Oncologists Discuss Choice of Frontline IO/TKI for Metastatic RCC

Deciding on a frontline regimen for advanced renal cell carcinoma (RCC) is challenging due to the multiple available combination regimens. In a virtual Case-Based Roundtable event, participants and moderator Che-Kai Tsao, MD, MS, discussed their choice in the context of goals of therapy for a patient with high disease burden. Tsao, medical director of the Ruttenberg Treatment Center at the Tisch Cancer Institute at Mount Sinai Hospital and associate professor of Medicine, Hematology and Medical Oncology at Icahn School of Medicine at Mount Sinai in New York, surveyed participants of their choice of therapy. Participants gave the reasons for their choice including familiarity, tolerability, and time to response, which they said could vary based on the needs of each patient with RCC.

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CASE SUMMARY

• A 65-year-old man presented with back pain for past 6 months and hematuria for 1 week. ​
• Laboratory findings: hemoglobin 11.4 g/dL, lactate dehydrogenase 980 U/L, all others within normal limits​
• CT scan of chest, abdomen, and pelvis shows high-disease burden, including multiple mediastinal and hilar nodes, deposits in 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 clear cell RCC.

DISCUSSION QUESTIONS

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

Che-Kai Tsao, MD, MS: What are your goals of therapy for this patient? This is extraordinarily important for us as medical oncologists, because we know that our patients present very differently. Some may have diffuse disease but are relatively asymptomatic. Some may have very active disease, and we have a short period of time to get disease control, but overall, when you see a patient like this, what are your goals of therapy for this patient, and do they differ in the short term vs the long term?

Ian Hantman, MD: Since this is a patient with metastatic disease, obviously it’s not curative intent, so [the goals] would be quality of life, to extend their overall survival, and symptom control. A lot of patients don’t have symptoms, but [we want] symptom control, and for them to also understand goals of care and get their thoughts on what is important to them, since they’re the ones who are the drivers of this.

Tsao: We often see patients who are very symptomatic, and the primary goal is to control the symptoms initially, but once they have disease control, do other factors now become more important? Does that enter your decision making about potentially deescalating TKI [tyrosine kinase inhibitor], as an example?

Hantman: Once I get their disease under control and their symptoms under control, I’d probably escalate and be more aggressive with treatment options for them.

Santosh Kumar, MD: It depends upon the patient. If the patient has a symptomatic disease burden, then you are trying to control the symptoms. We are trying to control the disease and prolong their survival.

Tsao: I think this paves the way to the next step as we look at the different combination therapies; they all have their pros and cons.

Stuart Feldman, MD: I chose TKI and an ICI [immune checkpoint inhibitor], basically following NCCN guidelines as a preferred regimen.¹

Tsao: Did anybody pick dual ICI and why?

Elliot Belenkov, MD: I have…experience with ipilimumab [Yervoy] plus nivolumab [Opdivo]. In my experience, it’s well tolerated. It doesn’t depend on patient compliance with the oral medication; [it’s] administered in the clinic, and the adverse event [AE] profile is also very favorable. You have to have a very determined patient to continue taking TKI for a prolonged period of a time. I found some people to be not very compliant with that because of the AEs. That’s my choice of first line, and it’s also on the NCCN guidelines.

Tsao: Thank you. Both are right answers. In the NCCN guidelines, for favorable-risk disease, the 3 IO/TKI combinations are considered category 1 recommendations, but ipilimumab/nivolumab is not; comparatively for intermediate poor-risk disease, all 4 combinations that were discussed here: axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab, ipilimumab plus nivolumab, and lenvatinib [Lenvima] plus pembrolizumab are all considered category 1 recommendations.¹

Tsao: Most of us chose cabozantinib/nivolumab. Some of us chose axitinib/pembrolizumab, and [there was] another vote for lenvatinib/pembrolizumab.

Krishna Ghimire, MD: Any of them could be OK options. My numbers are limited in regard to the experience that I have in terms of treating RCC, and nivolumab has been used in many different other disease states, cabozantinib as well. I found that combination very well tolerated, but I haven’t tried the axitinib/pembrolizumab combination so much. I’d like to know if that combination is better tolerated; similarly for the lenvatinib/pembrolizumab combination.

Tsao: What you have shared is consistent with a lot of the experience, which is that particularly with 40 mg of cabozantinib in combination with nivolumab, some have found this combination to be effective as well as very tolerable.

Tong Dai, MD: I chose cabozantinib/nivolumab as well, because of the tolerability and also because nivolumab can be given every 4 weeks, which is convenient. My experience from lenvatinib, not just from RCC, but from other diseases like hepatocellular carcinoma and thyroid cancer [is that] sometimes it can be difficult to tolerate.

Tsao: Are there specific AEs of lenvatinib that you’re concerned about?

Dai: [AEs] like mucositis; other AEs, like diarrhea and swelling, are relatively easier to manage.

Gabriel Jung, MD: My choice was cabozantinib/nivolumab. I feel more comfortable because I’ve been using the combination for the longest time. Any [of these] will probably be acceptable, but my go-to combination is cabozantinib/nivolumab. I like the monthly nivolumab injections along with cabozantinib, and most patients are OK coming in once a month to see me.

Tsao: Got it, so it sounds like tolerability and logistics favors cabozantinib/nivolumab for some of us. Dr Feldman, I had the impression that you picked lenvatinib/pembrolizumab.

Feldman: I’ve used it in a number of different tumor types, and I’ve had some very good results. I have 2 patients whom I ended up taking off treatment for metastatic uterine cancer. I’ve had very little issues with AEs, but it’s a small sample size.

Kumar: I use cabozantinib/nivolumab. I don’t know when the last time was that I used axitinib/pembrolizumab; it was probably a few years ago. I generally prefer cabozantinib/nivolumab.

Belenkov: I have been using axitinib and pembrolizumab because of familiarity.

I have more experience with axitinib and pembrolizumab….

Tsao: It was the first ICI/TKI approved by the FDA, so a lot of us have experience with axitinib/pembrolizumab. By using axitinib/pembrolizumab in the first-line setting, it allows us to consider cabozantinib or lenvatinib/everolimus in the second and third-line setting.

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DISCLOSURES: Tsao previously reported consultancy honoraria from Bayer, Exelixis, Lantheus, and Pfizer.

REFERENCE:

1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2026. Accessed October 27, 2025. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf