Trailblazing Urothelial Cancer Treatments: Enfortumab Vedotin & Pembrolizumab

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale. Sheppard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics program and co-directing the Cleveland Clinic Sarcoma program. Today I'm very happy to be joined again by Dr. Shilpa Gupta, director of the Genitourinary Oncology Program at Cleveland Clinic Cancer Institute. She has been a guest on this podcast in the past to discuss research and bladder cancer, and those episodes are still available for you to listen to. She's here today to discuss a trial of enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. So welcome back.

Shilpa Gupta, MD: Thank you Dr. Sheppard for the opportunity. Really excited to be back.

Dale Shepard, MD, PhD: Yeah, remind us a little bit about what you do here at Cleveland Clinic.

Shilpa Gupta, MD: I'm a genitourinary medical oncologist and I see patients with genitourinary cancers and my research interests are in bladder cancer.

Dale Shepard, MD, PhD: All right, well we're going to talk about bladder cancer today. We're going to end up talking about a trial looking specifically at patients with, as it turns out, any type of bladder cancer in terms of platinum sensitivity or tolerability. But give us a little bit of an idea. One thing that always comes up is cisplatin-eligible, cisplatin-ineligible. Tell us a little bit about what that means and how that defines how we first think about cancer treatment.

Shilpa Gupta, MD: So historically, cisplatin is what we had for our urothelial cancer patients for over four decades, but as you know, more than 50% patients who have urothelial cancer, they have a lot of comorbidities and they cannot get cisplatin. So there's this category of patients defined as cisplatin-ineligible back in 2011. For example, patients with ECoC performance status two or higher, patients with bad peripheral neuropathy, bad heart failure, hearing loss, and creatinine clearance less than 60 mils per minute. So those patients were defined as cisplatin-ineligible and we would offer them gemcitabine and carboplatin instead of gemcitabine cisplatin or cisplatin-based therapies like MBAC. And so that is how we always looked at bladder cancer patients up until recently when we had these new therapies which are effective in both cisplatin-eligible and cisplatin-eligible patients.

Dale Shepard, MD, PhD: And so really tell us a little bit about this combination that's been tested, was originally tested in one of those two categories, right?

Shilpa Gupta, MD: Yeah. So EV and PEMBRO, EV short for enfortumab vedotin, which is a novel antibody drug conjugate targeting nectin-4 antibody, and it has the active compound of MMAE and using a linker to link the two was first combined with pembrolizumab in a phase one two study called the EV 103, which was primarily for cisplatin-ineligible patients. And in that early study, even in just 45 patients, we saw remarkable responses like over 70%, which we had never seen in these cisplatin-ineligible patients with gem-carbo. And the median survival used to be six to nine months. And recently we saw the four-year follow-up of that cohort, which still held true with response rates of around 70%. And that whole promising activity led to the phase three trial in all patients regardless of cisplatin, unfitness or fitness. So this was an EV 302 study, which is a phase three study of EV and PEMBRO versus patients who got gem-cis or gem-carbo. So now we moved this to all platinum-eligible rather than only cisplatin-ineligible in the phase three study.

Dale Shepard, MD, PhD: And I guess that considering the importance historically of cisplatin in this disease, there must have been a fair amount of discussion about moving from an early phase trial cisplatin-ineligible, and then including cisplatin-eligible in the phase three as well. Is that accurate?

Shilpa Gupta, MD: Yeah, that's sort of accurate, Dale, because initially this study was a triplet arm where they were combining platinums with EV and PEMBRO. But when the results of just EV-PEMBRO were so fantastic that it was decided that let's just compare it to gem-cis and gem-carbo, we don't need to combine it with chemo. And that risk paid off because usually the early phase trials sometimes just don't show any activity in phase three trials.

Dale Shepard, MD, PhD: Or you might think somebody would be conservative and go from that trial to cisplatin-ineligible and then if that looked good, then go to eligible. So interesting. So give us a little bit of an idea. You gave us a little bit of the backdrop. What did this trial look like?

Shilpa Gupta, MD: This was a phase three trial. It randomized 886 patients, one-to-one, to EV and PEMBRO, which is given as a combination pembrolizumab for a maximum duration of two years. EV was actually indefinite. There was no stop date and the comparator arm was gem-cis or gem-carbo based on their eligibility for cisplatin for up to six cycles. And during the protocol, during the study conduct maintenance avelumab had become approved for patients who respond to platinum. So that was allowed, but it was not part of the protocol therapy. The standard of care arm had already changed during the study. In the study, around 30% patients in the control arm got maintenance avelumab. So the primary endpoint was PFS and OS and there were secondary endpoints like safety, response rates, patient-reported outcomes, and this study met the primary endpoints and really showed results, which were something we've never seen before in bladder cancer.

Dale Shepard, MD, PhD: And what was the magnitude of benefit?

Shilpa Gupta, MD: The magnitude of benefit was the PFS was doubled from 6.3 months in the control arm to 12.5 months with hazard ratio of 0.45. And the overall survival was doubled from 16 to 31.5 months with a hazard ratio of 0.47.

Dale Shepard, MD, PhD: Impressive.

Shilpa Gupta, MD: And this was regardless of whether they were fit for cisplatin or not.

Dale Shepard, MD, PhD: And so you one, would imagine the patients that are cisplatin ineligible tend to be maybe more frail and not do as well, but in this particular case didn't really matter.

Shilpa Gupta, MD: No. Yeah, but I have to add that in this, the cisplatin-ineligible patients were more on the fitter side. Their hemoglobin needed to be above 10. And typically-

Dale Shepard, MD, PhD: Just by nature of the trial?

Shilpa Gupta, MD: Yeah, the nature of the trial and want to also add that the response rates were 68% with this combination versus 44% with chemo and complete response rates of 29% versus 12.5%. So really unprecedented data that we have seen so far, it's become the undisputed front line standard.

Dale Shepard, MD, PhD: That's impressive. I guess even impressive change takes time. Is this something that was one of those things, the data comes out and it's one of the game changers that we don't oftentimes see at big meetings and that it has been adopted so far, or people, because it's new, been slow to adopt?

Shilpa Gupta, MD: I think this was adopted really quickly in the US because initially this combination based on the phase one study and more cohort study cisplatin-ineligible patients received accelerated FDA approval last year. So it has already been, people have started to use it and I think that option has been pretty quick. Even patients who were not cisplatin-ineligible were probably getting it in the community. And now that it has received the full approval, it's really become the standard. And I think it has really decreased the platinum use unless somebody has really contraindications to receiving EV, which are quite unique characteristics.

Dale Shepard, MD, PhD: So anytime we think about treating these tumors, we got to treat the tumor, we got to manage symptoms trying to improve overall survival. Tell about from a symptom standpoint, adverse events, differences, tell us about management of that.

Shilpa Gupta, MD: So yeah, with the chemo we saw the expected toxicities of myelosuppression and some neuropathy. But with the EV-PEMBRO combination that there's some unique toxicities from EV, particularly really significant peripheral neuropathy, over 50% patients get it. And it's not just sensory neuropathy, it can be motor neuropathy too. And a lot, many times we'll see patients really walking wobbly gait and they may hide their symptoms. So it's really important to have them walk in clinic and look at that. So that's been our practice because that can become really significant and takes forever to get better. But those reductions and those withholding really helps that. And once it returns to grade one, we can re-challenge at a lower dose, but we have to be really cautious. The other key toxicity unique to EV is the rash because nectin-4 is expressed on the skin. And this rash can become life-threatening too, if doses are not held or treatment not given.

And it can even present as Stevens-Johnson's and toxic epidermal necrolysis and they can be toxic deaths from this. So I think those two key toxicities we have to be very careful about because we don't usually see that with chemo. And another toxicity we've seen is catastrophic diabetes in patients who are not diabetics at baseline, it can lead to diabetic ketoacidosis, although less commonly than the rash and peripheral neuropathy, which occur in over 50% patients. And for diabetics, they need to have their HbA1c less than eight, and if their glucose is anytime above 250, they cannot receive EV. So I think these are some of the unique toxicities which we encounter with this. And it's important to keep this in mind.

Dale Shepard, MD, PhD: I remember back in the day when tyrosine kinase inhibitors started being used in kidney cancer, I mean the toxicity really became a limitation because people weren't used to those toxicities. You think we've learned from that and we've been able to adopt changes in terms of how to manage in this situation?

Shilpa Gupta, MD: I think we will learn eventually. I think depends on how many people are actually going to treat a lot of patients with this in the community. And then I think the education needs to be at the forefront for the rash. It cannot be taken lightly. I think a lot of people are already aware of immunotherapy related rashes and we've all seen that, but with the EV, it happens early on and if left untreated can really blow up. So it'll take its time just like with ipi-nivo, like we got used to the colitis with the ipi. But it all depends on how closely patients are being monitored.

Dale Shepard, MD, PhD: With the neuropathy particularly, how long does that typically take to resolve?

Shilpa Gupta, MD: It can take over six to eight months to resolve and that to get better, I've not seen it completely resolve in most of the patients, but it can resolve. But it takes a long time. But for the most part, if it's grade two and you hold the treatment, it takes some months to get better.

Dale Shepard, MD, PhD:

So I guess anytime you have something that looks really, really promising, it kind of becomes that frontline treatment. Of course, the next question is what comes next? And of course, platinum-based therapy might be a good consideration. So then you have neuropathy of cisplatin. And has there been concerns about challenging people who have had neuropathies with the EV-based therapies with cisplatin?

Shilpa Gupta, MD: That's such a great question, Dale and a million-dollar question right now because really I think on this study, patients who progressed on EV-PEMBRO, they got platinums like carboplatin. And I think the biggest challenge is that how many of them will actually be able to receive cisplatin if they get bad neuropathy. But I think platinums will really play a big role because they are effective drugs. And in the past they were always used in frontline. So I think in second-line they will be more effective than anything else we have right now.

Dale Shepard, MD, PhD: And of course this was for patients with metastatic disease. What's going on with these combinations in a neoadjuvant setting?

Shilpa Gupta, MD: Yeah, that's also a great question. There's already phase three trials being done in both cisplatin-eligible, an cisplatin-ineligible muscle invasive cancer with EV-PEMBRO. So in cisplatin-ineligible it is compared to single agent PEMBRO or upfront cystectomy. And in the cisplatin-eligible it's compared to gem-cis. And so that's really, we are waiting for the studies to accrue and see. And that will again, I think, change the landscape if it moves to that setting, then what in the metastatic setting. So it's really an exciting time, but this combination is something that people are really excited about in every setting.

Dale Shepard, MD, PhD: Historically, neoadjuvant studies in bladder have been tough. Has the excitement of this combination in the metastatic setting sort of eliminated some of that difficulty doing a new adjuvant study?

Shilpa Gupta, MD: I would say we don't know yet, but we are taking part in those studies and I think that it is somewhat more toxic than we see in the metastatic setting, especially after surgery. It becomes a little bit of a challenge to continue EV-PEMBRO for a long time. And that's why I'm really looking forward to the data from these new adjuvant studies as to what was the tolerability, because in my experience it has been more difficult than in the metastatic setting. And in the new adjuvant setting, when we see these toxicities, it's more challenging because these patients, if they have a great response, do they really need this treatment after surgery or not? But in the protocols they continue.

Dale Shepard, MD, PhD: And you mentioned treatment after surgery. I guess the question is if you catch people with early disease and you treat them, and you said the complete response rate was nearly 30%, is there ever do you think a world where people get neoadjuvant therapy complete response and don't have a cystectomy?

Shilpa Gupta, MD: That's again the big question that we actually have in the bladder cancer world now that if patients have a complete clinical response, should we not be aiming for bladder preservation? So there've been some data with the chemotherapy combined with immunotherapy in that setting. And now with the use of ctDNA, a lot of emphasis is being paid on that. If they have a complete clinical response and ctDNA clearance, then can we preserve their bladders? But that's still a research question. And to your point, I think that will be the big question we have. Why even do a cystectomy?

Dale Shepard, MD, PhD: It might significantly impact on quality of life.

Shilpa Gupta, MD: Yes.

Dale Shepard, MD, PhD: Interesting. What else do you find exciting in the bladder cancer research world?

Shilpa Gupta, MD: I think there's a lot of excitement with, I think the next class of drugs that we are so excited about, our antibody drug conjugates, so EV. Then we have another one, sacituzumab govitecan against Trop-2, we're waiting for the phase three data, and now the HER2 story has again resurfaced in bladder cancer. In the past they were herceptin and other drugs tried, didn't really pan out. And now we have HER2-ADCs and that is showing very promising activity in refractory setting. So I think the field is really exciting to watch how the evolution has been.

Dale Shepard, MD, PhD: That's great. So it sounds like a lot of exciting things that used to historically be a pretty tough disease that didn't respond all that well. So now it-

Shilpa Gupta, MD: Yes, it's really great.

Dale Shepard, MD, PhD: ... looks like a promising future ahead. Well thanks for being with us today.

Shilpa Gupta, MD: Thank you Dale.

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