The Uromigos Episode 100: The 100th Podcast—Looking to the Future

Chris Sweeney, Kala Sridhar, and David McDermott discuss the future.

Episode Transcript

Brian:
Welcome, everyone, to the special edition of The Uromigos 100th podcast. Tom and I are here, and we have a litany of special guests. Tom, I never thought we’d make it this far. Our first podcast was about February of 2020.

Tom:
When my life was good.

Brian:
All our lives were a lot better, pre-COVID. And Seth Lerner and Arjun Bellar were our first guests, as I remember, talking about KEYNOTE-057. And it’s really gone on from there. I never thought we’d make a hundred. I’m not sure why people don’t have anything better to do with their time, but we’re at about …

Tom:
Which projects do you think have worked well? We did a world tour. That was a calamity, obviously.

Brian:
The world tour was COVID-driven, yes. I liked the world tour because we got to talk about where we were going to eat and stuff like that.

Tom:
We should ask the audience at some point what they want to do, what we should do again, and whether we should go around because I thought that it was really interesting some of the areas.

I also think the debates have been quite popular. One of the questions I got around those debates I guess is how many topics. And maybe we should talk more about which debate topics we need to focus on.

Brian:
Yeah, the debates have been good. My favorite was when Bill Kaelin just destroyed you in that debate.

Tom:
I think if you look at the voting that’s not what happened.

Brian:
Yeah. I’m not [crosstalk 00:01:48] that the voting matters.

Tom:
Just because he seems to have this halo around him because he’s got this Nobel Prize. Brian, I guess what we are going to do today is we’re going to invite some friends along.

Brian:
Yup.

Tom:
But before we get there, I guess one of my questions would be, what do you think in terms of kidney cancer, what are you excited about at the upcoming ASCO meeting? And I’ll talk a little bit about bladder cancer.

Brian:
Sure, the adjuvant pembro data which we know is positive will be presented. That’s the biggest data and that’s clearly going to shape the field. Listeners can watch out for a podcast on that. That’s going to really shape the field.

We’re doing a 426 update. There’s some other bits and pieces as you like to say, but I’m not sure there’s anything else practice changing in kidney cancer that I’m aware of.

Tom:
There’s a randomized trial, isn’t there? Looking at one of the … I think it’s an RNA inhibitor? I think it is.

Brian:
CANTATA, that was ours, presented. That’s the other big study, I believe. And that was negative, we know that.

Tom:
There was a press release on that.

Brian:
Yeah.

Tom:
And then I guess in bladder cancer we’ve got; I think it’s actually compared to the last year or so it’s going to be quiet. We haven’t got a big practice changing randomized phase 3 or a big adjuvant trial. We have had some … Chris, have you just joined us?

Chris Sweeney:
I have Tom, yes.

Tom:
Chris Sweeney.

Brian:
Ladies and gentlemen.

Tom:
Welcome.

Brian:
Hey, Chris.

Tom:
I was just [crosstalk 00:03:30] talking about ASCO and bladder cancer, but actually I think we’re going to interrupt ourselves. Chris, you are our first guest on this hundredth edition, welcome.

Chris Sweeney:
It’s great to be here, hundredth edition. Look at you boys, you’ve grown up. Kala and David are in the green room.

Brian:
They’re in the green room right now, yes.

Chris Sweeney:
Okay, you might want to let them know that they’re in the green room.

Tom:
They were actually supposed to be surprised guests, Sweeney. So, but …

Brian:
I’ll text them.

Tom:
But that’s okay.

Chris Sweeney:
I got to meet them in the green room, so it wasn’t a surprise.

Tom:
Look Sweeney, 2 things. Firstly, what’s going to happen over the next hundred podcasts in prostate cancer? I want you to predict the next 12 months for me. Honestly, I think that there’ve been more changes in renal and bladder cancer in the last 12 months than in prostate cancer. What’s going to happen in prostate?

Chris Sweeney:
Tom, I’ll just correct you; I think there’ve been quite a few changes in prostate cancer you’re just not aware of.

Tom:
It maybe because I’m not very good at it.

Chris Sweeney:
It’s an alternative hypothesis. So, let’s just say what we have achieved with identifying patients who have strong benefits to PARP inhibition in metastatic castration-resistant prostate cancer, is a strong benefit for use of chemotherapy and how to use chemotherapy in castration-resistant disease with cabazitaxel clearly having survival benefit over metastatic, over hormone switch with the CARD trial.

And there’s going to be quite a bit of a SPLASH with the use of Lutetium PSMA, patients who have PSMA PET positive no discordant disease. And that’s not PSMA PET positive with Lutetium PSMA. So, stay tuned, that’s going to be a big one. It’s plenary actually at ASCO. So, and there was very promising data of Lutetium PSMA versus cabazitaxel, so that’s just metastatic CRPC.

Tom:
Chris, could you explain on the Lutetium PSMA story? What is the story around that? Because clearly, it’s a different way of treating patients, it’s a bit novel. And where is that going over the next … Is this a flash in the pan or is this going to be a whole new chapter for prostate cancer?

Chris Sweeney:
A whole new chapter for prostate cancer.

Tom:
Explain why that’s the case.

Chris Sweeney:
So, we note there’s a modest benefit with 1 radioligand, Alpharadin, Xofigo. And that’s limited to patients who have bone only disease and there’s a survival benefit.

Lutetium PSMA is a radioligand with the radioactive therapy. Joined to and labeled bind 2 and given with PSMA binding proteins, that delivers this quite potent radiation to Lutetium PSMA-expressing prostate cancer.

Brian:
And not just bone, right Chris?

Chris Sweeney:
Bone and soft tissue and liver.

Brian:
Yeah, wherever.

Chris Sweeney:
And when it was compared head-to-head with cabazitaxel in the right patients, it had a greater PSA response and a greater time to progression in overall survivals pending in that.

The vision study that we’ll read out is [inaudible 00:06:49] late-stage disease and it isn’t up against a really standard controlled. The Australians as they do great work and they actually said, let’s compare it with a standard cabazitaxel whereas it’s basically mostly I think going to be a hormone switch. All the chemotherapy options and it’s just a relatively inactive control on.

Brian:
Chris, do you think we’ll reach a day before we all retire where we’re not giving sort of nonspecific chemo to CRPC? That we’re only giving these sort of targeted beta radio nucleotides or otherwise?

Chris Sweeney:
I would say that’s a bit of chemophobic talk there. I think these chemotherapy options actually have major and profound clinical benefit.

Brian:
I’m not saying they don’t. I’m not chemophobic, I love it. But I’m just asking you, if you … [crosstalk 00:07:46] by the time with our thousandth podcasts, God willing, I was going …

Tom:
Sweeney listen, we haven’t got a huge amount of time. It sounds to me like you’re a chemo supporter. Just tell [crosstalk 00:07:57] me about this …

Chris Sweeney:
I think we’ll actually have biomarkers to define who would be worth the risk benefit ratio of Docetaxel and cabazitaxel more, so that’s a work in progress. I think we’ve had …

Brian:
Fair enough.

Tom:
I’ve got 2 questions for you. Beyond Lutetium, are there other radio nucleotides which are going to have an important role to play in this disease?

Chris Sweeney:
Yes. So, there’s whole bunch of them that being developed with different antibodies and different proteins parts of the prostate cancer.

Tom:
So, over the next 12 months, which is going to be the most exciting?

Chris Sweeney:
The only one we’ll really know about is Lutetium PSMA, but actinium and thorium based radioligand are being developed. But there’s also PSMA targeting with immune therapy with BiTE and things like that.

But to not forget about what I think we’ll actually learn most about with metastatic prostate cancer is in the hormone sensitive space as well. We will learn over the next 12 months whether there’s a therapy of ADT plus or minus.

Abi or Enza or [inaudible 00:08:54], that’ll come out over the next 6 months between ASCO and ESMO. We already know about with Enza, there’s a major PFS benefit, but no OS benefit with a short follow up.

Most of the patients will be those who had a clear benefit with dose attack in those studies. So high risk, high volume. When we put all the data together, it’ll be about 1500 patients, ADT dose versus ADT dose C plus the new hormones.

What I also will highlight is we’ve just got something accepted in European neurology. For the first time, we’ve shown that patients with the best prognosis metastatic hormone-sensitive prostate cancer, metachronous low volume disease, with a meeting survival to 8 years with just hormone delay.

With looking at the internet data of the interim analysis, we increased their three-year survival from 83% to 92%, with a hazard ratio of 0.4 [inaudible 00:09:53] therapy, that was just the Enza. That’s the first time that subpopulation has ever been shown to have survival benefit with anything, so that’ll be I think an advance. So, we’ll have more reliable prognostic markers to guide which therapies for which patients in a predictive manner.

Tom:
Sweeney you and I led a study together for the first time for IMbassador250. You’ve had a series of positive trials in your career. You joined up with me and we end up with a hazard ratio of 1.12, that was immune therapy.

Chris Sweeney:
So, Tom [crosstalk 00:10:25]

Tom:
Plus, enzalutamide. What’s going to happen to this immune therapy story and where does it end? Because we are still at our institution doing immune therapy studies. Are we doing the right thing? And what does the next 12 months hold for us in this environment?

Chris Sweeney:
So, it’s not a negative study, Tom. It’s an informative study. It tells us that unselected use of [inaudible 00:10:48] very important matter.

Tom has many informative studies positive in his career. We know that we really need to drill down into biomarkers to work out which of those patients actually have an immune infiltrate that sets them up to possibly benefit from this therapy. So, I think …

Brian:
Tom, we have another special program. I think we need to move on to bladder.

Tom:
Kala, welcome.

Kala Sridhar:
Thank you.

Brian:
Sweeney, we’re kicking you off the podcast.

Tom:
Sweeney, it’s never happened before, but we’re going to ask someone to leave. You could ask Kala one question on the transition. I think we should say that.

Chris Sweeney:
Kala, have you got some good news about your promotion?

Kala Sridhar:
I do, guys, thanks for asking.

Tom:
This is terrific news.

Kala Sridhar:
What’s that?

Tom:
Terrific news.

Kala Sridhar:
Yes.

Tom:
Go, fire away Kala, tell us all about it.

Chris Sweeney:
Drop me guys. Kala, great to hear from you again. Brian and Tom, keep up the good work, congratulations. And I look forward to hearing this podcast.

Brian:
Thanks, Chris. Kala, welcome to the 100th Uromigos Podcast.

Tom:
Kala, talk about your promotion quickly.

Kala Sridhar:
Absolutely, so I just found out I’ve been recommended for promotion to full professors starting July 1. So, super excited about that.

Brian:
Congrats.

Tom:
And it’s well-deserved, Kala.

Kala Sridhar:
Thank you.

Tom:
Kala, just talk to me couple of things. Firstly, the bladder cancer space has moved a lot since we started doing this 12 months ago. And in fact, there was that ODAC meeting recently where we did a couple of podcasts on. So, we’ve had new positive trials like Nivolumab, but we’ve also had some of the drugs being removed, which is unusual, almost unprecedented.

Where are we going with? And then of course we’ve got a new group of drugs with the antibody drug conjugates with the positive randomized trial as well. What’s going to happen over the next 12 months in urothelial cancer?

Kala Sridhar:
I think it’s been super exciting. And I think you guys have first done an awesome job in covering what’s been happening in bladder and kind of digesting and dissecting that all out.

So, looking ahead, I think that in the neoadjuvant setting it’s going to be interesting to look at some of the dual combinations when we’re looking at epitinib or Durva. Some of that looks really interesting and perhaps the one that I’m watching the most in that setting is something like EV plus pembrolizumab, just because I think it’s got an all-user type approach in the sense that you can use it in patients who have poor renal function or maybe not as good performance status. So that’s really what I’m watching in the neoadjuvant setting.

I think the adjuvant setting has been very interesting with 1 negative study, 1 positive study. There’s another large study coming in the adjuvant setting. There’s also interest in looking at things like FGFR in that setting and the use of biomarkers like ctDNA. So that’s kind of interesting in the [crosstalk 00:13:43].

Brian:
Kala, just to back up to neoadjuvant, do you think let’s say by podcast number 200, will get to a space where there’s an established neoadjuvant non chemo regimen, whether it’s pembro EV or whatever? Do you think we’ll get there, where there’s an established regimen that the platinum and eligible patients should get?

Kala Sridhar:
I think there will be just because the outcomes in patients who don’t get anything in that setting is really not very good. And we are seeing a good bubbling of the current studies in that setting. I think we’ll get to something in that space. Something more than nothing in patients who are Cisplatin ineligible.

Tom:
It might be podcast 300 rather than 200, Brian. Kala the next question, it’s a group of questions I wanted to ask you about was, we’ve tried very hard to identify biomarkers in urothelial cancer. And one of the interesting things is when we do the prospective studies, the biomarkers don’t seem to work well, and it brings the trial down. But when we have positive ITT trials everyone comes in and says, the biomarker population seem to do really well.

How have we got into this paradox where we all seem to think the biomarker works but it never seems to work when we test it in the trials?

Kala Sridhar:
I think it’s a good question. I think there are so many variabilities as far as the biomarker is concerned, even looking at PD-L1, the expression. Is it immune cells? Is it tumor cells? Like where is it? And what level is the cut off? I think there’s so much noise and so many things at play that when we do these large trials sometimes what we’re seeing is not what we want.

And certainly, we’ve seen for example in the test or study, where actually patients in the adjuvant setting, those who are IC 23 actually had a worse hazard ratio. So, I don’t think we’re quite there yet. And I think we have to be very careful going forwards with the biomarker point of things.

But I think it’s important that every study we do does try and incorporate the biomarkers into things. I think what was interesting, there was a podcast I think you had with Pam Sharma and Michiel Van Der Heijden.

Brian:
One of our papers of the month, I believe.

Kala Sridhar:
I think so. And it was really interesting because one of the things that I remember from that podcast was where they talked about when patients in the neoadjuvant setting if they had a PCR, how important it is to actually look at that PCR tissue, and we haven’t typically done that thinking there’s no tumor left.

But really understanding what’s happening at the immune biomarker level in that tissue I think is particularly important. And the corollary to that is, in patients who have not had a PCR maybe we’re actually looking at a resistant phenotype and I think Pam had mentioned that. So, I think that type of information is really important as we move forward in the biomarker realm.

Brian:
And Kala, what do you think is going to happen in the refractory space? So pretty established chemo, the maintenance Nivolumab is a standard of care. What else is going to happen? Obviously, there’s been developments. But where is that space going?

Kala Sridhar:
So, I think the antibody drug conjugates those are really very exciting. So enfortumab vedotin with response rates upwards of about 45 to 50%, this is a well-tolerated drug. I think that drug in combination and with pembro in the frontline setting is what I’m watching closely.

I think the other antibody drug conjugate is also interesting. Cross trial comparisons notwithstanding, response rates a little bit lower but still a completely different mechanism of action, different toxicity. So, I think that begs the question of how do we sequence these drugs optimally going forward.

But really, we now have a number of different options in bladder which is virtually unheard of.

Brian:
Right.

Kala Sridhar:
So, I think it’s very exciting and …

Tom:
Kala my last question, FGF inhibition, where’s that going?

Kala Sridhar:
I think, again the nice thing about this drug is it’s an oral drug something like Erdafitinib, which in the current COVID context I think has been really nice for some patients. So, it avoids multiple visits to the hospital. Response rates are respectable. I think the challenges that’s only 15% or so that express this.

So, I’m curious about the combinations of maybe FGFR and IO and seeing where that’s going. I think there’s an adjuvant trial looking at FGFR. I think that’s particularly interesting, especially in patients who may have already had neoadjuvant. So, I think that’s where we’re seeing with FGFR, and I think there’s other targets coming along as well. But really very exciting, multiple different angles that we’re exploring at this time.

Tom:
We’ve got our third special guest David who’s arrived. Kala, you’ve got an opportunity to ask David 1 question before he leads.

Brian:
Ask him a bladder cancer question.

Tom:
And see how it goes. Make it as difficult as you’re like.

Kala Sridhar:
Sure. What’s the most exciting thing from your perspective, David?

David McDermott:
I can’t talk intelligently about bladder cancer, so I’ll skip that.

Tom:
David, Kala’s just got promoted to a professor which is very exciting.

David McDermott:
That is exciting, I didn’t know that. Congratulations.

Brian:
We just found out.

Kala Sridhar:
Thank you.

Tom:
Kala, thank you very much for joining us.

Kala Sridhar:
Most welcome.

Tom:
And we’re going to see you really soon.

Kala Sridhar:
Sounds good. Take care guys.

Brian:
Thanks Kala.

Kala Sridhar:
Well done.

Brian:
Congrats.

David McDermott:
Bye, Kala.

Kala Sridhar:
Bye, thank you.

David McDermott:
Bye-bye.

Brian:
David, welcome.

David McDermott:
I’m glad to be let in. I had sort of a flashback of my college days there for about 20 minutes when there was a party, I knew about for some reason I couldn’t get in, I don’t know.

Tom:
I can talk to you about that if you want David.

Brian:
I have a picture of you, I have a picture in my mind that’s very entertaining. Welcome to the hundredth podcast. We can’t believe we’ve made it this far. Thank you for all your contributions. We’re going to wrap up with renal cancer, kind of talking about highlights and mostly we’re focusing on where we’re going.

Tom:
Before we go there Brian, let’s just talk about a couple of things. Firstly, our most popular podcast was the CLEAR trial, but actually our most popular debate David, was your discussion when you defended the immune combination piece in what you described as a very unfair and unbalanced podcast.

Brian:
Why was that unfair? Because I won the debate?

Tom:
I don’t know, David. Why did you feel …

Brian:
Sour grapes.

Tom:
Why did you feel it was unfair, David? And has your position changed at all?

David McDermott:
Here’s the thing, you have a tendency to interrupt Tom on these things.

Brian:
Well, I’m not supposed to that.

Tom:
No kidding.

David McDermott:
And you were interrupting on Dr. Rini side during the debate. The thing that was unfair, I don’t think the podcast was unfair. But what followed which was the Twitter question wasn’t fair.

Brian:
Right.

David McDermott:
Because it was a multiple choice. And you gave I think it was 3 choices, and 2 of which were VEGF PD1. And then claimed that VEGF PD1 was somehow more preferred.

Brian:
Well, there’s more VEGF PD1 choices, David.

Tom:
Do you suggest we just leave some out altogether with that?

David McDermott:
No, just group them all together. As Dr. Sweeney says, when you do the same study 4 times, and you get essentially the same result …

Tom:
The same good results.

David McDermott:
The same good results, yes. But the point is that question was designed to …

Brian:
This sounds like sour grapes to me.

Tom:
I can see you’ve not emotionally moved on David.

David McDermott:
Well, you asked [inaudible 00:21:24]. You’re just bringing all back all sort of stuff that I have sequestered.

Brian:
I will say on a lighter note, I think our most popular paper of the month was your KEYNOTE-427 pembro and clear cell and not clear. I’m looking at it now, 837 listeners.

Tom:
And David you’ll be aware that the ESMO committee met. One of the reasons I wanted it there was the ESMO committee met, and we have got an E-update coming out very soon. Actually, pembrolizumab will appear in those guidelines now based on that data. So those are practice changing trials that you performed, which I think are important.

David McDermott:
Wow.

Tom:
Of course, Cabozantinib will appear and Sunitinib. And Cabozantinib will get a 2b recommendation and Sunitinib and pembro will get 3b. But I think that was an important piece of work.

David McDermott:
Is that clear cell and non-clear cell or just …

Tom:
No, I’m talking exclusively about peri-renal cancer. So, we’re writing some guidelines for peri-renal cancer which we’re going to come up quite soon.

David McDermott:
Okay, interesting. Well, that’s good. I’m glad that I showed up for this call to find that out. That’s good, it made my day more happy.

Tom:
David, I’ve got a question for you.

David McDermott:
Yes, sir?

Tom:
People tell me that you eloquently speak about what people call treatment free survival. And I heard you give a talk recently at the IKCS about cure and how it’d be nice to follow the test this cancer model where you give a period of therapy for clear cell kidney cancer, and then stop.

Do you want to just articulate your position on that in terms of the future, and why you think that’s an achievable goal?

David McDermott:
So, the argument that I made at the IKCS meeting was we’re already curing patients with metastatic disease. It may not be a large number but if you look for example at the ESMO open paper from last year, you look at some of those responders who are out several years now after responding with no therapy.

So those patients are certainly in remission and some of them are probably cured. So, I would say we’re probably curing them. And if you agree with that, then my argument was we should work our primary goal not our only goal, but our highest goal should be to try to create more cures much as they did with testicular cancer 40 years ago, that was my point.

We’re nowhere close to where testicular cancer is now, of course. But decades ago, they decided we could cure some of these patients let’s cure more of them. So, let’s do some things to create more [inaudible 00:24:00].

And that doesn’t mean giving IO therapy to everyone, because as Brian cancer, cell paper points out, there’s just some patients who are never going fit and we shouldn’t be giving immune checkpoint blockade to those patients. We should be doing trials. But there are some patients that will, and we should identify and stop their treatment once they’re responding because many of those people don’t need chronic therapy.

And I guess the other connection I was making to testicular cancer, and this is similar to lymphoma too which some are made on the podcast, and I agree with her. As we find patients who are recurring after PD1 blockade, there may be some patients who want to take an aggressive next step to try to [inaudible 00:24:45]. And there are therapies that are in clinical testing early like CAR T or TIL therapy or something like that might allow patients to get a deeper remission, maybe a cure after they have failed PD1.

The biggest question for the field is what salvage is a PD1 patient? And I’m not saying we know the answer to that, but we should be aiming our trials towards that for some patients.

Brian:
David, I have a comment and a question. My comment is, I think I missed what Tom has said because that’s when I was in the airport, and it was super loud. Tom, you have kicked me off a podcast. We have [crosstalk 00:25:21].

Tom:
And I also reassure Brian that your heavy breathing has come into this podcast as well, which I was waiting for. So, congratulations on the heavy breathing and the airport display.

Brian:
Thank you very much. And so, my question David, is what percent of patients who walk in the door with metastatic kidney cancer right now do you think we can cure?

Whatever regimen you want. So, if a patient said, doc what’s my chance of being cured or at least in remission? Let’s use those words interchangeably, like doing really well for a long time. Give me a number.

David McDermott:
In remission, I’d say it’s somewhere it’s no higher than 30 or 35%, but it may be somewhere between 20 and 30% of patients, I think. And that supposition comes from the CheckMate 214 experience, where there’s about a third of patients who haven’t progressed on that study. To me that’s the bar. Some of those patients are cured. Some of them need chronic therapy. But it’s not zero.

Brian:
I think that’s right. I think that’s the number I usually [crosstalk 00:26:30].

Tom:
David, talked to me about stopping treatment. I was on a ESMO Asia guidelines committee meeting this morning, which was really interesting. And lots of people in Asia but also in Europe want to know, can we stop therapy? Lots of patients are paying for the therapies themselves. Do they need to go on indefinitely? And so, if we can stop, when can we stop?

And of course, Ipi/Nivo where it kept going with Nivolumab. But the pembro I’ll stop after 2 years in 426. If you have a complete response, can you stop sooner? Could you just address that issue for me?

David McDermott:
So, I think the trials that need to be done and they probably could get done XUS because of the issues you talk about. A lot of these exciting therapies because they’re not reimbursed in most many places in the world, is a trial of treating to certain time point. For the sake of argument, let’s say 1 year and you then take the patients in response, and you randomize them to stopping versus continuing.

That’s a slightly different trial design than a lung cancer trial that was done in Europe. One of the CheckMate BMS trial in that setting they just stopped everyone at a certain time point not based on response. I think that group of responders that can stay off, not all of them. We’re not treating melanoma here where 90% of them who come off therapy stay and responds at least so far.

I don’t think it’s that high, but it’s a non-zero number. And we need to design the right trial to prove it because to your point the indefinite use of PD1 blockade is totally made up. Even the two-year time point is made up.

The first trial of the PD1 with what became Nivolumab was 1 dose. You could only get more than 1 dose if you were responding. And we allowed this to happen, when I say we the investigators who were part of these trials, we allowed this continuous thing.

Tom:
You make it sound like the Cuban Missile Crisis, don’t.

David McDermott:
Here’s the thing, you could be proud. I’m sure you’re proud that you have helped develop certain therapies for let’s say bladder cancer. I’m certainly proud of your accomplishments.

But if you ask the question, are these drugs actually getting used in most parts of the world? The answer is no fucking way, and part of it …

Tom:
David we’ve never had swearing on a podcast.

David McDermott:
Sorry.

Brian:
It’s a family show.

Tom:
Most of all, David …

David McDermott:
All right, I’m sorry. But my point being …

Brian:
You’re getting worked up there.

David McDermott:
… if the therapy had this end time, a stopping time, you would get more people getting it reimbursed. So, we have over by allowing indefinite therapy, we limit the number of people around the world, but these diseases who can get our drugs, that’s all. I’m sorry for cursing.

Brian:
We’re over-treating [crosstalk 00:29:30]

Tom:
No, David, I’m only messing around. I’m more than happy with your … because it is such an important issue, and I agree with you. And in fact, it was something we talked about for some time this morning, much more than some of the issues.

Let me put this to you, do you think this issue is more important than the conversation between Lenvatinib, pembrolizumab and Axitinib and pembrolizumab?

David McDermott:
Absofrigginlutely.

Brian:
I think he’d just does it.

David McDermott:
No, I didn’t. I did not. That therapy, that conversation is a waste of our time. We have better things to do than to argue about which VEGF PD1 combination is best.

We can build on those things, move on, and still insist on selecting patients because I said that paper, that cancer cell paper, Motzer, Rini et al, suggest, not everyone should be getting these drugs. And it gives us a pathway forward. We should follow that kind of work forward, not giving the drugs to every single person.

Brian:
I agree David. I’m going to vote you MVP of this podcast too. Your enthusiasm aside from the swearing. I think you’re absolutely right. I totally agree with you with all those points about biomarker based, arguing over combo a versus combo B who cares, it’s boring, doesn’t advance the field, doesn’t help patients in my opinion.

David McDermott:
I appreciate your support. And I think the reason this is going to be increasingly important is biomarkers when you’re talking combos are hard, particularly when you’re designing the trials as 2 -arm studies, instead of 3 -arm studies or whatever, it’s almost impossible.

But now we’re going to get back into a very important question starting with ASCO this year, which is, who should get single agent PD1 in the adjuvant setting? And that’s a very interesting question.

And in melanoma, I can tell you, where all stage 3 patients can get it in the US, both pembro and Nico. We started out using a lot of it and are now dialing back some of our use in lower risk stage 3 patients in part, because of sort of the therapeutic index question is like, because toxicity in that setting is completely unacceptable if it’s permanent. So, all of them [inaudible 00:31:47] still insisting on for the first metastatic decision, but certainly for the adjuvant decision, I think.

Brian:
That’s a good analogy I think, you’ve done in melanoma.

Tom:
David, my last question’s going to be across to Brian on this. And Brian, one of my criticisms of the renal cancer field has been our lack of enthusiasm around biomarker development. And you and other colleagues have developed this 7 category RNA signature.

And I heard you say again at the IKCF, you talked about actually doing a perspective randomized trial with an RNA signature, that seems perhaps a step too far for me as things currently stand. Do you want to just talk a bit about how that might work and why you think that’s a good idea?

Brian:
I think as David said, I think we need to start doing the trials to develop biomarkers and not just make them passengers on these big phase 3s, that doesn’t do us any good. It hasn’t done us any good, hasn’t helped patients.

So, I think we need to start doing biomarker trials. We’re going to try and assign patients to a certain treatment based on cluster. That’s not the only way to do it, maybe it’s not the best way to do it. My dad comes and I have had long conversations about this. So, I’m open and I think we need more than one approach. If we’re going to develop a biomarker it’s going to be more than one approach looking at different biomarkers, randomization or not.

But I think the point is we need to start doing that hard work. Otherwise, it’s just a lot of talk and its nice papers, but it’s not really helping patients. We’re over-treating some, we’re mistreating some, and or under treating others.

Tom:
With [inaudible 00:33:20] the PFS for the biomarker positive with the PDL positive is 0.45 compared to Sunitinib.

Brian:
And the survival.

Tom:
No, the PFS, the S is more complex, but PFS isn’t. And then in the OS, it’s about 1.0 it’s really sort of striking. And so, do you think that actually your 7 gene signature is a better biomarker than the PD-L1 biomarker? Wouldn’t it be easier just to use PD-L1 to start with?

Brian:
It would, I don’t know if it’s better or not. PD-L1 even though the chemistry may just be a poor man’s RNA seek, that’s possible. So, we don’t know until we test it, but we can test that. These are testable hypotheses. We just need to do it. We just need to do perspective or else will never know.

David McDermott:
Right.

Tom:
I think we’re going to wrap this up, David. All of the other guests have had the opportunity to ask the subsequent guest a question. I guess you’ve got the opportunity to ask Brian and myself a question of your choice.

David McDermott:
I’ll ask a question, okay. Here’s a question, this is related to the podcast. So, when is this podcast going to become a video podcast? So, we can actually see the participants.

Tom:
Brian has the perfect face for podcast, of course.

David McDermott:
There you go. And so maybe including slides and things like that, a little bit more dynamic.

Brian:
I think it’s pretty dynamic. We’ve had 56,000 listeners; David thank you very much. We appreciate your input.

David McDermott:
I’m just saying …

Brian:
The nice part is I can do it from the airport or my car.

Tom:
Maybe we should do a 3-monthly video Brian, but that would be …

David McDermott:
I think your goal should be your own YouTube channel, actually.

Brian:
We’re going to have a virtual suggestion box on Twitter. Maybe we’ll put that out there for how to improve the podcast. We’ll make that number one.

Tom:
We certainly should do that, how to improve the podcast, because there is room for that undoubtedly. David, as always, it’s been for fantastic having you with and I hopefully we’ll see you really soon. Brian, any last comments from you?

Brian:
No, just thanks to all our listeners for sort of making this possible. It’s a lot of fun. We learn a lot. We get to debate our friends and colleagues and other things. So, thanks for listening. We hope to do a hundred more.

David McDermott:
Yes, congratulations guys. You’re performing at fine public [inaudible 00:35:47].

Brian:
And David, by the way, you’re the first person in a hundred podcast to swear on the podcast.

Tom:
That is true actually.

David McDermott:
Okay, see you soon everybody.