Aly-Khan Lalani: Pleasure to be here. Thanks for having me.
Leslie Ballas: You are here at GU ASCO presenting CYTOSHRINK. Can you please tell us what is this trial? Who is it for? What did you find?
Aly-Khan Lalani: Yeah, great question. I'm happy to share. So CYTOSHRINK was our kind of idea that came on the heels of the SURTIME and CARMENA trials in 2019 that was looking at cytoreductive nephrectomy for Stage IV or De Novo Advanced RCC patients. And considering whether surgery would be helpful, the feeling was at that era that perhaps in a targeted therapy setting, patients should largely get systemic therapy, especially if they're intermediate or poor risk. On those heels, we had considered the utility of stereotactic body radiation therapy as a form of early cytoreductive treatment to help these De Novo Advanced RCC patients. So CYTOSHRINK is a trial that's investigator initiated run at six centers in Canada and one in Australia, looking at doing SBRT with Nivo/Ipi versus Nivo/Ipi alone in these De Novo Advanced RCC patients. So we conducted a two-to-one randomized trial looking at these patients where they all had to be intermediate or poor risk. We allowed the primary renal mass to be up to 20 centimeters. And these were all patients who had biopsy-proven advanced disease, largely clear cell, but we allowed non-clear cell patients. And this trial was randomized two-to-one to the interventional arm where all patients got a cycle one of Nivolumab and Ipilimumab or all say Nivo/Ipi.
And then the SBRT, which was given at 30 to 40 Gy in five fractions, and then the rest of Nivo/Ipi, and then the maintenance Nivolumab per standard of care. And the control arm was simply the available Nivo/Ipi per standard of care. And we stratified this by IMDC risk groups. As mentioned, a two-to-one randomization where our primary endpoint one was a one-year PFS rate. And then we looked at other important measures like overall survival, quality of life, investigator-assessed response rate. But then also we have exciting correlatives to come, which we can talk more about later where we had every patient's tissue biopsy, serial blood collections, and serial gut microbiome samples. So in this trial, there was 43 patients in the interventional arm, 24 patients in the control arm. And this trial was conducted during COVID. So I would just say that to open a trial on World Cancer Day in February 2020, at that point I came to GU ASCO having recruited our first patient, and then due to a pandemic essentially being paused for at least eight months in most centers, certainly we wanted to complete this trial. We're very fortunate that our sponsors felt the same. And so we did complete recruitment in April 2024. And so in this two-to-one randomized trial, we looked at the one-year PFS rate of the and by risk groups as a stratification.
So what we found interestingly is that unfortunately there are some patients in this trial that were very high risk. So we had a good balance of intermediate poor risk patients, but despite randomization, our interventional arm, getting SBRT to the primary renal mass, these patients had larger primary tumors that extended beyond the kidney, more T3, T4 lesions. They all had larger size of the largest dominant mass. They had more measurable sites of disease, and they also had more poor prognostic sites of metastasis like bone and liver metastasis at almost threefold higher. So our one-year PFS rate was not statistically significantly different between both arms. The one-year PFS rate in the medians were fairly balanced with a hazard ratio of 1.2. Those who got treatment per protocol, and this was important, this was a pre-planned analysis that we had in the protocol, all fared better. Medians were all much more improved in both arms over 10 months in the interventional arm, around 13 months in the control arm. So that hazard ratio was now closer to unity. So we did not find differences in the PFS rate. However, as OS is ongoing, medians have not been reached. We are interestingly seeing a subset of patients really benefiting, and how do we see that? So we have response rates that are pretty well-balanced between both groups. All partial responses, 33% in the interventional arm, about 42% in the control arm.
But at last follow-up, two years of follow-up, we have 10% in the control arm with ongoing responses, 50% in the interventional arm having ongoing responses with SBRT. So I think there's... And happy to discuss where we take this, because I think that's the exciting next part is clearly there's a subset that's going to benefit. We want to follow for overall survival in the whole group, but particularly those that are benefiting and then answer some important questions through our biomarker work.
Leslie Ballas: Yeah. Great study. There's a lot of interest in using SBRT/SABR in metastatic renal cell carcinoma. Your patient population, as you mentioned, that got the intervention, that got the SBRT were extremely high risk. And so there is always the question that when you have patients that are that high risk, what would it take to even show a progression-free survival advantage?
Aly-Khan Lalani: It's a great question. And so obviously our intent at the time prior to COVID was we knew what a De Novo patient would look like. I think there's no question that in our countries where there were pauses in general with trials, but also with some healthcare measures around the COVID-19 pandemic, patients were presenting later, but they were presenting, I would say, a bit more advanced, even for De Novo patients. And I think we observed that even despite randomization. I do think that when we look at our intermediate risk population and our poor risk, there is a difference. Statistically, it is not there given the numbers and confidence intervals, but we can observe clearly that these patients in the intermediate risk group behave differently than poor risk. So I think there is something to be said, even when you look at the surgical cytoreductive nephrectomy trials, and then you look at systemic therapy trials of putting, let's say, three drugs together in first-line MRCC, different population, but poor risk patients in that group also didn't benefit. So there's something about optimizing the best care for patients where maybe the intermediate risk patients tend to do better. I think we allowed a laxity in terms of how big the primary renal mass would be. Could that be a little different as we move forward?
But I also think a big question is we were answering early cytoreductive radiation after a first cycle of Nivo/Ipi. I think this is still an important question to ask about radiation in the setting because there might be ways of doing more response adapted or a little bit of a later radiation after systemic therapy has gone in and then seeing those patients who could get SBRT, which other trials will be looking at. So we took a swing at a question that we thought was important. I think we still have lots of follow-up. I'm going to be really excited to hopefully chat with you in the future about those who got treatment beyond progression, more common in the interventional arm. Those who had downstream nephrectomies, more common in the interventional arm. And we have correlatives on all of these patients. So I think there's going to be a lot to come.
Leslie Ballas: Yeah. It sounds like you've got a lot of interesting data that you can still present to us. Additionally, the question I have as a radiation oncologist is about the dose of radiation that was chosen. We know from published data from FASTTRACK that fewer fractions, higher dose per fraction seems to be beneficial. And the current NRG-GU012 trial, the SAMURAI trial is looking at three fractions, 42 Gy. Your dose fractionation was quite a bit lower than that. Do you think that that played a role in your outcomes?
Aly-Khan Lalani: It's a great question. At the time of protocol development, prior to some of the data having read out, as you said, we were considering the importance of getting radiation in. Perhaps there was some comment or thought at the time that in terms of the synergy, the potential immune modulation potentiation and perhaps effects that could be more disparate throughout the body, would slightly more fractions, but at a lower dose, ensure that it's not inhibitory to some of the T-cells that we want to liberate. So at the time, back in 2019 when this was being written, was that the five fractions would be the right prescription frequency, and then how much could we get in over those doses at the time? So that's why it kind of settled at roughly 40 Gy by 5 fractions for a variety of clinical and perhaps preclinical reasons for a randomized phase two trial. I think since then we've seen that there's no question. SBRT has helped localized disease. It helps with oligoprogressive, oligometastatic disease and where we play with that dose will be important. So I will also be excited to see where our future trials read out. And then I think this will be a great opportunity to pull a lot of our data together and try, and all of us try and help answer this question. Is it early cytoreductive? Is it response adapted? What is the dose? Does the backbone of systemic therapy matter? We have a pure doublet IO we thought was quite clean and frankly available at the time. How does an IO-TKI play in that realm? So there's much more to come in this setting.
Leslie Ballas: Dr. Lalani, thank you so much for joining us today and just talking about CYTOSHRINK. I know we're going to have lots more to talk about in the future, and I look forward to those discussions.
Aly-Khan Lalani: Thanks for having us as well.