Recent Advances in the Treatment of Metastatic Urothelial Cancer - Petros Grivas
Petros Grivas, MD, PhD, Associate Professor, Clinical Director of Genitourinary Cancers Program, University of Washington, Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center
Ashish Kamat, MD, MBBS Professor of Urology and Wayne B. Duddleston Professor of Cancer Research at MD Anderson Cancer Center in Houston, Texas.
Ashish Kamat: Welcome. It gives me great pleasure to welcome a good friend and an expert in the field of bladder cancer, Dr. Petros Grivas from Seattle Cancer Center. You are a leader in the field, thank you for joining us today. We're at GU ASCO where there's a lot of exciting things happening, a lot of posters, presentations, development. I want to ask you a little bit about two things. First, your view on where the field is heading when it comes to the second and third-line therapies for bladder cancer?
Petros Grivas: Thank you so much, Ashish, for having me here and I have to share the enthusiasm with you. We are living in an era where urothelial cancer, in general, is undergoing a revolution in terms of the therapeutic developments in the field that has been stagnated for many decades. Over the last few years, we had a development of immune checkpoint inhibitors and, as you know, we have five of them approved for the platinum-refractory setting and we're using checkpoint inhibitors in the clinical practice both in the platinum-refractory setting or in the frontline setting for cisplatin-ineligible, not fit patients. And in this frontline setting, we may use the PD-L1 expressions biomarker to potentially inform our decision.
In addition to this wave of immune checkpoint inhibitors, we have the development of new agents and two of them have had recent FDA approvals for metastatic urothelial cancer. The first of the two is erdafitinib, an FGF receptor inhibitor that is targeting specifically activating mutations infusions in FGF receptor two and FGF receptor three and that's the accelerated approval by the FDA for patients who have metastatic urothelial cancer refractory-platinum therapy, so second line and beyond, that the tumors have these particular genomic alterations. There is a Phase III trial with erdafitinib being compared to either salvage chemotherapy or pembrolizumab in order to evaluate the optimal second-line therapy in this disease, immunotherapy or targeted therapy. And there is also, I would say, a plethora of other FGF receptor inhibitors being tested in clinical trials, which I think is very exciting.
In addition to the targeted therapy field, I would say that we have amazing data and significant enthusiasm with a different class of agents, antibody-drug conjugates. And there is a number of them out there. One that comes to mind is enfortumab vedotin and this agent was very recently approved by the FDA. Again through accelerated approval and both erdafitinib and enfortumab vedotin were approved based on a single-arm Phase II studies based on impressive response rates that some of them were durable and the manageable safety profile. But like erdafitinib, also enfortumab is now undergoing a Phase III trial being compared to salvage chemotherapy and the results are pending.
Both of those agents are now available to patients and there are multiple logistics and details and nuances about the utilization of those agents in metastatic disease, but definitely represent a new tool that the physicians and advanced practice providers and nurses have in the management of those patients. I think going to the future we have a wave of new different clinical trials who are testing combinations and sequences of agents and on that note, I would mention that we have two other press releases that happened very recently and I would like to comment briefly on that issue.
One of those press releases had to do with a JAVELIN Bladder 100 trial. This particular trial is in the first-line setting of advanced urothelial cancer patients who complete first-line chemotherapy with platinum gemcitabine and they have four, five, or six cycles of chemotherapy. They got randomized in this clinical Phase III trial to either avelumab, anti-PD-L1 agent, versus best supportive care alone or available plus best supportive care. The press release on January 6th, 2020 saw that avelumab prolonged overall survival compared to best supportive care alone in all-comers regardless of PD-L1 expression and in the subset of patients with high PD-L1 expression of the tumor tissue raising the question whether switch maintenance before progression might become, in the future, the standard of care in patients in the frontline setting who complete first-line chemotherapy. The data not been presented yet, but there are pending presentations in one of the next few meetings that we have.
The second press release was in the adjuvant setting. They'll have the adjuvant IMvigor010 trial, that asks the following question: does atezolizumab immune checkpoint inhibitor anti-PD-L1, versus observation make a difference in the adjuvant setting? And the press release showed that atezolizumab did not prolong disease-free survival. It was, unfortunately, a negative trial that pretty much does not change the management in the adjuvant setting. I think this data is important to follow along and see the actual presentations, but overall there is significant, I would say change and evolution in the field of bladder and urothelial cancer.
Ashish Kamat: Right. Now I mean you raise a lot of important points and I'll want to flip back over to EV, but before that, your thoughts on the adjuvant trials. So it didn't meet their statistical significance, but do you think there's still a role for adjuvant therapy in the maintenance fashion in these patients?
Petros Grivas: I think it's a great question. I think there are two other clinical trials in the adjuvant setting, the AMBASSADOR trial, Andrea Apolo and colleagues, that is looking at pembrolizumab versus observation in the adjuvant setting and the results of another study at CheckMate 274 with nivolumab placebo, again the adjuvant setting. So we'll have to see what happens in those two trials in the pure adjuvant setting. And to be honest with you, I was positively impressed that the IMvigor010 finished accrual because the adjuvant chemotherapy trials almost never finished accrual in the past so there's more enthusiasts to complete adjuvant trials. Now if you think about the switch maintenance setting in metastatic disease, in my opinion, slightly different. Because in that scenario you have an established metastatic disease and you have either response or stable disease with chemotherapy frontline and then you try to maintain or sustain this benefit with immune checkpoint inhibitors. So slightly different settings which I think are maybe irrelevant in the readout of the study.
And of course, it has to do with trial design and the patient population. But in my opinion, the switch maintenance setting is slightly different than the pure adjuvant setting in the context of metastatic disease was already established in the maintenance setting in metastatic disease versus the micrometastatic disease in the adjuvant setting.
Ashish Kamat: Right, and that might be another reflection of doing combination searches sequencing. Sometimes your patients are, there's an attrition rate where the patient not able to get to a second-line or third-line therapy if you don't give them the benefit of a combination early on. Tell me a little bit more about the EV. Now that's a nectin-based ADC and as we all know nectin is highly expressed in all the bladder cancer tissues that have been tested. From your perspective, do you foresee that EV is going to be able to have a role in earlier lines of bladder cancer?
Petros Grivas: I think it's a great question Ashish, and as we mentioned before, EV, or enfortumab vedotin, is now approved by the FDA as an accelerated approval for patients in the third-line setting after they have received platinum-based chemotherapy and a checkpoint inhibitor. So this is based on the label third-line setting. Some people may use it later, but based on the impressive response rates about 40% in the third-line setting. I think it's a very, very important tool that we have in our armamentarium. Based on that, there is an ongoing Phase III trial comparing it with chemotherapy. But to your point because of this impressive results, there is now a notion and interest to try to move it in earlier lines of therapy and we'll show data from ESMO 2019 from Dr. Hoimes and colleagues from the EV-103 trial that actually combined pembrolizumab anti-PD-L1 plus enfortumab vedotin, EV, and the data looked very promising.
Of course with a caveat, it was only based on 45 patients selected in a Phase 1b study with a short follow up. So taken with a grain of salt, but the overall response rate in the frontline setting in cisplatin-ineligible, not fit patients was 71% with a combination of pembro plus EV with a 93% RECIST control rates.
Ashish Kamat: Right.
Petros Grivas: Very impressive data which in my opinion support the launching of a larger Phase III trial, especially for cisplatin unfit patients, which I think is going to happen. Now the data with EV pembro is not practice-changing yet but definitely generating enthusiasm and I think based on our discussion we're going to see trials in the frontline setting. The other question is, and I would like your opinion on that, do you think it's relevant timing to try to move it into the neoadjuvant setting or even in non-muscle invasive disease or we think it's premature at this point of time? We'll have to make these decisions.
Ashish Kamat: No, I think looking at the efficacy of EV, moving it earlier into the neoadjuvant setting is clearly a place where it should be studied and you're leading some efforts in there because we have obviously platinum-based therapy. But it's not been adopted by the community more than say 25-30% across the United States and having another agent that has such great efficacy and can be given for a short duration minimizing toxicity in the neoadjuvant fashion, I'm sure you agree, would clearly be a way to move that needle and increase adoption and get our patients to have, say, PCR. Before we close a quick question because we hear about the potential adverse events of erda and EV and in comparison with IO, which are, say have no side effects. For our audience, could you just put that in perspective, with as far as the adverse events of EV and erda compared to IO's?
Petros Grivas: It's a great question. And the immunotherapy, as you mentioned, can result in immunotherapy adverse events. It is very important to notify and educate and discuss with our providers in our medical teams, how do I let it go nice and properly manage immune-related adverse events. Thee symptoms from the disease sometimes can confound the picture in terms of the toxicity profile of erdafitinib the FGF shutter inhibitor and in enfortumab vedotin, the anti-nectin-4 antibody-drug conjugate a little bit different compared to immunotherapy.
Specifically for erdafitinib, we have to pay attention to the labs. We have to measure phosphate level, phosphorus level, and this may have implications in those titrations but can happen two weeks after you start therapy. For example, if your phosphorus level is below 5.5 and there is no visual toxicity side effects in the eyes and no greater more other toxicity you can actually titrate the dose up from eight milligrams to nine milligrams for erdafitinib, so that's why it's important to stay on top of thinking of that particular nuance and follow the packet insert.
Other side effects with erdafitinib I just implied that visual toxicity can happen, so an ophthalmological exam is mandatory at least monthly in the first four months, ideal at baseline and then happens once every three months because central serous retinopathy can occur, blurred vision can occur in about 20-25% of patient. So extra attention in today's visual toxicities with erdafitinib and also dry eyes, dry mouth, dry skin, dermatological toxicities, nail changes, appetite changes and a few other things can happen. I would say overall it's a manageable toxicity profile but requires extra attention from the medical team to optimize the management of patients. Those holes or deductions may need to happen with erdafitinib in that sense.
Enfortumab vedotin is different. As I mentioned before you described the base of the patient that you may have some chemotherapy-like toxicity like fatigue, weakness, anorexia, maybe nausea, but there are particular side effects like peripheral neuropathy, skin rash and I would say rarely hyperglycemia that can happen and hyperglycemia can happen in about 10% of the patients. This is important to keep an eye on those labs for patients getting in enfortumab vedotin for this high glucose that can happen in patients even without diabetes. And the special disaggregation with higher BMI or overweight patients but it can happen to anybody. So extra attention to that because that particular side effect, hyperglycemia, could be life-threatening if you don't pay attention. So I think keeping a close eye leading the pack and educating each other is important. And of course, for the benefit of neuropathy, the prior administrators from platinum-based chemotherapy may also contribute to neuropathy. So important to optimally again recognize, educate the patients who sometimes may under-report adverse events to recognize those events early and manage them properly with those holds productions as needed.
Ashish Kamat: Right. And again just a shout out to you because you've done a lot of effort and I know you're doing studies in order to kind of standardize AU reporting. Thanks again, Petros, for taking the time to sit down and chat with us today. This is going to be very useful for our audience and best of luck with all your presentations at GU ASCO this year.
Petros Grivas: Thank you so much, an exciting meeting and thank you so much for having me.
Ashish Kamat: My pleasure.