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Alicia Morgans: Hi, I'm so excited to be here with Dr. Shilpa Gupta, who is the director of the GU Oncology program at the Cleveland Clinic. Thank you so much for being here with me today.

Shilpa Gupta: Thank you. I'm so glad to be here.

Alicia Morgans: Wonderful. So Shilpa, you did a wonderful presentation at ASCO 2023, really big data, really exciting oral abstract, really giving us the four-year outcomes on EV and pembrolizumab from a study that was started many years ago. Can you tell us a little bit about your presentation? Yeah.

Shilpa Gupta: Absolutely. So EV-103 was a phase one study, which looked at EV in combination with pembrolizumab as monotherapy in different settings in urothelial cancer. And cohort A and the dose escalation part had 45 patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible and received EV pembro as their frontline treatment. The data was previously reported for response rates of 73% back at ESMO in 2019 and the publication came out earlier this year and now we are presenting the four-year follow-up this year, which is really exciting.

Alicia Morgans: Wow and right before we started filming, we commented that four year follow-up in metastatic urothelial carcinoma, particularly in a cisplatin eligible population was almost unfathomable just a few years ago. So tell me a little bit about this combination. As you said, we've heard some of the data before, but give us the updated data from the four-year follow.

Shilpa Gupta: Yeah, so in the follow-up we saw that the overall response rates were 73% by BICR and there was over 95% concordance with the investigator assessed response rates, which were reported earlier. So that was pretty impressive and reassuring. And the tail of the curve really is well maintained. The median duration of follow up was 47 months and the median progression-free survival is 12.7 months and median overall survival exceeded two years at 26 months and at two years over 41% patients remained progression-free. So all this really tells us that the responses are rapid and very durable and the tail of the curve is well maintained and that's all very reassuring in this patient population. Alicia, as you know.

Alicia Morgans: Absolutely. So one of the things as we think about implementing this in our clinical practice, though we always have to think about the adverse events and I think if we're doing follow up on this long of a duration, there may be some adverse events that might be new but maybe not. Were there any new safety signals that came out with this longer term follow-up?

Shilpa Gupta: There were no new safety signals with the combination on longer follow-up and the key toxicities that were seen were rash, peripheral neuropathy, alopecia and ocular disorders. Fortunately, these toxicities are manageable if we are really paying attention to the patient's symptoms and doing a thorough examination and adjusting the doses and giving treatment breaks. For example, rash and hyperglycemia tend to occur early on and with adequate dose adjustments it tends to resolve very early peripheral neuropathy on the hand comes around 2.7 months and then takes about seven months to resolve. But that does require very careful dose monitoring and dose modification. So these were what has been reported before. I will add that the key toxicities attributed to EV are the rash, peripheral neuropathy and ocular disorders. Key adverse events of interest from pembrolizumab are consistent with what has been previously reported, but the combination of these two drugs resulted in higher incidences of rash, specifically bullous dermatitis. So this is something we need to be very cautious about with this combination.

Alicia Morgans: So tell me a little bit about that. In clinical practice, are there warning signs that you might alert practicing clinicians to, if they see this they should refer to dermatology?

Shilpa Gupta: Yeah, absolutely. I think every patient visit we should do a thorough skin exam because patients tend to under report their symptoms as especially when they're clinically feeling well. And that's especially true for peripheral neuropathy. It's important to do a quick neuro check, make the patients do a small walk test just to make sure they're not have a waddling gait because all these tend to occur and patients tend to hide their symptoms with the fear of getting dose reduced or withholding the medication. So I think for the practicing clinician in the community who don't have much experience with this combination, it's just a thorough of physical exam and history taking and stopping the drug whenever there's side effects and taking time to resume it. Refer to dermatologist if you see early signs of rash and for peripheral neuropathy really there's no treatment. It's just goes with time.

Alicia Morgans: Yeah, definitely. If I see patients with an ocular oral rash, any rash that's painful, dermatology right away. And to your point with peripheral neuropathy, this is usually a later occurring symptom, but one that if we're very proactive about we can do those dose reductions, dose holds and eventually discontinuation if necessary. But we can often manage this I think with some smart tweaking of the dose. Do you have any tips there?

Shilpa Gupta: Yeah, so in the combination the EV was given day one and day eight every three weeks as opposed to EV monotherapy in the refractory setting, which is day 1, day 8, day 15. So I mean I tend to give longer breaks or reduce the dose to one meg and even further down if needed. And many times it's just those tiny breaks which patients do report feeling better and you can resume it.

Alicia Morgans: And one other thing just to comment, it's certainly a peripheral neuropathy that's sensory, but have you seen sometimes a motor neuropathy or even a proprioceptive type neuropathy, are these possible too?

Shilpa Gupta: Yes, these can happen too. Peripheral neuropathy is the most commonly seen neuropathy, but we've seen motor neuropathy with this.

Alicia Morgans: Okay, very good to know. But certainly it seems like a tolerable combination and one that can get patients these durable responses. Any other comments or other outcomes that you want to report from your presentation?

Shilpa Gupta: Think from the cohort K, that was the EV pembro versus EV mono. We also saw the QOL outcomes, which were reported earlier this year, and that goes in favor of the combination. Patients feel better because their disease is responding. And I think all eyes are on the EV-302, which is the randomized phase three trial that has completed accrual comparing EV pembro to the platinum based regimen. And we'll see what that data shows. And if these results hold true for that, then it's possible that this might become the standard for all patients.

Alicia Morgans: Absolutely. So what do you think, can you give us some summary on this, particularly in the context of the approval and the patients who might benefit? How does this presentation kind of mailed with that and potentially contribute to your clinical decision making?

Shilpa Gupta: So currently in the U.S. this has already received an X-rated approval by the FDA for patients who are cisplatin ineligible per the Galsky criteria meeting one or more of those criteria. But as you know that we have level one evidence from the JAVELIN Bladder 100 trial where GemCarbo followed by avelumab maintenance in those who don't progress. We see improvement in overall survival. So I think that's level one evidence. This is based on the smaller studies, but it all depends on what the patient in front of us is like. If a patient has poorly controlled diabetes, has high BMI, you know, want to be really cautious with EV and historically GemCarbo is better tolerated. So I think it'll depend on the patient in front of us.

And if we recall from the JAVELIN Bladder 100 study patients with visceral metastases did not derive that much benefit as those with lymph node only metastases and EV pembro this cohort, 83% patients had visceral metastases, of which 30% with liver metastases and the activity in the liver lesions is pretty exquisite. So I think if somebody were to present with bulky liver mats and diffuse metastatic disease, I would certainly go with the EV pembro for rapid durable responses. But we can't ignore what level one evidence we have so far. So it's really good to have multiple options that we can tailor according to our patients.

Alicia Morgans: What a wonderful world we live in now when it comes to therapeutic options for this patient population that has had high unmet medical needs now has a few ways to try to make things better. Helping patients live longer and better is always a good thing. And thank you so much for your time today and congratulations again on your fantastic presentation.

Shilpa Gupta: Thank you, Alicia, I appreciate the opportunity.