A roundtable discussion, moderated by Peter O’Donnell, MD, discussed the advanced urothelial treatment landscape, as well as recent trial data from ESMO 2023. Dr. O’Donnell was joined by Terence Friedlander, MD; Matthew Galsky, MD; and Jonathan Rosenberg, MD.
In the next segment of the roundtable series, the panel shares treatment sequencing decisions based on a few patient scenarios Dr. O’Donnell presents.
Dr. O’Donnell: Let’s try to tie this all together and actually talk about how we might sequence all these therapies that we now have all this availability. Terry, let’s start with you, and then we’ll see if there’s any differences across the panel. Let’s imagine a metastatic urothelial cancer patient who has had no prior therapy, nothing in the perioperative setting, who gets EV [enfortumab vedotin]/pembrolizumab frontline, and then ultimately progresses. What are you using next?
Dr. Friedlander: The options, as I see them, are to give platinum-based chemotherapy plus/minus avelumab maintenance, that’s not been tested. Or to give sacituzumab, which is approved here in the United States. If they have an FGFR mutation, they can get erdafitinib. I would probably gravitate toward platinum-based chemotherapy, although I think it is kind of intriguing to give sacituzumab govitecan as a second-line agent and avoid the toxicity of platinum. I don’t think we really have any data to support that. If you look at the response rate to sacituzumab govitecan in later-line settings, it’s about, and I’d like to hear what you guys think, equivalent to what you might get from platinum, or at least it’s in the ballpark of what you might expect from platinum. One is going to be much more expensive than the other. But I would probably go with platinum, but I’d be intrigued by sacituzumab govitecan as a second-line agent. I’d love to hear what you guys think.
Dr. O’Donnell: EV/pembrolizumab so far?
Dr. Galsky: I think gemcitabine/cisplatin or cisplatin-based chemotherapy works via cytotoxic mechanisms in the bulk of patients who achieve a response. Then in the smaller subset who do great, that’s based on an immunomodulatory effect. I think that whether or not that immunomodulatory effect overlaps enough with what’s achieved with immune checkpoint blockade, such that that will be negated in the second-line setting after patients progress on EV/pembrolizumab, I don’t know that. I think some prospective data on gemcitabine/cisplatin after EV, I think would be nice just to sort that out, because those are responses that are not lasting months. Those are the patients that we see that have these really long responses. To throw that out when we don’t have unlimited drugs in this disease, I think would be a shame. For carboplatin-based chemotherapy, I’m much more inclined to go to sacituzumab govitecan next, and I’ve done that already.
Dr. O’Donnell: If they were cisplatin-eligible, I’ll push you a little bit, Matt, EV/pembrolizumab, then you go to gemcitabine/cisplatin. Are you adding the nivolumab in there?
Dr. Galsky: No. Not after EV/pembroliz.
Dr. O’Donnell: Jonathan?
Dr. Rosenberg: I generally agree with what Matt outlined. I think it’s hard to get as excited about gemcitabine/carboplatin in the second-line setting. I think we’re going to start to see a lot of anecdotes about what happens post-EV/pembrolizumab. I’ve already got a few. Platinum-based chemotherapy may not be dead in that context, is my gut feeling. Until we’ve given a little bit of gemcitabine/carboplatin after EV/pembrolizumab, I don’t know that we should say we wouldn’t do it. But I think any of them are options, and I think a lot of it is going to come down to toxicity from prior therapy, and what is going to be most compatible with the patient’s goals and quality of life. As anything, a clinical trial is a better option.
Dr. O’Donnell: Let’s spin it forward. We’ll start with Jonathan this time. Let’s say same patient scenario, they get EV/pembrolizumab first, now they’re progressing, but you’ve got FGFR-positive this time, what are you using second?
Dr. Rosenberg: If they’re a cisplatin candidate, I would still go with that route and reserve an FGFR3 inhibitor later. If they’re not, I would probably give an FGFR inhibitor as second-line therapy post-checkpoint, as opposed to sacituzumab govitecan perhaps. I don’t know what the right answer is though.
Dr. O’Donnell: Yeah, we don’t. That’s why we’re debating it. Matt?
Dr. Galsky: I would do the same.
Dr. Friedlander: Yeah, I might do the same as well. I think it’s so hard to know here, and a lot of it comes down to patient preference. The nice thing about erdafitinib is it’s oral. If you have a patient who lives far away, maybe they’ve had 9 months or so of EV/pembrolizumab, and they’ve been coming to the hospital 2 out of every 3 weeks, it’s a lot of visits, especially if you live far away. There might be some attractiveness to just trying an oral therapy. That said, I already mentioned that erdafitinib does have significant risk for adverse events, so we have to just be cautious about thinking holistically about the patient.
Dr. O’Donnell: Let’s change the scenario. Now we’ve got a patient, no prior chemotherapy in the perioperative setting, but they get adjuvant nivolumab after their cystectomy and they progress. You do the year of adjuvant nivolumab, and they progress at 9 months after you gave the adjuvant nivolumab. We’ll start with you, Terry.
Dr. Friedlander: Nine months after completing the adjuvant nivolumab?
Dr. O’Donnell: After completing, their last.
Dr. Friedlander: We talked about this a little bit earlier on stage and in the larger session. The consensus seemed to be just to give EV alone for patients who’ve already had nivolumab. I mean, you guys can certainly expand on that. I might still be intrigued to give EV and pembrolizumab if there’s been a delay between the checkpoint inhibitor and the frontline. The reason is that when you look at those PFS [progression-free survival] curves for EV/pembrolizumab, it’s leveling out around 30% or 40%, both in EV-103 and at least in the early looking EV-302.
If you believe that there’s some sort of synergy happening, if there’s some sort of immunogenic cell death that EV is causing, we don’t know that giving another checkpoint inhibitor is beneficial, but we also don’t know that it’s harmful. If you can generate that long-term durable response by giving EV and pembrolizumab together, if there really is some magic there, then I would be more willing to do it. I mean, these are patients who have a poor prognosis if they’ve already progressed after getting a checkpoint inhibitor. Yes, it’s more costly and there’s maybe more risks for adverse events. But depending on what the patient’s goals are, I might be more inclined to try EV/pembrolizumab even if they’ve had a prior checkpoint inhibitor, and at least some space if they didn’t have rapid progression through the checkpoint inhibitor.
Dr. O’Donnell: Matt?
Dr. Galsky: Yeah, I agree with that. If progression happens off adjuvant treatment versus on adjuvant treatment, I view those scenarios very differently. Say, you’re doing the first scan 3 months after completing, so that’s going to be the earliest time, unless someone progresses clinically before that. If I see progression on that scan, I’m sort of on the fence. If it’s on the 6-month scan, then yeah, I’m much more inclined to giving immune checkpoint blockade again.
Dr. O’Donnell: Jonathan, feel the same?
Dr. Rosenberg: I don’t disagree. I just think the same thing.