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Charles Ryan: Hello, I'm joined today by Dr. Thomas Powles from Barts Cancer Center in London, where he is the Director and a Professor of Genitourinary Oncology. ASCO GU 2019, you're presenting some exciting data in kidney cancer, the interface of targeted therapies with immunotherapies. Tell us about your work.

Thomas Powels: The work is that of a huge group of people, who have taken part, maybe over the last ... the journey starts 10, 12 years ago with the VEGF targeted therapy, actually. The study I'm presenting is the integration of those VEGF targeted therapies with the newer generation of immune therapies. We're combining axitinib, which is a classic, quite specific VEGF targeted therapy with activity particularly in sunitinib-refractory disease, as well as a license. We're comparing that with pembrolizumab, which is a drug as a monotherapy has a 39% response rate in metastatic clear cell kidney cancer. 

By combining those two drugs together, we hoped that we could shift the bar. One of the reasons we feel that's possible is VEGF targeted therapy has, well, it facilitates T cell trafficking, it has some immune component to it, and so we feel there's the potential for immune synergy. Also, we know drugs like sunitinib and axitinib are good at getting in control of the disease. Immune therapy less good at that, but we know the immune therapy's good at long-term durable remissions. Maybe by giving the two, we can get in control of the most and get long-term durable remissions. That's the rationale for the study.

The study design, Keynote 426, is a randomized Phase 3, about 900 patients, 450 in each arm. Sunitinib is a benchmark control, as you can imagine, versus the combination. Axitinib at standard doses, five BD, the same with pembrolizumab, every three weeks. The results of the trial were positive. They were actually very positive, so we had response rates in the region of 60%, where sunitinib 35%, which is obviously very significant.

Charles Ryan: Pembrolizumab alone, you would expect 30% or so, and you're saying 60% with the combination?

Thomas Powels: Yeah. It looks, it's higher than you ... that looks sort of additive. It looks additive to me. Then, you've got a PFS advantage and that PFS advantage: 0.69. You look at those figures and say, "Well, that's actually obviously a significant advantage for the combination, as well. That's obviously hit its endpoint." The really striking thing about this trial was the overall survival advantage and that has a hazard ratio of 0.53, which means a 47% reduction in the risk of death. We've not seen those sorts of figures in kidney cancer before. I mean you might remember none of the original sunitinib trials actually hit a significant, so it might be cross over other issues with that. This really is in that respect very groundbreaking to get down and a 47% reduction in the risk of death is a huge issue for patients. That really is moving the bar in the living longer direction by giving both the drugs up front.

It's important to talk about other issues. There's tolerability, adverse events. The adverse event profile actually similar for both in terms of Grade 3, Grade 4 toxicity. A few percentage points higher for the combination. When you look in detail at those adverse events, they are the expected adverse events, and so they're ranging, of course, from the hypertension, the associated with the axitinib lethargy, some immune-related adverse events with the combination. There is obviously some education and training around that combination, which is important. My overall take from the study was that we hit maybe the response rates and the PFS that we were expecting, but that survival signal was much better than I expected.

It's unusual, for example, to have a better survival signal than a PFS signal. That is suggesting to me anyway, that there is more than just giving the two drugs together, which suggests to me that it might actually be that hypothesis that the VEGF targeted therapy and immune therapy together are facilitating groups of patients that weren't otherwise potentially benefiting.

Charles Ryan: The complete response rate and PR response rate, between the two?

Thomas Powels: The complete response rates at this early stage is 5.9%, so about 6%, and we need to watch those data. The overall sort of ... This isn't the first hit, the first, interim analysis. That's actually now the final analysis because of trial design. Doesn't mean you don't keep testing, you can only test once. We will obviously watch that population. It may increase with time. We don't know yet.

One of the things about response, which I think is important, is CR is 100% disappearance of target lesions. If you've got bone metastasis, that can't happen, so that that population is excluded. What we, my personal experience is there are subgroups of patients with bone metastasis who do go into long-term durable remission. I actually think we need to use or develop better tools to identify the long-term winners, and that might not be CR. It might be patients who have an 80% reduction in target lesions or patients who disease-free or progression-free at 12 months without. These might be a better way of saying these are the real winners in the future. Because CR in years gone by ... I think we used to use X-rays, we'd stick them up and say, "Oh, it's disappeared, CR, great." That's not what we're doing anymore. I think that as the technology's moved on, I think the tools we use to measure need to move on as well.

Charles Ryan: Highly likely that we'll have a new standard of care, you think, for first-line therapy? I mean, I think it's-

Thomas Powels: Yeah. I mean I think one of the positive things about this, we treated a lot of patients in the trial. I think it was about 30 patients. I mean my nurses will come back and the patients will come back and clearly those patients are doing better and that you can see they're tolerating the treatment, they continue on treatment, they're all respond or respond. They're responding as you would expect in the trial. When you give that, well, when I've given that combination, it's a combination that I would want to give my standard-of-care patients in the future. I not only with the trial positive but my personal experience reflected that, which I think is important.

Charles Ryan: Where do you think we go from here?

Thomas Powels: Why it's complicated isn't it? Because we've now got two regimes. Ipilimumab and nivolumab, with a survival advantage, it has a ratio of 0.63, an intermediate in poor-risk patients and we've got the survival. We've got axi/pembro has a ratio of 0.53, hitting response, progression and survival. We need to think a bit about is there an issue around patient selection or should all patients have one treatment or the other. We don't know the answer to that, those questions. The community will have to look at the data and work out for themselves how they feel about these two regimes. I think that's a debate that we need to have.

Then, the second thing is where do we go next. This sounds ambitious, but we need to be curing 50% of kidney cancer patients, and that's what we need to do. We just need to work out how we're going to do that. At the moment, we've got tools, what we know are very active. We need to be combining them. Maybe selecting patients in a different way, so we select patients who we think are going to benefit from immune therapy. Clearly, there're immune triplets that we need to be exploring and we also need to be exploring immune therapies, immune doublets and putting in VEGF-type targeted therapies.

Remember testis cancer, which we cured, we needed three drugs?

Charles Ryan: Yep.

Thomas Powels: HIV, you needed a triple therapy?

Charles Ryan: Yeah.

Thomas Powels: Now there's toxicity-

Charles Ryan: Lymphoma.

Thomas Powels: Lymphoma. Perhaps, we do need to be building. There will be a toxicity cost associated with that, but we need to be in, our goals now need to move away from palliation into cure, in my opinion.

Charles Ryan: Isn't it fun to be talking about this?

Thomas Powels: It's terrific.

Charles Ryan: Well, congratulations and thank you for your thoughts and insights. We're looking forward to seeing further work. Always a pleasure.

Thomas Powels: Pleasure, likewise. Thank you.