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Alicia Morgans: Hi, my name is Alicia Morgans and I'm a GU Medical Oncologist and Associate Professor of Medicine at Northwestern University in Chicago. I'm so excited to have here with me today, a good friend and colleague, Dr. Petros Grivas, who is an Associate Professor and the Clinical Director of the GU Cancers Program at the University of Washington. Thank you so much for being here with me today, Petros.

Petros Grivas: Thank you so much for having me, Alicia. It's a great pleasure as always.

Alicia Morgans: Wonderful. Well, I wanted to speak with you a little bit about an ASCO presentation that you and the team are doing this year, ASCO 2021, talking about a PrECOG study that is really looking at neoadjuvant nivolumab with or without lirilumab in the neoadjuvant setting for cisplatin-ineligible patients who have muscle-invasive bladder cancer. Can you tell us a little bit about, first, what is lirilumab? Then also, of course, how you designed this study and how you hope that it moves the needle for patients with muscle-invasive urothelial carcinoma?

Petros Grivas: Thank you so much, Alicia, for asking this important question and we are very excited about this work. This has been a very, I would say, long project and long pursuit and effort through the ECOG-ACRIN GU subcommittee. I can tell you, it started through a very nice and productive dinner we had during an ECOG-ACRIN meeting a few years ago, and we initially pursued the concept that got support from the sponsor and we were able to get the study run and completed through PrECOG, which is a fantastic organization, working in the context of ECOG-ACRIN, but a separate organization. We got the study supported with funding as well as drug supply.

This particular study, it's a neoadjuvant trial in patients who are, as you said, not fit for cisplatin, cisplatin-ineligible or unfit patients, or later [inaudible 00:02:04] to include those who refuse cisplatin in the neoadjuvant setting, who received either nivolumab, anti-PD1 agent, alone or the combination of nivolumab plus lirilumab, which, as you correctly pointed out, is an antibody against KIR. KIR is an inhibitory receptor impacting the NK cells, so the lirilumab molecule is supposed to take away the inhibition and therefore activate natural killer cells. The idea behind this is you want to engage both the adaptive immune system with T-cells and the innate immune system with NK cells. And the hypothesis has been that if you activate both the innate and the adaptive immune systems, you could potentially have the additive/synergistic approach. You get more T-cells, NK cells in the tumor microenvironment in the bladder, and the hypothesis was, that could translate into a higher pathologic complete response rate. The ultimate goal here is whether we can use a combination going forward.

The particular primary endpoint of this neoadjuvant study was safety and feasibility. When we designed the study, which was almost three years ago, we were not sure whether neoadjuvant immunotherapy was safe. This was before the PURE-01 and the ABACUS, and many other neoadjuvant immunotherapy trials were presented. So we wanted to make sure that we did not harm the patients by delaying the curative intent of radical cystectomy. So the primary endpoint was safety and feasibility, defined as treatment-related grade 3-4 adverse events, as well as the proportion of patients who did not make it to radical cystectomy within six weeks from the end of treatment.

Obviously, as we conducted the study, the results of other neoadjuvant immunotherapy trials came about showing that this approach seems feasibly neoadjuvant. Also, we had built in some important relevant efficacy endpoints. The key secondary endpoints we had back in the day was the CD8+ T-cell density and whether we can introduce more CD8+ T-cells in the tumor microenvironment, in the tumor tissue, in the bladder tumor, and obviously pathological complete response rate, pathologic downstaging, and of course, biomarker work, which is ongoing.

We presented the results at the ASCO 2021 Annual Meeting, and we are very, very excited. Overall, 43 patients were enrolled in the study, and from those 43, we were able to have 40 available patients that we had data that we could present. Overall, as you see the breakdown of the patients, the majority had clinical T2 disease, 37 out of 43, and the other relevant point was that one of the most important reasons for cisplatin-ineligibility was kidney dysfunction, as you could imagine. Also, it's important to know that the study met the primary endpoint, and this was a safe and feasible endeavor. As I mentioned, almost the entire cohort went through surgery, with just one patient who withdrew consent and was not treated because he withdrew consent before neoadjuvant treatment. This means that 42 patients got neoadjuvant treatment and I think only one patient did not make it to cystectomy. So 41 patients out of 42, all but one, made it to cystectomy. So this is a safe approach and everybody did that within six weeks from the end of neoadjuvant immunotherapy.

Pathologic complete and pathologic partial responses were lower than expected with nivolumab by itself and with the nivolumab/lirilumab combination, compared to other neoadjuvant trials. However, the combinations had numerically higher response rates, which is interesting. Obviously, the next steps here have to do with the ongoing phase 3 trial called ENERGIZE, with many colleagues leading that trial, comparing neoadjuvant chemotherapy to neoadjuvant chemotherapy plus nivolumab plus/minus an IDO1 inhibitor, and this trial is ongoing. But overall, we are going to present more granular results [inaudible 00:06:34], and obviously going to pursue a lot of detailed biomarker work in tumor tissue, blood, and urine.

Alicia Morgans: That's fantastic, and I'm just wondering, are there specific side effects that you can identify associated with this newer agent targeting KIR and the NK cells? Because I think that this is not something we have necessarily been used to employing in our armamentarium for urothelial carcinoma.

Petros Grivas: Important question, Alicia. I would say that the question was whether, especially the combination of anti-PD1 and the anti-KIR, could potentially increase toxicity just because you pretty much engage both adaptive and innate components of the immune system. However, we saw that this treatment was very well tolerated. If you look at the grade 3-4 treatment-related adverse events, there were none with nivolumab alone, we had 12 patients with nivo alone, and there were no grade 3-4 treatment-related adverse events. Patients got only two doses, four weeks apart, in the first cohort, nivo alone, and then after we completed this cohort of 12 patients and we saw no grade 3-4 treatment-related adverse events, then we started serially, sequentially, the second cohort of nivolumab plus lirilumab. The same thing, two doses, four weeks apart. So only two doses per cohort.

In the combination cohort we had, as I mentioned, in this particular cohort, a significant number of patients, we had only 7% grade 3-4 treatment-related adverse events. Particularly, there were four patients, one had arthralgia, another had gout, and two with hip pain. So [inaudible 00:08:17], but overall, very well-tolerated suggesting the safety and feasibility of combining these two agents, especially in the curative-intent setting.

Alicia Morgans: Also really important, of course, and exciting, given that this is a new combination, a neoadjuvant setting, and also, of course, is a chemo-sparing approach. So what are your thoughts in terms of the next steps? Do we see a signal strong enough with this combination that we think we can move forward?

Petros Grivas: Alicia, despite the, I would say, very impressive safety and feasibility of this treatment either with nivo alone or the combination of nivo with lirilumab, this study was not randomized, it was pretty much two separate cohorts, and cohort two with a combo was started after the nivo alone cohort was completed. However, the efficacy in terms of pathologic complete response was a little bit lower than expected. For example, the pT0N0 rates with nivo alone were only 8% and with a combination, nivo plus lirilumab, the rate was 18%. If you think about pathological downstaging to non-muscle invasive disease, the corresponding percentages were 17% and 29%. Again, suggesting that the pathological downstaging is higher compared to pT0N0, however, the question is whether the combination has enough activity signal to move it forward.

So far, the company has made the decision to actually close the program with lirilumab. So probably it's difficult to reverse that decision, and most likely, I think the next steps will be defined by the ongoing phase 2 with nivolumab. For example, there is a phase 3 ENERGIZE trial that I mentioned a few minutes ago, but there is also a separate trial in cisplatin unfit patients with nivolumab plus NKTR-214 versus nivolumab versus no perioperative therapy, which is also a very exciting trial. So the phase 2 trials at least do not continue lirilumab, but still, they will evaluate the nivolumab as a single agent and in combination.

Alicia Morgans: So thank you for sharing that and also just for emphasizing, I think, for all of our listeners that negative data is just as important as positive data in so many respects, and this was not actually completely negative. We did see what we think is a little bit greater response in terms of path CR associated with the combination. But at the same time, if it's not sufficient to put our patients into that as a treatment algorithm, then it is important for us to sort of check the box and say, "We investigated, and this is not the way forward, at least for now." So I think it is so important just to remember that these kinds of trials, whether positive, whether negative, whether strongly positive or weakly negative even, are so important for us to understand and to report back. I appreciate you sharing your expertise on this, Dr. Grivas. So as you think about the trial, and congratulations for finishing this phase 1B, what are your thoughts in terms of summaries for the listeners in terms of take-home points for this combination and this study?

Petros Grivas: Absolutely, Alicia. Just to one more time report, that this was a safe and feasible treatment with nivo alone and the combination nivo with lirilumab, and this did not compromise the ability of patients to get safe radical cystectomy within six weeks from the end of treatment. Very quickly to summarize the secondary endpoints of efficacy, pathologic complete response defined as pT0N0 was 8% with nivo alone, 18% with a combination, and pathological downstaging to non-muscle invasive disease, 17% with nivo alone, and 29% with a combination.

Overall, we are working hard here to do biomarker work. I think this study provides a great infrastructure for tumor tissue, blood, and urine biomarkers, and we are very excited to do that. I think an informed hypothesis for dissecting further the tumor biology, that in my opinion, can have applications in further clinical trials. I think this biomarker work can open horizon [inaudible 00:12:43] for further, I would say, combination therapies in the neoadjuvant or other therapy settings.

Alicia Morgans: Fantastic. Well, thank you so much for sharing your expertise with us today, Dr. Grivas.

Petros Grivas: Thank you so much, Alicia, for having me, and it's always a pleasure to discuss with you. Again, great work, and congratulations to all the investigators from eight different cancer centers. This trial could not have happened without them, so thanks to them, and the patients and the families, of course, as well as the PrECOG team, the GU subcommittee leaders, Dr. Hahn who is the bladder subcommittee chair, the GU committee chair, Dr. Carducci, and my previous mentee and current colleague, Dr. Vadim Koshkin, who is now at UCSF, and had played the main role in this trial, and of course, as I mentioned, the entire list of investigators and staff who work very hard to get this done, who are looking forward to furthering discussion for after ASCO. Thank you again.

Alicia Morgans: Thank you.