Avivit Peer: Great. Thank you for the invite. Well, this is a study checking the concept of can we improve EV-pembro with a triplet strategy? So is the addition of another checkpoint inhibitor to this combination and a co-formulation with EV-pembro can improve the results without a too heavy price.
Elizabeth Plimack: Right.
Avivit Peer: This is a phase one, two study testing 124 patients that were randomized to three study arms. So each arm received the EV and pembro and one arm received addition of favezelimab. This is an anti-LAG-3 antibody inhibitor. The second arm was vibostolimab, the anti-TIGIT inhibitor together with the EV-pembro. And the last one is EV-pembro alone.
Elizabeth Plimack: And this is in the metastatic setting.
Avivit Peer: First-line metastatic setting.
Elizabeth Plimack: Right.
Avivit Peer: This is the primary objective response is response rate and safety, of course. Secondary endpoints are duration of response and progression-free survival as it is in the phase one, two studies. So this study showed that objective response rate was pretty similar among the treatment groups. With the anti-TIGIT arm, the response rate was numerically lower. And it comes with toxicity. So we see a lot more Grade-3-to-5 with the anti-TIGIT, a lot more treatment discontinuation with the co-formulations and immune-mediated adverse events, skin reaction, severe skin reaction, infusion-related adverse events, and thyroid dysfunction that was more pronounced with a combination. The holy grail is still EV-pembro. And this is a negative study and it will not proceed for further evaluation.
Elizabeth Plimack: Okay. So I guess the idea was to take a backbone that's powerful and see if it can be improved upon with these novel immunotherapeutics.
Avivit Peer: Yes.
Elizabeth Plimack: You saw expected higher rates of immune-mediated toxicity-
Avivit Peer: Exactly.
Elizabeth Plimack: It sounds like. And this was a platform to really pick a combination that maybe could be taken forward, but neither of these two fit that.
Avivit Peer: Yeah.
Elizabeth Plimack: So what do you think about the trial design and how might that be used going forward with EV-P?
Avivit Peer: This will be explored with probably... We have different triplets going on in that arena. So not more immune checkpoints, that's a neglected approach.
Elizabeth Plimack: Right.
Avivit Peer: But other triplet approach have more ADCs, different target, different payloads together with the EV-pembro. Maybe it will improve it, maybe it will be more toxic and not worth the additive value response-wise. But a lot of studies are ongoing for different triplets or different sequencing, maybe maintenance sequence after EV-pembro and progression. And other venues are explored, but we have to keep in mind that EV-pembro is a holy grail, but not all patients respond to EV-pembro. And a good number of patients progress. Half of the responders will progress. So now that we have this powerful tool, we have an appetite for more.
Elizabeth Plimack: Yes.
Avivit Peer: And this study design lays the ground for more studies, different combinations.
Elizabeth Plimack: Right. That's great. I think a lot of people look at EV-P in that high response rate and say it's going to be really hard to power a study to improve to that.
Avivit Peer: Yeah.
Elizabeth Plimack: And conversely, a lot of us in the clinic look to the unfortunate few patients who don't respond to EV-P and really want something second-line there. So I totally agree. I think sequence might be the way to look at it. And then if something really powerful comes up in sequence to then sort of move it forward with more data.
Avivit Peer: Yeah. We learned in kidney cancer that triplets don't really add any significant benefit. It's very minor and comes with a lot of toxicity.
Elizabeth Plimack: Right.
Avivit Peer: I don't know if it's going to be a success as a triplet, but maybe a sequence or maybe the subgroup of patients that will have more information about NECTIN-4 and other expression that will be decided they're more resistant to EV-P. As more data comes away, maybe they will be eligible for triplet.
Elizabeth Plimack: So you raise a really important point if we can define the group of people who are at risk to not-
Avivit Peer: Responding.
Elizabeth Plimack: Respond to the EV-P, that might be a group to then start testing more of these agents in combination. That's a great idea.
Avivit Peer: Yeah. We don't know everything. We know nothing. Who is responding, who is not? Much more data are coming. This, especially with the early setup of perioperative EV-P, I think we will learn in the near future more about resistance and that can lead us to wiser choice.
Elizabeth Plimack: Yeah, absolutely.
Avivit Peer: Yeah. So exciting. It's very exciting.
Elizabeth Plimack: Very exciting times in bladder cancer, yeah.
Avivit Peer: And I would say that negative studies are really important. They teach us a lot.
Elizabeth Plimack: They do.
Avivit Peer: Sometimes not less than positive studies.
Elizabeth Plimack: Right. And doing it in this small focused way instead of launching a big phase 3 with a triplet, I think makes a lot of sense.
Avivit Peer: Yeah, exactly.
Elizabeth Plimack: So thank you.
Avivit Peer: Yeah.
Elizabeth Plimack: Well, thank you so much for sharing your thoughts today. Thanks for presenting these really important data. And exciting times for bladder cancer.
Avivit Peer: Thank you for having me. Thank you.