Results of Cohort K of the EV-103 Trial EV Monotherapy or in Combination With Pembro in Previously Untreated Cisplatin-Ineligible Patients With Locally Advanced or Metastatic Urothelial Cancer - Guru Sonpavde

December 12, 2022

Alicia Morgans and Guru Sonpavde discuss the results of Cohort K of the EV-103 trial presented at the 2022 European Society for Medical Oncology (ESMO) Annual Congress. There remains a critical need for effective and tolerable first-line treatment options in locally advanced or metastatic urothelial cancer. In second and later-line settings, both EV and pembrolizumab have independently shown an overall survival benefit. Dr. Sonpavde sets the backdrop by reviewing the phase Ib trial looking at enfortumab vedotin (EV) plus pembrolizumab in the first-line setting of cisplatin-ineligible patients with metastatic disease which found a high response rate of 73% and median PFS of around a year, median survival slightly exceeding 2 years. EV-103 trial is the second study, a randomized phase II study, the Cohort K of the EV-103 trial. The patient population is the same, cisplatin-ineligible metastatic disease first line, not selected based on any biomarker, which looked at EV-pembro, but compared it with EV alone.


Guru Sonpavde, MD, Bladder Cancer Director, Dana Farber Cancer Center, Faculty, Harvard Medical School, Boston, Massachusetts

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi, I'm thrilled to be at ESMO 2022 with Dr. Guru Sonpavde of Advent Health Cancer Institute of Orlando, Florida. Thank you so much for being here.

Guru Sonpavde: Thank you, Alicia.

Alicia Morgans: Wonderful. Guru, you are always the person that I go to for advice when it comes to urothelial carcinoma. You're a good friend and a great advisor and really have a sense of the bigger field. Now, one of the big things presented at ESMO 2022 is Cohort K, looking at enfortumab vedotin and pembrolizumab. I'd love to hear your thoughts on that. How do you put it into context? What do you make of these results?

Guru Sonpavde: Right. The backdrop is that a phase Ib trial looked at EV plus pembrolizumab in the first-line setting of cisplatin-ineligible patients with metastatic disease and found a high response rate of 73% and median PFS around a year, median survival slightly exceeding 2 years. So this is a second study. This is a randomized phase II study, the Cohort K of the EV-103 trial, that in the same population, cisplatin-ineligible metastatic disease first line, not selected based on any biomarker, which looked at EV-pembro, but compared it with EV alone as kind of a control group. So far we only have access to the abstract. What the abstract mentioned is that the response rate in the EV-pembro group is approximately 65%. So that's somewhat close to the 73% you saw in the initial phase Ib non-randomized study, and the control group of EV alone had a response rate of 45%.

So again, you see an incremental improvement. I believe that we need to see more data when the presentation comes out on Monday afternoon, in addition to the things like duration of response and PFS. We know that the duration of response for EV alone was reported in the abstract to be around 13 months. So that's pretty good for EV because the DOR was not as long in the salvage setting, so maybe EV is more active as you go up to the first-line setting. So I think that these are very interesting data and we need to wait and see this data lead to some kind of provisional approval, potentially, when the regulatory agencies look at it.

Alicia Morgans: Absolutely. To your point, we see this in so many solid tumors, where we move our treatments that are developed, usually in later lines, into earlier lines. They seem to be more effective and really exciting that there does seem to be incremental benefit with the addition of pembrolizumab. And as you said, the details of adverse events, for example, have not been really reported in detail for Cohort K yet, but certainly based on the earlier data, there didn't seem to be any synergistic adverse events or immune-related adverse events, in particular, that might suggest that the immune related events were heightened in this setting. What is your take on that?

Guru Sonpavde: I agree. I think the toxicity profile is consistent with what you would see with EV and pembrolizumab. One of the questions that will arise is, if EV-pembro is approved, at least provisionally for the first-line cisplatin-ineligible patients, how do you select patients for EV-pembro versus the JAVELIN paradigm in cisplatin-ineligible patients, which the community standard would be gem-carbo, followed by maintenance avelumab. I think that in that situation, you would need to discuss the data with the patients. JAVELIN, of course, is proven on the basis of a phase III trial, good follow up, survival improvement.

Also, gem-carbo is not neurotoxic. It's a little bit easier to give than EV, potentially, in some patients at least, because of the neuropathy and the skin rash issue. These toxicities need to be discussed with patients, and so there might be patients who would still qualify for either EV-pembro or the JAVELIN paradigm based on their preference and based on things like frailty and preexisting neuropathy that might make a difference to whether you'll pick EV-pembro or gem-carbo followed by avelumab.

Alicia Morgans: Yes. And to your point, certainly there are patient factors that we might consider, or patient preferences, but we don't yet know how to predict which patients are going to have that stable disease or better from gem-carbo, which is required then to go into the avelumab maintenance. And so that's what I'm also thinking about, is I'm trying to think through, if I have the opportunity to make a choice between these two regimens, how do I do that without knowing who's going to respond to gem-carbo? What do you think?

Guru Sonpavde: That's a very good point. The EV-pembro data is, of course, in all-comers, whereas the JAVELIN paradigm applies to patients who have stable low responding disease. So I think a big point in favor of EV-pembro would be the high response rate and a very low rate of progressive disease as the best response. So you can think of a patient who's more symptomatic, who needs rapid relief of symptoms, where you might want to pick your regimen like EV-pembro, just because of a very low PD as best response rate. I think that efficacy, as opposed to the toxicities that I mentioned before, they all need to factor into a discussion with the patient.

Alicia Morgans: A lot for us to figure out in clinical practice, but some exciting decisions for us to make. That being said, I know you're also developing other paradigms around ADCs, and of course EV is one of those, enfortumab vedotin, but sacituzumab govitecan is also a really exciting antibody-drug conjugate. You have a really innovative trial that I'd love to have you highlight.

Guru Sonpavde: Right. We are very excited about this study, and thanks for asking. This is a phase I study that's combining the two antibody-drug conjugates approved in urothelial carcinoma, so enfortumab vedotin and sacituzumab govitecan. We thought of combining them because these drugs hit different membrane targets Nectin-4 and Trop-2, and they have different payloads. One is the auristatin tubulin antagonist, and the other one is a topoisomerase I inhibitor in sacituzumab. So we're combining these two drugs in a phase I study. It's ongoing. We are quite excited about the potential of this regimen. They also have non-overlapping toxicities, so we think it should be feasible, but we need to wait for the data. Obviously, the next step would be to combine this doublet with an immune checkpoint inhibitor, which would be, I think, quite exciting.

Alicia Morgans: Absolutely. Remember hearing about this study and thinking, "Oh my goodness, Guru has done it again." This sounds crazy, but patients are enrolling and it does seem feasible. A little growth factor support I think can be useful potentially, but otherwise, patients seem to be tolerating the treatment so far.

Guru Sonpavde: That's right. I think it's ongoing. We are allowing growth factor support based on ASCO guidelines. You must remember that most patients with urothelial carcinoma will satisfy ASCO guidelines in terms of age or comorbidities. So we are using G-CSF support liberally per ASCO guidelines.

Alicia Morgans: Absolutely. Well, great, and I certainly know that we're all looking forward to hearing how that reports out, and then hopefully hearing about the triplet combination study in the future. As you think about the overall landscape of urothelial carcinoma, which has been rapidly evolving and continues to do so, where do you see things going? How are you thinking through this landscape on a day-to-day basis?

Guru Sonpavde: Yeah, I think that there's, of course, the arrival of adjuvant nivolumab in high-risk muscle invasive patients, which could also shake up the first-line space in the subsequent therapies. Nivolumab, of course, was approved in all-comers in the adjuvant setting in US, while in Europe it's only approved for PD-L1-high patients. So there's going to be some differences based on that across the Atlantic.

But I think that the chance that EV-pembrolizumab will make it to the first line, not only for cisplatin-ineligible disease now, but down the road when the EV-302 phase III trial comes out, across the board, whether the patient is cisplatin-eligible or not, I think the chances are pretty good, but not a certainty, of course. So we need to wait for that. I think the JAVELIN paradigm of gem-platinum followed by avelumab will remain, will still exist despite EV-pembro, just because of some benefits of using, for example, especially the cis-ineligible patients, using gem-carbo instead of EV-pembro just because of the toxicity, the ease of administering gem-carbo as opposed to EV-pembro. However, clearly, EV-pembro has a pretty good chance of replacing the JAVELIN paradigm, although it's not a certainty for now.

Alicia Morgans: Absolutely. As you talk through earlier, there are pros and cons and long-term treatment with any regimen, we have to think about what that looks like for the patient and how toxicities may come into play, and certainly, that's going to factor into these regimens that, at this point in time, may be used for long periods of time as our patients are living for longer and longer, and our therapies are becoming more effective. What are you most excited about in terms of learning different clinical trials on the horizon? What are you looking forward to hearing about in the near future?

Guru Sonpavde: Well, we are still waiting for survival data from the CheckMate 274 adjuvant nivolumab study, which we still have not seen survival. If you remember, we only have the DFS improvement that led to its approval in the adjuvant space. We are waiting for adjuvant data from pembrolizumab in the same setting. Remember, a third trial with adjuvant atezolizumab was negative. Of course, at this ESMO, we have many negative data sets for adjuvant RCC kidney cancer treatment following the pembrolizumab success. All these drugs are not alike, so we need to wait for the other adjuvant data in bladder with pembrolizumab, for sure, and the survival data with adjuvant nivolumab. And of course, we'll wait and see how EV-pembrolizumab pans out as the data roll out from the randomized phase II trial you hear here, and then the phase III trial hopefully soon.

Alicia Morgans: Well, great. Well, thank you so much for going through the Cohort K data, your really exciting trial of EV plus sacituzumab govitecan, and certainly for talking through the landscape and what you're looking forward to in the future. I really, really appreciate your guidance and expertise in these areas.

Guru Sonpavde: Thank you, Alicia.