CYTOSHRINK is our phase II investigator-initiated trial testing the addition of early cytoreductive SBRT to combination immunotherapy for de novo advanced RCC. The idea came up in 2019 when we first designed the protocol on the heels of the SURTIME and CARMENA trials which questioned the routine use of cytoreductive nephrectomy in most IMDC intermediate- and poor-risk patients. So we saw SBRT as a convenient, safe modality that has very high local control in localised RCC and can be used to metastatic sites in advanced disease, to try and leverage this to the primary renal mass in first-line de novo RCC patients.

What was the study design?

This was a randomised phase II trial, a 2:1 randomisation for all patients who presented brand new with de novo advanced RCC, had to have biopsy-proven disease, IMDC intermediate or poor risk, eligible for treatment with nivo/ipi which was an available standard of care at the time. The 2:1 randomisation went to the experimental arm. All patients got cycle 1 of nivo/ipi followed by SBRT at a prescription of 30-40Gy in five fractions and then the remaining nivo/ipi and then maintenance nivolumab, per standard of care. The control arm was simply nivo/ipi and maintenance nivo per standard of care. Stratification factors were IMDC intermediate and poor risk.

Then really our main primary outcome was one-year PFS rate but also overall survival, quality of life and several very innovative correlative biomarkers that will be part of a future presentation.

What were the results of this study?

What we found in this population which opened in February 2020, preceding COVID and there was a pause due to COVID, is that we had a lot of presentation with quite advanced disease. So we had a very typical first-line population in terms of mostly male, balanced between IMDC risk groups, mostly good performance status and clear cell histology. But we did note that patients in the experimental arm were more likely to have larger primary renal masses that extended beyond the kidney, they had more poor prognostic sites of metastatic disease, including more bony mets and liver metastasis, almost three times higher, and generally larger tumour burden in their body.

Now, when we look at our results, the one-year PFS rate was actually similar in terms of 12 months between both arms. The per-protocol analysis, which is patients who got four cycles of nivo/ipi, all patients fared better, that was also quite similar between both arms. But we did notice something interesting. In terms of responses, and these are patients who have a primary renal mass in their body so it’s quite a large burden of disease, response rates were not dissimilar but the ongoing responses were 10% in the control arm and 50% in the interventional arm, which tells you that there’s some sort of durability when you’re adding SBRT that we need to understand better. Overall survival is still pending its readout.

What is the clinical significance of these results and what is next for this study?

CYTOSHRINK is the first randomised trial testing the addition of early SBRT to combination immunotherapy for advanced RCC. We think as an investigator-initiated trial we’re very grateful for all those who supported us to get here.

There’s a lot more to come. One, our PFS rate was not different between both arms, there were some notable baseline imbalances that is just the case for a randomised phase II trial, but we have lots ongoing. Overall survival, these ongoing responses, patients who got treatment beyond progression, which we saw in the interventional arm. We saw patients who had downstream or subsequent nephrectomies in radiated cancer, so we’re going to be looking more at them. Then we are going to be presenting our correlative work which is tissue biopsy at baseline, serial collections of blood biomarkers and serial collections of gut microbiome samples which will really add some interesting scientific work to what we saw clinically.