Ashish Kamat: Hello everybody, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, and joining me today is a friend, an expert, and a true colleague when it comes to everything bladder cancer, Professor Andrea Necchi. Andrea, congratulations on your ESMO presentations, everything was so well done and well refined, and we thank you for taking the time to come and share your presentation and everything that you did at the ESMO with us in UroToday. So, please share with us the primary results of the GDFATHER-NEO trial.

Andrea Necchi: Thank you, Ashish, and thanks UroToday for the opportunity. So, what we presented at the ESMO meeting this year is the primary findings of a phase two, blinded study of neoadjuvant nivolumab, and the GDF-15 neutralizing antibody, visugromab, or placebo. As neoadjuvant therapy prior to radical cystectomy in patients with MIBC, who were ineligible for or refused radical cystectomy, the primary results of the study was called the GDFATHER-NEO Trial. These are my conflicts. So, as you know, the background is that typical of patient with MIBC refusing or being unfit for standard neoadjuvant cisplatin-based chemotherapy, the prognosis is still poor for this patient, there is a clinical need to invest more on novel therapies, particularly better tolerated therapies as compared to chemotherapy combination.

And we have a lot of play through already presented or published study, putting neoadjuvant immunotherapy into the context of the treatment of these patients. And interestingly enough, combination of immunotherapy and chemotherapy from phase two studies did not provide a huge disconnection in pathological response rates from the phase two studies presented thus far. And there is an increasing, as Ashish will know, there is an increasing concern whenever a patient achieve a [inaudible 00:02:00] response to a neoadjuvant therapy as to whether it is a case of undergoing radical cystectomy. GDF-15 is an interesting target, this is emerging in oncology, in solid tumor oncology. It was first discovered by a German gynecologist actually, because it's a part of TGF-β superfamily member linked to feto-maternal tolerance, and that later on it was discovered as being over-expressed, one of the most over-expressed cytokine in cancer, and very highly expressed in certain tumor types including urothelial cancer.

And based on this, technology was developed for creating the antibody called visugromab, which is a GDF-15 neutralizing antibody. The initial safety and efficacy data have been published in nature by Ignacio Melero and colleagues on various tumor types, including a cohort of urothelial cancer, with extraordinary response rates in patient with very deeply pretreated tumors, immune therapy also pretreated to the tumors. So, the possibility of rescuing immunotherapy-resistant tumor is not working in this combination and this study, and this study is being developed today in other indications, in other tumor types, in immunotherapy-resistant tumor.

And the GDFATHER-NEO trial actually is the first trial in immunotherapy-naive patients. And the study that we present today, and at ESMO is in fact a proof-of-concept small study, providing data on the combination nivolumab and visugromab, or nivo and placebo, a short course of neoadjuvant therapy in these patients. There's design of the study shown here, pretty typical, pretty classical study for neoadjuvant therapy in this patient population, T2-T4A, N0, M0, MIBC, ineligible or refusing cisplatin-based chemotherapy, pure predominant urothelial carcinoma histology. Primary endpoint was pathological complete response rate. Interestingly, and we were brave enough to put the radiological response, radiological response rate as the core primary endpoint in this study, with all the limitations of CT or MRI scans, but we wanted to look also at the rate of imaging response in this patient population.

And at the end of treatment, three courses of nivo and visugromab every four weeks before restaging. Patients had to choose between radical cystectomy, it was the supportive standard of care, or Re-TURBT in case of denial of radical cystectomy. In total, 31 patients were enrolled, 29 actually were available for efficacy analysis on both the radiological and the histopathological responses. The characteristics of the patients, the baseline population, and the trial total population and bi-arm are shown on the right-hand side. Pretty well-balanced in terms of PD-L1 expression, clinicality stage, a huge proportion of patients in both arms, almost 40% of patients presented with clinical T-3 and T-4. So, it's not actually a typical study, very much enriched in T-2 study, but we also included patients with more advanced disease, and most of the patient presented with baseline evaluable RECIST lesion in the bladder prior to start treatment.

This is another point that is infrequently reported in similar studies. So, the RECIST assessment of baseline disease and then response that we will see in the latest slides. Safety was pretty good, no grade four or five adverse events were being reported, the median time from cycle one, day one, to surgery or cystectomy, TURBT, was pretty much in line with the protocol, and what is actually the safe window opportunity for this population. On the left-hand side, you see the rates of treatment-related adverse events. If you look at the grade three events in both arms, in particular with the combination of nivo and viso, the rates were, the overall G3 side effects were all lower than 10%, very mild, very well tolerated, and rapidly recovering. On the right-hand side, you see the serious cases that were just recorded in three cases, and there were two cases of discontinuation of treatment due to treatment-related adverse events.

All this in the nivolumab and placebo arm, due to immune therapy related side effects. The pathological findings are shown here, the primary end point are shown here. Overall, 33% of the patients reported the pathological complete response to zero on the nivo, and the visu arm. Overall, 66, almost 67% of the patients had the downstaging in the nivo and visugromab arm as compared to 21.4% in the nivolumab and placebo arm. There were also... So, there is clearly a signal for an effect size that is clearly measurable in the combination therapy, as compared to placebo, when combining to nivolumab in this population, and due to the fact that most of the patients responded in the experimental arm, the vast majority of the Re-TURBT patients fall into the experimental arm, as it is highlighted here. Most of the Re-TURBT instead of cystectomy has been done in the nivo and visugromab arm, one patient was not available for surgery in the nivo and placebo arm because it was an interrupted treatment due to toxicity.

This is the distribution of these pathological responses based on the patient subgroups, it is not worded it here that the vast majority of the responders in nivo and visugromab arm fall into the category of CPS high patients, PD-L1 expression patients. There were three cases with major response downstaging to PTA disease or CIS residual disease among the T3 and T4 patients. And so, overall, the breakdown of the data by characteristics clearly favor the combination therapy instead of nivolumab monotherapy here. Radiological response, as I said, is interesting, again, with all the caveats, all the caveats are radiological response assessment, and certainly this is an investigator assessment for radiological response, we certainly need, as it says, as an additional step to centralize the imaging and to centralize and to have a centralized assessment and confirmation of these responses.

But overall concrete responses have been reported in the vast majority of nivo and visugromab arm patients, pathological partial responses in 60% of the patients in the nivo and Visu arm. It was pretty clear association in the nivo and Visu arm between radiological responses and pathological responses here, almost all the patient with the Path CR fall into the category of clinical or radiological complete responses. So, there was just one case of PCR missing, there was actually unavailable for RECIST response because of the fact that he had no baseline RECIST assessment. So, all the PCR fall into the category of clinical imaging response and the vast majority of the major responses, if not all of the responses, major pathological responses have been included in this column. So, it remains a difficulty in dissecting the residual minimally infiltrating disease, pTI, pTA, pT1 disease versus Path CR, but the responses are all there, [inaudible 00:10:24] included an imaging response, at least in the combination therapy arm.

Regarding biomarkers, we have all the baseline assessment, only the baseline assessment of circulating biomarkers in tumor microenvironment characteristics, that show that the baseline biomarker characteristics were similar between the two arms, with regards to the level of GDF-15 circulating in both arms. There were no difference in major circulating chemokines between arms. And on the right-hand, side on the right box, you see that the TME profile is showing basically the rate of immune infiltration or immune activation of the baseline tissue before treatment is very much similar between the two arms. So, there is no major disconnection or a major reason for the biomarker standpoint to justify such a huge difference between arms. So, in conclusion, we have a signal of improved activity by combining visugromab to nivolumab neoadjuvantly in this patient population.

The treatment confirmed the phase one data of very good tolerability, if not zero in the case of severe or grade four side effects, there was no difference in the baseline characteristics, clinical and biomarker characteristics between arms. Certainly the combination of warrants further the investigation in this patient population, maybe even tripling the combination therapy, maybe looking, for example, on ADC, immune therapy, and visugromab triple combination in this setting. There are certain limitations to me primarily represented by the small sample size first, the study was conceived just to be proof of concept design, and proof of concept study, and for sure the rate of Re-TURBT instead of cystectomy, and being enriched in the experimental therapy arm may be bias for the pathological findings.

The phase two program of Visu is expanding in multiple solid tumor types, and in the same ESMO meeting, we also have the updated data from the phase one study, in the oral session presented by Melero in the developmental therapeutics session, that will show that in the immunotherapy pretreated population results in terms of durational responses are pretty much confirmed, and outstanding in the urothelial cancer population. There was a huge effort, despite the small numbers of the patients, the effort is always huge in these similar studies, the efforts from the patient side, from the family members, from the trial staff, investigators, supporting staff, and for sure the sponsor. Thank you.

Ashish Kamat: Thank you, Andrea. Again, as always, excellent job in first of all conducting the study, leading it, and presenting the data. I have a couple of quick questions for you. So, if you look at the data, clearly impressive CR rates, whether you do it with radiologic, you do major, you do complete clinical response. But it appears that most of them are actually occurring in the combination arm, and a lot of the side effects are actually occurring in the monotherapy arm. So, how would you tease out the contribution of components and is there, as a follow-up question, any mechanistic rationale to using it as monotherapy?

Andrea Necchi: Yeah, thank you. We don't have data so far for... To answer your last question. In theory, yes, but we don't have any data so far with monotherapy of the GDF-15 inhibition. The initial development was looking at the fact that GDF-15 is an immunosuppressive agent. So, the natural concept was the natural translation into the clinic was the combination therapy. But it's certainly a point that is missing in our puzzle, and something that would be worth accumulating in the near steps. Regarding the difference, for sure it is striking. It's striking for both reason, for the combination therapy in terms of the responses that we have seen, but also when looking at the poor outcomes and poor responses with nivo monotherapy. I think that it is almost exclusively related to the small numbers. I remember where we started with the pembro in the PURE-01 study, the first 10 patients, we were just on the very similar line with the nivo results here.

So, it's the most due by chance, I think. This is the reason why I would consider the path major response, when dealing with small numbers, instead of looking at the Path CR, it is better to look at path major response, this is the more stable endpoint as compared to Path CR. And here, with the 22% major response rate with nivo, we are approaching the results, for example, that Petros Grivas has reported in another small study with nivo monotherapy, or comparing with the lirilumab in the European Urologic Oncology paper. And in the monotherapy, the rate of major responses is pretty much similar to that reported in this study. So, nothing particularly striking to me, this completely understandable based on the small numbers. And the same for toxicity. When dealing with small numbers, you may be on the bad side of the curve when looking at the few cases of developing immune-related side effects.

So, I think that we cannot stay at the moment, that there is clearly a poor activity of nivolumab in this patient population. We can state that the effect size is pretty much evident, so there is a contribution, an addition of something, a contribution of the nivolumab towards the primary endpoint or towards the radiological response, but based on this, we have certainly to expand the arm and maybe adding a third arm with the Visu monotherapy. So, we are just at the beginning, but the signal is there, and it's pretty much in line with the phase one data in urothelial cancer that have been obtained. So, it's a story that should be matched with the phase one program, and I think that the drug is there, it's a very intriguing story here. The drug was born in an academic setting, in a German academic setting, it is pretty much exciting, what could be the potential for changing the way we treat and the way we implement responses in this patient population.

Ashish Kamat: Great. Thank you so much Andrea, and thank you for joining us today.

Andrea Necchi: Thank you.