Treatment Goals Guide First-Line Choices in Metastatic RCC

Treatment selection in metastatic renal cell carcinoma (RCC) requires balancing the need for rapid disease control with long-term outcomes, quality of life, and tolerability. In a virtual Case-Based Roundtable event, Daniel Geynisman, MD, medical oncologist at Fox Chase Cancer Center of Temple University Health System, moderated a discussion with oncologists in the Southeast region on treatment goals and first-line therapy considerations for a patient with metastatic clear cell renal cell carcinoma.

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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 scan 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, along withlytic destruction of L4 and L5 vertebrae, left superior pubic ramus, and right ischium.
• Biopsy of renal mass and bone biopsy confirmed metastatic clear cell RCC.

DISCUSSION QUESTION

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

Daniel Geynisman, MD: How do you view metastatic RCC in terms of treatment expectations?

Tarek Chidiac, MD: Overall survival, make them live longer, and get a response as soon as possible—faster response, highest response, longer survival, and with a regimen that is better tolerated, so they can have mileage.

Joseph Attallah, MD: I echo what Dr Chidiac mentioned. I think once we're in stage IV, treatment is palliative, so quality of life is very important. Also, the urgency of getting a response if the patient has high-volume disease and you need to get a response as soon as possible, or you have the leverage to wait if the patient doesn't have any visceral crisis or impending organ failure.

Geynisman: Absolutely. You mentioned the word "palliative.” I'm just curious, I'll ask: Do any of you use the word “cure” or “potential for cure” when you meet a newly diagnosed patient with metastatic kidney cancer? Do you propose that as a potential option for them as a goal?

Attallah: No. I usually start the discussion, but the goal of treatment is palliative [and] to control the disease. Sometimes we get lucky, and the patient can go into a very long-term remission. But cure for stage IV RCC is challenging.

Chidiac: If you have oligometastatic disease, yes, but not with bone metastases.

Aneel Chowdhary, MD: I would agree with Dr Attallah and Dr Chidiac on both these points that, again, we do at least want to have patients have reasonable expectations that this is stage IV disease. But again, our median survivals are, with any regimen you choose now, 46 to 47 months. So, I do tell patients that we have very extensive data now; we have excellent median survivals. I think in all of our practices, we're going to have a few patients whom, even with oligometastases, you can radiate. I have patients who are 6 to 7 years out now… Again, cure may be a strong word here, but long-term survival is definitely very possible now, especially with oligometastases.

Geynisman: I agree. I think it’s an interesting and controversial point. Some oncologists—genitourinary oncologists and kidney cancer experts—like to use the word “cure,” and the goal is “to cure.” I tend to agree with what you all are saying which is that you have to set appropriate expectations. Certainly, you can hope for the best, and sometimes, as you say, patients do have excellent responses and long-term remission. But that's certainly not the norm, even nowadays.

POLLING QUESTION

A decision was made to initiate a tyrosine kinase inhibitor (TKI)-immune checkpoint inhibitor (ICI; IO) regimen. What first-line metastatic/recurrent regimen are you most likely to choose for this patient?

1. Axitinib (Inlyta) + pembrolizumab (Keytruda)
2. Cabozantinib (Cabometyx) + nivolumab (Opdivo)
3. Lenvatinib (Lenvima) + pembrolizumab
4. Cabozantinib
5. Other

Chidiac: What was the patient's performance status?

Geynisman: We didn't say, but let's assume the performance status is 0 to 1. Maybe somewhat limited by the pain from the bone metastases, but otherwise, it's fine.

It looks like we have a 60/40 split for dual IO vs TKI-IO, and no one else is choosing anything else. So, could we have somebody who chose dual IO give their rationale or thoughts?

Vikas Singh, MD: I picked IO-IO combination. When we started treatment for stage IV metastatic RCC 5 to 7 years ago, we started with ipilimumab [Yervoy]-nivolumab, then IO-TKI combinations came along, and they looked really exciting with their higher response rates. But in the last few years, with longer follow-up with CheckMate 214 [NCT02231749] and other IO-TKI regimens, it looks like everyone has almost similar survival with similar hazard ratios, so I think the choice of IO-IO and IO-TKI boils down to your personal preference and patients' need for immediate response or not.

For this particular case, this patient seems to have minimal symptoms, some bone pain. He's not in visceral crisis. Labs are reasonably stable, so I don't think I need an immediate response with a TKI, so I feel like IO-IO is a good start, and then we can save effective TKI as a second-line option.

Chowdhary: Especially if performance status is good, I would go with dual IO.

Geynisman: I heard about response, I agree; the key differentiator is response rate. Visceral crises—do we need that immediate response? Can [the patient] tolerate dual IO? What about someone who chose TKI-IO? What are your thoughts?

Chidiac: I like the lenvatinib-pembrolizumab combination because it gives the highest response rate. I've had great experience with it; I've not really had many dose reductions of lenvatinib, and then I keep going with it. Every time I do, I get a complete response. It's really crazy. My experience is maybe not as extensive as yours, but I've had maybe at least 5 patients that I treated that way.

Geynisman: Absolutely. Personal experience matters—what you're comfortable with, what you've seen. And you're right, the lenvatinib-pembrolizumab in the trial did have the highest response rate, over 70%.¹

Any other thoughts? Anything that you're thinking about that folks haven't said when you're making this decision?

Lukas Delasos, DO: One thing I get concerned about with dual IO is high-grade immune-related adverse events. So, when we're talking about palliative intent treatment, I do get worried about long-term effects of combination immune therapy.

Geynisman: You're all bringing up valid points, and like I said, I think you can make arguments on both sides. I think the answer is probably somewhere in the middle, and it depends, and I think it's good to have both options and discuss both options.

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DISCLOSURES: Geynisman previously disclosed a consulting or advisory role with Exelixis, UpToDate, Pfizer, AstraZeneca, Seattle Genetics/Astellas, Eisai, Merck, Myovant Sciences, 2nd.MD, and NCCN, as well as institutional receipt of research funding from Merck, Astellas Pharma, Harpoon Therapeutics, Arvinas, CG Oncology, Novartis, and Regeneron.

REFERENCES

Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. Published online 2024. doi:10.1200/JCO.23.01569