Matthew Galsky: The KEYNOTE-B15 study was a randomized phase III study of neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab followed by cystectomy with adjuvant enfortumab vedotin, pembrolizumab as well versus gem-cis followed by cystectomy, this study enrolled 808 patients, randomized them one-to-one to those two arms. The primary endpoint was event-free survival that was determined centrally. Then the key secondary endpoints were overall survival and pathological complete response rate. This is the sister study to KEYNOTE-905, which already read out at ESMO last year and is published in the New England Journal of Medicine, which was done in a cisplatin-ineligible population, so the control arm was cystectomy alone. Here there's an active comparator.
Elizabeth Plimack: Right. I think you hit the high watermark for OS and EFS, right?
Matthew Galsky: Yes.
Elizabeth Plimack: I'm really excited to see. That's great. What were the key sort of new things we learned from this study that add to what we already knew from 905?
Matthew Galsky: This is a much larger study than 905. The number of patients on the experimental arm of this study on the EV pembrolizumab arm is about the size of the 905 study. I think much more robust dataset just from a size standpoint. The other thing that we've learned, which I think we've learned with the EV pembrolizumab program in advanced disease is that the data is remarkably consistent and reproducible. The path CR rate almost identical between the two studies, 55.8% on this study was a percentage point higher on the other study. That lines up quite well. I think some of the differences, the long-term outcomes were a little bit better on this study than on KEYNOTE-905, which I think reflects the comorbidities of patients who are cisplatin-ineligible.
Elizabeth Plimack: Let's talk a little bit about the sandwich design. Both studies had a sandwich design with neoadjuvant cystectomy and then an adjuvant portion. The CONSORT diagrams, which are great by the way, we see all the detail on how patients flowed through that. But at the end of the day, I think you said about 51% of patients actually completed the full sandwich in this study. How do you think we should contextualize that information when we're faced with a patient with either toxicity, or conversely an excellent path CR that's now looking at more therapy? Do they need it? Do they not? How would you think we should think about that?
Matthew Galsky: I think the path CR question is probably the more challenging one because we don't really know if that's actually a patient who would benefit from more treatment or not. I think that's hard to say. We need to answer that question, obviously. From a toxicity standpoint, that's somewhat easier. I think what these data show you is that a largish subset of patients didn't get the full treatment, but the trial still produced these large benefits. And so, if you have to stop for toxicity, your patient may still be deriving this large benefit from treatment.
Elizabeth Plimack: Just the clinical pearls, people take this to the clinic. If someone's having a toxicity attributed to EV, do you stop both the EV and the pembrolizumab, or do you just peel off the EV and continue the pembrolizumab?
Matthew Galsky: Of course, depends on the EV-related toxicity of whether or not you can take a break for one cycle, resume at a lower dose, et cetera, et cetera. If you really have to stop though, then continuing pembrolizumab makes sense. We have data for single-agent pembrolizumab in the neoadjuvant setting with healthy path CR rates. We don't have the data from the phase III KEYNOTE-905 single-agent pembrolizumab neoadjuvant arm of the study.
Elizabeth Plimack: Right, arm, yeah.
Matthew Galsky: But we do have other data sets with single-agent pembrolizumab. So I think it makes sense to continue that to cystectomy.
Elizabeth Plimack: Excellent. Great. Is this the new standard of care for muscle-invasive bladder cancer?
Matthew Galsky: I think it's the new standard of care. I think we're in a somewhat analogous situation to the metastatic setting. So we have two phase three regimens that showed a benefit compared to older treatment. In the metastatic setting, it's basically identical. Cisplatin-based chemotherapy plus immune checkpoint blockade versus EV pembrolizumab, here we have those two type regimens. I think despite having positive trials in both settings, the effect size is a bit larger with one regimen than the other. Because cross-trial comparisons are complicated, it's hard to say definitively, but if one has to choose which one has to do when you counsel a patient going with the regimen that produces the larger effect size, I think, makes sense.
Elizabeth Plimack: Right. By effect size, are you talking about pCR?
Matthew Galsky: I'm talking about pCR, I'm talking about EFS, I'm talking about OS. If you look at the hazard ratios, they're all a bit better.
Elizabeth Plimack: Yeah, absolutely. Well, congratulations, and thank you.
Matthew Galsky: Thank you.
Elizabeth Plimack: It's a good day for bladder cancer today.
Matthew Galsky: Thank you.