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Sam Chang: Hello everyone. My name is Sam Chang. I'm a Urologist in Nashville, Tennessee, at Vanderbilt University. And we are quite fortunate to have actually, an updated presentation by Dr. Yohann Loriot, Medical Oncologist at Gustave Roussy, in Paris, France. He's going to actually be presenting his GU ASCO 2022 presentation on the LEAP-011 study. So Dr. Loriot, thank you so much for being with us today.

Yohann Loriot: You are welcome. And thank you for the invitation. So LEAP-011. So what was the background of the trial? So as you know, the pembrolizumab monotherapy is approved by the FDA for first-line therapy for patients with locally advanced or metastatic urothelial carcinoma, who were unable to receive any platinum-based chemotherapy, regardless of PD-L1 status, and for cisplatin-ineligible patients, whose tumor expressed PD-L1.

And there is some data, a lot of data, suggesting that angiogenesis is a mechanism of resistance to immunotherapy. So lenvatinib is a tyrosine kinase inhibitor that could inhibit VEGF, FGFR receptors, and PDGF receptors. And we had a Phase Ib study, the KEYNOTE-146 study that investigates this combination of pembrolizumab and lenvatinib, including patients with urothelial carcinoma. And we observed some promising preliminary activity in 20 patients. The overall response rate was 25%, and the median duration of response was not reached

So we built on this preliminary data, and we developed the LEAP-011 trial, which was a randomized double-blind Phase III trial that evaluates this combination of pembrolizumab plus lenvatinib, versus pembrolizumab plus placebo, in patients with metastatic urothelial carcinoma, who were ineligible to receive cisplatin-based chemotherapy. And in this trial, we included a subset of patients who were deemed ineligible for both cisplatin and carboplatin, so very frail patients.

We planned to enroll more than 600 patients, and like many Phase III trials, there was an IDMC that reviewed the safety data every three months, I would say. And the IDMC determined the benefit to risk ratio of pembrolizumab plus lenvatinib and based on the data we had, the IDMC made the recommendation to stop accrual. So during ASCO, I presented the data we had for more than 400 patients. And these populations were again, frail populations of patients because 80% of the patients were deemed ineligible for both cisplatin and carboplatin-based chemotherapy, and two-thirds of the patients had visceral metastases.

And unfortunately, when we look at the primary endpoint of PFS, there was no difference between the two arms. The median PFS was 4.5 months with pembrolizumab plus lenvatinib, versus four months with pembrolizumab plus placebo.

Now, if we look at the overall survival data, we have similar trends. There was no difference between the two arms, the hazard ratio was 1.14. In terms of overall response rate, 33% with pembrolizumab plus lenvatinib, versus 28.9% with pembrolizumab plus placebo. So no big difference between the two arms.

And regarding the safety, of course, that was something very important to look at. So the safety was generally consistent with the combination of pembrolizumab plus lenvatinib. There was no new safety signs that were detected in this trial. But again, the benefit to risk ratio for pembrolizumab plus lenvatinib was not considered positive. And so, it's a study stop enrollment.

But generally speaking, I have to say, that the anti-tumor activity observed with pembrolizumab plus placebo was consistent with the previous results of KEYNOTE-052, so pembrolizumab monotherapy, in a similar population of patients, but the combination is not helpful, and so the trial was stopped at this stage.

Sam Chang: Well, I think, you and your group, obviously, deserve huge credit for putting together this placebo randomized, controlled trial. What are some of the possible reasons you think, that the combination... because it does make sense in terms of throwing a multiple action kinase inhibitor, works along different pathways, FGFR, VEGF, those types of things, in combination with immunotherapy makes sense, has made sense in advanced kidney cancer and other things. What do you think, in this particular population that you studied, perhaps didn't show the benefit of combination, so, possible hypotheses?

Yohann Loriot: It's probably about the selections. As you know, in bladder cancer, we have different subtypes, and this subtype could be very different. The luminal subtype, for example, is an immune desert, and there is no angiogenesis. And by contrast, we have also, one side of patients who are a basal subtype, where there is an immune infiltration, but also angiogenesis, and probably, these patients with basal tumors benefit more from this combination. That is something we want to investigate in the LEAP-011 event. We will collect the tumors and we will do this analysis.

Sam Chang: Anything else that you all plan on doing? It makes me think of the atezolizumab trial, and going back and looking at the possible benefits, the predictive impact of circulating tumor cells. You mentioned obviously, that molecular characterization could make a big difference. Although honestly, that data still confuses me on, who is more sensitive to chemotherapy, and who is not.

Yohann Loriot: Yes. Yes.

Sam Chang: Now, we don't know, in terms of your study, but as data comes out, it's still unclear to me, the risk-benefit. But clearly, there are different types of tumors with different characteristics. What other possible things are you looking back, in terms of all this data, that you've collected that is helpful?

Yohann Loriot: Yeah. So again, I think, as you know, there are no good biomarkers for angiogenesis inhibitors, but that makes sense to look at the subtypes. Because again, we can hypothesize that patients with a high angiogenesis signature may benefit from lenvatinib, so that is the first step we will try to address.

The second point is probably, the selections. We selected patients in the trial based on their cisplatin ineligibility, and platinum ineligibility. Maybe that is something we have to review. And we have to do some prognostic analysis in this trial, to see if we can come up with different classifications, based on different clinical and biological factors, beyond the historical classification of cis-ineligibility and platinum ineligibility.

Sam Chang: And so Dr. Loriot, any plans on future trials with this combination that you can think of? Or if not, where else do you think the next combination doublet, triplet, may be different, or combinations of perhaps, antibody-drug conjugates. Where do you think you would go next?

Yohann Loriot: So maybe the first place, that there are other clinical trials that combine immunotherapy and angiogenesis inhibitors, like the COSMIC-021. And there was also, a Phase III trial, that combined cabozantinib, and immunotherapy as maintenance. So the story is not totally completed. But as you said, there is another combination that is very exciting, typically, drug conjugates. And for example, EV plus immunotherapy, maybe sacituzumab plus immunotherapy. The safety is good, and we observed a very good activity, in terms of overall response rates, in a preliminary study. So that is something that is currently being investigated in Phase III trials, with the EV-302 study, for example. But also, in the neoadjuvant setting, there are multiple Phase III trials that address this kind of combination, an] antibody-drug conjugate.

Sam Chang: Well, Dr. Loriot, again, I think you deserve personal commendation for all your efforts and being able to accrue more than 400 patients, to get the answers here, an idea in a frail population, considering the number of patients with visceral metastases, as you said, and poor performance status, in this select population, there doesn't seem to be a difference between the pembrolizumab monotherapy.

Yohann Loriot: You're totally right. I think we have to push this trial on this frail population of patients. And there are other trials that address this question. For example, the NORSE trial, which combines erdafitinib plus immunotherapy, could be a very good option in these patients. This trial is still enrolling, so we will see the data may be in the coming months, so that is something. It's very important to enroll patients who are deemed ineligible for chemotherapy, just to see whether or not we can give them alternatives to chemotherapy.

Sam Chang: Well, again, my thanks, and kudos to you and your team. And I look forward to seeing you again soon.

Yohann Loriot: Thank you.