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Dr John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care and research. I'm your host, Dr. John Leonard. And today, we will be reviewing some of the latest updates from the 2022 American Society of Clinical Oncology or ASCO annual meeting. ASCO is the world's leading organization for physicians and oncology professionals who care for people with cancer.

For the first time since the meeting went fully virtual due to the COVID-19 pandemic, this year's annual ASCO meeting was hosted in a hybrid format, offering both in-person and virtual attendance options. This important conference connects oncology professionals from around the world to discuss the newest state-of-the-art research and treatment updates. Also, we have a bit of a tradition here at CancerCast. After the ASCO annual meeting, we take a closer look at some of the most impactful research that's been presented and we discuss it here on the CancerCast podcast.

Our guest today is Dr. Manish Shah. Dr. Shah is a fellow of the American society of clinical oncology. He's Director of the Gastrointestinal Oncology Program and Chief of the Solid tumor Service at Weill Cornell Medicine in New York Presbyterian hospital. Dr. Shah has also served on several ASCO Leadership Committees, including the Cancer Education Committee and is past chair of the ASCO Clinical Guidelines Committee. Together, we'll review some of the most significant research findings from the 2022 meeting. Dr. Shah will discuss updates in solid tumor oncology and I'll mention a few updates from the field of hematologic malignancies.

So Dr. Shah, it's really great to have you here, And I know we've done this several times in the past, so it's great to have your overview and summary of what's hot and important that people should know about from the ASCO Annual Meeting. And we actually happened to fly back together. So, we even talked a little bit about the great things that have been happening.

first, can you just let our audience know why is it that medical meetings and research meetings like ASCO are important to the field? And specifically, how does the ASCO meeting potentially impact cancer care for patients?

Dr Manish Shah: Thanks so much, John. it's great to be here on this CancerCast program. And it's a great question, why is ASCO such an important meeting? I think this past one was particularly important this was the first time since the COVID pandemic where we all met, as a group. And I think there were over 40,000 participants. And really, we're able to connect with our collaborators, colleagues from around globe about different aspects of cancer care.

I think ASCO is such an important meeting because it brings all of oncology together. So you're able to see aspects of, where the field is moving in all different areas, whether that be in healthcare services or blood-based assays or melanoma, immunotherapy, GI cancer is what I focus in. It really allows us to bring a lot of people together. It's very educational. I think 80% of the content is intended to help educate all the different people on oncology, both oncologists, but also surgical oncologists, radiation oncologist, nurse practitioners. It's really a terrific meeting and it's I think very, very helpful to ensure that patients are getting the best care possible around the globe.

Dr John Leonard (Host): So I'd like to start by asking you, what are some of the most important or high impact studies that were presented? And I know your focus is primarily in the solid tumors, so what are some of the things that really have gotten your attention as potentially either practice-changing or just highlighting major advances in the field?

Dr Manish Shah: The plenary session is, a common area to start where it really highlights some of the most important abstracts are presented. And I think one of the first ones that is very important is the DESTINY-Breast04 study, which examined a new drug antibody conjugate called trastuzumab deruxtecan in HER2-positive breast cancer. And that study was positive, it showed that this drug does have activity. But the exciting thing in this particular abstract was that it looked at tumors that didn't have high expression of HER2 or just have high expression. They also looked at tumors that had borderline or intermediate or low expression of HER2. And this new drug, trastuzumab deruxtecan, had efficacy in there. So it actually vastly opens the door on how many patients might benefit from this new treatment.

And then another abstract, which is really going to be practice-changing, is in rectal cancers, specifically in tumors that are mismatch repair deficient. This is a specific type of rectal cancer where the tumors have mutations in DNA repair. And this occurs in about 5% of rectal cancers. And there was an immune therapy called dostarlimab, it's a drug that's given IV every three weeks. And it was given prior to surgery, and it turned out that patients who met these criteria, the tumors that were mismatch repair deficient, all of them, a hundred percent, had a clinical complete response, meaning that the tumor disappeared radiographically. There are a few patients that had surgery and pathologically, there were no tumors as well. So that could be enormously practice-changing. That was actually highlighted in the New York Times just before the meeting as well.

Dr John Leonard (Host): Why does that drug seem to work so well, given that there are very few medications that are given to solid tumor patients, and the tumor completely goes away? also what percentage of rectal cancer patients is this applicable to? And is it potentially applicable to other types of cancer?

Dr Manish Shah: Great question. So, I was joking with my friends that I think We're now seeing lymphoma level of response, rates, which I think you could relate to. So, PD-1 inhibition or PD-L1 inhibition, essentially, these are drugs that activate the immune system against the cancer. Tumors that have a mismatch repair deficiency, they aren't able to repair their DNA as they go through multiple cycles of cell division. And this leads to new antigens called neoantigens that the immune system can recognize. The tumors then place a break on the immune system so the immune system doesn't respond to them and these drugs have been revolutionary to try kind of unmask that break and allow the immune system to attack these tumors.

And we've known about the efficacy of these drugs for a long time. In fact, pembrolizumab achieved a tumor agnostic approval for mismatch repair-deficient tumors across solid tumors several years ago. What makes this novel is that they use the drug not in the metastatic setting or not after failing prior treatment, but actually prior to metastatic disease, prior to any other treatment. So in that context, there may be very little immunosuppressive kind of signals in the tumor or in the body. And that may have lended itself to such a high response rate with this drug.

drug, dostarlimab, is just one of several drugs that target this pathway. Other drugs include pembrolizumab or nivolumab or avelumab. They all target the same pathway. And I think most of us feel that they would all work similarly well. So it's not specifically this drug, it's more the context of when the drug was given.

think that this is really a game-changing thing. And then, the third thing that I want to highlight is the impact of circulating tumor DNA and how that may change practice. This is where you can take a blood sample, a peripheral blood sample, and then specifically look for mutations that are reflective of the cancer and then make decisions based on that. there's a study that came out, two studies actually, that came out that showed the impact of that. So, ASCO was really a busy time for us and a lot of really great work has been presented.

Dr John Leonard (Host): I'll highlight briefly a couple of studies in the hematologic malignancies. And then, I think we'll come back to your thoughts on a few studies where perhaps they didn't receive as much attention, but are worthy of closer look. So in the hematologic malignancies, there was a major presentation around stem cell transplantation and high-dose chemotherapy in multiple myeloma suggesting some benefit there, but perhaps not necessarily an overall survival benefit, but a benefit in keeping the disease quiet for longer, so to speak. And I think is an important area to get into the details of for patients with multiple myeloma who are considering that approach.

There was a study, the ECHELON-1 study that looked at patients who were receiving therapy for initial treatment for advanced stage Hodgkin lymphoma. The standard therapy for a number of years has been ABVD chemotherapy, a combination of four drugs. This study swapped in for the drug bleomycin a newer drug an antibody drug conjugate called brentuximab vedotin. That study has been published several years ago in the New England Journal of Medicine, showing a progression-free survival benefit, basically keeping the disease quiet for a longer period of time. And now with further followup, six years of followup, it was reported that there is now an overall survival benefit, meaning patients living longer. And so there was some debate in the field as to how compelling these data are. But the fact that there is an overall survival benefit provides a bit more evidence supporting that regimen. Although there are some alternative approaches still being studied. And this regimen, the AVD regimen, is being studied as initial therapy for Hodgkin's lymphoma in comparison to the ABVD regimen without bleomycin, but swapped in with an immune checkpoint inhibitor, similar to the category you referenced earlier, Manish, nivolumab, and that's ongoing in a national randomized phase III trial. So an important national phase III trial ongoing in Hodgkin lymphoma.

And then, we had another trial that had been long awaited called the SHINE trial that evaluated patients, typically older patients, with mantle cell lymphoma, a group of patients who in some cases are considered for autologous stem cell transplantation. But this population was group of patients that was not being considered for autologous stem cell transplantation. And it looked at the Bruton's tyrosine kinase or BTK inhibitor as part of initial therapy. So the patients were randomized to receiving bendamustine, rituximab chemo-immunotherapy followed by rituximab maintenance or the same regimen, adding ibrutinib, the BTK inhibitor as part of the initial regimen and as part of the maintenance regimen. And this study also showed a progression-free survival benefit, but did not show an overall survival benefit. And in fact, some added toxicity was observed with the addition of a ibrutinib. And so this suggested that while the BTK inhibitors are valuable as a second or later line of treatment in mantle cell lymphoma patients, that pushing them and using that drug or that category of drugs as part of the initial therapy didn't seem to have quite as much benefit as one might hope or expect. And in fact, that you can potentially continue to just save it for a second-line therapy and essentially the overall survival, meaning how long patients live, may be quite the same. And so these were some interesting data in the hematologic malignancies that I think are quite important and worthy of attention for people interested in that area, even though ASCO tends to be a little bit lighter in the hematologic malignancies and more in favor of new data in solid tumors.

So Manish, what are some of your thoughts about either studies that perhaps got a little bit less attention or other studies that we haven't yet touched on that are potentially practice-changing for people to know about?

Dr Manish Shah: So one study that I wanted to highlight is a study called the DYNAMIC study, which involved CT DNA or circulating tumor DNA, and briefly mentioned it earlier. you take a blood sample and, by deep sequencing, identify mutations in the blood from the DNA that's circulating that reflects the cancer. And so you can identify the presence or absence of malignancy. The DYNAMIC study looked at patients with stage II colon cancer, and they were divided into patients who are CT DNA positive or negative. And they're able to treat whether you were positive or negative with chemotherapy. And they compare that to patients who received standard of care. And it turned out that the CT DNA approach was actually equivalent to the standard approach, but because we were able to identify this small amount of tumor DNA, we were able to give chemotherapy to about half the patients that would have gotten it otherwise. So we're able to minimize chemotherapy with this newer technology. So that was really exciting. I think CT DNA will have lots of applications across different malignancies and probably even hematologic malignancies where the idea of minimal residual disease is more common.

Dr John Leonard (Host): Do you think that will be practice-changing for that group of patients? That seems like a really potentially nice advance to be able to tell a large group of patients not to require or not to receive additional chemotherapy. Is it at a point where one could use that in practice right now? Or are there more studies to be done?

Dr Manish Shah: It's pretty new technology. I think there's some people that are acting on it now, but I think a lot of people would want to see more data. And there actually are ongoing trials that will result in the next several years that will build on these data. One study that we're participating in, it's a national study, is called the CIRCULATE-US study, which is similarly looking at CT DNA, but in a stage III colon cancer population. And the question there is twofold. One, is if you're negative, can you deescalate treatment, like reduce the treatment that would be prescribed? And if your CT DNA-positive, if there is evidence of tumor cells or tumor DNA in the blood, then the question is, would you benefit from escalating or being more intensive with your chemotherapy? So I think this study, but there are other studies as well, will add to the literature. And I think this will be practice-changing over time, but it is quite exciting.

One other thing with regard to CT DNA was another application, which people don't really think about, and that's with the CodeBreaK 100 study. This was a lung cancer study, which led to the approval of a new KRAS G12C inhibitor called sotorasib. so this is a new class of drugs that is targeting KRAS. KRAS historically was a protein that was untargetable, but actually they are a class of drugs that are now targeting different mutations. And this one is targeting KRAS G12C specifically. And in lung cancers that have this mutation, you have about a 40% response rate and that's led to an approval of this drug. The CT DNA application on this study was to track the disease and to identify mechanisms of resistance. So that's another application that could be useful for us to figure out what is causing breakthrough through a targeted therapy, and that may help us better target the resistance.

Dr John Leonard (Host): Another category of treatment that's been getting a lot of attention, particularly in the hematologic malignancies, certain forms of leukemia and lymphoma, are other immunotherapies like CAR T-cells. We've talked about this in the past on CancerCast, including the idea that a patient can undergo a procedure to have some of their blood removed, the T-cells removed, which are specialized immune cells. And they can be re-engineered in the lab to better fight tumor cells, and then be given back to the patient, usually after some light forms of chemotherapy and these immune cells can go after the tumor cells. And these have now been approved in certain aggressive lymphomas, follicular lymphoma, mantle cell lymphoma, and acute lymphocytic leukemia.

Practical in some ways or a more user-friendly version of CAR T-cells is actually the concept of bi-specific antibodies. And bi-specific antibodies are antibodies, immune proteins that rather than going after one target, they go after two targets. One arm of the antibody or the immune protein can bind the tumor cell. And another arm of the antibody can bind immune cells. And so it basically brings the immune cell in proximity to the tumor cell, helps to activate it and helps those T-cells in this particular case to go after the tumor cells more aggressively. And this has advantages over the CAR T-cells. Well, we don't have as much of a track record with these bi-specific antibodies and so we don't know exactly how long they will work and exactly what situations they work best in, but they are easier in that they are simpler to use. They can, in some cases, be given as an outpatient. They don't require necessarily the same same pre-treatment chemotherapy and they have less side effects. So they may not work quite as effectively. They may be kind of a CAR T-cell light in practice. But in fact, we saw more data, particularly in the aggressive lymphomas with bi-specific antibodies. And I think this is a much easier way to deliver this form of immunotherapy because you don't necessarily need a specialized center. It can be potentially largely given in a doctor's office. And these are coming onto the scene in lymphoma. In fact, one called mosunetuzumab recently appears to be becoming available in Europe. And we'll see more data with these and potentially approvals in the future. So I think this is an exciting area as well, that patients with various forms of blood cancers should pay attention to

Dr Manish Shah: Sounds like there's lots of excitement in both heme and solid tumor malignancies this year.

Dr John Leonard (Host): another area that I think is very important is the area of disparities research. And this was a theme in many sessions of ASCO. And we know that certain populations of patients, particularly those with certain ethnic and racial groups, as well as socioeconomic status and other factors are often people that have less favorable outcomes with cancer therapy, for a variety of reasons. They often can be diagnosed at a later stage. They may have less access to state-of-the-art therapies. And also in some cases can have less favorable outcomes to therapy. And so this is an important area. We had Dr. Erica Phillips from the Meyer Cancer center at Weill Cornell New York Presbyterian Hospital recently join us to talk about this in more detail, but there were a number of sessions on this at the ASCO meeting. And it becomes increasingly evident that, while there are many factors that account for these differences amongst different groups of patients, that really socioeconomic status seems to be a key driver that patients that are under-insured that may be economically disadvantaged and therefore have less access to medical care and screening in some cases, that these can be really important factors in accounting for less favorable outcome for some groups of patients and really an area that we need to focus on, also an area that we need to help to provide support for clinical trials, as we try to be inclusive as we think about offering clinical trial opportunities to broader groups of patients.

So, Manish, I know this comes up in solid tumors as well. I don't know if this was a focus in some of the sessions you saw at ASCO as well, but clearly big area that we need to continue to work on.

Dr Manish Shah: I agree completely. And in fact, it was mentioned in the plenary session. So the very first abstract I talked about with trastuzumab deruxtecan, they actually commented that there were relatively few underrepresented minorities that were included in the trial. And that was a point of discussion that we need to figure out a way to enroll these patients, so we can ensure that the benefits of these new drugs are applicable across the spectrum of ethnicities and races that we see.

Dr John Leonard (Host): So Dr. Shah, any other comments that you have about areas that our listeners should keep an eye out for, things that might be coming out in the future that may impact patients or research areas or technologies on the horizon that you think have a great deal of promise based on what you've seen at the ASCO meeting?

Dr Manish Shah: Yeah. think the other thing that I should mention at least how treatment is evolving for colon cancer is that we're becoming more and more specific. And as we are, we're actually offering better care and better survival for our patients. So specifically, EFGR inhibitors for many years, about 15 years, for RAS wild-type tumors. And over the last 15 years, things have evolved to be more specific that we need to be KRAS wild-type, NRAS wild-type, BRAF wild-type and so forth. But there was an abstract that suggested that if you actually have a left-sided tumor that's extended RAS wild-type, you would have even more benefit with an EFGR inhibitor. And then, other work that suggested that intermittent dosing might be helpful. So I guess what I'm getting at is that there may be times where we could use CT DNA and intermittent treatment dosing and other aspects to better tailor care to give patients, higher quality and longer duration of survival with kind of being smarter and more specific with our treatments. I think that's what we're going to see over the next several years.

Dr John Leonard (Host): Before we wrap up, I want to take advantage of having you here today. you lead the solid tumor program at Weill Cornell Medicine in New York Presbyterian. And I know that a major focus of your work is multidisciplinary care as well as clinical trials. You lead one of our efforts here, working with the National Cancer Institute at bringing trials forward. if you can give in a nutshell any major areas of clinical trials that you and your team are working on, that you want to highlight that certain groups of patients might find interesting or potentially want to participate in depending on their individual situation. Any themes you think are really important for patients to know about as far as your research program.

Dr Manish Shah: Thanks so much, John. What a great opportunity. So, as you mentioned, and actually what ASCO really highlights is that drug development really begins with clinical trial participation. over thousands of patients, the number of patients that participate in trials is relatively small and there are many reasons why that might be. But what we want to avoid is the patients not knowing that there are trials that exist that might be very helpful or very important.

So, some studies that I think I might highlight, at least from the solid tumor group, we have a lot of studies examining PSMA in prostate cancer. This is a new target that, when added with radiation, can actually be practice-changing. And there are a couple of new drugs that have been approved in this setting. We have a very active, ongoing research program in our genitourinary group with regard to breast cancer. We're doing a lot of work with triple-negative breast cancer and early-onset breast cancer as well. And I think that there's lot of efforts there that would be exciting for patients and notable to hear about. And then within GI cancers, we're doing a lot of work on circulating tumor DNA that I mentioned As well as patients with esophageal cancer that may not be great candidates for surgery, we have active programs for that disease as well. So across the board, we have many different active opportunities.

Dr John Leonard (Host): Well, thanks very much, Dr. Manish Shah. It's been great hearing from you and your insights on the American Society for Clinical Oncology Meeting in 2022. Clearly, medical research and clinical trials and translational research in cancer care is essential to making progress. And conferences like this really are essential in making this information available, things that are going to and already are today leading to better selection of treatment for patients, new therapies, improvement and outcomes and survival and quality of life for our patients. So thank you for joining us today. It's been a great discussion.

Dr Manish Shah: It's my pleasure. Thanks so much.

Dr John Leonard (Host): I'd like to invite our audience to download, subscribe, rate, and review CancerCast on Apple Podcasts, Google Podcasts, Spotify, or online at weillCornell.org. We also encourage you to write to us at This email address is being protected from spambots. You need JavaScript enabled to view it., with questions, comments, and topics. You'd like to see us cover more in depth in the future.

That's it for CancerCast, conversations about new developments in medicine, cancer care and research. I'm Dr. John Leonard. Thanks for tuning in.

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