Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago in the U.S. I'm so excited to have here with me today a good friend and colleague Dr. Rana McKay. Who's an Associate Professor of Medicine and a GU Medical Oncologist at UC San Diego. Thank you so much for being here with me today. Dr. McKay.

Rana R. McKay: Thank you for having me. It's a pleasure.

Alicia Morgans: It is especially a pleasure because I wanted to talk with you about your fantastic discussion of KEYNOTE-564 at ASCO 2021. Really phenomenal job helping us think through the data. Can you tell us a little bit about your presentation and help get the rest of us on board if we missed that great talk.

Rana R. McKay: Absolutely. So just as a way of background, renal cell carcinoma is actually a pretty common malignancy. It's a top 10 cancer in both men and women, and it's really becoming... Its incidence is increasing really with the use of medical imaging and us scanning patients for various reasons. And unfortunately for patients who have renal cell carcinoma, well a subset of patients are cured with surgery alone. There are patients that are at high risk of developing metastatic disease. And at the present time there really aren't any adjuvant-based treatment strategies that have demonstrated improvements in overall survival for patients who are at high risk for disease recurrence.

 Just historically a series of adjuvant cytokine trials were conducted in the late 1980s, 1990s, early 2000s. No cytokine therapy was demonstrated to improve disease-free survival. Then we see a series of adjuvant targeted therapy trials. Given the efficacy of these agents in the metastatic setting they were explored in that adjuvant and preoperative setting. And in essence, there was mixed results, but largely negative. So the ASSURE trial was the largest of these phase 3 trials that tested adjuvant TKI therapy that in essence was a negative trial. The S-TRAC trial tested advent sunitinib versus placebo in a more homogenous patient population patients who had pT3 or 4 disease or lymph node positive disease.

And while that trial was positive for disease-free survival, adjuvant sunitinib was associated with significant toxicity and decline in quality of life. It's interesting that the KEYNOTE-564 trial also included patients who were M1 receptor to any D, that's no evidence of disease. Because we use metastasectomy in the treatment of advanced kidney cancer. And the historic data of tyrosine kinase inhibitors in this setting, and you would imagine that these were your highest risk patients, were actually negative. This was actually based on a ECOG-ACRIN study looking at pazopanib for patients who had M1 NED RCC.

So that's just a little bit of a way of background for KEYNOTE-564. Obviously, checkpoint inhibitors have demonstrated improvement and overall survival for patients with metastatic disease. And now they're being tested in multiple solid tumors for patients with localized or locally advanced disease. And really to date there's only two diseases for which checkpoint inhibitors are approved in the adjuvant setting. Melanoma historically checkpoint inhibitors have been approved and more recently just this past month of May approvals in esophageal and GE junction tumors. So KEYNOTE-564 I think is really actually a landmark study in RCC. It's the trial that randomized patients one-to-one to treatment with pembrolizumab given every three weeks for one year versus placebo.

The primary endpoint was disease-free survival which was investigator-assessed. And honestly in the context of a placebo-controlled study that's randomized, I think investigator assessment is acceptable in this context. The trial enrolled patients who had high grade pT2 disease, that's grade 4 sarcomatoid differentiated tumors all the way to M1 NED. So, the spectrum of risk of recurrence is really heterogeneous in this trial population, raging from 20% chance of recurrence up to 80% chance of recurrence. So I think really heterogeneous patient population.

With regards to the top line data, this is the first cut of this data that we're seeing, this is the first interim analysis of three interim analyses and a final OS analysis that's to come. The trial was positive for the primary endpoint of investigator assessed disease-free survival. The hazard ratio was at 0.68 which was statistically significant, so a 32% reduction in the risk of recurrence or death. Medians are not yet reached for either pembro or a placebo, but we see a very clear separation of the curves very early on that continues on throughout the trial with a 12-month rate of a recurrence or disease-free survival of 85.7% compared to 76.2% with placebo.

And I think what's really exciting about this though it's still pretty early is the data around OS. And there really aren't a ton of events, as of yet there's I think 51 events at the time of this data cut. But the hazard ratio for overall survival was 0.54, the confidence interval was 0.3 to 0.96 but hasn't yet met the threshold obviously for significance. It's still pretty early on. And we're seeing efficacy across all of the subgroups independent of age, sex, performance status, PD-L1 status, and also metastatic staging. So the trial was not enriched for those M1 NED patients, they really comprised a small minority of the patients that were enrolled. And the bulk of the patients enrolled were M0. So this is just really groundbreaking data. It's really exciting to see. Finally, we have an immunotherapy that has demonstrated signal of efficacy in the adjuvant setting for kidney cancer.

Alicia Morgans: So it is phenomenal because it's not like adjuvant therapies have been profoundly understudied in kidney cancer. I mean, we have made attempts and really fallen a bit short with our other options. So this is really exciting as you say. And it's also interesting as you mentioned prior to us starting this recording, that there seemed to be multiple diseases that are just gaining approval potentially in the adjutant setting in terms of solid tumors for checkpoint therapies. Of course we know that there's not an approval but nivolumab in the adjuvant setting in urothelial carcinoma also seemed to at least prolonged disease-free survival. Overall survival is still pending, but so meaningful in a urothelial carcinoma population. What are your thoughts on disease-free survival in this adjuvant kidney cancer population?

Rana R. McKay: I think disease free-survival is definitely a meaningful endpoint here. And I take it back to if we look at ODAC and the FDA's regulatory guidelines for guiding industry on designing studies in this context. And I think disease-free survival prolongation can represent clinical benefit if we take into account the magnitude of the benefit outweighed by the toxicity of the treatment. And clearly in this context we're seeing an efficacious regimen with limited toxicity profile, which I think is clinically beneficial. At the end of the day what makes people live longer and feel better?

So I do think that DFS is important and it's going to be exciting to see the quality of life data emerge from this study. You know adjuvant TKIs I think really struggled, that was our reference standard. And the toxicity in the adjuvant setting was very different compared to the toxicity in the metastatic setting. A large majority of the adjuvant trials that were conducted with TKIs actually required upfront dose modifications of the starting doses of the TKIs just because the toxicity profile was very different than that that was observed in the metastatic setting. So I think seeing a regimen and a therapy that is efficacious but also tolerable with good safety profile I think is really key regarding the utility of DFS. How clinically meaningful is DFS?

Alicia Morgans: I completely agree. Now can you remind everyone how long were people treated with pembro in this adjuvant setting?

Rana R. McKay: So very good question. They were treated for one year. And I have to say that that one year metric is somewhat arbitrary. You know there's no data around guiding where we selected that one year, like why not six months? Why not 18 months? And I think it's historic just based on the way a lot of the adjuvant RCC studies had been historically designed. But I think investigating different intervals of therapy is probably the next step to consider. And I think attempting to move into the space of looking at biomarker-based trials in this context, is there an opportunity to escalate therapy for people at higher risk and deescalate therapy for people at lower risk?

As I stated, this trial really included a heterogeneous patient population with broad differences with regards to their risk of recurrence. So maybe those with lower risks can get by with six months of therapy whereas those with higher risks maybe they need therapy escalation, maybe IO plus TKI combo. You know hard to say, but I think this is the next phase of adjuvant studies that we need to be thinking about as a field with regards to designing. And it's now that we start designing those studies to read out in the next five to eight years.

Alicia Morgans: Absolutely. And that's why I love talking to you because you're always thinking about the next trial and how we answer those important questions. And you have to think, like you said, a number of years before you even can use the data. Because it does take some time for these things to read out. So I'll look forward to hearing your proposals in some of our common meetings and hope that we can get some of your study ideas off the ground. So as we wrap up, what would your bottom line message be to listeners? And again, congratulations on a fantastic discussion.

Rana R. McKay: You know I think this is a paradigm shift. It's the first positive phase 3 study of an adjuvant immunotherapy and RCC. And RCC akin to melanoma has been a disease that's been very responsive to immunotherapy. And I think the DFS prolongation that we see I do believe this actually demonstrates clinical benefit as we discussed given the magnitude of the benefit and the limited toxicity. We're going to have to see with longer follow-up what happens with OS. And obviously very interested in looking at all the subset analyses to come and quality of life data, biomarker data. But I do think that these trial results are practice changing.

Alicia Morgans: Well thank you so much for sharing your thoughts. Your expertise is always so appreciated, your interpretation always so wise. So we appreciate your time and your excellent discussion today. Thank you.

Rana R. McKay: You're welcome. Thank you for having me.