Charles Ryan: Hello from ASCO 2019. I’m sitting here with Tom Powles. We’re having a great conversation about immunotherapy and renal cell cancer. Tom, tell us about how you choose a frontline therapy for kidney cancer.

Thomas Powles: It’s become really confusing, and the reason it’s become confusing is because we’ve got a choice now and it’s terrific. I was in a room not that long ago, really maybe two or three years ago when people were saying to me, “We should be aiming for five-year survival for our metastatic kidney cancer patients.” And people looked at each other as if to say, “How on earth are we going to achieve that?” And we’ve hit that reality.

Charles Ryan: Amazing.

Thomas Powles: And that’s really important. And as I see it, there are three groups of drugs. There are the VEGF-targeted therapy, the single agent. We’ve just rewritten the EAU guidelines. And those EAU guidelines essentially have totally replaced those and put them as sort of a second line treatment.

And now instead of VEGF-targeted therapy being the backbone, it’s immune checkpoint inhibition, PD-1 therapy essentially. And then there are two choices. The second drug you bolt on, currently you bolt on axitinib, which is a VEGF-targeted therapy, or you bolt on ipilimumab, which is CTLA-4. And on those guidelines in intermediate and poorest disease, you can choose either. In the good risk patients, Ipi/Nivo doesn’t have a label. And in fact the sunitinib in that trial, to some people it’s a bit better. There’s a debate around that, which I’m not going to talk about today, but in broad terms, so Axi/Pembro, good in intermediate and poorest patients, Ipi/Nivo, intermediate and poorest patients.

And there are some patients who are not fit for immune therapy for whatever reason, which I’m not going to talk about specifically. And those are the sunitinib patients now from a global perspective, and that’s how I think we should be looking at this.

Charles Ryan: But what presses you to make the ipilimumab decision when you have Axi/Pembro? What’s the margin there?

Thomas Powles: If we look at the intermediate and poorest patients where there’s a genuine choice, I think you need to look in my opinion at four really key parameters. And the debate going on the community has not been resolved yet. The first is one looks at survival as the primary endpoint of those two trials. And the survival endpoints were the hazard ratio for survival for Axi/Pembro was 0.53. There are more mature Ipi/Nivo data and that more mature data in those intermediate and poorest patients started at 0.63.

One number seems lower than another, in terms of, but the reality is they’re both having a significant survival environment. We never hit survival frontier before. Now you might say I’m going to pursue that 0.53, that’s really attractive and therefore I’m going to choose Axi/Pembro for my patients. But you might say actually 0.53 and 0.63 come within the same bracket of one another.

Charles Ryan: Yeah when you look at the patient mix in the trial it’s really hard to say that there’s a difference there.

Thomas Powles: So I’m nervous about saying you have to pick Axi/Pembro because that number is lower than that. And I think we need to have that. That’s a grownup discussion. I know. So that’s number one. That doesn’t mean that 0.53 isn’t really important. And if you said to me four or five years ago, we could get those sorts of results, I’d say, “That’s fantastic.” So that’s number one. You’d look at that. Number two is clearly response and progression free survival or a secondary endpoint. Response is important for patients.

What’re the chances of getting in control? Reducing the tumor size? And again, Axi/Pembro has resulted in about 60% which is higher than 40% of IPI/Nivo. But it becomes quite complicated because there’s also this CR issue of complete response where the target lesions disappear completely. And the converse of that is IPI/Nivo looks at about 10% whereas Axi/Pembro looks more like 6%. now those numbers aren’t 30%.

Charles Ryan: Right.

Thomas Powles: If they were curing a third of patients, I would say, “Put that to one side.”

Charles Ryan: Right.

Thomas Powles: You know, and so that debate also has a grayness around it, you know, the just as the initial one did. So again, I’m nervous about people standing up saying, “You have to do it because of this.”

Charles Ryan: Right.

Thomas Powles: Cause I’m not bought into that just as I’m not bought into that original discussion.

Charles Ryan: Good. Go ahead.

Thomas Powles: So then and the progression free survival issue. Well, many people say if you give Axi and pembrolizumab together, your PFS is 15 months, which is very, very long. But you’re giving both drugs together and other people say, “What if you sequence the drug? How does that work?” And that debate, again, that can be had. But clearly, when you look from the back of the room from that, you’d say, well Axi/Pembro to achieving those three goals, Ipi/Nivo achieving not specifically those three goals as well probably. But they have got the CR, which some people say is important.

And so that context of that debate is really moving now. The last piece which is relevant is about quality of life. Ipi/Nivo data we’ve seen that quality of life in that environment. So and that looks impressive. We wait for Axi/Pembro, and then the last piece is the maturity of data and we’ve got 30-month followup practices for Ipi/Nivo.

We don’t yet have that more mature data for Axi/Pembro. So I think when you look at those intermediate and poorest patients, you say there is a genuine choice. I can see why that choice is there. I think that you know, issues around overall survival, which looks very impressive, particularly for Axi/Pembro. You look at other parameters and you can see arguments for and against for both. And that puts us in a difficult position because it’s entirely reasonable to choose both and we probably need to get together as a community and work out what we’re more comfortable with.

And I suspect a lot of it will come down to some of the finer detail. Be some doctors will say, “Well I want to keep going with the VEGF-targeted therapy and just add in the pembro.” There’ll be some people who might be a bit nervous about getting immune combination therapy. I don’t think you need to be nervous about that, but I can see why that might. Other people said to me, “Well, you know, you have issues around giving two immune drugs.” So actually I think that the debate is not black and white and it’s not clear, you have to give that and you shouldn’t give that.

Charles Ryan: I think it’s really important that clinicians hear that from you because if you look at guidelines and you know, certainly the sort of feeling people get from the conversation is that there is a better, there is a singular best choice. And what you’re saying for the clinician is that the Axi/Pembro is going to, you know, potentially be more favorable for some people with intermediate and high risk. You’re compromising perhaps a little bit on the complete response rate, but you’re maybe having a slightly better safety profile. Is that fair?

Thomas Powles: I think it’s not miles away. I think the way I’d summarize it is that from the back of the room, the OS data, the response rate in the PFS for Axi/Pembro looks better.

Charles Ryan: Yeah.

Thomas Powles: There are some subtleties within the data, which I can see why people would be pursuing IPI/Nivo and I could see a debate taking place about the pros and cons of those. The important thing, I think and the message that I’d like to get across … I also talked about the maturity of data, I think that’s relevant. The message I wanted to get across is I’m keen that we don’t enter into a black and white debate around this when we say, “We have to do this” And someone else comes, “No, no, no. You have to do that.”

Charles Ryan: Right.

Thomas Powles: I’d like it to be a balanced discussion. I can see both sides of it and obviously as the data matures and things go on for Axi/Pembro we’ll get more information, but you know, as it currently stands, it looks very compelling.

Charles Ryan: Great. Well, thank you for your thoughts. Really important for the clinicians to hear this, about these two different regimens for upfront kidney cancer and thank you for your work and that was a pleasure to talk to you.