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Alicia Morgans: Hi, I'm so excited to be here at GU ASCO 2024, where I have the opportunity to speak with Professor Toni Choueiri about KEYNOTE-564. And you gave a wonderful oral presentation on this at this meeting.

Toni Choueiri: Thank you. This was really a labor of love. For the first time in kidney cancer since the first randomized clinical trial in 1973, I was not born, we have an overall survival benefit from any adjuvant treatment in kidney cancer. So our patients, our investigators waited for 51 years. KEYNOTE-564 was already a positive study based on the primary endpoint of disease-free survival, which we presented, and it was hosted also by UroToday, thank you, in 2021.

And of course, overall survival was a key secondary endpoint that needed to mature. And then we finally had almost 70% of the events. And now we can say that the study met its overall survival endpoint with over a 38% decrease in the risk of death. We also updated the KEYNOTE-564 with disease-free survival because we have now around 58 months of follow-up. Still stands. And we looked at late toxicities around 60 months of follow-up, and there weren't any new toxicities like late-term side effects from a year of pembrolizumab.

So we're very happy for our patients. It's also the only positive study of any cancer, any solid tumor, with a PD1 pure adjuvant study. So it's a big day for the adjuvant field.

Alicia Morgans: It absolutely is. And can you remind everyone which patients these were? And then tell us exactly, pembro for a year, just tell us exactly what the treatment was. Because for only one year of pembrolizumab, this is a pretty incredible improvement, right?

Toni Choueiri: Absolutely. It's patients at some risk of recurrence. So after surgery, a patient needs to have clear cell RCC. That's where pembrolizumab data was mostly in. And the patient needed to have stage 2, grade 4 or any stage 3, T3, N plus, T4, but also there was a small group of patients that had metastases, oligometastases and resected within a year of nephrectomy, what we call M1 NED. And the patient would receive 17 cycles, almost a year of pembrolizumab versus placebo. The disease-free survival endpoint was met.

We looked at subgroup analysis in the past for disease-free survival. All the hazard ratios were less than one. And now for overall survival, we looked at also subgroups, smaller number of events, but also the benefit. You know? If you take out the M1 NED and you focus just on the patients that I mentioned with stage 3 or T4, the benefit is there. If you look at patients that are intermediate-high, the bit over 80% intermediate-highs. You take out T4, N plus, M1 NED, the highest of the highest risk still... Actually, the hazard ratio is even lower for OS. So we are quite encouraged by these results. And I can't think of a better venue to present this than San Francisco and discuss it on UroToday.

Alicia Morgans: Yes. Wonderful. Well, as people are trying to think about practice and how they apply these data, and certainly they've been thinking about this for years because the drug was approved in this patient population based on the DFS benefit that we talked about a few years ago, how do you think about that? What makes it actually worth it to use this agent? Some people get out of surgery and say, "Basically, I've had enough. Why should I bother doing this?"

Toni Choueiri: That's a good question. In any adjuvant, even in the highest risk, M1 NED, surgery alone, irrespective of this is kidney, bladder, prostate, or even breast cancer cures a significant, I would say, proportion. Sometimes a significant minority.

But here, since we met OS, we cannot say that pembrolizumab only delays recurrence so we can hit if there's a recurrence with a surgery, a localized treatment, or with systemic therapy. Patients live longer, so patients are cured. This is another reason to discuss with the patient and say, "Here, you have an overall survival. You do have potentially also a cure." So I think the use and the discussion will soar. Of course, it's always a discussion with the patient, but the use is going to be more and more prevalent. And we are going to end up with a population of patients at some point cured, but also a population of patients whose tumor progresses on adjuvant pembrolizumab for which we don't know what to do. Is it the same as a progression on metastatic disease on checkpoint inhibitors? I don't know. The biology might be a bit different.

Alicia Morgans: These are the questions that we're thinking about in urothelial cancer too. I mean, these progressions on adjuvant can be really tricky, and we still need to figure out, as we have this data maturing, what do we do next. But I think it's so important, certainly that we have the OS data to your point, that you're not just delaying. You're actually curing more patients.

Toni Choueiri: Absolutely.

Alicia Morgans: And that at the end of the day is so important. So, one more question. And I know you went through the subgroup analyses for disease control, but did your subgroup analyses find that there was any difference in the signal of adverse events in patients who were older, perhaps patients who had other comorbidities? How did they fare in terms of those?

Toni Choueiri: Yeah. No, I think this is a fair question. We looked at treatment discontinuation due to adverse events, steroid use. There wasn't a signal. This is still a controlled population where patients need to be after surgery still feeling great. You know? So we did not see that. We also looked, Dr. Morgans, at the treatment received after progression. And we didn't see a major difference. Anyone. This is parallel. This is against a pattern of how to treat patients after progression. So we've seen not just systemic therapy, but we've seen localized therapy. And after adjuvant a year, you may have one to two lesions that you decide to take to surgery, observe, do radiation. So we've seen all that, and it seems to be balanced between both arms.

Alicia Morgans: Wonderful. So if you had a message to give to clinicians, to patients who really want to think about this data, what to do next, what would your message be?

Toni Choueiri: There are two messages. One, and most important, listen to UroToday. The second message. The second message is now we have stronger data and we need to build on adjuvant pembrolizumab. We still cannot pick the patient who will a hundred percent relapse or a hundred percent respond. We don't have a PSA after surgery. We don't have a ctDNA test in renal; the tumor doesn't shed. So we have to do everything like we did decades ago by the clinical and pathologic criteria, which is not great, but that's what we have for renal cell cancer.

And I think physicians should discuss seriously with their patients that now pembrolizumab can extend life. The hazard ratio and the decrease in the risk of death we feel is not only statistically significant but also clinically relevant.

Alicia Morgans: Absolutely. Well, congratulations to you. Thank you so much for sharing your expertise. And I really look forward to answering all the other questions that you've raised in this conversation.

Toni Choueiri: Thank you so much for having me, and thank you, UroToday.