Real-World Factors Influence Choice of IO/TKI Regimen for mRCC


During a Targeted Oncology™ Case-Based Roundtable™ event, Deepak Kilari, MD, discussed with participants what real-world patient conditions would impact their choice of frontline therapy for metastatic renal cell carcinoma. This is the second of 2 articles based on this event.

Deepak Kilari, MD

Associate Professor

Medical College of Wisconsin

Cancer Center - Froedtert Hospital

Milwaukee, WI

Deepak Kilari, MD

Associate Professor

Medical College of Wisconsin

Cancer Center - Froedtert Hospital

Milwaukee, WI


  • Please discuss your real-world experience with IO/TKI (immunotherapy/tyrosine kinase inhibitor) regimens in metastatic renal cell carcinoma (mRCC). ​
  • How does the safety profiles of these regimens compare?​
  • How often do you have to modify/interrupt/discontinue for toxicity with IO/TKI combinations?​
  • To what extent does/should the TKI guide treatment selection? How much consideration do you give to the TKI? ​

DEEPAK KILARI, MD: Does your real-world experience mirror what we see in the trials? Are you seeing more toxicities with these IO/VEGF-TKI combinations in your real-world practice compared with what you see [in the trials]?

JONATHAN S. TREISMAN, MD: I’m mostly experienced with the pembrolizumab [Keytruda] and axitinib [Inlyta] combination and I would say [they are] similar. Do you make anything of the number of patients who came off the drug with the lenvatinib [Lenvima] and pembrolizumab in the CLEAR study [NCT02811861]?1

KILARI: I do. Each of the IO/TKI regimens have their own tolerability and safety profile. When I look at these things, I ask myself how familiar I am with these drugs but also what is the discontinuation rate of each of these drugs? Is it going to be constant dose reductions, holds, and putting back the patient on [treatment]? I do take into account what the adverse event profile is and how many patients had to stop on the trial or how many patients had to dose interrupt. We’re fortunate in the sense that we have good pharmacists and nurses to help us out. At the same time, it becomes a burden sometimes on providers when you constantly have to dose reduce and dose modify treatment for patients. It does factor into my decision as to which regimen I pick.

TREISMAN: Do you think that maybe you don’t need so much of the medicine if they can do well even though they’ve discontinued?

KILARI: You can make a very good argument that way, saying that they have discontinued the drug, [yet] they have pretty good outcomes. That is one way of looking at it. But it’s also emotionally burdensome on a patient to constantly come to clinic [and receive a] dose reduction or dose hold. The nurses and the pharmacists tend to prefer…[not having] to worry about constant dose reductions.

TREISMAN: I agree with you entirely [but] we’re not using [a regimen] the right way if we have to take them off the drug but [we still say], “Look at how great it works in that setting.”

KILARI: You’re right. The prescribing information [gives the dosing schedule] but we all do different things sometimes. For cabozantinib [Cabometyx], I do 5 days on, 2 days off. I get away with it and patients do well with this. We all come up with our own combination [approaches] as time goes by, so you’re absolutely right in that sense.

MICHAEL HUSAK, MD: [What about] patients with Von Hippel-Lindau [VHL] gene mutations? How would that change your choice?

KILARI: We don’t know the answer to that. Belzutifan [Welireg] is only approved at this point for patients that have a germline [mutation], VHL syndrome itself and not the sporadic [gene mutations].2 But most of these patients do have sporadic VHL. Belzutifan is probably making its way up to the first line in all the trials. But [with] the lack of an FDA approval and if the insurance companies don’t approve it, I probably would stick with cabozantinib/nivolumab and lenvatinib/pembrolizumab because I don’t think we have enough data to say what the outcome is for patients that have sporadic VHL. There are data in the second- or third-line setting saying it works.3

HUSAK: How many of these patients in the clinical trials have brain metastasis, or were they excluded?

KILARI: From my understanding, they were all excluded from these trials. But I think we have good data saying that VEGF-TKIs do have some blood-brain penetration, and the blood-brain barriers are [weakened] from the brain metastases.4 If they have brain metastases that were treated, we would favor a VEGF-TKI/IO combination.

HUSAK: Thank you.

KILARI: If this patient progresses on cabozantinib/nivolumab, what would you recommend for this patient [as a] preferred second-line and third-line option?

AMRUTH PALLA, MD: You can pick any TKI. If they progress on cabozantinib/nivolumab, you could probably use single-agent axitinib. I don’t know if we have comparisons between the TKIs in second line, but I would probably choose a TKI depending on patient adverse event profile.

KILARI: You’re right, in the sense that I probably would pick lenvatinib plus everolimus [Afinitor] or axitinib if they received cabozantinib/nivolumab in the first line, and then in a third line…tivozanib [Fotivda] is another option that has level 1 evidence.5 After IO/VEGF-TKI combinations, that’s another option and I would pick that in the third line based on the FDA label at this point.


1. Motzer R, Alekseev B, Rha SY, et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716

2. FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. News release. FDA. February 1, 2022. Accessed March 30, 2023.

3. Choueiri TK, Bauer TM, Papadopoulos KP, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27(5):802-805. doi:10.1038/s41591-021-01324-7

4. Hirsch L, Martinez Chanza N, Farah S, et al. Clinical activity and safety of cabozantinib for brain metastases in patients with renal cell carcinoma. JAMA Oncol. 2021;7(12):1815-1823. doi:10.1001/jamaoncol.2021.4544

5. NCCN. Clinical practice guidelines in oncology. Kidney cancer, version 4.2023. Accessed March 30, 2023.

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