John Leonard, MD (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 research that came out of the 2024 American Society of Clinical Oncology, or ASCO, Annual Meeting. ASCO is the world's leading organization for physicians and oncology professionals caring for patients with cancer. ASCO focuses on collaboration, research, education, and the promotion of high quality, equitable patient care. The ASCO Annual Meeting is held every year in Chicago, and it is the largest global oncology conference. It features state-of-the-art research presentations and the latest oncology insights from oncology professionals around the world.

We've had a great tradition here at CancerCast where I have met and reviewed on a yearly basis after ASCO with my colleague, Dr. Manish Shah, and he's here today to discuss some of the key takeaways and exciting updates from the ASCO meeting. Dr. Shah and I will review the most essential research presented this year. He will discuss solid tumor oncology, and I'll talk a bit about hematologic malignancies. Dr. Shah is the Director of the Gastrointestinal Oncology Program and Chief of the Solid Tumor Service at Weill Cornell Medicine and NewYork-Presbyterian Hospital. In addition to his many roles and responsibilities, Dr. Shah has also served on a number of ASCO leadership committees including the Cancer Education Committee and past chair of the ASCO Clinical Guidelines Committee. And Dr. Shah, I do believe you are also a fellow of ASCO, if I'm not mistaken. Is that correct?

Manish Shah, MD: That's right. I became a fellow a few years ago. It's quite an honor.

John Leonard, MD: So, let's start a little bit by talking about what ASCO is, but more importantly, how you think of conferences and how patients should think of conferences, like ASCO when research is presented. How does that help the field? How does that help patients and their caregivers?

Manish Shah, MD: Absolutely. And thanks again for having me this year. It's really something I look forward to, and I enjoy talking to you in this venue. So, ASCO is really a tremendous organization. I think the membership is over 50,000 individuals, mostly medical oncologists and hematologists. But then, also, a lot of other disciplines are represented, including Radiation Oncology, Surgical Oncology. There's representation from industry and drug development, as well as patients and patient advocates. It's our premier venue for providing learning. So, I think, a lot of what happens at ASCO is updating other members on the latest cutting-edge research.

But as part of that, we also learn what is the best approach to management for different cancers. And then, we are able to build on that with the research that's being presented. It also offers a venue for interaction and exchange of ideas – from all aspects of cancer care, including what are the needs of individuals who have survived cancer, about developing cancer at an early age when it seems particularly unfair, and what are the support services for that. It also talks about issues like drug shortages and how we can manage that. So, it really is a comprehensive venue for patient and physician education, for interaction and exchange of ideas, a venue to kind of expand where are the holes of clinical care and where we can work to improve patient outcomes and also to identify other needs that we don't realize that we need.

John Leonard, MD: At ASCO, there are a couple different sessions or types of sessions. One whole group falls into the broad category of education sessions, and that is really, as you mentioned, kind of a summary of a disease topic, the management of a type of malignancy or a clinical scenario, and really gives you the basics and the state-of-the-art. Then, the bigger categories tend to be the scientific presentations, which are when abstracts, kind of short summaries, are put together by groups of researchers. And then, they're submitted for presentation, and they're selected based on the impact and the quality of the work. The plenary session, which is just a handful of abstracts that are deemed to be so important and so practice-changing that basically the entire audience is available to attend, and really nothing else competes because these are the highest impact presentations.

It kind of moves down from there to oral sessions that are focused on different disease entities, such as lung cancer or gastrointestinal cancers, and then poster presentations where people walk around and meet with investigators standing in front of a poster with their work. There are some abstracts that you can read on your own. And so, it's a whole range.

I think what I'd like to start with is having you touch on what you think was the most relevant and important out of the plenary session.

Manish Shah, MD: A nice thing about the plenary session is that they really highlight clinical trials that are practice-changing, meaning that they impact patient care right away. They advance the field, and they provide data on how best to manage certain things. And there are a few of those at this year's ASCO plenary session.

One of them I'll start off with is Abstract Number 1, which is the perioperative chemotherapy, FLOT, versus neoadjuvant chemoradiation, CROSS, for resectable esophageal adenocarcinoma. It's called the ESOPEC trial. So, this was a study in esophageal cancer. Most patients with esophageal cancer, they actually present without the cancer having spread past the esophagus, because the esophagus is the tube that connects your throat to your stomach, and it's the tube that allows passage of food to get into your digestive system. And if there's a cancer in the esophagus, it causes early on symptoms of dysphagia, where it feels like food's getting stuck, because there's a partial obstruction because of the cancer. And in the United States, for a long time, we've primarily practiced with giving chemotherapy in combination with radiation followed by surgery. and we thought that was the best way to try to give patients the best chance of cure for locally advanced esophageal cancer.

Out of Europe, actually, out of Germany, there was a regimen of chemotherapy without radiation. The chemotherapy regimen was called FLOT, F-L-O-T, and it was a combination of three different chemotherapy drugs, and that showed some very beneficial effects, as well, in this population. So, this was a randomized study, meaning patients were assigned by a computer algorithm to receive either chemotherapy alone without radiation before and after surgery, or assigned to what we would say is our standard approach, chemotherapy combined with radiation followed by surgery. And it was about a 440-patient study. And what we learned was that patients who are assigned to the FLOT chemotherapy regimen had an improvement in survival compared to chemotherapy with radiation followed by surgery. And the way that we look at that is something called the Kaplan-Meier evaluation, where we track the survival of patients after starting on the trial from time zero all the way up until the full follow-up. And what we see is that the patients who are assigned to the FLOT chemotherapy arm, they had a better survival from early on, as early as six months after starting the trial all the way through five and six years. And it's measured by something called a hazard ratio that tells you the relative benefit. And in here, the hazard ratio is 0.7. So, there was a 30% benefit with receiving FLOT over receiving chemotherapy with radiation. This was an important practice-changing study.

The nice thing about the plenary sessions is that they also offer an opportunity for a discussant to review the abstract and to critique it to sort of see is this something that makes sense, put it into context with the field and what are the implications. And the discussant did mention that the CROSS or the chemotherapy radiation arm didn't do as well as we had seen in the past, but this was a randomized study. Patients were equally assigned to one or the other. And based on that we would think that most patients, particularly the ones that may have lymph node involvement or had deeper tumors at diagnosis, these are the patients that are likely to benefit the most with receiving FLOT and not requiring radiation.

John Leonard, MD: Great. Where do you think the next direction in this area is going to go, as far as kind of the follow up study, knowing your connection to this part of the field?

Manish Shah, MD: That's a great question. And it reminds me that every trial is the beginning of the next trial. And that's how we think of it in drug development. I'm sure you do as well in lymphoma. We learn a lot from the trial and participating, but then it actually leads to the next questions.

So, for esophageal cancer, very recently, there were several approvals for immunotherapy drugs. These are drugs that activate the patient's immune system against the cancer. And so, the field is moving to try to combine immunotherapy with the preoperative treatment for patients with esophageal cancer to see if we can increase the chance of cure even further. And in fact, one of the other abstracts that was presented in the plenary session was an abstract that looked at giving chemotherapy with radiation and nivolumab. This was an ECOG, or the Eastern Cooperative Oncology Group study. And that looked at chemotherapy with radiation either with nivolumab, which is an immunotherapy called a checkpoint inhibitor, or placebo. And the endpoint of that study was to see if the pathologic complete response rate was higher with the nivolumab. And unfortunately, it didn't demonstrate that. But we do know that immunotherapy after chemotherapy with radiation and surgery does improve survival. So, I think the way that the field is going is how do we integrate immunotherapy in combination with the best treatments for patients with locally advanced esophageal cancer to improve the chance of cure.

John Leonard, MD: I will build on that, and if you listen to this podcast regularly, we've talked about the immune checkpoint inhibitors. If you think of tumor cells as having a shield to protect them from the immune system, the checkpoint, so that is the check, so to speak. The checkpoint inhibitors remove that shield so the immune system can better go after the tumor cells. And that's a category of drugs that is useful across a broad array of different types of tumors, in the solid tumor area in particular. We talked about last year the fact that the immune checkpoint inhibitors, when combined with chemotherapy, were making a big difference in Hodgkin lymphoma. And I'll just jump in with one lymphoma abstract, a newer inhibitor, an antibody that inhibits PD-1 in this family of immune checkpoints. It's an antibody calledcamrelizumab , and that was tested in combination with chemotherapy in a rare type of lymphoma called NK/T-cell lymphoma, which is challenging. It's more commonly associated with people from the far eastern countries for a variety of reasons. And this had an interesting study in combination with chemotherapy, where the results seem better than expected with chemotherapy. This was an early study in a rare cancer, but another place where these immune checkpoint inhibitors might have utility.

Why don't we move to another area? I'll let you go ahead and pick one from your list.

Manish Shah, MD: I'll stay with the theme of immunotherapy. So, another, I think, very important abstract was the NADINA trial. That is a trial in melanoma. This was the neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic resected stage 3 melanoma.

We talked about the immunotherapy just now as a shield. What we're learning is that there may be many different targets that need to be overcome to break down that shield. One is PD-1 and nivolumab attacks that, and the other is CTLA-4 and ipilimumab attacks that. And so, this trial was examining whether the combination of nivolumab and ipilimumab given before surgery was better than the current standard treatment, which would be surgery followed by nivolumab. This was a phase III trial, and patients were assigned either to the two courses of the nivo-ipi combination followed by resection of the tumor-draining lymph nodes. And then, if there was a major response, you didn't do any more treatment. Alternately, if there wasn't a major response, there was still some residual cancer, you would continue with nivolumab. And that was the experimental arm. And the standard arm is for stage III melanoma to do a lymph node dissection and then do nivolumab for about a year. Four hundred and twenty-three patients were randomized, so a pretty sizable study, once again, a global study. And there was a significant difference in a new endpoint called event-free survival. So, this means that they tracked patients after enrolling on the study to see if they had any kind of event, meaning either a local recurrence or metastatic recurrence of the melanoma, or if something happened and the patient passed away or something like that. And even at one year, patients who were assigned to the nivo-ipi arm had an 83.7% event-free survival, meaning essentially 84% of the time, they were fine, no issues, no recurrence within the first year. Whereas in the control arm, which was adjuvant nivolumab, the event-free survival was 57%. So really, quite a big difference in terms of event-free survival.

And the other thing that they look at is that, in melanoma, there's another protein called BRAF that has a significant impact on the management of the disease. And this treatment was beneficial in patients who were both BRAF wild-type, meaning that the protein was normal and in those patients that had a mutation. And then, the last thing I want to mention is that there were about 60% of patients who had a major response, meaning that if you did just the two months of therapy before surgery, they didn't need any more treatment. So not only was it better in terms of event-free survival, we actually required less in terms of treatment. You only needed two months of treatment before surgery versus doing surgery and a year of treatment afterwards. So, I thought that was really, really quite impressive as well.

I think this is another indicator that immunotherapy is really transformative in oncology, both heme malignancies and solid tumor malignancies. It's just changing the way we think of how we can treat disease.

John Leonard, MD: Another form of immunotherapy that was highlighted at ASCO, and I'm not going to focus on one particular abstract, but just kind of a broad array, is the concept of bispecific antibodies. And bispecific antibodies have been approved in lymphoma for a period of time really over at least the last year, if not longer. And the concept of a bispecific antibody is that this is an antibody, antibodies being immune proteins that typically bind a target, in the case of cancer, typically on the tumor cell, although it can be targeting something else, like an immune cell. But a bispecific antibody, as the term bi references, has two parts to it. One is a piece of the antibody, the immune protein, that binds the tumor cell, a target on the tumor cell itself. And the second piece. So these are like Y-shaped, so if you think of the upper part of the Y, one arm of the Y binds the tumor, the other arm of the Y brings in and binds to an immune cell. And so, bispecific antibodies basically are engineered to bind on one arm to the tumor and on another arm to the immune system to bring them together to fight the tumor cell.

We have a number of these that are approved in the treatment of different forms of lymphoma. Some of them are in clinical trials, and others are in early development. These include antibodies like mosunetuzumab, epcoritamab, glofitamab. There are others in clinical trials, as well. Those are all approved for different types of lymphoma. And then, we also now have them in multiple myeloma, where they basically, again, bind the myeloma cell or the myeloma early cell and then bring in the immune cell with the other arm to go after multiple myeloma. And so, there were additional studies, really suggesting that when you add these therapies with other treatments, you can improve efficacy.

Interestingly, these bispecific antibodies do have some immune-related side effects. They can be related to infections, and in some cases, low blood counts. They also can cause something called cytokine release syndrome, where they induce an immune response that can be in the realm of the flu because the immune cells get activated and turned on. They release chemicals that can stimulate or be associated with an immune response. And in rare cases, these can be more significant, but these are a side effect of these approaches. But nonetheless, these are very promising and impactful new treatments in certain forms of lymphoma and certain situations in multiple myeloma. So, there were some studies looking at them in combination as well as a single agent in different clinical settings. And I think this is a really important form of therapy that's also pretty practical compared to some of the other therapies like CAR T-cells, which I'll mention a little bit later where there's bit more in the way of logistics needed. The bispecific antibodies are a little more like traditional medications where you can take them off the shelf and use them as opposed to manipulating immune cells as part of the treatment.

All right. Dr. Shah, what's next? I know there was some lung cancer data that got some attention out there. I don't know if that was on your list.

Manish Shah, MD: That's a great segue. There was an important trial in lung cancer called the LAURA study. And so, we're moving away from immunotherapy here. And actually, interestingly, we talked a lot about how immunotherapy is really transformative. In lung cancer, about 15-20% of patients have something called an EGFR mutation. That's a mutation in the epidermal growth factor receptor, which if there is a mutation, it actually drives the lung cancer growth. And in this specific population, immunotherapy actually is not very effective. So, in lung cancer, in stage III lung cancer, the standard approach is to do chemotherapy with radiation. And there was a trial several years back called the PACIFIC trial that added durvalumab, which is another immunotherapy after the chemotherapy and radiation. And it was really quite striking, and it did provide a survival benefit and is now what we do as standard treatment.

But in the stage III lung cancers that have this EGFR mutation, the durvalumab was no better than placebo. So really, it was an unmet need and that's where the LAURA study took hold. In patients who have stage III lung cancer that is treated with chemotherapy with radiation, the investigators randomized patients to receive osimertinib, which is an oral pill. It's called a tyrosine kinase inhibitor. It specifically blocks this EGFR mutation. And they were comparing that to placebo. This was roughly a 210-patient study. One-hundred forty were assigned to the osimertinib, and 73 were assigned to placebo. And the progression-free survival was strikingly different. At two years, 65% of patients assigned to osimertinib had not had progression in this study. Whereas with the placebo, only 13% of patients at two years had not had progression. That's a five-fold difference in the progression-free survival if you received adjuvant osimertinib after chemotherapy and radiation for stage III lung cancer. So, this is really, really quite impressive. The hazard ratio is 0.16, so an 85% improvement over the course of the curve with using adjuvant osimertinib.

And the other interesting thing about this is that they did look at overall survival as well. So, there are two endpoints that maybe I should mention. After we do definitive treatment for localized disease, we're often, as oncologists and investigators, looking at the time to progression. Did the cancer come back and how long did it take? And then, the survival, did patients survive longer? The two measurements are called progression-free survival and overall survival.

So, on the LAURA trial, the osimertinib arm had a 85% improvement in progression-free survival. It really prevented the cancer from recurring. But at least at this early look, the overall survival was no different in the two arms. So, what it means is that in the patients who received placebo and they had disease progression, they went on to receive osimertinib, and their disease was controlled. They didn't pass away. I think what it really is telling us here is that, if you have a target and the target is driving cancer growth, then our ability to hit the target can really be transformative. We still believe that hitting the target early before the cancer progresses is going to be helpful. So, I think, with time, we're going to see that patients who were assigned to the osimertinib arm probably will have a better survival, but it may take many, many years because the target is so effective in the metastatic setting. But you're right, this is an important lung cancer trial that got a lot of noise, and I think is clearly practice-changing. My colleague down in Emory, Suresh Ramalingam, led this study.

So at the ASCO session, this is a huge auditorium. I think probably over 5,000 people are in the audience. There are others that are listening on a video cast. It's just a big honor to present, and it's a big event. And it's a big stage for drug development and these investigators.

John Leonard, MD: All right. I'm going to give each of us one more chance to highlight another area before we wrap up. I'm going to mention the area of CAR T-cells. This is something that we've talked about on this program before, and it's really an important area in hematologic malignancies, particularly leukemias lymphomas, multiple myeloma, and lots of clinical trials as well as some approvals. The idea of a CAR T-cell, which stands for chimeric antigen receptor T-cell, is again going to these T-cells that are immune cells that typically fight infections. They can be through a fancy blood donation, removed from a patient's body just through a special kind of blood donation. They can then be sent to a laboratory, a company that can engineer them to essentially be fired up to fight a tumor cell. They're re-engineered to basically bind to tumor cells more specifically and also to be kind of energized to go after them. Then, the patient, they're sent back to the hospital or the treatment center. The patient gets some light chemotherapy to make some space, then these CAR T-cells are infused into the body like a blood transfusion, and they can then go on to treat the tumor cells. And these have made a big difference in certain types of lymphoma, certain types of lymphoid leukemias in particular. They're moving along in multiple myeloma as well, and they're also being studied in autoimmune disorders, in certain forms of solid tumors, mostly in clinical trials. They've really, for certain scenarios, changed the standard of care. And there are a large number of them in clinical trials engineered in a little bit different ways to go after different clinical situations.

So, CAR T-cells have become the standard of care in a number of settings, particularly lymphoma and some leukemias. But I just wanted to highlight two that were presented at ASCO. Most of the CAR T-cells in lymphomas and lymphoid cancers are focused on, B cell leukemias and lymphomas, but a less common type is the T-cell. And there was some data looking at a CAR T-cell that targets CD7. CD7 is a target on T-cell lymphomas and leukemias. And this showed some early clinical data, so this is using a normal T-cell that's reengineered to fight a tumor T-cell that has a specific target on it. And while this was a small study, these were exciting and interesting results where a substantial number of patients had tumor responses, and those in many cases lasted months to years But this is a particularly relevant scenario, because the T-cell lymphomas in many cases can be more difficult to treat, not always, and so, having a CAR T-cell to fight T-cell leukemias and lymphomas is of some potential value as these move through clinical trials.

The other scenario that I wanted to highlight is that liso-cel, which is one of the approved CAR T-cells for certain types of B-cell malignancies, was reported on for a specific type of lymphoma called Richter's transformation. This is when patients have an underlying indolent type of lymphoma called CLL or chronic lymphocytic leukemia. It's also called small lymphocytic lymphoma. Sometimes, these types of leukemia and lymphoma can change to a more aggressive type that traditionally is much harder to treat. And these data with liso-cel suggested that some patients can benefit from a CAR T-cell approach. And this is, I think, important data, because this option has been explored in small numbers of patients. And as time goes by, we're getting more data suggesting that this approach could have potential value for patients with Richter's transformation, which, as I said, can be, in many cases, more difficult to treat. So, encouraging data there. Dr. Shah, your last topic. Go ahead.

Manish Shah, MD: Thank you. I found a couple of abstracts, very, very interesting that involved artificial intelligence. That's a big craze. Everyone is excited about ChatGPT and what it could do. So, this abstract in particular was out of the Stanford group, and it looked at the pathology of patients who are getting immunotherapy in gastric and esophageal cancers. And they looked at 30-40 different features of the pathology specimens using high-definition fluorescent microscopy to characterize different types of immune cells. These included the cytotoxic T-cells, or the T helper cells, natural killer cells. So the immune system is very complex in the microenvironment of the tumor, and you might imagine that there are thousands of features that you could identify, and we're just not sure which features are the ones that are most important in predicting which patients might benefit or not.

So, these investigators used a computer algorithm and then artificial intelligence to try to identify these features. And they, in fact, identified a novel spatial biomarker, so the distance between lymphocytes and neutrophils, or lymphocytes and macrophages, or lymphocytes and other lymphocytes. And if this distance was small or large, they were able to put it into a good or bad risk category, and they were able to really predict with pretty high fidelity how well patients might do with immunotherapy.

So, I think that really is quite exciting on several fronts. One is that we're always learning how AI can help us. And I think this is one example where the AI was able to look at images and characterize features and then identify which features might be more important. So, that was interesting. But it opens up another avenue of research. What it's really telling us is that the interaction between the different immune components as reflected by the distance between the two cells, that interaction might be very important in predicting who might benefit from immunotherapy.

So, the next step in the research is going to be what is driving those distances, you know, the immune system functions in a very complex way. It often secretes something called cytokines or immunokines. These are proteins that provide a signal to neighboring cells to either come closer or to stay away or go away. And so, these cytokines likely are important in these spatial features of these interactions between lymphocytes and neutrophils or lymphocytes and macrophages that are predictive in this model. So, I think it opens up lots of avenues of research, and it's really quite exciting to see and it's really a reminder of how cutting edge ASCO can be.

John Leonard, MD: Well, thank you so much, Dr. Shah. It's been great to have you here, and I really appreciate all the time that you put into putting together your analyses of these presentations. It's really helpful, and I know that our audience enjoyed it.

Manish Shah, MD: Thank you so much for having me. It's really a pleasure for me to be here. And I look forward to 2025.

John Leonard, MD: Great. Well, I'd like to invite our audience to download, subscribe, rate, and review CancerCast on Apple 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 Cancer Cast, conversations about new developments in medicine, cancer care, and research. I'm Dr. John Leonard. Thanks for tuning in.

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