Adapting Stereotactic Radiation to Treatment Response in Metastatic RCC

Systemic immune checkpoint inhibitor and tyrosine kinase inhibitor (TKI)–based combinations have become the backbone of treatment for metastatic renal cell carcinoma (RCC). Meanwhile, advances in stereotactic radiation have challenged the long-held view of RCC as a radioresistant disease. How and when to integrate local therapy into that backbone based on how a patient responds remains an open and evolving question.

At the 2026 European Society for Medical Oncology (ESMO) Congress, CancerNetwork® spoke with Shankar Siva, MBBS, PhD, FRANZCR, a professor and radiation oncologist who leads the Stereotactic Ablative Body Radiotherapy (SABR) program at the Peter MacCallum Cancer Centre in Melbourne, Australia. Siva discussed several aspects of response-based adaptive treatment, a topic addressed in an educational session at the congress:

• when to consider cytoreductive SABR in primary metastatic kidney cancer;
• how to sequence stereotactic radiation with systemic therapy;
• what is known about immune-mediated and abscopal effects;
• which toxicities warrant close monitoring;
• how multidisciplinary teams might refine response assessment.

CancerNetwork: How do you define the optimal window and biomarker criteria for determining whether a patient with primary metastatic kidney cancer should undergo cytoreductive SABR vs continuing with an immune checkpoint inhibitor doublet or TKI-based combination?

Siva: Response-based adaptive treatment in kidney cancer is an evolving space, whether we are talking about stereotactic radiation delivered to the primary or metastatic sites or about alternative local therapies like surgery. Both were discussed in the educational session today at ESMO. The idea of response-based adaptation is either escalation or de-escalation of treatment, and that can include the systemic therapy or the local therapies.

We discussed the opportunity of using novel biomarkers, such as circulating tumor DNA [ctDNA] in the blood, or imaging biomarkers, specifically functional imaging with fluorodeoxyglucose [FDG] PET, prostate-specific membrane antigen [PSMA] PET, and carbonic anhydrase IX [CAIX] PET scans, as a window to assess when to adapt treatment strategies. At the moment, however, it is still clinically driven.

When we think about using radiation or surgery to the primary kidney in a patient who is responding to systemic therapy, we typically consider it around the 12-month time point. There is some variability around this, and it can be as long as 2 years. However, data from the [phase 3 CheckMate 214 trial (NCT02231749)] indicate that most patients who are responding will plateau at around 12 to 24 months.¹ Rather than intervening up front, the intervention could come at the 12-month time point.

There are, of course, ongoing randomized trials, such as [the phase 3 PROBE/SWOG S1931 trial (NCT04510597)] and the [phase 2 SAMURAI/NRG-GU012 trial (NCT05327686)], which are investigating nephrectomy and SABR, respectively.^2,3 But they are doing it up front, so we will soon find out whether early intervention is better or whether it should be delayed to 12 months after initial response to systemic therapy.

When adapting therapy based on early tumor kinetics or partial responses, how do you sequence stereotactic radiation to the primary renal mass or oligometastatic sites without increasing cumulative toxicity or forcing holds in systemic therapy?

Sequencing is an important question. In fact, it has not been investigated prospectively in trials all that well. What we do have is a recent publication in JAMA Network Open from the TOaSTT registry.⁴ This international registry was led from Europe and housed in Zurich, and our group at Peter Mac in Melbourne was also involved. The investigators looked at the timing of stereotactic radiotherapy with TKIs and immune checkpoint blockade.

Sequencing often requires a short pause if someone is on a TKI. The half-life of most TKIs ranges from hours to a few days, whereas checkpoint inhibitors have a very long half-life, often up to a month or so. It does not make much sense to interrupt immunotherapy in that context. Usually, we would give a brief pause on either side of the stereotactic radiation in the context of a TKI. If we are using a longer course of treatment, we would just continue the TKI.

The registry found that patients who did not have a pause in TKI or immunotherapy probably did just as well, potentially even a little better, than patients who had a pause. Our preference is to continue systemic therapy wherever possible.

Given that RCC has historically been viewed as radioresistant, what immune-mediated mechanisms or abscopal effects are engaged when combining SABR with immunotherapy, and how does this approach affect long-term outcomes?

RCC has always historically been discussed as a radioresistant disease; that is the way I was trained, and it is often a preconception in the community as well. The major game changer has been advances in technology that allow us to deliver very precise but very high-dose treatment, which is the SABR approach. Because of that ability to give a high dose of radiation, what we considered a radioresistant disease has become quite responsive. We are routinely seeing control rates in excess of 90% at 1 and 2 years after treatment, which is impressive given that it can be delivered in as little as 1 treatment, or up to 5, in an outpatient, noninvasive setting.

We have seen abscopal effects. Most people who have practiced long enough have seen a patient or 2 with regression of distant metastatic sites after irradiating one site. But this has been very difficult to reproduce. We cannot predict it well, and there is no clear biomarker for it, so understanding which patients will have this kind of response is really challenging.

We have conducted trials combining immune checkpoint blockade and other immunotherapies with radiation, and a few simple lessons have emerged. First, starting with radiation and then adding an anti–PD-(L)1 agent seems to be a nice approach. Second, the toxicity profile does not seem to be synergistic; it seems to be additive. You get the radiation adverse effects [AEs] locally and the systemic therapy AEs systemically, but they do not multiply; they just add together.

In terms of strategy, we are trying to treat as much disease as possible. The idea of irradiating just one spot and eliciting an abscopal response with immunotherapy has not proven so gratifying in clinical trials. What we are trying to do more often is to ablate as much as we can, take away the maximal tumor burden, and allow the systemic therapy to work on less volume of disease.

From a toxicity management standpoint, which acute or late treatment-emergent AEs require close monitoring when implementing response-based radiation alongside active systemic therapy?

Response-based adaptation often comes into play when a patient has oligoprogression, meaning one or a few areas of the cancer escape control of an otherwise effective systemic therapy. These are the situations that might prompt a switch to another drug earlier than expected. Here, we use metastasis-directed therapy, often SABR, to control those sites.

These metastases may be in areas that are quite sensitive to AEs. Areas we worry about include the upper abdomen with TKIs, or the upper abdomen with immunotherapy because of colitis. If we are treating abdominal nodes, adrenal metastases, or targets close to the bowel, there may be an additive effect of a TKI-related gastrointestinal AE plus the radiation AE. In those situations, we might pause the TKI for a period of time or take extra care with the radiation dose when the patient is receiving an immune checkpoint inhibitor.

Pneumonitis is another issue, particularly when treating multiple lung metastases. Again, the strategy is either pausing systemic therapy for a couple of days or taking particular care with the precision and dose of radiation. Ultimately, in response-adaptive treatment, we know the systemic therapy is mostly working, and there may be 1 or 2 areas where it is not. In that instance, a very targeted form of metastasis-directed therapy like stereotactic radiation is a very appealing approach.

How can radiation and medical oncologists on multidisciplinary tumor boards standardize response evaluation criteria, such as ctDNA clearance vs RECIST imaging dynamics, to guide adaptive local consolidation in primary metastatic disease?

This is an important question, and again, it is in the bucket of things we are not exactly sure about. That said, we know that standard CT-based response assessment criteria such as RECIST are not really adequate. Even pathologic response assessment, when metastases or the primary [tumor] are resected, is still in the research and hypothesis-generating space in terms of what it means for the patient.

Ideally, we need a combination of approaches: patient factors; clinical factors, such as how good and how durable the response has been; and imaging criteria. I alluded to functional imaging with PET, which is an exciting area. We are seeing that PET scans can tell us much earlier than CT scans how well a patient is responding to drug therapy or to stereotactic radiation.

Finally, an emerging space is urinary biomarkers such as kidney injury molecule-1 [KIM-1] and ctDNA biomarkers. These could offer less invasive ways than resecting a metastasis or the kidney to understand whether a patient may be safely de-escalated, perhaps even stopping treatment for a period, or may need additional systemic therapy to consolidate the effect of current treatment.

References

1. Atkins MB, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: 8-year follow-up with analyses in favorable-risk patients from the phase 3 CheckMate 214 trial. Presented at the 2024 Kidney Cancer Research Summit; July 11-12, 2024; Boston, MA. Abstract 8.
2. Comparing the outcome of immunotherapy-based drug combination therapy with or without surgery to remove the kidney in metastatic kidney cancer, the PROBE trial (PROBE). ClinicalTrials.gov. Updated October 8, 2026. Accessed October 28, 2026. https://tinyurl.com/y5fpswhp
3. Hall WA, Karrison T, McGregor BA, et al. NRG-GU012: Randomized phase II stereotactic ablative radiation therapy (SABR) for patients with metastatic unresected renal cell carcinoma (RCC) receiving immunotherapy (SAMURAI). J Clin Oncol. 2023;41(suppl 16):TPS4604. doi:10.1200/JCO.2023.41.16_suppl.TPS4604
4. Looman EL, Thoma SGC, Schaule J, et al. Adverse events after metastases-directed stereotactic radiotherapy and biological cancer therapy. JAMA Netw Open. 2026;9(1):e2553809. doi:10.1001/jamanetworkopen.2025.53809