Cancer Topics - Immunotherapy Breakthroughs in Esophageal Cancers

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. 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