Insights into the MAIN-CAV Trial for Patients with Urothelial Cancer

Podcast Transcript

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

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma programs. Today, I'm happy to be joined by Dr. Shilpa Gupta, director of genitourinary medical oncology at Taussig Cancer Institute and co-leader of the genitourinary oncology program at Cleveland Clinic Cancer Center. Shilpa was previously a guest on this podcast to discuss breakthroughs in bladder cancer research and that episode is still available for you to listen to. Today, she is here to talk to us about research presented at the ASCO meeting this year, specifically MAIN-CAV & platinum-ineligibility in metastatic urothelial cancer. Welcome back, Shilpa.

Shilpa Gupta, MD: Thank you, Dale. Thanks for having me. Really delighted to be here.

Dale Shepard, MD, PhD: Absolutely. I gave a little bit about your titles here, but what is it you do here? Give us a little background.

Shilpa Gupta, MD: I've been here now for three years, Dale. I'm a genitourinary medical oncologist. I treat all patients with GU cancers, but my primary focus of research and interest is bladder cancer. I treat a lot of patients with different stages of bladder cancer and I do a lot of clinical and translational research.

Dale Shepard, MD, PhD: Very good. Well, we're going to talk about research. We're going to talk about this trial called MAIN-CAV. Give us a little bit of an idea what is this MAIN-CAV trial. What are we trying to address with this trial?

Shilpa Gupta, MD: The MAIN-CAV trial is a trial that I'm leading through the NCI Alliance Cooperative Group. It's a trial that has really evolved with the standard of care evolution for metastatic urothelial cancer patients in the past after they receive platinum-based chemotherapy if they had a response or stable disease. We just used to watch them until they progressed when immunotherapy was an option from 2016 onwards. A landmark study, the JAVELIN Bladder 100 trial that was presented in 2020 showed that when these patients who get platinum-based chemotherapy as frontline therapy and have a response or stable disease, when they got avelumab immunotherapy compared to just best supportive care, they had an improvement in overall survival by over seven months. That led us to thinking how we can further push the envelope and intensify their value map backbone. Initially, this trial was being developed as a frontline therapy approach and then we modified it to make it like maintenance trial where patients who get frontline platinum-based chemotherapy and then our candidates to receive avelumab, we are randomizing them to receive avelumab as the standard of care versus avelumab and an oral tyrosine kinase inhibitor, cabozantinib.

There's a lot of synergy between cabozantinib and immunotherapy agents in urothelial cancer. There's plenty of data and we wanted to tap onto that approach. These drugs are not cross resistant. So that's the idea behind this trial. It's about a 654-patient trial. It's already activated in the US this year. It'll get activated in the Canadian clinical trials group next year and the primary endpoint is overall survival.

Dale Shepard, MD, PhD: Excellent. We have an issue in oncology. It seems that patients always wonder, when am I going to be done with treatment? They'll take anti-hypertensives for 20 years, but they want to know, when am I done with this treatment? How receptive are patients to this whole concept of maintenance therapy? Has that been a barrier at all?

Shilpa Gupta, MD: Yeah. That's a great question, Dale. The maintenance therapy, the original approval of avelumab, there was no end date to it and it's an every two-week infusion and thus become burdensome with a lot of other issues patients face. Patients like the general idea of trying to maintain responses to their cancer, but at some point, when they near two-year mark and they're doing really well, we talk to them about stopping. However, to address this exact question in our MAIN-CAV trial, we put an end date of maximum treatment of two years for both the arms because we don't think that patients need to be treated beyond two years. There needs to be an end date and that's the whole idea behind immunotherapy. I think you're right, with treatments that are every two week infusions, it is a big barrier financially as well as physically.

Dale Shepard, MD, PhD: I guess I think sometimes it takes a while for things to catch on. Bladder cancer is not horribly common and a lot of people get treated in the community from a maintenance standpoint when the data was available that maintenance therapy might help. Is it being adopted? Are people getting maintenance therapy?

Shilpa Gupta, MD: Yeah. People are getting maintenance therapy. We have actually looked at it in a systematic way with a trial we also presented at ASCO called Paradigm study where we actually interviewed community and academic oncologists, but mainly community oncologists to see what their perceptions were revolving around frontline therapies and how much they were utilizing maintenance. Historically, over 60% of patients never saw second line therapy in bladder cancer, but based on what we found, over 90% people were aware of and using maintenance therapy and talking to their patients about it.

Dale Shepard, MD, PhD: That's great. This is being done through a cooperative group. Tell us a little bit about that mechanism just for people who might not be aware.

Shilpa Gupta, MD: Yeah. It's a really great mechanism. The National Cancer Institute has several cooperative groups like the SWOG, which we are a part of, the Alliance Cooperative Group, ECOG-ACRIN, and the Alliance previously used to be the CLGB group. This trial, we are running through them. That's a great mechanism to get your own idea to fruition and really get the support of the NCI to launch it at hundreds and hundreds of sites and then even collaborate with international cooperative groups like we are doing. I'll say the process was a great learning experience for me because the whole concept, from the idea and evolution, did take around three years to finally get to see the light of the day, but it happened at the right time right when avelumab got approved and our study was the first in the space.

But I'll say the leadership and the mentors we have in these cooperative groups really provide great feedback and help us take our ideas and get feedback and work on it. That whole experience also to go through the NCI GU steering committee with their feedback and polish the protocol, that was a great learning experience for me.

Dale Shepard, MD, PhD: I don't think a lot of people realize the magnitude of effort that goes into some of these trials. We don't have results to talk about yet because this is an ongoing trial, so just really more about logistics here. What's involved here? Number of sites, you're talking about international sites. What else is involved? How many sites are we looking at? How many investigators? How big of an effort is this? I don't think a lot of people realize the work that goes into getting these answers.

Shilpa Gupta, MD: Right now, we have over 150 sites activated in the US. A lot of them are still getting activated, but once all the sites are up and are on board, we usually have over 600, 700 sites because a lot of these trials, through the cooperative groups, the good thing about these are these not as complicated as some of our other early phase trials as well as they rely mainly on standard of care. The financial aspect of that is not to do unnecessary blood work and things like that. We rely a lot on our community partners. So we have a community champion for this trial. They'll propagate it to open at a lot of sites. For example, at Cleveland Clinic, we've opened at our community sites also. I think nationally, it's important that more and more sites get on board because every patient counts.

Then internationally, we are teaming with Canada where avelumab also got approved and they also pay a lot of importance to financial aspects, treatment durations. They were very excited to get this trial open because they have access to avelumab and they want to offer treatments which can intensify that. They've been involved in the original JAVELIN Bladder 100 trial too. But yeah, it's a lot of effort to try to... As the PI, it's our job to get the word out there, have more and more sites get on board, answer all the questions about eligibility that come to us every day by email, which if something is not clear in the protocol and at the same time, based on the sites that are getting started, they have feedback. We make notes to come up with an amendment in future. I would say it's all a great learning experience to be involved in every aspect of leading such a large trial.

Dale Shepard, MD, PhD: I guess for anyone who might be listening, it's important to realize these trials aren't necessarily just at big centers, that they may be available locally and maybe just giving a standard therapy might not be the best option.

Shilpa Gupta, MD: Absolutely.

Dale Shepard, MD, PhD: What else is exciting right now in this space? This is certainly a very novel approach. What else is currently being studied that's interesting?

Shilpa Gupta, MD: Yeah. I think the treatment paradigm is really evolving in bladder cancer and frontline therapy is going through a lot of evolution. Platinums have been the backbone forever. Unlike lung cancer, platinums and immunotherapy combination has not shown to be better than platinums. But at the ESMO meeting that is happening right now, we'll see more data coming from antibody drug conjugate enfortumab vedotin and pembrolizumab frontline combination in cisplatin-ineligible patients. We at the clinic also have a phase III trial looking at that combination versus platinum followed by maintenance immunotherapy. So I think that is a trial we are really keen to see what the results show sometime next year. In general, the antibody drug conjugates are really very hot right now based on the activity that they're showing.

Dale Shepard, MD, PhD: I guess back to briefly this MAIN-CAV trial, when do we expect that we'll have an answer?

Shilpa Gupta, MD: We have built in an interim analysis, so I think once we have a set number of patients enrolled to go over the safety data because cabozantinib has not been combined with avelumab before, so I would think sometime next year, we'll have a good magnitude of patients enrolled, especially after our Canadian friends get on board.

Dale Shepard, MD, PhD: Then that way, at least you have an initial idea.

Shilpa Gupta, MD: Yes.

Dale Shepard, MD, PhD: Continuing the trial makes good sense.

Shilpa Gupta, MD: Yeah.

Dale Shepard, MD, PhD: And of course, I'm sure you get the question all the time from people enrolled in the trial. Any early hunch on if it's being helpful or not?

Shilpa Gupta, MD: It's way too early, Dale, I wish.

Dale Shepard, MD, PhD: Oh, I know. That's why I thought I asked the question just because I know you get it all the time.

Shilpa Gupta, MD: Right, right, right.

Dale Shepard, MD, PhD: You mentioned something called platinum-ineligibility and that's another thing I know you've had interested in that. What exactly is that mean and explain that to us.

Shilpa Gupta, MD: You know how in bladder cancer, our patients' median age is in the 70s and cisplatin has been the standard of care, but a whole lot of patients are not eligible to receive cisplatin. This criteria was developed by Dr. Galsky many years ago, how to identify patients who can't get cisplatin. So some of the key factors were creatinine clearance less than 60 or hearing loss greater than grade 2, heart failure or just poor ECOG performance status and bad peripheral neuropathy. So that guided us as to if these patients can't get cisplatin, we'll offer them carboplatin. So that was a rough guide for trial enrollment and whatnot. Then couple of years ago, immunotherapy, when they were studying frontline pembrolizumab and atezolizumab in this patient population that cannot get cisplatin, FDA put a label restriction based on phase III interim data that patients were doing worse with single agent immunotherapy as compared to carboplatin and they restricted it to use it only for platinum-ineligible patients. That is those who can't get carboplatin or those who have tumors with high PDL1.

But there was no definition for who can't get carboplatin. It's just investigators' discretion. So we initially actually took on this effort and did a survey of medical oncologists treating bladder cancer in the US, around 60 of those. We threw several questions like, what is your threshold for deeming someone not eligible for carboplatin? Gave them variety of ranges like 60, 55, 45 and things like that. Then peripheral neuropathy, ECOG performance status, age, hearing loss, and heart failure. We found that majority of the respondents thought creatine clearance of 30 is a good cutoff for deeming somebody carboplatin-ineligible and age did not really matter, hearing loss did not really matter, ECOG performance status 3 or higher, peripheral neuropathy grade 2 or higher and that became a rough guide.

Now with so much changes with enfortumab vedotin, pembrolizumab in the frontline, some data and we wanted to also see what people are doing after avelumab got approved. So we revisited this survey this year and sent out the same questions and asked what they are doing for frontline. Has carboplatin use gone up based on the maintenance avelumab data? We found that everybody is using maintenance immunotherapy. As far as the criteria go, majority still said that creatinine clearance of 30 is the cutoff, peripheral neuropathy grade 2 or higher, ECOG performance status grade 3 or higher, and significant heart failure. So any one of these criteria, we have just provided a clinical decision-making tool to consider that someone not able to get carboplatin. Because the problem is when we are deeming patients who can get carboplatin as platinum-ineligible, we are doing them a disservice because single agent immunotherapy is not as good as carbo followed by immunotherapy. So the whole idea is to avoid overcalling off these platinum-ineligible patients.

Dale Shepard, MD, PhD: You want to make sure that people that can actually benefit from carbo get it.

Shilpa Gupta, MD: Get carbo, yes.

Dale Shepard, MD, PhD: Right. Correct. From a dissemination of that information, I know you've presented about this, but is this getting incorporated into guidelines or FDA guidance or what-

Shilpa Gupta, MD: We are working on writing the consensus paper right now and just discussing at meetings and also taking it to the next step. We are now doing a similar survey in our European countries to see what the patterns there are. In the EAU guidelines actually, they refer to these criteria for platinum. In the NCCN, it's not a formal part of that. But the other thing we are doing is roughly using these criteria to design trials for platinum-ineligible patients and we are involved with that frontline trial.

Dale Shepard, MD, PhD: So really directly working on protocol development because we both know that sometimes the criteria is somewhat arbitrary.

Shilpa Gupta, MD: Right. Right.

Dale Shepard, MD, PhD: That's important because if you only have so many things to use, then if you're intentionally not using one, that's a big deal.

Shilpa Gupta, MD: Yeah.

Dale Shepard, MD, PhD: What other things do you find exciting in bladder cancer right now just in general?

Shilpa Gupta, MD: In general, I think a lot of excitement about the localized bladder cancer treatment with immunotherapy antibody drug conjugates, incorporating more multidisciplinary care for patients who could get bladder preservation and don't necessarily need surgery, and also, how to improve outcomes with surgery with perioperative therapy. So I think we are working a lot in our multidisciplinary teams to see how we can improve outcomes of these patients with all these therapies.

Dale Shepard, MD, PhD: Well, very well done. Great to see you leading such an important trial trying to retool how we think about how to use our drugs, which is really, really important. So great insights. Appreciate you being with us.

Shilpa Gupta, MD: Thank you, Dale. Thanks. Delighted to be here and thanks at all as always.

Dale Shepard, MD, PhD: To make a direct online referral to our Taussig Cancer Institute, complete our online cancer patient referral form by visiting clevelandclinic.org/cancerpatientreferrals. You will receive confirmation once the appointment is scheduled. This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google play, Spotify, SoundCloud, or wherever you listen to podcasts. And don't forget, you can access real-time updates from Cleveland Clinic's cancer center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.