Sam Chang: Hi, I'm Sam Chang. I'm a urologist in Nashville, Tennessee, and today we have Dr. Matt Galsky. I have affectionately called Matt off the record, off the air as the man, and once you spend some time listening to this, I think you'll understand the reason why he really is one of the true thought leaders in advanced urothelial cancer and actually other GU malignancies.

Matt Galsky: Thank you.

Sam Chang: Thank you so much, Matt, for spending some time with us. I could wax poetic about him more honestly, but I want him to talk a little bit about the results presented at GU ASCO 2023, looking at the long-term results of CheckMate 274, which is the use of adjuvant nivolumab for those patients that have had treatment in terms of resection of the disease. Now, this was both bladder and some upper tract patients as well, I think.

Matt Galsky: That's right.

Sam Chang: Matt, thanks again for spending some time with us, but we look forward to hearing about this update.

Matt Galsky: Thank you. CheckMate 274, big randomized phase III study enrolling patients with muscle-invasive urothelial cancer at high risk for recurrence after radical surgery. As you pointed out, could include bladder primaries or upper tract primaries. High risk was defined as patients with greater than or equal to T2 disease in the surgical specimen if they had received neoadjuvant chemotherapy. If they hadn't received neoadjuvant chemotherapy, they had to be cisplatin ineligible and have T3 or higher disease in the surgical specimen.

Sam Chang: Okay.

Matt Galsky: Randomized 1:1 to receive adjuvant nivolumab versus placebo. Adjuvant nivolumab was given for up to a year. That study presented, published in New England Journal of Medicine. Minimum follow up at the time of that initial report was 5.9 months, and that led to FDA approval of adjuvant nivolumab. So now we're reporting extended follow-up results, with a minimum follow-up of 31.6 months. The median follow-up is three years now.

Sam Chang: Okay. All right.

Matt Galsky: And of course, important data in terms of extended follow-up, because remember, this is a fixed duration of treatment. So these patients did not continue nivolumab until progression. They got treatment for a year, and then it was stopped. And so, demonstrating that the effect continues after stopping a fixed duration of adjuvant treatment is important.

So, what we show is the co-primary endpoints of the study. Disease-free survival in the all-comer population, and then disease-free survival in the subset of patients with tumor PD-L1 expression greater than or equal to 1%. That's the assay and cut point that's used with the nivolumab program. In addition, we show secondary and exploratory endpoints. The secondary endpoints are non-urothelial tract recurrence-free survival. That's a mouthful. But this was mandated in terms of an endpoint because disease-free survival does include recurrences within the urothelial tract.

Sam Chang: Which are upper tract. Right.

Matt Galsky: Yeah.

Sam Chang: Okay.

Matt Galsky: That's a secondary endpoint. And then exploratory endpoints, importantly distant metastasis-free survival, and then this new endpoint that was presented for the first time at ASCO GU, which is called PFS-2, which is progression-free survival 2, which is measured from the time of randomization to the time of progression on subsequent next line therapy. So for instance, a patient gets randomized to placebo, develops metastatic disease, gets immune checkpoint blockade for metastatic disease, and then progresses. So measured from that time point.

Sam Chang: Okay, got it.

Matt Galsky: So, all of these endpoints, if you look across the intent-to-treat population, the hazard ratio favors adjuvant nivolumab versus placebo, with hazard ratios in the 0.7 range. And then in patients with tumor PD-L1 expression, regardless of those endpoints that I just mentioned, they're all within the 0.5 range, 0.5 to 0.55 range. So, really incredibly stable effect of adjuvant Nivo versus placebo over time now with the third database lock with medium follow up of 3 years.

Sam Chang: Of 3 years plus. So, with that, that begs the question, okay, 1 year. So would it have been better if you'd gone 2 years? Would've been just as good if you'd stopped at 6 months? Tell me, was there any specific rationale regarding that 1 year? Just historic controls comparisons to atezolizumab, others using that space. Why 1 year?

Matt Galsky: It's basically made up and it was used from what was being used as adjuvant immune checkpoint blockade duration in other solid tumors, but I think your point is a good one. It's a great question. Adjuvant chemotherapy, we certainly give for shorter durations of treatment.

In terms of why not longer? Well, certainly the notion of adjuvant therapy is that you can eradicate micrometastatic disease in a subset of patients and translate a non-curative situation to curative. That's the idea. Whether or not that can be achieved, it remains to be seen with much longer follow up. But that's the idea. And so, one would certainly want to fix the duration of treatment. Otherwise, if you just continue treatment, you might show that you can delay recurrence, but not necessarily prevent recurrence.

Sam Chang: And make a difference in terms of the actual disease outcome. When you look at the data, because now you've got long-term follow up, you've got both bladder and upper tract, which then leads me to ask a question about upper tract, a smaller population, a smaller subset of not only patients overall, but within the study, hard to tease out sometimes. But what about for the upper tract disease? Very similar findings?

Matt Galsky: The population was capped at 20%. So if you look at the distribution, it's about 19-20% of patients with upper tract disease on both arms. When you look at the forest plots, the magnitude of benefit does not seem as great, but I think as we all know, we have to take forest plots subset analyses with the grain.

Sam Chang: With a grain of salt, yeah.

Matt Galsky: So, hypothesis generating, there's some biological plausibility why upper tract disease might not behave the same way is bladder, which I think it makes us, potentially, even more prone to over interpreting subset analyses. But at the end of the day, these are hypothesis generating.

Sam Chang: Okay. Got it, got it. What's the next step with this current data? Are we done, basically, in terms of the follow-up length? Are some of these patients continuing to be followed? What's the next step with CheckMate 274?

Matt Galsky: We don't have overall survival data yet. Overall survival's a key secondary endpoint. It is blinded until the data's mature, in it's an event driven analysis. So that's going to be the next key piece of information.

Sam Chang: That's going to be big, obviously very big. Any idea, another year or two, another 6 months, we really don't know?

Matt Galsky: Yeah, the investigators are blinded to that, so I think it's hard to know for sure.

Sam Chang: Got it, got it. With these combinations, not only combinations, but timing, additive, et cetera, where are we going to go next? What's most exciting for you in terms of, all right, we've got some effective interventions at this point, where next that excites you?

Matt Galsky: I'll make another plug, and this is a plug for the Alliance MODERN study, which is in development and hopefully will be open within the year. The MODERN study enrolls patients with bladder cancer who've undergone cystectomy and have similar features to those patients enrolled in Checkmate 274, and then employs MRD testing using the Signatera assay. In patients with detectable ctDNA, they're randomized to adjuvant nivolumab standard of care versus adjuvant nivolumab plus the LAG3 inhibitor relatlimab.

Sam Chang: Okay.

Matt Galsky: So, double immune checkpoint blockade versus single immune checkpoint blockade, escalating treatment in patients who are ctDNA positive. In patients who are negative, the randomization is to standard of care adjuvant Nivo versus observation, with initiation of Nivo at the time of molecular conversion from ctDNA negative to positive, as long as there's no metastatic disease on scan. So trying to answer questions in both populations.

Sam Chang: Right. I see, I see. So basically, in the adjuvant setting, following the extirpative surgery, the radical cystectomy, then basically randomizing it based upon that. I think, in many ways, it attempts, just as we've talked about in the past, of maximizing perhaps care for those patients who may benefit, but also attempting to see if we can minimize it in those that are.

Matt Galsky: Yeah, absolutely.

Sam Chang: That's exciting news. Matt, as always, very much appreciate spending time with you and always learn so much.

Matt Galsky: Thank you.

Sam Chang: Appreciate your insight very much.

Matt Galsky: Thank you.