Oncology Today with Dr Neil Love: Key Presentations on Genitourinary Cancers from the 2022 ASCO Annual Meeting (Video Interview)
Oncology Today with Dr Neil Love: Key Presentations on Genitourinary Cancers from the 2022 ASCO Annual Meeting
![]() Sandy Srinivas, MD Featuring an interview with Dr Sandy Srinivas. Published July 28, 2022.
Rationale for and efficacy data from the Phase II SALV-ENZA trial of salvage radiation therapy with enzalutamide or placebo for high-risk recurrent hormone-sensitive prostate cancer DR LOVE: So the first thing I want to ask, but I was very surprised when you talked about this SALV-ENZA trial which sounds like a really great idea. I mean you just saw that paper adding abi to ADT. So these are people who have PSA elevations after surgery, who are going for salvage radiation. Makes perfect sense, add in a hormone. They looked at enzalutamide and saw progression-free survival. But the thing that surprised me was they didn’t get ADT, right? DR SRINIVAS: Right. Because remember, unlike abi, which decreases androgen biosynthesis, enzalutamide, apalutamide and darolutamide, they just block the androgen receptors. So they’re just really not letting anything percolate through the androgen receptors. So patient’s testosterone levels, if anything, are higher. So as a monotherapy, it’s been quite interesting. One thing that I had asked the authors at presentation was, was there an increased incidence of gynecomastia? So that’s what happens when you have normal levels of testosterone and you block the androgen receptor. In the Short study, they did not note an increased incidence of gynecomastia, maybe because it was only for 6 months you didn’t see that. But definitely interesting and it’s very patient-appealing because a lot of patients, when they undergo salvage radiation, detest the idea of having their testosterone levels down. And then especially with things like ADT, like LHRH agonists, your recovery of testosterone takes quite a long time. So this was an appealing drug. DR LOVE: Absolutely. Actually, I don’t know, do you remember that adjuvant trial was like the biggest trial in the history of oncology. it was like 9,000 patients. And I remember the thing about they gynecomastia. I think some people would radiate their breast, or whatever. But I just think quality-of-life-wise, it seems like you’d be feeling a lot better just on enzalutamide without ADT. DR SRINIVAS: Uh-huh. Yeah. But I mean I think we need overall survival. We need bigger trials. It’s a very small study, 80 patients. DR LOVE: Yeah, but when you think about the whole arena, like it kind of fits in with all the other stuff. Every time you add an anti-androgen, you see benefit. You see a lot of survival. I know it’s not this exact situation, but M0 disease. Hormone-sensitive disease. So, it doesn’t seem like a huge stretch. I gather that you’re not exactly enthused about actually trying it right now if you could? Or would you? DR SRINIVAS: No, I’m not committed to it yet because there are some things that are unknown. I think we don’t know about the duration of therapy. We don’t know whether any patients need it. You know, the field is really moving towards can you escalate? Are there patients who could be de-escalated? There are genomic data that’s been looking at as to who needs it and who doesn’t. But I think it’s very early on and I like the concept, but I don’t know whether I’m ready to jump into that yet. Results from clinical trials evaluating abiraterone, docetaxel or apalutamide for patients with hormone-sensitive prostate cancer DR LOVE: It wasn’t at ASCO, but I’ve heard a lot of people talking about that STAMPEDE data that was I think presented at ESMO or something, but it made sense. I know it wasn’t at ASCO, but I’m just kind of curious what your thoughts were about it? Maybe you can just briefly comment on what they looked at and whether you would like to bring it into your practice? DR SRINIVAS: Yeah I think the STAMPEDE definitely has a much longer follow-up. And it was quite convincing that patients who have high risk, the addition of abi to ADT and radiation resulted in improved outcomes. So I think that’s already being incorporated. We are much more — we have longer follow-up combining ADT plus abi in this high-risk patient population. So this is the next generation, trying to see if we can improve on it. DR LOVE: You were talking about some data in terms of cardiovascular events, and you mentioned, I think it was with PARP. But I’m just kind of curious where we stand right now with abi and cardiovascular events, abi/pred. DR SRINIVAS: I think it exists because there is increase in hypertension. There is an increase in mineralocorticoid excess. So, all of that in a patient population who’s at risk. People who are elderly have a vulnerable — who are vulnerable to atrial fibrillation. So I think that’s definitely real and it exists, but I think people have gotten more comfortable with awareness to be able to manage it. And given that there are alternates now, so if you have somebody who’s very high risk, cardiac averse, we use some of these AR targeted drugs. DR LOVE: So you also mentioned from ASCO the update on ENZAMET and also referred to other trials looking at docetaxel in hormone-sensitive metastatic setting, PEACE1 and ARASENS. And I’ll tell you that I think there’s a lot of confusion in general medical oncology about this. I think people have the feeling that you all are using docetaxel in younger patients, particularly higher risk. I’m not sure I even understand the exact logic from how you get this out of these trials. But bottom line is, what do you think the evidence shows us about whether or not to use chemo/docetaxel in hormone-sensitive metastatic disease? DR SRINIVAS: I think that’s still an open question. We know that docetaxel works. We know that these hormonal drugs work. Who is it appropriate to do triple therapy? And I think that’s where there is some confusion. We know that patients with high volume who present with synchronous disease, they have the worst outcome. So the idea really is to throw everything at that patient upfront so that they can get the best outcomes. So I do offer it to patients who are young, who are fit for chemotherapy, to do ADT plus docetaxel and add 1 of these drugs, be it abi, darolutamide, or now you have enzalutamide. So I think for the patient who’s high risk/high volume de novo disease, who’s chemo-fit, I think triple therapy may be appropriate. DR LOVE: So I also was curious about, you were talking about some data form the TITAN trial looking at apalutamide. Whenever we do webinars I just sit there and wait for somebody to bring up circulating DNA because somebody always, no matter what they cancer is, as long it’s solid tumor, somebody is going to ask about it. So I thought it was really interesting that they went back looked at this trial in terms of circulating DNA. Also, in terms of AR aberrations. Because you kind of hear a little bit about maybe there’s a relationship between chemo and that. I thought it was interesting that they looked at that. What did you come away with? Do you feel like this is maybe going to be something for the future? DR SRINIVAS: I mean I think ctDNA, we have always — PSA has been such a cheap marker to follow in prostate cancer, whereas in other diseases like bladder cancer for instance, I’m much more open to looking at circulating tumor DNA. Is circulating tumor DNA going to be superior to PSA? In the past, being able to find this enumerate ctDNA has been quite a challenge. I think technology is improving. It may be more a biomarker for prognosis. I don’t know whether it’ll be practical to use every day to make treatment decisions. TheraP trial: Three-year overall survival with 177Lu-PSMA-617 versus cabazitaxel for metastatic hormone-resistant prostate cancer DR LOVE: You also commented on the follow-up from the Thera-P study, a really interesting trial comparing lutetium to cabazitaxel. One thing that you mentioned that I hadn’t heard before was, and it really makes a lot of sense, that there were a number of people who dropped out once they realized they were getting cabazitaxel. Makes sense. Lutetium is not approved. Patients want to try to get it. But first of all, do you think had a significant effect on the data? DR SRINIVAS: I think it did. Any time you have a crossover, making overall survival. DR LOVE: Oh yeah, that’s another thing. DR SRINIVAS: We see this in large Phase III trials, right, so dropouts, crossover. I just thought that it was asking too much out of this trial. It’s such an incredible trial that gave us so much information about cabazitaxel versus chemotherapy versus this lutetium, and I don’t think it should hamper any interest in moving lutetium early on. There are already many trials looking at bringing lutetium to an earlier-line therapy. I do think cabazitaxel is very appropriate for some patients because almost a third of patients don’t respond to lutetium. So it’s not a drug for everybody. It is expensive. You have an associated scan that needs to be done with it. We are beginning to understand that patients maybe with significant liver metastasis, those that a PTEN loss, RB differentiation, may have very aggressive disease and may need chemotherapy. So, to me, it just feels like we have a choice. They all have Category 1 recommendations and we just have to pick the right drug for the right patient. DR LOVE: That’s interesting though. I think usually, if there’s a crossover, people don’t even think about survival. I mean it’s interesting, but you certainly wouldn’t expect it. But it’s also interesting in terms of the way this plays out clinically. Do I hear you saying maybe in a patient who’s symptomatic, needs a response, you might think more about cabazi? DR SRINIVAS: I don’t know. I mean patients, you look at their response was pretty good with lutetium. This is what I would do. I would do the PSMA scan. And at this meeting there were a lot of other things came up that if you had a SUV-mean that was greater than 10, those patients responded much better to lutetium. So I think we’ll start looking at things like that to determine who should get lutetium. So if do a PSMA scan, and it’s not that impressive, I’m going to give them cabazitaxel. If their SUV-mean is really high, I think those patients definitely responded better to lutetium and had a much improved overall survival compared to those with a low SUV-mean. DR LOVE: What about the issue, if you could, of using lutetium before docetaxel in an older patient, doesn’t want chemo, or you may be concerned about it. If you could, are there situations where you would use it before docetaxel? DR SRINIVAS: I mean right now the VISION study, which really looked at patients who had had completely refractory disease, so they had to have had a taxane. In fact, 50% of them had 2 taxanes, both docetaxel and cabazitaxel. So at the NCCN, the decision where lutetium-617 was approved was exactly in these patients who had had prior hormonal and docetaxel. There are clinical trials looking at PSMA in the pre-chemotherapy space. So we certainly want to encourage patients to participate in those trials so that we know truly whether there is an improvement pre-taxanes. And I think we will get there. But right now, given that there are multiple clinical trials asking that question, we would definitely want those trials to be completed. DR LOVE: So we could talk for a long time about lutetium, but just 1 more question, which is, I’m curious what you actually see in terms of tolerability? You hear about dry mouth. Like, what actually do you see in these patients? DR SRINIVAS: So I would say it’s relatively well tolerated. To me, as we were part of the VISION investigators, definitely found fatigue, which I think is common to all of these treatments. There is an on-target to salivary glands and to the kidney. So, certainly keeping an eye on that is important. Dry mouth does happen with these drugs. And people are looking at ways by which we can alleviate dry mouth. So patients have dry mouth. Not much by way of renal dysfunction, even though there is expression of PSMA in the kidney. So, 2 big things that I see is some decrease in blood counts, fatigue, and some minor dry mouth. Clinical data with abiraterone acetate in combination with PARP inhibition for patients with metastatic hormone-resistant prostate cancer: Results from the PROpel and MAGNITUDE trials DR LOVE: Let’s tackle the PROpel and MAGNITUDE landmark studies that were just initially presented a few months ago at GU ASCO and you talked about some follow-up data presented at ASCO specifically related to olaparib in terms of toxicity in the PROpel trial, and some more data from the MAGNTITUDE study of niraparib. So, first of all, maybe you can just briefly summarize the initial data set that was presented? How you reacted to it and how you read your investigator colleagues’ reacting to it in terms of taking it into practice? DR SRINIVAS: I think it’s probably one of the most confusing issues right now in prostate cancer about who is appropriate to get a PARP inhibitor. So we know that patients who have HRR-positive, especially those you have BRCA, they’re the ones who benefit the most. So we know that from the PROFOUND study and that’s what led to the approval of olaparib. Rucaparib is also approved in patients with BRCA-positive disease, but in the castrate-resistant setting. What was really interesting was the PROpel study and I must admit that I was surprised at the results. There was an earlier Phase II trial, which was a very similar design, where they took all patients who are abi-naïve, and randomized them to either abiraterone plus placebo, or abi plus olaparib. And that trial did show that whether you were HRR-positive or not, there was a benefit to the combination. That was the impetus to go on to doing PROpel. And I was really surprised that the trial had identical results to the Phase II. And to me, it’s really unclear why that is. Why do patients who don’t have HRR benefit from this combination? And I don’t know the answer to that. And I think that’s what the field is struggling. But suddenly, the improvement in PFS was pretty impressive. So we’ll wait for the overall survival. But I think the bigger question is, has the field moved away from this? Because abi use is now almost — I mean it’s moved, as you had mentioned earlier, we are using it in the localized setting, with radiation. So in my practice, I don’t know if I will have a patient who becomes castrate-resistant who would not have seen abi or 1 of these drugs. DR LOVE: Well, but they’re going to come in prospectively. So when you see somebody like — you’re going to see people like that I’m sure, right? DR SRINIVAS: I’m not sure. Because they would have all received abi or 1 of these hormonal drugs in the hormone-sensitive setting or in the localized setting, I think, unless it’s somebody coming from another country who have never had access to these drugs. Finding somebody in CRPC who’s never received 1 of these drugs is going to be a minority. DR LOVE: Hmm, that’s a really interesting perspective. I guess the other thing is what these data mean in general, particularly the 2 trials? We were talking about general medical oncologists, again they’re looking at these data, but they’re looking at other data. The thing that’s always struck me as weird is that in ovary, niraparib is the one that has the data in HR-proficient. And that’s where it’s approved — it’s part of the approval. It’s also approved with germline BRCA, or somatic BRCA, also. And here, as you said, they didn’t see any benefit. DR SRINIVAS: Certainly patients who are BRCA-positive have a worse outcome. And I think they will benefit from the combination upfront, rather than do sequential. DR LOVE: That’s an interesting perspective as well. I think that a lot of people are going to be tempted to do that. It’s interesting, again, sorry to make the comparison, but in ovary when you compare directly niraparib and olaparib in BRCA germline, it kind of looks the same. And most people feel like, theoretically it’s a coin toss. But I’ve heard people say they think the olaparib data is more, impressive than niraparib in prostate in these 2 studies. Do you agree with that, or you can’t really compare? DR SRINIVAS: No, I do. I’m perplexed by the PROpel data. I think that was definitely more convincing, the magnitude of benefit was more. I just don’t understand the science fully behind it. And it would be great if we see an OS. But putting MAGNITUDE AND PROpel together, I think the BRCA patients, I’m convinced today that if somebody comes in who’s BRCA-positive and abi-naïve, I’m going to use the combination. Everybody else I’m just going to sit tight until it plays out a little bit better. DR LOVE: So I have a feeling I know how you’re going to answer this question because you seem to be an evidence follower very strictly, but what about an anti-androgen plus olaparib or niraparib? Too big of a leap for you? DR SRINIVAS: Yes. They’re about the same, but I don’t know. Yes, I would hold off. DR SRINIVAS: You were commenting on the safety data that was presented from the PROpel study. What’s your critical take on that? What was it that came out that you thought was most important? Also, you didn’t comment on AML and MDS, I think there was not that much of an issue. Is that right? DR SRINIVAS: Yes, not that much of an issue. The Phase II trial had some cardiovascular deaths, so it was very reassuring that in this large PROpel trial that there wasn’t any cardiovascular deaths. There was an increase in venous thromboembolism. I don’t know whether — I mean it’s a patient population that’s older. They are at risk. Certainly, there was an imbalance and that’s something to keep an eye on. Current role of neoadjuvant chemotherapy with immunotherapy for patients with metastatic urothelial bladder cancer (UBC); updated long-term outcomes with enfortumab vedotin from the EV-301 trial DR LOVE: So let’s talk about urothelial bladder cancer. And you started out with neoadjuvant trial looking at chemo plus IO, specifically durvalumab. Can you kind of summarize where we are in general about the use of IOs upfront in metastatic disease? We have data like this; it’s beginning to look at neoadjuvant chemo/IO. We’ve seen that in lung cancer, for example. There was an approval there. Obviously, you have the maintenance strategy or the JAVELIN strategy, but also the failed trials of chemo plus IO, unlike lung. So, where do we stand right now in terms of IOs in this up-front setting? DR SRINIVAS: So IOs in the upfront setting, I think for metastatic disease chemotherapy still seems to reign supreme. So if somebody, whether you can get cisplatin or whether you can get carboplatin, that seems to be better, followed by maintenance IO. That’s the highest level of evidence we have and I think since the JAVELIN trial was presented, that uptake has become quite prevalent in the urothelial community. The up-front immunotherapy I think is really for that small fraction of patients who are completely chemo-ineligible. So we do see those patients, very old patients, very frail, where they are unable to get even carboplatin-based chemotherapy. That probably represents about 10- to 15% of all patients with metastatic urothelial cancer. In that patient population, I think single-agent IO is very reasonable. In the neoadjuvant setting, it’s a little unclear. Again, there chemotherapy, if you can get chemotherapy, that’s the best treatment. And all of these trials that were listed up here demonstrate that as well. But if you have somebody who has visible nodal disease for instance, who has muscle-invasive bladder cancer, you do a scan and they have visible nodal disease, taking that patient to an operation you know is not going to serve them well. If they are chemotherapy-ineligible, I usually do a PD-L1 testing, and if they’re PD-L1 high, I would be willing to give them neoadjuvant immunotherapy, sort of assess their response, and then take them to surgery. So I think there is some room, but definitely right now it’s more individualized than personalized. DR LOVE: So you also commented on data presented at ASCO from the EV-301 trial looking at enfortumab. Of course, that was the trial that actually got it approved. What did we see in this follow-up? And what’s your experience been with erdafitinib in terms of efficacy and tolerability in your own practice? DR SRINIVAS: So enfortumab is the ADC against nectin and approved in refractory setting. Definitely a very effective drug. We are seeing consistent data from the 301, which is very similar to the earlier line therapy. So there is a trial combining enfortumab with pembrolizumab in the frontline space, and that had a pretty remarkable response of almost 70% with 16% CRs. So that data is being awaited. Enfortumab is a good drug. People have to get comfortable using enfortumab. It has some side effects especially neuropathy, skin toxicity. DR LOVE: You were commenting on the fact that it’s good for people to get used to using this drug. And you’ve had a lot of experience with it. What would you say to people who have less experience in terms of clinical pearls that are important in keeping people on the drug? DR SRINIVAS: Yeah, I would say watch out for skin toxicity. And if they were to have skin toxicity, jump on it sooner by taking care of it either with topical steroids or if that increases, patients may even need systemic steroids. Partner with dermatologists who have been incredibly helpful helping us manage these side effects so that patients can stay on drug. And the second one is neuropathy. Most of these are quite manageable with reductions or dose delays. DR LOVE: So I always like to mention to people in other specialties outside of GU, that bladder has 5 lines of therapy approved. I think that’s a record in metastatic disease. Clinical pearls for preventing and managing adverse events with erdafitinib, sacituzumab govitecan or enfortumab vedotin in patients with UBC DR LOVE: The other alternatives that are out there past chemo and IO, first of all erdafitinib in patients who have FCR mutations, but also sacituzumab. A lot of times I talk to oncologists, they use erdafitinib, it’s the first time they’ve ever used it. And that happens all the time in general medical oncology. Again, in terms of some pearls from you having used these drugs, I think sacituzumab is a different story because they’ve used it in breast, but any pearls about keeping people on erdafitinib? And also your experience with sacituzumab. DR SRINIVAS: I think erdafitinib is interesting. It’s our first FGFR drug that we have. So I would say test early because until you know that they have the mutation, you’re not going to be offering it. So my first advice would be do a next-generation sequencing early on. I typically do it once patients have, they’re on their first line for metastatic disease. That way I have all of the options lined up. Second, erdafitinib, there are issues with hyperphosphatemia, which is the one that I find challenging to take care of because diets that restrict phosphate is quite challenging for patients to adhere to. So again, you need a multidisciplinary team, giving patients some counseling about what they can eat so that you can help keep them on the drug, especially for those patients who are positive where you know you can have a benefit with PFS with this drug. With sacituzumab, I like the drug. I’ve used it post-enfortumab for patients who have had refractory disease. And what I like about it is that the payload is very different compared to enfortumab. This has SN38, so it’s very similar to irinotecan. So, patients major side effects are diarrhea as opposed to neuropathy. So, I like the fact that we have options with different side effect profile, that you can match it for patients appropriately. But I think, in general, ADC is a very effective way to deliver chemotherapy, and we are fortunate in bladder cancer to have 2 drugs. And at this meeting, since we saw drugs targeting HER2, really excited about the possibility of having an ADC against HER2 and looking forward to those trials in the future. DR LOVE: There’s so many drugs now with eye issues, mostly antibody drug conjugates, but not only — because erdafitinib also has eye issues. And one of them is central serous retinopathy, which you don’t hear too much about with other drugs. So, can you talk a little bit about the practical issues in terms of ophthalmic issues? DR SRINIVAS: We’ve been fortunate to partner with ophthalmologists. They were part of our investigator team. So that all of these patients, whether it was on erdafitinib or enfortumab, required an eye exam at baseline and they did it at successive intervals. I do think it’s an issue for community practitioners to be able to screen for these problems and refer them appropriately. But at least to be aware that these patients need an eye exam. And if they were to have any symptoms, then have an ophthalmology referral is important. DR LOVE: Do you know what patients usually complain of, if they do complain, when they have central serous retinopathy? Is it like a field defect or blur? What is it? DR SRINIVAS: It’s interesting. They actually start off with dryness, dryness of the eyes is the first thing they complain of. And then it’s visual issues. So just at each visit, even asking about this, having some of those eye charts, which I think every practice has, would be some practical things for people to be aware of and then do the appropriate referrals. DR LOVE: So one more question about enfortumab, because there is so much excitement about adding an IO or pembrolizumab. There’s a neoadjuvant study everybody all excited about. Do we know whether or not people who’ve had prior IOs do better with enfortumab, because that would kind of maybe encourage that strategy? DR SRINIVAS: I mean right now where enfortumab is approved after 301 is in patients who have had chemotherapy and IO. So we already know that. But I think, just like in the ovarian space, we define platinum-resistance as, right? I don’t know, I think as we get multiple IOs, we don’t know what that IO resistance time should be. Because immunotherapy is approved now in the adjuvant setting. So if somebody gets nivolumab and then who has metastatic disease, what do you do for that patient? I think we are beginning to define these terms better. And since all of these drugs are moved to the frontline space, subsequent therapy is definitely a challenge and I think we are learning. HER2 expression in UBC and emerging data with the novel HER2-targeted antibody-drug conjugate RC48 alone and in combination with toripalimab; tolerability of antibody-drug conjugates DR LOVE: I’ve been hearing about HER2-positive bladder cancer. What fraction of people are HER2-positive overexpressed? And also, the other thing that came out was HER2-mutant. What do we know about that in urothelial bladder? How often? DR SRINIVAS: I think we don’t know. I mean overall, prior to this meeting, HER2 was about 12%. Didn’t seem like a huge player. But I think we are beginning to learn, are we doing the right test? It appeared that it could be as high as 50%. So I think it depends on what you test; how you test. DR LOVE: Yeah. I mean breast cancer is only 15-, 20% HER2-positive. So if it’s 10 or 15%, and then HER2-low. We know 1+, 2+ FISH negative, I don’t know what that is in bladder. I don’t even know whether these drugs would work. But the bottom line is there’s another HER2 antibody drug conjugate RC48-ADC, a novel humanized anti-HER antibody drug conjugate that they reported with toripalimab, an anti-PD-1 agent that I guess is not approved, or not available. But I guess a typical IO. It looks like a 1-arm study that you talked about in your talk, very impressive waterfall plot. And then you also commented on the data looking at monotherapy with the antibody drug conjugate, and that waterfall plot looks pretty good, too. So I guess the bottom line is, what is this agent? What kind of toxicity does this thing have? Is it different? Breast cancer, they have 2, T-DM1 and T-DXd, 2 antibody drug conjugates. How does it compare to those 2? Where is this all heading? You said it was your favorite abstract of the meeting. DR SRINIVAS: I love the abstract. And I think for an ADC, you’re looking at the target. You have to look at the linker, and you have to look the payload. And each of these are different for different drugs. This drug, RC48, the payload and the linker look very similar to enfortumab, which is very different from — so not all ADCs are created equally. DR LOVE: Absolutely. DR SRINIVAS: Sacituzumab, it appears have a different payload. The linker may be different. We talk about cleavable linkers and non-cleavable linkers. So I think there’s a different level of potency. There’s different level in terms of the payload. But interesting, I thought that this drug would be incredible in urothelial cancer where it doesn’t have the skin toxicity. Because unlike nectin, which is present in skin, this would have a different side effect profile. And if you look at the toxicity, that sort of made sense. The toxicity were all related to the MMAE, so mostly neuropathy, some nausea/vomiting. You didn’t see much by way of skin toxicity. So it’s nice to have different choices, that I think people will have different patient profile for whom 1 drug might be appropriate, compared to something else, when you have different choices. DR LOVE: So, what about tolerability? As you said, you see all kinds of interesting things with antibody drug conjugates. The second name of vedotin, as you said, when you think about brentuximab, for example, you think peripheral neuropathy. Is that pretty much the issue here? DR SRINIVAS: Yes. Based on the MMAE. Based on the payload. DR LOVE: And then reversible if you catch it early enough? DR SRINIVAS: Yes. I think, at least what our experience with enfortumab is, if you decrease the dose, if you delay the dose, then neuropathy is reversed. DR LOVE: So we’ll definitely keep our eyes on that. and I would imagine these other drugs are going to get a look. Another paper you commented on was COSMIC-021, because we’re about to talk about renal, but this is cabo and atezolizumab. So, TKI and IO. What did they see there? And do you see a future for that type of strategy in urothelial cancer? DR SRINIVAS: I mean VEGF-TKI in urothelial cancer has not really made it to the frontline, other than erdafitinib, which inhibits the FGFR pathway, didn’t find much for VEGF. It didn’t matter whether it’s in the maintenance setting. There was also a trial that was presented called the ATLANTIS trial, where they took patients who had chemotherapy and similar to JAVELIN, they put them on maintenance cabozantinib. And that trial also was not very — there wasn’t a strong signal. Based on COSMIC-021 with the 3 cohorts, I would say that we’re not seeing a big signal for VEGF-TKI in bladder cancer. Follow-up efficacy and safety data from the KEYNOTE-564 trial; practical implications of the safety data with adjuvant pembrolizumab for renal cell carcinoma (RCC) DR LOVE: All right, let’s talk about renal cell cancer. And you commented on the follow-up data presented from KEYNOTE-564, looking at adjuvant pembro. Can you just kind of remind us of the main findings of the study, and then what they reported at ASCO? And then your clinical experience using this strategy? DR SRINIVAS: So KEYNOTE-564 was a very important trial where they took patients post-nephrectomy and they identified patients as intermediate-high risk, high-risk patients, and they also took patients who had metastasectomy and who were NED. And they were then randomized to either pembrolizumab for 1 year or placebo. The primary endpoint was disease-free survival. The secondary endpoint being overall survival. And at ASCO last year, there was an improvement in DFS with the hazard ratio of around 0.62, favoring the use of pembrolizumab. And that led to the FDA approval. We are still awaiting the overall survival results. So at this year’s ASCO, there was just some updated information. One thing is that the dropout or the patients who had adverse events related to pembrolizumab was 20%. So that really gives a lot of investigators pause, that many of these patients may be cured. Patients with RCC, if they are cured, you’re now giving them 1 years’ worth of therapy, and 1 in 5 have a side effect that they may end up living with for the rest of their lives, especially we know with immune checkpoint inhibitors, for instance. Though with PD-L1, it’s a little low. If you get hypophysitis, for instance, you’re on corticosteroid replacement for the rest of your life. So I think people are a little bit cautious. They want to wait to see overall survival before you can completely commit everybody to adjuvant pembrolizumab. But certainly for those patients who were metastasectomy and who were NED, the hazard ratio was like 0.29. That number is small, but I think for somebody who’s had a brain met resected, I would definitely be open as opposed to somebody just having their kidney removed, I want to wait to see what the overall survival is. DR LOVE: So, when you say, in general, you want to wait for survival, do you bring it up to patients and say, look, you might have read about this. People are doing it, but I don’t really recommend it? Or do you just say, okay, and we’re going to follow you. I mean do you kind of offer it to patients? DR SRINIVAS: Yes, I do. I think one of the challenges in kidney cancer is, how do you really assess risk? So there are many, I go to the — I mean there are many nomograms. UCLA has 1. The Mayo Clinic has 1. So I sit with my patient when they come in post-nephrectomy and tell them what their risk, at least based on the prognostic factors that we know, and say, “Hey, listen, you have a 20% risk of the disease coming back. And this is 1-year data with pembrolizumab.” So most patients, they make a decision based on the distance they’re at. How beat up they are post-surgery. Do they want a break off the medical system? We sort of present it to the patient. And then the good thing is, we also have clinical trials. So, when we have a clinical trial, that’s much easier to put the patient, offer them the trial, and that’s something that we do all the time. Emerging data with the novel agent belzutifan for advanced clear cell RCC DR LOVE: I’ll tell you the trial I want to go on if I get in that situation, the one you were talking about that adds in belzutifan to pembrolizumab. That sounds super interesting. DR SRINIVAS: Yes. DR LOVE: Any thoughts about that? And I was kind of surprised it even exists. Pretty cool idea. DR SRINIVAS: Yes, That’s the national trial today for patients with kidney cancer post-nephrectomy. So, we will have that open at our institution within a month. And definitely something that’s encouraging. Really the HIF-2, has not been druggable for the longest time. So being able to target that has what led to the belzutifan being approved in VHL. And its approval is based on having shrinkage, not just in kidney, but patients with VHL have hemangioblastomas, they have pancreatic mets. And patients undergoing surgery for hemangioblastomas in their brain and spinal cord are really a challenge. So having a drug that will at least allow them to have lesser operation, I think is a big value added in that disease setting. It's not yet approved in RCC. So I think this allows the drug to be tested in earlier lines. So I’m very excited about that trial. And hope that that benefits a large number of our patients. DR LOVE: Yeah, I remember the graphic of surgical procedures in those patients. And when they start the drug, it just stops. They stop having surgery. It’s amazing. How many people do you have in your practice with that, incidentally? DR SRINIVAS: Well, Stanford is a VHL site of excellence. So I have more than a dozen patients who are now on belzutifan. DR LOVE: Really? DR SRINIVAS: Yes. DR LOVE: Amazing. So I think a lot of people aren’t — I mean I’m kind of impressed by what you see. I know maybe not as much as with the VHL syndrome, but it looks like it has activity in sporadic RCC. Which is why that adjuvant trial sounds so interesting to me. I’m not sure people are quite aware of it. From your point of view, at least at this point, I want to get back to the more conventional questions, but since we got into it. I’m just kind of curious, not just the numbers, but what kind of activity does it have in sporadic RCC? DR SRINIVAS: In sporadic RCC, in this trial that was presented earlier in ASCO, a few years ago, and now this is an update, overall response rate is about 25% in patients who had 3 prior therapies. So that’s pretty impressive that you get a partial response. And the stable disease and disease control rate was close to about 80%. So definitely an active drug in this heavily pretreated population if we see this much activity, bringing it earlier makes a lot of sense. DR LOVE: And tolerability issues? DR SRINIVAS: Tolerability, the 2 big side effects to be aware of is hypoxia and anemia. That’s the on-target. Because it affects the HIF, you do have issues with anemia. So in clinical practice I haven’t seen too much by way of hypoxia, but we definitely see anemia. And when hemoglobin drops below 10, we have patients hold the drug and do some dose adjustments. DR LOVE: So hypoxia, like dyspnea type hypoxia? DR SRINIVAS: Yes. We have them measure their O2 sat. And if it drops less than 92, we have them call us and make dose adjustments. But fortunately, I haven’t seen any hypoxia yet. DR LOVE: I think that’s a new one for oncology, hypoxia. I’m not sure I’ve heard that one before. It’s kind of cool. Current practice and potential advances in the first-line treatment of metastatic RCC DR LOVE: Let’s finish out with the age-old question. It seems like age-old, but I know it’s not that long, which is first-line therapy of metastatic RCC. You commented on some data that was presented at the ASCO meeting from the CheckMate 9ER study. But maybe you can just provide an overview of where we are with the various VEGF-TKI/IO trials. And, of course, the anti-CTLA-4/IO strategy, ipi/nivo. Like, where we are in terms of data? and where you are in terms of deciding what alternative you’re going to take? DR SRINIVAS: So we have 4 options for patients with metastatic RCC who come to see for frontline. You can either do ipi/nivo or you can choose an IO + TKI. And there are 3 TKIs, cabozantinib, axitinib, or lenvatinib. All incredible data. In general, I think if you want somebody to have a rapid response, the IO/TKIs do a better job at it, compared to ipi/nivo. Ipi/nivo has the most mature data and has the best data in terms of durability of response. So I have more than a dozen patients who have completed all of their therapy and they’re on no treatment, and they’ve had a durable CR or a durable PR. So I think that’s the biggest attribute of ipi/nivo. Of course, only half of the patients have a response, so you have to be selective. And I think if people don’t have a response after the first cycle, you should be quick to switch them to a TKI. But between these 3 TKI combinations, I think all of them have incredible data. My advice would be pick a TKI that you’re comfortable with, that you’re comfortable managing the side effects, and stick with it. DR LOVE: So a final paper you commented, I don’t know if it’s ever going to get into prime time, tivozanib, TIVO. What I’ve heard about it is, it seems to be well tolerated for a VEFG-TKI. I’m curious what the current role is. They presented some follow-up data at ASCO. A future role? I think I’ve seen a study, maybe a small one, adding an IO to it, which makes sense. But right now, does it have a role in your practice? DR SRINIVAS: I think it does because you’re seeing patients with RCC go from frontline to second line to third line to fourth line. So there’s definitely a need for additional therapy. People are living longer. And they may have side effects with IO that you can’t use another IO again. That there is a definitely a role for monotherapy TKI. And I think, to your point, tivozanib is very well tolerated. So, other than hypertension and some issues with fatigue, it’s a remarkably well-tolerated drug. So I definitely use TIVO in either the third line or fourth line. And it’s nice to have when you’ve exhausted some of your other options. So TIVO/nivo is a trial looking at tivozanib plus nivolumab in the frontline setting. And it makes sense because tivozanib is a very well-tolerated drug. And in my mind, I think it will be very similar to axi/pembro. DR LOVE: Yeah, interesting. Yeah, that will be interesting if it looks similar to what’s seen with axi/pembro. I guess you would imagine it might be easier to use. DR SRINIVAS: Yep. DR LOVE: So we’ll see. We’ll see. |