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'll be reviewing some of the latest updates from the 2023 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. ASCO aims to conquer cancer through collaboration, research, education and the promotion of high quality, equitable patient care. The ASCO Annual Meeting is the largest oncology conference in the world, and it brings together global oncology professionals to discuss the newest research and treatment updates.

We're continuing with our tradition this year where an esteemed colleague of mine, Dr. Manish Shah, is joining me on the CancerCast podcast, where we'll discuss some of the most significant research that was presented at this year's ASCO meeting. He'll focus on updates in solid tumor oncology, and I will cover the latest in hematologic malignancies.

Dr. Shah is the Director of the Gastrointestinal Oncology Program and, more importantly, Chief of the Solid Tumor Service at Weill Cornell Medicine and New York Presbyterian Hospital. In addition to his many accolades, Dr. Shah has served on several ASCO leadership committees, including the Cancer Education Committee, and is past chair of the ASCO Clinical Guidelines Committee. Dr. Shah is also a fellow of ASCO, which is really a special recognition for leaders in the field and something that highlights his contributions not only to the field, but to ASCO in general.

So, Manish, thank you so much for joining us today. It's great to have the chance to meet with you and to have you get some of the takes from ASCO, which is one of the leading meetings in the world on this topic.

Manish Shah, MD: Absolutely. It's great to be here. I really like this tradition. I think this is our third or maybe fourth year in a row. And I look forward to it, I must say. So, thank you for having me again. And once again, ASCO did not disappoint. What an exciting meeting.

Dr. John Leonard (Host):  So, maybe we'll start beyond what I just mentioned earlier about what is ASCO, maybe you can briefly describe what the ASCO meeting is from the patient or caregiver perspective as to how it works from the standpoint of hearing new information and what people should take away from things that were presented at the meeting that may pertain to their area of concern.

Manish Shah, MD: So, ASCO, as you mentioned, is our flagship meeting that occurs every year in early June. It reaches about 50,000 people who come directly. And then ever since COVID, one of the few good things about the pandemic is that we learned how to do these hybrid meetings. So, on top of the five-day meeting that was in person in Chicago this year, all of the key educational videos and slide decks and presentations are also available online for us to review and to learn from and to expand our knowledge and change practice as needed. And so, it allows for many of us an opportunity to focus on things that we maybe didn't see or don't see regularly and then come back to the other stuff that we missed at a later date.

I think from a patient and caregiver standpoint, it's probably the most important educational meeting in oncology. It really level sets how best practices should be across solid tumor oncology as well as malignant hematology. And I think the last aspect of it, but by far not the least, is that it allows for interaction between other investigators that you work with on a regular basis. And that actually can often stimulate new ideas and new research avenues that may lead to changes in practice five to 10 years down the line.

Dr. John Leonard (Host):  Great. So, why don't we go ahead and get started. I'll let you go ahead and maybe kick us off with one or more of the key solid tumor presentations that caught your eye and that may be of interest to our audience.

Manish Shah, MD: I'll start off with the late breaking abstract number one, which was the PROSPECT trial. This was a trial in patients with rectal cancer. Rectal cancers are cancers of the GI tract, they're low in the pelvis. And because of their location, a standard part of the treatment paradigm, in addition to chemotherapy and surgery, included radiation therapy. And the reason why it was because the pelvis bones, the structure of the pelvis actually narrows as the colon gets all the way to the anus. And so, rectal tumors that are low down, they are often challenging to resect, and the radiation helps control the disease that might be there and reduce the risk of recurrence in the lower pelvis.

So, the PROSPECT trial was actually one of the cooperative group studies that was many, many years in the making. The study recruited patients from 2012 to 2018, but the beginnings of the study really began in 2008, so about 15 years ago, and that gives people a sense of the time and effort and dedication it takes to do these large practice-changing studies. And the question that was being asked in the PROSPECT trial was, "Is radiation really necessary in all patients with rectal cancer?" This was a randomized study where patients were randomized to standard treatment at the time, which was chemotherapy plus radiation, followed by surgery, followed by more chemotherapy. And that was compared to the experimental arm, which was chemotherapy initially alone. And then based on the response to that chemotherapy, people were then allowed to get radiation or if they had a good response, they were able to avoid radiation and go to surgery. 

The intent of the study was to demonstrate that the selective use of radiation could be equivalent, or technically the term is non-inferior, to doing the standard of care, which at the time again, was chemotherapy plus radiation, followed by surgery, followed by chemotherapy. And the upshot of the study was that the selective use of radiation is in fact non-inferior to doing radiation plus chemotherapy in everybody. There was no difference in survival. But most importantly, there's something called the local recurrence rate or what's the likelihood of local recurrence. And the rate of local recurrence was about 1.5-2% in both treatment arms. So, a very low rate of local recurrence, whether you use radiation or not.

And then, the last thing I'd say is that, in the selective radiation arm, only 9% of patients received radiotherapy. So, the way that the study was done, it was able to avoid radiation therapy in about 91% of patients who were eligible. So, this is clearly a practice-changing study, and it really highlights some of the benefits of this process.

Many of the listeners may have seen the New York Times headline that occurred a couple weeks ago. The initial headline was something like, "Clinical trial demonstrates an ability to avoid brutal radiation for rectal cancer," and they corrected it in real time. An hour later, they removed the word brutal. Because radiation does have a role in some patients and it's really quite beneficial and the side effect profile is different. So, there are patients who would benefit from radiation, who can tolerate it well, it's just that this trial allows us to be more selective in who gets radiation, and who doesn't

Dr. John Leonard (Host):  Great. So, it sounds like that's really a practice-changing abstract and it obviously makes a big difference for people in that situation in being able to help them avoid radiation, which has its own set of side effects and adds time and inconvenience on top of that. So, good news there. It’s an interesting kind of scenario where more and more we seem to be seeing in oncology the idea of reducing or eliminating part of treatment and having a similar outcome in the right patient with even less therapy, kind of the precision strategy, if you will.

Manish Shah, MD: No, I think you're absolutely right. I think that is a trend. Historically chemotherapy, is thought of a kind of a blunt tool, right? We give these drugs that actually attacks most cells that are dividing, and cancer cells divide more than other cells in the body. So, that's where you get your therapeutic threshold, but it's not selective killing. So, cells that also divide are your white blood cells or your red blood cells or cells of the GI tract, and that's why the most common side effects of chemotherapy are a drop in the blood counts or GI symptoms like nausea, vomiting or diarrhea. Our newer treatments are targeted therapies, so we're able to be more selective on who we're treating with these new treatments. And then, the technology is actually evolving in a way that we can maybe be more selective in what treatments we're giving as you pointed out. I think last year we talked about the DYNAMIC study where we're looking at something called circulating tumor DNA and making a treatment based on that blood test. And that's also been practice-changing and also allowing us to be more selective in who we're treating.

Dr. John Leonard (Host):  Do you want to take on another one while you're at it? You're on a roll.

Manish Shah, MD: Yeah, sure. So, the other study that I wanted to highlight was actually the ADAURA trial. This is in lung cancer. So, let me just give a little bit of background on that. Lung cancer is a very, very common worldwide disease, more than 2 million patients a year get lung cancer. The landscape for treating lung cancer has evolved a lot in the last 10 or so years. You can't treat lung cancer without knowing what the mutation status is of the tumor, because there are so many targeted drugs that are specific to specific mutations in lung cancer. So, one of the most common mutations in lung cancer is a mutation of the epidermal growth factor receptor, EGFR. And a mutation in that receptor activates this growth signal that keeps the cancer growing and proliferating. And there's a class of drugs that are called EGFR inhibitors that block this pathway directly. It doesn't cause DNA damage, it isn't toxic to other cells. It directly just blocks this pathway, which is upregulated in lung cancer.

So, a very good drug in this field is a drug called osimertinib, which is a next generation EGFR inhibitor. The ADAURA trial was a randomized trial looking at patients who had lung cancer who had their tumor resected, but they had a high risk of disease. So, they had stage II to IV lung cancer that was removed, resected. And patients were randomized to receive their standard treatment, surgery and then, sometimes they got chemotherapy or sometimes they didn't. But then after they completed their standard therapy, they were randomly assigned to receive osimertinib or no further treatment, so no targeted agent. The current standard of lung cancer is chemotherapy for some patients, but many patients don't receive chemotherapy. The benefit of survival is only about 5% or so.

What was presented at ASCO, was the overall survival analysis of this randomized study. So, we knew from a couple years ago that, by giving osimertinib, you could delay the chance of recurrence. That was called disease-free survival. But what we learned from ASCO this year is that the overall survival improved significantly with the use of adjuvant osimertinib. There was about a 50% improvement in survival by the use of this pill, versus not doing it. So with relatively minimal side effects and, , I won't say that there are none, there are some, you have a 50% improvement in survival with the use of this drug versus not doing it. And just to give our listeners some perspective, chemotherapy gave about a 5% improvement in survival. So, this is aa 10 times greater improvement in survival for patients who have an EGFR mutation who receive osimertinib. So, it's again tailoring therapy specifically for this mutation in this high-risk population. And I think this is definitely practice-changing also.

Dr. John Leonard (Host):  That certainly is good news and positive news in general. Maybe I'll let you take a brief break and I'll highlight one of the heme malignancy studies. There tends not to be as much in heme malignancies or blood cancers at ASCO, relatively speaking. So, you're going to get more of the airtime here today. But I do want to highlight one study, and I have to give a little disclaimer that I was a co-author on it, though a small part of the study. It is really a national cooperative group study led by the National Cancer Institute, through its cooperative group network of doing large national trials that really answer, in many cases, practice-changing questions.

And this study looked at Hodgkin lymphoma. Hodgkin lymphoma is a less common form of lymphoma, but is a curable lymphoma with chemotherapy and, in fact, is common, relatively speaking, among those in the adolescent young adult age range, which is in the range of the teenage years up until 39. And in fact, this was a cooperative study of the adult cooperative groups as well as the children's oncology group participated. So, children were included in this study. The standard therapy for many years for patients with advanced stage, meaning in multiple areas, Hodgkin lymphoma, was a regimen of chemotherapy called ABVD, adriamycin, bleomycin, vinblastine, dacarbazine. And a few years ago, a newer drug called brentuximab vedotin, which is in the family of drugs called antibody drug conjugates was swapped in for the B, bleomycin. So, it was BVAVD, kind of confusing with the letters. But that regimen was shown to be better than ABVD. Although it did have some more side effects, it was better with regard to keeping people in remission longer, i.e., preventing relapses and ultimately curing more of the patients with their initial treatment. And in fact, more recently, data have shown that there is an overall survival benefit, meaning people live longer with the BVAVD.

Now, in the meantime, the immune checkpoint inhibitors, which are very commonly used in a variety of mostly solid tumors. And Manish, you're very familiar with them I know from other contexts. These were shown to be active and useful in Hodgkin lymphoma. And so, one of the immune checkpoint inhibitors, these are drugs that essentially block the tumor's ability to shield itself in some ways from the immune system, i.e., the immune checkpoint. It can remove the immune checks, so to speak, and allow the immune system to do a better job of going after the tumor cells. One of those drugs is nivolumab. And nivolumab has been active among other checkpoint inhibitors in Hodgkin lymphoma in the relapse situation. And this study swapped in nivolumab for brentuximab vedotin. So, it was NAVD versus BVAVD. And this is a large national study, a randomized trial of close to a thousand patients across the country. And the bottom line is that this study, surprisingly, was positive at a very early time point to the point that the Data Safety Monitoring Committee stopped the study early as far as reporting the results because of the fact that the results for the newer regimen, the NAVD, were so much better. The chance of relapsing with one year of follow-up was halved or was reduced by 50%. And in fact, the one year, what we call progression-free survival, was 94% versus 86%, essentially, again, reducing at that one-year time point the risk of relapse by half at that early time point. And in fact, NAVD was better tolerated, it had less infections and, generally speaking, a more manageable side effect profile, particularly with regard to neuropathy and some of the infectious complications. So, this is very much a potentially practice-changing study.

There is some caution that it's only a year of follow-up, and the overall survival of patients will need to be followed as well as longer term data, but certainly is quite remarkable in a disease where outcomes are relatively good to see such an even further dramatic improvement in outcomes at the one-year mark. And so, this, I think, has a high potential to change standard of care. We do need follow-up, but it's quite possible that the immune checkpoint inhibitor, nivolumab plus AVD may soon become a standard treatment for initial therapy of Hodgkin lymphoma. And I know many people in practice are already thinking about using it in that setting based on these data.

Manish Shah, MD: That's terrific. The breadth of where immune checkpoint blockade has really shown benefit is just really remarkable.

Dr. John Leonard (Host):  All right. Why don't you give us another one?

Manish Shah, MD: So, another study, which isn't the most common disease, but it actually, I think, is very important and highlights some of the challenges of drug development, is the Indigo study, which is actually in a low-grade glioma. So, this was one of the plenary session talks as well. And essentially, what this was is that low-grade gliomas, they tend to have a mutation in a gene called IDH, which is one of the growth factor genes for many different cancers. It's important in cholangiocarcinoma as well.

The challenging part of this is that after surgery for a brain tumor, in a low-grade tumor, sometimes you could identify a possible recurrence in the brain, but it's not clear if it's truly a recurrence or not. And sometimes these recurrences can be very delayed, and people can live many years and even decades with these low-grade tumors in the brain, functioning very, very well.

The current standard of practice is either to treat with some kind of chemotherapy or to watch the lesion and have close monitoring. So, it's a really challenging area to develop drugs in because the practice patterns are so heterogeneous. But again, we have a target. We have this IDH mutation that occurs in about half of these tumors. And there's a new drug that actually can block this IDH pathway. So just to give some perspective, of all the types of different brain tumors. This is really a potential indication for about 5% of them, the diffuse and anaplastic astrocytomas and the oligodendrogliomas, they're all sort of grade 2 or low grade. This study was a randomized study of about 300 patients, who had a possible recurrence of this low-grade glioma. And people were randomized to receive the IDH1 inhibitor, either with radiation or just radiation alone. And the benefit of the regimen was really quite impressive. There was a significant improvement in overall disease-free survival. So in the control arm, patients on average had disease progression at about one year. And in the treatment arm, the disease progression was at 27, 28 months, so quite an extensive benefit.

Many people felt that this was a very important study. This is only the second drug approved for gliomas, so that's really remarkable. But, because some patients will just be able to be followed by a watch and wait approach, it's not clear how impactful this will be, and we don't really have an overall survival advantage yet. This was just looking at disease-free survival.

I think this is a very important study. It is another targeted agent. I think this is the theme over the last several years at ASCO, that if you're able to identify a target for a tumor, and a drug that hits that target, there's a high chance of benefit and a high chance of getting the drug approved. But then, the challenge is on the backdrop of the variants in the disease. Some diseases are very aggressive and the target immediately improves survival. And some diseases are much more indolent and hitting the target may improve survival, but it may just delay recurrence. And then, the question is, "Is that a true benefit?" So, these are some of the things that we think about with these data, but it's clearly a drug that will be approved and will be available to our patients.

Dr. John Leonard (Host):  Great. Well, before I give you a final word or two on any other things you want to highlight, I just want to mention a category of drugs that are getting a lot of attention both at ASCO, at other meetings and FDA approvals in some settings. The category of drug is called bispecific antibodies. And that is a group of antibodies. Antibodies are immune proteins that go after tumor cells or can be used to deliver a drug to a target in a more specific way. They can also, like some of the ones we've talked about earlier, affect the immune system or other targets in positive ways. These are antibodies that are specially engineered to directly activate the immune system in a specific way.

People may have heard, particularly in the heme malignancies in lymphoma and certain leukemias, the idea of CAR T-cells. T-cells are immune cells that in the concept of CAR T-cells are removed from the patient, engineered in a laboratory, and then, kind of re-engineered to go after tumor cells and are very potent tumor fighters as well as immune cells in general. So, these T cells can be taken out of the person and re-engineered or they can be engaged and recruited to tumors inside the patient.

So, these bispecific antibodies, which are now approved in certain lymphomas, also in multiple myeloma and in certain other areas, are basically antibodies, immune proteins that with one arm bind the tumor cell and, with the other arm, bind an immune cell, in this case, particularly T-cells. So, there are several of these that are available. They typically are targeting –  the ones that are approved – CD20 in the case of lymphoma, which is present on B-cells in B-cell lymphomas and then, CD3, which is a target on these immune T-cells. And so, the idea is that if you envision a person, in one arm, they're grabbing the tumor cell and, in the other arm, they're grabbing an immune cell and bringing it toward the tumor so that that immune cell goes after the tumor. This could be a potent way of harnessing the immune system and can be, in many cases, an effective anti-tumor treatment. It also has some of the immunologic effects of these CAR T-cells in that it can activate an immune response that can have some side effects. But with the bispecific antibodies, can be less toxic and more convenient because the cells don't need to be removed from the patient, the antibodies can be taken off the shelf and injected into the patient. And so, it's a less complicated way of doing some of these immune types of therapies.

And so, the first of these approved in lymphoma was mosunetuzumab. This was approved for follicular lymphoma. And then recently, in just the last month or so, we have the approval of epcoritamab and glofitamab. And these are approved for patients with primarily diffuse large B-cell lymphoma, an aggressive type of lymphoma. And so for the most common types of lymphoma now, we have these new bispecific antibodies that can be slotted in not so much as the initial treatment, but in the relapse setting and can in some cases, I think, provide a very durable response in these studies. Somewhere in the range of 60 to 70 to 80% of people have anti-tumor responses. These typically last a year or two, but in some cases can be longer. And this is a very potent form of therapy that I think we're going to see used more and more in patients with relapsed B-cell lymphomas, also in multiple myeloma, as I mentioned, and in combination with other treatments in clinical trials. And so, there were data on these both at ASCO and at other meetings more focused on hematologic malignancies. And I think for people with B-cell lymphomas and with multiple myeloma, these are agents that might come in handy and are worth learning more about and potentially talking to your doctor about.

So, Dr. Shah, you want to give us a last point or two, some quick hits on things that were of interest to you that we haven't touched on yet?

Manish Shah, MD: We talked a lot about immunotherapy and how that's actually changing the landscape across many cancers. One of the things that I don't think is talked enough about are the side effects of these immunotherapies. And there are two abstracts that I could highlight very quickly that addresses that to a certain extent. So, unlike chemotherapy where the side effects result from damage to the normal cells by the drug, the immunotherapy, the side effects tend to happen by overactivation of the immune system against some other normal part of your body. So if you have an overactive response to the immunotherapy that attacks your colon, you might end up getting colitis and then suffer from diarrhea.

So, a rare side effect with immunotherapy is myositis where they have inflammation of the cardiac muscle. And there was an abstract that was presented that identified patients that did have myocarditis or myositis ended up developing an antibody against the receptor called the acetylcholine receptor, which is a very common receptor on these muscle cells. So, what happened is that in the process of the immune cells being activated against the tumor, they also activated antibodies against this acetylcholine receptor, which is on the muscle cell. And the implication of this is that now that we know that this is what's happening, instead of just giving drugs to suppress the immune system, what we can do is something called plasmapheresis. That would be a process of taking out the plasma, removing these antibodies that are attacking the muscle cells, and then blunting the immune response. And that might be a better and faster way to reduce or avoid the cardiac toxicity that rarely happens.

And then, the other thing that can happen with immunotherapy is that the immune system can attack the Islet cells in the pancreas, causing diabetes. In another abstract, that looked at over 16,500 charts, they were able to identify three different patterns of diabetes that were induced by the activity of the immunotherapy in these patients. And again, these are rare side effects. But by understanding how these happen we might be able to blunt those side effects or treat them better. So, I think these were two important kind of abstracts that highlight-- ASCO is not just about drug development, it's also about how to improve patient's side effects and reduce toxicity. It really puts the patient at the center of this oncology universe.

Dr. John Leonard (Host):  Great. Well, I want to thank you very much for this wonderful summary. I appreciate all the time. And really, your insights are very helpful in putting things into perspective, not only for our audience, but for me too. I learned a lot from talking with you. So, thanks very much, Manish. I really enjoyed it and look forward to having you back again in the future, as well.

Manish Shah, MD: Thanks so much for having me.

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 cancercast@med.cornell.edu 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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