Welcome to The GU Cancer Sessions with the Video Journal of Oncology (VJOncology).
This roundtable discussion features Elizabeth Plimack (Fox Chase Cancer Center, Philadelphia, PA), Rana McKay (University of California San Diego, San Diego, CA), Thomas Powles (Barts Cancer Institute, London, UK).
The panel examines the latest learnings in bladder and kidney cancer presented at the ASCO 2021 Annual Meeting, including the use of immunotherapy and bladder-sparing approaches in urothelial carcinoma, as well as adjuvant immunotherapy in renal cell carcinoma, updates from the CLEAR study, and novel approaches in RCC.
“We’re entering a new chapter of urothelial cancer looking at immune therapy because we’ve got randomized trials in this space, immune therapy and bladder-sparing approaches. And so I think it’s a very exciting time and it was my highlight for ASCO actually.”
– Thomas Powles
Adjuvant pembrolizumab in RCC
“I think it’s really an exciting time in renal cell carcinoma because the field has just been changing so rapidly. I do think that the adjuvant pembrolizumab data are really groundbreaking in that they are catapulting us into a new era of adjuvant-based trials in RCC. I think it’s been a long time coming. We’ve all been eagerly awaiting the results of what are going to be the outcomes for adjuvant IO therapy. And I think we’re just beginning to see the start of a series of trials that are likely going to be reporting out in the next several years that are likely going to change the way that we practice.”
– Rana McKay
mRCC and ones to watch
“I actually thought that the work from Dr. Pal and the City of Hope group looking at CBM588 with nivo/ipi compared to just nivo/ipi alone in intermediate, poor risk, newly diagnosed RCC was pretty provocative. You know, I think we’ve all, you know, been intrigued by the microbiome and the role that it can play within, you know, response to immunotherapy and cancer therapy in general. Also investigator-initiated with this probiotic, which demonstrates a signal that there could potentially be improved responses, but again, the numbers are so low. The control arm had a response rate of, I think 20%, which is, you know, below the bar for nivo/ipi from the phase three trials. But I, you know, I’m excited to see the potential for the approach, you know, in the future.”
– Rana McKay
Elizabeth Plimack: Hi everyone. I'm Elizabeth Plimack, GU medical oncology here at Fox Chase Cancer Center in Philadelphia, and I am joined by friends and colleagues, Tom Powles and Rana McKay. And we are going to chat today about the kidney and bladder updates and abstracts presented at this year's virtual ASCO meeting.
Elizabeth Plimack: So let's start with urothelial. There were a lot of sort of follow-up data presented from larger trials that we saw earlier in the year, Tom, but one of the most intriguing sort of approaches that I think we saw explored and presented here was the approach in muscle-invasive setting. So localized bladder cancer, muscle-invasive, where the standard of care is neoadjuvant chemotherapy. Obviously there's been a lot of really exciting research around incorporating immunotherapy into this space. We saw Matt Galsky's presentation on neoadjuvant nivolumab with chemotherapy, with a bladder preservation approach. And I'm just wondering what you thought about that abstract and how it fits into this space in general, as it's been evolving.
Tom Powles: Well, Betsy, firstly, it's nice to see you and Rana, it's nice to see you too. Thank you so much for inviting me and asking me to take part. I do think that this is a really exciting area of urothelial cancer, and the reason why that's the case is I think it's probably in the long-term going to be the area where we can save most lives. I'm always thinking we're going to struggle with metastatic disease. We've really struggled to cure the majority of patients there. But with this earlier disease, it does look like it's more immunologically primed, firstly, and secondly is we have this tempting data with neoadjuvant chemotherapy, which showed that we could cure some patients and in the meta-analysis. But we also have this challenge where about 60% of patients relapsing and dying at the moment, or about 50 or 60%, so I think it is the right place for these drugs.
Tom Powles: And there was some terrific data from Andrew Anekki two or three years ago in the neoadjuvant setting with pembrolizumab, which really set a bar with a path-CR rate of about 40% with only three cycles of pembrolizumab. There was some atezolizumab data in that space as well, which was not too dissimilar to that. It also lent itself to some nice biomarker work because one got sequential tissues that we could understand a lot about the disease, and so it really struck me as an area where we could move forwards. And what we actually saw from there was actually a plethora of other studies and we had immune combination trials, and we've had chemo combination trials, which actually have shown similar path-CR rates overall. And we can talk about that in a second, but what I thought was terrific about ASCO this year is we then went into what I would call the third generation of trials, which is bladder sparing, which I'll talk about first, but also the combination with radiation, which I'm happy to talk about after.
Tom Powles: By the way, these were all investigator-initiated trials. Super important to remember that in bladder cancer, we're quite good at doing this. I do kidney cancer too, and I think we're less good. I'd like to congratulate my colleagues in the US and Europe for doing these successfully, very hard to do.
Elizabeth Plimack: Absolutely.
Tom Powles: In this trial, it's basically a cisplatin eligible group. Patients received gemcitabine and cisplatin and they received nivolumab as a triplet, and then at the end of four cycles of treatment they did a cystoscopy to define what they decide is a clinical complete response, which is a complicated issue, I'm not going to talk about now, but it is something we need to address in the future. And those patients that were in a clinical complete response were then able to go undergo basically a period of observation on immunotherapy to work out how long that immune response could last for that complete response.
Tom Powles: And actually what Matt's study showed is 31% of the original cohort, which I think was 48%, went into this clinical complete response, and of those 31% of patients, the majority stayed in clinical complete response. Now the followup is only about 12 months, and it's short, and it's weak, but it is tantalizing that there is the possibility that this is an attractive approach because then the second part to it is there was a Spanish group which did durva/treme and radiation therapy. And then there was another US group, which Arjun Belar led, which looked at gemcitabine radiotherapy and pembrolizumab as triplet therapy. The regimes were slightly different. The way they gave radiation therapy was slightly different, but that's what happens in investigator initiated trials from around the world. It's not a bad thing. It's not a bad thing.
Tom Powles: What they also show was actually quite high C- or path-CR or clinical complete response rates in the region of about 50%, but they also showed about 75% of patients disease free at six months and 12 months respectively. Now, yes, of course we've got short follow-up, but this does lend ourselves to I think a new chapter of urothelial cancer looking at immune therapy because we've got randomized trials in this space, immune therapy and bladder-sparing approaches. And so I think it's a very exciting time and it was my highlight for ASCO actually.
Elizabeth Plimack: I agree. I mean, I think it's fascinating to see bladder-sparing approaches moving to the forefront. It's harder to ask the question about doing less than doing more and I absolutely echo your sentiment that we should congratulate these investigators for leading investigator-initiated work. I mean, most of the oral sessions were investigator-initiated studies and that's sort of where we come up with the new ideas that aren't picked up elsewhere. Question for you, combining chemotherapy with immunotherapy? We have a lot of data in the metastatic space. We didn't really gain too much by adding immunotherapy to chemotherapy in that setting. Do you think that neoadjuvant space is different? And if so, how and what should we look for in the future around this question?
Tom Powles: So I think the question you've asked is a difficult one. I don't know the answer to it. In the metastatic space, unlike in lung cancer, and actually we even saw some nasopharyngeal data ASCO this year showing a really terrific hazard ratios by combining chemotherapy with immune therapy. And I don't know why it's not working in urothelial cancer, but it doesn't look like it is in the metastatic space. 130 and 361 showed us that, remember, in those trials, patients are also getting maintenance immune therapy after completion of chemotherapy, and that's likely to be deriving some benefits. So when the hazard ratios are coming in the mid- 0.8 or 0.8, and the response rates 47 versus 45%, it's hard to convince yourself we're adding very much. Logic dictates that if you translate that into the neoadjuvant setting, it won't make a big difference if you use the same drugs.
Tom Powles: And actually when you look at the single agent data across trials, and there was a Memorial study with atezolizumab and chemotherapy that were presented just recently at ASCO, but there've been previous studies with pembrolizumab and indeed with nivolumab and chemotherapy from different groups. And you look at the path-CR rates they're coming in between 45 and 50%, which isn't actually that different from what you would see in chemotherapy alone and not that different from the single agent therapy of 40%. The early point is as much as I'm hoping it's going to be different, the early pointers are that we aren't going to see a big bounce in path-CR. Now we don't know about disease-free survival and overall survival yet, and that's really important. We haven't really validated that immune therapy biomarker yet, and that's also relevant.
Tom Powles: Nevertheless, I'm not expecting to see a huge bout in path-CR. If you want my hypothesis about what's going on, I think there are two possibilities. The first is when one looks at lung cancer and urothelial cancer, there are huge differences biologically between the two, obviously, but TMB and PD-L1 are high for both. But we do have this quite powerful TGF-beta stromal influence in urothelial cancer, which appears less prominent in lung cancer. And it may be that that is having an effect on T-cell trafficking involved in this synergistic effect. It's possible. I'm not suggesting it's correct, but it's a hypothesis.
Tom Powles: And the second hypothesis, which I think we can learn from the breast cancer field, is when you use different chemotherapy drugs, not all chemotherapy is the same. We all know not all chemotherapy is the same and actually some are more myelosuppressive than others. Some are having different effects on Tregs. And the assumption that gemcitabine is going to do the same as a taxane immunologically is a probably as flawed as saying all the PD-L1 biomarkers are the same. We know that's not true, and therefore we know that different chemotherapy drugs are likely to have a different effect.
Tom Powles: Gemcitabine is immunogenic Domestos. Now people have said to me before it's because they can affect the Tregs as well. Yes, there might be some truth in that, but the reality is I suspect that the gemcitabine's causing the problem. And that's why we probably ought to explore perhaps other combinations. And I think that's why the enfortumab vedotin combination, which is also being tested in the neoadjuvant space, which is a different agent with a different payload MMAE rather than gemcitabine, which is less myelosuppressive, may turn out to be important. So we will answer that question in the end Betsy.
Elizabeth Plimack: So that's a great segue to more enfortumab vedotin and to the metastatic space. So when we're talking about metastatic disease, obviously our paradigm changed with the JAVELIN 100 data that you presented last year, where we start mostly with chemotherapy. We saw the frontline studies read out with a minimal benefit to PD-L1 high patients with checkpoint alone. So we've really moved away from that, but then comes the follow-up data for enfortumab vedotin with pembrolizumab. What did you think of those data and where do you... Do you think that's coming to us clinically? Do you think it'll be a frontline approach? And what are your thoughts about sort of operationalizing that?
Tom Powles: I mean, I think that the question you've asked it might be the most important question in metastatic urothelial cancer at the moment, in my opinion. The reason I think that's the case is the data that's coming out with EV plus pembro looks like we're getting more durable, longer-term responses. I think the longer term data... It's a small cohort of patients and it is important to stress that, but I... You were involved as well, Betsy. The original Mike Atkins... I remember I was in the room when we were, when we were back in rooms, when Mike Atkins at a SITC meeting presented the axitinib and pembrolizumab renal cancer data. And it was almost too good to be true. And as it turns out, it was true and we did see response rates that were additive. And we see now response rates of 50 and 60%, and we saw a recent disease free survival progression-free survival of 24 months for LEN/PEM.
Tom Powles: You know, who would have imagined we'd have seen that. I think the enfortumab vedotin/pembrolizumab data, it has the same feel to me with that. The markers that are coming out of that data set are consistently better than you would expect. And I'm really excited about a study called EV-302, which is EV plus pembro versus frontline chemotherapy gem/cis or gem/carbo as the control arms. As time changes, there are some challenges with the study, and that's a good thing because it suggests the move, the field is moving forwards. But that study is going to be an incredibly important trial, and I'd like to think we will beat chemotherapy in my opinion. I think we will beat chemotherapy that trial.
Elizabeth Plimack: Yeah, no, super exciting. Well, we will circle back to you at the end for also... I know you had some really quick picks for us to highlight in urothelial, but let's switch gears just for a minute to renal cell carcinoma. More than a minute because there's a lot to talk about. So Rana, so excited to have you with us. I know you did an excellent discussion, the adjuvant plenary session. You don't need to repeat all the points you made, but how do you suggest we view the data as we have it currently? What are you looking to in the future and where do you see this fitting for us clinically, both short-term and long-term?
Rana McKay: Well, thank you so much for having me, Betsy. I think it's really an exciting time in renal cell carcinoma because the field has just been changing so rapidly. I do think that the adjuvant pembrolizumab data are really groundbreaking in that they are catapulting us into a new era of adjuvant based trials in RCC. I think it's been a long time coming. We've all been eagerly awaiting the results of what are going to be the outcomes for adjuvant IO therapy. And I think we're just beginning to see the start of a series of trials that are likely going to be reporting out in the next several years that are likely going to change the way that we practice.
Rana McKay: You know, it's been, not say unfortunate, but I think we were all excited around the VEGF adjuvant data. I think we were eager for it, but then when it came out, it was a little bit of a downer. You know, there was a signal with regards to disease-free survival, but the toxicity was great. There was detriments on quality of life and there was really no signal with regards to overall survival. Now, these trials were not necessarily designed with OS as their primary endpoint, but there was nothing. The curves were not really separating. They were literally lying on top of each other.
Rana McKay: And I think the data is still... It's still way early. I think there's only been, you know, 25% of the OS events that were suspected to occur thus far for like final analysis. So I think it's still pretty early, but I think the fact that we're seeing a tremendous disease-free survival benefit this early on, and also beginning to see a signal for OS. Again, it's still early. And I think we, our patients are living longer and living better and we need to kind of, once we start having more events, see how things settle out. But I think this is going to be the start of a new era.
Rana McKay: I think there's a lot of questions to be had because the design of the subsequent trials to be reported. There's perioperative approaches where you prime with one dose of nivolumab and then continue for nine months. There six months. This study was 12 months. There's a lot of different iterations on duration of therapy. and we really haven't... It's somewhat arbitrary the selection of, you know, six versus 12 versus nine, but I think the reason... I think this data is really groundbreaking because, like I said, it just catapults us into this new era of...
Rana McKay: And the quality of life data too. You know, we were surprised with VEGF inhibition because the toxicity profile and quality of life impact is dramatically different in the adjuvant setting. And half of the trials conducted needed to undergo dose modifications, but the regimens were too toxic. And so the fact that we're seeing, you know, a toxicity and AEs kind of comparable to that in the metastatic setting, and we saw a little bit of, you know, insights into treatment, discontinuations, things like that. It was, you know, I've been 17% of patients underwent treatment discontinuation for AEs in the pembro arm. So not that that we would see with VEGF TKI. So definitely groundbreaking.
Elizabeth Plimack: For sure. I mean, I agree with you. I think I'm really excited about this approach. We wouldn't be in oncology if we weren't optimists and I'm excited to see immunotherapy make it dent in this space. I think mechanistically it works as well. So I'm going to ask Tom and Rana the question that's all over Twitter, which is: what will you do with the next patient you see in clinic that comes to you with high-risk pathology to the adjuvant treatment? Would you discuss sunitinib, recommend it, discuss pembrolizumab, recommended it, or sit tight and observe? Tom, what would you do?
Tom Powles: So think that it's a difficult question. And I think that the, the ESMO guidelines committee, which I'm involved with had met and had this discussion, I'm very happy to share it with you now. There is a genuine need to see overall survival and that's unanimously agreed by almost everyone I meet because inevitably we are over-treating probably 50% of the patients who will never need the treatment. And the treatment is associated with irreversible long-term toxicity in a small proportion of patients, some of which can be devastating. So I think that there is that important statement. The study was well conducted and is robust, and I think that there was the inclusion of the M1NED population. And some people were saying to me, "Well, how much of that population? How much is that skewing that survival signal?" We don't know that yet. And that is important to some people who I've spoken to.
Tom Powles: I think that when you ask people what they think of the results and that's includes the group that I've spoken to the results are better than people were expecting. And I think the thing that seems to be swaying people's opinion, and I think the thing that will sway the patients as well in the end will be the trend towards overall survival and the plausibility of immune therapy, biologically, having long-term cure, because we've kind of seen that in the metastatic space.
Elizabeth Plimack: So I'm going to try to do the impossible, which is pin down Tom Powles. Next patient in your clinic, high-risk pathology, they say, "What should I do?" What do you recommend?
Tom Powles: I would say to them that there are risks associated with having this therapy, because I don't know that you will live longer, but if I, but if I was in your position, I would probably have it.
Elizabeth Plimack: Interesting. Rana, what would you say?
Rana McKay: Yeah, no, I think that it's all about goals of therapy for the patient. And I think every patient that walks in through the door has a different, different goals and different, you know, things that are of value to them. And I think our job is to kind of relay the data and help interpret that data. And, you know, I think what we're all optimistic about is, you know, is there going to be a tail on the curve? Are people going to actually be cured with the receipt of adjuvant therapy that otherwise would not be? That may not necessarily be captured by us just looking at medians. And so I think that that is sort of the hope that we are all holding onto, but we haven't shown that in data thus far. And so personally at the present time, I think the data...
Rana McKay: You know, in the US sunitinib is FDA approved for use, and I can count on my hands the number of times I've used sunitinib in the adjuvant setting. These data, even as they stand right now in my mind are better than that, you know?
Tom Powles: I agree with that.
Rana McKay: And so, you know, so that's, I think, my point for recommendation around a therapy is that we have an FDA approved therapy that's not the greatest, and this is better than that. And so I think sharing that, weighing the pros and cons, I think, you know, for... You've got a young patient with very high resilience. These are, like you said, M1NED. Even though those patients only were 15% of the patient, you know, it was actually skewed towards the lowest risk patient, which is why I was like baffled to see the outcome that we saw because the majority of patients, if you calculate their, like, UISS, it's like 50 to 80%, like, you know what I mean? It's actually better risk. And so they're not, I don't think that those patients are skewing the data, but we have to see and also patterns of progression we have to look at. But nonetheless, I think this is better than where we're currently at right now. So I think it takes that discussion of saying, you know, depending on what is important to you, you know, driving for this issue, I probably would lean towards it in a very high risk patient.
Elizabeth Plimack: Right. I mean, I think that's mostly what we're hearing. I'll, I'll counterpoint that gently to say, absolutely, it's a discussion and there's always the right patient to take that risk based on the fact that we hope and think that OS will be positive. But the only thing that gives me pause is we have such good combinations in the first-line metastatic space, which I'll use to segue to that discussion for you, Rana, that it's possible that we actually do better and sort of erase that OS benefit that we get with early treatment with single-agent with our more robust and more powerful combination therapies. And that's why I think OS might be negative. I don't think it'll be negative, but I think if it is, it might be because we have such good treatments subsequent when people recur more than that it didn't work. And so I do want to see OS before I would recommend it to a patient.
Elizabeth Plimack: But great to have this conversation, great to have these data to talk about. And I think the longer we keep our patients with renal cell alive, the longer it will take for the events to happen, but it's a good problem to have. So we'll sit tight and wait for that, but Rana, let me segue to metastatic disease. There's been an explosion in this space recently and we saw some really important, I think long-term follow-up data from some of the earlier studies that have read out. Do you want to talk to us about sort of the highlights that you gleaned from those updates?
Rana McKay: Absolutely. So I think, you know, we saw updated data from the CLEAR trial, which was a trial randomizing to len/eve and len/pem versus sunitinib, and we saw the quality of life data that were presented from that study and, you know, first off it's, it's a profoundly positive study. And as Tom alluded to earlier, you know, PFS of almost 24 months, which is pretty incredible, I think even pinned against, you know, trying not to compare across these trials, but that's pretty impressive, especially when you look at the control arm, which had a PFS of around like nine months or so, which is, you know, different than the PFS control arm that we saw for, you know, KEYNOTE-426. So I think that data is pretty impressive. I think we've all had this hesitation that, oh gosh, the, you know, the toxicity profile may be a little bit, you know, worse with the len/pem, you know, 70% of patients had, you know, grade three, four tox, you know, 23% of patients or so had to stop the lenvatinib, but it was actually really encouraging to see that the quality of life data appeared to be, you know, improved over sunitinib when you look at len/pem.
Rana McKay: Now I have to say, the quality of life analysis are not to say a little bit troubling, but they're, you know, they're exploratory endpoints. What is statistically significant versus what is clinically meaningful is variable. And, you know, when the instruments... The type of instruments that are utilized are all different across the studies, when the instruments were deployed, they're all utilized different across the studies. Who's filling out the quality of life questionnaires? Like if I'm sick in the hospital, I'm not filling out of quality of life questionnaire. So I think there's a lot of, you know, by potential bias that comes in when you look at quality of life, that has to really be accounted for, but I have to say it was great to see the data get presented and, you know, Andrea actually broke down sort of some of these nuances and the biases that that can exist in quality of life analysis.
Rana McKay: But at the end of the day, I think the point is that it was comparative data. It was, you know, a randomized trial where you at least head, you know, the same pool of patients that were filling out the sunitinib questionnaires. And so, you know, I think the fact that patients are potentially having improved quality of life is nice to see. So that data got presented and, and we've seen that quality of life data presented from nivo/cabo showing a similar type of effect. We saw the data from CheckMate 214. I think the KEYNOTE-426, again, different instruments, different time points, didn't seem to be worse than sunitinib, you know, and that patient population had a lot more favorable risk patients. So maybe they're just not as sick from their disease and that is skewing why the results look the way that they do.
Rana McKay: But nonetheless, I think it was nice to see that at least there wasn't, you know, detriments or at least it's on par with Sutent or in some domains a little bit better than Sutent. So it was nice to be able to see that.
Rana McKay: And then we also saw the updated data. I think this is the last data cut for KEYNOTE-426, you know, with, you know, almost four years of up and, you know, continues to be a very efficacious regimen. And, you know, I hate to do this, but in my mind, I thinking, you know, durability of these regimens and IO-IO compared to like, you know, IO-VEGF, if you're looking at the PFS curves, I'm looking at the OS curves, you know, there seems to be with nivo ipi sort of a tail that emerges starting around 30 months, and just holds steady there for like right around 30%. And I don't know that we're seeing that. I don't know that the studies are designed for us to be able to see that, but, you know, I still kind of, now that we're having longer follow-up from KEYNOTE-426, you know, the big question continues to be durability. You know, when you're thinking of, you know, IO-IO versus IO-VEGF, but it's great to be in this situation where we have, you know, four very active regimens that have demonstrated improvements in overall survival and response rates.
Elizabeth Plimack: Yeah. It's, it's hard when the tails are full of hash marks for censoring and that's where, you know... Hopefully this won't be the last OF 426. I always say we need, you know, we need to follow these patients until they all die of something else or cancer to really know who we've cured. But yeah, it's good. It's good to see the long-term sort of durability of the landmarks still being hit, which is nice. And then I think we... That kind of covers the major updates we saw, right? For the first line metastatic. Good. So Rana, any abstracts that you thought, you know, maybe sort of really early data or things that were more provocative than definitive that you think were compelling or that we should keep our eye on?
Rana McKay: Yeah. You know, I actually thought that the work from Dr. Pal and the City of Hope group looking at CBM588 with nivo/ipi compared to just nivo/ipi alone in intermediate, poor risk, newly diagnosed RCC was pretty provocative. You know, I think we've all, you know, been intrigued by the microbiome and the role that it can play within, you know, response to immunotherapy and cancer therapy in general. And first off, I'd have to just commend them on putting together a randomized trial in this space with-
Elizabeth Plimack: Also investigator-initiated, right?
Rana McKay: Yeah. Also investigator-initiated with this probiotic, you know, agent that demonstrates a signal that there could potentially be improved responses, but again, the numbers are so low. The control arm had a response rate of, I think 20%, which is, you know, below the bar for nivo/ipi from the phase three trials. But I, you know, I'm excited to see the potential for the approach, you know, in the future. So, so definitely I think continue to watch out for things to come from that group.
Elizabeth Plimack: Microbiome, fascinating space. Tom, I'll send the same question over to you: what were your sort of key abstracts from ASCO that might've been a little early, not yet practice changing, but things that made you kind of raise an eyebrow and say "that's one to watch"?
Tom Powles: Well, I liked Jonathan Rosenberg's, and the group that he led, the study with rogaratinib plus atezo frontline FGF-altered urothelial cancer with response rates, 58%, only a handful of patients, but you might remember that we, of course you do, but we've looked at combinations before with VEGF with, with other targeted therapies, immune therapies in a personalized approach in the second line setting without great success. And so I think this is maybe saying, if you move it frontline, maybe it works a bit better. And so I'm excited about a study called NORSE, which is a randomized trial of erdafitinib versus erda plus PD-1. So I'm excited by that. And I think that was something which was a little bit buried perhaps, but you know, there was so much other things to talk about at the meeting. And the other thing, I think I agree with Rana, I think that there is this issue around quality of life, assessment of patient reported outcomes. And, and we need to look really under the bonnet at the detail before we saw making big trial comparisons saying "this one has it and this one doesn't." I worry about that being an oversimplification.
Elizabeth Plimack: Excellent. This was so much fun. Both of you, really fun to discuss these abstracts. I can't wait so we can do it in person. Hopefully, hopefully next year or before, but I'm glad progress continues despite the pandemic. It's great to have the opportunity to talk about them and think about them and really exciting for our patients that, that we're moving the bar, which is great. So thank you, Tom. Thank you. Rana.