Rapid Disease Control Drives Frontline Choices in Metastatic ccRCC

Treatment selection for newly diagnosed metastatic clear cell renal cell carcinoma (ccRCC) continues to evolve as clinicians weigh the need for rapid disease control against the potential for durable long-term responses. During a virtual Case-Based Roundtable event, Daniel Landau, MD, hematologist/oncologist at the Medical University of South Carolina, and oncologists in Georgia discussed their preferred frontline treatment approach for a patient with poor-risk metastatic ccRCC and considered the role of immunotherapy-based combinations in this setting.

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CASE SUMMARY

• A 65-year-old man presents with back pain for past 6 months and hematuria for 1 week.
• Labs: Hg 11.4 g/dL, lactate dehydrogenase 980 U/L, all others within normal limits
• CT of the chest, abdomen, and pelvis shows high disease burden, including multiple mediastinal and hilar nodes, deposits in left lower lobe of lung, enlarged axillary nodes, and enhancing mass in left renal parenchyma with renal vein infiltration; lytic destruction of L4 and L5 vertebrae, left superior pubic ramus, and right ischium
• Biopsy of renal mass and bone biopsy confirmed metastatic ccRCC

DISCUSSION QUESTION

• What are your goals of therapy for this patient?
  • Do they differ in the short term vs the long term?

Daniel Landau, MD: …This is a patient that's going to need urgent therapy; this is somebody who is already anemic. It doesn't really say what their Karnofsky score is, but to me it sounds like they're probably already a little bit beaten up. So, this sounds like they're probably going to be a poor-risk patient… When this patient is sitting in front of you in the office, what are you telling them? What are you thinking? What is your conversation like?

Carlos Osmon, MD: I guess from the practical point of view, you have 2 options. If you want a rapid response, or you're expecting a rapid impact, you would probably go with [immuno-oncology therapy; IO] plus a tyrosine kinase inhibitor [TKI]. You will not be wrong if you go IO-IO, but I think, because of the nature of the poor prognosis and all of that, to your point of using your best gun upfront, that probably would be what I would favor.

Landau: Very, very reasonable. So, I think when this patient is sitting there, and we're discussing their situation, we're going to have to explain to them that, of course, this is going to be a palliative setting. Our goals are not going to be cure; our goals are going to be control and hopefully extension of survival. And I think your point is very well taken about that rate of attrition, where we need to be as aggressive as we can early on. Would anybody else like to volunteer their thoughts?

Venu Thirukonda, MD: I agree with Dr Osmon as well. I think this patient with skeletal metastatic disease, especially in the lumbar vertebrae, I think we need response fast. You don't want this patient having cord compression and paralysis, so I would favor TKI plus IO combination. That would be the short-term goal to get a quick response. That's what I would do.

Landau: Perfect. I think we all agree that this is a patient who is going to get into trouble very, very quickly, so I think that most of us are going to take a very similar approach, so that's all very reasonable.

POLLING QUESTION

What type of regimen are you most likely to recommend as first-line systemic therapy for this patient with newly diagnosed metastatic disease?

1. Dual immune checkpoint inhibitor [ICI]
2. TKI-ICI
3. Single-agent ICI
4. Single-agent TKI
5. Other

EVENT RECAP

Before reviewing any trial data, most participants favored an ICI-TKI combination as first-line systemic therapy for this patient with newly diagnosed metastatic disease, with 60% selecting this approach. The remaining 40% chose dual immune checkpoint blockade, while no participants selected single-agent immunotherapy, single-agent TKI therapy, or another regimen.

Landau: I always say that there truly are no wrong answers, but there are probably some answers that are a little bit better than others. So far, I don't see anybody picking a single-agent option. I don't think that I would either. It seems that TKI with IO is the general preference… So, then the question is going to be, which TKI? Any thoughts on that?

Osmon: I think the situation is not black and white in my mind, but I would like to reserve cabozantinib [Cabometyx] for down the road, go with axitinib [Inlyta] and pembrolizumab [Keytruda] as the next step, and then upon recurrence, if you have a change—because there's a great deal of attrition as you mentioned—you will have cabozantinib in your back pocket.

Landau: Whoever picked dual immunotherapy, would you like to talk a little bit about why that was your choice?

Eiran Warner, MD: I usually pick it for first-line metastatic just because of the tail of the curves, trying to get the best chance of getting patients in long-term control. I really only do a TKI-immunotherapy combination if I need a quick response, so visceral crisis, uncontrolled pain, a reason I need a quick response, but as someone who I feel I have 4 to 6 weeks, I'm probably going to pick the immunotherapy.

Landau: Right. I always think about this, because when the ipilimumab [Yervoy]-nivolumab [Opdivo] data hit The New England Journal of Medicine, there was actually a commentary in that [journal] asking if this is finally the cure to renal cell cancer. Because those patients that do achieve a deep response with IO-IO do quite well in the long term. The challenge is trying to predict who is that patient that's going to have that [complete response (CR)] or near CR, and who would benefit more from a TKI, and that's something that we still obviously don't know very well.

EVENT RECAP

Landau and participants subsequently reviewed the NCCN Guidelines from 2026 on first-line therapy for kidney cancer with clear cell histology.

Landau: [Previously], ipilimumab-nivolumab was actually not category 1 for favorable risk, but that's been updated recently, so we see that really everything that [Dr Osmon] was mentioning is all right here in the NCCN: IO-TKI combination, IO-IO. Single-agent is included; cabozantinib is included as a single-agent option. I used to use that when the cabozantinib vs sunitinib [Sutent] data came out, but nowadays I think it's almost always a combination. Anybody feel differently? Does anybody still use a single-agent TKI or single-agent IO in the metastatic setting?

I see a lot of head shaking and a lot of people saying no, which I agree.

Osmon: There are data that cabozantinib as a single agent as a third-line treatment does produce some reasonable responses,¹ but not that many at all. But at least that has some support from the literature.

Landau: I'm with you completely. I mean, the, the original label for cabozantinib was as a salvage therapy, which was mostly after sunitinib, but there were patients in that study that had also had prior IO therapy and still saw activity from cabozantinib, so your point is well taken. But I think in the first-line setting, I don't think many of us are going to favor single-agent use.

Michelle Ojemuyiwa, MD: I have a patient who has [interstitial lung disease] from an autoimmune disease, so we talked about a single agent, but I thought there were data for low-risk or low-burden [suggesting] you can't consider a single agent?

Landau: There are—it's not considered a category 1, but it's still in the recommended category, so it is certainly not wrong, especially in a setting like that where a patient may not be a great candidate for IO. But the category 1 preferred options are essentially all combinations at this point.

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DISCLOSURES: Landau previously reported serving on speakers bureaus for Pfizer and Sanofi.

REFERENCE

1. Domański P, Jarosińska J, Kruczyk B, et al. Activity of cabozantinib in further line treatment of metastatic clear cell renal cell carcinoma. Real-world experience in a single-center retrospective study. Contemp Oncol (Pozn). 2023;27(3):190-197. doi:10.5114/wo.2023.133545