Comparing Choices for IO/TKI Combinations in Advanced RCC


During a Case-Based Roundtable® event, Shilpa Gupta, MD, led a discussion on the combination of immunotherapy and tyrosine kinase inhibitors for patients with advanced renal cell carcinoma in the second article of a 2-part series.


  • In the intermediate/high-risk cohort, what factors lead you to think the patient may progress? ​
  • What drives your selection of first-line therapy for favorable-risk clear cell metastatic renal cell carcinoma (mRCC)?

SHILPA GUPTA, MD: Between the available immunotherapy and TKI [tyrosine kinase inhibitor] combinations [for patients with mRCC], which is your preferred therapy?

Shilpa Gupta, MD

Shilpa Gupta, MD

Director of Genitourinary Medical Oncology

Taussig Cancer Institute

Co-leader of the Genitourinary Oncology Program

Cleveland Clinic

Cleveland, OH

PALLAVI JASTI, MD: Initially, I used axitinib [Inlyta] plus pembrolizumab [Keytruda] a lot because it was the first one on the market,1 but more recently, most of my patients are getting cabozantinib [Cabometyx] plus nivolumab [Opdivo].

BAIDEHI MAITI, MD: I wanted to add, if somebody has an active autoimmune disorder, I would factor that in [when choosing treatment] as well, and I wouldn't consider ipilimumab [Yervoy] plus nivolumab in that setting.

GUPTA: [In that case], would you only use a TKI and avoid immunotherapy altogether?

MAITI: It depends on how intense [the patient's autoimmune disorder] is and if I can work with...whoever is addressing that. So, I might use a TKI and pembrolizumab or the cabozantinib/nivolumab combination, but if there is an active autoimmune disorder, I'll probably avoid those altogether.


  • What are your key takeaways from recent data examining the use of TKI and immunotherapy combinations in this patient population?
  • What is your real-world experience with these regimens?

ANEEL CHOWDHARY, MD: There's a significant survival benefit [with these combinations], especially in intermediate- and poor-risk patients, but the reason we're losing that benefit is because of the immunotherapy, in my opinion. If you look at ipilimumab/nivolumab, the benefit in survival vs TKI is maintained...because [the patient is] on immunotherapy to begin with.2 I think that is the benefit that's carrying over. Patients on sunitinib [Sutent], for example, are getting on immunotherapy later and that survival benefit may be lost. But progression-free survival and the median duration of response are important parameters here, [and show] that these regimens are still very effective; it’s just that when you cross over to immunotherapy later...the [regimens] are losing some of the survival edge.

GUPTA: If you recall from the [CheckMate 9ER study (NCT03141177)], around 10% of patients discontinued cabozantinib due to adverse events [AEs] and discontinuation due to [AEs associated with] nivolumab was also around 10% to 11%.3 With lenvatinib [Lenvima], the discontinuation rate was 25.6%, and...we also see that patients who start at the 20-mg mandated dose [of lenvatinib]…28% are stopping pembrolizumab and 13% are stopping both,4 as opposed to less than 10% on [for those patients on] cabozantinib/nivolumab.3 So I think this is everybody's clinical experience too, and I don't think anybody in the group said they don't see these challenges with lenvatinib/pembrolizumab.

ALEXANDER BARSOUK, MD: For me, I will probably use more cabozantinib upfront. I've been using it [early and have had] a good experience. [I haven't] had much concern when...using cabozantinib in the second-line setting because there are strong data [for it and it's] associated with a good quality of life. In my personal experience, it's a good combination and user friendly, but sometimes you have to dose reduce the cabozantinib.

GUPTA: So you're saying early on that you would use only cabozantinib, but you are now a more open to using a doublet because of [these data]? Is that fair to say?

BARSOUK: Yes, before I would use a different doublet...[but earlier ones were] kind of toxic. Now I would use more cabozantinib/nivolumab and not worry about what to use in the second-line setting, because there are so many options available nowadays.

MAITI: I took up axitinib/pembrolizumab initially and got very comfortable with it, but now with the current data I have switched to cabozantinib/nivolumab.... For [patients with] symptomatic high disease burden, especially if they have liver metastases, I probably lean towards lenvatinib/pembrolizumab, but that will probably be the only situation. Otherwise, I would pick cabozantinib/nivolumab.

1. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. April 22, 2019. Accessed May 2, 2024.
2. Motzer RJ, Tannir NM, McDermott D, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277-1290. doi:10.1056/NEJMoa1712126
3. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384:829-841. doi:10.1056/NEJMoa2026982
4. Grünwald V, Powles T, Kopyltsov E, et al. Survival by depth of response and efficacy by International Metastatic Renal Cell Carcinoma Database Consortium subgroup with lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma: analysis of the phase 3 randomized CLEAR study. Eur Urol Oncol. 2023;6(4):437-446. doi:10.1016/j.euo.2023.01.010
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