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Petros Grivas: Thanks very much for having me here. It's fantastic and I'm really impressed on the quality of the talks. My disclosure is that at the end of this talk, I will not ask a question to myself. I will start by giving you some idea about the infrastructure of the ECOG-ACRIN Cooperative Group. Of course, in the United States there are multiple cooperative groups, SWOG, NRG, Alliance, ECOG-ACRIN, and, of course, there are so many initiatives in addition to the amazing work that the GU Committee is doing. So let me give you some examples of the amazing work that is being done, and I'm honored to be part of some of this work.

In terms of the structure of the ECOG-ACRIN, there are multiple committees like the Developmental Therapeutics Committee, Imaging, Laboratory Science and Pathology, Therapeutic Studies, and Cancer Control Outcomes, in addition to the particular disease groups, and, of course, GU Committee is a separate one along with breast, sarcoma, and many others. Shout out to a good friend, Keith Flaherty at MGH and Christine Spencer at NYU for leading the Developmental Therapeutics Committee and the Genomic Subcommittee where we're developing different concepts. Again, it's great to work with all of them and participate in meetings and cooperative groups.

A couple of words about different opportunities within the ECOG-ACRIN Cooperative Group. I will start by saying that ECOG-ACRIN is one of those groups working closely with the NCI and, of course, is being funded by federal resources, federal money. Of course there are different venues for trial development within the ECOG-ACRIN Group. Many of you might know the effort we are doing with the NCI called ComboMATCH, evaluating combination of targeted therapies or non-immunotherapy combinations, in other words drug conjugates, targeted therapies, in the effort to overcome resistance to single-agent targeted therapies. We have, of course, ECOG-ACRIN NCI mechanism and we are working with drugs that have agreements, CRADA, with the National Cancer Institute.

Of course, we have a third mechanism called PrECOG, which is a little bit different. As you seen that slide, the difference is PrECOG works as a liaison, as a CRA, clinical risk associate, between cancer centers and industry in companies. It's a much faster mechanism to get small phase II trials done. Actually, we had a trial recently done in the neoadjuvant setting with bladder cancer with PrECOG and we were able to get it up and running relatively quickly. Obviously navigating a trial through the ECOG-ACRIN mechanism or the ComboMATCH, it's much more elaborate with much more bureaucracy, as Johan mentioned before. And in a kind of funny way, good doing trial with PrECOG, it's easier, it's like driving a jet ski. However, the ECOG-ACRIN ComboMATCH is much, I would say, logistically, more challenging. It's like having a cruiser or a battleship. However, the impact you can have by doing studies through ECOG-ACRIN, SWOG, other groups, and through the ComboMATCH, it's really impactful having a huge amount of cancer centers collaborating together. So, different aspects and opportunities and venues for different phenotype of trials.

Very quickly about the advantage of collaborating within the cooperative groups. I give talks to mentees and young investigators and they ask me, "Why should I be involved in cooperative group trials? It takes forever to open a trial. Why should I do that?" Right? Obviously there are many answers to this question. Key opinion leaders across several fields are available, experience in trials across phases and different cancer types, mentoring, which is very important and I asked Ashish before about his amazing work he has done on that part, and, of course, advising our portfolio development through actual conception. I think the talent is there and also the variety of cancer centers, well equipped to conduct trials across different phases, using different modalities, radiation, surgery, systemic therapies, and, of course, the ability to include rare tumor types. That was a topic of discussion prior multiple speakers.

As I mentioned before, if we think about the different opportunities that we have, registration trial is a big effort, a big mission for ECOG-ACRIN. You can do that through the ECOG-ACRIN mechanism, but also the PrECOG, this, let's say, more efficient, smaller infrastructure that's available, and, of course, international collaboration, which is relevant to this meeting, is possible through the ECOG-ACRIN or the PrECOG groups. Of course, it depends on the ability of the company to commit drag supply and distribution, which is a major issue even within the United States. If you don't have the ability to see drug, individual pharmacies, you may have logistical hurdles even within the same institution. Of course, there are already international collaborations. I think, Andrea, you have been involved yourself in collaboration between ECOG-ACRIN and different international members, including here in Italy.

A couple of words about the ComboMATCH. Many of you might have heard about the previous effort, the NCI-MATCH. I was involved in that effort as well. We realized that if you target a specific target in the cancer cell, you develop resistance, and I think Noel's question earlier today was about that. The need to have evaluation of concurrent and alterations. So ComboMATCH is trying to address this hypothesis, but if you have a genomically-driven approach and you can target more than one target in the cancer cells, you might actually hit the redundant pathways. What Jeff illustrated earlier today so eloquently, that if you have a genomic mapping through the work you're doing, you can actually map out potential targets and develop hypothesis for clinical trials. So we definitely collaborate with Jeff and others in the field to have this opportunity to design the genomically-driven and biomarker-driven clinical trials. Obviously the goal here is to reverse resistance early on and improve upon efficacy. You have to have, of course, safety as an endpoint as well.

It's a wordy slide, but maybe one take home message from this slide is that you need to have significant evidence of at least additive, if not synergistic, effect in preclinical models in order to have a very promising, robust concept that can go through the ComboMATCH mechanism. So you have at least a couple of very robust in vivo models that can show that if you target A and B together, it's going to work better than having target A or target B alone. Obviously this requires huge infrastructure, genomic sequencing, as I mentioned, and this opportunity of this big trial will also allow translational biomarkers, tumor tissues, circulating tumor DNA, collected in a serial manner, and, of course, on study biopsies to understand, again, the pharmacodynamics. Are you hitting your target, and of course, at the end, can you understand mechanisms of resistance? And that's what can inform future biomarker-driven trials.

We have a village of people, a city of people, statisticians, clinical trialists, and a lot of bioinformatics folks, genomic folks, as we discussed earlier with Jeff. And I think that's a beautiful way to develop drugs. It's a hypothesis-generating study signal finding and that's in one slide. Infrastructure, you have a designated lab and we can have genomic testing that's standard of care that is being used in different institutions. There is no funding dedicated from the NCI for the genomic sequencing, so we rely on commercial available platforms like what Jeff said or academic development platforms as well. If the patient has genomic alterations that may be of interest, can go through this ComboMATCH mechanisms and consent eligibility criteria. This MATCHBox can help with allocation of particular treatment for this particular arm, and then the patient starts treatment and we have biopsies during treatment and at the end.

This is the first wave that actually is launching. I am honored to be part of the Working Group of Genes and Agents for the ComboMATCH trial. I'm learning a lot myself about this mechanism and it's a very robust filter and review process, how we select out of multiple proposals, those that have the highest chance, highest promise, to develop a positive result. And these are the first 1, 2, 3, 4, 5, 6, 7, I think I count 8 or 9 groups there that are actually planned to start in the next couple of months, probably the beginning of 2023. This is really, really exciting to see the first wave of those trials and different targets being developed.

There are multiple examples of other targets that are being looked at and every 2 weeks we have a call with the Genomic Subcommittee and we discuss the potential concepts and review and give feedback to young investigators who come up with ideas targeting, for example, HER3 or HER2 or another target, TROP2, in different tumor types. This can be a basket trial design across tumor types or it can be a cancer type-specific design, only for bladder cancer or breast cancer, depending, of course, on the target and the biological role of this target in particular tumor types. So it can be either an umbrella study or a basket study or individual tumor type.

Obviously a lot to say about the GU Cancer Committee led by the amazing Dr. Mike Carducci from Johns Hopkins. We have Dr. Naomi Haas leading the Renal Cancer Subcommittee, Dr. Glenn Liu leading the Prostate Cancer subcommittee, and Dr. Noah Hahn, a good friend, the Bladder Cancer Subcommittee. Very quickly I want to illustrate examples, just the flavor, of what we're doing in the Bladder Cancer Subcommittee. Of course, we don't have enough time to cover all the amazing work being done in prostate cancer and kidney cancer, which is really, really humbling to see what my colleagues are doing in the ECOG-ACRIN group with Naomi, Glenn, and Mike's leadership. But I'll to tell you a little bit about bladder cancer specifically. I'll go by disease states and I will start by the non-muscle invasive bladder cancer.

We heard brilliant talks today with Ashish's work with IBCG and collaborations with FDA and CI workshops, we will now have definitions and also relevant endpoints in clinical trials. One example is a trial led by Dr. Max Kates in collaboration with Noah Hahn. They're both in Johns Hopkins, this is BCG naive non-muscle invasive bladder cancer. We will recognize the issue of BCG shortcuts in the United States. The FDA is open to trial designs that are actually potentially evaluating new agents, as you know compared to intravesical BCG. Max has designed the study, 870 patients, intravesical chemotherapy, gemcitabine-docetaxel, compared to in intravesical BCG. Primary endpoint is high-grade event-free survival. The trial is now approved by CTA, is ready to go, and we are very excited to have this up and running and certified by the presence or not of CAS in the two cohorts.

Another study, and I was telling Phil about this a few minutes ago, is the ECOG-ACRIN 8192. That trial actually is chaired by Dr. Jeannie Hoffman-Censits, and I'm honored to be the co-chair along with Dr. Margulis. That trial is specifically for patients with upper tract urothelial cancer for both cisplatin-eligible patients and cisplatin-ineligible patients. The form is being randomized, dose-dense aMVAC, with or without durvalumab. Chemotherapy plus/minus durvalumab is actually supported by great work by the ECOG-ACRIN 8141 that Vitaly and Jeannie already published that looks at dose-dense aMVAC as a single regimen that saw the pathological complete respond rate about 14.14%, but significant downstaging. The question is, can you improve upon that with addition of durvalumab? This is actually already up and running. I just considered my first patients a week ago, so looking forward for more centers and sites to open the trial. In the cisplatin-ineligible, unfit patients, durvalumab-gemcitabine combination. And, of course, we're going to do this through the mechanism of ECOG-ACRIN, the collaboration of multiple cancer centers in the United States.

Moving to bladder preservation, that's another exciting study I'm honored to be part of as a translational co-PI with other colleagues, is SWOG-MRG 1806. This is in bladder preservation. Patients get maximum TURBT, and they get randomized to chemotherapy and radiation, with or without atezolizumab. So the question is, do you add benefit, do you add value or not, by adding Atezo, anti-PD-L1, to chemotherapy radiation backbone? Primary endpoint is bladder intact event-free survival and patients get randomized, as I mentioned, after maximum TURBT, it's up to nine doses of atezolizumab. This trial is more than halfway done. We're hopeful to finish accrual in the next year or so, so looking forward to be able to present the data in the future.

Another trial with my colleague Dr. Monika Joshi, she's in Penn State in Pennsylvania, this is a stage III patient population with lymph node-positive disease. We don't know how to treat these patients, really, based on prospective trials. We do induction chemotherapy and then in patients, after induction chemotherapy first, they get randomized to chemo radiation plus/minus durvalumab. And then there's a second randomization to adjuvant durvalumab or not. This is a very, very important trial. Hopefully we'll be able to continue accrual and great effort.
Moving to metastatic disease, just a few examples. There's so many trials to cover, of course, here, but this is another trial that my good friend and colleague, Dr. Shilpa Gupta, who is at Cleveland Clinic, this is the MAIN-CAV phase III trial in the switch maintenance setting. As Andrea mentioned before, we had the practice-changing JAVELIN Bladder 100 trial that established avelumab as a switch maintenance therapy in patients with response, or stable disease, to chemotherapy in first-line treatment in advanced urothelial cancer. So the question is, building upon the avelumab alone maintenance therapy, do you add value by adding cabozantinib on that? So it's patients who get platinum-based chemotherapy, they have response stable disease, they get randomized to avelumab alone, standard of care by itself or with cabozantinib. This is up and running, and again, I'm honored to champion this trial through the ECOG-ACRIN mechanism.

This is a trial schema slide that Noah presented a few weeks ago at ECOG-ACRIN just to show you the different trials that we have mapped out in bladder cancer and how cooperative groups play a role in the different disease settings and spaces. As you see, I showed you with red, other trials that are being done by cooperative now and I showed you Max Kates' trial Intravesical chemotherapy versus BCG. There's an Alliance trial, it's pembrolizumab-gemcitabine, and there is also interest in doing intravesical treatments in those patients with these agents, which is, I think, very, very interesting. Joshua Meeks has done some pilot studies with intravesical Pembro.

I told you about the bladder preservation trial. I told you about the neoadjuvant upper tract. There is also a great trial by go higher in Alliance looking at patients with DNA repairing gene mutations. These patients may get chemotherapy in the neoadjuvant setting, and depending on the response on neoadjuvant chemo, there is evaluation of potential bladder preservation there. Very innovative trial. We need more data in this setting. Of course, many more trials in nutrition. Matt Galsky is doing a trial based on circulating tumor DNA in the adjuvant setting. And, of course, many trials in metastatic disease. We're now thinking about the future and whether we should develop trials with antibody-drug conjugates plus immunotherapy. A lot, of course, to cover, but definitely impressive data in the field and many, many trials that we try to map out.

Very, very last slides here, two slides about cancer screening. My personal bias is that 10 years from now, hopefully we'll put many more resources, we'll have, hopefully, more successes in cancer prevention. Going back to ancient Greek, literature and histor, Hippocrates was saying that an ounce of prevention might be more important than tons of treatment, so my dream, if you wish, is whether we can use more efficiently the technology, the tools we have, to prevent cancer can. And can we do that in a primary prevention, avoiding risk factors, eliminating smoking, reduce obesity, implementing vaccines, can we do also early detection like secondary prevention? In these two slides, I'll very quickly show you my thoughts. I made these slides for ECOG-ACRIN disciplinary session a couple of years ago.

Can we use ctDNA for cancer screening? I was honored to represent ECOG-ACRIN in a working group in the NCI led by Dr. Monica Bertagnolli, who is now the NCI director. Monica is a great visionary. We talked about using ctDNA as a platform there and we had discussions about the patient population, the testing strategy. How are we using liquid biopsies that Jeff mentioned earlier? How do we design these study in a very heterogeneous population across different risk factors? How do we select our patients based on germline mutations, maybe smoking, patients who have high risk, high propensity of developing cancer? What will be the right endpoint in this cancer screening trial? How do we do this in a centralized operation through the NCTN, the National Cancer Trial Network? How will we collaborate with industry and having existing studies being used in that way and how we develop funding mechanisms and have a cohesive work incorporating labs and clinical practices in a compliant way in order to eliminate disparities and develop strategies for cancer screening in the clinical trial setting?

Of course, as I finish here, my talk, I think the National Clinical Trial Network represent this amazing opportunity to do practice-changing trials, leading this effort for using ctDNA for cancer screening health detection, detection of minimal residual disease. Of course, we need a large number of patients to do these studies, evaluate the resistance mechanisms of treatments, evaluate concordance between tumor tissue and ctDNA. Of course, we need, as I mentioned before, collaborations, databases, and registries as an additional platform to complement clinical trial data. You need, of course, think tanks, working groups, and at the end of the day, you need a team in a global level to eliminate disparities and make this a feasible approach with enough sample sizes to answer these questions. Again, in my humble opinion, ideally prevent cancer, should be detected much earlier, in order to improve outcomes. A lot of, of course, data points here, but I think it's in stimulation for discussion. Thank you so much for the invitation, mila grazia. Thank you.