Read the Full Video Transcript

Sam Chang: Hello, everyone. My name is Sam Chang. We are here at GU ASCO 2024, and I have the great pleasure and honor of actually sharing some time with Dr. Shilpa Gupta. Shilpa is actually at the Cleveland Clinic, and we'll be talking a little bit about the MAIN-CAV study. So, tell us a little bit about that and its future role in treatment and maintenance therapy for those patients with advanced urethral carcinoma.

Shilpa Gupta: Thank you, Sam, for having me. It's an honor for me to be here with you. MAIN-CAV is the first phase III study where we wanted to intensify the maintenance treatment. As you know, platinums had been the standard of care for the longest time, and then JAVELIN Bladder 100 studies settled the role of maintenance avelumab after platinum in patients who do not progress. It showed an improved survival compared to best supportive care. That was a 7-month improvement, which was great. We wanted to see if we can further intensify the avelumab backbone, so we designed this study a few years ago. Patients who get any platinums four to six cycles and they get randomized within 3 to 10 weeks to maintenance avelumab versus avelumab and cabozantinib 40 milligram dose, which is a VEGF inhibitor already approved in many cancers because of the potential additive nature.

Sam Chang: Right, perhaps the synergistic effect with two different mechanisms.

Shilpa Gupta: Perhaps, yes.

Sam Chang: Got it. Right.

Shilpa Gupta: And non-additive toxicities, non-cross resistant mechanisms. Some differences from the JAVELIN study where we limited the total treatment duration to 2 years because we really don't think patients need to be treated beyond that, and we used fixed-dose avelumab. The primary endpoint is overall survival, postulating a 7-month improvement over maintenance avelumab. The trial is currently ongoing in the US and also within the Canadian Clinical Trials Group. This trial, I think, answers an important question of the maintenance therapy, and we've seen a new standard now of EV and Pembro. We are trying to see if we can change the primary endpoint to progression-free survival to make it a smaller study and be able to read out sooner.

Sam Chang: Find it and then read out sooner. I see.

Shilpa Gupta: And read out sooner.

Sam Chang: And then with that combination, the total of 2 years, that's the combination of receiving the first-line platinum and then avelumab or avelumab plus Cabo. Total of 2 years.

Shilpa Gupta: Right. Avelumab and Cabo for a total of 2 years.

Sam Chang: Exactly. So it's basically intensification, but actually shortening the length of time that you get it. And so, at this point, how are we doing in terms of enrollment?

Shilpa Gupta: We have enrolled close to 70 patients in the US. As you know, unfortunately, there was a shortage of platinums in the US for the longest time, so the study did have some setbacks. Now we are over that hump, and we are trying to perk up the accrual and also banking on our Canadian colleagues where they won't have access to EV/Pembro for some time.

Sam Chang: Period time, absolutely.

Shilpa Gupta: I do think EV/Pembro is the standard now, but we have to remember, only about 30% of patients in the control arm got maintenance therapy. So we really don't know.

Sam Chang: We don't know. We don't know the answer. Exactly. Perhaps you may not be able to have a clear idea, but when you look at the side effect profile of the combination, does it look like, at least theoretically, we don't think there'd be worsening, what have you seen with the early data?

Shilpa Gupta: We have seen that there have been no safety concerns. The study had very strict rules of data safety monitoring committee reviewing, and they have not seen anything concerning whatever we have known from the toxicities of TKI and immunotherapy.

Sam Chang: This combination. Exactly.

Shilpa Gupta: Right, right. We are using a 40 milligram dose, which is what for the combination is approved.

Sam Chang: Okay. When you look at a 7-month improvement on top of the avelumab 7-month improvement, that's quite ambitious in terms of more than a year of added survival. When you're looking at the progression-free rate that you are hoping for, and that's progression defined by x-ray, by CT scan, how do you define progression in terms of this cohort?

Shilpa Gupta: As you know, patients could go on this study even if they have a complete response to chemo. So any progression on scans.

Sam Chang: Got it.

Shilpa Gupta: We are considering that and just confirming that to make sure it's not just a flare-up. But we will use a lot of correlatives, including iRECIST, to look at those features as well.

Sam Chang: As you look at the landscape of combination therapies, combining a TKI with immunotherapy, do you think that's going to become the standard either in the advanced setting, the neoadjuvant setting? What do you think of those combinations? Because we see that with advanced kidney cancer, we're seeing that now with urothelial. Tell me your overall thoughts regarding the combinations.

Shilpa Gupta: I think, mechanistically, it makes sense. VEGF plays an important role in the pathology of urothelial cancer and progression, and I think we've seen data with the Cabo/Nivo, Cabo/Nivo/Ipi, as well as Cabo/Atezo in refractory settings. We will have a Pembro/Cabo study presented here. So I think it's an important role to play in terms of targeted therapy for urothelial cancer, and I think it still needs to be explored further because even when EV/Pembro becomes the standard of care, then what next?

Sam Chang: Right, right.

Shilpa Gupta: We have a great front-line therapy, but we want to be forward-thinking and know what else we can do for patients.

Sam Chang: In terms of the next steps. Because the great benefit that we now have is we've got these trials that we're looking at, hopefully, to help answer these questions. I mean, this is an exciting time compared to, I'm much older than you, Shilpa, I look much older, I am much older than you, but comparatively speaking, 15, 20 years ago as I was starting a practice, we had no options. We had very few options and nothing to really actually hang our hats on. Now we have these trials, just like yours, looking at not only maintenance, but what can we do in addition to the maintenance to actually have an even longer-term effect. Give us, what do you think time frame-wise, before we get the readout with MAIN-CAV? You think a year, 18 months? What is your thought?

Shilpa Gupta: I think it'll be a bit more than that if we are able to get the primary endpoint of progression-free survival, it's currently under review, then I think the next couple of years.

Sam Chang: Oh, fantastic.

Shilpa Gupta: Because then we will only need 200 patients. And I'm hoping that whatever the future may be, whatever progress we made with accrual, we can still answer important questions, look at the mechanisms of response and resistance, and then think of the next big strategy.

Sam Chang: Great.

Shilpa Gupta: But keeping my fingers crossed for this study.

Sam Chang: Absolutely. Well, Shilpa, thank you so much for spending some time with us, and I look forward to your future trials and everything that you bring because we really consider you such a big leader here in urologic malignancy. So thanks again.

Shilpa Gupta: Thank you, Sam, for your kind words.