Podcasts about hematology oncology division

In today's episode, supported by BeiGene, Alexey Danilov, MD, PhD, hosted a discussion with Nicole Lamanna, MD, about the use of zanubrutinib (Brukinsa) in patients with chronic lymphocytic leukemia (CLL). Dr Danilov is the Marianne and Gerhard Pinkus Professor of Early Clinical Therapeutics, the medical director of the Early Phase Therapeutics Program for the Systems Clinical Trials Office, co-director of the Toni Stephenson Lymphoma Center, and a professor in the Division of Lymphoma at the Department of Hematology & Hematopoietic Cell Transplantation at City of Hope in Duarte, California. Dr Lamanna is an associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at the Columbia University Herberg Irving Comprehensive Cancer Center in New York, New York.  In our exclusive interview, Drs Danilov and Lamanna discussed key efficacy data from the final comparative analysis of the phase 3 ALPINE trial (NCT03734016) in patients with relapsed/refractory CLL, zanubrutinib-associated toxicities to consider when using this agent, and what the future looks like for BTK inhibitor–based therapy in CLL.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor for Lung Cancer, Dr. Charu Aggarwal, and Cancer.Net Specialty Editor for Thymoma, Dr. Ryan Gentzler, discuss what people with early-stage non-small cell lung cancer should know about their treatment options before and after surgery, called neoadjuvant therapy and adjuvant therapy, respectively. Dr. Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine. Dr. Gentzler is a thoracic medical oncologist and Associate Professor of Medicine in the Division of Hematology/Oncology at the University of Virginia (UVA) Comprehensive Cancer Center. View disclosures for Dr. Aggarwal and Dr. Gentzler at Cancer.Net.  To begin, Dr. Gentzler will discuss what people with early-stage non-small cell lung cancer should know about neoadjuvant treatment options before lung surgery. Welcome, Dr. Gentzler. Dr. Gentzler: Hi, this is Ryan Gentzler from the University of Virginia. We're here to discuss the role of neoadjuvant chemotherapy and immunotherapy for the treatment of locally advanced non-small cell lung cancer. So first, I thought I'd address some of the data and definition of what is neoadjuvant treatment. So when we think about treating lung cancer that is not metastatic, that is earlier stage disease, there typically involves multimodality treatment. Sometimes these lesions or tumors can be very small and can be stage I and treated with surgery alone or perhaps radiation alone and no further treatment is needed. But the vast majority of lung cancers that are considered early stage are in fact either larger tumors, involve lymph nodes, and typically fall into the category of stage II or III lung cancers. And these are cancers that often require multiple treatments beyond the local surgery approach alone. When we think about how we deliver that treatment, it can either be given before surgery or after a surgery. If we give treatment before a surgery, we call that neoadjuvant. If it is given after the surgery, we call that adjuvant. And most of the data that we have today in lung cancer uses one or the other of these approaches, and we don't typically give treatments both before and after, at least in terms of the chemotherapy part of that treatment. Historically, most of the data exists in the adjuvant treatment of lung cancer going back several decades that showed that the benefit of chemotherapy after a surgery, particularly for those with stage II and stage III lung cancer, derived a clear benefit of survival by giving chemotherapy after surgery. More recently, with the advent of immune therapy, which we have used in patients with stage IV lung cancer as well as those with stage III lung cancer who cannot undergo surgery, those immunotherapy drugs have been shown to improve overall survival and improve clinical outcomes for a wide range of patients with more advanced disease. And so in the last 4 or 5 years, we have really looked at new trials that have added immunotherapy in what we call perioperative space, either before surgery or after surgery for those that have surgically resectable disease. I'm going to focus on the neoadjuvant approaches that we have seen today, and this largely all started with data from Patrick Forde out of Johns Hopkins and Jamie Chaft from Memorial Sloan Kettering looking at single agent treatment with nivolumab immunotherapy. This was no chemotherapy given for 3 treatments prior to or three cycles prior to surgery. And that trial demonstrated a high degree of patients with tumor reduction and more importantly, we saw that the pathologic response, meaning how much tumor was left under the microscope at the time of surgery, was higher than what anyone anticipated with just immunotherapy alone. That launched a whole series of larger randomized prospective trials evaluating largely the combination of chemotherapy and immune therapy prior to surgery. Now, before we get into some of the results of these trials, I really wanted to emphasize some of the theoretical advantages to neoadjuvant approach. Now, the first potential advantage of giving neoadjuvant treatment is that we know when you start with immunotherapy and chemotherapy regimens and that's the first type of treatment, everyone is guaranteed to get that treatment. And we know that the completion rate prior to surgery is higher than it is after surgery. These patients can get all of the prescribed treatment and will be more likely to get it than if they get it after surgery. So this is one advantage. The other is potentially starting these medications which go throughout the body and treat the cancer, wherever it may be, earlier. We know that one of the risks of all cancers, but lung cancer in particular, is that even with good surgery and removing all of that cancer, there is a chance that there are cancer cells left behind, which leads to risk of recurrence in the years to come after surgery. Naturally, if we start the treatment that can eliminate those cancer cells, wherever they may be, and do that first, perhaps we catch this earlier with fewer cells that have escaped and have a more likely chance of success of eliminating the cancer and resulting in a cure. The third, I think, is one that we still have yet to learn more about, but if we give immunotherapy in particular, these are medications that activate the immune system, particularly the type of immune system cell called a T cell. If that T cell is able to recognize tumor cells, it is more likely to be able to continue to attack those tumor cells. And if we give that treatment prior to removal of the tumor, perhaps that activates the immune system in a more robust way that it can go after these cancer cells and eliminate those that are left behind after the surgery. If you give the immunotherapy after a surgery and the bulk of the tumor, most of the cancer cells have been removed, it may be harder to find those antigens or foreign proteins that are expressed in cancer cells. So the immune system may not be as robustly able to go after cancer if you give it solely after a surgery. Another potential advantage of neoadjuvant approaches is that it really helps us learn as oncologists how well a cancer is responding to a treatment. If we give these treatments for 4 cycles after a surgery, we don't know whether it's eliminating those residual cancer cells or whether it is totally ineffective. If we give it before a surgery and we see that there is tumor reduction or that there is a complete elimination of the cancer, we know that that treatment was an effective treatment at attacking the cancer cells and eliminating them. We know that the cancer was sensitive to that treatment. We can then better prognosticate how well the patients are going to do after surgery. We know based on the latest data that if you achieve what we call a pathologic complete response with chemotherapy and immunotherapy prior to surgery, meaning there are no cancer cells left when we look at that surgical specimen under the microscope, we know that those patients have a much better likelihood of surviving for longer periods of time than those who have active cancer at the time of surgery after prior treatment. And so neoadjuvant approaches allow us in a 2-month time frame to get a great sense of how well our treatments are working and able to prognosticate outcomes based on how well those cancer cells have been eliminated at the time of surgery. One large phase 3 trial called the CheckMate 816 trial was a randomized phase 3 trial and that enrolled patients with stage IB through IIIA non-small cell lung cancer using the old staging system of the 7th edition. These would all now be categorized as stage II and stage III non-small cell lung cancer patients. And it randomized these patients to 3 cycles of chemotherapy plus nivolumab, which is an immunotherapy drug, and compared that to patients treated with chemotherapy alone for 3 cycles. After these 3 cycles of chemotherapy, which is about a 9-week time frame, patients had surgical resection of their tumors. And then after surgery, patients received no further treatment, although treating physicians were allowed to give additional treatments like chemotherapy or radiation if they thought it would be beneficial for these patients, although it was not mandated by the study. One of the first results we saw from this study was that there was a much higher rate of pathologic complete response of 24% of patients achieving a path CR [pathologic complete response] with the nivolumab plus chemotherapy combination compared to only 2.2% with chemotherapy alone. This was highly statistically significant and demonstrated a clear benefit for those receiving the immunotherapy. The other main endpoint of this study was event-free survival, meaning that the time that the patients were alive and without any significant event like cancer progression or death after the enrollment of the trial. And in this analysis, the median event-free survival was significantly longer in those who have received the immunotherapy plus chemotherapy combination prior to surgery. One of the potential concerns about neoadjuvant treatment is that it may render patients unfit for surgery who otherwise could have had their cancer removed. When we look at the outcomes from this CheckMate 816 trial, it actually did not appear to be the case to a large degree. In fact, those that got the nivolumab plus chemotherapy combination were more likely to proceed on with surgery, and the majority did; 83% received the planned surgery. There were patients who were unable to receive surgery due to adverse events of their treatment, but that was only 1% of patients enrolled in the trial. Other reasons for canceling the surgery included disease progression, meaning the cancer got worse to the point where they could not undergo surgery, or other reasons, such as the patient declined surgery, or it was found to be unresectable at the time the surgeon wanted to remove the cancer, or poor lung function.   One of the insights we got from the surgical data from this trial were that those who received the combination of chemotherapy and immunotherapy had slightly higher rates of smaller surgeries like a lobectomy compared to a pneumonectomy for those who had received [chemotherapy alone.] There were also fewer numbers of patients who required a conversion from a minimally invasive surgical procedure to an open surgical procedure if they were getting the immunotherapy combination. A higher number of patients also were able to have complete resection of their tumor if they received the immunotherapy/chemotherapy combination. The length of hospitalization was slightly lower, and the rates of pain were slightly lower in those who received the combination as well. These comparisons were not statistically significantly different, but numerically, there seems to be at least a trend toward benefit in surgical outcomes in this neoadjuvant chemotherapy/immunotherapy approach. And I think this makes sense. We know that this combination is more able to eliminate a cancer and make it a pathologic complete response when we look at it under the microscope, and therefore, if there is shrinking the tumor to a higher degree, naturally, it seems there would be more likely of completely removing the tumor, using a smaller incision to remove that tumor, shortening the length of stay in the hospital and recovery time and pain control. All makes sense if we know that the treatment itself is able to reduce that size of the tumor. There are many other phase 3 trials ongoing studying the impact of immunotherapy plus chemotherapy in the neoadjuvant setting. The AEGEAN trial has recently reported data at the AACR meeting this year in 2023 with similar results that we saw with the CheckMate 816 trial. There are 3 other phase 3 trials that are ongoing, one of which we will see later this summer called the KEYNOTE-671 trial evaluating pembrolizumab plus chemotherapy in the neoadjuvant setting and then 2 other trials evaluating nivolumab, the CheckMate 77T trial, or atezolizumab in the IMpower030 trial. Each of these more recent trials typically have used 4 cycles of chemotherapy plus immunotherapy prior to surgery and also continued the immunotherapy after surgery for a period of time, most commonly approximately 1 year. From the data we have seen so far, it remains uncertain whether additional immunotherapy beyond the 3 or 4 cycles given in the neoadjuvant setting provides any additional benefit. We still do not understand what to do with patients who did not achieve a pathologic response whether further treatment would be of any additional benefit. We do not know if there will be further benefit even in those that achieved a pathologic complete response whether a slightly longer duration of immunotherapy would further improve outcomes in that group. We suspect with longer-term follow-up over the years of all of these phase 3 trials that some of these questions will be answered. So what are some key questions that patients should ask when considering a neoadjuvant chemotherapy/immunotherapy approach? I think the first question that's key is what is my tumor stage? We know that the trials that enrolled patients with a neoadjuvant approach enrolled patients using our current staging system would be a stage II or stage III lung cancer. And this is where it gets really tricky is, what subdivision of stage III is it? We tend to think of stage IIIA's as being one that it would be surgically resectable, with a smaller number of stage IIIBs, and then stage IIIC, one that we would not typically recommend surgery for. I think the next question within the tumor stage is, is this based on imaging or based on the biopsies? And we know that biopsies are really the best way to stage locally advanced cancers, particularly getting samples of lymph nodes in the mediastinum. Sometimes what looks like a stage I or stage II on imaging is, in fact, a stage III based on biopsies that are done at the time of surgery. It's ideal to know that information prior to making the decision about surgery so that that surgery is not futile.   On the opposite side, sometimes there is imaging suggestive of lymph nodes that are enlarged in the mediastinum, and it's presumed that this is a more advanced stage III and is not surgically resectable. However, if you go and biopsy those lymph nodes, sometimes they are benign. Sometimes they are inflammation related to infection or cancer but do not actually contain cancer cells. And so we typically advise that getting biopsies of lymph nodes in the mediastinum, at least any that are particularly suspicious, is highly recommended for these locally advanced cancers. I think the next question that's key to ask is, what are my tumor biomarkers? And there are multiple biomarkers that we look at in non-small cell lung cancer that help us decide what is the best treatment. What is the best approach? What is the best medicine to treat the cancer? We know that one of these biomarkers that is a key is a mutation. So multiple different mutations can occur in lung cancers, particularly those that are adenocarcinoma subtypes. And these mutations may be less likely to benefit from immunotherapy and we may want to take a different approach with surgery, chemotherapy, and potentially targeted therapies that specifically target that mutation that exists in the tumor. The other key biomarker here is PD-L1. We know that tumors with a higher level of PD-L1 are more likely to respond and benefit from immunotherapy. As of right now, that PD-L1 status plays a more important role in the adjuvant setting. All of the chemotherapy plus immunotherapy combinations in the neoadjuvant setting seem to benefit the group as a whole regardless of that PD-L1 status. But still, an important biomarker that we should have prior to making all final decisions on treatment. I think another question that should be asked any time you have an earlier stage cancer is, is my tumor surgically resectable? And there can be many reasons why cancers are not resectable, perhaps due to the anatomy of where the tumor is located, if it invades into the mediastinum, for example, or is near large blood vessels, or perhaps because there are too many lymph nodes and this is a more advanced stage. And so I think the main reasons for not being surgically resectable would be the tumor is too large, if the stage is too high, or is it more of a function of fitness for surgery and that can be because of other underlying lung disease. Perhaps removing part or all of a lung would not be safe due to impaired lung function to begin with. And I think it's important to understand that sometimes stage III lung cancers are resectable and sometimes they are not, and understanding the reason why they are not, I think, is important. And then I think lastly and ultimately when we're talking about a neoadjuvant approach, you want to ask your treating oncologist, "Would it be better to give my treatment before surgery or after surgery?" And really discuss the pros and cons with the physician and have them incorporate all of the factors that go into these treatment decisions. How well you'll tolerate chemotherapy, other medical conditions that may play a role in the likeliness of getting through those treatments safely, perhaps underlying diseases that may increase the risk of immune-related side effects with immunotherapy. You really want to factor in all of these things and discuss the pros and cons of a systemic treatment first versus surgery first before making final decisions on how to treat locally advanced lung cancer. All right. Thank you. ASCO: Thank you, Dr. Gentzler. Next, Dr. Aggarwal will discuss what people with early-stage non-small cell lung cancer should know about their adjuvant treatment options for after lung surgery.   Dr. Aggarwal: This is Dr. Charu Aggarwal. I'm the Leslye Heisler Associate Professor for Lung Cancer Excellence at University of Pennsylvania's Abramson Cancer Center. And today I will talk to you about the use of adjuvant immunotherapy in the setting of early-stage non-small cell lung cancer. We'll start by discussing what adjuvant therapy is, what types of options we have for adjuvant therapy, what kind of testing is important, and what options there may be in terms of adjuvant immunotherapy. So let's get started. Early-stage lung cancer comprises of stages between stage I to stage III. These stages vary by the size of the tumor as well as the level of lymph node involvement. In the setting of very early-stage lung cancer, such as stage I and stage II, as well as some select stage III lung cancers, we recommend surgical resection. And in these patients, the use of additional treatment is recommended based upon the pathological determination of the tumor size as well as the lymph node status. If usually lymph nodes are involved, we recommend adjuvant chemotherapy, and also, many experts will deliver adjuvant chemotherapy for tumors that may be larger than 4 centimeters even in the absence of lymph node involvement. The data for adjuvant chemotherapy comes from several large clinical trials that were conducted about a couple of decades ago now that demonstrated not only an improvement in preventing recurrence of the cancer but also a modest improvement in overall survival, really laying the ground for improvement and therefore becoming the gold standard. Four cycles of chemotherapy are usually administered about 6 to 12 weeks following surgical resection, and this is really the basis of our treatment in the early-stage setting. In today's time and age, we now have several other options. We have treatment options that include molecular therapy, which is biomarker driven, as well as the use of immunotherapy. So it's actually very important for us in the adjuvant setting--or in the post-surgical setting--to test for mutations such as EGFR. It's also important for us to test PD-L1 status. So let's dive into why each of these may be important. Patients with EGFR mutations, especially those with sensitizing mutations in EGFR exon 19 or 21, now have the opportunity to receive a targeted therapy in the form of osimertinib, which is an oral drug, very targeted and specific for the EGFR mutation that has been studied in a clinical trial setting in patients with early-stage non-small cell lung cancer. In patients with stage IB to IIIA non-small cell lung cancer with EGFR mutation, use of osimertinib was associated with a significant improvement in our ability to delay the recurrence of cancer. Based on this significant improvement, FDA approved therapy with osimertinib, and it is currently available and ready to use. We usually recommend it for 3 years, so daily therapy for 3 years, and patients are monitored with routine CAT scans and lab work. For patients who don't have an EGFR mutation, we do recommend broad panel testing. Of course, this is not the standard, but I think it's important for us to identify patients who may not benefit from immunotherapy. Patients that have an ALK mutation, for example, or ROS1 translocation, may not have the best chances of responding to adjuvant immunotherapy, and therefore, I think testing should be performed to make sure that we are having a shared decision-making conversation with our patients about the use of the correct adjuvant options. In terms of adjuvant immunotherapy, we now have 2 approved agents. One of them is atezolizumab, and the other one that was just recently approved is pembrolizumab. Atezolizumab was approved on the basis of a large clinical trial called the IMpower010 study, which randomized 1,280 patients with stage IB to IIIA non-small cell lung cancer to either 1 year of atezolizumab or best supportive care. Of note, all of these patients had to have had adjuvant chemotherapy that included a cisplatin platinum chemotherapy. In the first analysis, we found that the disease-free survival or the probability of the patients remaining cancer-free was significantly improved in those patients that had a tumor expression of PD-L1 greater than or equal to 1% and received atezolizumab compared to patients who did not receive atezolizumab. On the basis of this positive primary endpoint, the U.S. FDA approved the use of adjuvant atezolizumab for patients with stage II to IIIA resected non-small cell lung cancer after surgical resection and adjuvant chemotherapy. Recently, we heard that this does lead to small but significant improvement in overall survival. There is a trend towards improvement in overall survival. However, the data are quite immature at this point, and we do need longer follow-up to be able to follow this trend. The greatest magnitude of overall survival benefit was found in patients who had the PD-L1 greater than or equal to 50%. So it's important to know what the PD-L1 level of a patient may be when I'm thinking about adjuvant immunotherapy because adjuvant immunotherapy is most likely to benefit those that don't have an actionable mutation, such as EGFR, and those that have the highest PD-L1 staining, at least in the IMpower trial. Secondly, the PEARLS clinical trial is a clinical trial that evaluated the use of pembrolizumab, which is another immunotherapy agent, again, in the adjuvant setting. For this clinical trial as well, there was a small but significant improvement in disease-free survival, again preventing the probability of recurrence in all patients that received pembrolizumab compared to the best supportive care. And basically, this led to also an approval by the FDA for the use of pembrolizumab. Again, now we have 2 options. Both of these are administered for 1 year. What should patients know about therapy? These drugs are usually administered once every 3 weeks. They are given intravenously. Sometimes, we can change the treatment schedule to be either once every 4 weeks in the case of atezolizumab or every 6 weeks in the case of pembrolizumab. These may be associated with some side effects. Immunotherapy side effects that are most common are fatigue, chills, myalgias, or basically a feeling of pains in the body or joints. But also, some serious life-threatening reactions can occur such as activation of the immune system to such an extent that the immune system may start to attack the body's organs. So this may lead to swelling or inflammation in the organs that may manifest itself as colitis if the gut gets inflamed, or pneumonitis if the lungs were to get inflamed, or pancreatitis if the pancreas were to get inflamed. Any organ in the body can really get inflamed. We've certainly seen cases of thyroiditis. We've seen cases of polyarthritis. We've seen cases where the brain may also get inflamed or the pituitary may get inflamed. So there are definitely some life-threatening reactions or side effects that can occur with the use of immunotherapy that should be closely monitored. The benefit of having used immunotherapy in the metastatic setting is that now we have a lot of experience managing these side effects. And if recognized early, these side effects can be managed appropriately with the use of steroids as well as holding therapy. Many of the times, we can even reinstitute immunotherapy without significant harm to the patients. However, I think immunotherapy benefits as well as side effects should be discussed in detail with the provider, especially in the adjuvant setting. Patients may ask if neoadjuvant immunotherapy along with chemotherapy is a better approach compared to adjuvant immunotherapy. At this time, we don't have a clinical trial that is comparing neoadjuvant chemoimmunotherapy followed by surgery to an approach that is surgery followed by adjuvant immunotherapy. In general, I would say that if the decision by a multidisciplinary team has been made to proceed with surgery, careful discussion should be had about adjuvant chemotherapy as well as the use of adjuvant immunotherapy, and molecular testing should be performed. All patients with early-stage disease should have a multidisciplinary tumor board discussion, which includes engagement with surgeons, radiation oncologists, pulmonologists, pathologists, and medical oncologists so that they can ensure that many experts have had the chance to weigh into their case as well as come to the right conclusion on whether or not to use new adjuvant chemoimmunotherapy or just to proceed with surgical resection. ASCO: Thank you, Dr. Aggarwal. You can learn more about neoadjuvant and adjuvant treatment options for early-stage non-small cell lung cancer at www.cancer.net/lung. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care.   And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology.  Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate. 

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. The theme of the 2023 ASCO Annual Meeting was “Partnering With Patients: The Cornerstone of Cancer Care and Research.” From June 2 to 6 in Chicago, Illinois, and online, cancer researchers and clinicians from around the world gathered to discuss the latest cancer research and how to ensure that all people receive the cancer care they need. In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field presented at the meeting and explain what it means for people with cancer. In today's episode, our guests will discuss new research advances in treating non-small cell lung cancer, small cell lung cancer, and mesothelioma.  Dr. Charu Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine in Philadelphia, Pennsylvania. She is also the 2023 Cancer.Net Associate Editor for Lung Cancer. Dr. Melina Marmarelis is an assistant professor at the University of Pennsylvania, the Medical Director of the Penn Medicine Mesothelioma Program, and the co-director of the Molecular Tumor Board at the University of Pennsylvania. She is also the 2023 Cancer.Net Specialty Editor for Mesothelioma. Dr. Kristin Higgins is a radiation oncologist, Professor and Vice Chair in Clinical Research in the Department of Radiation Oncology at Emory University School of Medicine and medical director of radiation oncology of The Emory Clinic at Winship Cancer Institute's Clifton campus location. She is also a 2023 Cancer.Net Advisory Panelist for Lung Cancer. You can view disclosures for Dr. Aggarwal, Dr. Marmarelis, and Dr. Higgins at Cancer.Net. Dr. Aggarwal: Hello and welcome to this Cancer.Net Research Round Up podcast. Today, we will be talking about the latest research from the Annual Meeting of the American Society of Clinical Oncology from June 2023, and I'm joined today by 2 experts in the field of lung cancer. Before I introduce them, I'd like to introduce myself. I'm Dr. Charu Aggarwal. I'm an associate professor for lung cancer excellence at the University of Pennsylvania's Abramson Cancer Center. I'd now like to introduce Dr. Melina Marmarelis. Dr. Marmarelis: Hi, so happy to be here. I'm Melina Marmarelis. I'm an assistant professor at the University of Pennsylvania and the medical director of the Penn mesothelioma program. Dr. Aggarwal: And Dr. Kristin Higgins. Dr. Higgins: Hi, everyone. I'm Kristin Higgins. I am a thoracic radiation oncologist at Winship Cancer Institute of Emory University. I'm a professor and vice chair for clinical research for radiation oncology. Dr. Aggarwal: Fantastic. So today, we'll talk about relevant research as it applies to practical implications in the clinic for practitioners, but most importantly, patients with lung cancer. I'd like to start off by discussing 2 key studies, and I would love for perspectives from our faculty here. The first study I want to highlight is the ADAURA trial. This is a trial that has already sort of changed practice in most recent years when the study was presented at the Annual Meeting of the American Society of Clinical Oncology in 2020, but we have new updates on this study as of 2023. So, in brief, this was a study that looked at the value of administering an oral pill called osimertinib that is a tyrosine kinase inhibitor against the EGFR, or the epidermal growth factor receptor, in patients with non-small cell lung cancer. We know that non-small cell lung cancer is quite a heterogeneous disease with some subsets of patients having mutations that may render them increasingly sensitive to the effects of these tyrosine kinase inhibitors. In fact, these pills have been used in the metastatic setting for several years based on an improvement in overall survival. What the ADAURA study tried to do was ask the question if this pill would add an incremental advantage after receiving curative-intent surgical resection in those with early-stage lung cancer. So this study enrolled patients with stage IB to IIIA non-small cell lung cancer after surgical resection and focused only on those patients that had sensitizing EGFR mutations with EGFR exon 19 deletion or L858R mutations. Patients could receive chemotherapy after having the surgery and then were basically randomized into 2 groups, one of whom received osimertinib at a dose of 80 milligrams once daily for a total of 3 years. Patients were followed up for recurrence. We already know from the earlier results that patients who received osimertinib had a better chance of delaying the recurrence of disease. However, what we found at the Annual Meeting this year is that the administration of this osimertinib also improved overall survival, which is really what we all look for in the oncology world. If you're administering a therapy, especially for a long duration, we want to be able to see a survival benefit, and that's what we saw. In fact, in patients who received osimertinib, there was a 49% less likelihood of dying from lung cancer compared to those who did not receive osimertinib. This, I think, is practice-affirming. It may not be practice-changing because some of the practitioners started using osimertinib after its FDA approval in December of 2020, but I think it just confirms our practice as it delivers an overall survival advantage in these patients. One thing that's increasingly important is to identify patients who have this mutation, so now we have efforts underway locally as well as nationally to perform molecular genotyping on all patients with lung cancer so that we can adequately and appropriately treat those with early-stage lung cancer following curative resection or following surgery. Melina and Kristin, what are your thoughts? Dr. Marmarelis: Well, I think these results are really important because it did, as you say, affirm kind of what we're already doing, but I think the most convincing part of this for me is the prevention of spread of disease to the brain. This is not comparing osimertinib after surgery versus osimertinib ever, which I think is a difficult part about interpreting this trial. But I think the fact that it prevented disease from going to the brain is really meaningful to everyone, to patients, to the physicians that are caring for them, so I think that's a really important endpoint. Dr. Higgins: I agree with Melina. I think this is really exciting for our patients. It's exciting to have more treatment options for early-stage lung cancer. I think patients that are diagnosed with early-stage lung cancer are highly motivated to do everything they can to improve their likelihood of being cured. So I tend to have a lot of conversations about side effects and toxicities with patients that have questions and are sort of wondering how it will affect their quality of life, and of course, that is an important piece of it because patients that do have curable lung cancer are probably starting off with a better overall quality of life, but I think generally speaking, our patients have tolerated it well. I'm also kind of excited from a radiation oncology point of view. We treat patients with stereotactic body radiation therapy [SBRT] that are medically inoperable. And we have another trial with a cohort looking at osimertinib for those patients that have EGFR mutations, too, and that's ongoing, again, applying the same concept of trying to really use these SBRTs that work really well in the advanced setting, moving them into earlier stages of disease to help us care for more patients. So overall, I think it's really exciting, and I think it's a huge win for the clinical research community. Dr. Aggarwal: Well, that's wonderful. And I think this certainly advances the field as this is the first targeted therapy approved for patients with early-stage non-small cell lung cancer. I should add that AstraZeneca, the company that makes this drug, has provided institutional research funding to my institution, and I also serve as an advisor to them, but I was not involved personally in the research of this clinical trial. I'd like to move on but stay within the field of early-stage lung cancer and talk about another study called the KEYNOTE-671 study, and this is important because it really applies the idea of using immunotherapy before and after surgical resection in patients with early-stage lung cancer. Just to give a little bit of background to our listeners, we now have 3 approvals for the use of immunotherapy in patients with early-stage lung cancer. Two of those are in the adjuvant setting, meaning that if a patient undergoes surgical resection or surgery for early-stage lung cancer, they can receive either atezolizumab or pembrolizumab following that surgery, and that has been shown to improve outcomes in terms of reducing the chances of recurrence. We also have another approval, which is the third approval in early-stage lung cancer, where 3 cycles of chemotherapy and immunotherapy are administered prior to surgery, also called as the neoadjuvant chemo-immunotherapy approach. This drug that has been approved in combination with chemotherapy is nivolumab, and this approval came from a clinical trial called CheckMate 816 that showed both that patients who received this neoadjuvant chemo-immunotherapy approach had a higher proportion of patients who had complete response or pathologic complete response in their tumors at the time of surgery and also showed that the chances of the disease coming back after surgical resection was much lower amongst those that had received this intervention. The current study, the KEYNOTE-671 study, builds upon this concept and adds both a before-surgery intervention as well as an after-surgery intervention. So what this study did was it enrolled patients with early-stage, stage II to IIIB non-small cell lung cancer, and patients in the intervention arm received 4 cycles of chemotherapy in combination with pembrolizumab, underwent surgery, and then received immunotherapy with pembrolizumab for up to 13 cycles. Patients in the control arm received only chemotherapy prior to surgery and then placebo for up to 13 cycles after. This was a large study with about 786 patients randomized, and what we found was that those patients that received the intervention had a much higher likelihood of remaining disease-free or event-free following surgical resection as well as in the early analysis, an improvement in overall survival with about a 27% reduction in the risk of death. So I do think that this is the first study that shows us that use of both neoadjuvant as well as adjuvant. So sort of this perioperative approach of using immunotherapy before and after surgical resection can actually lead to improved outcomes. This is ultimately what we want for our patients, improvement in overall survival, improvement in cure rates, etc. The study has been silent on the use of radiation therapy, although it has gone into details in terms of the kinds of surgery that was done. Kristin, what are your views about this? Dr. Higgins: I think postoperative radiation after resection for non-small cell lung cancer has sort of started to fall out of favor because of the Lung ART trial that was published in Europe, a randomized phase III trial that showed no differences in disease-free survival or overall survival. And that's not to say that there aren't more study questions on ways to give it safer and ways to incorporate radiation in with the chemo-IO approach, and there are some novel ways to do that, and we're going to see some data presented at the World Lung Cancer Conference looking at some of those novel approaches. But standardly, when patients receive neoadjuvant chemo-immunotherapy followed by surgery, we typically would not offer radiation. There are instances, though, when patients have positive margins, for example, and in that situation, it's sort of a discussion on a case-by-case basis. But ideally, we're hoping that most of these patients that go to surgery are able to get a complete resection, and that's really the key component of the decision-making for deciding if patients are eligible for this approach. Dr. Aggarwal: I agree. Melina, any additional thoughts on this trial? Dr. Marmarelis: I think it's an exciting trial for the reasons that you mentioned. I think it does bring up a number of questions about whether both neoadjuvant and adjuvant immunotherapy are needed. I tend to like the idea of having immunotherapy present when the tumor is present before surgery, so I like kind of having that on board, but I think we still don't know which is more important. Dr. Aggarwal: So it certainly raises many more questions, which hopefully will be answered in the future. KEYNOTE-671 trial was conducted by Merck that produces the drug Keytruda, or pembrolizumab. We have received institutional research funding for other trials. I was not personally involved in this clinical trial. I do serve as an advisor for Merck. I think we'll bring you more research from the ASCO Annual Meeting. And I'll turn it over to Dr. Marmarelis to discuss some more exciting research. Dr. Marmarelis: Thanks, Charu. So perhaps it's not surprising that one of the exciting things I picked from ASCO has to do with mesothelioma. And I just want to put into context a little bit about why this trial was important. This is IND227. It was a cooperative group trial done across Canada, France, and Italy, and this was chemotherapy plus or minus pembrolizumab in patients with pleural mesothelioma that did not undergo surgery. So this was their first treatment, and they were not undergoing surgery. And the reason this trial was important is that in the last few years, we had results from CheckMate 743, which was looking at IPI/NIVO, so a combination of immunotherapies versus chemotherapy. And there was an improvement in survival for those that received double immunotherapy, and that improvement was most pronounced in the non-epithelioid population, which is actually a smaller subset of pleural mesotheliomas. And so as we've seen in the lung when we look at immunotherapy versus chemo, it raises the question of whether combination immunotherapy plus chemotherapy would actually be better for all and, in particular, for all histologies in pleural mesothelioma. So this was looking at that concept. It took the standard chemotherapy, carboplatin-pemetrexed or cisplatin-pemetrexed, and then combined it with one immunotherapy, so slightly less than the combo immunotherapy seen in CheckMate 743, and that was pembrolizumab. And what they saw was that there was a small overall survival improvement in the group that got pembrolizumab. Again, that was most pronounced in patients in the non-epithelioid group, so those with sarcomatoid or biphasic histology. And this is really a prelude to several other trials that are coming out in mesothelioma, namely the DREAM3R trial, which is looking at chemotherapy plus or minus durvalumab. That control arm also includes IPI/NIVO, so that will be really important to be able to compare those, and then also the BEAT-meso trial, which is looking at chemotherapy-immunotherapy but also with an anti-VEGF agent, bevacizumab. So I think this was an important trial. It's a little bit of proof of concept, but there's still a lot that we're looking forward to. It's not quite practice-changing in the clinic, although I think it's certainly an option that people are using, but I'm looking for more data going forward. Dr. Aggarwal: It's incredible to see how far we've come in mesothelioma within the last decade. We are introducing immunotherapy. We're introducing novel agents in the first-line setting. Dr. Marmarelis: The other trial that I was interested in was KEYNOTE-789, which is looking also at patients with EGFR mutations and those that had the original osimertinib as their first-line treatment or another tyrosine kinase inhibitor and then had disease progression on that TKI. And this is an area of huge need. We have patients that do really well on targeted therapies, and then they have disease progression, and we're looking for additional targeted options, but we're also looking for effective chemotherapy options. And one of the questions that has risen from this is whether there's a role for immunotherapy. We know that immunotherapy alone in patients with EGFR mutations is not very effective when you look at a broad population, but in combination with chemotherapy, it's possible that it can add some benefit. So this trial looked at those that had EGFR mutations, had disease progression after a targeted therapy, and then it randomized them to chemotherapy plus or minus pembrolizumab, so chemotherapy plus or minus immunotherapy, and interestingly, it had no difference in the progression-free survival or the overall survival. So the 2 arms were really similar in terms of outcomes. There was also no difference in the overall response rates of the amount that the drug actually shrinks the tumor. So it really doesn't look like immunotherapy is adding much to chemotherapy for these patients. I think we still need to look a little bit closer because there are probably some patients with EGFR mutations that could benefit from immunotherapy, but we're really not very good at identifying those. One of the questions that comes up in this space is whether to add anti-VEGF treatment in addition to chemotherapy and immunotherapy. So there are some upcoming trials looking at that. Dr. Aggarwal: I think this was a trial that was actually very important and again, practice-affirming that this idea of continuing chemotherapy without adding immunotherapy, patients are not losing much. In fact, they're not gaining anything by adding immunotherapy as shown in this clinical trial. I think continuing immunotherapy, so continuing osimertinib, may be important in this setting also because we know that osimertinib can cross the blood-brain barrier. It can provide that CNS [central nervous system] protection. Dr. Marmarelis: Yeah, I think that's a great point that the comparison here is not chemotherapy plus osimertinib. It's chemotherapy alone. So I agree that the control arm is not quite what some of us do. I agree. I do the same as you do. I also just want to mention that the KEYNOTE trial and the previous trial about mesothelioma used pembrolizumab, which is made by Merck. We have received institutional funding, and I've served as an advisor as well as received honorarium from Merck.   Dr. Aggarwal: Melina, those were 2 very important studies and certainly, I think, answer some very relevant questions in clinic in the management of patients with EGFR-mutant lung cancer, for example. And then I think we look forward to more practice-changing data in mesothelioma. Kristin, I would love to hear research from ASCO from you. What caught your interest? Dr. Higgins: So I have a special interest in small cell lung cancer. And I think there was one important small cell lung cancer trial that I wanted to review with everyone. It was SWOG S1929. And SWOG is the Southwest Oncology Group, and it's a cooperative group that conducts clinical trials in cancer funded by the National Cancer Institute. And this is a randomized phase II trial of atezolizumab and chemotherapy followed by randomization to continuing the maintenance of atezolizumab with a PARP inhibitor. Now, we know from prior data that PARP inhibition is attractive for small cell lung cancer because PARP is expressed frequently in small cell lung cancer, and there is a biomarker called Schlafen-11 that preclinical data and prior data has shown can predict response to PARP inhibition. And this trial was sort of a proof-of-concept trial, a small, randomized phase II trial testing whether or not that Schlafen-11 biomarker could be used to direct therapy. Now, in this trial, there were 309 patients that were registered. They then had to have their tumor samples sent for central testing for the Schlafen-11 expression. One thing that I think is important to bring up is that in small cell lung cancer, there's this belief that it's really hard to get tissue samples from small cell lung cancer and it's a difficult thing logistically because it's just a lot harder to access these tumors. But interestingly, in this trial, 80% of patients had tumors that were evaluable for the biomarker, and the median time to the test result was only 7 days. So patients were able to get their tumor tested, get it sent out, get results in a rapid manner, and then be randomized based on these results. The primary endpoint for this trial was progression-free survival, and the primary endpoint was met. Progression-free survival was 4.2 months versus 2.8 months. Now, I think many people will say the magnitude of benefit here is not very much, but it's small cell lung cancer, and we don't have a lot of positive trials in this space, and we also don't have many trials that have used a biomarker to direct therapy. So I think for those reasons, it's really exciting to see these results. It was also conducted within a cooperative group with multiple different sites across the United States, and the fact of the matter is that we can do trials like this in small cell lung cancer patients, and I think it will sort of serve as a precedent for future trial design. Now, the overall survival for the trial is still premature. It didn't look that much different with the PARP inhibitor, but that doesn't mean that, again, things could change with more follow-up. And I really like the approach of this trial design, and I'm excited to see biomarker-driven trials in small cell lung cancer. Charu and Melina, what do you guys think about this study? And what do you think about our small cell lung cancer patients and our ability to conduct future trials like this? Dr. Aggarwal: I think this is certainly an advance. As you pointed out, Kristin, it shows us that we can conduct trials in the space. I think it offers a lens into the potential of personalized therapy in small cell lung cancer, which has eluded us for a very long time. The standard of small cell lung cancer has not changed significantly for a very long time, so I think this is very exciting and can't wait to see more things come in the future. Dr. Marmarelis: Yeah, I agree. I think we've always been asking for additional biomarkers, especially in such a difficult disease like small cell. And so this is really exciting to see potential biomarkers and that it was feasible to actually pose that question and study it. So that part's really exciting. Dr. Higgins: Great. And I should also say I was not involved in the study, and I'm not associated with any of the pharmaceutical companies that were involved in the study for S1929. And the final study that we wanted to talk about was the phase III LUNAR study, and this is sort of a different type of trial in the setting of advanced non-small cell lung cancer. It was studying tumor treatment fields with standard of care in metastatic non-small cell lung cancer after progression with platinum-based therapies. And first, I just want to step back and explain what tumor treating fields are. Tumor treating fields are applied to a patient with a transducer that's placed on the skin, and what it does is it applies an electrical field, and that disrupts mitosis when the cancer cells are trying to divide. And the mechanism of cell death is a little bit unclear. There are sort of many mechanisms that are postulated, one of which is immunogenic cell death, but we don't really know, I think, what's happening. But there have been studies that show improved results with tumor treating fields and other diseases. For example, particularly in glioblastoma multiforme, tumor treating fields are used in combination with surgery, radiation, and temozolomide (Temodar). So it's something that's being used in other disease sites, and this is some of the early data that we've seen in metastatic non-small cell lung cancer. And so in this trial, 276 patients were randomized to tumor treating fields plus standard of care or standard of care alone. Now, I should mention that this trial began enrolling patients in 2016, and so the standard of care was very different. After platinum-based therapies, the standard was considered docetaxel. Of course, platinum-based therapy alone for frontline treatment of advanced non-small cell lung cancer is also not the standard of care anymore. And so I think with that in the background, it does make interpretation of these results somewhat difficult, and that's probably the major caveat to this study. But nonetheless, patients were randomized, 276 patients. The primary endpoint of the study was overall survival. They were looking at progression-free survival and overall response rates as secondary endpoints as well as overall survival in patients that received immunotherapy versus just chemotherapy alone. And the trial was positive. Overall survival was improved. The median overall survival was 13.2 months for patients that received tumor treating fields with standard of care versus 9.9 months for standard of care alone. If you look at 3-year survival, it was 18% versus 7%. I think this is a new type of therapy for our patients with non-small cell lung cancer. It is somewhat of a difficult thing to wear the transducer, and you have to wear it for many, many hours. So that is one thing that I think can be difficult for patients that are using this treatment, but nonetheless, it is something new for advanced non-small cell lung cancer. I do know that the technology of tumor treating fields is being studied in other settings for non-small cell lung cancer, for stage III non-small cell lung cancer, for example, and also in the frontline setting. I think this trial kind of speaks to the fact that the landscape of advanced non-small cell lung cancer is changing so rapidly, and when we're studying something novel, we have to make sure that we make these trials feasible for enrollment so that we can get them completed rapidly, and we can get a readout and it doesn't become obsolete based on this shift in the standard of care. So I think it just really kind of drives home that we need to make sure that we're taking that into account with trial design. It's not standard of care changing right now, but it'll be interesting to see how the data evolves over time. Melina, I'm interested to hear your point of view because I know that these can be used in mesothelioma, maybe not that frequently. What is your experience with tumor treating fields, if any? Dr. Marmarelis: Tumor treating fields are approved as a device in pleural mesothelioma in the first-line setting in combination with chemotherapy. They have been used off-label in other settings, but that's the device approval. The trial that looked at tumor treating fields in mesothelioma was a single-arm trial, so there was no control arm, and it was really actually just looking at the safety of the device. So I have not used it personally in mesothelioma, although I know of patients and I know of real-world studies looking at its use, and I think it's potentially an interesting modality of treatment, especially in combination with immunotherapy, given that it really doesn't have a lot of additive toxicity. But I think the question is really, which patients are benefiting from it, and which patients are able to actually wear the vest in the case of mesothelioma? Dr. Higgins: Yeah. Any thoughts, Charu? Dr. Aggarwal: I agree, and I think this is going to be largely driven by patient experience. I think this is going to be quite onerous to wear this, carry the suitcase, so I would be very interested in patient reported outcomes as well as patient experiences and stories, which will really drive our use here. Dr. Higgins: Yeah, that's a great point. I should say that this trial was sponsored by Novocure. My institution does have other Novocure studies underway, and we receive research funding, but I was not involved in the study, and I did not personally receive any research funding. Dr. Aggarwal: Thank you, Kristin. This has been a wonderful review of practice-changing and some promising research that came out of the ASCO Annual Meeting. I hope our listeners enjoyed it, and we'll be sure to update you with the next annual research conference. Thank you, everyone. ASCO: Thank you, Dr. Aggarwal, Dr. Marmarelis, and Dr. Higgins. 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ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In the Research Round Up series, ASCO experts and members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, our guests will discuss new research in lung cancer, lymphoma, and childhood cancer that was presented at the 2022 ASCO Annual Meeting, held June 3-7 in Chicago, Illinois. First, Dr. Charu Aggarwal will discuss 3 studies looking at treatment options for people with non-small cell lung cancer. Dr. Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine in Philadelphia, Pennsylvania. She is also the Cancer.Net Associate Editor for Lung Cancer. You can view Dr. Aggarwal's disclosures at Cancer.Net. Dr. Aggarwal: Hello and welcome to this Cancer.Net podcast. I'm bringing you updates from the Annual Meeting of the American Society of Clinical Oncology, held in Chicago in 2022. I'm Dr. Charu Aggarwal. I'm the Leslye Heisler Associate Professor for Lung Cancer Excellence at the University of Pennsylvania's Abramson Cancer Center. I will be discussing updates on 3 studies today that offer insights and new advances in the management of patients with non-small cell lung cancer. I don't have any direct relationship with any of these companies or studies, and you can view a list of my disclosures on the Cancer.Net website. First off, I would like to talk a little bit about advances in the management of patients with EGFR exon 20 mutations. We know that a lot of advances have been made in the management of patients with non-small cell lung cancer, and much of that has been attributed to the fact that we are now able to deliver targeted therapy for a subset of patients. EGFR mutations form one such subset where we have a lot of oral drugs that are available, and we can offer these that improve survival, and patients can avoid chemotherapy, immunotherapy, and other IV infusional therapies. Within the subset of EGFR mutations lies this unique subset of EGFR exon 20 insertion mutations, which have been historically harder to target with currently available EGFR inhibitors. And over the last 5 years, we have seen tremendous growth of opportunities, targets, and new drugs for this subset of patients. The mutations in this subset forms about 2% to 5% of all non-small cell lung cancers. But now we have 2 FDA-approved drugs in this space, one being intravenously administered, amivantamab, and another that is orally available, mobocertinib. We covered this in a podcast as well as a blog, so please check those out on our Cancer.Net website. But building upon that progress, there is now another drug that was reported at ASCO. This drug is called CLN-081. And we saw preliminary activity in a phase 1 and 2 study of this molecule or this drug in patients with EGFR exon 20 insertion mutations. It's an orally available drug. The top line data is that it is safe, it is effective, it was tested in different doses. It was tested at less than 65 milligrams, 100 milligrams, and 150 milligrams, again, as I mentioned, administered orally, and we saw responses and patients that had previously received other therapies and may have progressed on other therapies. And what we found was that this drug also tends to have activity against brain metastases, which I think is this huge unmet need in the management of such patients. So I think more to come, but again, I think offers us an insight into what may be in the future, an attractive drug for our patients with EGFR exon 20 insertion mutations. So stay tuned, more on that in the future. Shifting gears, I would like to now talk about one of the common mutations. So we talked about EGFR exon 20, which is about only 2% to 5%, but the largest subset of mutations in non-small cell lung cancer really revolves around KRAS mutations, and these form about 30% to 35% of all mutations in non-squamous, non-small cell lung cancer. And amongst this group there is another subset which is KRAS G12C non-small cell lung cancer, that forms about 13% of all lung cancers. We have 1 approved drug already in this space by the name of sotorasib that is FDA approved for the management of patients with this particular mutation after having received 1 prior therapy, be it chemo-immunotherapy or immunotherapy. At this year's ASCO meeting, we heard data from a study called KRYSTAL-1, which looked at the activity and safety of another molecule called adagrasib, which is an orally available drug targeting KRAS G12C, again, in a similar population of patients with advanced and metastatic non-small cell lung cancer harboring a mutation. We found that this drug is again effective, the overall response rate was about 43%, the majority of the patients had stabilization of disease, about 80%, and many patients were able to remain on treatment with stabilization of disease. We found that this drug does have side effects and adverse events and most commonly of this were diarrhea, nausea, vomiting, and fatigue. Many patients did require dose reductions, but the activity of the drug remained despite dose reductions. Now, what would be the advantage of this drug against the currently available sotorasib? In another smaller study reported at ASCO, there seemed to be activity in the brain, including intracranial penetration with the use of this molecule, adagrasib, which has not been demonstrated before with other KRAS G12C inhibitors, so I think that makes it a potentially attractive option. Again, I will say that the report of this intracranial activity was in a very small subgroup of patients, so I think needs to be further corroborated in a larger study. Shifting gears again and talking about our last study, so I would like to highlight what do we do if, in case, patients don't have a targetable mutation. I want to highlight that we do have a lot of available options, and we are continuing to improve upon available options. The way we treat such patients is by using immunotherapy, either alone or in combination with chemotherapy. But what do we do after this treatment stops working? Researchers from the Southwestern Oncology Group, or SWOG, launched a massive national effort called Lung-MAP, which is basically a clinical trial that evaluates several different strategies all at once, either for patients with targetable mutations or for patients without a targetable alteration. And they reported results from a study that evaluated the combination of pembrolizumab with ramucirumab in patients that may have progressed after frontline immunotherapy. Now, pembrolizumab is immunotherapy, so the concept was, can we continue immunotherapy beyond progression and perhaps get some synergistic activity by using ramucirumab, which is a drug that prevents blood vessels from forming in the tumor itself. It's an anti-angiogenic agent, meaning that it is a targeted molecule that prevents blood vessel formation and promotes tumor death. What they found was that patients that received pembrolizumab and ramucirumab were more likely to live longer, so overall survival was longer for patients with this combination compared to a physician investigator discretion choice, such as chemotherapy in combination with ramucirumab or other chemotherapies that are otherwise used in the second line setting. And interestingly, we did not find a significant improvement in shrinkage with this combination of pembrolizumab and ramucirumab or a significant reduction in the time of progression-- or, sorry, prolongation of the time of progression of disease. But the overall survival findings are interesting, and I think that's why we are including them in this podcast because that's one of the approaches that is leading to an improvement in survival and improvement in outcomes. I will point out that this is a phase 2 study. These results would need to be validated in a large prospective phase 3 trial so that we can account for certain confounding factors that may have led to these results. Having said that, I think there's a tremendous excitement, there's tremendous excitement in this field. I gave you examples of, or highlighted, 3 studies: one in patients with EGFR exon 20 insertion mutations, another in KRAS G12C mutations, and the third in patients who may have already received either immunotherapy or chemoimmunotherapy. We will continue to update our Cancer.Net website with updates as they come through, new advances, new studies, so thanks for following, thanks for listening, and more to come. Stay tuned. Thank you. ASCO: Thank you, Dr. Aggarwal. Next, Dr. Christopher Flowers will discuss new research in treating people with different subtypes of lymphoma, including mantle cell lymphoma and diffuse large B-cell lymphoma. Dr. Flowers is the Chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center and was appointed Division Head ad interim of Cancer Medicine in August 2020. He is also the 2022 Cancer.Net Associate Editor for Lymphoma.   You can view Dr. Flowers' disclosures at Cancer.Net. Dr. Flowers: Hello and welcome to this podcast that is a review of late breaking abstracts from the ASCO Meeting and recent updates in lymphoma. I'm Dr. Christopher Flowers, professor and chair of the Department of Lymphoma and Myeloma and Interim Division Head for Cancer Medicine at The University of Texas MD Anderson. And it's my great pleasure to discuss with you some of these late breaking abstracts. I do have some disclosures that are related to the content that I will present from this year's ASCO Meeting and recent studies in lymphomas. Those are available at Cancer.Net. Those relate to my role as a consultant for the development of clinical trials in lymphomas and research funding that MD Anderson has received from companies related to my role in clinical trials in lymphoma and clinical trials across cancers. So, the ASCO Meeting had a host of new information that was presented. Some of that information centers around key clinical trials. One that was a pivotal clinical trial, the SHINE clinical trial, looked at patients with mantle cell lymphoma, a rarer lymphoma subtype, that looked at the combination of bendamustine and rituximab, a standard chemoimmunotherapy combination, compared to that same chemoimmunotherapy combination, bendamustine, rituximab, plus the Bruton's tyrosine kinase inhibitor ibrutinib. Ibrutinib, as some of you may know, is a kind of therapy that is typically used in the relapse setting for patients with mantle cell lymphoma when they have their disease come back. And the SHINE clinical trial was looking at adding it to frontline therapy. What this randomized, controlled trial in the phase 3 setting found was that patients who received the combination of bendamustine, rituximab, plus ibrutinib had improvement in their progression-free survival, meaning that the time that it took for their disease to come back or them to have deaths related to the lymphoma was longer for patients who received this combination. About 2.3 years longer than the group that received bendamustine, rituximab, plus placebo. And in total, that led to a median progression-free survival of 6.7 years. That study has now been published in the New England Journal of Medicine and was led by my colleague Dr. Michael Wong from MD Anderson. Dr. Wong also led another study that was presented at the ASCO Meeting looking at CAR T-cell therapy for patients with mantle cell lymphoma. That study has now been published in the Journal of Clinical Oncology, and it looks at brexucabtagene autoleucel, a kind of CAR T-cell therapy, where that-- the CAR T-cell therapy was successfully manufactured for 71 of the 74 patients in the trial. 68 of those patients received an infusion and the median progression-free survival, so the average amount of time that it took for patients to have progression of their disease, was about 25 months. And so a marked benefit for those patients who were receiving CAR T-cell therapy when their mantle cell lymphoma came back. There also were major breaking abstracts at the ASCO Meeting in the area of diffuse large B-cell lymphoma. As many of you may know, diffuse large B-cell lymphoma is the most common type of lymphoma that occurs in the United States. And there was a breaking trial that was presented in December at the American Society of Hematology Meeting describing polatuzumab, a CD79b antibody drug conjugate, as a new drug in the substitution of frontline therapy for patients with diffuse large B-cell lymphoma in combinations with rituximab, cyclophosphamide, adriamycin, and prednisone, or the pola-R-CHP arm, that compared favorably to rituximab and CHOP chemotherapy, which has been the standard of care for patients with diffuse large B-cell lymphoma. And that trial showed an improvement in progression-free survival. At this year's ASCO Meeting, Franck Morschhauser presented results from looking at subsets of that patient population. Those patients who had BCL2 by immunohistochemistry that was positive or MYC expression by immunohistochemistry that was positive, or both of those, what we call double-expressor lymphomas, those who have poorer risk than standard groups. And those double-expressor lymphomas, treated with pola-R-CHP, had improvement in progression-free survival compared to R-CHOP with a hazard ratio of 0.64 in that group. We also saw in a multitude of analysis that that supported the benefit of pola-R-CHP in patients with both BCL2-positive and MYC-positive diffuse large B-cell lymphoma. Another area that has been very hot in diffuse large B-cell lymphoma clinical trials is the role of bispecific antibodies. Bispecific antibodies are antibodies that bind both to CD20, a marker on the diffuse large B-cell or the lymphoma cells, and to the marker CD3, which is a marker on T-cells which brings the normal T-cells of the immune system in close proximity to the lymphoma cells and then leads to immune-directed killing of lymphoma cells. The agent glofitamab is an agent that was presented by Michael Dickinson at this year's ASCO Meeting in an abstract. And in this study, 107 patients who received more than 1 dose of steady treatment went on to have complete responses in about 35% of patients. And this showed that glofitamab induced durable complete responses and had a very favorable safety profile in patients with relapsed and refractory diffuse large B-cell lymphoma. And in this trial, they compared that also for patients who had prior exposure to CAR T-cells and showed that responses were also good in those patients. Another set of studies has also looked at bispecific antibodies and a whole host of other areas with multitude of other agents. Another study that was presented at this year's ASCO Meeting explored the use of bispecific antibodies in the frontline setting in combination with the R-CHOP regimen that I just discussed. In that study, Lorenzo Falchi presented results of the subcutaneous bispecific antibody epcoritamab in combination with R-CHOP. This was a relatively small study of 33 patients that showed that the combination of epcoritamab plus R-CHOP was something that was safe and tolerable. There were no new treatment emergent adverse events that led to discontinuation of epcoritamab in the study. And there are some adverse events that are of special interest that we see with the bispecific antibodies, and those include the kind of immune-mediated adverse events that we can also see with CAR T-cells, like cytokine release syndrome, or CRS, or neurologic toxicities that we can see there that are also called ICANS. What we've seen in this trial, that about 42% of patients had some form of cytokine release syndrome, but that most severe form of cytokine release syndrome, those that were greater than grade 3 in severity, was only in 3% of patients. And likewise, the neurologic toxicities, or ICANS, that were grade 2 was in only 3% of patients. Relatively few patients completed all therapy by the time that this was presented. Only 10 patients had completed 6 cycles of therapy, but that showed an overall response rate that was quite high in that patient population. There were a whole host of other trials that were presented at this year's ASCO Meeting, and those portend improved kinds of outcomes on the horizon for patients with lymphomas across the spectrum. And I think it's an exciting time moving forward for clinical trials in lymphoma and hopefully, to see new therapies that emerge for the management of this disease. One of those new therapies that happened outside of the ASCO Meeting was the recent FDA approval of CAR T-cell therapy in the relapse setting for follicular lymphoma. And this was based on the ELARA clinical trial. And I think the future is quite bright for therapies and for patients with lymphomas broadly. ASCO: Thank you, Dr. Flowers. Finally, Dr. Daniel Mulrooney will discuss new research in childhood cancers, including a study comparing treatment options for Ewing sarcoma, and several studies on neuroblastoma. Dr. Mulrooney is an Associate Member in the Division of Cancer Survivorship at St. Jude Children's Research Hospital. He is also the Cancer.Net Associate Editor for Pediatric Cancers. You can view Dr. Mulrooney's disclosures at Cancer.Net. Dr. Mulrooney: My name is Dr. Dan Mulrooney from St. Jude Children's Research Hospital. I'm the Deputy Director of the After Completion of Therapy Clinic at St. Jude and primary care for survivors of pediatric solid tumors. The annual ASCO Meeting is typically quite busy and full of research presentations sharing knowledge and advances in cancer treatment and care. Today, I'd like to highlight some of the exciting presentations in pediatric cancer. Please note, I do not have any relationships to disclose related to any of these studies. At this year's meeting, one of the highlights was a European study in patients with relapsed or refractory Ewing sarcoma. Ewing sarcoma is a rare bone cancer that typically occurs in adolescents or young adults. While challenging to treat, it is difficult to cure in patients who have relapsed, and studies are needed to improve the care of these patients. Investigators from 13 European countries and Australia and New Zealand studied the most common relapsed therapies, which include irinotecan and temozolomide, gemcitabine and docetaxel, topotecan and cyclophosphamide, or high-dose ifosfamide. The study enrolled 451 patients between 2014 and 2021 and randomly assigned them to one of these four treatments. Based on response rates, the first 2 arms were dropped and the study was largely a comparison between topotecan cyclophosphamide and high-dose ifosfamide. The main outcome was event-free survival. Event-free survival is a common way in a clinical trial to see how well a treatment works. It measures the time from treatment that the patient remains free of complications, such as return or progression of the cancer. But investigators also looked at overall survival, toxicity, and quality of life. The 6-month event-free survival was better for high-dose ifosfamide at 47% compared to 37% for topotecan cyclophosphamide. The median overall survival was also better for high-dose ifosfamide compared to topotecan cyclophosphamide. The results were best for children younger than 14 years old versus those 14 or greater. Toxicities included fever and neutropenia, nausea, vomiting, and diarrhea. Patients receiving high-dose ifosfamide had more neurologic and kidney toxicities, which might be expected since ifosfamide is known to affect these organ systems, while only descriptive measurements of quality of life appeared higher for those children treated with high-dose ifosfamide compared to topotecan and cyclophosphamide. The strength of this trial is its large size, particularly for a rare cancer, and the fact that it randomized patients to the most commonly used treatment regimens for relapsed Ewing sarcoma. Importantly, data did not previously exist comparing these different treatments. While the results of this study are promising, clearly more needs to be done, and there was a lot of discussion at the ASCO Meeting about how to further improve survival in these patients. This study provides some information for doctors and patients, but importantly, provides data to advance future trials, which will concentrate on incorporating new targeted drugs with high-dose ifosfamide. This study is ongoing and is adding additional arms to continue to improve the outcomes for patients with relapsed or refractory Ewing sarcoma. In addition to this study in Ewing sarcoma, several studies investigating neuroblastoma were presented. Neuroblastoma is the most common extracranial solid tumor in children and for children with high-risk disease requires intensive and prolonged treatment, including chemotherapy, surgery, radiation therapy, and stem cell transplantation. Treatment for these patients has improved since the introduction of immunotherapy, particularly an antibody directed at a particular antigen named GD2 on the neuroblastoma cells. One study showed improvement in outcomes using this antibody for children with relapsed or refractory neuroblastoma, and another study demonstrated feasibility of using this antibody earlier in treatment, which was not previously known to be safe and tolerable. In what is called the BEACON study, investigators tested whether the antibody, called dinutuximab, would be effective when combined with chemotherapy for relapsed or refractory neuroblastoma. They enrolled 65 patients from 2019 to 2021 and randomized these patients to either chemotherapy alone or chemotherapy plus dinutuximab. The median age of these children was 4 years. The overall response rate, which means either a complete or partial response, was 18% for the chemotherapy-only arm but improved to nearly 35% for those treated with chemotherapy and dinutuximab. The progression-free survival was 27% for chemotherapy only and improved to 57% for those treated with chemotherapy and the antibody. There was no change in overall survival, though investigators think this may have been due to some patients who had progressive disease and crossed over to the antibody arm of the study. This presentation was followed by a study from the Children's Oncology Group, which investigated the feasibility of adding antibody treatment earlier in the treatment regimen for neuroblastoma. Prior studies had used antibody later in treatment when the tumor burden is thought to be lower. The endpoint of this study was tolerability measured by toxic deaths or unacceptable toxicities, such as adverse reactions to the medication. For example, sustained low blood pressure requiring a ventilator or breathing machine, or severe neuropathy. 42 high-risk neuroblastoma patients were enrolled from 8 different children's hospitals between 2019 and 2021. 41 of the 42 were able to complete the induction chemotherapy plus the antibody. There were no toxic deaths or unacceptable toxicities. Importantly, 85% were able to complete the next phase of treatment, called the consolidation phase, and 79% were able to complete the following phase after consolidation, called post-consolidation. One-year event-free survival was 83%, and 1-year overall survival was 95%. Now, it's important to know these are still early results, and the trial recently closed, and some of the patients have only completed therapy within the last year. Both of these studies add to the knowledge of chemoimmunotherapy for children with high-risk neuroblastoma. These studies provide a foundation for larger randomized trials that will further advance the care of these children. And finally, another study looked at race, ethnic, and socioeconomic disparities among children treated for high-risk neuroblastoma on Children's Oncology Group studies. There were no differences in event-free survival, but there were differences in overall survival based on ethnicity. The 5-year survival was lowest for Hispanic patients at 47%, 50% for non-Hispanic other ethnicities, which included Asian, Native American, Native Hawaiian, or Pacific Islanders, and 62% for non-Hispanic Black and non-Hispanic White children. Importantly, these investigators also studied household and neighborhood poverty. Overall, survival was lower for children living in poverty, though some of these differences went away when accounting for other factors, such as stage of disease or high-risk features. This study is important because it highlights the increasing need to collect data on clinical trials that may contribute to inequities in outcomes. While most studies collect data on the race and ethnicity of participants, other factors known as social determinants of health, such as income, neighborhood, education, access to health care, and insurance coverage, may also contribute to outcomes in pediatric cancer patients. Overall, the studies highlighted here and presented at this year's ASCO Annual Meeting focused on difficult-to-treat cancers, such as relapse or refractory disease, and they have laid the groundwork for future investigations to continue to improve survival rates for all children diagnosed with a malignancy through improved therapies and by addressing potential social barriers. Thank you for listening to this brief summary of the new research in pediatric oncology presented at the 2022 ASCO Annual Meeting. ASCO: Thank you, Dr. Mulrooney. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Dr. Yustein is a pediatric oncologist and physician-scientist with significant training in molecular and cellular biology. During his time as the Director of the Faris D. Ewing Sarcoma Center at Texas Children's Hospital, he recognized the need for improving our understanding of the molecular pathogenesis of sarcomas and the identification of new therapeutic avenues, especially for patients with therapeutic resistant and/or metastatic disease. His laboratory has tremendous interest and experience in merging innovative murine models and patient-derived resources towards garnering molecular insights into sarcoma initiation, development/resistance and metastatic progression and translating these findings towards testing novel therapeutic interventions for these aggressive malignancies. His laboratory has developed and characterized robust metastatic genetically engineered mouse models (GEMM) for pediatric sarcomas, including osteosarcoma (OS), which recapitulate the human disease initiation and progression. Subsequently, his lab has derived primary sarcoma lines from the GEMM tumors that can be orthotopically transplanted into wild type C57BL/6 mice and monitored using in vivo imaging for further characterization of sarcoma development and progression. He recently moved to Atlanta to join Emory University as a Professor in the Department of Pediatrics, Hematology-Oncology Division and the Director of Solid Tumor Translational Research Children's Healthcare of Atlanta and the Aflac Cancer and Blood Disorders Center. --- What We Do at MIB Agents: PROGRAMS: ✨ End-of-Life MISSIONS ✨ Gamer Agents ✨ Agent Writers ✨ Prayer Agents ✨ Healing Hearts - Bereaved Parent Support ✨ Ambassador Agents - Peer Support ✨ Warrior Mail ✨ Young Adult Survivorship Support Group ✨ EDUCATION for physicians, researchers and families: ✨ OsteoBites, weekly webinar & podcast with thought leaders and innovators in Osteosarcoma ✨ MIB Book: Osteosarcoma: From our Families to Yours ✨ RESEARCH: Annual MIB FACTOR Research Conference ✨ Funding $100,000 annually for OS research ✨ MIB Testing & Research Directory ✨ The Osteosarcoma Project partner with Broad Institute of MIT and Harvard ... Kids are still dying with 40+ year old treatments. Help us MakeItBetter.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, experts will discuss targeted therapy for lung cancer, including 2 new treatments that target a specific type of mutation or change in the EGFR gene in some cancer cells, called an EGFR exon 20 insertion. They will explain how targeted therapy works to treat cancer, why this specific mutation is different from other, more common EGFR mutations, and what these 2 new treatments mean for people with this type of cancer. This podcast will be led by Dr. Charu Aggarwal, Dr. Xiuning Le, Dr. Vamsidhar Velcheti, and Marcia Horn. Dr. Charu Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine in Philadelphia, Pennsylvania. She is also the Cancer.Net Associate Editor for Lung Cancer.  Dr. Xiuning Le is an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at the University of Texas MD Anderson Cancer Center in Houston, Texas.  She is also a Cancer.Net advisory panelist for lung cancer.  Dr. Vamsidhar Velcheti is the director of thoracic medical oncology at NYU Langone's Perlmutter Cancer Center in New York, New York, and is also a Cancer.Net advisory panelist for lung cancer. Marcia Horn is the President and CEO of the International Cancer Advocacy Network and the executive director of the Exon 20 Group in Phoenix, Arizona.  View full disclosures for Dr. Aggarwal, Dr. Le, Dr. Velcheti, and Ms. Horn at Cancer.Net. Dr. Charu Aggarwal: Hello and welcome to this Cancer.Net podcast on new research in lung cancer. I'm Dr. Charu Aggarwal from the University of Pennsylvania. I'm also the Cancer.Net Associate Editor for Lung Cancer. I'm here today with my colleagues from the Cancer.Net Lung Cancer Panel. First is Dr. Xiuning Le from the University of Texas MD Anderson Cancer Center. Hi, Dr. Le. Dr. Xiuning Le: Hi, everyone. This is Xiuning Le from MD Anderson. I'm happy to be here as one of the discussants. Dr. Aggarwal: Next is Dr. Vamsi Velcheti from the NYU Langone Perlmutter Cancer Center. Vamsi? Dr. Vamsidhar Velcheti: Hi, this is Vamsi Velcheti. I'm so glad to be here with you. Dr. Aggarwal: And our special guest today is Marcia Horn, the president and CEO of the International Cancer Advocacy Network and the executive director of the Exon 20 Group. Hi Marcia. Marcia Horn: Hi, everyone. Wonderful to be here. Dr. Aggarwal: So good to have you all. Before we begin, we should mention that Marcia has consulted with both Takeda Oncology and Janssen on survey research for the Exon 20 Group. You can view full disclosures for this podcast at Cancer.Net. Our podcast today is going to be about targeted therapy for non-small cell lung cancer, and specifically, 2 new treatments that target a specific type of mutation or change in the EGFR gene in some cancer cells. This mutation is called an EGFR exon 20 insertion. Dr. Velcheti, I'll start off with you. What is targeted therapy, and how does it work? Dr. Velcheti: So thank you, Charu. Lung cancer is a very complex biological disease. There are a lot of genes in the tumor cells that could be mutated, and understanding the type of genetic changes or mutations in the DNA of these tumor cells helps us really develop treatments that are very focused on that particular patient's cancer. Having a specific gene alteration could render tumors more susceptible or vulnerable to certain treatments, and these are what we call targeted therapies. And in lung cancer, these are especially important because there are a lot of drugs developed for patients with certain unique genomic aberrations, or changes in the DNA, and it's ushered in a whole wave of new treatments for patients with lung cancer, and it's really an exciting time for patients with lung cancer. Dr. Aggarwal: That's terrific. And I would like to focus on the mutation aspect a little bit more. Dr. Le, can you talk to us [about] whether all mutations found in lung cancer, can all of them be treated? Dr. Le: Like Dr. Velcheti was talking about, lung cancer is really a complex disease. And oftentimes in 1 lung cancer, we can detect more than 1, multiple mutations. Some of them function as driving the cell growth. Some of them function as a brake. We call that a tumor suppressor to release the cell from being suppressed. Clinically, we usually classify all the mutations that can be detected in the lung cancer into the 2 groups. One is called actionable. The other group is called not actionable. Actionable, meaning when we detect a mutation, we, as clinicians, can actually offer a specific targeted therapy to act on the mutation. Therefore, detection of the actionable mutation oftentimes translates to the patient potentially having the opportunity to get targeted therapy targeting that potential actionable driver oncogene. As of today, we're talking, the development of lung cancer treatment has been so advanced. We have 9 actionable genetic alterations that can be detected in non-small cell lung cancer. Even since 2 years ago, there are 4 new additions, so a total of 9 as of today, and EGFR exon 20 is one of the newest being approved in 2021, so really good news. Dr. Aggarwal: I know we've come a long way, and EGFR exon 20 insertions have been known for a long time. However, we've also known that they are not perhaps as sensitizing as the other EGFR mutations. Dr. Velcheti, could you shed some light on what is unique about these mutations in terms of testing as well as application of therapies? Dr. Velcheti: We have known about EGFR mutations in lung cancer for a very long time, and there have been quite effective treatments for EGFR activating mutation-positive lung cancer patients. However, not all mutations in the EGFR gene are the same. Depending on the location of the sequence change in the gene, they could have a different degree of response to EGFR inhibitors. So when we talk about EGFR exon 20, we're talking about a subset of these EGFR gene mutations which is in an area of the EGFR gene, a change in the sequence of the EGFR gene, that doesn't necessarily respond so well to the novel EGFR inhibitors that we have been using for a long time. So the clinical implications, and it's something to kind of think about and remember, is that the way we test for these mutations is very different. You could do comprehensive genomic profiling, or in some cases, there are some tests that actually test for a specific type of gene mutation. So it's something we call “hotspot panels.” Those are tests using certain techniques that actually only pick up certain EGFR genes, and they don't pick up all the gene mutations that happen in the EGFR gene. So it is very important to kind of keep that in mind because now we have drugs approved for exon 20 mutations. If you don't actually pick them up on a test, then obviously, we can't identify those patients for treatment with these exciting new treatments. And also, just as a quick plug, given that we have so many new drugs approved for different types of gene alterations in lung cancer, it is even more important now to focus on doing really good biomarker testing with comprehensive genomic profiling looking at a wide panel of genes, rather than focusing on certain kinds of gene mutations. So this is what we call comprehensive genomic profiling. That's absolutely critical in order to identify patients for the right treatment with targeted therapy. So it's extremely important to do that upfront so that we have patients kind of matched up to the right treatment. Dr. Le: I do also want to add with Dr. Velcheti in that I fully agree that exon 20 is oftentimes not on the hotspot PCR-based testing, so please use a comprehensive, what we call, next-generation sequencing base. I also want to say that also, exon 20 can be detected in liquid biopsy. So it's not you have to do the tissue biopsy if the patient has the opportunity to get liquid biopsy. As long as it's a good, comprehensive panel, it should also be able to detect that. Dr. Aggarwal: Absolutely, can never underemphasize the benefits and importance of comprehensive testing. Marcia, I'll turn to you. You lead a large group called the Exon 20 Group. How common is the EGFR exon 20 insertion-- how common is this mutation in people with lung cancer? Marcia Horn: It's not at all common. In fact, EGFR exon 20 insertion mutations in non-small cell lung cancer are exceedingly rare, a total of about 2% of all NSCLC and about 9 to 10% of all EGFR mutations. And it's an insertion mutation that hits, for the most part, never-smokers and members of Asian populations, although we at the Exon 20 Group have seen diagnoses in virtually every racial and ethnic group imaginable. The Exon 20 Group was established in 2017 as a special project of ICAN. It was founded by an EGFR exon 20 insertion patient, Kevin Hamlin, and his brother, Bob Hamlin, who's a senior lecturer at MIT. What we all wanted to do was get an international working group put together, and before we knew it, we had this huge global coalition of not only many hundreds of patients for EGFR exon 20 insertion and HER2 exon 20 insertion representing about 54 countries, but we had care partners, family members, several hundred leading thoracic oncologists, medical oncologists, and members of the community oncology setting as well, plus biotechs, pharmas with drugs in the exon 20 pipeline, and members from molecular profiling labs and the basic sciences in exon 20 bench science. So altogether, we're working to turn this into a chronic and manageable disease, and for the last 4 and a half years, we've been connecting our patients to promising clinical trials, especially the 2 newly approved drugs, and our angel buddy program provides our patients with peer-to-peer counseling to help them through side effects. So we're all united in blasting this disease off the planet and making the patient journey far more manageable. Dr. Aggarwal: Incredible. I'm just so proud of what all you've achieved, and you serve such an important mission in terms of patient advocacy and, more importantly, support. Dr. Velcheti, there have been 2 new recently approved targeted therapies to treat non-small cell lung cancer that harbors an EGFR exon 20 insertion mutation, and really, these drugs have come to us within the last few months. How does the first drug, mobocertinib, work to treat this cancer? Dr. Velcheti: Yeah, definitely. I think this is a really exciting time for thoracic oncology as we have more to offer our patients, especially for exon 20 and EGFR exon 20 specifically. We have 2 drugs now, FDA-approved, and mobocertinib is a small-molecule inhibitor. It's an oral drug, and this has been approved for patients who have EGFR exon 20 mutation. This is for patients who have already had platinum-based chemotherapy, and they have progressed, and these patients could now be treated with mobocertinib. Certainly, the activity, it seems like a very active drug. It's very promising. It's kind of similar to the other small-molecule targeted therapies that we have, but it does have side effects. Patients could potentially have diarrhea, which is kind of similar to other EGFR small-molecule inhibitors or drugs in the class, so it's something to kind of know when patients are being treated with this drug. Certainly, it's really nice to have more treatment options for these patients. So I think now we haven't had any EGFR small-molecule inhibitors show significant efficacy in this patient population, so this is a really welcome approval for patients. And there's also a new drug, which I'm sure Dr. Le is going to be talking about, amivantamab, which could also be an option for these patients. Dr. Aggarwal: Speaking of, let's turn to Dr. Le about amivantamab. Can you tell us a little bit more? Dr. Le: Yeah, amivantamab, again, represents a very exciting approval. I think, like Dr. Velcheti was talking about, the small-molecule inhibitor, but amivantamab represents a brand-new class of potential agents for exon 20 and many other oncogene targets in lung cancer. So amivantamab, as the name signifies, is an antibody drug. It's not an oral drug. It's an IV drug. The antibody has 2 heads, basically. One is targeting EGFR. The other is targeting another oncogene called MET. So it's a bispecific antibody. The mechanism of action is also different than the small-molecule inhibitor such as mobocertinib in that it's not disabling the ATP-binding kinase activity of EGFR, rather than its antibodies to go after the EGFR on the cell surface and disable or internalize the receptor a different way. So I say that we're excited because it represents a really brand-new group of targeted therapy that we're probably going to see coming in the next decade, not just limited to the small-molecule inhibitor, of course, from the research, and also opens opportunity for future combinations. In terms of usage, so again, this medication is approved in patients who have EGFR exon 20 insertion, who had prior treatment. It's an IV treatment, and then the IV is rather frequent, every 2 weeks. The drug showed really great safety and then induced response in about 40% of the patients, a nice addition to the tools we have that we can battle the disease. Dr. Aggarwal: It's amazing that we have 2 drugs in this space. Can you talk, in your personal experience, pros and cons of each approach and if there is any data to guide using 1 drug versus another or in sequence? We'll start with you, Dr. Le, and then we'll go to Dr. Velcheti. Dr. Le: Yeah. So that's a very good question. I don't think we have the 1 perfect answer because we haven't conducted either head-to-head trials or sequential trials. When I'm in my clinic, I tell my patients that both of them are valid options. And most likely, 1 patient will be receiving 1 and the other because I think each of the medications also have a limit of after a certain time, the disease will continue to progress. So we shouldn't be ruling out either of them rather than thinking of them as being the sequential treatment. One thing I do also discuss with the patient is the drug administration - one is IV; one is oral - and then toxicity profile. The amivantamab, the most common issue is the infusion reaction in the first time that the patient's receiving it. However, after that's properly managed, the drug is really easy to tolerate down the line. So usually, I present both options to patients. I would have to say that numerically speaking, the response rate of amivantamab is higher than the reported of mobocertinib. So sometimes, together with the patients and family, we decide to go for amivantamab first and then save oral TKI as the next option, but really, there's no right or wrong. And then I tell the patient most likely, they will be receiving both in the end. Dr. Aggarwal: Your thoughts, Dr. Velcheti, on that approach? Anything different that you do? Dr. Velcheti: No, I completely agree with Dr. Le. Both of them are very different drugs. So Dr. Le mentioned they work in very different ways. They have, most importantly, very different adverse event profile. So we don't know about what the right sequencing should be. We don't have those studies to really inform us. But I do the same thing that Dr. Le just mentioned. Given slightly higher response rates, we tend to use amivantamab first, but again, it's really patient preference. I've had patients who said they don't want to have IV infusions. They prefer oral treatment. They don't want to come into the hospital that often. And there are some patients who are really concerned about the diarrhea. So it's really hard to kind of know what would be the perfect sequence, and especially, it's a rare population, so it's going to be really hard to do a trial, to kind of do a cross-trial comparison. That's all we have here in terms of making decisions. The other thing to also consider is, do we use these 2 drugs, one after the other, if they progress? I think given that they work in a very different way mechanistically, I do think if you progress on mobocertinib that doesn't necessarily mean you will not respond to amivantamab and vice versa. So I would encourage trying sequential approach. And also the other thing to also keep in mind is there are a lot of clinical trials with exciting drugs which are in the pipeline, and, of course, some of the data has already been presented and those look really promising. So I highly encourage patients to kind of consider participating in clinical trials. Dr. Aggarwal: That's such a fantastic summary. And Marcia, I will turn to you. What do these new drugs mean for patients with this rare subset of an actionable mutation? Marcia Horn: I totally agree with Dr. Le and Dr. Velcheti and their comments based on their deep, deep experience with EGFR exon 20 insertion patients. No question that, from the point of view of the Exon 20 Group, we were totally thrilled at the FDA approvals of both amivantamab and mobocertinib. And we, like everyone else, affectionately call both drugs as ami and mobo. These drugs are providing a concrete lifeline of hope, for the first time, that patients' lives can be extended and patient journeys can be manageable in terms of side effects. So what we're really excited about in the Exon 20 Group is not only the continuing clinical development of ami and mobo and other promising drugs in the pipeline, as Dr. Velcheti said, but we're looking forward to seeing ami and mobo in combination with second drugs. We're awaiting data down the road, obviously, from the ongoing amivantamab plus lazertinib trial that is recruiting, in part, EGFR exon 20 insertion patients, and we're really excited about drugs that can be combined with mobocertinib as well. We want a robust pipeline of numerous choices and good compounds. Dr. Aggarwal: And Marcia, given the amount of information in this subgroup, what questions should patients ask their doctors about these new treatments? Marcia Horn: We really think it's important for patients on diagnosis to ask their clinicians what the method of communication is going to be between patient and physician. This is not only important on diagnosis of EGFR exon 20 insertion mutated cancer, but it's really, really important when the patient is accessing either ami or mobo or a drug in clinical trials. So patients need answers on who is going to be answering their questions about side effects when they write those questions into a patient portal, and they have to have the sense that somebody is going to be listening to them in the event that the collateral medications that an oncologist may be giving them in conjunction with a clinical trial drug or in tandem with either ami or mobo-- if those collateral medications are not tamping down on side effects to the extent that we all want to see, we, for sure, want that patient to be talking to the treatment team, the study team, or whoever, and getting some quick answers because frankly, nothing is more tragic than a patient withdrawing from a drug for failure to manage toxicities, and we never want to see that happen. We do everything possible at the Exon 20 Group to make sure patients are outfitted with angel buddies who have lived, battle-hardened experience with that particular drug, and these drugs are manageable. Dr. Aggarwal: So much excitement going on in this space, and we are thrilled to be able to offer these approaches. But I will just summarize that we wouldn't be able to extend these benefits if we don't test, and comprehensive testing remains critical in diagnosing and delivering appropriate therapy. Thank you so much, Dr. Le, Dr. Vamsi Velcheti, as well as Marcia, for joining us today for this Cancer.Net podcast. You can learn more about lung cancer and how it's treated by visiting Cancer.Net. Thank you, everyone. Dr. Le: Thank you. Marcia Horn: Thank you. ASCO: Thank you, Dr. Aggarwal, Dr. Le, Dr. Velcheti, and Ms. Horn. Learn more about lung cancer at www.cancer.net/lung. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

Caris Precision Oncology Alliance™ Chairman, Dr. Chadi Nabhan, sits down with Dr. Charu Aggarwal, the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania Perelman School of Medicine. Together they discuss the latest findings and top abstracts in thoracic oncology that were presented at this year's ASCO meeting. For more information, please visit: www.CarisLifeSciences.com

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, 3 Cancer.Net Associate Editors discuss new research in lung cancer, breast cancer, and sarcomas presented at the 2021 ASCO Annual Meeting, held virtually June 4-8. First, Dr. Charu Aggarwal discusses new research on targeted therapy and immunotherapy to treat non-small cell lung cancer. Dr. Aggarwal is a medical oncologist and Leslye M. Heisler Associate Professor for Lung Cancer in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine. She is also the Cancer.Net Associate Editor for Lung Cancer. View Dr. Aggarwal's disclosures at Cancer.Net. Dr. Charu Aggarwal: Hello, I'm Dr. Charu Aggarwal. I'm a thoracic medical oncologist, and I'm here to talk to you about research that was recently presented at the 2021 ASCO Annual Meeting. I will be discussing 3 studies of interest, and I should say that I do have a relevant disclosure to share. I have served as an adviser and consultant to AstraZeneca, which produces 1 of the compounds called durvalumab, for which I will be discussing research on. So let's start off with what was the most exciting or practice-changing research in thoracic oncology presented this year. We know that lung cancer as a field is changing quite fast and, in fact, is really becoming a poster child for application of targeted therapies. At this year's ASCO Annual Meeting, we heard about sotorasib, which is a first-in-class oral therapy that selectively and irreversibly targets the previously undruggable KRAS G12C mutant protein. KRAS G12C is an oncogene, or a molecular mutation, that occurs in patients with non-small cell lung cancer and accounts for about 13% of all patients with metastatic non-squamous non-small cell lung cancer. In a clinical trial called the CodeBreaK 100 phase 2 trial, patients with metastatic non-small cell lung cancer with this particular mutation in KRAS G12C were enrolled to receive sotorasib, which was administered orally at a dose of 960 milligrams once daily. Patients could have received previous chemotherapy or immunotherapy. And what we found was that out of the 124 patients that received therapy on this single-arm clinical trial, about 37.1% of the patients had objective clinical response, meaning that their tumors shrank when assessed by radiographic imaging. Patients on this clinical trial had a median overall survival of about 12 and a half months, and patients were [responding] noticeably, with a response as early as 6 weeks, which was the time of the first assessment. Overall, this drug is very well-tolerated and, in fact, welcome news that the FDA approved use of this therapy for second-line and beyond treatment of patients that harbor a KRAS G12C mutation. So this is immediately practice-changing, it applies to a lot of our patients, and I think will serve as a really nice, immediate next therapeutic option in the second-line setting for our patients. The next study that I want to talk about is the updated analysis of a trial called PACIFIC. We heard a 5-year update on this clinical trial at this year's annual ASCO meeting. For patients that have locally advanced non-small cell lung cancer, the current standard of care involves using combination chemotherapy and radiation, usually with a platinum-based chemotherapy for 6 to 7 weeks, followed by 1 year of immunotherapy with a drug called durvalumab. This standard of care has been based on a clinical trial called PACIFIC, which was first released in 2017, and then updated in 2018, showing a significant advantage to the use of this agent in the consolidation setting. At this year's meeting, we saw a 5-year update of the patients that were enrolled onto this large, phase 3 clinical trial. Patients were randomized to either receive 1 year of durvalumab or placebo following concurrent chemoradiation therapy for stage III non-small cell lung cancer. At 5 years, we saw a consistent advantage in overall survival compared to placebo for patients that received durvalumab for 1 year following their definitive chemoradiation therapy. While these results are not immediately practice-changing, these are absolutely practice-affirming because looking at these curves at the 5-year time point really enable us to deliver the confidence to our patients that administering this 1 year of immunotherapy will help and improve overall survival and really improving the chances of cure following treatment for locally advanced, metastatic non-small cell lung cancer. The last study that I would like to discuss is a study of adjuvant immunotherapy that is using immunotherapy after surgical resection for early-stage non-small cell lung cancer. While the study is not immediately practice-changing, I think this does represent a new paradigm. Currently, the standard of care in the post-surgical setting involves chemotherapy in case of involvement of lymph nodes and/or additional radiation therapy depending on which level of lymph nodes may be involved. This study, called the IMpower010 study, asked the question if immunotherapy in this setting following surgical resection and chemotherapy could provide a benefit. They looked at about 1,200 patients that were enrolled following surgical resection and had received 4 cycles of chemotherapy. Patients were then randomized to receive 1 year of immunotherapy with atezolizumab or best supportive care and were followed for survival. At this year's meeting, we heard that patients who received atezolizumab, especially those patients that had stage II or IIIA non-small cell lung cancer, had a reduced chance of recurrence. Following the use of 1 year of atezolizumab, the chances of reduction in recurrence were about 34%, indicating that this is a positive study. I should add that atezolizumab for this indication has not been currently approved. Therefore, it is not practice-changing. However, I should also add that this is the first study of its kind to show an improvement in recurrence outcomes with the use of immunotherapy in the early-stage non-small cell lung cancer setting, making it a very notable study for this subgroup of patients. Again, I think this has been a very exciting year for lung cancer research. And that wraps up our brief summary of new research in thoracic oncology from the 2021 ASCO Annual Meeting. Thank you for listening. ASCO: Next, Dr. Norah Lynn Henry discusses two studies looking at new treatment options for early-stage breast cancer. Dr. Henry is an Associate Professor in the University of Michigan's Division of Hematology/Oncology in the Department of Internal Medicine and is the Breast Oncology Disease Lead at the Rogel Cancer Center. She is also the Cancer.Net Associate Editor for Breast Cancer. View Dr. Henry's disclosures at Cancer.Net. Dr. Norah Lynn Henry: Hi, I'm Dr. Lynn Henry, a breast cancer oncologist from the University of Michigan Rogel Cancer Center. Welcome to this quick summary of updates in breast cancer from the 2021 Virtual ASCO Annual Meeting. I have no conflicts of interest for any of the trials that I will talk about. Today I'm going to focus primarily on treatment of non-metastatic breast cancer, especially that occurs in patients who have inherited mutations in BRCA1 or BRCA2. When these 2 genes have mutations or changes that decrease their function, it increases the risk of someone developing breast cancer as well as other cancers. But it also can give us clues as to which types of treatments these cancers may respond to. I'm also going to talk about a second study that was smaller, that looked at whether allowing patients to keep their ovarian function after chemotherapy is actually a safe thing to do. One of the biggest stories from at the ASCO Annual Meeting was the results of the OlympiA trial. So in this trial, researchers studied a type of medication known as a PARP inhibitor, which is known to be effective for treating patients with metastatic breast cancer who have inherited mutations in those 2 genes I mentioned, BRCA1 and BRCA2. However, it was not known whether giving PARP inhibitors to patients with non-metastatic breast cancer would actually decrease the likelihood of their cancer returning. Therefore, in the OlympiA trial, researchers tried to answer this question. The OlympiA trial enrolled almost 2,000 patients who had inherited mutations in either BRCA1 or BRCA2. These patients had been diagnosed with either estrogen-positive or negative breast cancer, but HER2-negative breast cancer and were at high risk of having their cancer return. In this trial, patients were randomized like the flip of a coin to treatment with either the PARP inhibitor called olaparib or to a placebo for 1 year. Patients took the study medication in addition to their usual treatments. They had mostly all had chemotherapy already, and they took it at the same time as their anti-hormone therapy. After following patients for 3 years, the researchers found that the patients who got olaparib had more than a 40% decrease in the likelihood of their cancer coming back compared to those who got the placebo. The medication was pretty well tolerated. There was some nausea and vomiting, fatigue, and lowered blood counts, although there were some rare but serious side effects that can occur. So there are some concerns about using the medicine in everybody. The follow-up of the patients has been fairly short so far, only 3 years. So it is not yet known whether taking this medicine will enable patients to live longer after breast cancer. This is a medication that has already been approved by the FDA for treatment of patients with metastatic disease. And based on these data from the OlympiA trial, ASCO guidelines now recommend that olaparib should be considered as part of treatment for patients who have either a BRCA1 or a BRCA2 mutation and who have early-stage breast cancer who are at high risk of having their breast cancer recurrence. So to switch gears a little bit, I'll talk about the other study I also found interesting. Often very young women who are diagnosed with breast cancer would like to become pregnant after they undergo treatment with chemotherapy. For these patients who want to become pregnant in the future, we often treat them with a medicine to block the function of their ovaries during chemo, sort of to put them to sleep with the hope that it will increase the likelihood that their ovaries will wake up and resume functioning again after chemotherapy is complete. However, we have worried that preserving the function of the ovaries might increase the risk of breast cancer returning, especially for women who have hormone receptor-positive breast cancer. This is because ovaries make estrogen, which is important for those types of cancers to survive. Investigators from Italy conducted a randomized study called PROMISE-GIM6 in which patients were treated either with standard chemotherapy or they got standard chemotherapy plus the ovary-blocking medicine. Now that they followed women on this study for more than 12 years after their diagnosis of breast cancer, they presented their final results. Importantly, they found there was no difference in the likelihood of cancer returning or in survival for patients who did or did not have their ovary function blocked during chemo. So these results should be very reassuring for patients who want to try to preserve their ovary function while they're getting treatment for their breast cancer. Now, there were a lot of other research findings presented that were related to treatment for breast cancer at the meeting. Importantly, we got glimpses of the many new drugs on the horizon for treatment of breast cancer. And we eagerly await the results of large, randomized trials so that the drugs that work can be used to care for patients with breast cancer. But for now, that's it for this quick summary of important research from the 2021 Virtual ASCO Annual Meeting. Overall, we continue on a fast track with breast cancer with many new and exciting therapies being actively studied, as well as research helping support our patients to do better than ever before. Stay tuned to Cancer.Net for future updates from upcoming breast cancer conferences. ASCO: Thank you Dr. Henry. Finally, Dr. Vicki Keedy discusses two studies in metastatic synovial sarcoma. Dr. Keedy is an Associate Professor of Medicine in the Division of Hematology/Oncology and the Clinical Director of the Sarcoma Program at the Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center. She is also the Cancer.Net Associate Editor for Sarcoma. View Dr. Keedy's disclosures at Cancer.Net. Dr. Vicki Keedy: Hello, my name is Vicki Keedy, and I'm a medical oncologist at Vanderbilt University Medical Center, and I specialize in the treatment of patients with sarcomas. Today, I'm going to talk about 2 important studies discussed at the 2021 ASCO Annual Meeting. The first is the SPEARHEAD-1 trial, which is a phase 2 trial for patients with metastatic synovial sarcoma or myxoid/round cell liposarcoma. I'd like to note that my institution participated in and enrolled patients onto this trial, and I have participated as an advisor to this trial. The study evaluated an immunotherapy-based treatment called afami-cel, which targets the MAGE-A4 protein. This protein, also called an antigen, is commonly found in synovial sarcoma and myxoid/round cell liposarcoma cells. Afami-cel is called a T-cell receptor therapy, or a form of cellular immunotherapy. This therapy uses a patient's own immune cells called T cells and engineers them to be able to recognize and eliminate cells that express the MAGE-A4 protein. For this trial, patients could be between 16 and 75 years old but must have had 1 prior anthracycline, such as doxorubicin or ifosfamide-based chemotherapy. For this therapy to be effective, patients' cells must also have a specific group of markers called HLA-A02. HLA-A02 testing is performed on the patient's blood sample, while MAGE-A4 is tested on the patient's tumor tissue. Patients who are eligible for this treatment have their T cells collected through a blood draw called leukapheresis. Patients then receive a short course of chemotherapy, followed by infusion of the T cells. Patients receive no further chemotherapy unless the cancer were to progress. The majority of patients on this trial have synovial sarcoma. The results show that 39% of patients had a partial response, meaning a decrease in tumor size by more than a third, and 2 patients had a complete response. While the number of responses is exciting, what is most exciting about these data is that these responses seem to last a long time despite the patients not receiving any further treatment for their cancer. Common side effects occurred to the chemotherapy portion of the regimen and were similar to what we would expect for chemotherapy. However, 1 particular side effect of interest for cellular therapies is called cytokine release syndrome. This occurs when inflammation occurs in response to the T-cell infusion. Patients can experience fever and flu-like symptoms or more serious illness. In this trial, 59% of patients experienced cytokine release syndrome, but only 1 patient had a more serious or grade-3 reaction. Patients must be re-monitored closely in the days and weeks following their infusion and are often hospitalized for part of this monitoring. A downside to this technology is that it requires both the correct HLA typing as well as tumor MAGE-A4 expression. In this trial population, only about 1 out of 3 patients were potentially eligible based on these 2 requirements. Having said that, the results of this trial suggest that T-cell receptor therapy against MAGE-A4 expressing synovial sarcoma and myxoid/round cell liposarcomas is a very exciting advancement for patients who are eligible for this type of treatment. Currently, this treatment is only available within a clinical trial, as it is not yet FDA approved. Another important study reported this year were the results of catequentinib compared to dacarbazine in patients with metastatic synovial sarcoma. My institution also participated and enrolled patients on the study. Catequentinib is an oral therapy called a tyrosine kinase inhibitor. It blocks the signaling of multiple receptors that are responsible for tumor cell growth and invasion. Dacarbazine is a cytotoxic chemotherapy that is commonly used to treat patients with several types of sarcomas. To be eligible for this trial, patients must have had at least 1 prior anthracycline-containing regimen. Patients could've had a prior tyrosine kinase inhibitor, such as pazopanib, which is currently FDA approved for most sarcomas in the United States. This trial met its main endpoint of improving progression-free survival or, in other words, slowing down tumor growth, compared to dacarbazine. Although the improvement was relatively small, from 1.6 months with dacarbazine to 2.9 months with catequentinib, the data showed that there are a portion of patients who experience much longer benefit with nearly a quarter of patients still having stable disease at 1 year on the drug compared to 4% with dacarbazine. Side effects were as expected with this class of drugs, including diarrhea, fatigue, elevated liver enzymes, and high blood pressure. Catequentinib is not yet approved for use outside a clinical trial. And it is not known whether it is superior or equivalent to pazopanib, which is FDA approved for non-liposarcoma sarcomas. These are only 2 examples of the interesting and important research being done to improve the treatment of patients with sarcoma. And while both happened to include patients with synovial sarcoma, the class of cancers known as sarcoma are actually 50 to 100 different cancers. Although it will not be possible to have a trial for every sarcoma subtype, through collaboration and patient education, we're able to research the individual sarcomas as the distinct entities that they are. Thus, it is important for patients with a metastatic sarcoma to go to centers that have trials for their specific disease when available. With this approach, we'll see even more advancements in the future for patients with sarcoma. Thank you very much for your time, and I hope I have more exciting findings to discuss in 2022. ASCO: Thank you Dr. Keedy.   You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

On today's episode, meet Dr. Charu Aggarwal. Dr. Aggarwal is the Leslye Heisler Assistant Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine. She is an active member of the Abramson Cancer Center (ACC) where she serves as Physician Leader for the clinical research program for Airways Malignancies. Dr. Aggarwal specializes in the management of patients with lung and head and neck cancer, with a specific and clinical research focus on the development of novel immunotherapeutic approaches, and the discovery and application of biomarkers to guide therapy and monitor treatment. She serves as the local and national principle investigator for multiple clinical trials focusing on the development of “targeted” immunotherapeutic approaches including cellular therapy and CAR-T for solid tumors.

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor Dr. Michael Williams talks about new research and advances in the field of lymphoma, including 3 recent U.S. FDA drug approvals. The research discussed was presented at the 2020 American Society of Hematology Annual Meeting, held virtually December fifth through eighth. Dr. Williams is the Chief of the Hematology/Oncology Division and Director of the Hematologic Malignancies Program at the UVA Cancer Center. He is also the Byrd S. Leavell Professor of Medicine and Professor of Pathology at the University of Virginia School of Medicine. View Dr. Williams’ disclosures at Cancer.Net. Dr. Williams: Hello. This is Dr. Michael Williams. I'm professor of medicine at the University of Virginia Health System in Charlottesville, Virginia, and I'm pleased to welcome you to this podcast for Cancer.Net. I'm reporting on some of the exciting updates that were just presented at the American Society of Hematology Annual Meeting. Typically, this is a meeting of 30 or 35 thousand clinicians and investigators from around the world. This year, as with so many meetings, we met virtually, but I would say very successfully done. Lots of exciting new data, and I'll try to give you a glimpse of what some of the progress has been. Before I start, I'll mention a few disclosures. So I have research grants that are awarded to the University of Virginia for clinical research from Celgene, Janssen, Pharmacyclics, and TG Therapeutics. And I have served as a consultant for Celgene, Janssen, and Pharmacyclics, as well as Kyte Pharmaceuticals, which is a division of Gilead. So the advances this year weren't just at the meeting. There were 3 new drug approvals in the past 6 months for lymphoma. Tazemetostat, which is an EZH2 inhibitor, was approved for relapsed/refractory follicular lymphoma patients who have a mutation in a gene called EZH2. So they showed good tolerance of this treatment with high response rates in these patients with the mutation. So it provides another important treatment option for people with relapsed follicular. A new approval for relapsed diffuse large B-cell lymphoma was a novel monoclonal antibody called tafasitamab given in combination with lenalidomide that also showed good responses and generally very good tolerance in people with relapsed aggressive lymphoma. So a welcome addition again to our treatment options. And then finally, a chimeric antigen receptor T-cell therapy or CAR-T was approved for relapsed/refractory mantle cell lymphoma. And I will say a bit more about that agent as we get into the discussion about CAR-T therapy for mantle cell. The first abstract presentation that I want to mention is in chronic lymphocytic leukemia or small lymphocytic lymphoma which, of course, is really 1 disease. It's just a spectrum of whether you have more of a leukemic phase or a lymph node enlargement component to your disease. Treatment in CLL has really shifted in recent years away from cytotoxic chemotherapy and is now well established that most patients needing treatment, whether for newly diagnosed disease or for patients who have been previously treated with other regimens, that targeted therapies such as Bruton tyrosine kinase inhibitors or a BCL-2 inhibitor venetoclax can get very high response rates. There's been interest among many groups in testing combinations of targeted drugs, and we heard an update of a report called the CAPTIVATE study that combines ibrutinib plus venetoclax. Both of these are oral agents. As a randomized study for patients with CLL who need treatment and have not been previously treated for their CLL. And what this study did was provided a combination of the 2 drugs as first-line therapy, and they showed that after a period of about 12 cycles of combined treatment, that you had very, very high remission rates. They used a very sensitive method, a molecular method, to detect minimal residual disease. And if patients were in a deep molecular remission, so undetectable MRD at the end of treatment, they were randomized to continuing with either no therapy or with just ibrutinib alone. And it was found that after a year, there was really no difference. So it shows that with combination therapy, you can get a deep enough remission to have a durable and ongoing response for those patients. They also randomized those who still had detectable residual disease to either ibrutinib alone or a combination of ibrutinib plus venetoclax, and they showed that their outcome at the end of treatment was likewise similar. So it shows a very good non-cytotoxic-chemotherapy-based approach to treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma. So the second item I wanted to bring your attention was for another form of indolent or low-grade non-Hodgkin lymphoma called Waldenstrom macroglobulinemia which is also identified as lymphoplasmacytoid lymphoma. And in this study, they used a combination of ibrutinib plus rituximab, an anti-CD20 monoclonal antibody, versus placebo with rituximab alone. So this study is reporting now long-term follow-up with more than 5 years since the onset of treatment initiation in 150 patients. So rituximab by itself was a standard of care for patients with Waldenstrom at the time the study was designed. We now know that ibrutinib can give very good responses, especially when given in combination with rituximab. And indeed, they showed that now with 5 years of follow-up, that the response in terms of the serum IgM level, which is a marker for activity of this disease, improvement in anemia as well as objective response rates were much improved with the combination of ibrutinib plus rituximab versus rituximab alone. They also showed that there was a delay in the time that a patient needed another line of therapy for progressive disease when they had that combination. So important long-term follow-up there confirming the safety and activity of ibrutinib and rituximab for that disease. And then finally, I'll give an update on 1 of many reports at this meeting on CAR-T cell therapy. So just to remind those of you who may not be so familiar with this, it's a technique of cellular therapy, wherein a patient who's got disease progression with follicular lymphoma or mantle cell lymphoma or diffuse large B cell lymphoma, the patient undergoes a procedure where T-cells are removed from their blood, and then in the laboratory, they are reprogrammed to attack the patient's lymphoma cells. So the reprogramming is done, the CAR-T cells, the chimeric T-cells are expanded, and then shipped back to the treating center where the cells are infused intravenously to the patient. There is already an approval of CAR-T cell therapy for diffuse large B-cell lymphoma as I mentioned. It is now approved CAR-T called axicabtagene ciloleucel or axi-cel is approved for mantle cell lymphoma, and what we heard at this in Boston. She gave an update on treatment of relapsed refractory follicular lymphoma and marginal zone lymphoma with the axi-cel CAR-T. So what Dr. Jacobson and her colleagues reported was for patients with relapsed and refractory follicular lymphoma, the overall response rate was 95%, with 80% of these patients being in a complete remission with ongoing follow-up. In those with marginal zone lymphoma, the numbers of patients treated were smaller, but they also showed high-response rates, 85% with 60% achieving a complete remission. And at a year of follow-up, most patients were remaining without evidence of disease progression. So a very promising advance in follicular lymphoma. It also raises the possibility that we may be able to use CAR-T cell therapy instead of traditional autologous stem cell transplantation for relapsing patients. But this is something that will have to be tested in formal clinical trials before becoming established as a new standard of care. So by the end of the meeting, it was clear that progress continues at a very rapid pace across the fields of human logic malignancies, lymphomas, leukemias, multiple myeloma, and others. So it reminds us that it's important if you're dealing with 1 of these disorders that you make sure you've done your due diligence in getting another opinion if that's warranted, at seeking out clinical trials which help bring some of these most promising therapies to the clinic and help us advance the progress in treatment as rapidly as possible. So I'd like to thank you for your attention today and wish you all the very best in the year ahead. ASCO: Thank you, Dr. Williams.  You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. Every year, the ASCO Annual Meeting brings together attendees from around the globe to learn about the latest research in the treatment and care of people with cancer. This year, attendees from 138 countries worldwide gathered virtually for the ASCO20 Virtual Scientific Program, held Friday, May 29 through Sunday, May 31. In the annual Research Round Up podcast series, Cancer.Net Associate Editors answer the question, “What was the most exciting or practice-changing research in your field presented at the ASCO20 Virtual Scientific Program?” In this final episode of 2020, editors discuss new research in the fields of central nervous system tumors and lymphoma. First, Dr. Glenn Lesser will discuss new research on a form of non-Hodgkin lymphoma that begins in the central nervous system, and research into a possible treatment for breast cancer that has spread to the brain. Dr. Lesser is the Louise McMichael Miracle Professor and Associate Chief in the section on Hematology and Oncology in the Department of Internal Medicine at Wake Forest University, with joint appointments in the Departments of Anesthesiology, Neurosurgery, and Public Health Sciences. He is also the Cancer.Net Associate Editor for Central Nervous System Tumors. View Dr. Lesser’s disclosures at Cancer.Net. Dr. Lesser: Hello. My name is Glenn Lesser, and I'm a professor of medical oncology and director of medical neuro-oncology at the Wake Forest Baptist Comprehensive Cancer Center in Winston-Salem, North Carolina. I'm also the editor of the brain tumor section for ASCO's Cancer.Net. And today, I would like to briefly discuss what I think are 2 of the most clinically relevant research studies on brain tumors that were presented at this year's ASCO's Virtual Scientific Program. I should say right up front I have no disclosures or relationships that are relevant to the particular studies I'll be discussing today. Unlike the progress we've seen in the treatment of many cancers over the past few years, patients with brain tumors and the physicians who care for them have not seen the same rapid advance in effective treatment strategies. Cancer that begins in the brain, so-called primary brain tumors, and the more common situation of cancer that spreads to the brain after originating elsewhere in the body, so-called metastatic or secondary brain tumors, still have relatively few effective treatment options available. However, I believe that the 2 abstracts we'll discuss today may impact the way that we treat certain primary and metastatic brain tumors in the future. The first study I'd like to talk about was presented by Dr. Omuro on behalf of a group of international colleagues that described a randomized study of standard chemotherapy with or without low dose whole brain radiation in patients with a brain tumor known as a primary central nervous system lymphoma, which I may also talk about as a PCNSL for abbreviation. Non-Hodgkin's lymphoma is a relatively common cancer that involves the blood and lymph nodes throughout the body. Primary central nervous system lymphoma is the term used when patients develop a non-Hodgkin's lymphoma that's confined to the central nervous system which is really made up of the brain, the spinal cord, the spinal nerves, and the spinal fluid. This turns out to be a pretty rare diagnosis with only about 1,500 new cases of this cancer occurring in this country each year. This type of lymphoma is important, though, because it's very treatable in most patients, and a significant percentage of our patients can be cured with appropriate therapy. Because the disease is so rare, we really don't have the results of large clinical trials to help us determine the best treatment approach for patients with primary central nervous system lymphoma. And as a result, there are a variety of controversies over how to initially treat patients who develop this lymphoma, so-called induction therapy, as well as what type of treatment to give once the disease has been made to go away, or so-called consolidation therapy. In the past, radiation therapy to the whole brain was used to treat patients with PCNSL. And most of these patients who were treated with radiation-containing regimens had their tumors respond, although the cancer frequently returned within a year or 2. This approach has really fallen out of favor over the last few decades because of the very high incidence of neurotoxicity or brain damage from the radiation that was seen in surviving patients. Unfortunately, a significant number of those patients who were treated with high doses of whole-brain radiation therapy developed a progressive irreversible dementia over the years following the radiation treatments, and a particularly high incidence of this toxicity was seen in patients who are over the age of 50. With current multi-agent chemotherapy regimens, a high percentage of treated patients are having their lymphomas go away. Unfortunately, a significant number of patients still have their disease come back within months or years of this treatment. And so strategies to consolidate or lock in that initial good result with treatment are being evaluated. These strategies may involve high doses of different types of chemotherapies, consideration of bone marrow or stem cell transplant, and even long-term maintenance treatment with oral chemotherapies. More recently, low doses of whole-brain radiation therapy have been explored as a way to try to prevent these lymphomas from coming back with a thought that the low doses of radiation might have minimal long-term brain toxicity as compared to the high doses of radiation given in the past. So this study that was presented at ASCO involved about 91 patients with primary central nervous system lymphoma. Half of them received the low-dose whole-brain radiation therapy after their tumors were treated with several months of multi-agent chemotherapy, while the other half did not get the radiation. After a follow-up period of 4 to 5 years, the results of this treatment were that the patients who received the low-dose radiation in addition to chemotherapy lived longer and had a significantly higher rate of their tumor going away and staying away at least at the 2-year follow-up tie point. Now, data is not yet available on the neurocognitive outcomes in both groups of patients. That is how well their brains were functioning with tasks like memory, calculations, and personality. The improved results seen in this group of patients who got radiation suggests that this approach may be one effective way of helping to consolidate the treatment of primary central nervous system lymphoma after the induction chemotherapy. These results, however, can only really be fully interpreted and applied once we have more long-term information on whether the patients treated in this fashion suffer from the high rate of neurotoxicity and dementia that was seen in prior studies using the higher doses of radiation. With further follow-up, this study should provide us with some definitive information on whether the strategy of adding low-dose radiation following standard induction chemotherapy is a good one for patients with primary central nervous system lymphoma. The second study I'd like to talk about was presented by Dr. Nancy Lin, again on behalf of an international group of colleagues, and described the results of a trial adding a new drug called tucatinib to a standard chemotherapy regimen of trastuzumab and capecitabine in women with HER2-positive breast cancer involving the brain. Now, many common cancers have a tendency to spread to the brain if they recur after initial treatment. This metastatic or secondary involvement of the brain occurs in over 200,000 patients a year in the U.S., and new treatments for brain metastases are desperately needed. Women with advanced breast cancer are particularly susceptible to developing brain metastases, particularly if they have the subtype of breast cancer known as HER2-positive disease. In HER2-positive disease is defined that way because of the presence of the HER2 protein on the surface of breast cancer cells. Although a number of effective treatments have been developed for patients with HER2-positive breast cancer involving the body, including some common drugs like trastuzumab and pertuzumab, these agents have not been particularly effective in either treating breast cancer that has spread to the brain or preventing the breast cancer from spreading to the brain in the first place. One of the main reasons why these chemotherapy drugs have not been effective in treating breast cancer metastases in the brain is that unlike the other organs in our bodies, the blood vessels of the brain are formed in such a way that they carefully restrict what substances in the blood are able to leave the blood and spread into the brain. Normal blood vessels in our body are somewhat leaky. And fluids, proteins, drugs can leak out of those vessels into the tissue with some freedom. The blood vessels of the brain, however, are lined by cells that tightly joined together to create a blood-brain barrier that is not leaky, and that barrier protects the brain from compounds that are circulating in our bloodstream which could adversely affect brain function if they were able to get into the brain in any concentration. Because of this barrier, most of our standard chemotherapy and anticancer drugs simply cannot cross the barrier to reach the cancer cells within the brain. In part, because of this, patients whose cancer had spread to the brain have typically been excluded from most of the clinical trials evaluating new drugs and treatments for breast cancer. The study reported by Lin at ASCO tested the ability of a new HER2-targeted drug, tucatinib, which because of its chemical structure has good penetration across this blood-brain barrier. Earlier smaller studies had suggested that this drug did indeed get into the brain at concentrations that could effectively treat breast cancer involving the brain. In this study, almost 300 patients with metastatic breast cancer involving the brain were treated with a standard chemotherapy regimen with or without the tucatinib. Serial brain scans were obtained in order to measure the response of the brain metastases to the treatment. These were typically MRI scans of the brain. The study results showed that the use of tucatinib in patients with breast cancer involving the brain reduce the risk of the growth of their brain disease by about two-thirds and improve their overall survival by at least 6 months. These results have recently been published in a more complete form in the Journal of Clinical Oncology. And these results really strongly support the use of tucatinib in combination with the standard chemotherapy regimen of trastuzumab and capecitabine in patients with HER2-positive metastatic breast cancer involving the brain. Although neither of the new approaches I've just described cure the majority of patients treated with either the primary CNS lymphoma or brain metastases from breast cancer, both describe new approaches that really potentially move us further along the road to having more effective treatments for patients with brain tumors. These studies are also outstanding examples of why well-done clinical trials that carefully test and evaluate the beneficial effects as well as the toxicities of new cancer treatments are critical to our goal of finding new therapies to treat our patients with cancer. Thanks very much. ASCO: Thank you, Dr. Lesser. Next, Dr. Michael Williams will discuss several studies that looked at new ways to treat different types of lymphoma. Dr. Williams is the Chief of the Hematology/Oncology Division and Director of the Hematologic Malignancies Program at the UVA Cancer Center. He is also the Byrd S. Leavell Professor of Medicine and Professor of Pathology at the University of Virginia School of Medicine. He is also the Cancer.Net Associate Editor for Lymphoma. View Dr. William’s disclosures at Cancer.Net. Dr. Williams: Hello. This is Dr. Michael Williams. I'm a professor of medicine at the University of Virginia hospital in Charlottesville, Virginia, where I'm chief of the hematology oncology division and the physician lead for cancer services here at UVA. I have a few disclosures, clinical trial grant support from Janssen and Pharmacyclics to the University of Virginia. I've received honoraria for medical education conferences from Xian Janssen, and I have been a consultant for Kite Pharmaceuticals in the past. So what we're going to talk about today are some of the highlights in lymphoma that were presented at the recent virtual meeting of the American Society of Clinical Oncology focused on lymphoma. So the field continues to move forward very rapidly. It's really a dynamic time for advances in treatment of lymphoma and related disorders. The exciting thing is that patients in the not-too-distant past may have had limited options, especially in the setting of recurrent lymphoma. We now have new approaches that are really quite interesting, quite effective, and I think are going to change the way we practice for these particular diseases. So the first of these I'm going to talk about is for classical Hodgkin lymphoma, also called Hodgkin's disease. So the good news is here, that the vast majority of people with Hodgkin lymphoma are cured by their frontline therapy but not all do achieve a remission, or if they do, they may relapse a year or 2 or sometimes later after their initial therapy. And these patients, historically, have not had as good of a long-term outcome as those who remained in their initial remission. So investigators from an international team of lymphoma experts conducted the KEYNOTE-204 study that compared an immune checkpoint inhibitor - it's a form of immunotherapy called pembrolizumab - versus a standard agent brentuximab vedotin, which is a drug antibody conjugate that delivers a chemotherapy agent directly to the Hodgkin tumor cells. So these were patients who had either not responded to their initial treatment, in other words were considered to be primary refractory, or had relapsed later. Many of them relapsed within 12 months, which is, again, a worrisome timing for relapse in that those patients may be more chemotherapy resistant to traditional treatments. So in this study, it was a 1-to-1 comparison of about 300 patients. And the study found that those who received the checkpoint inhibitor pembrolizumab had a better response in terms of their remission rate and a more long-lasting response than those patients treated with brentuximab vedotin. At 12 months, about 54% of patients remained in remission as opposed to about a third of patients on brentuximab. Although, there were some continued relapses over the next year, there were some patients who achieved more durable response. So it was a very encouraging finding. The side effects were as would be expected. There were some autoimmune problems with the immunotherapy checkpoint inhibitor and peripheral neuropathy in those who got brentuximab. So these investigators concluded that for patients with this form of relapsed and chemotherapy-resistant Hodgkin's lymphoma, that pembrolizumab should be considered the preferred treatment option and a new standard of care for these patients. Now, the second trial that we'll talk about relates to a specific form of non-Hodgkin lymphoma called lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. This is a lymphoma where an abnormal immunoglobulin, a high molecular weight IgM, is produced. That can cause problems of hyper viscosity and headaches, vision changes, shortness of breath, in addition to some lymphoma-related symptoms. And what they did is compared 2 targeted agents for people who needed treatment, whether they were relapsed or had not had prior treatment at all for their Waldenstrom's. And the drugs that they chose were Bruton tyrosine kinase, or BTK, inhibitors. These are a very active class of drugs in B-cell lymphomas including Waldenstrom's. And the first of these that became available several years ago and was FDA approved is ibrutinib, and a second agent more recently approved is zanubrutinib. The latter being a bit more targeted to the molecule that we're trying to inhibit in the tumor cells. And it's similar in many ways to a third drug that's available called acalabrutinib. But in this study, they're comparing ibrutinib with zanubrutinib. And what they found is that, in about 200 patients, that both drugs were very effective in achieving a response. Slightly higher response rates for zanubrutinib, but really no significant difference in the progression-free and overall survival for these patients. So both drugs were very active and very reasonable for treating patients. There were fewer side effects, however, with zanubrutinib, in particular toxicities such as the development of atrial fibrillation and diarrhea or bruising and bleeding, which happened in a small percentage of patients on ibrutinib. So those side effects seemed to be less with the more targeted drug zanubrutinib. So they appeared to be similar in efficacy but perhaps a better safety and toxicity profile with zanubrutinib. Now, ibrutinib is approved in the United States for relapsed Waldenstrom macroglobulinemia. Zanubrutinib is approved for mantle cell lymphoma, so not for Waldenstrom. So the final entity that I want to discuss is really using a treatment that many of you no doubt have read about. There's been a lot in the news about the use of CAR T-cell, or chimeric antigen receptor T-cell therapy. So this is a form of cellular therapy. And by that, I mean that in patients who have relapsed aggressive lymphoma, usually diffuse large B-cell, a patient who has relapsed disease has T-cells. Those are part of their immune cellular defenses. And those T-cells are removed and they're genetically reprogrammed and then expanded and reinfused to patients. So they're reprogrammed so that the immune effects are targeted against the patient's lymphoma cells. So this is an approved therapy in aggressive relapsed large B-cell lymphoma. But at this meeting, investigators from a number of centers in the United States reported the interim results of a study using a CAR T-cell called axicabtagene ciloleucel, or Axi-cel, for patients with indolent or low grade lymphoma that, nonetheless, is recurring, needs treatment, and has been resistant to at least 2 or more prior therapies. So I'm going to focus in this study on the results with follicular lymphoma. They did also study a small number of patients with another type of indolent low-grade lymphoma called marginal zone. But looking at the follicular lymphoma patients, they were heavily pre-treated. Most of the patients had had 3 or more prior therapies. Most of them were refractory or, in other words, resistant to the current and the most recent chemotherapy they had received. And about a quarter of the patients had had a prior stem cell transplantation for relapsed disease but had now relapsed even after that therapy. And what they found in the first 80 follicular lymphoma patients they studied is that 95% of them responded and 81% achieved a complete remission. The duration of response was really quite good. So with a follow-up of a little over a year, about two-thirds of patients were still in remission. Whether these patients may be cured of their follicular lymphoma or may experience a later relapse is going to require more follow up, but very promising early results for this treatment of patients with otherwise resistant follicular lymphoma. There are significant side effects with this type of therapy, including something called cytokine release syndrome, which is like an intense inflammatory reaction. Fortunately, the severe forms of this occurred in a minority of patients, under 10%. There can also be neurologic events that can range from tremor or confusion, and rarely even patients becoming unresponsive. Fortunately, most everyone recovers from this. And in this trial, the more severe forms of these neurologic events occurred in about 15% of patients. So a very promising early set of data for another group of lymphoma patients, in addition to those with large cell lymphoma. So if you are in a situation of highly resistant and progressing follicular lymphoma, including follicular lymphoma that may have transformed from the lower grade into a higher grade large cell lymphoma, then considering a CAR T-cell therapy or a clinical trial of other novel approaches is certainly worth considering. And I'll finish by just saying that it's a fast-moving field. There's a lot of benefit if you have a newly diagnosed or a relapsed lymphoma to talk with your oncologist and consider whether a second opinion may be in order and what clinical trials might be relevant for your situation because, nowadays, we often find that taking part in such a trial provides access to some of these very promising new agents and allows us to move the field forward and bring these newer treatments online so that they can benefit as many patients as possible. So a very exciting time in the field of lymphoma, lots of important new data presented at ASCO, and I'll look forward to updating you on future advances in another podcast. ASCO: Thank you, Dr. Williams. Learn more about the research presented at the ASCO20 Virtual Scientific Program at www.cancer.net/blog, and subscribe to Cancer.Net podcasts on Apple Podcasts or Google Play to catch up on the other episodes in the Research Round Up series. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

September is Childhood Cancer and Sickle Cell Awareness Month. In this episode of the Inside Pediatrics Podcast, Dr. Girish Dhall shares exciting news from the Pediatric Hematology-Oncology team, including new collaborations and clinical trials available to patients, research and fellowship training opportunities, and a significant jump in the division's U.S. News & World Report ranking among the top programs in the country.

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. Every year, the ASCO Annual Meeting brings together attendees from around the globe to learn about the latest research in the treatment and care of people with cancer. This year, a record 42,750 attendees from 138 countries worldwide gathered virtually for the ASCO20 Virtual Scientific Program, held Friday, May 29 through Sunday, May 31. In the annual Research Round Up podcast series, Cancer.Net Associate Editors answer the question, “What was the most exciting or practice-changing research in your field presented at the ASCO20 Virtual Scientific Program?” In this first episode, 3 editors discuss new research in the fields of leukemia, colorectal cancer, and lung cancer. First, Dr. Jessica Altman will discuss 2 studies in myelodysplastic syndromes and acute myeloid leukemia. Dr. Altman is Associate Professor of Medicine in the Hematology Oncology Division at the Feinberg School of Medicine, Northwestern Medicine. She is also the Cancer.Net Associate Editor for Leukemia. View Dr. Altman’s disclosures at Cancer.Net. Dr. Altman: Hi, everyone. My name is Jessica Altman. I am a leukemia physician at Northwestern Memorial Hospital in Chicago, and I am pleased to talk today about some interesting studies that were presented at ASCO 2020 and really use that as a marker of the excitement that is ongoing in the field of myeloid malignancies. In both myelodysplastic syndrome and acute myeloid leukemia, there have been a lot of novel therapies that have been recently approved, and other agents that are currently ongoing in a clinical trial. I think it's important for me to mention that the studies that I will be discussing today, I do not have any direct conflicts of interest, but I am involved with the development of other novel therapies. I'll be talking about two studies today. The first one is a clinical trial, and the second one is a palliative care study that was conducted. The first study that I would like to discuss is the study presented in an oral session at this year's ASCO presented by Dr. David Sallman on behalf of his group at Moffitt and a large clinical trial network of other investigators. They studied the combination of a novel agent called magrolimab, which I'll mention more in a moment, in combination with a standard lower-intensity chemotherapy called azacitidine. This is studied for the treatment of high-risk myelodysplastic syndrome and acute myeloid leukemia. Magrolimab is an antibody that blocks something called PD47, which is a macrophage immune checkpoint and essentially a signaling cancer that says, "Don't eat me." And this antibody allows the engulfment or destruction of tumor cells and also is able to eliminate the really deep stem cells that cause the development or maintain the leukemia and MDS. So in this study, the investigators conducted a trial of azacitidine in combination with magrolimab, and they treated a handful of patients with both myelodysplastic syndrome and acute myeloid leukemia. And what they found was that the combination therapy was both well tolerated and resulted in a better-than-anticipated response rate. So better than what we would anticipate with a low-intensity chemotherapy alone. In particular, they found a nice response rate in individuals whose leukemia or MDS expresses a specific mutation. That mutation is called TP53, and that mutation has been associated with a poor chance of response to the available therapies and particularly a short duration of response. This trial is particularly exciting to me because it demonstrates the ability to combine novel therapies with lower-intensity treatments and allows what we hope for will be a higher chance of response. This is with a relatively limited study, and further trials in this space involving this agent and combination are planned and are ongoing. There are other agents that are also targeting the TP53 mutation, and those are things to watch out for as well. I'd like to move on to a supportive care study that was presented as well. This was a study that was presented by Dr. El-Jawahri, and funded by the Leukemia and Lymphoma Society. This is a study that looked at patients with acute myeloid leukemia receiving intensive chemotherapy. The relevance and importance for the study is because supportive care trials, and particularly looking at palliative care in general in acute myeloid leukemia have not frequently been done to date. And the background for this study is that individuals with acute myeloid leukemia frequently can experience decline in their quality of life and mood during their hospitalization for induction therapy. And it is not uncommon for adults with acute myeloid leukemia to receive aggressive care at the end of life. So this group sought to examine the effect of an integrative palliative and oncology care and affect quality of life, mood and symptoms associated with things like post-traumatic stress and with a huge emphasis on end-of-life outcomes. And what this group found was that the integrative palliative and oncology care model for patients with acute myeloid leukemia receiving intensive chemotherapy led to improvements in patients' quality of life, their psychological distress and the care at the end of life. And the investigators asked for consideration of palliative care as a standard of care for all adults with acute myeloid leukemia, from really thinking about the incorporation of palliative care model, from diagnosis and throughout treatment and not just reserving that to the end of life. Thank you for your time. I was very excited with the numerous clinical trials in the myeloid neoplasm space presented at this year's ASCO. And the work that was presented is really a marker of how much excitement there is that's ongoing in this field. Thank you. ASCO: Thank you, Dr. Altman. Next, Dr. Jeffrey Meyerhardt will discuss 4 studies in colorectal cancer. Dr. Meyerhardt is the Douglas Gray Woodruff Chair in Colorectal Cancer Research, Clinical Director and Senior Physician at the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute, Deputy Clinical Research Officer at the Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School. He is also the Cancer.Net Associate Editor for Gastrointestinal Cancers. View Dr. Meyerhardt’s disclosures at Cancer.Net. Dr. Meyerhardt: Hi my name's Jeff Meyerhardt from the Dana Farber Cancer Institute in Boston, Massachusetts. I'm going to speak about some of the key abstracts that were presented at this year's virtual ASCO meeting in 2020. I have no pertinent disclosures related to the abstracts I'm going to discuss. So the first and probably the most prominent and abstract, which was presented in the plenary session, was a study called KEYNOTE-177. It was a study specifically for patients with a certain subtype of metastatic colorectal cancer, what's called microsatellite unstable tumors. It's a way that colorectal cancers first emerged when they developed from normal cells to abnormal cells. It only constitutes about 3 to 5 percent of metastatic colorectal cancers. But we know a lot about those cancers because some of them are related to inherited conditions and some are not related to conditions, but they land up at those other cancers that seem to be much more susceptible to immunotherapy. And in fact, they're the ones that immunotherapy indicated for in terms of colorectal cancer. And so the study that was presented was comparing patients receiving what's called a checkpoint inhibitor and a type of immunotherapy, in this case, pembrolizumab, to standard chemotherapy. So chemotherapy that we would typically give as initial treatment for metastatic colorectal cancer. Currently, the indication with the FDA is that patients would receive immunotherapy later as a later line of therapy, if other things weren't working and this was really to say, should we be giving it much earlier on? So as a randomized trial, it was about 300 patients and they compared starting just with an immunotherapy, pembrolizumab versus chemotherapy and either a drug called bevacizumab or a type of a another inhibitor called an EGFR inhibitor, cetuximab.  And it lands up starting with the pembrolizumab had a real significant improvement in progression free survival. It was a comparison of actually 8.2 months with standard treatments, which is what we see in a lot of trials versus 16.5 months. That's essentially for the times we had to switch to different therapy and all these other endpoints were also met in terms of a 12-month and two years of progression free survival. It was a statistically significant event, and it really will change practice for that subpopulation of patients with metastatic colorectal cancer. What's still really important is to try to figure out for the rest of the patients how immunotherapy can benefit them. And that unfortunately, we don't have as much data yet. Another abstract presented this year at ASCO was a sort of update of what's called the BEACON trial, and this is, again, another subgroup of colorectal cancers, colorectal cancers that have a particular mutation in them, what's called a BRAF mutation. We know that occurs in somewhere between 5 and 10 percent of colorectal cancers. They can sometimes be a more aggressive cancer and there were multiple drugs that have been tested in multiple combinations of those drugs over the past 10 years, but the largest effort was really looking at trying to give patients a standard treatment to combining a BRAF inhibitor, in this case, encorafenib, which is an oral pill, with an EGFR inhibitor called cetuximab and also potentially adding a third drug, binimetinib, which is called a MEK inhibitor, also an oral pill. And the study, the BEACON study, which was a large international randomized study compared those three arms. The main comparison was saying, should you have two drugs compared to control or three drugs compared to control, control being standard treatment. And looking at both of those compared to standard treatments. They weren't actually meant to compare the two to three drug and initially the results suggest that three drugs was optimal. But the study that was presented at ASCO and ultimately actually led to the actual FDA approval, is using a two drug combination. So encorafenib and cetuximab, which again was better than control and really becomes the standard for later line treatment of BRAF mutated colorectal cancer. We don't know if that should be the initial treatment. That study is now about to get started to say, "Should we start with BRAF directed therapy?" but we know that if you had progressed in other standard treatment, that is certainly an option that should be considered. There were two studies that looked at adjuvant therapy for colon cancer. Adjuvant is after someone has surgery and then they receive chemotherapy to reduce their risk of recurrence, one of them was a follow up to an effort to look at how many months of adjuvant therapy is necessary. This was called the IDEA collaboration. It was an international effort that included 14000 patients randomized to three months of treatment versus six months of treatment. And what we learned from that is for patients, particularly, who have a better risk tumor. So they all have stage III disease. Meaning they had surgery, the pathology showed some lymph nodes in the sample, but they didn't have evidence of metastatic disease at the time when they were diagnosed and those patients that they received three months of therapy if they only had one to three positive lymph nodes or not all the way through the bowel wall. Three months of therapy seemed to be just as good as six months, particularly when you do a combination of oral drug capecitabine with an IV medication called oxaliplatin and those with higher risk disease, those patients should probably receive six months, though in some cases, three months also seems to be sufficient. And this was a follow up to show that actually overall survival also was not inferior to do three months versus six months in those patients who have better risk disease or with capecitabine and oxaliplatin. The second adjuvant trial was one that I actually led. It was a large trial that was run through the National Cancer Institute. It was looking at standard chemotherapy in stage III colon cancer, same population I just discussed, and whether adding celecoxib, which is what's called a Cox-2 inhibitors. It's kind of like aspirin, a little bit more specific. And then there was a lot of data that those type of drugs could be helpful in patients to reduce polyps and may potentially be beneficial in patients who already had colorectal cancer. So we conducted a large clinical trial, comparing standard chemotherapy with the celecoxib or standard chemotherapy alone. And unfortunately, adding the celecoxib didn't actually add any statistically significant benefit. There was a slight improvement, but it wasn't statistically significant. So it is a negative study and unfortunately does not move the field in terms of improving outcomes for patients with stage 3 colon cancer. There are still some ongoing studies, specifically looking at aspirin that we await to see if that would make a difference in outcomes. So those are some of the highlighted studies focused on colon and colorectal cancer from ASCO this year. Thank you very much. And again, my name's Jeff Meyerhardt from the Dana Farber Cancer Institute. ASCO: Thank you, Dr. Meyerhardt. Next, Dr. Jyoti Patel discusses 3 studies in non-small cell lung cancer. Dr. Patel is the Medical Director of Thoracic Oncology and Assistant Director for Clinical Research at the Lurie Cancer Center of Northwestern University. She also serves as Associate Vice Chair for Clinical Research in the Department of Medicine. She is also the Cancer.Net Associate Editor for Lung Cancer. View Dr. Patel’s disclosures at Cancer.Net. Dr. Patel: Hi. My name's Jyoti Patel. I'm a professor of medicine at Northwestern University and associate editor of Cancer.Net for lung cancer, and I'm going to talk about some of the most exciting lung cancer abstracts that were presented at the 2020 ASCO Annual Meeting. One of the most important and, I think, impactful to patients and practice-changing studies was actually selected as a plenary session abstract, and plenary abstracts are those that are rated the highest of all of the thousands of abstracts that are submitted, so whenever there's one in our particular disease site, we're always really excited, and we've been waiting for this ever since we heard from a press release that a positive study on lung cancer was going to be presented. The study was called the ADAURA study. And the ADAURA study was sponsored by AstraZeneca, and I have worked as a consultant for AstraZeneca in the past.  So the study was looking at a drug called osimertinib, in patients who had early-stage lung cancer which was surgically resected. So as we know, a minority of patients, unfortunately, have stage I and stage II lung cancer, and about 30% of patients have stage III lung cancer. For many of these patients, surgery is the primary modality, and we do surgery with curative intent. However, despite doing surgery, there is a significant chance that the cancer can recur. So the study was looking at osimertinib as adjuvant therapy in patients with resected lung cancer. Osimertinib is an EGFR tyrosine kinase inhibitor. It's a targeted therapy that blocks the EGFR protein, which is often mutated in patients with lung cancer. So osimertinib is the treatment of choice for patients with advanced lung cancer that harbor an EGFR mutation. That mutation occurs in about 15% of American patients, and higher proportions of patients in some parts of the world. These patients, early on, had surgery, and then they were found to have an EGFR mutation, and then they were randomized to either three years of osimertinib as a daily tablet, versus a placebo, and the endpoint of this study was disease-free survival, so that's the length of time until there's evidence that the cancer has recurred. In this study, taking osimertinib significantly reduced the chance that the cancer would return within those three years, and the magnitude of benefit was highly significant. So with higher stages of disease, the likelihood that the cancer could come back is higher, and so the benefit was greatest in patients with stage 2 and stage 3 disease, and in fact, in patients with stage 3 disease, it decreased the recurrence rate by almost 85%. So really, really significant and impactful to our patients. Some people have questions about whether this should now be a standard of care, because we're not really showing whether we're improving the overall survival of patients. Many oncologists, myself included, think that survival with no evidence of disease is really meaningful for patients. It's going to be important, as the study matures, to see what the overall survival data look like, but in the three years of taking the drug, which is relatively well tolerated, the survival benefits, to me, translates to better quality of life, return to function and work, and staying away from catastrophic complications of cancer recurrence, like cancer coming back in the brain, or in the bone, and really impacting quality of life. And the next study I want to discuss is a study looking at immunotherapy and chemotherapy in patients with non-small cell lung cancer. So the study is called 9LA. It's a CheckMate trial, so BMS studied their drugs nivolumab and ipilimumab in combination with chemotherapy. My institution has received research funding from BMS for the study of nivolumab and ipilimumab, and I've served as a consultant in the past. In this study, patients who were treatment-naive, so hadn't received prior therapy, were randomized to either chemotherapy, which was an older standard, admittedly, versus a combination of a short course of chemotherapy, so only for six weeks, in combination with the immunotherapies nivolumab and ipilimumab. The rationale for giving chemotherapy with immunotherapy is multifold. So one is that chemotherapy kills cancer cells, and in doing so, it releases neoantigens, or proteins, that might make the immunotherapy more effective. It sort of targets these cells as foreign, and it kind of helps amp up the immune system. It also sort of decreases the cancer burden, and we know that immunotherapy tends to be more effective when there's fewer sort of volumes of cancer to treat. So this was a really interesting design, and impactful because the chemotherapy is given for such a short course, so the ongoing toxicities of chemotherapy over several months, it sort of goes away. So less fatigue, less lowering of blood counts. The study was looking at overall survival, and the study was positive, and this led to an FDA approval in May. The study showed that, in the initial time in which chemotherapy and immunotherapy were given, patients did quite well, and then they sort of plateaued, and at 12 months, almost two-thirds of patients were on the immunotherapy, compared to about half of patients which were on chemotherapy. And so that was significant. Although these results are comparable to other treatment options we have with ongoing chemotherapy and immunotherapy, are in patients with really high PDL numbers of immunotherapy alone, I think this trial is important for patients because it offers a different alternative. Having a short course of chemotherapy may make a lot of sense for patients. The cumulative toxicity from chemotherapy, it can't really be understated. Although our chemotherapies are better tolerated than ever before, the idea of just six weeks of chemotherapy and then going into immunotherapy, I think, is really an attractive one, and may give us options from multiple other treatments down the line. So I think this is important for patients. I think it certainly makes life a little bit more complicated for medical oncologists because now we have multiple options to discuss with patients, but at the end of the day, that's the best way we can personalize therapy for our patients, really taking into account overall disease status, as well as patient preferences, and tolerance of toxicities, and aims in the future. The last study that I want to highlight is a study called the DESTINY study. I don't have any disclosures for this study. This study was looking at a subgroup of patients with lung adenocarcinoma with HER2 mutations. So there have been a lot of targeted therapies that have gained our attention and FDA approvals in the past couple of years, and it's really exciting. We're understanding that development of targeted therapies is based on early assessment of mutations in our patients, and we have a host of mutations, now, with FDA approved drugs. Just in May, drugs targeting RET, or R-E-T fusions was approved. Another drug targeting MET exon 14 skipping mutation was approved. HER2 mutations represent a subset of patients, a small subset of patients, about 2% of lung cancer patients, and they've been really difficult to treat. We know about HER2 because it's often a target for breast cancer, but in lung cancer, it's often a small mutation that causes activation, that causes the cells to grow. We haven't had a lot of really great options for these patients, and although there are multiple drugs in development, this particular trial gained a fair bit of attention because it looks quite promising. So this study was looking at trastuzumab deruxtecan, and that's an antibody-drug conjugate. So the idea is it's an antibody that binds to HER2-- which is on cancer cells. When it binds to that target, the drug conjugate, or the payload, is released into the cancer cell. So there's less toxicity. It's a targeted therapy with very sort of directive toxin to the cancer cells. There are a number of antibody-drug conjugates in development, and some are FDA approved for other indications. In this study - it was a single-arm study - patients with HER2 mutations received the antibody-drug conjugate, and they saw a really significant response rate. Almost all patients had some disease diminution, some response, with about 60% of patients having what we call a partial response, a 30% reduction in tumor cells. What was also exciting was that some patients have been able to show that their responses are quite durable, and so the disease control has lasted. Certainly, this is an early trial. Only about 39 patients were treated. So we look forward to further studies of this compound, but finally, it's nice to have something that looks this promising in this particular patient population. ASCO: Thank you, Dr. Patel. Learn more about the research presented at the ASCO20 Virtual Scientific Program at www.cancer.net/blog, and subscribe to Cancer.Net podcasts on Apple Podcasts or Google Play for additional episodes in the Research Round Up series, released throughout the summer. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor Dr. Michael Williams will discuss some of the new research in lymphoma that was presented at the 2019 American Society of Hematology Annual Meeting, held December seventh through tenth in Orlando, Florida. Dr. Williams is the Chief of the Hematology/Oncology Division and Director of the Hematologic Malignancies Program at the UVA Cancer Center. He is also the Byrd S. Leavell Professor of Medicine and Professor of Pathology at the University of Virginia School of Medicine. View Dr. Williams’ disclosures at Cancer.Net. ASCO would like to thank Dr. Williams for discussing this research. Dr. Williams: Hello, and thanks for joining us for this podcast. My name is Michael Williams. I'm Professor and Chief of Hematology/Oncology at the University of Virginia in Charlottesville. And I'm pleased to discuss some exciting advances in lymphoma that were presented at the American Society of Hematology meeting held in Orlando in December 2019. My disclosures are that my research group here at the university, through the university, has received research support from pharmaceutical companies AbbVie, Pharmacyclics, and Janssen, and I have received honoraria for speaking at conferences from Xian-Janssen in China. So what I'm going to talk about today are 2 reports about the management of localized diffuse large B-cell lymphoma, an update on a novel therapeutic approach for relapsed mantle cell lymphoma. And then, I'll finish with a brief introduction of an agent that is showing promise for treating highly resistant relapsed lymphoma that was presented in the plenary session during the ASH meeting. So let's start with localized diffuse large B-cell lymphoma. So DLBCL is the most common subtype among the many forms of non-Hodgkin lymphoma. Usually, people present with advanced stage disease. But as many as 25 to 30 percent may have a disease that's localized to just 1 site or a very localized area of lymph nodes, so these would be stage I or stage ll patients. And the first report that I'll comment upon was presented by Dr. Laurie Sehn at the BC Cancer Agency in Vancouver, British Columbia. So they did a retrospective review looking at 319 patients treated in British Columbia over the past 15 years. So these were patients who had a nonbulky mass, they were localized disease. And the treatment currently for this disease is that people get either 6 cycles of a regimen such as rituximab and CHOP chemotherapy or more limited chemotherapy. Typically, 3 cycles of R-CHOP followed by radiation therapy. The importance of this study is that it is exploring a mechanism to de-escalate therapy, if you will, by avoiding the use of the radiation therapy. So what they did, is patients with localized disease received 3 cycles of rituximab plus CHOP therapy and then underwent a PET scan. So PET scans, unlike CT scans, are nuclear-medicine imaging that shows the functional uptake of radioactive glucose by the sites involved by lymphoma. So if you become PET negative after the three cycles of rituximab, CHOP therapy, then it seems likely that you've got a very highly responsive disease, and you may be able to avoid radiation therapy. So they did the PET scan after 3 cycles, and for those who were PET negative, then those patients received 1 additional cycle of rituximab CHOP, and that was the end of their therapy. If they were still PET positive, then they moved on to radiation therapy to the involved area. So what they found was quite interesting that of the 319 patients, 254 were negative after their PET scan. And so went on, virtually all of them, to just getting 1 more cycle of rituximab CHOP as planned. The outcomes for those patients were that very few of them relapsed over the next several years. They followed patients now, for about four years or more, in most cases, and they found that the overall, 5-year progression-free survival was 88% for those who were PET negative. For the subset of patients who were still PET positive, and got the radiation therapy, their outcome was somewhat worse, in that there was only 74% who were still progression free. The overall survival for these patients was 90%, at 5 years, for those who were PET negative and 77% for PET positive. So what this study shows us, is that a PET scan after 3 cycles, can inform us about patients who are 90% likely to have good control of their disease, with just 4 treatments, and you can avoid the exposure to radiation therapy. Those who were still PET positive still did well: 3 out of 4 were still in remission beyond 5 years but not quite as good an outcome. So these are patients who may be candidates for an alternative approach to try to do better with their long-term cure rates. So that leads us to the second presentation that I want to discuss. This was presented by Dr. Daniel Persky on behalf of the Southwest Oncology Group, which is part of the National Clinical Trials Network, in the United States. So they had a very similar approach. They studied patients with localized Stage 1 or 11, nonbulky diffuse large B-cell lymphoma, and they got standard rituximab CHOP therapy, and then a PET scan after the third cycle. Just as in the paper I discussed from British Columbia. Those who had negative PET scans got one additional cycle of rituximab CHOP. Those who were still PET positive got involved-field radiation therapy and treatment with a radio-labeled monoclonal antibody. Essentially, a radioactive form of rituximab, which has given us a single dose about a month after they'd finished their involved-field radiation therapy and then they got a follow-up PET scan, thereafter. So this study went on for several years, at multiple sites around the country. They enrolled 132 patients, and of those patients, 110 were PET negative after their third cycle. So only 18 needed to go on to this additional radiation therapy and the systemic treatment with the radio immuno therapeutic called Ibritumomab tiuxetan. They followed these patients now for 4 and a half years, and only 5 patients have progressed, and only 2 have died of their lymphoma. So of those who progressed, 3 of them had gotten just the R-CHOP alone. There was another patient who was PET positive but declined getting the radiation therapy who progressed. And then, another patient who had only 1 treatment was rituximab CHOP but then went off treatment due to toxicity. So similar, and in fact, almost identical to the British Columbia report. Five-year freedom from progression of their disease was 87%, and the overall survival was 90%. So these patients can do quite well, since many times, the location for localized DLBCL is in the head neck. There can be significant late effects of radiation therapy. So I think these studies reassure us that patients with localized disease can have very durable outcomes and cure rates. It's important to note that there's a higher rate of late relapse beyond three years in patients with localized DLBCL compared to more diffuse extensive disease suggesting that there may be some differences in the biology of a localized disease. So very important data, and data that gives us the opportunity to de-escalate treatment in localized large cell lymphoma. So let's switch gears and talk about mantle cell lymphoma. There's been a lot of progress in this disease over the past decade. Much of it related to the use of nonchemotherapy targeted agents such as Bruton’s tyrosine kinase inhibitors including ibrutinib and the Bcl-2 inhibitor, venetoclax. There was a study reported last year by an Australian group led by Dr. Constantine Tam. This study was updated at the ASH meeting with a longer follow up. So these were patients with Relapsed/Refractory disease, heavily pretreated. Many of them, previously, having had intensive chemotherapy and a stem cell transplant. And half of them had mutations in a gene called TP53, which is correlated with frequent chemotherapy resistance and high relapse rate. And what they found by combining the targeted agents ibrutinib and venetoclax, that they got very high response rates. The majority of patients responded although, there were a few who were primarily resistant, and about a third of patients, actually, got very deep remissions. PET negative and negative for minimal residual disease detection. If you look at the subset, of the highest risk patients, with the TP53 mutation, half of them achieved a complete response rate, and some of these patients have had durable responses. There have been a few patients who've had deep responses, who've been able to come off treatment. And overall, the duration of response at 2 and a half years is 74%. But what this study shows us, is yet again, that these novel targeted drugs that are typically better tolerated than cytotoxic chemotherapy can have very good and indeed dramatic responses, and so is showing a lot of promise. It reminds us that in mantle cell, whether it's newly diagnosed or relapsed, that talking to your oncologist about clinical trial opportunities can often avail you of some of the most promising new approaches. And indeed, that's true for all forms of lymphoma, that clinical trial options should be part of the discussion with treatment planning. I'm going to finish by just mentioning another novel agent that is being applied to patients with highly resistant relapsed disease. This is a molecule called mosunetuzumab, and this is a bispecific antibody. So there are a number of these now that are in clinical development, and some are FDA approved for treating leukemias and certain lymphomas. This one is designed to basically connect a body's immune system, the T cells, with the B-cell lymphomas by using an antibody that can recognize each of those and bring them physically together. So this was presented by Dr. Steven Schuster; it was a multinational study of this bispecific antibody in patients with very aggressive relapsed/refractory lymphomas including, diffuse large B-cell and transformed follicular lymphoma. And what they found in this study, is that response rates were 64%, with 42% of patients achieving a complete remission. So it's still early, but quite promising because these are patients who had failed CAR T-cell therapy. They may have failed transplant, or they were patients who needed a treatment to bridge them over to get to a CAR T or another treatment such as an allogeneic stem cell transplant. The toxicities were generally manageable and similar to those seen with other bispecific antibodies. So it's early, but across subtypes of patients with aggressive and relapsed lymphoma, I think this is another promising molecule, that may well provide good therapeutic options via a clinical trial for patients who have very limited other options to manage their disease. So thanks again for joining this podcast. There was a lot of other exciting data that we didn't have time to go through, so I encourage you to continue learning about what's new in the field, discussing with your oncologist, or with a consulting specialist in lymphoma, to make sure you can avail yourself of the best in current diagnostics and therapeutics. Thanks very much. ASCO: Thank you, Dr. Williams. Learn more about lymphoma at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play. This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org. Cancer.Net is supported by the Conquer Cancer Foundation of ASCO, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/support.

ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer. 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses. In this podcast, Cancer.Net Associate Editor Dr. Michael Williams will discuss some of the new research in lymphoma that was presented at the 2018 American Society of Hematology Annual Meeting, held December first through fourth in San Diego, California. Dr. Williams is the Chief of the Hematology/Oncology Division and Director of the Hematologic Malignancies Program at the UVA Cancer Center, and Byrd S. Leavell Professor of Medicine and Professor of Pathology at the University of Virginia School of Medicine. ASCO would like to thank Dr. Williams for discussing this topic. Dr. Williams: Hello. This is Michael Williams. I'm a professor at the University of Virginia Health System in Charlottesville, Virginia, and I'm reporting today on some exciting advances in lymphoma that were presented at the Annual Meeting of the American Society of Hematology, which was held in San Diego, California in early December 2018. Well, there were a number of areas of lymphoma that had important reports, and I'm going to just give you a small sampling of these today. We'll start with a new treatment option for patients with follicular lymphoma. Traditionally, this type of lymphoma, when it's symptomatic and needs therapy, the treatment of choice has been chemotherapy combined with a monoclonal antibody such as rituximab or obinutuzumab. But investigators, in a multicentered trial, decided to test whether you could use a chemotherapy-free treatment approach for patients like this by using rituximab combined with lenalidomide, which is also known as Revlimid, as a substitute for chemotherapy. And this is based on the fact that Revlimid plus rituximab has synergistic activity in patients with relapsed disease, so maybe we could see acceptable, high responses when it would be compared directly with rituximab plus chemotherapy. So the way the trial worked is this. Patients who needed therapy, who had advanced-stage follicular lymphoma—they had never had any therapy before—were randomized to either the rituximab-lenalidomide combination or a rituximab-chemotherapy combination that could include the regimens CVP or cyclophosphamide, vincristine, prednisone, the same combination given with daunorubicin, or the CHOP regimen, or rituximab combined with bendamustine. So over 1,000 patients were treated in this multinational study and the goal of the treatment, of the study was to prove that, actually, the ritux-lenalidomide was superior to the chemotherapy regimens. So the results showed, not superiority, but comparability. The complete remission rate between rituximab-len and ritux-chemotherapy were really identical, 48 and 53 percent, and the 3-year likelihood that the patients were progression-free, so had had no recurrence of their disease, was identical as well: 77 to 78 percent. There was no difference in survival which was 94% at 3 years in both arms. The toxicities differed, however. There was more rash with the lenalidomide combination, whereas low blood counts and the need for growth factor support such as G-CSF was greater with chemotherapy. And it was also interesting that some of the traditional risk factors didn't seem to apply, as much, for lenalidomide. So what would be considered higher risk patients treated with chemotherapy, seemed to do somewhat better with the lenalidomide combination. The importance for a patient with untreated follicular lymphoma who needs therapy is that a chemotherapy-free approach with rituximab plus lenalidomide can be considered equivalent to rituximab-chemotherapy. It’s worth discussing this with your oncologist when you're considering what treatment to use initially. The next subtype of lymphoma that I want to discuss is diffuse large B-cell lymphoma, and there's 2 presentations that I'm going to summarize. One, in patients with advanced stage disease, meaning stage III or IV. This identifies patients who have disease both above and below the diaphragm, to make it stage III, or stage IV means they've got bone marrow or other sites of involvement such as liver or bone. And the question being asked in this trial, which was part of the International GOYA trial, will take just a moment to explain. So the original GOYA trial compared whether a newer form of anti-CD20 monoclonal, namely obinutuzumab, which is also called Gazyva, how that would compare with the standard established monoclonal antibody, rituximab. And the initial findings of this study found that there was no benefit for the newer antibodies. So rituximab and CHOP chemotherapy was equivalent to obinutuzumab and CHOP chemotherapy in overall outcomes. But there was an opportunity with this trial to answer a question that's been out there for many years, and that is how many cycles of treatment does one need? So the investigators took advantage of this large study which included 712 patients who were randomized to rituximab plus CHOP. Just over 500 of them received 6 cycles, and the remaining 186 received 8 cycles. Even the patients who got 6 cycles of CHOP chemotherapy also got an additional 2 doses of rituximab, so the immunotherapy monoclonal antibody was equivalent between the 2 arms. And the results of this showed that there was really no difference at all with a followup of about 3 years. Response rates were equivalent and there was no difference in the patients staying in remission. It didn't matter in terms of survival which was excellent in both arms. There was, however, more toxicity in patients who received 8 cycles, including cardiac problems, infections, etc. These results showed that, I think we can finally put to rest the use of 8 cycles of rituximab-CHOP chemotherapy for advanced-stage large cell lymphoma. It's been an unknown entity because we never had a direct comparison of these. So we can now say that 6 cycles plus the additional 2 doses of rituximab is a standard for advanced-stage diffuse large B-cell lymphoma. Now, what about patients who have limited-stage, so stage I or II diffuse large cell lymphoma? That means just a single lymph node area's involved or 2 adjacent lymph node areas. In the past, these were treated either with 6 cycles of rituximab-CHOP or sometimes cycles of R-CHOP plus local radiation therapy. And in this study, which took a long time to complete; it began in 2005, but it enrolled 592 patients who were then randomized to either 4 cycles or 6 cycles of treatment. Radiation therapy was not planned for any of these patients except for very specific locations of involvement such as testicular DLBCL where radiation therapy is a standard. So the take-home message after over 5 years of follow-up for patients on this study showed that 4 versus 6 were identical. So 89% of patients were still in remission at 3 years after completing treatment, and the overall survival was really impressive, 98 to 99 percent in the 2 arms. So there was no benefit with limited-stage favorable disease. Now, who are these patients? So younger than age 60, stage I or II disease, and normal LDH. They did not have bulky disease, meaning there was no nodal mass more than 7 and a half centimeters. So if you fit those criteria, then you can benefit from a de-escalation of treatment and be spared the additional 2 cycles of R-CHOP. Now, sticking with the topic of diffuse large B-cell lymphoma, a challenging problem in our field is for patients who relapse after their initial therapy, or in some cases, fail to respond to a treatment like rituximab-CHOP or an equivalent immuno-chemotherapy regimen. And a very exciting advance in the field, over the past few years, has been the development of chimeric antigen receptor T cells or CAR Ts. Traditionally, what we've done with patients who relapse or have resistant diffuse large cell lymphoma is to give them a second-line, high-dose chemotherapy regimen, and if they showed a good response to that, they could then go to a dose-intensive treatment with a follow-up consolidation by autologous stem cell transplantation. And with that, you can cure, overall, about 40% or so of patients. The CAR T-cell approach takes a very novel immunotherapy effort, and that is that a patient's own T-cells are removed from the peripheral blood, and then in the laboratory, they're modified and reprogrammed so they can attack the patient’s diffuse large B-cell lymphoma cells that are resistant to chemotherapy. So there were 2 important follow-up studies, each of them involved 1 of the agents, the CAR T-cell products, that are approved by the Food and Drug Administration for patients with relapsed or refractory diffuse large cell lymphoma. The first used the CAR T known as axicabtagene ciloleucel. It's quite a complex name, but it goes by the abbreviation of axi-cel or the trade name is Yescarta. So in this study, the investigators wanted to show that this is a treatment that can be extended to many centers with the product, the CAR T being made in a central facility by the pharmaceutical company. So it was a retrospective study of 295 patients at 17 international centers: a lot of patients across a broad spectrum of sites in North America and Europe. Virtually all the patients were able to develop and obtain a CAR T product. It included patients with some of the higher risk forms of the DLBCL such as double and triple-hit lymphoma. About 3% of patients died during the treatment, although only 1% of these were felt to be related to the treatment itself. The response rates were quite good, with about 80% of people responding. The complete remission rates at 30 days after the CAR T infusion were 47%. So it proved that you can use this centrally manufactured product. So the patients T-cells are collected at the local center, they're shipped to the manufacturing facility, the CAR Ts are generated, sent back to the home institution, and then infused. And I'll say a word in a moment, after I introduce the next paper, to explain some of the side effects of this treatment. So the second study was also presented at the ASH meeting and published simultaneously in the New England Journal of Medicine in early December 2018. So this used the second FDA approved CAR T known as tisagenlecleucel or Kymriah. In this study, there were 93 patients who were able to receive a CAR T-cell infusion, 40% of them achieved a complete remission, and another 12% had a partial response. And that a year after their documented response, two-thirds of these patients were maintaining the response, including 79% of those who achieved a complete remission. So this trial again confirmed across multiple centers that CAR T-cells can be an effective therapy. The side effects of both of these drugs can include something called cytokine release syndrome where the immunologic effects, essentially, release cytokines into the blood that can mediate a capillary leak, respiratory troubles, and low blood pressures, that can, in some cases, require intensive care unit support. This can be managed by other mediators that tamp down the cytokine effect such as an interleukin-6 antagonist. The other toxicity which is less well understood and problematic can be neurologic effects which can include confusion, speech alterations and even coma. But again, approaches and treatments to identify and manage this are being developed. So CAR Ts have become established. They're available at a number of centers, but it's important to consider this as a treatment option in the setting of relapsed or refractory diffuse large cell lymphoma. The long-term curability is still unknown, although it's encouraging that patients with very resistant disease who'd get a good response can maintain that response out to a year and more. So we're going to be very interested to see how the longer-term follow-up comes together. The final topic I wanted to mention today is Waldenstrom macroglobulinemia. So this is a unique form of indolent B-cell lymphoma where the lymphoma cells release a monoclonal immunoglobulin into the blood known as IGM. Now, IGM is a very large antibody, and because of that, when the levels are very high, patients can have problems with high viscosity or thickening of the blood, which can cause confusion, vision changes, sometimes respiratory problems. And these patients also can become anemic or develop enlarged lymph nodes or enlarged spleen. So one of the standard treatments for this disease is, again, the immunotherapy monoclonal antibody rituximab, but the responses are typically incomplete and somewhat short-lived. So it was exciting, a couple of years ago, when the targeted tyrosine kinase inhibitor, ibrutinib, which targets the bruton tyrosine kinase in malignant B-cells. This is an agent that's approved in chronic lymphocytic leukemia, and certain lymphomas such as mantle cell, marginal zone, as well as lymphoplasmacytic lymphoma or Waldenstrom macroglobulinemia. So here's the study. Investigators had shown that if you combine rituximab with ibrutinib, that the response rates were improved as compared with rituximab by itself. And in a follow-up study that looked at this over a longer period of time, these benefits of the combined therapy were confirmed. These included patients without prior treatment or with prior treatment, with either chemotherapy or rituximab. And there was a confirmed benefit for the ibrutinib-rituximab combination in patients, whether they had had treatment before or not, and regardless of certain genetic markers that we use to assess risk in Waldenstrom. It was also shown that because these treatments continue indefinitely, as long as patients are responding and tolerating therapy, that the response rates improved over time. The side effects of treatment with ibrutinib are well-known, now, after several years of use across a variety of diseases, as mentioned, and include diarrhea, sometimes rash. You can see problems with easy bruising or bleeding, atrial fibrillation, and sometimes skin rash, or muscle and joint aches. But most patients are able to continue therapy and to benefit from it over an extended period of time. So the combination of ibrutinib plus rituximab was shown to add benefit compared with rituximab alone, and again, is a treatment approach and option that you could consider whether you have previously untreated or relapsed Waldenstrom macroglobulinemia. So overall, it was a very exciting meeting. We've had practice-changing data presented, and I've given you just a sampling of those. I think it's important for anyone dealing with lymphoma, or related malignancy, such as CLL or multiple myeloma to be very encouraged by the progress in the field, the opportunity to get much better responses with less toxicity and with minimal or no use of traditional chemotherapy. So we're pleased to be able to offer these treatment approaches for our patients. And I thank you for your taking part in the podcast and hope you found it useful. Thanks again. ASCO: Thank you, Dr. Williams. Learn more about lymphoma at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play. Cancer.Net is supported by ASCO’s Conquer Cancer Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/support.

“If there is one medicine you can recommend that will take care of pain, nausea, appetite, sleep, [and] anxiety instead of writing prescriptions for five different medicines that all might interact with each other or the chemotherapy, or whatever cancer treatment the patient is getting, I think it's a useful drug." -Dr. Donald Abrams, M.D.  Dr. Donald Abrams, M.D. is an integrative oncologist at the UCSF Osher Center for Integrative Medicine, Professor of Clinical Medicine at the University of California San Francisco, and was chief of the Hematology-Oncology Division at Zuckerberg San Francisco General Hospital from 2003-2017. He became a fellow in Hematology-Oncology at the UCSF Cancer Research Institute in 1980 during the time the first cases of AIDS were being diagnosed. He was one of the original clinician/investigators to recognize many of the early AIDS-related conditions. He conducted numerous clinical trials investigating conventional as well as complementary therapies in patients with HIV including therapeutic touch, Traditional Chinese Medicine interventions, medicinal mushrooms, medical marijuana and distant healing. It was his work with these patients that brought Dr. Abrams into the world of using cannabis for medicinal purposes. Since completing a Fellowship in Integrative Medicine at the University of Arizona, Dr. Abrams has been providing Integrative Medicine consultation to people living with and beyond cancer at the UCSF Osher Center for Integrative Medicine. He co-edited the textbook Integrative Oncology with Dr. Andrew Weil, M.D. Our discussion includes: Does cannabis cure cancer? Cannabis (also known as Marijuana) key terms and historical context Pros and cons of cannabis for cancer patients and survivors Symptoms cannabis can be used for Optimal methods of consumption Is it bad for you or dangerous? Research and evidence See the show notes and links at www.cancercan.blog

Expand your consciousness around medical cannabis (aka marijuana) with expert Dr Donald Abrams, Chief of the Hematology-Oncology Division at San Francisco General Hospital and a Professor of Clinical Medicine at the University of California San Francisco. We explain the cannabinoid system, THC, CBD aka cannabidiol, limitations surrounding cannabis research, current and future medical uses for medical cannabis (marijuana), and potential conditions it may benefit. We take a deep dive on the potential harms of medical cannabis and how to counsel patients on safe use. Plus, the return past guest and new correspondent, Dr Molly Heublein, Assistant Professor of Medicine from UCSF. Thanks to Dr Molly Heublein for writing and producing this episode and it’s show notes! Full show notes available at http://thecurbsiders.com/podcast Join our mailing list and receive a PDF copy of our show notes every Monday. Rate us on iTunes, recommend a guest or topic and give feedback at thecurbsiders@gmail.com. Clinical case from Kashlak Memorial:  MM is a 62 yo woman with a history of osteoarthritis and breast cancer, now on an aromatase inhibitor. She struggles with aching and stiffness in her hands, shoulders, knees, and hips. A friend suggested she try medical marijuana. She wants her provider’s opinion on if this is safe and effective. Time Stamps 00:00 Intro 01:30 Picks of the week 03:40 Guest bio 05:11 Getting to know our guest 11:03 Clinical case 11:40 Limitations for cannabis research 12:59 Discussion of THC and cannabidiol 14:50 Smoking versus ingesting cannabis products 16:40 Recap of cannabinoid mechanism of action 18:30 Cannabis and cannabinoid products available 20:20 Synthetic THC (dronabinol) 21:46 How “recommending” cannabis and dispensaries work 25:46 Conditions that respond to medical cannabis 29:15 Potential harms of medical cannabis 34:51 Future directions of cannabinoid medicine research 37:24 Cannabis induced hyperemesis syndrome 39:00 Possible lung cancer risk 40:12 Take home points 42:54 The Curbsiders recap and share their views on the medical cannabis controversy 49:40 Outro Tags: marijuana, medical, cannabis, weed, pot, oil, budtender, law, psychoactive, thc, cbd, cannabinoids, endocannabinoid, system, receptor, substance, harm, adverse, safety, pain, nausea, emesis