How Disease Burden Shapes First-Line RCC Treatment Selection

First-line treatment selection for metastatic clear cell renal cell carcinoma (ccRCC) requires balancing rapid disease control with long-term efficacy and tolerability. For patients with symptomatic, high-volume disease, clinicians must consider whether immune-based therapy plus a tyrosine kinase inhibitor (IO-TKI) or dual immunotherapy (IO-IO) is better suited to their disease burden and treatment goals.

In a virtual Case-Based Roundtable event, Neeraj Agarwal, MD, FASCO, medical oncologist and co-director of the Prostate Cancer Program at Dana-Farber Cancer Institute, moderated a discussion with oncologists in California on how disease burden, symptoms, and treatment goals inform first-line regimen selection.

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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 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 righ ischium
• Biopsy of renal mass and bone biopsy confirmed metastatic ccRCC

DISCUSSION QUESTIONS

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

Ashkan Lashkari, MD: For a patient like this, there are 2 goals. One is initial pain control, symptom control, and of course to be able to offer a treatment that provides the best control of this disease for a prolonged period of time, where you can obviously try to prolong their life with quality of life. So that's how I would approach this. I think considerations for managing their back pain may include palliative radiation if indicated or neurosurgical evaluation if the spine is compromised. I had a patient very similar to this that presented exactly this way, minus the hematuria, but they had to undergo surgical stabilization of his spine, and then we were able to initiate radiation and systemic therapy afterwards.

Neeraj Agarwal, MD, FASCO: I gather that everything is important: objective response, progression-free survival [PFS], and overall survival [OS], because we need immediate palliation of symptoms. Because we don't see response, patients are likely going to progress and won't receive second-line therapy. OS is always a gold standard, but we need all of them for improved quality of life. Anyone else?

Sarah Hassan, MD: [My treatment goals] would be more so related to the patient—taking away the patient's discomfort and trying to alleviate his symptoms, so it'd be one of those. Also, when you're looking at therapy…it'd be more of adverse effect profile, tolerance, that sort of discussion with the patient.

EVENT RECAP

The group reviewed data from 4 key trials: CheckMate 9ER (NCT03141177), KEYNOTE-426 (NCT02853331), CLEAR (NCT02811861), and CheckMate 214 (NCT02231749).

DISCUSSION QUESTIONS

After reviewing the trials, what is your preferred regimen for this patient? If your preference has changed, what impacted your decision?

Lashkari: I think that there are a lot of options available, and I think what we would choose for the patient often comes down to what we're trying to achieve. If we're looking for an objective response to palliate, then I think introducing a TKI into the combination is critical. In this particular case, with this patient, since the patient has bone-predominant metastases, the cabozantinib [Cabometyx]-nivolumab combination would be the most preferred because of cabozantinib’s predilection to treat bone metastases, and so that would be my recommendation for this patient. I think if patients have low-volume disease, ipilimumab [Yervoy]-nivolumab [Opdivo] is what I like to use because you can use the TKI potentially down the road, and you have the opportunity to achieve a long-term remission, especially when patients are not symptomatic and have low-volume disease.

Agarwal: I agree. Thank you.Dr Lashkari said bone metastases; what about liver metastases? Is this as much of a concern? And how do you rate objective responses as one of the goals for treatment in any of these patients?

John Schwerkoske, MD: For me, in patients with liver metastases, I can't think of having one recently. I have a patient with brain metastases; I have some patients with lymph node metastases. But depending on the degree of liver metastases and dysfunction, I might still lean towards ipilimumab-nivolumab. I kind of like that [regimen] because you have the chance of getting patients into remission. I know everybody's worried about the toxicity with these CTLA-4s, but it seems fairly manageable. I haven't had any patients getting super sick and not being able to turn the ship around.

With bone metastases, I've had maybe a little bit better success with cabozantinib. I've had patients on all of them, and probably the least favorite would be lenvatinib [Lenvima]. I think axitinib [Inlyta] might be my personal favorite, but I have a few patients on cabozantinib and are doing really well.

Agarwal: Thank you. And I would say, objective response in high-volume disease is a major desired efficacy parameter for all of us… Thank you for chiming in and sharing your perspective. I agree with you.

DISCUSSION QUESTIONS

• What other factors drive your selection of first-line therapy for metastatic ccRCC?
• Based on your own experience, how does the efficacy and safety profile of TKI-IO regimens compare with those of IO-IO regimens?

Agarwal: Let’s now talk about high-volume disease. A typical patient with metastatic RCC comes to you with more than 5 sites of metastasis, which is not very unusual—what other factors are you looking at, assuming the patient is 62 years old and otherwise a fairly healthy man? PFS, objective responses, OS—are any of them more important than others? That's the [first] question. Number two, if the patient is symptomatic, or if we want to achieve responses early, does it change anything for you?

Umair Ghani, MD: If there's high-volume disease or a symptomatic patient, I prefer cabozantinib-nivolumab. I like the different mechanism of actions of TKI plus IO. I feel like dual IO takes a little bit longer to work; that's why I prefer that for low-volume disease… Also, looking at the overall response vs complete response [CR], I don't really care about CR that much. PFS and OS data, and then definitely quality of life are more important. Dose reductions are common with TKIs.

Rubens Costa, MD: I echo others' opinions. If you have lower-volume disease without symptoms, I tend to favor IO-IO; if not, IO-TKI. Whatever combo one chooses, I think it's reasonable and appropriate. It looks like the response rates are higher if you're doing some indirect trial comparison with pembrolizumab [Keytruda]-lenvatinib, but it looks like that there are some real-world data that suggest perhaps patients receiving cabozantinib-nivolumab may do better [in terms of safety]. There are some cohorts from Japan [showing this],¹ and I believe that cabozantinib-nivolumab is probably the number one prescribed in the US as well, with some US data² showing that perhaps that's the best combination as far as IO-TKI.

Agarwal: Modern TKIs [like] lenvatinib and cabozantinib are very potent TKIs with very high responses, as we have seen. So, I agree with you, regardless of the population. Anything else?

Dawood Findakly, MD: I think that for the brain, the data on IO-TKI are stronger. That will make a difference. But still, the patient is symptomatic. I think age plays a factor; dosing-wise, I think weight also plays a factor…but I echo what was mentioned before. I would do IO-TKI, and usually with the lower-dose ipilimumab, we don't get much adverse effects compared to the higher dose that we use in melanoma, so that's a good thing. But ideally, I usually tend to give more IO-TKI combinations.

Agarwal: The only concern I have with ipilimumab is that you're done with 4 doses of ipilimumab. Three is the most we use and is the median, and then diarrhea and colitis can happen around a year after. That's unpredictability of ipilimumab as far as colitis is concerned, and by this time, the patient is getting belzutifan [Welireg]… I think that will be the only concerning, unpredictable adverse effect of ipilimumab, which I think may dissuade people from ipilimumab. But otherwise, I think I agree with you. It's a pretty well-tolerated regimen.

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DISCLOSURES: Agarwal previously disclosed receiving travel support from Pfizer, Exelixis, and Johnson & Johnson/Janssen.

REFERENCES

1. Yanagisawa T, Mori K, Kawada T, et al. A real-world comparison of nivolumab plus cabozantinib and pembrolizumab plus lenvatinib focusing on safety outcomes in metastatic renal cell carcinoma: results from the JK-FOOT consortium. Cancer Immunol Immunother. 2026;75(3):84. doi:10.1007/s00262-025-04288-6

2. Isachanka M, Cetin O, Kaur H, Areesawangkit P, Teker G, Kozyreva ON. Metastatic renal cell carcinoma treated with pembrolizumab–lenvatinib versus nivolumab–cabozantinib: A real-world analysis. J Clin Oncol. 2026;44(16_suppl). doi:10.1200/jco.2026.44.16_suppl.e16519