ASCO Education

Get the inside scoop on major immunotherapy breakthroughs in esophageal and gastroesophageal junction (GEJ) cancers. Drs. Ronan J. Kelly (Medical Oncologist, Baylor University Medical Center) and Jacob Kettle (Pharmacist, University of Missouri) discuss recent practice-changing clinical trials, new drug approvals, and their application in practice. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: elearning.asco.org | Contact Us (Air date: 4/21/2021) TRANSCRIPT [MUSIC PLAYING] ANNOUNCER: The purpose of this podcast is to educate and inform. This is not a substitute for 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. [MUSIC PLAYING] JACOB KETTLE: Welcome to the ASCO e-learning podcast episode focusing on immunotherapy for esophageal and gastroesophageal junction cancer. My name is Dr. Jacob Kettle. I'm an oncology clinical pharmacy specialist and pharmacy manager at the University of Missouri Health Care's Fischel Cancer Center. Today, I'm joined by medical oncologist, Dr. Ronan Kelly. Dr. Kelly is the director of oncology at the Charles A. Sammons Cancer Center and the WW Caruth junior chair in immunology at Baylor University Medical Center in Dallas. We have a lot of great content to explore today, so really, some things that are truly practice-changing. But to facilitate learning, let's start with a brief patient case. SB is a 64-year-old male who initially presented to his primary care physician with a two month history of dysphagia with solids, unintentional weight loss of 25 pounds, and fatigue. Endoscopy revealed a tumor in the distant third of the esophagus and pathology confirmed an invasive moderately differentiated adenocarcinoma. Preoperative workup patient was stage II. Following chemotherapy and radiation, esophagectomy demonstrated 5 of 20 lymph nodes positive. So while we're going to focus predominantly today on the role of adjuvant therapy with immunotherapy treatments in esophageal and GE junction tumors, to truly appreciate these advancements, I think it first requires understanding the challenges of the disease state. So Dr. Kelly, would you mind summarizing the historical treatment landscape and how there's been such substantial unmet needs in this patient population? RONAN KELLY: Sure. And thank you, Dr. Kettle, and thank you to the ASCO team for the invitation to participate in this podcast today. If we look at esophageal and gastroesophageal junction cancers, there really hasn't been that many breakthroughs in recent years. We've really been relying on two major ways to treat stage II and stage III disease. And we're going to talk about operable disease for the first part of this podcast. At the present time, the standard of care had been either chemoradiation with the cross regimen, which was published by van Hagen and Allen in 2012, so almost 10 years ago now. And there has been concern about the use of low dose chemotherapy with that regimen. People have wondered about the need for really systemic doses of chemotherapy. It's very well-tolerated, but again, the concern was, are we minimizing the systemic treatments using chemoradiation? However, that really had been the favored regimen for many years. In the last couple of years, we've probably seen people moving away from low dose carboplatin/paclitaxel into more of a FOLFOX type regimen with radiation, and then having the surgery. The other way to do this is perioperative chemotherapy, which really, the current standard had been the FLOT4 regimen. This was a regimen that emerged from Germany, published in 2019, using chemotherapy for four cycles before surgery and four cycles after surgery. There is a challenge there, however. The FLOT regimen is mostly, if you look at the study design, was predominantly a gastric cancer with 44% gastric cancers, 33% GE junction. IRC were 2 and 3. And then, 23% being Siewert type 1, which is, they didn't have any esophageal patients per se in this study. But the challenge with the FLOT regimen is less than half of patients can actually complete the post-operative chemotherapy once they've had surgery. It's only 46%. And of that, you do see quite significant grade 3/4 neutropenias. Approximately half the patients get that with 18% getting grade 3/4 infections, 35% needing GCSF support. So we really needed to see if there was something we could do after chemoradiation rather than just chemotherapy alone. And so that was really the reason why we were looking to see if we could maybe introduce an immunotherapeutic strategy into that adjuvant setting. And that was the design of the CheckMate 577 study, which I know we'll talk about in a few minutes. JACOB KETTLE: Yeah, perfect. I think it definitely characterizes, as a disease state, one that is very challenging. And kind of despite our best intentions and efforts, as historically, we just-- patients inevitably relapse, at least around 50% or so. Would you say it's a fairly accurate characterization of the problem? RONAN KELLY: Yeah. If you look at the five year overall survival rates as well, we're really-- what we know is that if you have a pathologic complete response to chemoradiation, you really can do quite well. The five year overall survival is the order of approximately 50%. But if you're not in that, and the majority of patients are not in that, 70% to 75% of our patients do not achieve a pathologic complete response to neoadjuvant chemoradiation. And we have known that those patients do poorly. The problem is, we haven't really had any large prospective randomized phase III studies. Also, we haven't had a global study to show us how poorly those patients do. And so the CheckMate 577 study was probably the first one, truly a global study done all around the world, which was able to enroll different patients, different histologies, different racial backgrounds, to really help answer that question. JACOB KETTLE: Perfect. So I think one of the most fascinating things in oncology practice, really, across the board, is to watch how checkpoint inhibitors have really transformed the landscape of so many different tumor types. And we've seen this migration where these drugs presented first in the second, third latter line metastatic space, and migrated to first line metastatic space. And now we're starting in several disease states to see them to move into the adjuvant therapy. And that, as Dr. Kelly has already alluded to, is kind of the principle behind CheckMate 577. It's looking at-- it's really one of the first large randomized control phase III trials to explore neoadjuvant immunotherapy in the setting of esophageal and gastroesophageal cancer. So Dr. Kelly, if you wouldn't mind, spend a little more time summarizing the trial design in the patient population and CheckMate 577. RONAN KELLY: As you know, we have seven checkpoint inhibitors approved in the metastatic setting for multiple different cancers. But as you mentioned, now they're starting to move into earlier stage diseases. The only approval right now for a solid tumor in the adjuvant setting is in melanoma. We have seen positive studies there with nivolumab and pembrolizumab in CheckMate 238 and KEYNOTE 054. But that's when standing alone on its own. We've known melanoma as kind of an outlier, if you will, exquisitely responsive to checkpoint inhibition. So then, along came this, gastroesophageal junction study, the CheckMate 577. Really, in my mind, breaking the mold, almost introducing a new era because we've now seen positive results in another adjuvant setting. So I said it was a global phase III randomized double blind placebo-controlled trial. Patients were eligible if they had stage II or III esophageal cancer or gastroesophageal junction cancer, did not enroll gastric cancer patients on this study. They could either have adenocarcinoma or squamous cell carcinoma. All patients had to have that neoadjuvant chemoradiation followed by surgery. They couldn't be treated with just chemotherapy alone. They had to have the chemoradiation. And they had to have an R0 resection. And then once they recovered from their surgery, we gave them a window from 4 to 16 weeks to recover. Remember, an esophagectomy is a very large oncologic procedure to have to recover from. So many patients did need that 12 weeks upwards to recover from having their esophagus removed. Every patient had to have residual pathologic disease. So they had to have greater than YPT1 1 or greater than YPN1. So we excluded those patients, the 20% to 25% that have a really great response to chemoradiation. So we took out all the patients with, if you will, the best biology in terms of the great responders to chemo/rads. And we took the really poor responders, the other 70% to 75%, and said, what can we do in those patients who haven't achieved a path CR. Can we help them rather than just watch and see when their tumor occurs? And so that was the design of the study. We randomized, in a 2 to 1 manner, 794 patients with 532 getting nivolumab, 262 getting placebo, which is the current standard of care because there was no role for additional treatment at that time. And the primary endpoint that we've presented so far was disease-free survival. The secondary endpoint is overall survival. We don't have that data yet. It's ongoing. But we presented median follow-up data at ESMO in 2020 at the plenary session. We presented this data. And the median follow-up was 24.4 months. And so that was really the design of the study. As I said, geographical regions that enrolled, we had 38% from Europe, 32% from US and Canada, 13% Asia, and 16% rest of the world. And if you look at the practice-changing studies that have really driven our current standards of care, they've all emerged from single countries like the UK or Holland or Germany or Japan. We haven't really had a global study like CheckMate 577 at this early stage operable disease study, which I believe has changed the practice of care. JACOB KETTLE: So I think actually, too, as a pharmacist, one of the things that I thought was unique about the trial design was the nivolumab dosing schedule, 240 milligrams every two weeks for 16 weeks, or eight total treatments, and then 480 milligrams every four weeks for up to a year. And I think this is the first time, at least that I'm aware of, we've seen kind of an explicitly described induction-type maintenance plan with nivolumab. And I think, kind of been urging our practice to do something similar to this for some time. So it was kind of exciting to see it prescribed out in that fashion. Because it really fits with the adverse effect and monitoring profile of these drugs. You kind of, in that first 16 week period where the colitis, hepatitis type effects are more common, you're seeing the patient more often. You have more frequent therapies. And then you kind of draw things out when they cross that threshold. So I thought that was one thing. Again, with my background in pharmacy, I thought that was unique about the trial design. That was specific. So I know everyone's waiting to hear it. What were the key outcomes from this study? RONAN KELLY: Well, if you look at the patients that we enroll, as I said, it was a 2 to 1 randomization. In terms of the tumor location, 60% for esophageal cancer, 40% for gastroesophageal junction cancer. In terms of histology, the breakdown, because again, certainly, in Europe and in Asia, adenocarcinoma is the more common subtype than squamous. We saw 71% of patients had adenocarcinoma. We had 29% having squamous cell. And then the disease stage was 66% had the more advanced stage III disease at the start, 34 had stage II. And then, so if you look at the overall tolerance, the treatment was really well-tolerated. And we may come to that. But 89% of the patients received a dose intensity of greater than 90%, which really is great for an adjuvant study. But if you look at the primary endpoint, which was the disease-free survival, we doubled the disease-free survival from the placebo arm to the nivolumab arm. The median disease-free survival was 11 months in the placebo arm and 22.4 months in the nivolumab arm. This had a hazard ratio of 0.69, p-value of 0.0003. So overall, nivolumab provided a 31% reduction in the risk of recurrence or death, and as I said, a doubling in the median disease-free survival. And if you look at the Kaplan-Meier curves, there's clear separation of the curves. And you can see how poorly those patients who were just being observed to 11 months with disease-free survival. And we know, unfortunately, disease-free survival is a pretty good surrogate for overall survival in this setting. So, you know, I think, I hope that the days of just watching someone who has gotten lymph node positive disease on surgical pathology report may be coming to an end, I hope. JACOB KETTLE: Yeah, I think we'll all be anxiously waiting on the overall survival data to mature. But this is remarkable, that degree of an improvement in this population that, as you've said, really, we desperately needed to find new avenues to serve them and improve their outcomes. That's outstanding. I know the data is early and I'm curious if you have any indications of impact of histology or biomarkers. Or do you feel like the benefit's going to be fairly universal? Or maybe it's too soon to tell. RONAN KELLY: No. So in the data that we present, everyone was actually expecting squamous cell to do much better because we just know squamous histology is doing better with esophageal and esophagogastric cancers. If you look here, we did see a benefit from squamous over adenocarcinoma. But the median disease-free survival in adenocarcinoma group versus placebo was 19.4 months versus 11.1% months. That was a hazard ratio of 0.75. If you look at the squamous cell histology, yes, it was better. It was 29.7 months versus 11 months. And that had a hazard ratio of 0.61. But we were very excited to see that benefit in the adenocarcinoma setting because we see that really shows proof that there's efficacy there. We didn't see any major difference in terms of lymph node status. We saw some, if you were greater than YPN1, we saw hazard ratio of 0.67. We measure tumor cell PD-L1 expression, and that's all we've been able to report so far. We did not see tumor cell PD-L1 expression greater than 1% having an impact. What I will say is Dr. Kettle, the manuscript is hopefully coming out soon. And we were asked to do post-hoc analysis looking at CPS. So that data will be in the manuscript. JACOB KETTLE: Yeah. That's outstanding and exciting, for sure. Nonetheless, this is more therapy. And you are going to be exposing patients to more potential to adverse events. Are there any patients who you would not consider a candidate for this treatment? RONAN KELLY: Dr. Kettle, if we just look at the treatment-related adverse events with potential immunologic etiology, because that's really the one you're trying to see is the nivolumab causing some immune adverse events, really didn't see that many. The majority of TRAs were grade 1 or grade 2. Those that were grade 3 or 4 occurred in less than 1% of patients in the nivolumab arm. And there was no grade 5 treatment-related immunologic adverse events. And as I said, we were worried at the start-- not worried, but we were concerned, would we see pneumonitis? Because, as you remember, we've given chemoradiation to these patients. And we haven't really had any data when we were designing this study on how effective PD-1 inhibitors would be in early stage diseases. So it was very gratifying to see that very low incidence of pneumonitis. If you compare it to the placebo arm, we saw 0.8% pneumonitis in the treatment arm, and 0.4% in the placebo arm, so very good. And then, if you look at the tolerability of the quality of life data, really, measured by all of the patient reported outcomes that we use, we saw very similar overall health status between the nivolumab and placebo arm. Is there anyone you wouldn't give this to? Well, of course, the usual patients that are contraindicated for a checkpoint inhibitor, like severe autoimmune disease. Patients who would not be eligible for this are patients who haven't had the standard design, like I told you about. This was post-chemoradiation. So we don't have data yet if you just give perioperative chemotherapy and don't use radiation. We're waiting on one of those studies. That's KEYNOTE 585, to answer that question. So we can't just start using this for all patients with early stage disease, just those patients who got chemoradiation followed by surgery and if they haven't had a complete pathologic response. It's already actually made its way into the NCCN guidelines. So I know that happened in December of 2020. So doctors in the US have started taking this up. It was given category 1 evidence by the committee, so I know a lot of people around the country are already using this as their new standard. JACOB KETTLE: Yeah. I'm actually really glad you brought up the quality of life data. Because I think, to me, as we start having more treatment options available, I think it becomes increasingly important that we, as clinicians, remain sensitive to patient values and what they experience. And seeing that quality of life data, which was, I think I saw it was published online in January in JCO. But really shows that very equivalent addition of nivolumab to these patients did not diminish their health-related quality of life compared to placebo. And I think that really highlights the fact that we've got a very positive risk-to-benefit ratio with this therapy. And I think it just underscores what a remarkable improvement this is to add to our arsenal for patient care. I do want to circle back briefly, then, to our patient case. So Dr. Kelly, in your opinion, what would be the best therapy, the optimum treatment for that hypothetical patient we discussed moments ago? RONAN KELLY: So assuming there's no contraindications to a PD-1 inhibitor, then in my opinion, the new standard of care is someone who has lymph node positive disease like you mentioned would be. Rather than just watching them with close observation, it would be adjuvant nivolumab for a year. Now as I said, not everyone made it through the whole year. But 89% of patients had greater than 90% of the dose intensity. So it shows that it's well-tolerated. When is the optimal time to start? Again, what we looked at-- and this data may come out in our manuscript. We looked at less than 10 weeks after surgery versus greater than 10 weeks. So we'll see that in the manuscript. But I think people can really start whenever the patient feels like they've regained their strength after their oncologic operation. JACOB KETTLE: Excellent, so I think that's going to summarize where we wanted to talk about for adjuvant care. I think, let's move forward and talk just briefly about in the metastatic setting, and kind of the role of immunotherapy there. So I'm going to present another hypothetical patient case. That one is CJ. This is a 61-year-old female with a previous history of gastroesophageal junction cancer, for which she completed trial modality therapy approximately two years ago. No previous treatment with immunotherapy for that. On follow-up, she notes recurrence of progressive dysphagia. The CT revealed a mass in the gastroesophageal wall, liver, and adrenal gland. These were all confirmed via biopsy to be recurrence of the original squamous cell cancer. Her combined positive score was 15. Her ECOG performance status currently is zero. And so, again, as we start to see these new options as you said, likely established a new standard of care in the adjuvant setting, the reality is, we're going to continue to see patients in the metastatic setting, whether it be those diagnosed before the availability of checkpoint inhibitors in that space, or those who were just diagnosed in later stage disease. So I think it's worth discussing. Amidst all the other options we have, what's the role, Dr. Kelly, at least, the current state for immunotherapy in those with relapsed or metastatic disease? RONAN KELLY: Yeah, it's a great question. Thank you. I think 2020 will go down as an amazing year for esophageal and gastric cancer because we saw so many phase III studies being presented towards the latter part of the year, which I think everyone has accepted they've changed practice. They all came out at the same time. As you know, we had a plenary session at this year's ESMO, specifically just all around gastric and esophageal cancer, which never happened before. But at that meeting, in addition to CheckMate 577, which we've spoken about, we saw two additional ones that I believe in the metastatic setting have changed practice. We saw CheckMate 649, which is nivolumab plus chemotherapy, which really broke the barrier for that one year overall survival in the metastatic setting. If you look at the primary endpoint of that study was overall survival in patients with CPS, PD-L1 expression greater than 5. And the endpoint there was 14.4 months for the novel treatment arm versus 11.1% months for the standard chemotherapy arm, hazard ratio of 0.71. So really, a groundbreaking result because we've been struggling to break through that 12 month overall survival barrier. And that also has now been put into the NCCN guidelines as of December as well, 2020. So I think that was given category 1 evidence also. And we're waiting for FDA approval for all of these things. We hope that that will come in the middle part of the year. But the NCCN has kind of already put them into the practice guidelines. And then the other one in my mind, which changed practices, Dr. Kettle, is KEYNOTE 590. This was involving pembrolizumab plus cisplatin 5FU. It was more of an esophageal rather than a gastric study. And here, again, they looked at chemotherapy versus chemotherapy plus pembrolizumab. And we saw, again, if you look at the CPS greater than 10 population, 13.5 months versus 9.4 months, hazard ratio there is 0.62. If you look at just all patients rather than selecting by CPS, the overall survival rate was 12.4 months versus 9.8 months, hazard ratio 0.73. So I know you're going to talk a little bit about the role of these biomarkers and selecting patient according to CPS. But we're beginning to see that in these studies now. It's getting quite complicated, I would say. Let's wait for the FDA approval. Let's see what the FDA say if they put some stringent guidelines around what the CPS cutoff should be for those metastatic studies. But I would love to hear your opinion on where you see that going. JACOB KETTLE: Yeah. I think you said it. The role of biomarkers is, by far, going to be the most complex piece of this whole puzzle moving forward. And I think a lot of this won't translate very well via audio. But one great example is our studies with single agent pembrolizumab in the second line setting. The current guidelines suggest a CPS score greater than 10 to be able to use pembrolizumab in that space versus a CPS score greater than just 1 for third line or subsequent settings. And there's all kinds of other little caveats out there with different agents and nivolumab versus pembrolizumab, and whether we're combining them with other treatments or using single agent. Then, of course, we have tumor mutation burden, microsatellite instability all in this mix. And I think what's challenging, truly, is for clinicians like myself, I don't really have a very strong background in a lot of this immunology. So it's tough to wrap your head around how to apply these things and operationalize it into your patient care when it seems like there's new guidance and differences and things like that. I don't know that I'm versed enough to have a really strong opinion over which biomarker is preferential. So I actually was curious for you, Dr. Kelly. Where do you gravitate towards and where do you see-- what biomarkers do you see shaking out in the future? RONAN KELLY: Yeah. You know, it's really fascinating. I think we look at this as a very exciting time, probably, some of the most exciting time we've ever had in gastroesophageal and gastric cancer. Because we're now seeing real movement, right? We're seeing tremendous benefits moving forward. But we still have a long way to go where we cannot rest on our laurels here. But if you were to say, what are the biomarkers that people would check in 2021 when someone walks in the door in their clinic? Obviously, PD-L1 status should be done reflexly. We believe CPS score is a better way to do that. So the pathologists are getting used to doing CPS score and giving us the breakdown, whether it's greater than 1%, greater than 5%, greater than 10%. In addition to that, microsatellite instability mismatch repair deficiency should be checked, especially in gastric gastroesophageal junction. Because you don't want to miss that if that is there, because those patients can have, really, a dramatic response. And the FDA approval there is around pembrolizumab. And then we've also seen an approval for TMB high, or tumor mutation burden high greater than 10 mutations per megabase again for pembrolizumab. So that can be something doctors can keep in their armamentarium if they're checking for TMB. And so that's really where we are. HER2 status is always present, of course. We've seen some really nice breakthroughs this year in the HER2 story with trastuzumab/deruxtecan being approved in the second line setting for those patients who are HER2 positive. So it's been a great year, absolutely. I know it's complicated with all the different CPS, but we're working on hopefully creating easy-to-use guidelines for doctors, community doctors, so they can quickly lock it up and see. And as I said, we're waiting on FDA approval, wait on FDA guidelines and how they're going to look at the CPS story. JACOB KETTLE: Well, I think one of the most challenging things to grasp, especially with CPS, is that we're kind of used to biomarkers elsewhere in oncology, lung cancer, breast cancer, those kind of things where it's kind of a yes or no question. It's either present or it's not present. And that's radically different here when we talk about PD-L1 status, or CPS, or however you want to define it. Because it's the degrees of scale. And it seems to be different in all kinds of different malignancies. And I think that that really tends to be one of the harder pieces to grasp as we kind of really get immersed in this immunotherapy space. RONAN KELLY: Yeah, I would just comment on that. It's a real concern of a lot of people, I think. Because I think the academic doctors, obviously, who have a lot of time to follow the literature and involved in the studies, they'll be more well-versed in the different CPS cutoffs. But the community doctors who are so busy and treating multiple different tumor types, it's not going to be easy for them to keep up. So I think we're going to have to do a good job in helping them. And whether that's via pathway-directed treatments where the pathway may have to cut off so they can see that, I think that may be the easier way, rather than try to remember it all. It's going to be too complicated to remember. JACOB KETTLE: So with all that in mind, let's revisit that metastatic case. Where would you land for treatment with this patient? RONAN KELLY: Yeah. So as I said, it looks like this is a squamous cell esophageal. In the NCCN guidelines, we have the KEYNOTE 590 study, which was for esophageal cancer. And so that would be pembrolizumab. Again, we'll wait to see if there is an FDA guideline around what the CPS score may be. And if the question had been gastric or gastroesophageal junction adenocarcinoma, then I think CheckMate 649 would be the new standard of care, which is chemotherapy, so FOLFOX plus nivolumab. So just depends on whether it's an esophageal or whether it's a gastric GE junction, depending on which of those checkpoint inhibitors we'll see of people using. JACOB KETTLE: I think it's daunting, as complicated as these things are turning out to get. But I think from a patient perspective, it is really exciting to see when you venture out into these complexities, it means you're developing newer and better treatment options and more complex ways and more sophisticated ways of delivering care. So I really appreciate your insight on all those issues. I think, let's just close up by talking about where do we see things continuing to evolve, particularly in the area of immunotherapy, but maybe even in a broader sense, in esophageal and GE junction tumors moving forward? RONAN KELLY: There was a whole host of studies. Obviously, we won't go through them all in metastatic first line setting, second line setting. If we just take it in terms of the only study that's shown positive results in the adjuvant setting is CheckMate 577, I mentioned, there is another one we should see soon. But that's not with chemoradiation, it's with chemotherapy alone. So it's perioperative chemo plus pembrolizumab. That's KEYNOTE 585. So let's see. Let's see if there is a benefit using that approach. We cannot just assume that'll be positive. We've seen other studies negative in this space. So we'll have to wait and see what KEYNOTE 585 shows. If you look at some of the other studies in the US, ECOG-ACRIN have a study which is not too dissimilar from CheckMate 577, but they're giving nivolumab in the neoadjuvant setting when you're giving chemoradiation. And then, instead of doing nivolumab alone in the adjuvant setting after your operation, they're doing nivolumab plus or minus ipilimumab. So let's see if there's a benefit. Or, will there be more toxicities? Maybe patients won't be able to tolerate that. So we'll have to see. And then there's another one I'll just briefly mention. For those patients who are not eligible for surgery but, say, have locally advanced gastroesophageal junction cancer at GE junction who can't go for surgery, there is a definitive chemoradiation study with pembro, which is KEYNOTE 975. So there's a-- I know we have a whole host of other different IO-IL combinations emerging. We'll have to wait and see how those pan out in the future. JACOB KETTLE: Yeah, I don't think there's going to be any shortage of new content to stay familiar with, which again, exciting for patients. RONAN KELLY: But really, a tremendous year. If you look back, so just to summarize, if I could for the listeners, we've gone from really just relying on chemoradiation in early stage, stage II and III esophageal/gastroesophageal junction cancer, to now chemoradiation followed by surgery. And now, if you don't have a great response, you can get adjuvant nivolumab for a year. I think it's a major step forward. We showed a doubling in the disease-free survival from 11 months to 22.4 months. And we'll wait to see what the overall survival will show. Hopefully, that'll be available in the next year or so. But we have to just wait and see. And then, in the first line metastatic setting, I think CheckMate 649, KEYNOTE 590, very big breakthroughs this year. In the HER2 positive setting in the second line, we saw trastuzumab/deruxtecan emerge. So there's four major practice-changing studies that have just come in the last six to seven or eight months. Amazing, really, for our field. And we've got a lot more to come. We saw gastroesophageal, squamous cell have two approvals in the last year with nivo and pembro both approved. And then, as you very well pointed out, the TMB and the MSI status is also-- patients are eligible for checkpoints. So very major advances just in a very short period of time, I think. JACOB KETTLE: It's inspiring, frankly, to see all this innovation in a way that innovation that directly impacts patient care and quality of life and outcomes, and all that part of our mission. Again, it's inspiring. I truly thank you for your time today sharing your insights and expertise, and hope the same as for our listeners. Thank you all for joining. RONAN KELLY: Thank you for the invitation. Thank you very much. [MUSIC PLAYING] ANNOUNCER: Thank you for listening to this week's episode of the ASCO e-learning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

How has Covid-19 has affected cancer care? Listen to the experts discuss postponing and modifying cancer treatment during a pandemic. Moderated by Dr. Helen Chew, featuring Drs. Mary-Beth Percival, Oliver Eng, and Toni Choueiri. We hope you enjoy this episode of the ASCO eLearning Podcast. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: elearning.asco.org | Contact Us (Airdate: 4/8/2021) TRANSCRIPT [MUSIC PLAYING] SPEAKER 1: The purpose of this podcast is to educate and inform. This is not a substitute for 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. DR. HELEN CHEW: Hello and welcome to ASCO's podcast episode focused on cancer therapy modifications during the COVID-19 pandemic. My name is Dr. Helen Chew, and I'm a medical oncologist and fellowship program director at the UC Davis Comprehensive Cancer Center. I am pleased to introduce our four guest speakers today. Dr. Toni Choueiri is a medical oncologist specializing in genitourinary cancers from Dana-Farber Cancer Institute. Dr. Choueiri is also director of the Lank Center for Genitourinary Oncology and the Kidney Cancer Center and a Professor of Medicine at Harvard Medical School. We are also joined by Dr. Mary Elizabeth Percival from Seattle Cancer Care Alliance. Dr. Percival is a hematologist oncologist specializing in AML and myelodysplastic syndrome. She's also serving as an Assistant Professor of Medicine at the University of Washington and Fred Hutchinson Cancer Research Center. Our next guest speaker today is Dr. Oliver Eng, a surgical oncologist and Assistant Professor of Surgery at the University of Chicago. Dr. Eng focuses on treatment of cancers of the abdomen. And finally, we are also joined by Dr. Jennifer Sheng, a medical oncologist and Assistant Professor of Medicine at Johns Hopkins University. Dr. Sheng primarily treats patients with breast cancer. Many oncologists around the world have been struggling with providing quality care during the pandemic. We are excited to launch a discussion of experiences at different institutions, guidance, and lessons learned that our listeners may apply in their own practice. Starting with you, Dr. Choueiri, can you tell us about the International Survey of Oncologists you and your colleagues conducted in 2020 about the impact of the pandemic on decision making? DR. TONI CHOUEIRI: Oh thank you, Dr. Chew. And I want to really thank ASCO for always being at the forefront here of educating the oncology community about the latest here, and we're all in this pandemic. And I remember where everything started, and we were just getting ready to see what we could do to protect our patient, our health care worker, with this novel coronavirus. So one thing we've done as a group we started an online survey between March and April for a month. And that involved around 340 plus oncologists from 28 countries to understand what is the readiness measure taken by oncologists to protect patient and health care workers here? We really had no idea. We found first that the pandemic, really every country had an outbreak over 99%. PPEs were over 90% provided, and the telemedicine started early on. Around 80% of folks did telemedicine. We also saw that we did not have any routine testing for oncology patients. Only 3% performed systematic testing in all patients. Then when we asked the oncologists, knowing we had no data, what do they think about systemic therapy? The vast majority thought that systemic therapy here you have to consider comorbidities and age. They also felt that hormonal treatment and tyrosine kinase inhibitors were relatively safe. On the other hand, cytotoxic chemotherapy and immune therapies potentially are not safe. Now we know for the future, when future studies done as part of CCC19 database and other, that there was no increase in mortality with immune checkpoint inhibitor, neither with cytotoxic chemotherapy in large part except perhaps if you consider the timing. And finally one of the thing the survey showed that oncologists were still focused on neoadjuvant adjuvant first line metastatic disease, but they were kind of hesitant, more hesitant to recommend later line therapy in metastatic disease. So no doubt decision making by oncologists has been influenced by the ongoing COVID pandemic at that time. That was a year ago at the start. DR. HELEN CHEW: That's really interesting. Did you find any of those results surprising? DR. TONI CHOUEIRI: Well I would say, I would say no. But a lot of folks have their own biases overall. I do find that in a way that there are, for example, chemotherapy, and second, third line that extended survival and quality of life, folks seem to be hesitant. I didn't find it surprising we didn't have testing that folks-- patient didn't get testing much. I was a bit surprised that telemedicine immediately made it, and it was around 80%. But that also included phone encounters. But this was overall a very large survey, and the median age of the oncologist were around early 40s. DR. HELEN CHEW: Finally, can I ask you did you notice any regional differences since these were international survey? DR. TONI CHOUEIRI: Yeah, absolutely. I mean in Europe there were from Italy and from France, at that time, things were obviously worse. There were some differences. That's a very good question depending where you are. And some of it folks did not experience, but they had the next door, if you want, experience more so than their own experience. DR. HELEN CHEW: Thank you. Doctors Percival and Sheng, how has the COVID-19 pandemic impacted delivery of cancer therapy at your practice? What have been the major challenges in delivering quality patient care during the pandemic? DR. MARY-BETH PERCIVAL: This is Mary-Beth Percival Yeah. So I would say that we didn't exactly conduct a survey, but instead my colleagues and I who care for patients hemalignancies at the University of Washington and the Fred Hutchinson Cancer Research Center got together and said, what evidence based guidelines can we come up with that may help to guide the care of patients, particularly those with hemalignancies? As many of you are aware, the first patient in the US who was diagnosed with COVID-19 was from the Seattle area. So we kind of had a sneak peek into the pandemic before it officially became a pandemic. We've been relatively spared compared to some other areas, but certainly our patients with hemalignancies are at an increased risk of complications. So I think that there were a number of changes that happened pretty quickly, and Dr. Choueiri spoke about some of these, like the increased use of telehealth when feasible was very rapidly taken on by both patients and providers. And we thought that that was a really important way to really reduce the number of touches that our patients had because they tend to require a lot of visits and a lot of care. And so if we can eliminate any of those we thought that that would be important. We pretty quickly instituted screening for patients and providers on the entrance to the cancer center and were able to provide masks and rapid COVID testing, which is something that's still going on now and also really increased over time that asymptomatic COVID testing prior to procedures, and surgeries, and scheduled hospitalizations, prior to chemotherapy when possible, doing things like double testing when patients are admitted for a neutropenic fever in the setting of a hemalignancy because its sensitivity with the second test may improve for patients that are on, for example, the transplant service. They get weekly testing even when asymptomatic with the thought that they're at such high risk of complications given their immunosuppression that really knowing about that, and monitoring that, and also for the safety of patients and providers around them that it's important to do that. I think another shift that really happened in our cancer center was trying to focus on outpatient regimens when that was possible. We weren't really sure what the hospital capacity constraints would be like when the coronavirus pandemic initially hit, and so making sure that that was going to be possible. And for a while we had really stringent transfusion thresholds for our patients who are transfusion dependent. So we lowered some of the hemoglobin and hematocrit goals to really be able to make sure that there was going to be enough supply given the decreased donor availability. And then I think the final thing that was something that I think really pretty quickly impacted the delivery of cancer care at our site was to have, and I think this is important for oncologists all the time and so sometimes we need a reminder, but having early discussion about goals of care. And I think that it was pretty evident from some of the initial data that came out for patients from China and elsewhere where the pandemic first hit that patients with a history of malignancy or active malignancy, and this has been confirmed by subsequent retrospective studies, had really significantly worse outcomes when they were impacted by the virus. And so I think that that was really important for us to think about in talking to our patients about what they would want, especially when resources might be limited. DR. JENNIFER SHENG: So similar to Dr. Percival, our group at Johns Hopkins decided to gather the entire group of breast medical oncologists as well as a few select surgical oncologists, radiation oncologists, and patient advocates to help us create guidelines for the management of breast cancer during the COVID-19 pandemic. And our hope from doing this was to create a stage and subtype specific approach to help guide others in their decision making process. Ultimately, similar to Dr. Percival, I think it's important to remember that cancer care is very individualized, and so of course, we did factor in things such as age as well as comorbidities. And we did try to make visits less frequent when possible. And we ultimately relied pretty heavily on electronic means of communication, phone calls, video visits, and messaging through the electronic medical record. There are other changes that we made during this time. So for instance, we tried to minimize the use of steroids in order to reduce immunosuppression whenever possible, and as a result of doing that we more heavily relied on medications such as olanzapine or other antiemetic regimens. Additionally, we used prophylactic growth factors more frequently to reduce the risk of neutropenic fever. We also tried to be mindful of patients and having to go to the pharmacy to pick up a lot of the medicines, and we would prescribe 90 day supplies instead of 30 day supplies. And we would try to anticipate this well in advance so that patients could opt for mail order or pharmacy delivery services during this time. For breast cancer specific patients that were on ovarian function suppression we were actually able to work with the insurance companies to allow a monthly self injection at home so they wouldn't have to come to the clinic every four weeks. And additionally, we really thought about looking at people who are clinically stable and seeing if we could push out some of their imaging. So for instance, echocardiograms which may be done every, let's say three months, sometimes we'd stretch out to four months if they were clinically stable and didn't have any cardiac issues. Other imaging, such as a bone density scan, sometimes we would defer that depending on the situation. And similarly some of those antiresorptive or bone agents that we use in the adjuvant and metastatic setting sometimes we would try to see if we could defer that that timing. And ultimately I think that we tried to just be really vigilant about how patients were feeling, and we would implement screening calls the day before their visit, inquire about any potential COVID-19 symptoms, and then we would actually screen them for COVID-19 symptoms again on the day of their visit. So overall I think we tried to implement as broadly as possible very safe measures for all of our patients and our staff. DR. HELEN CHEW: Thank you and follow up to that, either Dr. Percival or Sheng, did you encounter any resistance to some of these changes that you made? DR. MARY-BETH PERCIVAL: I can comment first. I actually think that there was not a lot of resistance. I think perhaps initially that was because of fear. A lot of patients were really nervous about congregating in any kind of public space even if they realized that we're always weighing the risks and benefits, and that we felt that if we were asking them to come in that the benefit of being seen in person was actually going to be there. But I think it also speaks to the fact that now later, when sometimes patients don't want to come in when we do think it's actually a lot safer and there hasn't been a lot of transmission in outpatient hospital or clinic settings, I think that now patients are getting very used to telehealth. And in a lot of ways I think that's great, but it's going to be interesting to see what the ramifications are from insurance reimbursement when some of the emergency policies that have been put in place by first the Trump administration, now the Biden administration expire. So I don't know. It's going to be a hard roll back if we are not able to offer telehealth to the same degree to our patients, especially when I'm for example, at an academic medical center with a really large catchment area. Two weeks ago I was on the phone or telehealth with somebody who is in Fairbanks, Alaska, 1,500 miles away so. DR. JENNIFER SHENG: Certainly, I agree with that sentiment that we had a wide range of responses. And I think when it was ever with regards to perhaps delaying imaging or delaying treatment there was a lot of anxiety, but if it was, for instance, let's convert to a video visit, I think that probably three quarters of my patients are really enthusiastic about not having to drive to clinics, being able to do this call with me while sitting on their sofa, being able to be next to their significant other or family member was really important because unfortunately in our clinic, even now, we actually don't really allow any visitors with the patient. And I think having that family member or friend, there is so critical. So I think that there was mixed responses overall. DR. HELEN CHEW: And follow up to that, Doctors Eng and Percival, can you discuss the adjustments to care you have made in response to the COVID-19 pandemic? What major factors played to your decision to modify care? DR. OLIVER ENG: Sure. So thanks again to ASCO for the invitation to participate in this panel. And so I think from a surgical perspective, it definitely offers some different challenges that are complementary to the challenges that we've discussed already. And so I think when the pandemic arrived and we were just going through the initial stages, there was a lot of uncertainty with the impact of the pandemic itself and surgical patients. And certainly the earlier literature that came out demonstrated high morbidity in patients with cancer who underwent surgery. And so it sort of generated a lot of sort of downstream thoughts about how do we approach surgical cancer care during this pandemic, and how do we navigate this? And I would say initially, when COVID first arrived, we essentially stopped surgeries, elective surgeries, for some time. And I think that was what was done at many centers as well because we just did not know the consequence of these things. And so a lot of what I wrote about initially when this was happening was that typically surgeries are thought of as being dichotomized between elective and emergent or urgent procedures, but as you know, cancer care falls somewhere in between in most instances. And so I think it's a little bit simplistic to think about it in this dichotomous way. And so one of the aspects that we talk about was cancer timing and sort of prioritizing surgical cancer cases during this time of not only just postponement but backlog of cases once cases were resumed. And so I think this is kind of a joke, but a lot of us who do surgery were sort of sidelined during this period so then we all just started writing at University of Chicago. And so a lot of us were putting out papers regarding this. And so one of my colleagues, Dr. Kiran Turaga, put out a paper which discussed what was called a safe postponement period of surgery which looked at the fact that the typical time period between when systemic therapy was received, and in what surgery was performed, and is there safe window after that or sort of within that several weeks where we can actually perform surgery and not have a inferior outcome? Again this is just retrospective, it gives us some idea of how to prioritize surgery and that paradigm. But also it's a complex decision making process, not just the surgery itself, but the institutional resources required for hospitalizations after surgery, the staff that are involved. And not only just staff but trainees as well, and making sure they're compliant with [INAUDIBLE] making sure they're safe, first and foremost, during this whole process. And then working COVID testing into this whole algorithm itself was challenging, to say the least. DR. HELEN CHEW: Thank you. Dr. Percival, do you want to add anything in addition? DR. MARY-BETH PERCIVAL: Sure. I think that it's interesting to hear about things from the surgical perspective. It's not something that plays into the care of my patients with hemalignancies, particularly AML, as much as for other specialties, but it's certainly interesting to hear about that. So I think AML is typically a disease that we approach with curative intent, and induction chemotherapy, which is kind of the mainstay of initial treatment, is generally started on an urgent, sometimes emergent, but more of an urgent basis. And so I think we and colleagues were really trying to figure out what would be supported by the literature when we put together recommendations that were published in the Journal of Oncology Practice. So we have done some trials at our institution, one for what we call early hospital discharge. So instead of keeping patients in the hospital for an entire month, we usually discharge them after receipt of induction chemotherapy to get close outpatient follow up. And so we suggested that that might be something if other centers were equipped to be able to provide the necessary supportive care as an outpatient to consider to decrease hospital utilization, especially in the setting of hospitals being overwhelmed by COVID patients. We also had a pilot study that was done also out of our center for outpatient induction chemotherapy. So maybe patients could be completely outpatient to receive their chemotherapy, which is not generally how we think about things for AML patients. But there is some supporting literature to suggest that that might be possible. So for example, moving to diffuse large B cell lymphoma, for example, there are some regimens where older patients receive abbreviated chemotherapy and consolidated radiation therapy. So looking at things like that that are reasonable alternatives with evidence behind them was really kind of what we wanted to do to disseminate recommendations and try to be as specific as possible. I would say one thing that I think is probably going to be talked about on another ASCO podcast but that has come up a lot at our academic medical center is clinical trial enrollment. And so similar to surgeries being cut off completely for a while, clinical trial enrollment was slowed almost to a halt because basically all phase I and phase III trials were closed. Phase II trials were felt, in a lot of cases it was taken on a trial by trial basis, but felt to offer opportunities for patients that they wouldn't be able to achieve in other ways. And I think that there are going to be a lot of long term downstream effects from that clinical trial enrollment stuff that we are yet to see, and I think particularly for patients with relapsed/refractory disease and that kind of thing, that's going to be something that really comes up in the future. And I think also in terms of things like referrals to our center that some of that may decrease as well if we are not able to offer clinical trials to the same extent in the future. So I think there are just a lot of things that come up when we're caring for patients and modifying therapy for patients. And I think there's going to be a lot that will come out in the future, even though we're moving more towards whatever our new normal is going to be like and having more access to trials and other more standard procedures these days. DR. HELEN CHEW: Thank you both. Doctors Eng and Sheng, what guidelines or protocols have you relied on to make decisions on therapy adjustments since the start of the pandemic? DR. OLIVER ENG: Great. Thanks for that question. So in the realm of surgery, we actually, my colleagues at the University of Chicago actually, put out a paper which we, again, like I mentioned, the dichotomization of elective versus non-elective procedures was a bit simplistic. And so we actually devised a scoring system here at University of Chicago. We termed it medically necessary time-sensitive procedures. And so it took into account the procedure itself, the disease, and patient factors. And we were all required to submit a score for each patient we were proposing to do surgery on during this period. And basically, procedures were selected in conjunction with the actual score the patient was assigned, because it was felt to be attributable to appropriate risk within the context of the pandemic. And so at least at an institutional level, we utilize this not only during the first wave but the second wave as well, and it seemed to be able to triage patients appropriately based on all these aspects. But of course, like we have discussed, cancer care is individualized. And so it is still difficult to try and put a number to a patient, for sure. But we did certainly consider each patient individually with all aspects of their care. I think from a regional perspective, in the state of Illinois we've come together and formed the Illinois Cancer Collaborative which has developed COVID-19 guidelines as well throughout the state which has been a nice collaboration amongst a lot of the hospitals and distributed amongst the communities. And certainly societal, national recommendations have been put forth as well. The Society of Surgical Oncology has put forth guidelines for multiple disease sites, and so that's been the consensus recommendation from leaders of our society. I think just to give a little perspective, my specialty is primarily in peritoneal malignancies and metastatic malignancies, and so certainly patients who are undergoing cytoreductive surgery for a low grade disease, for example, was postponed for some time. And patients with higher grade disease were kept on systemic therapy for longer, and then certainly when they're within that window for operations, sort of recommendations for delaying operation dependent on the aggressiveness disease were adjusted accordingly. And so that's just one aspect of all the recommendations that were put forth. DR. HELEN CHEW: Dr. Sheng? DR. JENNIFER SHENG: Yeah. So I think we heavily relied on seeing what our peers nationally and internationally did during these times. The COVID-19 Pandemic Breast Cancer Consortium did release guidelines and recommendations. So we certainly relied on those because they provided a tiered approach to prioritizing surgery, radiation, and systemic therapy interventions by urgency, and within those guidelines there was certainly discussion about weighing the risks and benefits of delivering immunosuppressive therapy, about a delay of non urgent surgeries, the use of neoadjuvant systemic therapy due to deferral of many breast surgeries during the initial pandemic, and also discussion of the genomic tumor profiling on core biopsy specimens to guide neoadjuvant therapy decisions. And so from there, our group thought that it would be prudent to just really gather together and really create more focused guidelines with a few more specifics about how to care for early stage breast cancer, metastatic breast cancer, and I think I briefly highlighted, some of the changes that really applied to many of our patients regardless of their stage. And then I think more specifically for patients who had metastatic breast cancer, for instance, we would try to consider oral regimen as opposed to IV regimens, and really tailoring that to patients and also trying to decrease the total number of visits to the cancer center. We would also defer some of the re-staging scans and lengthen the intervals between scans of patients who are clinically stable. We were able to extend the interval between port flushes for patients to 12 or of longer. And we really tried to be really cautious when we looked up the side effect profile of a lot of the agents that we use. So for instance, really trying to balance the risk of pneumonitis for the use of immunotherapy, the risk of interstitial lung disease with certain types of [INAUDIBLE] II therapy that have been approved, and really thinking about some of the oral agents that we provide for metastatic hormone receptor positive breast cancer that require some more frequent blood work and labs and seeing what if we could delay that if we were able to implement initial endocrine therapy. So overall I think that everyone was trying to think of ways to keep our patients as safe as possible. And there were quite a few institutions and organizations that gathered, like minded individuals to be able to come up with these guidances. DR. HELEN CHEW: Thank you both. Dr. Choueiri, in the upcoming months as the vaccination rolls out, do you think you will start reverting to pre-pandemic patient management at your institution? DR. TONI CHOUEIRI: Oh, thank you for your question. Actually, I mean the short answer is I don't know. I think it's hard to say who is in control. I know who is in control. The virus is in control. Yes, there are a lot of signs, positive signs, happening, but we don't know what later on things going to happen. I personally think that stuff won't go back to normal immediately. First, we can't expect everyone, all our patients, to be vaccinated despite our recommendation. Second, I would think that some folks are comfortable doing what they learned and they still want to have a mixed telemedicine. I'm talking not just physician but patient. They want a mix of telemedicine, face to face, and we have to see what's the implication of that is. There are some implications, of course, for out-of-state consult if patients have licenses there. There are indication on billing perhaps, although some preliminary data shows that this is going well. What I want to say is some silver lining, hopefully, that our clinical operation and our clinical trials operation could be a bit more efficient after we learned how to be overall more efficient. We recently wrote with Doctor [INAUDIBLE], a German oncology, a piece about that. I think there will be a transition. The good thing is that there are processes, safety processes, best practices now that we know very well that we didn't know at the beginning of the pandemic, and that actually is reflected by a study we did in the Mass General Brigham Health Care System where we looked at the screening for cancer and compared the three months between March and June index case, the three months where we had the first pandemic, if you will, in the first peak, compared to three months prior, three months after, and three months into 2019. We saw, because of cancellation of a lot of elective procedure, we saw 80% decrease in screening. But that picked up. It didn't pick up completely, but it did pick up because we have safety measures in place. So I think it will be a gradual increase, and we just have to learn as we go. DR. HELEN CHEW: Thank you. Yes, it's certainly been a learning process. And I think some of the changes we've made are probably here to stay. DR. OLIVER ENG: Yeah, I think the one thing that should not be forgotten is the impact on patients and their perception of delays, and it's very easy to think of this from an academic perspective of OK, it's safe to delay because of disease biology, and so and so and, make decisions based on the duration of therapy and so forth. But to call a patient, which all of us have had to do, to delay the therapy for a variety of reasons and explain why. I think it's something that we need to be cognizant of when we are making these decisions and really being transparent with the patients about the fact that we're taking consideration not only their risk but the risk to the community as well. And it's just made things a lot more complex. And time will tell as to the sort of sequelae of everything, all the decisions that are made in this period. DR. TONI CHOUEIRI: I like that Oliver. I think that's very sensible honestly. I think there's wording. Sometimes it's not from us, it's the patient who want to delay. But I think the word delay does have some negative connotations, and actually, funny enough, when we did our paper in Journal of Oncology about screening, which went down, then up, and compared this, a reporter asked me directly, he said look, these patients were delayed. Did you missed the diagnosis? And you can't-- it's just a bit, so the word we used is kind of postponed. I think despite it is a bit the same, but I think it looks-- because delay is negative. Delay implicates that we're missing something while it's mostly postponing some things that normally maybe you would this is not BEP for testicular cancer that you would anyhow want to delay, but this is postponed. So this was very sensible, and I agree with you. DR. HELEN CHEW: Thank you. So that is all we have time for today. Thank you all for your time to share your valuable perspectives. For listeners that want more, look out for upcoming episodes in ASCO's eLearning series on COVID-19's continually evolving impact on cancer care. [MUSIC PLAYING] SPEAKER 1: Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.

In this episode of the ASCO eLearning Podcast, Gregory Masters, MD, and Christina Dieli-Conwright, PhD, MpH, dive into the exciting benefits of exercise for patients with early-stage cancer, advanced disease, and how exercise could preemptively lower risk. To hear the latest eLearning Podcast episodes as soon as they are available, please subscribe on Apple Podcasts. To access our entire library of podcasts and other amazing eLearning content, visit elearning.asco.org. TRANSCRIPT CLIFFORD HUDIS: Hello, I'm Dr. Clifford Hudis, CEO of ASCO, dropping into your feed to let you know about a special episode of the ASCO in Action podcast featuring the extraordinary career of Dr. Richard Schilsky, ASCO's chief medical officer. Rich and I discuss the advances that have revolutionized cancer care over the last 50 years and much, much more. Here's a preview of the episode. RICHARD SCHILSKY: The 1980s, in many respects, were the doldrums of progress in clinical oncology. There really was not a lot of innovation in the clinic. But what was happening and what was invisible to many of us, of course, was that was the decade of discovery of the fundamental biology of cancer. That's when oncogenes were discovered, when tumor suppressor genes were discovered, when it became clear that cancer was really a genetic disease. And that is what transformed the field and put us on the path to targeted therapy and precision medicine as we think of it today. CLIFFORD HUDIS: You can find the ASCO in Action podcast on Apple Podcasts or wherever you are listening to this show. And you can find all nine of ASCO's podcasts, which cover a wide range of educational and scientific content and offer enriching insight into the world of cancer care at podcast.asco.org. SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for 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. GREGORY MASTERS: Hello, I'm Dr. Gregory Masters. I'm a medical oncologist at the Helen F Graham Cancer Center in Delaware. CHRISTINA DIELI-CONWRIGHT: And my name is Christina Dieli-Conwright. And I'm a member of the faculty at the Dana-Farber Cancer Institute in the division of population sciences and department of medical oncology. GREGORY MASTERS: We would like to discuss the role that exercise and physical activity can play in providing excellent cancer care to your patients. And we'll start with a brief case presentation to review how exercise can improve the care in patients with early-stage cancer. The first patient is a 51-year-old postmenopausal female who presented with stage IB hormone receptor positive, HER2 negative breast cancer. Sentinel lymph node biopsy was negative. And she underwent lumpectomy, followed by radiation therapy. She had a low recurrence score on the 21-gene expression assay and saw a medical oncologist to consider additional therapy. She agreed to take anastrozole off for five years. At the end of the office visit, she poses the question, besides surgery, radiation, and hormonal therapy, what else can I do to improve my chances? CHRISTINA DIELI-CONWRIGHT: What is the role for exercise in patients with early-stage cancer? GREGORY MASTERS: Well, Christina, it's important to understand that exercise can help improve and maintain a healthy lifestyle in most patients, regardless of a cancer diagnosis. But there's a particular benefit in cancer patients and, also, in helping to reduce the risk of cancer as well. Studies show a decreased risk of getting certain cancer in patients who exercise on a regular basis. There's a decreased risk of developing cancer of the breast, colon, endometrium, kidney, bladder, esophagus, and stomach. The hazard ratio is 0.6 to 0.9 for developing these cancers. That is, there's a 10% to 40% reduction in the risk of getting one of these cancers. The evidence is convincing, with both statistically and clinically significant reductions in developing cancer. There's also evidence that sitting time or complete inactivity may increase the risk of cancer. Multiple types of exercise can help, including both recreational or leisure time exercise and occupational physical activity. Those who are very active at work may achieve a similar benefit. CHRISTINA DIELI-CONWRIGHT: How does this affect quality of life and cancer outcomes? GREGORY MASTERS: So exercise can help reduce the risk of developing cancer. But exercise also improves health in patients who are being treated or have been treated for early-stage cancer. Physical activity has been correlated with improved cancer-specific and all-cause mortality. That means physically active patients are less likely to die of their cancer or other causes. A hazard ratio for death is 0.67 to 0.7 for breast, cancer, and colorectal cancer patients. That means there's a 30% reduction in the risk of death in those who exercise regularly. This holds for both prediagnosis exercise and postdiagnosis exercise. So patients who are already in an exercise routine when diagnosed and those who begin an exercise program after their cancer diagnosis can achieve benefits from exercise. There appears to be a dose-response relationship. So the more one exercises, the better, within reasonable guidelines. The American Cancer Society estimates that about 15 million cancer survivors alive in the United States may benefit from exercise. But there are some limitations to these studies. There may be patient recall bias, meaning that some patients may overestimate their activity to please questioners. These data also come from nonrandomized studies for the most part. So other factors, such as a healthy lifestyle, may also be at play. Some studies compare the highest to the lowest risk groups to calculate the risk ratio. So the data may overestimate risk reduction in some patient groups. Another benefit is that symptoms can improve with exercise, leading to a better overall quality of life. Studies have shown an improvement in fatigue, physical functioning, and physical fitness, and a reduction in depression and anxiety. And of course, the added benefit comes that overall cardiovascular risk may be reduced with exercise. CHRISTINA DIELI-CONWRIGHT: Is it safe to exercise during chemotherapy and/or radiation therapy? GREGORY MASTERS: Exercise is safe in the cancer population. In studies looking at adverse events in patients enrolling in a postdiagnosis physical activity program do not show unexpected safety concerns. Nonetheless, there remain major challenges in implementing these recommendations in the broad cancer patient population. One problem can be getting providers to adopt the recommendations. Another issue is time constraints for both patients and health care providers. There may be knowledge deficits in providers. And although 79% of oncologists agree that referral to an exercise program is important, in one ASCO survey, only 10% to 20% of providers actively refer patients to these programs. One strategy for getting providers and their patients engaged may be to assess, advise, and refer. This is one way to support providers in the steps needed to boost participation. There can also be constraints from a patient-care side. Getting patients to follow through on our recommendations can be a challenge. And we need to focus on behavioral changes. Patients need a strong support system, including not only their oncologist, but also family and caregivers, oncology, nurses, physical therapists, occupational therapists, and trainers to help them with their routines. Specific programs can be helpful, such as Livestrong at the YMCA. A patient's access to this care can be limited for various reasons, socioeconomic or otherwise. But we know that cost, insurance coverage, and time out of work can be a challenge. It may be difficult for these patients to commit more time and effort to an exercise routine after going through extensive treatment. And we know there's a dire need to reach underserved populations. This is a perfect time to remember the focus of Dr. Lori Pierce, the current ASCO president, who has as her theme, equity, every patient, every day, everywhere. Remember, we can all work together to help our patients strive for their best health through exercise. And for our early-stage breast cancer patient, to help her improve her chances, in addition to standard care, I would recommend a regular exercise routine, perhaps with referral to a specialist in exercise physiology. CHRISTINA DIELI-CONWRIGHT: Greg, are there specific clinical concerns to address? GREGORY MASTERS: As a medical oncologist, before I refer a patient for exercise, I consider comorbid medical conditions, such as cardiac, pulmonary, orthopedic, central nervous system, and neurologic complaints, and any post-operative limitations that may be appropriate. Thank you. CHRISTINA DIELI-CONWRIGHT: I have the pleasure of discussing a second case with you today. And this case is a 60-year-old male who underwent surgery five years ago for stage II colon cancer. Earlier this year, his CA tumor marker was elevated. And a CT scan showed new metastatic disease in the liver and lung. Biopsy confirmed metastatic adenocarcinoma. Molecular testing shows the cancer is KRAS mutation positive. Symptoms include fatigue, anorexia, and mild cough. And he still gets occasional diarrhea since surgery. He begins chemotherapy with FOLFOX and bevacizumab. At the next visit, he has increased complaints about his energy level and mild depression. He asks, besides chemotherapy, what more can I do to improve my quality of life? So I'm here to share with you today the role of exercise and its benefits in a case just like this, with patients with metastatic cancer. GREGORY MASTERS: What is the role for exercise in patients with advanced cancers? And how does it affect their quality of life, symptom management, and prognosis? CHRISTINA DIELI-CONWRIGHT: So this is a very interesting question, given that very few studies, intervention studies specifically with exercise, that have actually targeted specifically patients with metastatic disease. However, there are pilot studies that have smaller patients enrolled that have shown that exercise is feasible and safe for patients with metastatic disease. And to date, exercise in patients with metastatic disease, although few, have shown to improve quality of life and physical function. And by physical function, I'm referring to how quickly an individual is actually able to walk and the distance by which they're able to walk over a certain period of time. So importantly, we need to emphasize that research is actually heavily lacking in this population. So further and ongoing research that has yet to be published is underway and needed to determine whether exercise can impact symptom management and also improve prognosis in patients with metastatic disease. GREGORY MASTERS: What safety precautions should a patient be aware of when performing exercise? CHRISTINA DIELI-CONWRIGHT: So it is advised to have an understanding of one's own physical personal strengths and weaknesses as well as prior medical history before initiating exercise. And perhaps this is even more important in an individual with a metastatic diagnosis. Importantly, consideration of daily aches and pains, overall well-being, time since last exercise was performed regularly are important, but just a few examples of considerations to understand. This basic information will really help to determine which forms of exercise are safe and which forms of exercise should be future recommended. Consulting with a medical oncologist prior to starting an exercise program is advised. And subsequently, that physician may also refer that patient to see a professional exercise specialist. In line with this recommendation, there actually are specialized exercise professionals with unique training in exercise for cancer patients, who can assist in providing personalized exercise guidance for patients with cancer. And it is possible to seek out those recommendations using a website provided by the American College of Sports Medicine. GREGORY MASTERS: Will exercise during treatment aid in how well a patient tolerates treatment? CHRISTINA DIELI-CONWRIGHT: Exercise during treatment may aid in how well a patient tolerates treatment. However, there is no scientific evidence yet to support this, specifically within the metastatic population. Logically, we do know that exercise during treatment has many physical health benefits, such as maintaining strength and physical endurance. And that may help to keep the patient fit so that they're able to better withstand the treatment as opposed to if they were not fit. However, studies are underway to help to continue to support this logic. GREGORY MASTERS: What are the best ways to help patients understand this information and to get them to initiate and stick with an exercise routine? CHRISTINA DIELI-CONWRIGHT: So this is a fantastic question and this is a question that highlights the challenges of individuals difficulties adhering to regular exercise, in general, throughout the lifetime. However, there are some great resources specific to individuals diagnosed with cancer that are worth mentioning. For example, website and organization referred to as cancer.net offers a number of brief articles focused on exercise that provide great readings around the benefits of exercise before, during, and after treatment, et cetera. Often the easiest way to get started and to stick with exercise is to start with an enjoyable activity that will be based on one's personal preference and to start small. It's not necessary to choose an activity that is completely unenjoyable or for an excess amount of time because then that will often result in a person not adhering to what they're trying to achieve. Exercise can often appear very daunting when it's examined in a very high volume or at a very high intensity if that's the only way that it's thought to be able to be performed. So starting simple by taking short walking breaks to reduce sitting time can actually go a long way. And there's more and more research to support the benefits of reducing sitting behavior. Individuals are also more likely to stick with an activity when they enjoy the activity and when it is not too time consuming. Another tidbit is exercising with family, friends, or in a group setting when it's safe can also promote consistency with exercise. Nowadays, there are a lot of virtual exercise programs in light of the COVID pandemic that actually can involve exercising in a group with family or with friends but being socially distant via virtual platform. Also important to note, when approaching more advanced forms of exercise, such as weightlifting or training for a specific event, such as a running event like a half marathon or a 3K, 5K, it is definitely helpful to seek professional assistance, even if for a single consultation. This way you're on a straight and clear path of how to safely go about performing the exercise. And specifically, with our patient diagnosed with metastatic disease, exercise is safe and feasible. However, relying on consultations by medical oncologists and also exercise professionals will really help to put that individual in safe hands to get off on a safe start in order to perform the exercise and help to benefit the improvements of quality of life and strength and physical function that we know are well-established among cancer survivors. Thank you so much for your time. GREGORY MASTERS: Now that we have reviewed these two cases, let's consider how these cases are related. There's evidence that exercise benefits patients with both early-stage cancer and advanced disease. There's also evidence that exercise can help reduce the risk of cancer prior to diagnosis. Based on these studies, there's strong evidence supporting our recommendations to patients that they become more active. Beyond understanding the data, sometimes the hardest component of this is getting patients to implement our recommendations. The take-home point should be that exercise helps both groups of patients and that we should be recommending exercise for this patient population. CHRISTINA DIELI-CONWRIGHT: The key teaching points from our session today should be recommending exercise for patients with early-stage or advanced cancer is evidence-based and will improve multiple health outcomes. The goals, therefore, are coming up with the best way to teach our patients this information and helping them to act on that knowledge. Barriers may include lack of energy, which limits patients initial interest to pursue exercise as therapy. GREGORY MASTERS: Thank you for listening to this week's episode of the ASCO eLearning Podcast. SPEAKER: To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning center at elearning.asco.org.

Dr. Stephen Hunger is a Professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania. In today's ASCO eLearning Podcast, Dr. Hunger will discuss two patient cases related to CAR T-cell therapy. While the two cases are similar, the recommended treatments can be different. We hope you enjoy this episode. To hear the latest eLearning Podcast episodes as soon as they are available, please subscribe on Apple Podcasts or Google Play. We truly value your feedback, so please leave a review. To access our entire library of podcasts and other amazing eLearning content, visit elearning.asco.org. Transcription: The purpose of this podcast is to educate and inform. This is not a substitute for 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. Hi, my name is Stephen Hunger. I'm a professor of pediatrics in the Perelman School of Medicine at the University of Pennsylvania, and chief of the Division of Oncology and director of the Center for Childhood Cancer Research at the Children's Hospital of Philadelphia. My career has focused on clinical, translational, and basic research regarding childhood Acute Lymphoblastic Leukemia, or ALL. One of the most exciting recent advances in cancer medicine is the development of Chimeric Antigen Receptor-redirected, or CAR-T cell therapy for relapsed in refractory pediatric B cell ALL. Today, I will present two cases that have similarities, but also important differences that highlight key questions and uncertainties regarding when and how to use CAR T cells in pediatric ALL. Currently the only CAR T cell product FDA approved for treatment of children and young adults up to age 25 with relapsed refractory ALL is tisagenlecleucel, trade name Kymriah. Additional CAR T cell products are in the late stages of testing, and will likely become FDA approved soon. My discussion today will focus on tisagenlecleucel, which can persist for years following therapy. Indeed, the first child treated at CHOP for ALL with CAR T cells in 2012 still has detectable CAR T cells over eight years later. Our first patient is Sue, who is currently 15 years old and has B-ALL that relapsed for the second time. She was first diagnosed at age 7, at which time she had an 80,000 white blood cell count. She was treated with standard chemotherapy with an excellent response, but relapsed during maintenance therapy 22 months following her diagnosis. Because this relapse occurred on therapy, she was considered high risk, and allogeneic transplant was considered the therapy of choice. She entered a second remission and became MRD negative after two cycles of consolidation therapy. Her brother was HLA identical, and she underwent a matched sibling transplant in MRD negative second remission following a cyclophosphamide mind plus total body radiation preparative regimen. She engrafted rapidly, had no GBHD, and was weaned off immunosuppression by six months post-transplant. One year post-transplant, she presented with bone pain and was found to have a second bone marrow relapse of B-ALL. Her leukemia cells were CD19 positive. Our second patient is 15-year-old Damian, who was diagnosed with CD19 positive B cell ALL four months ago. His initial white blood cell count was 80,000, and the cytogenetic and molecular studies did not show any known high or low-risk features or targetable lesions. He was treated with standard chemotherapy, but did not enter remission with 50% blasts at the end of four weeks of induction therapy. He received one month of consolidation chemotherapy with a Children's Oncology Group augmented BFM regimen, but still had 35% blasts after that therapy. He then received a four-week course of the CD3/CD19 BiTE blinatumomab, but again had 30% blasts at the end of that therapy. The blasts remained strongly CD19 positive. His 17-year-old sister is fully HLA matched. Both of these patients have relapsed refractory ALL, and meet the FDA approved indication for tisagenlecleucel, which is patients up to 25 years of age with B cell precursor ALL that is refractory or in second or later relapse. Sue is in her second relapse, and thus qualifies. Refractory is not defined precisely in the indication, but I think all would classify Damian as having refractory ALL, given that he has failed to enter remission with three different regimens. The pivotal trial that led to the approval of tisagenlecleucel was called ELIANA, and the results were published in the New England Journal of Medicine in 2018, with my colleague Shannon Maude being the first author. Of note, that study prohibited patients who had received prior CD19-directed therapy, so Damian would not have been eligible to enroll. However, the FDA label does not mention this, and many patients have been treated with tisagenlecleucel following earlier blinatumomab therapy. Thus, Sue and Damian are good candidates for tisagenlecleucel. Both are also medically in good condition without active infection or end organ dysfunction. There are also important differences between Sue and Damien. Sue has relapsed post-transplant while Damien has an HLA-matched sibling, but has never undergone transplant because he has never entered remission. Transplant with high level marrow disease, as he has currently, 30% blasts, is generally viewed futile, and the best transplant outcomes occur when patients are MRD negative immediately pre-transplant. A key current question in therapy of relapsed refractory ALL is whether CAR T cells should be used as a definitive therapy with responders receiving no subsequent antileukemia treatment, or as a so-called bridge to transplant, a means to get patients to an MRD negative state so that they can then undergo transplant as definitive therapy. There is no current definitive answer to this question, and these two cases help to highlight the issues to consider. Both Sue and Damian undergo T cell apheresis with a good collection. Cells are sent to the manufacturer to make the CAR T cells, a process that takes about four weeks. They receive low-intensity maintenance therapy for two weeks with adequate disease control, and then no therapy is given for two weeks. Both have adequate manufacture of CAR T cells, and then receive lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by CAR T cell infusion. Both patients have mild signs of cytokine release syndrome not requiring intervention. At day 30 post-infusion, both Sue and Damian are in an MRD negative complete remission and have no detectable circulating B cells. What should happen next? While some feel that the long-term efficacy of CAR T cells have not yet been established, and that transplant should be used as a consolidative therapy in almost all cases, many others believe that a long-lasting CAR T cell product such as tisagenlecleucel can be used as definitive therapy in some cases. In the initial ELIANA publication, 81% of the 75 relapsed refractory ALL patients infused with tisagenlecleucel obtained in MRD negative complete remission within three months, usually after one month. And the 12-month event-free survival and overall survival rates were 50% and 76%. More mature survival data from ELIANA shows a two-year relapse-free survival rate of 61% among those achieving remission. Like Sue and Damian, the patients in this trial were heavily pretreated with a median of three prior regimens and 61% had previously undergone transplant. Knowing that many patients can survive long term with no further therapy post-CAR T cell infusion, there is limited enthusiasm for a second transplant among physicians, patients, or their parents if a good response is obtained and maintained. So for Sue, I would recommend close monitoring, but no additional therapy as long as she showed continued evidence of response for 6 to 12 months. I would repeat bone marrow MRD testing at 60 and 90 days and every three months thereafter, and measure peripheral blood B cell numbers monthly for at least six months. B cell depletion is a good surrogate for CAR T cell activity, as normal CD19 positive cells are also killed. If Sue remains MRD negative and has no circulating CD19 positive B cells for at least six months, then there is a good hope that no more therapy is needed. Damian is a more complicated case, as he has never undergone transplant and has an HLA-identical donor, and now has excellent disease control and is in good medical condition to undergo a transplant. There are short-term risks of transplant with a 100-day mortality risk of 5% to 10% for a teenager. And there are also long-term risks related to the transplant procedure and/or graft versus host disease. The long-term risks of tisagenlecleucel appear limited other than the persistent B cell depletion, but the longest followup is only eight years, and few patients have more than five years of followup. So we have no idea about the efficacy and potential risks 10 to 20 or more years post-infusion. Damian failed three induction attempts. If his leukemia comes back, one may never be able to get him back into a healthy MRD negative remission. So there is a good argument that his best chance for definitive therapy is with transplant. Given this, many would strongly recommend transplant as consolidative chemotherapy for Damian. However, it's also possible that Damian has now received curative therapy and will never relapse. Highlighting the uncertainty surrounding this question, our group at CHOP, which has treated over 300 patients with relapsed refractory ALL with CAR T cells, does not have a clear consensus on what to do for patients like Damian. It's our practice to summarize the potential advantages and disadvantages of transplant versus no further therapy, and help the patient and their family decide what is the best course for them. To summarize, tisagenlecleucel is an exciting therapy that provides new opportunities for children and young adults with relapsed and refractory ALL. However, the field of cellular immunotherapy is young, and there are many uncertainties, particularly surrounding the issue of definitive therapy versus bridge to transplant. Today, we lack the followup data needed to make definitive statements, and patients and families need to understand that and be full partners in these complicated decisions. Thank you very much for listening. Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning center at elearning.asco.org.

Dr. Raja Mudad is a medical oncologist specializing in lung cancer at Florida Precision Oncology. In today's ASCO eLearning Podcast, Dr. Mudad will discuss two patient cases related to the treatment of advanced non-small cell lung cancer harboring an EGFR mutation. While the two cases are similar, the recommended treatments can be different. We hope you enjoy this episode. To hear the latest eLearning Podcast episodes as soon as they are available, please subscribe on Apple Podcasts [https://podcasts.apple.com/us/podcast/asco-elearning-weekly-podcasts/id1375021523] or Google Play [https://play.google.com/music/listen?u=0#/ps/Igjyhvqqrvuc5mjvlljhzkpvgeu]. We truly value your feedback, so please leave a review. To access our entire library of podcasts and other amazing eLearning content, visit elearning.asco.org [https://elearning.asco.org/homepage]. The purpose of this podcast is to educate and inform. This is not a substitute for 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. Hello. My name is Raja Mudad. I'm a medical oncologist specializing in lung cancer. I work at Florida Precision Oncology, a practice dedicated to an academic approach in the treatment of cancer. Today, we compare two patient cases that relate to the treatment of advanced stage non-small cell lung cancer harboring an EGFR mutation. These two cases have similarities, yet the recommended treatments may be different. Let us look at the cases. Patient case 1, our first patient case is Roberto. He is a 34-year-old man with stage 4 non-small cell lung cancer harboring an EGFR deletion 19 mutation. The patient, a never smoker, presented with chest pain and was diagnosed with a pulmonary embolus. CT scan of the chest also demonstrated bilateral lung nodules. Biopsy revealed adenocarcinoma. Staging workup revealed multiple small brain metastases. Patient case 2, our second patient case is Heidi. She is a 60-year-old woman with stage four non-small cell lung cancer with an exon 21 mutation in EGFR gene. She presented with a cough. A CT scan of the chest showed a left lung mass. An endobronchial ultrasound guided biopsy revealed no evidence of mediastinal disease. And a biopsy was positive only in the mass showing adenocarcinoma. She was taken to surgery but found to have multiple pericardial nodules. No distant metastases were seen on the PET scan. The two cases are clinically similar. Would any of the differences lead you to select a different treatment for each patient? Let's take a look. The two patients have the exact disease, a similar stage, and mutations in the same EGFR gene. Their initial treatment is the same. The initial treatment in both cases, osimertinib, is considered the standard of care in the United States, with a median progression-free survival of 19 months. Roberto started on treatment with osimertinib, and the follow-up PET scan and brain MRI showed complete resolution of all of the abnormalities. In the second case, surgery was aborted, and the patient started on osimertinib. About 1.5 years after Roberto started on osimertinib, progressive disease developed with a new adrenal mass, a new bone metastasis, and progression in the brain. He received stereotactic radiosurgery to the brain. A repeat biopsy of the adrenal mass revealed the same histology but with a MET amplification detected on next-generation sequencing. About eight months after starting osimertinib, Heidi developed progressive disease, and a repeat biopsy confirmed the same histology and the original EGFR mutation but no additional abnormalities. As you can see, the two cases are similar at presentation. However, upon progression, both cases have peculiarities that make them different. Which differences in the two cases do you think may inform treatment choices? Would the differences lead your choice of treatment in a different direction, or would both patients receive the same treatment? If treatment is different, what is the difference that changes your choice of treatment? The standard of care for non-small cell lung cancer with an EGFR mutation upon progression on first-line tyrosine kinase inhibitor is generally chemotherapy, possibly combined with immunotherapy. In non-small cell lung cancer with an EGFR mutation, there are multiple suggested mechanisms of resistance to osimertinib. These involve new mutations in the EGFR gene, alterations in parallel or downstream oncogenes, such as MET, KRAS, and PIK3CA, or histological transformation to small-cell carcinoma. MET amplification is a very common abnormality seen in those patients. Upon progression, patients have several options, and their treatment should be directed based on the results of the repeat molecular evaluation. That is why it is important to repeat a biopsy on patients with disease progression. Nowadays, liquid biopsy is also helpful in detecting these abnormalities without the need for an actual biopsy. Roberto can benefit from a MET-directed therapy using a tyrosine kinase inhibitor. He did receive stereotactic radiosurgery to the brain due to the presence of mild symptoms. He is clinically doing well, so the need to initiate immediate systemic cytotoxic chemotherapy is not urgent. In this patient, I would offer him an oral MET inhibitor and repeat his imaging in three months. On the other hand, the second patient, Heidi, did not have an actionable mutation upon re-biopsy. The patient is best served by a clinical trial. However, if a trial is not available, or if she is not eligible, then systemic chemotherapy and immunotherapy would be the standard of care. In my practice, and based on the results of the IMpower 150 trial, the use of the combination of carboplatin, paclitaxel, atezolizumab, and bevacizumab is preferred. The subset analysis of the EGFR-positive patients in this trial favored the use of the quadruplet combination. Thank you for listening to this episode of the ASCO eLearning Podcast. For more information on the treatment of non-small cell lung cancer, including additional patient cases and opportunities for self-evaluation, please visit the comprehensive eLearning center at elearning.asco.org. Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. To make this part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning center at elearning.asco.org.

Dr. Doug Johnson is an Associate Professor of Medicine and Leader of Melanoma Program at the VanDr. Doug Johnson is an Associate Professor of Medicine and Leader of Melanoma Program at the Vanderbilt Ingraham Cancer Center in Nasheville, TN. In today's ASCO eLearning Podcast, Dr. Johnson discusses two patient cases related to stopping of anti-PD-1 and consideration of retreatment for metastatic melanoma. While the two cases are similar, the recommended treatments can be different. We hope you enjoy this episode. To hear the latest eLearning Podcast episodes as soon as they are available, please subscribe on Apple Podcasts [https://podcasts.apple.com/us/podcast/asco-elearning-weekly-podcasts/id1375021523] or Google Play [https://play.google.com/music/listen?u=0#/ps/Igjyhvqqrvuc5mjvlljhzkpvgeu]. We truly value your feedback, so please leave a review. To access our entire library of podcasts and other amazing eLearning content, visit elearning.asco.org [https://elearning.asco.org/]. The purpose of this podcast is to educate and inform. This is not a substitute for 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. Hello, my name is Doug Johnson. I'm an associate professor of medicine and leader of the Melanoma Program at Vanderbilt-Ingram Cancer Center. Today we compare two patient cases that relate to stopping of Anti PD-1 therapy in consideration of whether to re-treat patients that have metastatic melanoma. These two cases have similarities, yet the recommended treatments may be different. Let's look at the cases. Patient case one. Our first patient case is Dave. Dave is a 62-year-old man with metastatic melanoma involving the lungs and liver. He was treated with single agent nivolumab and he had decreasing size of one of his lung metastases but had increasing liver metastases when his first CT scan was performed. Since his melanoma has a BRAF V600e mutation, he was switched to BRAF and MEK inhibitors, which were later followed by progression and 12 months on therapy. Patient case two. Our second patient case is Rachel. Rachel's a 55-year-old woman with metastatic BRAF wild type melanoma involving the lungs and liver as well. She receives pembrolizumab with a complete response and therapy is stopped after 15 months of treatment. Two years later, she has growth of two of her lung lesions and a biopsy confirms that this is melanoma. So questions for consideration. As you can see, both cases involve progression of anti PD-1 therapy, but there are some differences. Do the differences lead your choice of treatment in a different direction, or would both patients receive the same treatment? In particular, would you consider anti PD-1 re-treatment for either or both of these patients? Some background. The standard treatment for metastatic melanoma, regardless of BRAF mutation status, is Anti PD-1 monotherapy, either with nivolumab or pembrolizumab. Approximately 44% of patients experience complete responses to treatment, many of which are durable. Many patients with complete or near complete responses have a discussion with their oncologist and elect to stop treatment after one to two years on therapy. However, about one third of patients who have a response ultimately experience disease progression. The treatments who either respond to Anti PD-1 and then later progress or patients who never respond at all is an important issue to consider. Options for these patients include ipilimumab monotherapy, ipilimumab in combination with nivolumab, or if BRAF mutated, BRAF and MEK inhibitor therapy. Re-treatment with Anti PD-1 may be an option as well. Other melanoma therapies have shown benefit with re-treatment with this type of strategy. For example, patients re-treated with BRAF and MEK inhibitors, provided they took at least a six week break off therapy, have nearly a 50% response rate to re-treatment. In addition, patients who benefited from ipilimumab then later progressed had at least a 20% response rate to re-treatment. So how are these cases related? Both patients experienced progression either on or following Anti PD-1 treatment. However, there are some key differences as well. Patient one progressed while still receiving treatment, and at least his liver lesions never responded to therapy at all. On the other hand, patient two experienced progression a long interval after completing treatment. She also had an objective response, in fact, a complete response to her initial course of therapy. So what should we do with these patients? Well, the answer, from my perspective, is patient one should not receive re-treatment with Anti PD-1 therapy. A recent publication by Dr. [? Betof ?] and colleagues in JCO studied 396 patients with long-term follow-up following Anti PD-1 treatment. This included 34 patients who were re-treated. None of the patients who initially progressed on therapy, so those who didn't have a complete response, were prolonged stable disease. None of those patients experienced long-term benefit with re-treatment. On the other hand, these patients did benefit from ipilimumab and nivolumab 25% of the time, with a 25% response rate. Additional patients also experienced stable disease in this group. Thus, either ipilimumab and nivolumab or [INAUDIBLE] monotherapy should be considered for patient one. Patient two, by contrast, had a durable complete response to therapy and progressed after completion of treatment. This patient could consider re-treatment with Anti PD-1. A study by Dr. Warner suggested that of patients in this position, those who had an initial objective response to treatment, only 15% of patients had objective responses. However, durable benefit was more frequently seen in patients who had complete or partial response to their initial course. Many patients had prolonged stable disease with re-treatment. Thus, re-treatment could be considered in this patient. Or we would also be reasonable to think about ipilimumab and nivolumab combination or ipilimumab alone. That would also be appropriate for this patient. In closing, thank you for listening to this week's episode of ASCO e-learning weekly podcast. For more information on treatment for metastatic melanoma, including additional patient cases and opportunities for self-evaluation, visit the comprehensive e-learning center at e-learning.asco.org. Thank you. [MUSIC PLAYING] Thank you for listening to this week's episode of the ASCO e-learning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at e-learning.asco.org.

Dr. Rodrigo Munhoz is a Melanoma/Sarcoma Oncologist at Hospital Sírio Libanês in São Paulo, Brazil. In today's ASCO eLearning Podcast, Dr. Munhoz discusses two patient cases related to challenges and barriers to treating cancer in developing countries. While the two cases are similar, the recommended treatments can vary depending on social, economic, cultural, religious, patient knowledge and other aspects. We hope you enjoy this episode. To hear the latest eLearning Podcast episodes as soon as they are available, please subscribe on Apple Podcasts or Google Play. We truly value your feedback, so please leave a review. To access our entire library of podcasts and other amazing eLearning content, visit elearning.asco.org The purpose of this podcast is to educate and inform. This is not a substitute for 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. Hello, my name is Rodrigo Munhoz, and I'm a melanoma and sarcoma medical oncologist at Hospital Sirio Libanes in Brazil. Today, we compared two patient cases treated in Brazil that describe challenges related to the access to systemic therapies for advanced melanoma in developing countries. These few cases share similarities. Yet, the recommended treatments can be largely different based upon sociocultural and religious aspects, among other variables that influence patients' choices, including enrollment into clinical trials. Let's look at the cases. Our first patient is Paolo, a 49-year-old man diagnosed with metastatic melanoma with asymptomatic CNS involvement in addition to lung and subcutaneous metastases. The patient was diagnosed with an intermediate risk primary melanoma of the right arm without nodal involvement a couple of years before. He presented for treatment considerations following disease relapse in the form of M1d disease with normal serum LDH level. Decision was made to proceed with first-line treatment with a combination of ipilimumab and nivolumab, a treatment covered by his private insurance plan. And he's scheduled to receive the first dose. Our second patient case is Rachel, a 65-year-old woman diagnosed with metastatic melanoma harboring a BRAF mutation. Following initial surgical treatment for a high-risk primary melanoma with nodal involvement, she developed short-interval metastasis with CNS, liver, and lung lesions. Although immune checkpoint blockers and BRAF and MAC inhibitors were not provided through the public health system, a clinical trial with a triplet combination of a BRAF inhibitor, MAC inhibitor, and an anti-PD-L1 agent was offered. Following discussions about the clinical trial implications, potential adverse events, and additional aspects described in an informed consent form, the patient declined any additional form of therapy and decided to pursue alternative treatments and healing through religion. As you can see, both cases are very similar in presentation, but with considerable differences in terms of treatment options and decisions. How can differences in access limit the treatment decision-making process and affect the patient's prognosis? How can socioeconomic and religious barriers determine one's decision about enrollment into a clinical trial? Advances in systemic treatment options for melanoma, both in the form of target therapy and immunotherapy through immune checkpoint blockade, have deeply altered the scenario for patients affected by this challenging disease. As an example, in a recent randomized trial, 52% of the patients with advanced melanoma treated with a combination of nivolumab and ipilimumab and 44% of those receiving single-lesion nivolumab were alive at five years. Similarly, a pooled analysis of patients receiving dabrafenib and trametinib showed robust activity of BRAF and MAC inhibitors in metastatic disease with response rates approaching 70% and almost 35% of the patients alive at five years. The efficacy of these agents was also demonstrated in patients with CNS metastases. These advances were also noted in the adjuvant setting. In randomized trials that included a majority of patients with stage III disease, pembrolizumab, nivolumab, or dabrafenib and trametinib resulted in significant gains in recurrence-free survival. Yet, these major breakthroughs are not homogeneously available throughout the globe. And many countries still face restricted access and significant inequalities in the treatments made available to the population. As an example, in Brazil, systemic treatment options offered through the public health system, which covers 80% of the population, are still largely limited to cytotoxic chemotherapy with DTIC being the most frequently prescribed agent. In this setting, enrollment into clinical trials represents an effective way to partially overcome these hurdles, extend the offer of active agents, and reduce these gaps. However, the conduction of a clinical trial brings additional challenges. In the cases described here, although very similar in presentation, several aspects were determinant in both medical and patient decisions, which may lead to distinct outcomes. For patient one, a standard-of-care treatment in line with the best scientific evidence was offered and available. In the second case, optimal care was limited by access issues. In addition, despite the possibility of inclusion in a promising clinical trial, social and religious aspects were also determinant in the patient decision. Despite the advances in screening, diagnosis, and treatment of solid tumors, including melanoma, access inequalities pose major challenges and demand a global agenda. Clinical research is an effective tool in reducing gaps and disparities in developing countries, but also largely influenced by cultural, social, and religious aspects, as exemplified by the cases described in this podcast. Initiatives designed to optimize access in developing countries must encompass not only a framework adapted to provide value-based care, but also effective education and communication tailored to patient preferences, as an example, religious belief, and socioeconomic status in discussions of treatment decisions. Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. For more information on the treatment of melanoma in global oncology, including additional patient cases and opportunities for self-evaluation, visit the comprehensive eLearning center at elearning.asco.org. Thank you for listening to this week's episode of the ASCO eLearning weekly podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive eLearning center at elearning.asco.org.

In this month's ASCO eLearning Podcast, Dr. Helen Chew, Professor of Medicine and leader of the Clinical Breast Cancer Program at University of California Davis Comprehensive Cancer Center, brings us two patient cases on systemic therapy for metastatic triple negative breast cancer. This podcast episode appears as a resource in ASCO eLearning's recently updated Genetics & Genomics course collection in the course Hereditary Breast and Ovarian Cancer Syndrome. Click the links to learn more about these courses, including CME and MOC credit details. If you are interested in purchasing a course or the entire collection, go to shop.asco.org Transcript Hello, my name is Helen Chew. I am Professor of Medicine and leader of the Clinical Breast Cancer Program at the University of California Davis Comprehensive Cancer Center. Today, we compare two patient cases on systemic therapy for metastatic triple negative breast cancer. Systemic therapy for metastatic triple negative breast cancer remains a challenge. The mainstay of therapy is cytotoxic chemotherapy. In March 2019, based on the Impassion130 trial, the anti-PD-L1 antibody, atezolizumab, was approved in combination with nab-paclitaxel for metastatic triple negative breast cancer that expresses PD-L1. However, for triple negative breast cancer without PD-L1 expression, immunotherapy is not an option. In addition, there are many indications for genetic counseling and testing, including patients diagnosed with breast cancer at age 45 years or younger and patients with triple negative breast cancer diagnosed at age 60 years or younger. Results of genetic testing may influence treatment options in metastatic breast cancer. Before we explore treatment options, let's look at two similar cases where treatment choices may differ. Can you identify the key differences? Let's begin with Case 1, a 45-year-old woman with metastatic triple negative breast cancer to the liver and lungs. Two years earlier, she had received preoperative anthracycline and paclitaxel for a stage II, triple negative breast cancer. She had a limited family history of cancer and underwent genetic counseling and testing. No pathogenic mutations were found in a panel of genes associated with hereditary cancers. At the time of her metastatic recurrence, biopsy of a liver lesion confirmed metastatic carcinoma, consistent with triple negative breast cancer. There was no PD-L1 staining. The patient received carboplatin and gemcitabine for 6 cycles. She now has disease progression. Case 2 is a 57-year-old woman who also has metastatic triple negative breast cancer involving the chest wall, liver and bones. Three years earlier, she had received adjuvant anthracycline and paclitaxel for a stage II, triple negative breast cancer. She had no family history of breast or ovarian cancer, but underwent genetic counseling and testing revealing a pathogenic germline BRCA1 mutation. At the time of metastatic recurrence, chest wall biopsy confirmed metastatic triple negative breast cancer with no PD-L1 staining. The patient received carboplatin for 6 cycles with an initial response. Nine months later, she has disease progression. In each of these cases, what option would you recommend for subsequent therapy? The choices include additional chemotherapy, such as capecitabine, eribulin or vinorelbine, or a PARP inhibitor. In Case 1, the correct answer is chemotherapy, including any of the named options. This patient does not harbor a germline BRCA mutation so would not benefit from a PARP inhibitor. In Case 2, the correct answer is a PARP inhibitor. In both the OlympiAD and EMBRACA phase III trials, patients with germline BRCA mutations and previously treated HER2-negative metastatic breast cancer were randomized to either chemotherapy of physicians' choice or to olaparib or talozoparib, respectively. Approximately 40-50% had triple negative metastatic breast cancer in these two trials. Patients who received the PARP inhibitors had significantly improved progression-free survival compared to chemotherapy in both trials. Both PARP inhibitors, olaparib and talozoparib, are approved for patients with HER2-negative metastatic breast cancer who have germline BRCA mutations. These two cases of metastatic triple negative breast cancer share similarities. Both cases met criteria for genetic counseling and testing, including the young age at diagnosis for Case 1 and the diagnosis of triple negative breast cancer at age 60 or younger in Case 2. Both cases were treated similarly at initial presentation and on metastatic recurrence. However, the key difference is that no pathogenic mutation was detected in Case 1. In contrast, a germline BRCA1 mutation was found in Case 2. PARP inhibitors are associated with improved progression-free survival compared to the chemotherapy given in the OlympiAD and EMBRACA trials in patients with germline BRCA mutations and HER2 negative, previously treated metastatic breast cancer. In addition, although both cases received a platinum-based regimen at metastatic recurrence, the TNT trial revealed that only patients with germline BRCA mutations and triple negative metastatic breast cancer had improved progression-free survival with carboplatin compared to docetaxel. No difference in progression-free survival was seen in the trial population of triple negative metastatic breast cancer without a germline mutation. Thank you for listening to this week's episode of the ASCO eLearning Weekly Podcast. For more information on the treatment of metastatic breast cancer, including additional patient cases and opportunities for self-evaluation, visit the comprehensive eLearning center at elearning.asco.org

Dr. Winston Tan, Medical Oncologist at Mayo Clinic, discusses the recent FDA approval of erdafitinib and enfortumab for second-line treatment of metastatic bladder cancer.

An interview with Dr. Scott Eggener of University of Chicago Medicine on "Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline." This guideline provides recommendations for available tissue-based prostate cancer biomarkers geared toward patient selection for active surveillance, identification of clinically significant disease, choice of postprostatectomy adjuvant versus salvage radiotherapy, and to address emerging questions such as the relative value of tissue biomarkers compared with MRI. Read the full guideline at www.asco.org/genitourinary-cancer-guidelines