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Alicia Morgans: Hi, I'm so excited to be here today with Dr. Shankar Siva, who is joining me from Melbourne at the Peter Mac, where he's a professor of radiation oncology. Thank you so much for being here with me today.

Shankar Siva: Thank you very much for having me. Very excited to talk to you.

Alicia Morgans: Wonderful. I'd love to hear a little bit more about a talk that you gave at EAU 2024 where you really enlightened the audience on the use of SABR for the treatment of oligometastatic kidney cancer. Can you tell me a little bit about that?

Shankar Siva: Yes, exactly. The talk covered three different areas in oligometastatic kidney cancer, and oligometastatic is not a clear definition, but roughly we could speak of up to five spots of cancer that have spread from the original primary, from the kidney. There are three settings that I'd like to highlight. One is de novo oligometastatic disease where we use SABR upfront to all sites of disease. The other approach, the second one, is when patients are in the oligo progressive setting and that really highlights patients who are having an otherwise effective systemic therapy, and then we use SABR in that setting. The third one is a metastatic setting.

For the first option, which is looking at patients who have de novo oligometastatic disease, there are some studies that have looked at the use of SABR to all sites of disease in patients who had a favorable type of pattern. These are patients who have a low burden of metastatic disease. Often, the studies that have reported have an average number of metastases of only one. Patients often have recurrent disease with some time interval between the original primary and their time of metastatic disease, putting them into more of an IMDC category of favorable risk metastatic kidney cancer.

This population has been studied prospectively in clinical trials. There are a couple of trials that have really been looking at this, and that's a group from Texas, from MD Anderson, Chad Tang and colleagues, and another group from UT Southwestern, Raquibul Hannan and colleagues. Both of these authors have produced prospective clinical trials, and these were reported in the last couple of years. The outcomes are very similar.

An outcome from local control rates, which is the local efficacy of the SABR, these are all consistent around the above 90% mark, about 92% at one to two years. The other item that they were looking at is how long can patients be free of systemic therapy? The delay in actually commencing systemic therapy. On average, this is about an extra year, which is quite useful. The median times are about 12 months. From a patient perspective, this means that they enjoy a long period of time without the potential toxicities and financial burden of ongoing systemic therapies.

The other setting, which involves patients who might have a slightly higher burden of disease but are still in that oligometastatic de novo setting, has been investigated at our own institution in a clinical trial called RAPPORT, which was published a couple of years ago as well. In this setting, we had patients who had slightly higher burden of disease, with a median number of metastases of three. Often, patients had presentations where the cancer was there and secondary spread occurred at the time of diagnosis, not recurrent oligometastatic disease. These were patients who were a little more unfavorable in terms of their risk profile.

In these patients, we ran a trial that combined a short course of immunotherapy, in this case, three weekly doses of pembrolizumab for a period of six months or eight cycles, alongside SABR to all of the sites of metastatic disease. In this setting, we had similar outcomes in terms of local control. The two-year local control rate was excellent at 92%. Impressively, we had very high response rates from this drug therapy and the combination of radiation. 63% of patients had objective responses, either complete response or partial response, from the treatment. Many of these patients had a long period of time without needing subsequent therapies, which is very nice from that perspective considering they had a more unfavorable burden of disease.

The second setting we are talking about is oligoprogressive disease. This occurs in the context of patients who have an otherwise effective systemic therapy, and then some small areas of cancer are not responding to systemic therapy anymore. They evolve and become resistant, and then they present as low-volume recurrence. This is called oligoprogressive disease, and SABR has a unique advantage in this context because it does not interrupt the systemic therapy. We can administer it around the time of the drug therapy. There are two trials as well that were looking at this context. One from, again, Hannan and colleagues at UT Southwestern, another from Patrick Chung and colleagues from Canada, a multicenter study that looked at the use of SABR in oligoprogressive disease.

These were in the TKI era, so this is from oral tablets rather than immunotherapy. Nevertheless, these studies show that the use of SABR in this context was very safe and often delayed the need for switching drug therapy by somewhere between eight and 12 months, which is very useful, again, from a patient perspective, to wring every last bit of efficacy from their drug therapy before needing to switch to a new line of treatment. In this kind of context, I think SABR is very useful.

The third one, which is a bit more off-piste and still under investigation at this point, is the use of SABR in patients with de novo metastatic disease with a higher burden. Maybe oligometastatic, maybe a bit more than that. This raises the question of what to do with the primary. In the context of immunotherapy, which is now the current era of using drug therapies in the first line for metastatic renal cell carcinoma, we don't know whether cytoreductive nephrectomy, or taking the kidney out, is the appropriate thing to do. There were some studies, the SURTIME and CARMENA studies in the TKI era, that didn't show a benefit in actually performing cytoreductive nephrectomy, which was a practice that we used in the interleukin era some decades ago. That's put the question in play; now there are studies addressing whether or not surgery has a role in the setting of immunotherapy.

There are also studies looking at this in the SABR setting, and there are a couple of trials that are currently running. That's the SAMURAI study from NRG and the CYTOSHRINK trial from Canada. Both of these trials are looking at the question of whether we should give SABR to the primary in addition to the immunotherapy, whether that be immunotherapy alone, immunotherapy combinations, or immunotherapy and TKI combinations. In this context, the obvious question is whether we should try to ablate all sites of disease that we can see. The response to that at the moment is that we don't have strong evidence for this, but if it can be done safely, then there is data from our institution and others that have looked at total metastatic ablation and shown that outcomes are better when we can treat all sites of disease rather than just selectively treating some spots. I think at the moment this is a very exciting area that we're going to explore in the future.

Alicia Morgans: Wonderful. I was going to ask you about the CARMENA study because I think that as we're thinking about a local treatment like SABR, it really does bring to mind, from my end, the CARMENA study, which did not show a benefit to treatment with surgery. I think there are some inherent clear benefits to being able to have a non-invasive treatment option. I wonder from your perspective, are you anticipating that you will see a benefit in this setting where surgery failed? Is it critical to have the immunotherapy on board? Is that something that you think is going to improve the abscopal effect or some other effect for the patients? Is this something that might just be icing on the cake but hopefully may not be necessary long-term as you continue to analyze this?

Shankar Siva: It's an excellent question. There are some unique synergies with the use of radiation in this setting. You touched on one, the synergy and interaction between immunotherapy and radiation, which we think may be a potential benefit, rather than doing a surgery that can be immunosuppressive with the anesthetic and the recovery time. We're talking about radiation, which we have trialed in multiple studies showing some synergy both in kidney cancer and others with immunotherapy. The other advantage of SABR in this setting is that we don't need to interrupt the systemic therapy. We can do this alongside the immunotherapy and, in fact, with these two trials that we're talking about, they're often given between cycle two and cycle three of the immunotherapy. There's no interruption. Patients who need their life-prolonging systemic therapy can start that straight away and then we can give the radiation to the kidney.

I think it's still important to have that drug therapy in the first place, in the background, because that is the proven mechanism of treatment. What we don't know, and this is currently being explored both for other nephrectomy and for SABR, is whether the treatment of the primary is actually going to make a benefit. I suspect in those patients where the primary disease is actually the bulk of the disease, and there's lower volume metastasis elsewhere, that's probably where we're going to see the most benefit from local therapies. I suspect that SABR might have a unique advantage in this setting.

Alicia Morgans: Which would be great, especially since, as far as I know at least, SABR has a really quite well-tolerated profile. Can you share some of the safety signals that have come out of the work that's already been done?

Shankar Siva: When SABR has been used alone in the context of oligometastatic disease, there have been consistent safety readouts from the studies that include both retrospective and prospective trials in the setting. That's roughly about a grade three toxicity rate of around 5%. There are not many reports of higher complications. Typically, they're grade three settings, which means a requirement for hospitalization. This would involve an adverse event that requires some medication and hospitalization to try to fix in the short term.

When you compare this to alternatives, things like metastasectomy and other surgical removal, these can be quite challenging and morbid if it's in the setting of bone, for example, which is a common site of spread. These all necessitate hospitalization and, by definition, are a bit more intense from a patient perspective. When combining the drug therapy, the safety signals are pretty similar in the same context. It's not that the side effects are amplified synergistically, it's more that they are additive side effects.

When we're using the oligoprogressive setting with the TKI, we're pretty much adding that 5% grade three toxicity rate to the known background rate of the TKI. Interestingly, in that oligoprogressive setting, patients have often been on that TKI, that drug therapy, for quite some time, the immunotherapy. They already know what their side effect profile is. We are just talking about an additional 5%. In the context of patients receiving combination therapy, so upfront immunotherapy and SABR to all sites in the oligometastatic setting, what we saw in the RAPPORT trial is that it was again additive. We had about a 5% grade three toxicity rate from the immunotherapy and a 5% grade three toxicity rate from the radiation. We combine that together, so it was about 10%. The most common side effects were things like pneumonitis because kidney cancer often goes to the lung, and that was a common site of radiation.

Alicia Morgans: Well, that does seem quite tolerable and really good to report that those are just additive toxicities, not synergistic, with no new safety signals, which is also really important. Just one final question, as you consider what the patient has to do in order to participate in a treatment like this, this does not sound like a long-term radiation therapy plan like those that we see certainly in prostate cancer or perhaps in other settings. What's the average number of cycles that you may see a patient getting SABR for their oligometastatic kidney cancer?

Shankar Siva: That's an excellent question. Generally, for example, in the US, SABR is known as SBRT, defined as up to five fractions of treatments. For the treatments that we've seen so far in the prospective trials, it's anywhere between one and five treatments, so can be really efficient. These are outpatient treatments. Patients can come in, get their one-hour radiotherapy, go home, and have dinner with their family. It's really quite tolerable and effective from the patient perspective.

From the repeated treatments, we don't actually often plan for repeated treatments. That's not part of the process. Often when we see control rates above 90% at two years, that's not something that we're expecting. However, some patients do inevitably have new sites of disease that pop up. In our practice and our reported series, we see that roughly about a third of patients have this ongoing oligometastatic type of pattern that is suitable for a further round of SABR. This might be one or two years later. They may come around for new sites of treatment and then again, repeat it sometime down the track. Now, in our own experience at Peter Mac, we have noticed that when using SBRT or SABR in lieu of systemic therapies—that first type of treatment and keeping the drug therapy on the shelf—we have about 35% of patients at five years who are still not on drug therapy and have just had one, two, or three courses of SABR in that period.

Alicia Morgans: Well, I really do commend you for such a fantastic lecture and for bringing us all up to speed on the use of SABR in the oligometastatic kidney cancer setting. This is something that clearly is changing the paradigm of treatment for the disease and certainly will continue to make a difference and continue to be studied for years to come. I so appreciate your time and your expertise. Thank you so much.

Shankar Siva: Thank you so much for the invitation. Appreciate it.