Exploring Upfront Cytoreductive Radiotherapy in Advanced RCC

The treatment landscape for de novo metastatic renal cell carcinoma (RCC) has shifted significantly following data from the phase 3 SURTIME (NCT01099423) and CARMENA trials (NCT00930033), which questioned the traditional role of upfront nephrectomy for International Metastatic RCC Database Consortium (IMDC) intermediate- and poor-risk patients.^1,2 At the 2026 ASCO Genitourinary Cancers Symposium, Aly-Khan Lalani, BSc, MD, FRCP, discussed the CYTOSHRINK trial (NCT04090710), a randomized phase 2 investigator-initiated trial designed to evaluate a novel cytoreductive strategy: stereotactic body radiation therapy (SBRT).³

The trial’s rationale was rooted in the hypothesis that providing an ablative dose—30 to 40 Gy in 5 fractions—to the primary kidney mass could synergize with standard-of-care immunotherapy. By combining SBRT with a checkpoint inhibitor doublet, nivolumab (Opdivo) and ipilimumab (Yervoy), Lalani’s team aimed to induce immune potentiation and improve systemic efficacy, particularly since patients with a primary mass in situ historically show lower response rates than those who have undergone prior surgery.

Key findings from the initial readout indicated that while 1-year progression-free survival (PFS) rates did not differ significantly between the SBRT-plus-immunotherapy arm and the immunotherapy-only control, certain clinical signals warranted further investigation. Notably, the intervention arm demonstrated a higher rate of ongoing responses at the last follow-up of 50% vs 10%, suggesting that SBRT may contribute to the durability of the immune response for a subset of patients.

Crucially, the study confirmed that this combination is well-tolerated. The integration of high-dose radiation did not lead to increased kidney injury or significant adverse effects, reinforcing that SBRT can be safely delivered alongside dual checkpoint blockade. As the trial moves forward, Lalani suggested that the focus will shift to extensive biomarker programs, including the analysis of the gut microbiome and serial blood collections, to better identify which patients benefit most from this focal therapeutic approach.

Lalani is a member of the Medical Advisory Board and an associate professor in the Department of Oncology at McMaster University.

CancerNetwork: What was the rationale for the CYTOSHRINK study?

Lalani: In 2019, when we designed this trial, the aim was to try to find an appropriate upfront cytoreductive approach for patients with de novo metastatic kidney cancer. At the time, we had data from SURTIME and CARMENA suggesting that perhaps surgery wasn’t the best approach for most [patients with] IMDC-intermediate and poor risk RCC. Our background was in considering the safety and the convenience and delivery of SBRT, which has been shown to be helpful with good control and renal function preservation in localized RCC, [and] that there might be an ability to use it for oligoprogressive or oligometastatic sites in the advanced setting.

Our thought was that providing an ablative dose to the kidney could improve the efficacy of standard-of-care first-line immunotherapy because, at the end of the day, we had observed that systemic therapy worked better in patients with a prior nephrectomy compared with those who had their primary kidney mass in situ. That was some of the background hypotheses we had. We also felt that adding SBRT to combination immunotherapy could lead to the upregulation of key immune modulation signatures, so we have a good biomarker component program to our trial as well.

What is the mechanism of action that SBRT is attempting to target?

SBRT allows the ablative dose to be delivered to organs while creating steep dose gradients to protect normal organ radiation. And as mentioned, it’s shown to be efficacious in localized RCC; in other diseases, it deals with oligometastatic or oligoprogressive sites. Our thinking at the time of trial design was that a certain amount of fractions, in our case 5 fractions, with a certain dose would lead to immune potentiation with the immunotherapy, while hopefully limiting the inhibitory aspects of putting 2 modalities together in terms of an immune response. In some way, we were trying to understand if we could create a potential for immune synergy with the SBRT and pure checkpoint blockade with nivolumab and ipilimumab.

What were the key efficacy data from CYTOSHRINK, and what are their potential clinical implications?

CYTOSHRINK was a 2:1 randomized phase 2 investigator-initiated trial looking at [patients with] de novo RCC. These [patients] were randomly assigned to receive nivolumab/ipilimumab, then SBRT at…30 to 40 Gy in 5 fractions and the rest of nivolumab/ipilimumab plus maintenance nivolumab against [nivolumab/ipilimumab] and maintenance nivolumab as a standard of care.

In terms of 1-year PFS rates, we did not find a significant difference between both arms. We did observe that at baseline, while IMDC risk groups were well-balanced, that in the era this was conducted—just at the start of [the COVID-19 pandemic]—there were a lot of high-risk patients who were presenting with more late-stage disease. Our interventional arm had more liver metastasis and bony metastasis, which is important to keep an eye on at baseline. We had a per-protocol analysis for patients who got 4 cycles of [nivolumab/ipilimumab] and patients in both arms did well; there was not a statistically significant difference between the interventions, and overall survival [OS] is still having ongoing fall.

What is interesting is that we found that the response rate for patients with a primary mass in situ was around 33% in the intervention arm and just under 42% in the control arm. But in those who had ongoing response at last follow-up, that [response rate] was 10% in the control arm vs 50% in the intervention arm…. We have lots of further follow up ongoing in terms of OS, quality of life, and we have a biomarker program in terms of tissue serial blood collection and serial gut microbiome collections in both arms.

We also know that patients in the interventional arm got treatment beyond progression. We’re going to uncouple that. We’re going to try to understand better those who got cytoreductive nephrectomies downstream from the upfront radiation. Having the correlatives there will be helpful. Ultimately, this was the first randomized trial looking at upfront, cytoreductive SBRT in patients getting combination immune checkpoint blockade.

There are more trials ongoing, perhaps looking at a later radiation component in terms of a patient’s care plan: to what extent could there be response-guided treatment? This is the first of many questions that will still be to come, and we’re excited to see the further follow-up of our data and the biomarker work as well.

Are there any safety concerns with this combination?

When we’re putting 2 modalities together, we wanted to make sure these are safe for patients, especially because, by definition, they are IMDC-intermediate and poor risk in many cases. What we found was very reassuring. SBRT was able to be delivered in the prescriptions we had embedded. In terms of the protocol, most patients got 30 to 35 Gy at 5 fractions. The ipilimumab component—the CTLA-4 of the upfront combination treatment—was well balanced, as was the maintenance nivolumab. We found that the safety of SBRT and [nivolumab/ipilimumab] was not compromised by bringing them together. The delivery of both appears to be reasonable and safe. That’s reassuring, because we’re going to have more trials looking at this moving forward. From a safety perspective, we actually didn’t find more kidney injury or other issues by putting modalities like this together.

What are the next steps for research?

This is just the first readout of CYTOSKRINK. We have our initial PFS end point, which was [observed], but we have much more to go. Considering ongoing responses, who are these patients? How can we understand them better? It will likely be more than the risk group that will help tell us that, although certainly IMDC prognostication is important with what we try to do. We have patients, as mentioned, who got treatment beyond progression. While they would have met a progression event, they are still on therapy. We need to understand them better. [There are] those who got treatment and then had a downstream nephrectomy. Then, OS accounting for these ongoing responses.

This is just the first initial readout of our data. What we’re really excited about, given this was a randomized phase 2 trial, was not meant to be definitive in terms of its design, but having correlatives embedded will be exciting, and that’s a whole separate part of this program. We have baseline tissue in patients, serial blood collections. There are lots of new biomarkers that, from the time of our trial design to what’s being apparently relevant in kidney cancer now, have emerged. We have samples that are primed to analyze for these new and evolving biomarkers. For us, there was the feeling that there could be different perturbations of the gut microbiome when you do this type of treatment. Now we have these samples that we can ask questions of as well.

Is there anything else that you would like to highlight that we might not have touched upon?

How we approached the [patient with] de novo advanced RCC, from our estimation, we’ve confirmed that systemic therapy up front is quite important. There are still great questions to ask about cytoreduction in these patients. There are trials ongoing, asking about a later response-adapted surgery, or where and what dose of radiation is the right dose to give here. It’s important that these patients are at least 30% of what we see in clinic. I think their outcomes are different than patients who had nephrectomy prior. There are still lots of questions we can answer.

Also, we’ve shown that radiation can be safely delivered with a combination 2-drug immune checkpoint blockade. I hope that this is the first foray of other trials that we’ll read out with their own takes on how to cytoreduce in this situation, because these questions come up in our tumor boards: patients have had systemic therapy, they’ve had a response, what do we do next? Or they have oligoprogression––a different question from what we were asking: how do we leverage SBRT? The focal therapy in patients with advanced RCC has so many different layers to it, and we took our stab at one of them, but there’s still more to come.

References

1. Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5(2):164-170. doi:10.1001/jamaoncol.2018.5543
2. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675
3. Lalani AK, Pond GR, Siva S, et al. CYTOSHRINK: a randomized phase II trial of cytoreductive stereotactic hypofractionated radiotherapy with ipilimumab/nivolumab for metastatic kidney cancer. J Clin Oncol. 2026;44(suppl 7):416. doi:10.1200/JCO.2026.44.7_suppl.416