Jaime Landman: Hi, this is Jaime Landman from the University of California Irvine, and it's Kidney Cancer Today. I'm here with my partner, friend, and cohost, Monty Pal.

Monty Pal: Thanks, Jaime, how are you? Monty Pal here from City of Hope. I'm a medical oncologist, and I am just delighted to have Shaan Dudani here. Shaan is a fellow of Danny Heng of Heng Database fame, and actually today, Shaan just had an article come out in European Urology, the Platinum Journal, related to work that he's done out of the so-called Heng Database. With that in mind, Jaime, I'm going to throw it to you for the first question.

Jaime Landman: Well, I'd like to know more about that database. Shaan, can you tell us a little bit about it?

Shaan Dudani: Absolutely. First of all, thank you for having me on the podcast. It's a real honor. The database in question is the International Metastatic Renal Cell Carcinoma Database, also known as the IMDC, and it's a database, which was started by Dr. Heng around 2005. It initially incorporated only patients with metastatic renal cell carcinoma from a number of centers in Canada and the United States. I believe the initial few centers were Calgary, Vancouver, Cleveland, and Boston.

It's subsequently grown to include now over 10,000 patients over the past 15 years or so across over 40 countries worldwide with some notable major centers included including the City of Hope, where Dr. Pal is from, the Dana-Farber in Boston, otherwise, Cleveland and Texas have representation, Canada and across the world, Italy, Australia, Belgium, et cetera. It's really a very comprehensive database, the largest database of metastatic kidney cancer patients treated. We've been able to answer a lot of interesting questions, which have been clinically relevant through this database.

Monty Pal: I've got a question for you. This is something only you can answer working with Danny Heng from day-to-day. There are two ways that you could refer to the database, either the Heng Database or the IMDC or International MRCC Database Consortium database. Does Danny call it The Heng Database or the IMDC?

Shaan Dudani: He calls it the IMDC, being the humble, humble guy that he is. Around the world, I think it's probably in terms of the prognostic criteria, which have been developed through the database, sometimes referred to as the IMDC Criteria or Heng Criteria. I think they're more well known as the Heng Criteria. But, he won't call it that to you.

Jaime Landman: He doesn't call it-

Monty Pal: Got it.

Jaime Landman:  ... The Me Database or The Me Criteria?

Shaan Dudani: He doesn't.

Jaime Landman: That's probably fairly reasonable. About how many patients do you have captured at this point?

Shaan Dudani: We're around 10,300, I think at this time. We're just in the middle of another update. We do updates two to three times a year. We usually do one in the fall and that's happening kind of as we speak, so that number's probably going to be over 10,500, I would say, in the next couple of months.

Jaime Landman: Well, that's pretty impressive. Let's get right into them. You have a paper, brand new, hot off the presses in European Urology, right?

Shaan Dudani: Yeah, that's right. It's very exciting.

Jaime Landman: It is. Can you tell us a little about it?

Shaan Dudani: For sure. In terms of the background, metastatic kidney cancer has had a number of revolutions, I'd say, in treatment paradigms, starting with the initiation of targeted treatment with sunitinib and sorafenib around 2005/2006. More recently, there's been introduction of immune checkpoint inhibitors into the armamentarium, around 2015, with the CheckMate study comparing nivolumab to everolimus in the second-line setting. Following on from that, from those studies, we had recent developments in the past couple of years showing that first-line immune combination therapies may be quite effective with metastatic kidney cancer.

In particular, the new immune combination therapies can be divided into combinations with two immune agents, which I'll call IO/IO agents, and this is really ipilimumab and nivolumab; there've been a number of other combinations, which have been shown to be quite effective compared to the historical standard of care sunitinib, which combined an immuno-oncology agent as well as the VEGF inhibitor. Some of these examples include axitinib and pembrolizumab, axitinib and avelumab, and bevacizumab and atezolizumab. They've all been shown to be effective, but what we don't know is how they compare against one another, and so the purpose of our study was to compare combinations of two immunotherapy agents such as ipilimumab and nivolumab versus ipilimumab ... versus, sorry, IO plus VEGF inhibitor combinations.

Monty Pal: That's not just a question. I think that's the question when it comes to first-line therapy in metastatic renal cell carcinoma. We have these two very dichotomous options that we can take. Tell us what your study ultimately showed. Was there one approach that was superior to the other ultimately?

Shaan Dudani: Ultimately, we did not show any differences in key first-line outcomes between IO/IO combinations and IO/VEGF combinations. The outcomes we looked at were response rates, time to treatment failure, time to next treatment, and overall survival, which is the kind of most important endpoint. Interestingly, in terms of second-line response rates, for patients who received VEGF-based therapies in the second line, including treatments such as axitinib, sunitinib, lenvatinib, cabozantinib; response rates were higher in patients who had received Ipi/Nivo in the first line versus those who had received an IO/VEGF combination. This is biologically plausible given that the patients who had received Ipi/Nivo were VEGF-naïve at the time of second-line therapy. This is something, which may play out with future analyses to have an important role in distinguishing who should receive or what type of treatment patients should receive in a first line. But as of now, there were no differences in key first-line outcomes, which I think is the major takeaway from the paper.

Jaime Landman: Shaan, that really just brings us down to the bottom line question. How do you choose a first-line approach when you're seeing a patient?

Shaan Dudani: I think there are a number of factors to consider. First of all, the IO plus VEGF combination therapies have only recently had their data presented, and in many countries, access to these combinations is not yet available, and such is the case in Canada, where I work. For us at the moment, ipilimumab and nivolumab is the de facto standard for patients with intermediate and poor-risk disease. In the near future though, I think this is going to be a very real question outside of the United States, and right now, is a very important question within the United States, where access to these therapies is, I believe, available.

I think the first distinction is we have to divide patients into favorable risk versus intermediate and poor risk. For patients with favorable-risk disease, I think IO/VEGF combinations are the unquestioned standard, as ipilimumab and nivolumab was not shown to be superior to sunitinib in this population. The real difficult question is for patients who have intermediate and poor-risk disease. I think the first thing to say about this population is that there is no right answer. The data do not suggest that one regimen is better than another in terms of efficacy, so other things would have to be considered.

The types of factors that would have to be considered would include cost, side effects, patient preferences, patient comorbidities. Obviously, patients have a history of difficulty with either bowel perforations, hypertension, or need surgery such as cytoreductive nephrectomy. Perhaps, they wouldn't be good candidates for a VEGF inhibitor. If patients have a history of maybe borderline autoimmune disease, a combination IO/IO would probably not be preferred. But, a lot of these other factors will need to be taken into account given that there are no clear differences in efficacy, I think.

Monty Pal: I think that's a very reasonable take on the data. But, let me ask you, so you've got this real-world experience from the IMDC. Actually, at SUO this year, I'm going to be giving a talk on real-world data versus clinical trial data, and the need for both. Do you think that this real-world data might potentially take the place of a clinical trial comparing VEGF/IO and IO/IO? Do we need those sorts of studies moving down the line or is that just a waste of time?

Shaan Dudani: That is a very interesting question. I think that the gold standard for comparing the efficacy of different treatment regimens is always going to be the randomized controlled trial. Where real-world evidence comes in is where there are questions, which cannot be answered by clinical trials or are currently not answered by randomized controlled trials, and such as the case here. I think if there were one or two regimens, it would be reasonable to perform clinical trials. But, we have a multitude of different regimens, which are now approved, and others, which are being studied, including, for example, nivolumab and cabozantinib, which also seems quite promising.

I don't think we're ever going to have head-to-head comparisons of all of these different regimens. Real-world data represents a means by which we can answer these clinically and policy-relevant questions, which we can't answer through clinical trials. I think, and to answer your question, clinical trial data will always be preferred, but in the absence of it, we still need to make decisions, and real-world data are the best that we're going to get.

Monty Pal: Very well said.

Shaan Dudani: We have to take it. Thank you. We have to take it in the context of its known limitations. Fortunately, I think in this situation, a major limitation with real-world evidence is selection bias, in that physicians may choose a certain treatment for a patient because they're inherently less sick or more sick. But in here, I think we have a situation where it's really a toss-up as to what the best choice is, and so that component of selection bias may be minimized in this real-world data set compared to some other real-world data sets, which may suffer from that bias.

Monty Pal: I couldn't agree with you more. It becomes a resource issue at some point, doesn't it? Do we invest in studies that answer questions amongst existing regimens? Do we try to forge ahead with trials that really explore novel therapies and combinations? But, I suppose, in essence, we could potentially even do both, don't you think?

Shaan Dudani: Yeah, and I mean this question may be obsolete, but there are studies going on right now of IO plus IO plus VEGF versus IO/IO. For example, cabozantinib plus Ipi/Nivo, I believe, is currently under study versus Ipi/Nivo alone. That will obviously be quite a toxic regimen, but I do think that you're right. Our resources are limited. We need to be judicious with the patients and resources that we have and make sure that we're asking the right questions.

Monty Pal: Well, Shaan, I just want to congratulate you on, again, this outstanding work. I think you've really done an amazing job in your career thus far. Just a quick question, I wanted to get a sense because you've obviously been incredibly prolific during your fellowship at Tom Baker. Can you give us a quick sense of some of the other projects that you're working on and excited about?

Shaan Dudani: Yeah, for sure. I think I'll stick to talking about further projects in relation to first-line immuno-oncology combination therapies. Some of the interesting questions that we wanted to ask of the database are, for example, what is the effectiveness of these combination therapies in variant histologies. As you well know, the most common type of kidney cancer, the most common histology is called clear cell renal cell carcinoma, but there are a number of other histologies, which are collectively known as non-clear cell renal cell carcinoma. In all of these landmark clinical trials, patients had to have the clear cell variant to be enrolled in the study. But, in the real world, in most places, even patients with non-clear cell disease are getting these immuno-oncology combination therapies. This is another area where real-world evidence can help us learn about how effective these treatments are in the non-clear cell population because they really weren't included in these landmark trials. We're also interested in learning about their effectiveness in other subgroups of interests like patients with different sites of metastases, for example, brain metastases, and in different prognostic groups like the IMDC intermediate, poor and favorable-risk groups.

Jaime Landman: Shaan, I'm going to torture both you and Monty with one last question because really this conversation has evolved in a very interesting way about the nature of the way we collect data. I'm going to go into like what kind of data we really should be looking at because I've always been confused. What is the optimal metric or endpoint we should be looking at? Is it progression-free survival, overall survival? What is the one kind of gold standard by which we should really judge our treatment regimens?

Shaan Dudani: All right, I'll go first, Monty, and then I'll let the more senior, wiser responder second. I'm definitely a believer in overall survival as the optimal endpoint. I think most people would agree with that, but there are some times, difficulties with overall survival in terms of measuring it in diseases where the survival is quite long. Sometimes, in certain malignancies when there are competing interests or other potential causes of death other than the cancer, it can be kind of muddy endpoint. I think in the case of most metastatic cancers though, emphasis on most, it is the most, the gold standard endpoint. I think in the case of kidney cancer, where survival, even for favorable-risk patients is in the range of, well, less than a year for poorest patients and up to three to five years for favorable-risk patients; it's really the gold standard endpoint. I would say overall survival is the key endpoint for differentiating these types of therapies.

Jaime Landman: Monty, as the certainly wiser and not so old guy, what's your thoughts on outcomes?

Monty Pal: Well, I have to tell you that this is one of those scenarios where I think the fellow has eclipsed the attending. That was such an eloquent answer, Shaan. I really have nothing else to add. OS, always going to be the high bar for us in RCC, I'm sure.

Jaime Landman: Well, good. Shaan, I got to tell you, thank you so much for your brilliant insights into the database, and congratulations on your new manuscript, truly amazing. Thanks for joining us.

Shaan Dudani: Thank you very much for the opportunity. It's an honor.

Monty Pal: Congrats, Shaan. Bye, bye.

Shaan Dudani: Thanks, Monty.

Jaime Landman: That's the end of another episode of Kidney Cancer Today. Thanks, Monty.

Monty Pal: Thanks, Jaime.