Alicia Morgans:  Hi, this is Alicia Morgans, GU Medical oncologist and associate professor of medicine at Northwestern University. I'm so excited to have here with me today, Dr. Guru Sonpavde who is the Bladder Cancer Director, and a GU Medical oncologist at the Dana Farber Cancer Institute in Boston. Thank you so much for being here with me today, Guru.

Guru Sonpavde:  Thank you, Alicia.

Alicia Morgans:  Wonderful. So, I wanted to talk with you a little bit about recent updates in urothelial cancer. We certainly had a number of those at ESMO, the virtual meeting 2020 in the scientific sessions that were already presented, and we've heard some really exciting press releases, really, just in the last couple of weeks. So why don't we start with some updates from ESMO 2020, and maybe start with the TROPHY trial. What is that trial and what are your thoughts on the data that was presented?

Guru Sonpavde:  Thanks, Alicia. So the TROPHY U-01 trial is a trial that is examining an antibody-drug conjugate called sacituzumab govitecan So this is an antibody-drug conjugate, the target Trop2 is a surface membrane antigen, and this drug has a different payload than enfortumab. It's a payload SN-38, which is the active metabolite of irinotecan. It is a topoisomerase I inhibitor. So the TROPHY U-01 trial looks at several cohorts of patients in a non-randomized setting and this is in patients who have metastatic urothelial carcinoma and had been exposed to both platinum-based chemotherapy as well as immune checkpoint inhibitors. This cohort had 113 patients and gave patients single agents sacituzumab govitecan in this [inaudible] setting, and the drugs sometimes lets just say it was active. The overall response rate was 27%, the median PFS 5.4 months, and the median survival was 10.5 months.

So there was activity seen even in patients with liver metastasis in the same degree. Toxicities were manageable, the main toxicities are GI toxicities with diarrhea and myelosuppression with [inaudible] fevers. [inaudible] fevers or grade three or worse diarrhea were seen in approximately 10% of patients so this was manageable. So this is a drug we see as yet another antibody-drug conjugate which is active in the post platinum and checkpoint inhibitor setting in metastatic urothelial carcinoma. This drug does have fast track designation and is potentially practice-changing in the future.  We will need to wait and see what the regulatory agencies say, and we also have a Phase III trial ongoing called the TROPiCS-04 trial that is comparing sacituzumab govitecan versus standard of care chemotherapy in the post platinum and PD-1 inhibitor study.

Alicia Morgans:  I agree with you. I think it's really exciting and I was fortunate to use sacituzumab govitecan in the Phase I trial setting, and really found that for many of the patients it was actually quite tolerable and seemed to be effective, and of course, phase one, these patients are so heavily pretreated. Sometimes they had been on multiple Phase 1's before that, so it is exciting to think that we may have another option that will be moving forward in urothelial cancer, a much-needed option, even though we've had some approvals we still will always need more. So thank you for summarizing that and I think next we have another study that was also done in the metastatic or unresectable urothelial cancer population, the DANUBE trial, the Phase III that we've actually been waiting for for a few years now, can you tell us a little bit about what we heard about that at ESMO?

Guru Sonpavde:  Right. So the DANUBE trial was a three-arm Phase III trial. More than a thousand patients in the first-line metastatic urothelial carcinoma setting, and what this trial did is compare durvalumab plus tremelimumab, so the combined checkpoint inhibitor approach compared with gemcitabine platinum, regardless of PD-L1 status, and also compared durvalumab alone with gemcitabine platinum in the PD-L1 high group.

So the results were somewhat disappointing because, with both comparisons, there was not a statistically significant improvement. So durvalumab was similar to gemcitabine platinum in terms of not improving or actually not improving survival, and also the durvalumab-tremelimumab combination was not better than gemcitabine platinum, regardless of PD-L1 status.

However, there was a slight trend towards improved survival with durvalumab-tremelimumab,  the p-value was 0.075, the median survival was 15.1 versus 5.1 months. When they did an unplanned subset analysis of durvalumab-tremelimumab versus gemcitabine platinum in the PD-L1 high group, there was a significant improvement, but this remains a hypothesis-generating analysis. So at the end of the day, this trial did not change the standard of care. However, what this does tell us is that perhaps the combinations of PD-1 and CTLA-4 inhibition has some signal there, and a faint signal of benefit. And so we need to wait for the CheckMate901 trial, of course, which is a BMS trial, which is comparing ipilimumab nivolumab versus gemcitabine platinum. Normally the intention to treat the overall population, but is also looking at the PD-L1 high population as a co-primary endpoint.

Alicia Morgans: I definitely agree and I think that there's more to hear about this story and I look forward to it but it is important that we do have this data, and negative data, is just as important I think for us in terms of recognizing and understanding where to go next in this disease. So a big presentation, important data, nonetheless, and like you said we'll continue to see where this goes. One of the other presentations in this setting was the KEYNOTE-361 data.  Can you tell us a little bit about that?

Guru Sonpavde:  So the KEYNOTE-361 trial had a somewhat different design than the DANUBE trial. This was also a three-arm first-line Phase III trial with a little more than a thousand patients, and what this trial did was compared gemcitabine platinum plus pembrolizumab versus gemcitabine platinum as the primary comparison. That comparison had to be positive to go on to the next hierarchically next comparison, which was a pembrolizumab alone versus gemcitabine platinum in a PD-L1 high patients.

So the disappointing result is that the combination of pembrolizumab with gemcitabine platinum did not achieve a significant PFS or OS and therefore the next hierarchical comparison of pembrolizumab versus gemcitabine would not even be done formally. So, overall these results are disappointing from the KEYNOTE-361 and this follows a horse on the heels of the IMvigor130 trial which did show an improvement in PFS for survival data are pending. So where do we go from here with KEYNOTE-361 is we still need to wait for the overall survival results from IMvigor130, which was gem platinum plus or minus atezolizumab. Also, the CheckMate901 trial, a BMS trial, which does have a sub-study on gemcitabine cisplatin plus or minus nivolumab in cisplatin eligible patients. There's also the NILE trial that is looking at gemcitabine platinum. We thought durvalumab alone or durvalumab plus tremelimumab with gemcitabine platinum sort of a quadruplet approach. There is also the exciting EV-302 trial, which is comparing EV (enfortumab vedotin) plus pembrolizumab with or without platinum versus gemcitabine platinum as a standard arm.

Alicia Morgans:  So it's so interesting that an unfortunate, another negative trial, but again, really important trial to inform us as we're making these choices, not necessarily unexpected that we would see what we saw but still heartbreaking nonetheless. But I have to comment on all of these Phase III trials and just acknowledge the patients and the investigators who have continued to push the boundary of what's possible. This is not the most common solid tumor in the world by far and we had a few decades ago, a lot of difficulties getting patients even into Phase II trials. So now to have Phase III after Phase III, after Phase III and more and more patients getting involved, I think is completely commendable and I appreciate and look forward to seeing more of this data continue to develop. As we round out ESMO 2020, I think we wanted to just touch up on some of the updates from the JAVELIN trial, which was a really exciting part of ASCO 2020 this year. Can you tell us a little bit about what was presented at ESMO?

Guru Sonpavde:  Sure. So the JAVELIN Bladder 100 trial is, of course, a practice-changing trial. This is, of course, a trial that's now published in the New England Journal of Medicine, which showed that switch maintenance of avelumab extended survival significantly in patients who had stable or responding disease with four to six cycles of platinum-based first-line chemotherapy. So now at ESMO, the investigators looked at some interesting retrospective analysis of the JAVELIN Bladder 100 trial, and one of them was a correlated biomarker study introspective analysis. So what was seen interestingly is that in these patients is also being considered whether a PD-L1 status or tumor mutation burden might predict for a greater benefit from switch maintenance avelumab, and so this was looked at. It looked like you did not need to have a particularly high TMB or PD-L1 status to benefit or not from switch maintenance avelumab. So at the moment, we cannot use any specific biomarker like PD-L1 status or tumor mutational burdens to select patients who are switch maintenance avelumab.

The investigators also looked at some other signatures and pathways that might get into a benefit. One of them of interest was the immune gene expression signature, but it didn't look like the immune gene expression signature and does predict for clinical benefit. But again, this is retrospective hypothesis-generating. They also looked at one of the biomarkers, which was the FC gamma receptor, so this is the end of the monoclonal antibody, avelumab, which potentially can engage with the body immune cells like [inaudible] cells and macrophages and other cells better, and therefore leading to a better activity for avelumab, so it did look like some FC gamma receptor radiance in patients may have some association with better activity with avelumab But again, this is hypothesis-generating yet. Another subanalysis that the investigator looked at was whether there was a differential benefit from avelumab based on their prior response to platinum being CR versus PR versus sustainable disease. So in the initial presentation at ASCO and in the paper, the investigators have lumped together partial response or better versus stable disease with prior platinum.

They had not teased out the CR versus PR with platinum chemo. So at ESMO, the presence of this data, and it did not look like even in patients who had CR with platinum-based chemotherapy there were trends. The hazard ratios were going in the same direction. These sub-analysis are not powered for formal reports and formal results, but it is reassuring to see that the benefits are still going the same way. However, some of us still have some questions about whether switch maintenance avelumab is warranted in everyone who had a CR with platinum-based chemotherapy. For example, patients who received cisplatin-based chemotherapy and had only lymph node-positive disease might be cured with cisplatin-based chemotherapy. And avelumab switch maintenance might be overtreatment in many of these patients, which might expose them to the risks of toxicities, as well as continuous treatment with a drug that may not be worth it. So I think that this needs for the analysis in terms of looking at biomarkers that might help us tease outpatients with CR who may or may not need switch maintenance available.

Alicia Morgans:  I completely agree with you. I think places like maybe even the Alliance or ECOG or other cooperative groups may be able to design some really elegant trials looking at these biomarkers prospectively to see if maybe we don't need the additional therapy, or can we stop it sooner, and they're doing this, I think in some aspects of kidney cancer and definitely have interest in a broader spectrum of GU cancer.

So whether it's them, whether it's someone else, I think that the work is, is absolutely necessary and anytime we can save patients from being exposed to additional therapies and potential toxicities, that's an important part of what we do. So thank you for bringing that up. I think the last few things I wanted to talk with you about are really scanned on data but very high on excitement. So we only have press releases for these last two. EV-301 press release came out, it looks like it's quite a positive study. Can you tell us a little bit about that and what your thoughts are?

Guru Sonpavde: Yes. So enfortumab vedotin is an antibody-drug conjugate that targets nectin-4, and has the toxic payload of MMAE, auristatin, which is a [inaudible] toxin. So this drug is FDA approved for patients who are progressing with metastatic urothelial carcinoma in the post platinum and post PD-L1 enabled setting. So EV-301 was conducted thereafter, which was a confirmatory Phase III trial to confirm these benefits from enfortumab vedotin. So this study being compared enfortumab versus standard of care chemotherapy, and this was supposed platinum and PD-L1 inhibitor patients, and this trial was important in a press release recently as being positive. So enfortumab vedotin extended overall survival compared to standard of care chemotherapy with a hazard ratio of 0.70 and also extended progression-free survival which was a secondary endpoint with a hazard ratio of 0.61. So a significant improvement in more than a primary and major secondary for enfortumab, which is very welcome news to our patients because these data should lead to a full approval [inaudible].

Alicia Morgans:  I agree and, and really do look forward to being able to use, this drug with confidence on more and more patients because it is a drug that I have seen have some nice activity in patients. I look forward to potentially moving it earlier, into the treatment paradigm as we do with any effective drug so more to come on that, but thank you for sharing that very, very exciting press-release. The other final press release that actually just came out only a few days ago was CheckMate 274, can you tell us a little bit about this, a little bit of a different setting, then adjuvant setting?

Guru Sonpavde:  So the CheckMate 274 trial was very exciting news to us because this is a Phase III trial that for the first time showed that an adjuvant checkpoint inhibitor, which is nivolumab and PD1 inhibitor. Extended disease-free survival, not only in the PD-L1 high patients but also in the overall intention to treat population patients regardless of PD-L1 status. So these were more co-primary endpoints in the CheckMate 274 trial. This trial, of course, comes on the heels of the IMvigor010 trial, which was presented at ASCO just a few months back, which was negative, which did not show an improvement in the same co-primary endpoints with adjuvant atezolizumab.

We, of course, have a third trial ongoing, which is evaluating pembrolizumab in the adjuvant high-risk muscle-invasive bladder cancer setting. That trial has somewhat slightly different endpoints, so it has an endpoints in the intention to treat the population regardless of the PD-L1 status of overall survival and disease-free survival. So really it is slightly different in terms of endpoint, but we are awaiting those data from the AMBASSADOR trial, but this is very welcome news for our patients with the positive CheckMate 274 trial.

Alicia Morgans:  Absolutely, and as we get that data out and are able to really dig into it, I think this absolutely could lead to some changes in treatment patterns. For sure, of course, we need to get our hands on the data, not just a press release, but really exciting news for our patients and certainly for the entire Bladder cancer community. So as you think about all that we just talked about and what a roundup of information it was, what would your sort of overarching message be to the community of folks caring for patients with urothelial cancer?

Guru Sonpavde:  That physicians need to be aware of the data that are emerging. One of the questions in the field right now especially is in cisplatin-ineligible patients with PD-L1 high expression, maybe no, both pembrolizumab and atezolizumab are also approved based of course, on Phase II data not Phase III data. Also in the same space, we also have the JAVELIN Bladder 100 trial paradigm of 4-6 cycles of gemcitabine platinum followed by switch maintenance avelumab. So that I think at the moment is the most in the discussion with the patients that tends to be long because the patients tend to have a strong pace for whether they want to go with chemotherapy first, or the immunotherapy first. But I think that the JAVELIN Bladder 100 trial does have Phase III data backing it up. Whereas the first-line checkpoint inhibitor approach, while valid, is not at Phase III data at the moment. I guess the last thing, the only one thing I wanted to say was still to say that metastatic urothelial carcinoma still is a highly challenging disease its not curable in the vast majority of cases, so please consider clinical trials in any setting for your patients.

Alicia Morgans:  I completely agree and I really just want to emphasize, I'm so appreciative to hear your thoughts and your expertise as the Bladder cancer director at the Dana Farber and as a friend and colleague, thank you so much for your time today, Dr. Sonpavde.