeting in Yokohama, Japan, brought together world-renowned experts, clinicians, med-tech, pioneers, and novel drug developers to discuss scientific innovations and disruptive technologies that are transforming cancer care today. I'm joined by Dr. Lillian Siu, the chair of the Breakthrough Program Committee. Dr. Siu is a senior medical oncologist at the Princess Margaret Cancer Centre and a professor of medicine at the University of Toronto. You'll find our full disclosures in the transcript of this episode, and disclosures of all guests on the podcast are available at asco.org/DNpod. Lillian, it's great to be speaking with you today. Dr. Lillian Siu: Thanks, Dr. Chua. I'm happy to be here. Dr. Melvin Chua: We were just at ASCO Breakthrough, and it showcased some incredible scientific innovations, and really showed us how technology innovations in precision oncology, biotech, and artificial intelligence are transforming cancer care. What are your thoughts? Dr. Lillian Siu: Yeah, it was a really exciting meeting, Melvin. The theme of this year's Breakthrough meeting was "Shining a Light on Advances in Cancer Care." And our Opening Session featured an illuminating keynote address by the renowned thought leader and tech trailblazer, Dr. Hiroshi or "Mickey" Mikitani, the founder and CEO of Rakuten and Rakuten Medical. In his address that was titled, "Innovative Technology and Oncology," he spoke so passionately about innovation and really seeing around the corner to predict what is coming and taking risks. And I think that's what medicine is about, not just what we have in front of us, but to predict and forecast what's coming. I totally was inspired by his address, and I think a lot of the audience felt the same way. He also spoke to us a bit about his company's development in photoimmunotherapy using novel technology and light therapy in head and neck cancer. And I think that's also an area of new technology that we should watch in the next few years. Dr. Melvin Chua: I totally agree with you, Lillian. And one of the quotes that he spoke about really spoke to my heart. He spoke about the 2 choices: whether to do or not to do and not to do is not an option. So, I think that was a very compelling message to a lot of our audience at the meeting. So, on this same note, innovation is a driving force in oncology, and we saw countless examples of this throughout the Breakthrough meeting. Were there any sessions that really stood out for you? Dr. Lillian Siu: There were so many exciting sessions. First of all, there is the "Drugging the Undruggable" session. This is a really important session because in the past we felt that certain cancer targets such as KRAS, MYC, etc., are not druggable. KRAS G12C is the poster child in this area. So, during this session we heard about many ways that we are now looking to target these so-called undruggable molecules in the cancer cell. And we talked about molecular glues, we talked about degraders, and really novel ways that are not yet reaching the clinic, called "cyclic peptides" were discussed by one of the speakers. The other session that is very interesting also is CRISPR and gene editing. Obviously, we all know a little bit about gene editing, really trying to change or knock in some genes that are important perhaps to change the function. And one of the sessions talked about trail targeted induced mesenchymal stem cells, and perhaps this is a way to, again, deliver novel therapies and novel treatments to our patients. There were many examples of how CRISPR and gene editing can be ultimately going to the clinic to benefit our patients in terms of therapeutics. I want to highlight another session, which is the CAR T-cell and Adoptive Cell Therapies. I think everybody knows about CAR T-cells, but in this session we talk about non CAR T-cells or newer things such as off the shelf NK cells, Natural Killer cells from cord blood. So, this way it is allogeneics, in other words, we don't have to rely on only a patient's donation of their samples, but actually get it from off the shelf from other donors. There are other ways to really use human induced pluripotent stem cells that we can armor them by transgenes and also CRISPR out any unwanted genes, for example, to enhance an effective function of T-cells. So many, many exciting ways to bring these cell therapies to the patients. And last but not least, I want to highlight Dr. Chris Abbosh, who is one of our keynote speakers, talking about molecular and minimal residual disease and early cancer detection using circulating tumor DNA or liquid biopsy. He talked passionately about the TRACERx study, which he is instrumental in terms of leading together with Charlie Swanson in the UK. This is a study that really has uncovered a lot of science about cancer heterogeneity. And in that study, he also studied circulating tumor DNA and really shed a lot of light about clonal and subclonal dynamics over time that changes. Dr. Melvin Chua: And just to touch on that point about innovation and how that translates to cancer care, I think it was great that we had those case-based applications in lung cancer, in breast cancer, and the virus-associated cancers. And I like how the speakers were able to bring in the Ying and the Yang, bring the West and the Eastern perspectives in these interactive sessions. I particularly enjoyed all of them. But the session on the lung case discussion where we know that there were this EGFR mutant lung cancers that are prevalent in this part of the world in Asia. I thought the interaction between the speakers was fantastic. On the same note about therapies and we heard about novel therapeutics at this meeting as well. I wonder what your thoughts are about some of the sessions, and do you think some of these technologies were able to be brought into practice? And your thoughts on the novel therapeutic session that happened at Breakthrough, do you think this will actually impact clinical care? Dr. Lillian Siu: Oh, for sure, Melvin. The 5 areas that were covered during the Novel Therapeutics session are really drugs already in the clinic. And for example, the first one was about antibody drug conjugates. We know there are now at least 12 antibody drug conjugates already approved by the FDA and many more likely to be approved in the near future. And the session really talked about what's next, how to improve upon ADC, for example, using better drug antibody ratio, talking about new payloads and really new formats that make perhaps ADCs even more potent in the future. There was a session on oral immunotherapeutics. It was really how to target the innate immunity. And I think novel oral immunotherapeutics is very important because we all know PD-1, PD-L1 inhibitors have been the backbone, but we need another Breakthrough. And having oral immunotherapeutics will make it very attractive for patients because they don't have to come to the cancer center to receive the drugs. Another part of that session was about T-cell engagers and bispecifics, really how to bring molecules to the T-cell, to the effective cells so that they are able to be phytotoxic to the tumor. We talked about also oncolytic viruses, how are the new ways to utilize this kind of natural agent to target the cancer cells. And lastly, we also talked about personalized cancer vaccine, which is obviously very timely. We all know a lot about vaccine now after the COVID pandemic and how do we use cancer vaccines to be a good therapeutic drug? I think especially important in the earlier disease stages as adjuvant therapy. Some exciting data, for example, in pancreatic cancer, as adjuvant really is groundbreaking for this whole topic of cancer vaccination. Dr. Melvin Chua: That's great. And for me as a radiation oncologist who's not so deep in drug development, hearing all the talks at ASCO Breakthrough was really informative for me and I learned a lot. In particular, you spoke about the whole session there was oncolytic therapy and the results in glioblastoma multiforme, we know it's a deadly disease, was certainly very impressive. And so, it speaks to the whole notion that in fact, some of this stuff is in fact reaching the clinic and making a difference in deadly diseases. I think there's a lot to take in from there. Dr. Lillian Siu: Melvin, you're so humble. I know you're a big expert in artificial intelligence and I think the whole session about AI applications in precision medicine really was not just in that session, but a whole theme that went throughout the entire meeting. So, I'm very interested to know what you think about some of the presentations around AI and disruptive technologies in precision medicine, such as next-generation multiomics, etc. What are your thoughts? Dr. Melvin Chua: Absolutely, I agree with you. And there was so much material within the AI session, the multiomic session, as well as the keynote [address] by Dr. Maryellen Giger, which basically speaks about some of the pre-existing or historical work on artificial intelligence in radiology. And I'd like to first talk about the keynote by Dr. Maryellen Giger. It was very nice that she elegantly showed how AI was in fact already in practice in radiology, where it helped to fulfill or address a need for radiologists. Almost 20 years ago, they were able to show that using computer vision, you were able to basically facilitate the calling of abnormal mammograms. And it was inspiring to see how these early thoughts have now basically accelerated a lot of the advances that we see that are in practice today. The other thing that was also was to see this global collaboration, the need for global collaboration in the artificial intelligence space and the radiologists are clearly leading the way. And I think part of the impetus for this effort came from an opportunity that arose during the COVID pandemic that clearly affected all facets of healthcare. That was a nice segue to the very sort of dense 1 hour session we had on precision oncology care with artificial intelligence. I think when we designed this session, we were very deliberate that we wanted to address all aspects of how AI could be applied. From real-world clinical data, we saw examples of how having good, well-annotated data sets could actually help to accelerate and facilitate liver cancer screening in Hong Kong. Then we also saw a very simple, practical application of AI in pathology, where apart from just having this tool to be able to extract features that could potentially predict outcomes of patients and predict drug responses, we saw a very practical example that applying AI in digital pathology could actually homogenize or harmonize the ways the pathologists review their cases. And so, I thought that was very neat and could speak to all our clinicians across both developed and developing countries. We also saw very exciting stuff on the use of AI in terms of calling out mutations because we know that next-generation sequencing is pretty much a cornerstone of how we practice in oncology today. And yet we know that there are prohibitive costs that preclude this technology in certain parts of the world. And it was nice to see how AI could actually lower the cost of some of these sequencing technologies like being used in liquid biopsy. And then finally, there was some fancy science as well that was showcased in the spectrum when we saw how industry as well as academics are thinking about integrating multiomic data sets to then be able to accelerate drug discovery, help define patients better, and so that we can think about how to look at precision oncology using targeted treatments for specific patient phenotypes. So I think this was a very nice transition to the Next-Generation Multiomic Technology session, where, again, some of these topics were touched on, ranging from liquid biopsies, and this was already covered in Dr. Abbosh's talk, which you spoke about, and as well as the preceding day session where we heard snippets of it. And it was again reinforced by the speakers when it showcased liquid biopsies. We have heard so much about it in the last decade and we see it made approved now for use in the clinic, but yet so much remains unknown, like the discrepancies between assays, addressing the cost of assays and, importantly, how we deal with the information. So, I think we are just at the tip of the iceberg here. A lot of the clinical evidence needs to be generated in due course to address some of these questions. At the same time, it was also nice to see some of the new technologies being applied in discovery science. So, we know that immunotherapy is a major player in oncology today, and the Breakthrough represents a forum whereby we're able to bring translational scientists to showcase their work. And we saw examples of that at this meeting where single cell technology, digital spatial technology, being able to apply that in pathology specimens and how the two are integrated to be able to review more novel science to us, to show us how immunotherapy works or doesn't work in some patients. Both of us have touched on so much content that was showcased at the Breakthrough, and I think this speaks to the impact, the learning experience we've had from Breakthrough and I think that's the intended purpose of this meeting. Dr. Lillian Siu: Yeah, I agree. It truly was a very exciting 3 days. And I particularly like the multiomics session where we see that the technology is so advanced just in a really short period of time. Over the last few years, we've been now able to go into single cell resolution where in the past I don't think we would ever dream of being able to do that. In fact, I recall in the single cell session, we can even see messenger RNA on the slide, which I thought was fascinating, something that I cannot imagine we can see by the naked eye. It really is an exciting time in oncology, Melvin, and the field is advancing with these new innovations and therapies, but at the same time, I think it's important that we do live globally and we need to work really also to help improve access to quality-assured cancer medicines and diagnostics in the low and middle income countries. What do you think about that part? Did we do a good job in addressing that in the meeting? Dr. Melvin Chua: Absolutely, Lillian. We had a special session that was chaired by Dr. Peter Yu and the lecture was delivered by Dr. Gilberto Lopes from the University of Miami. And we know that he's a strong advocate for this. And the session title spoke to this topic very pointedly, "How Science, Technology, and Practice Can Be Enabled in Lower- and Middle-Resource Settings." And I thought that the work that he highlighted, the whole ATOM coalition, was important. ATOM basically stands for Access to Oncology Medicines, and it was established last year by the UICC, the Union for International Cancer Control, along with global partners to improve access to anti-cancer drugs and to develop processes for ensuring quality delivery, as well as the optimal utilization of medicines in middle- and low-resource settings. And I think there's a lot more work to be done. Some of the information they showed was very compelling to me from this part of the world. But we know that Asia isn't very heterogeneous in terms of the resources, in terms of the culture. And I thought that the drug pricing, for example, how that should be addressed across the different countries is an important topic to pick up. And I hope his lecture only invigorates this conversation going forward. Dr. Lillian Siu: Yeah. Thanks, Melvin. I totally agree. That was very inspiring. Breakthrough is such a one of a kind, international gathering that we are not only able to network while we're there; we also have a session to really allow attendees to leverage international cancer networks, to learn a bit about them, all the way from, for example, some of the North American groups to Asia Pacific groups to even global groups, and how we interact between pharma and academia, really transcending boundaries. And I think it is really, really important for us to now have these networks address issues such as equity and cancer care innovation, novel approaches and so much more. And I think, I am sure you're going to do a good job in making sure that gets into the agenda in our next year's meeting in 2024. Ultimately, we hope that these collaborations in cancer research will help to improve the outcomes for our patients with cancer. Dr. Melvin Chua: Thank you again for sharing the great highlights of ASCO Breakthrough, and I'm really appreciative of your work, and your commitment to build a really robust program for this year. So, thank you. Dr. Lillian Siu: And thank you, Dr. Chua. And you can bet that I will not miss Breakthrough 2024 in Yokohama in August next year. I will be there. Dr. Melvin Chua: Okay, I'll hold you to that. And thank you to our listeners for your time today. You'll find links to all of the sessions discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Thank you again. 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. Find out more about today's speakers: Dr. Lilian Siu @lillian_siu Dr. Melvin Chua @DrMLChua Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Lillian Siu: Leadership (Immediate family member): Treadwell Therapeutics Stock and Other Ownership Interests (Immediate family member): Agios Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen Dr. Melvin Chua: Leadership, Stock and Other Ownership Interests: Digital Life Line Honoraria: Janssen Oncology, Varian Consulting or Advisory Role: Janssen Oncology, Merck Sharp & Dohme, ImmunoSCAPE, Telix Pharmaceuticals, IQVIA, BeiGene Speakers' Bureau: AstraZeneca, Bayer, Pfizer, Janssen Research Funding: PVmed, Decipher Biosciences, EVYD Technology, MVision, BeiGene, EVYD Technology, MVision, BeiGene Patents, Royalties, Other Intellectual Property: High Sensitivity Lateral Flow Immunoassay for Detection of Analyte in Samples (10202107837T), Singapore. (Danny Jian Hang Tng, Chua Lee Kiang Melvin, Zhang Yong, Jenny Low, Ooi Eng Eong, Soo Khee Chee)

Aug 10, 2023 • 25min

How Oncologists Are Confronting the Cancer Drug Shortage

Drs. Vamsi Velcheti, Taofeek Owonikoko, and Janakiraman Subramanian discuss their experiences navigating the cancer drug shortage in the United States, the impact on patients and clinical trial enrollment, lessons learned, and proactive strategies to mitigate future crises. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast today. I'm a professor of medicine and director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone. On today's episode, we'll be discussing the impact of the shortage of cancer chemotherapy drugs across the United States. This has been affecting several thousands of patients with adult and pediatric cancers and hampering enrollment in clinical trials. Among the shortages are very commonly used drugs like cisplatin, carboplatin, methotrexate, and fludarabine. Some of these shortages have persisted since the time of the pandemic in 2020. So today, to discuss this really troubling scenario, I have two outstanding colleagues, Dr. Janakiraman Subramanian, the director of thoracic oncology at Inova Schar Cancer Institute in Virginia, and Dr. Taofeek Owonikoko, a professor of medicine and the chief of the Division of Hematology and Oncology at the University of Pittsburgh Hillman Cancer Center in Pittsburgh. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available at asco.org/DNpod. So, a recent survey by the NCCN found that 90% of the nation's largest cancer centers have experienced a shortage in carboplatin, and 70% of the centers have reported a shortage in cisplatin. These are platinum-based chemotherapies we use frequently in patients with cancer, and these are often curative intent treatments for several cancers, and these are used in several tumor types, both solid tumors and hematologic malignancies. So, the scale of the problem is immense. Dr. Owonikoko, I'd like to hear your take on this situation and how are you dealing with this at the UPMC Cancer Center. Dr. Taofeek Owonikoko: Yeah, thank you, Dr. Velcheti, and happy to be part of this panel. As you rightly surmised, the chemotherapy drug shortage is what we've all experienced across the length and breadth of the United States. Our cancer center here in Pittsburgh is not an exception. We've had to be proactive as well as think outside the box to be able to manage the challenge. Just like every other cancer center across the country, maybe to varying degrees, we've had to look at patients in need of chemotherapy with these standard-of-care agents such as cisplatin or carboplatin, and to some degree docetaxel, during this past episode of drug shortage that we all went through. And while we did not have to, fortunately, cancel any patient treatment, we all went through it with bated breath; not sure of where the next batch of chemotherapy drugs will come through, but I would say in the past couple of weeks, we've actually seen some improvement in drug availability. But before then, we've had to have contingency plans where, on a weekly basis, we review our patient list and the drug regimens that they're going to need, and must make sure that we have enough drug on hand for those patients. And in situations where we thought we might not have enough drug; we also had a plan to use alternative regimens. We were proactive in having guiding principles that are consistent with ASCO's recommendations in terms of quality care delivery for cancer patients. So, I'm sure that this is more or less the same approach adopted by other leading cancer centers across the country. Dr. Vamsi Velcheti: Thank you, Dr. Owonikoko. And Dr. Subramanian, you're in a community setting, a large cancer center that serves a lot of patients in the state of Virginia. So, what is the scale of the problem at your institution and how are you handling it? Dr. Janakiraman Subramanian: First of all, Dr. Velcheti, thanks for having me here on this panel. And as you rightly said, this is a significant problem, and it is across the country like Dr. Owonikoko said. And as medical oncologists, we are not always thinking of drug shortages. Our focus is on taking care of our patients. So, this is one more issue that we need to keep in mind now as we manage our patients with cancer. When this shortage started, the biggest problem, as you know, was when we became aware of this was primarily in cisplatin and we had some of our patients who were getting curative treatment and we had to make a decision - can they get cisplatin or can they get carboplatin. And one of the things we did was to have an ethics committee that will review each patient that is being planned to receive cisplatin-based chemotherapy and come to a decision on how best we can support them. The template for some of this was based upon some of the triage mechanisms we used during COVID, as well as the ASCO guideline document for managing this chemotherapy shortage, which was one of the blueprints we used. And they have reviewed all cases, all patients that are being planned for cisplatin or carboplatin for that matter, and we come to a decision based on that. And we also have another committee that constantly monitors drug availability on a weekly basis and tries to forecast where the next problem would be as we take care of our patients. And particularly as a lung cancer doctor, we've had situations where we had to use carboplatin instead of cisplatin and even we also have carboplatin shortage. And so, the committee usually approves two cycles at a time, but thankfully so far we have not had a situation where we could not offer our patients the chemotherapy treatment. But we are very carefully monitoring the situation, hoping that this will improve. The other aspect of the shortage has been in 5FU. A lot of our GI colleagues; I treat esophageal cancer patients as well, where we've had to forego the bolus 5FU and have a 10% reduction on all 5FU infusions. And we've been using some of that dose reduction to ensure that we can have 5FU available for all our patients. And that's how we've been trying to manage this shortage situation here at Inova Schar. Dr. Vamsi Velcheti: Dr. Subramanian and Dr. Owonikoko, we are oncologists, we are treating patients, and the toughest part really is telling a patient that we don't have access to certain drugs and we have to switch treatments to perhaps another treatment regimen that may be suboptimal. And it's always a very anxiety-provoking discussion, and especially for patients with metastatic cancer, they're already under a lot of stress and it's a really difficult conversation. How do you handle that, Dr. Owonikoko? Dr. Taofeek Owonikoko: That's a conversation we all hope we don't have to have. And fortunately, with this current crisis, I've actually not had such misfortune of having to inform a patient that we don't have drugs to treat them or that we have to switch to something inferior. But conceptually, it's possible that could have happened and that would have been very difficult. But the one thing that we did, though, as part of our mitigation strategy was actually to inform the patient ahead of time because the way we handled this was to look at our inventory on a week-by-week basis. And if there are patients where we felt maybe they will be coming in towards the end of the week and we may not have enough drugs for them, to let them know the possibility exists that we might have to switch them to something different. While we did not have to do that for any patient, yes, there are patients that we had to give that heads up to, to say, "We're having this shortage. We're doing everything we can to make sure it's available. But just in case it's not available…" I think what is most important for most patients is to be aware of that decision ahead of time, to be able to process it, and to be transparent. The other challenge that we face was, if you have to choose between patients, what should be your guiding principles as to who gets the drug and who doesn't get it? I think it's very easy for all of us to say, "Oh, if it's curative intent, we do it. If it's not curative intent, we don't do it." It's a little more complicated than that because if we put the equity hat on, curative intent doesn't actually mean that that life is more valuable than somebody who cannot be cured. And this is where really, I think having people with expertise in ethics of care delivery and disaster management will be very important for us to proactively anticipate that, should this become a recurrent problem in the future that we actually have a well-vetted approach, just like we did during COVID where you have to ration resources that we have those people with expertise to help us as oncologists because not all of us, at least personally I can speak for myself, that is not my area of expertise and comfort. Dr. Vamsi Velcheti: Excellent points. Dr. Subramanian, anything to add? Dr. Janakiraman Subramanian: Oh, absolutely. I echo what Dr. Owonikoko said. These are conversations that we would like to hopefully never have with our patients. But this is a crisis that we are facing now. And personally, I can tell you two situations where we ran into this problem. But overall, though, we never had to stop a treatment or cancel a treatment for our patient. In the first situation, we had a young man with a rare germ cell tumor in the hospital for whom cisplatin was key. He was already in the ICU and sometimes the treatment start dates are not perfect, unlike what we do in the outpatient setting, depending on how well he's doing or the treatment start dates might move by a day or so. So we basically had to hold a certain dose of cisplatin for him. This brings the next question, which is how do we decide who gets cisplatin versus who can go for an alternative option? And I think Dr. Owonikoko made a great point where, just because it is a curative disease does not mean their life is more valuable. This is where I think trying to make that decision at an individual level, as an individual treating physician can be extremely hard. And that's why at our institution we have this ethics committee where we have oncologists, pharmacists, and ethicists that review these chemotherapy orders, particularly for cisplatin, and try to use some guiding principles that we learned from COVID as well as ASCO's guidance to decide how we assign our resources. That's one option, one way we have done it. And then in another situation that was faced by one of my GI oncology colleagues was a patient that was originally planned to go on a clinical trial where the chemotherapy backbone was FOLFOX and because we had the 5FU shortage, we could not offer that patient clinical trial enrollment. And that was a tough conversation where they had to tell them that they could not go on a clinical trial that they were looking forward to. And this then brings the next question, which is by foregoing the bolus 5FU and by the 10% reduction in the infusional 5FU, are we providing them inferior treatment? And it's a conversation that's had at a very individual level. I don't envy my colleague who had to have that conversation. It's a challenge and we try to do our best to communicate to our patients that we are trying to provide care without trying to compromise the effectiveness of treatment for them. Dr. Vamsi Velcheti: Thank you so much both of you. And we had the same issues here at NYU in New York City as well. It appears, you know, the degree of shortage and the drugs that are in shortage has been somewhat different at different locations across the United States. But the theme has been that we are having to ration treatments for our patients. And of course, there are some tumor types where there's really no adequate substitution, for example, GU cancers. I mean, you can't really not give them cisplatin. A lot of these are situations which have curative intent and young patients. So, it's really troubling. And I think one of the things that really came out of this is there's been a lot of push from professional societies that actually ASCO has been spearheading and some intense discussions with CMS and legislators to kind of provide more long-term fix for these things. And I think all of us have to be more engaged in those discussions with our professional societies like ASCO to kind of help promote awareness. So if you kind of think about it, these drugs are not that expensive. These are generic drugs that we've all been using for such a long time. And the fact that we can't provide these drugs for various reasons is kind of really concerning. We spend so much money on research and more expensive drugs and not being able to manufacture these drugs within the country and kind of having to rely on complex supply chains is troubling, and I hope the situation improves very soon. So, I know both of you are at large cancer centers that enroll patients on clinical trials. Of course, these drugs, especially carboplatin, for lung cancer, especially, are like core treatments that are used in managing cancer patients with lung cancer. So how is this affecting your clinical trial accrual? Are you prioritizing patients on clinical trials for these drugs? Have you had to make any decisions to hold clinical trial accrual for certain trials? Kind of curious to hear. Dr. Taofeek Owonikoko: Yeah, so I can maybe weigh in a little bit on that in terms of what we've had to do for patients receiving treatment as standard of care versus those going on clinical trials. As we all recognize that when a patient goes on a clinical trial, even if they are going to receive a standard-of-care regimen as part of that trial, it still has to be administered in line with the protocol. So, during the extreme period of shortage anxiety, we actually had consideration for perhaps not putting patients on trial if we're not sure that they will be able to continue to receive the protocol-mandated treatment, whether it's a control intervention or the experimental intervention. The good thing to come out of this is at least here at UPMC, we actually did not have any instance where we had to deny a patient clinical trial participation. But there were anxious periods when we already had patients enrolled and they were scheduled to receive a platinum-containing regimen and we were not sure whether or not we were going to have adequate supply of the drug for them while on trial. I think this really raises an important consideration going forward as we come out of this current shortage. I don't by any stretch of the imagination assume that this is going to be the last one we experience, but I think the lessons learned here, we have to also carry that forward both in the design of the trial as well as in the regulatory environment surrounding clinical trial conduct, to say, should another incidence of drug shortage are to happen, how do we actually operationalize that with respect to patients on trial, whether starting or already on trial? I think it's much more challenging when the patient is already on the trial, they've already started. It's less challenging if you just have to make a decision about somebody starting newly on the trial. But equally important is that by not allowing new patients to go on trial is denying something that potentially could be of benefit to them, albeit it is still a trial, it's not an established treatment option yet. Dr. Janakiraman Subramanian : I completely agree with Dr. Owonikoko. Those were very key points and issues that we face as well. In terms of my patients with lung cancer, we haven't had a problem in getting them on clinical trials. Even though we have had carboplatin shortage patients who are already on treatment, they were able to get the carboplatin. For new patients, we were still able to provide them carboplatin as well. The biggest problem for clinical trials has been primarily with my GI colleagues who have to use 5FU. And there, as I said before, we are unable to give bolus 5FU and there is a 10% reduction of the infusional 5FU. So, we can't have any of these patients go on clinical trials. And as a result, anything that has to do with 5FU has come to a screeching halt in terms of clinical trials for our patients. And I think I echo the point of Dr. Owonikoko that by no means this is the last drug shortage we're going to be dealing with and we are here today discussing this, also because this shortage has not ended. It's been ongoing. It's one of the longest drug shortages in my memory as a medical oncologist, and that's concerning. We still see that there is some improvement, but we haven't gotten past it yet. And therefore, as we develop clinical trials and we need to have methods to address drug shortages and how we manage patient enrollment as well as how do we manage existing patients who are already on a clinical trial and, if possible, what might be their options in that situation. We may not have all the answers, but it is definitely an issue that we need to think about in the future as we develop and implement newer clinical trials for our patients. Dr. Vamsi Velcheti: I completely agree and great points, both of you. And we've had the same issues with clinical trials at NYU Langone as well due to the shortage. It's been a challenge, and I think this is a problem that's so complex because of supply chain issues and the way the drugs are priced and incentives for manufacturing these drugs in the United States are not lucrative enough to actually onshore a lot of the production of these drugs. I think at the end of the day, I think we have to come up with some creative, innovative, reimbursement structures for these generic chemotherapy drugs. I think this would require a very complex economic solution that perhaps ASCO and other organizations should kind of really foster an environment of innovation to kind of help facilitate onshoring some of the manufacturing of these key drugs within the United States. I think ASCO is already trying to do that, trying to collaborate with all the stakeholders to kind of address this problem is very critical, and I think all of us have to be engaged in some of the advocacy efforts that are ongoing to kind of address these drug shortages. And this is not a short-term problem. So, Dr. Owonikoko and Dr. Subramanian, any final thoughts before we wrap up the podcast today? Dr. Janakiraman Subramanian: So, Vamsi, you mentioned the whole complex supply chain and the fact that we rely primarily on overseas manufacturers to get these drugs that are off-patent but still a key backbone of our cancer treatment. I think those are all key issues that policymakers and leaders in the field have to keep in mind. As an institution at Inova, one of the key mechanisms that have helped us to sort of stay ahead of the shortage was to have this inventory management team that monitors the inventory out there. And in fact, the inventory management team does have access to what the inventory is in some of their main suppliers in terms of the drugs. And they also have an idea of how many patients are going through treatment, what is the weekly usage of a specific drug like carboplatin. And they try to forecast what is coming down the road and try to prepare for it. And as we try to look for solutions, maybe a forecasting mechanism in a larger scale like either spearheaded by ASCO or by policymakers level that can, for the overall country, try to see where some of the inventory is for some of these critical drugs and try to prepare for it ahead of time, rather than wait till we hit the shortage and then try to find alternative suppliers to get the drug, which obviously doesn't happen quick enough. It takes months or even longer to catch up and get the inventory back to the level where we can comfortably take care of our patients. I think that is something we should be advocating for that as well as the professional societies should take a handle on that and see if they can support something like that as well as letting the institutions know ahead of time what's coming might be very helpful. Dr. Vamsi Velcheti: Yeah, very good point, Janakiraman, and I think that's a key takeaway here. I think we have to learn from other industries and try to– I mean this is not unique to healthcare by any means. I mean these chronic shortages due to supply chain issues, inventory management, there might be some learnings from other industries here that we probably should also focus on inventory management and improve supply chain logistics. Dr. Owonikoko, any closing thoughts? Dr. Taofeek Owonikoko: Yeah, I agree as well with all the points made by Dr. Subramanian and yourself. This is a chronic problem that requires a long-term strategy. I think it's both an economic problem as well as a regulatory problem. As we all know, part of the reason why we went through this current crisis is the regulatory decision by the FDA regarding safety of one of the manufacturers. So being proactive in terms of how these audits are conducted and giving people lead time I think will help avoid similar situations in the future. It's an economic problem. There's a reason why a lot of the big pharma companies are not producing these drugs. And if the cost of production is such that the amount of money you get paid is enough to cover your price, I think there is an economic issue there to be addressed. That is unfortunately not within the scope of what any one of us can do individually, but as advocates in terms of the structure of incentivizing new drug versus old drug, some of these newer drugs are quite expensive, but oftentimes they are used along with standard drugs that are not as expensive. So, where do we strike that balance where we do not stifle innovation but at the same time, we don't create a perverse incentive system where everybody just wants to come up with the newest, most expensive drug and nobody is interested in really producing the backbone chemotherapy and other agents that will make those new drugs work well. So, I think we have to pay attention. We have to advocate for our patients through our different institutions and organizations, and I hope that society as a whole that we've learned a lot of lessons from this crisis and that will help us craft some long-term strategies. Dr. Vamsi Velcheti: Thank you both Dr. Owonikoko and Dr. Subramanian for your time today to speak with me and our listeners and for sharing your insights with us on the ASCO Daily News podcast. Dr. Taofeek Owonikoko: Thank you. Dr. Janakiraman Subramanian: Thank you. Dr. Vamsi Velcheti: And thank you to our listeners for your time today. If you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcast. Thank you so much. 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. ASCO Resources Related to Drug Shortages are available here. Follow today's speakers: Dr. Vamsidhar Velcheti @VamsiVelcheti Dr. Janakiraman Subramanian @RamSubraMD Dr. Taofeek Owonikoko @teekayowo Follow ASCO on social media: @ASCO on X (formerly Twitter) ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Vamsidhar Velcheti: Honoraria: ITeos Therapeutics Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus 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. Janakiraman Subramanian: Consulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Daichi, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology, Lilly, Blueprint Medicines, Axcess, BeiGene, Cardinal Health, Takeda, OncoCyte Speakers' Bureau: AstraZeneca, Boehringer Ingelheim, G1 Therapeutics, Jazz Pharmaceuticals, Janssen Oncology Research Funding (Inst.): G1 Therapeutics, Tesaro/GSK, Novartis, Genentech, Novocure, Merck Dr. Taofeek Owonikoko: Stocks and Other Ownership Interests: Cambium Oncology, GenCart, Coherus Biosciences Consulting or Advisory Role: Novartis, Celgene, Abbvie, Eisai, GI Therapeutics, Takeda, Bristol-Myers Squibb, MedImmune, BerGenBio, Lilly, Amgen, AstraZeneca, PharmaMar, Boehringer Ingelheim, EMD Serono, Xcovery, Bayer, Merck, Jazz Pharmaceuticals, Zentalis, Wells Fargo, Ipsen, Roche/Genentech, Janssen, Exelixis, BeiGene, Triptych Health Partners, Daichi, Coherus Biosciences Speakers Bureau: Abbvie Research Funding (Inst.): Novartis, Astellas Pharma, Bayer, Regeneron, AstraZenece/MedImmune, Abbvie, G1Therapeutics, Bristol-Myers Squibb, United Therapeutics, Amgen, Loxo/Lilly, Fujifilm, Pfizer, Aeglea Biotherapeutics, Incyte, Merck, Oncorus, Ispen, GlaxoSmithKline, Calithera Biosciences, Eisai, WindMIL, Turning Point Therapeutics, Roche/Genentech, Mersana, Meryx, Boehringer Ingelheim Patents, Royalties, Other Intellectual Property (Inst.): Overcoming Acquired Resistance to Chemotherapy Treatments Through Suppression of STAT3 Selective Chemotherapy Treatments and Diagnostic Methods Related Thereto DR4 Modulation and Its Implications in EGFR-Target Cancer Therapy Ref: 18089 PROV (CSP) United States Patent Application No. 62/670,210 June 26, 2018 (Co-Inventor) Soluble FAS ligand as a biomarker of recurrence in thyroid cancer; provisional patent 61/727,519 (Inventor) Other Relationship: Roche/Genentech, EMD Serono, Novartis Uncompensated Relationships: Reflexion Medical

Aug 3, 2023 • 20min

AI Will Allow Doctors to Reclaim Time With Patients

Dr. Flora and Dr. Beg discuss the use of artificial intelligence in oncology, its potential to revolutionize cancer care, from early detection to precision medicine, and its limitations in some aspects of care. They also talk about 'pajama time' and the use of electronic medical records, highlighting the potential of AI to improve efficiency and reduce the burden of medical documentation. They explore the framework for evaluating opportunities in the AI field and announce the launch of a new journal dedicated to advancing AI in oncology.

Jul 27, 2023 • 29min

Managing the Side Effects of Endocrine Therapy for Breast Cancer

Drs. Hope Rugo and Kristin Rojas discuss advances in managing menopausal symptoms, fertility preservation, and bone health for women on endocrine therapy for breast cancer. They explore treatment options and emphasize the importance of education and choosing medications with favorable side effect profiles. The use of DHEA, estrogen therapy, and bisphosphonates for symptom management and prevention is also discussed.

Jul 13, 2023 • 23min

The Emergence of Triplet Therapies in ccRCC in the Frontline Setting

Drs. Pedro Barata and Naomi Haas discuss the emergence of clinical trials investigating triplet combinations in advanced renal cell carcinoma, factors that influence treatment decisions, strategies to personalize therapies in the frontline setting, including response-adaptive treatment strategies, and the use of biomarkers such as gene expression analysis to guide initial therapy. TRANSCRIPT Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata. I'm your guest host of the ASCO Daily News Podcast today. I'm an associate professor of medicine and also a GU medical oncologist at University Hospital Seidman Cancer Center, Case Western University in Cleveland, Ohio. I'm also an associate editor for the ASCO Educational Book. Today I'm really delighted to welcome Dr. Naomi Haas, the director of the Prostate and Kidney Cancer Program at the Abramson Cancer Center and professor of medicine at the University of Pennsylvania. Welcome, Dr. Haas. Dr. Naomi Haas: Thank you, Dr. Barata. It's a pleasure to be interviewed. Dr. Pedro Barata: Thank you. As you know, we've seen significant strides in the frontline treatment for patients with advanced clear cell renal cell carcinoma (RCC), and there are multiple doublet regimens that are now the standard of care for those patients. The goal for us to chat today is to discuss the emergence of clinical trials that are really investigating triple combinations and the factors that influence treatment decisions around triplet combinations for patients with advanced renal cell carcinoma. I want to congratulate you for the great work that you did in a recently published article in the 2023 ASCO Educational Book. So thank you for your contributions. And just before we get started, I just want to highlight that our full disclosures are available in the transcript of this episode. So, Dr. Haas, again, it's great to have you. Thank you for taking the time. Let me get started. So, we know that there are multiple standard of care doublet regimens, all of them immunotherapy-based combos, and they usually include 1 checkpoint inhibitor or 2, such as ipilimumab plus nivolumab or a combination of an immune checkpoint inhibitor with a VEGF TKI. And we have a number of examples like that. Can you tell us about the trials that have emerged exploring triplet therapies in the first-line setting for patients with advanced RCC? Dr. Naomi Haas: Sure, and I'm going to focus just on triplet therapies that are just about ready to go. But as you know, Pedro, there are probably many different combinations that we'll see in the future. Some of the combinations that have already been conducted as clinical trials include combinations of VEGF receptor tyrosine kinase inhibitors along with immune checkpoint inhibitors. I'll highlight one which was batiraxcept plus cabozantinib and nivolumab, and it's a combination of VEGF inhibitor, immune checkpoint inhibitor, and also an AXL inhibitor. So, most of these capitalize on other vulnerabilities with renal cell carcinoma. So, as you said, they build on the tyrosine kinase inhibitor pathway or on the immune checkpoint inhibitor pathway. Some of them are combining drugs such as CDK inhibitors. There was axitinib plus nivolumab plus palbociclib trial that is getting ready to launch. Others are combining the use of belzutifan, which is a HIF inhibitor in combination with VEGF inhibitor and immune checkpoint inhibitor. There are a couple of those that are ongoing, one of them looking at combinations with lenvatinib. And I think there are also trials getting ready to launch that are using it in combination with cabozantinib and nivolumab. Additionally, another very interesting direction is trying to affect the gut microbiome. And there was a clinical trial presented by Dr. Monty Pal at the gut microbiome session at ASCO, which combined CBM-588, which is a probiotic, in combination with cabozantinib and nivolumab. And that showed an improvement in progression-free survival compared to the combination of cabozantinib and nivolumab alone. And previously there was work published using CBM-588 in combination with ipilimumab and nivolumab. So that's an area of high interest to patients. But most of these combinations capitalize on either vulnerabilities, signs of resistance in pathways or in adding other pathways that have previously been unaddressed in renal cell carcinoma, and are combined with pathways that we know are effective. Dr. Pedro Barata: Wow, that's a fantastic overview of some of the approaches being considered in the frontline, so thank you for that. And actually to your point, some of them we've seen some data, others more later stages of development. So with that in mind, we also know that we have on one side of the story we have how much of these combos of triplets can actually be effective and help patients. From the other perspective is about tolerability, treatment options, and patient health. They're both very important considerations. Can you tell us a little bit about the safety profile of these triplet combos? I know we're talking about many different things. The microbiome triplet has a different safety profile than perhaps a combination with a TKI and different checkpoints, for instance. Can you tell us a little bit about what we expect from the safety profile when we start to combine these therapies in the upfront setting? Dr. Naomi Haas: Sure. I think 2 of the very tolerable triplet regimens have been the combination of the CBM-588 in combination with ipilimumab and nivolumab. Really in those combinations, the authors at least have demonstrated that there has not been a great difference between the two study arms of either the doublet or the doublet in combination with the CBM-588 trial. And that's based on basically changing the bacterial flora of the gut. The Avera trial, which was using the AXL inhibitor in combination with cabozantinib and nivolumab, also seems to have a very tolerable safety profile. Now, this trial was not compared to sort of a standard of care arm, so it's a little bit difficult. A standard of care arm that I would have considered for this clinical trial would have been to use either cabozantinib alone or cabozantinib with nivolumab. Instead, this was more of a dose-finding protocol. So, more work needs to be done with that, but the side effects of that combination additive to what we already know seem to be just infusion reactions from the AXL inhibitor. The trial that got the most attention so far has been COSMIC-313, which was combining cabozantinib with ipilimumab and nivolumab upfront. And of course, the concern with this triplet combination was that there was more hepatotoxicity seen and it was difficult to know whether the hepatotoxicity was from the combinations of the immune checkpoint inhibitors or the use of the cabozantinib. And although the trial showed an improvement in progression-free survival, it did not show as many complete responses as the comparator arm. And the other concern was that there was quite a bit of dropout due to toxicity. And of course, we don't have the overall survival endpoint for that trial yet. Dr. Pedro Barata: Great, thank you for that. I agree completely. We've seen many different safety profiles with these different triplets. Let me touch base on a slightly different topic, and that has to do with what kind of strategies can we think to personalize treatment for clear cell RCC in the frontline. And this is not necessarily applicable only to triplet therapy. There are also some efforts with doublets, but the goal is, I would argue, is response adaptive treatment strategies or even the use of upfront biomarkers such as gene expression analysis, for example, to help us guide initial therapy. Can you give us an idea what your thoughts are about what is coming? What do you think the future will look like in terms of developing this like a biomarker-based approach? What kind of factors or markers we can use to select who gets what in the frontline setting? Dr. Naomi Haas: Sure. So, I'll just highlight ahead of that that one important biomarker that we're already using is the IMDC criteria, which I think if that algorithm had not been developed, we would be struggling a lot in renal cancer and that's, of course, the algorithm that uses the thing such as performance status, hemoglobin, calcium, and time for the development of metastatic disease as well as the neutrophil count and the platelet count. And that has helped us divide categories of patients with clear cell renal cell carcinoma into poor risk, intermediate risk, or favorable risk categories. And that was recently validated in the immune therapy combinations that were previously been validated just in VEGF inhibitor therapies. But the other useful, let's start with clinical tools that I think are going to be very important are the health-related quality of life tools which primarily measure things such as functional health, as well as toxicity. And one of these is the FKSI-19 score which captures most renal disease-related symptoms, treatments, side effects, and functional well-being. And this has been implemented in some trials and are looked at over time whether the patient's functional status improves. And patients who are responding to therapies generally will improve as far as their overall well-being. Although that can be difficult as a tool because if patients are experiencing toxicity, those signs might not be apparent. But that's one tool that's being used. Now, people, both patient advocates and patients, have pointed out that it's very hard to use a tool like this in real life to implement in clinic, but there are efforts being carried out to make these tools a little bit easier so that people can use them day-to-day. So, I can see that being implemented more often. The others have to do with response assessments, and I think it's very important to look at immune-related responses which kind of builds on the resist response, but it uses two dimensions of measurement as opposed to one dimension of measurement. And looking at those, we know now that patients who have what we call a deep response, so something better than a 75% shrinkage or even a 90% shrinkage in a very short period of time tend to be those patients who behave like patients who have complete responses. And both progression-free survival and overall survivals seem to be going in a very encouraging way looking at these tools so you could see that this tool could be implemented in real life with treating a patient and if they have a very deep response quickly, you can feel, the physician or the APP, could be very confident that the patient is going to do well for a long period of time. I think the tools that we're waiting for the most, however, are as you said, the biomarker tools. And this is where we still have a lot of work to do, but one example of this is the transcriptomics which has been conducted in both the atezolizumab-based trials such as the IMmotion trials, and also to some extent with the JAVELIN trials, the avelumab and axitinib trials. And this goes back to looking at the tissues sample and looking at transcriptomics which show mRNA expression as well as some alterations in some of the important genes such as BAP1 and PRBM1. And those tools have been implemented, especially in the IMmotion trial, there were 7 clusters identified, and two of the clusters are groups of patients whose tumors have transcriptomics that indicate that they would respond well to a VEGF inhibitor. And a couple of them also showed very good responses to immune checkpoint pathways. There were additional pathways which suggested that patients wouldn't be responsive to either of these. And there is a trial called OPTIC that is funded by the Department of Defense (DOD) which is currently applying these transcriptomics, and then assigning patients to get either a VEGF IO therapy combination or a dual immune checkpoint inhibitor combination, based on their transcriptomics. And I think what everybody would really like to see is, number 1, that these transcriptomics consistently bear out that there isn't irregularity in using these as predictors. So, they do need to be validated. But I think if there was a quick and easy way to do this, to assign patients to therapies based on these profiles, that would perhaps go a long way in predicting what therapy a patient should start with. Another useful tool is the development of artificial intelligence. And there are a number of companies that are looking at these tools. We're implementing this retrospectively in the ASSURE trial, which was the adjuvant seraphinib synontib or placebo trial, for patients at high risk for RCC. And we're working with a company to identify, using AI, looking at the slides. And I think that if these kinds of techniques, which are already being used in prostate cancer, are something that can be developed, then what I could see in the future is that a patient's slide could be tested very quickly, and that that might also indicate things that perhaps we can't see under the microscope, as far as either a response to treatment or a risk. So, you could use that in the adjuvant setting to predict whether a patient might need adjuvant therapy or not. So I can see those being implemented. And then the third is looking at cell-free DNA. And there are many different mechanisms that have been tested in other solid tumors, using either circulating tumor DNA or cell-free DNA. Now, the circulating tumor DNA seems to be a little bit more difficult to assess in metastatic kidney cancer because it doesn't have the mutational burden and doesn't seem to have as many mutations and things floating around that can be captured. However, cell-free DNA, which has the capability of measuring DNA methylation profiles, does seem to be showing some promise, and there have been some publications. So this has also been tested in cancers of all stages and can be measured in both the plasma and in the urine. And that could be another helpful tool that needs to be validated, but that could be used to start a patient on treatment. And if the amounts of cell-free DNA went down with therapy, that could be a good indication, perhaps in advance of imaging, that a patient is doing well with therapy. So those are some examples that I see potentially being used in the future to help direct therapy, provided that we can make these tools, that we can validate these tools, and secondly, that these tools are relatively inexpensive and that they're nimble, that they could be used right away, that it wouldn't take a long time to get the results back to help guide. Dr. Pedro Barata: For sure. I couldn't agree more. What a masterclass of all the emerging tools that are being investigated in RCC, this is fantastic. So, I guess maybe one last question before I let you go. We have now a number of doublets, we have perhaps a triplet, if not more. If you were to guess, who do you think will be the ideal population for a triplet therapy? Some, in addition to all the tools you mentioned, maybe sarcomatoid features, etc. that might be part of the AI complement to what you mentioned earlier. But if you were to guess, do you think that 5 years from now, we're going to be offering a triplet therapy, whatever that triple therapy might be, to everybody, to certain populations? What can you tell us to help us predict what might happen in the near future to make us think about a thoughtful, shared decision-making process and try to predict who might be the ideal population for triplet therapy? Dr. Naomi Haas: So, I don't think we're going to use triplet therapy in everybody. And in fact, I hope we don't use triplet therapy in everybody because I have patients who have responded to single-agent nivolumab and remained in a continuous CR many years after they were treated that way. And I have other patients who really progressed very rapidly or relapsed very quickly after doublet therapy combinations. So, I think that what I would see in the future would be using the triplet therapy combinations in the challenging patients, the patients who we know we're not getting as far along with the doublet approach. And that's really our challenge. And I would see that perhaps some of this transcriptomics which indicates that there are subsets of renal cell carcinoma which are not going to respond well to a VEGF inhibitor or to an immune checkpoint inhibitor, that those are areas where there might be other relevant pathways where maybe the signal isn't quite as good with– maybe they have some response, but not an optimal response. And then combining another pathway into that would be a way forward to achieve a complete response in those populations. I also want to emphasize that it may be that triplet therapy isn't the way to go, but that triplet therapy can be more of an adaptive design where a doublet therapy is started, and then the third drug, a triplet, is added at a later time. And an example of that is PDIGREE, which is the combination of ipilimumab and nivolumab. And then following imaging, patients are assigned, depending on the response, to get either cabozantinib alone, cabozantinib with nivolumab, or to continue on just nivolumab alone. And that might be a better way to address toxicity. But some of these other triplet combinations, one could also see- you could start, for example, with ipilimumab and nivolumab, and if they were having a response but you wanted to heighten the response, maybe adding the CBM-588 as an adaptive response or adding a CDK inhibitor, but sort of staggering the combination so that you spare patients some of the toxicity. So, I think all of those approaches need to be tested. Dr. Pedro Barata: That is fantastic. Dr. Haas, this is an incredible podcast. You did highlight several triplet combinations that are currently under investigation. You highlighted very, very important ongoing clinical trials. You touched base on what the future might bring as far as tools that might help us decide or optimize patient selection. We talked about adaptive designs. So really outstanding work. And also, I think this reflects the fantastic work in the manuscript that you wrote in the 2023 ASCO Educational Book. So, thank you so much, Dr. Haas, for the incredible work that you have done and you continue to do in the GU field, and for taking the time to share your insights with us today on the ASCO Daily News Podcast. It's truly been a pleasure to chat with you today. Dr. Naomi Haas: Thank you. Dr. Pedro Barata: Thank you again. And thank you also to our listeners for joining us today. Really happy with talking about this topic with Dr. Haas. You can also find links to the studies that we discussed today in the transcript of this episode. And finally, 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 podcast. So again, it has been a privilege to be here today with Dr. Haas. Thank you for joining us and have a good day. 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. Pedro Barata @PBarataMD Dr. Naomi Haas Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Pedro Barata: Honoraria: UroToday Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Dendreon Speakers' Bureau (Inst): Caris Life Sciences, Bayer, Pfizer/Astellas Research Funding (Inst.): Blueearth, AVEO, Pfizer, Merck Dr. Naomi Haas: Consulting or Advisory Role: Pfizer, Merck Sharp & Dohme, Calithera, Eisai, Exelisis, AVEO, Roche/Genentech Expert Testimony: Lilly

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