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Alicia Morgans: Hi, I'm so excited to be here today to talk to Dr. William Hall, who's an associate professor of radiation oncology and surgery at the Medical College of Wisconsin. And Dr. Rana McKay, who's an associate professor of medicine at the University of California, San Diego. Thank you both so much for being here today where we are going to talk about SAMURAI, which is the first study in kidney cancer where we're looking at randomizing patients between radiation, no radiation. This is an NRG trial. And really I should emphasize it's the first cooperative group trial that's randomizing by radiation. Really exciting study that the two of you have designed.

Rana Mckay: Thanks so much, Alicia. It's great to be here.

William Hall: Thank you.

Alicia Morgans: Great. I'm wondering, first, can we talk, Bill, about the importance of this trial, really why we have the opportunity to do this? Because kidney cancer I think has historically been thought to be a cancer that's been difficult to radiate, maybe unresponsive, what do you think?

William Hall: Yeah, that's a great point. Radiation therapy has changed dramatically in the past 15 years and the doses of radiation that we're delivering today are completely different than the way radiation was given approximately 10 to 15 years ago. So, we are giving much, much higher doses of radiation with millimeter accuracy, highly focused on areas of malignancy, and able to precisely avoid areas of normal tissue. That has caused a real renaissance in revisiting the role of radiation therapy, specifically in tumors that have historically been felt to be either radioresistant, non-responsive to radiation, or associated with really high toxicities when they are radiated. And one of the great examples of that is kidney cancer. And we've seen in the past two to three years just tremendous data emerging with how effective radiation is in treating and controlling kidney cancer and how successful the outcomes can be in a very minimally invasive fashion for patients with this malignancy. So, those were sort of some of the historic changes that led to us, at least, conceiving of the trial initially and then designing it and moving it forward.

Alicia Morgans: Wonderful. And I love the name. I wonder if we can talk about this, Rana, can you share the schema with us and really help us think through which patients are actually participating in this trial and what's happening? What are your endpoints?

Rana Mckay: Absolutely. To go through the design of this study, another piece of background is, in 2018 the results from the CARMENA trial were reported that really began to call into the question sort of our approach of cytoreductive nephrectomy for people who presented with de novo metastatic disease. And the field had began to shift away from upfront cytoreductive nephrectomy for those poor-risk patients or patients with really advanced disease, a lot of negative risk factors. So, overlaying sort of the radiation renaissance and RCC with this shift in practice away from cytoreductive nephrectomy really prompted us to design SAMURAI. And this trial is designed for patients who have de novo metastatic disease with a intact primary patients who have intermediate or poor-risk disease, patients will be randomized two to one to receive either radiation therapy directed at the primary with standard of care combination immunotherapy treatment versus just standard-of care immunotherapy treatment alone.

And really any physician choice of doublet therapy that's life-prolonging will be permissible on the trial, including NIVO/IPI, pembro axitinib, nivolumab, cabozantinib, lenvatinib, and pembrolizumab. The primary endpoint for the trial is progression-free survival, including both patients who have not undergone a nephrectomy and looking at sort of radiographic progression. So, we're really looking at the radiographic progression piece, but also assessing, did patients need to undergo subsequent nephrectomy. Secondary endpoints are going to be safety, toxicity, response, response both in and out of the renal primary, overall survival. So, it's really an exciting phase two study that is being led by NRG, but really with champions across all the cooperative groups, ECOG, Alliance, SWOG, and really excited to have this be the first randomized trial in RCC through the co-ops.

Alicia Morgans: Again, congratulations team. I think it's really exciting that you're offering this and as you said, the CARMINA trial really did shift the landscape. One thing that I'm curious about though, you know are allowing investigators to really use the best standard of care immunotherapy based regimen that they feel comfortable with. And I think that that flexibility is going to be so important to clinicians. I wonder what's the timing of radiation during that therapy? Sometimes timing can make it tough, and so I'm just curious how restrictive are you in terms of when that radiation has to be delivered?

William Hall: Yeah. We're typically giving the radiation within the first one to two cycles of immunotherapy. And we do have restrictions around when the immunotherapy can be given in close proximity to the radiation. So, we have a period of time over which we hold the immunotherapy before and after the patients get radiation. It's important to note in this trial that the radiation's given over three fractions, so it's a pretty quick treatment course. Most of the patients will probably be finished with their course of radiation within one week. It may be longer in some patients, but we're anticipating that the vast majority will finish at the very longest within two weeks. So, it's a relatively short period of time for the radiation to be introduced. But we do have in the protocol clear guidelines for how you hold immunotherapy before and after SPRT administration.

Rana Mckay: It's kind of specifically around the oral TKI, stopping it a couple days before the radiation starts and after the radiation ends. And really the trial is designed to reflect real world practice. It's designed to be flexible. We're allowing multiple agents to be used, we're allowing sort of a fairly broad window in which the radiation can be completed within the first two cycles of treatment. And so, it's really designed at the end of the day to reflect what actually real world practice would be.

Alicia Morgans: And that's so thoughtful and I think it's so important just to emphasize as you said, that there are some safety parameters built in, but it's meant to really reflect what we do not impair or interfere with what teams are normally going to be doing. And so, should fit seamlessly into what you're doing in your practice anyway, because that's the way that it was very thoughtfully designed and also really thoughtfully designed to only have three fractions of radiation. That makes it a lot more simple to really integrate, given that it is such a discreet course. Now, Rana, I think that the thought is that these patients are going to be identified by medical oncologists like you and me, and we'll be really liaising with our radiation oncology colleagues to make this whole process happen. Do you have any suggestions on how to identify these patients and then how to best communicate and collaborate with our radiation oncology colleagues?

Rana Mckay: Absolutely, very good question. I think, one, it's understanding that as an investigator this trial is open across all the cooperative groups, any investigator who's interested in this study can go on CTSU site and look at the materials, go on ClinicalTrials.gov and initiate the process to get this study open at their site. With regards to when these patients come into the clinic, it's patients that present with de novo metastatic disease in an intact primary. So, of those patients, probably around 10% to 15% of patients who have advanced renal cell carcinoma have not had a prior nephrectomy is presenting with de novo metastatic disease. And this trial is really suited at those individuals, and particularly those individuals who are not interested in surgery upfront, who are not candidates for surgery upfront who really need to get their systemic treatment started. And this is sort of a nice trial where you can guarantee that they're going to get the standard of care with a two to one randomization, two-thirds of patients getting radiation therapy.

So, I think what I found to be successful at site is, in addition to sort of a lead principal investigator at the site, identifying a radiation oncology champion, somebody that you've already worked within radiation oncology and somebody that you've kind of reviewed the protocol with them and you can sort of liaison with that individual whenever patients come in that could potentially be candidates to expedite their referral to radiation oncology, getting them in and getting them started on the trial. And so, I think that'll be really successful.

Alicia Morgans: Wonderful. So, Bill, I know we talked before we started recording about sites opening across the country. That's still happening and is still in process. If there are clinicians who are interested, if there are patients who are interested in this trial, where can they find more information?

William Hall: Yeah, thanks so much for highlighting this and we're really enthusiastic about trying to get more sites to open the trial or patients that are interested in participating in the trial. So, ClinicalTrials.gov, which we can link to below the video is a really, really wonderful resource. It has most of the contact information for the clinical trial and exactly how you could get involved or get enrolled or sites that it might be enrolling it in treating patients on this trial in close proximity to where patients may live. So, that's a wonderful resource.

If you go to ClinicalTrials.gov, and you can search there, either we can link to it directly in the video or you could search for GU012, which would prompt this study to come up. That's probably the easiest term to search for. Or, you could search for the word SAMURAI, that's the acronym for the trials. And so, that would be a wonderful place for patients to find information about the trial. The other option for academic sites or community sites or cancer hospitals that want to open this trial is to activate it through CTSU. It's the standard cooperative group trial. So, if you have cooperative group trials open, particularly through the NRG Oncology Cooperative Group, this is one of those trials that you could open like many other trials, so the processes would be the same.

Alicia Morgans: Fantastic. Thank you both so much for going through this. I think there's going to be a lot of enthusiasm for the SAMURAI trial, as you said, a renaissance in radiation delivery for kidney cancer and opportunities within this setting to really make a difference where we are not as frequently doing nephrectomy. This metastatic population certainly could use a boost. So, thank you both so much for your innovative trial design and really for sharing the information about SAMURAI with us today.

Rana Mckay: Thank you.

William Hall: Thank you.