Selecting IO/TKI Therapy for mRCC Based on Patient Profile


During a Targeted Oncology™ Case-Based Roundtable™ event, Deepak Kilari, MD, discussed with participants their impressions of tyrosine kinase inhibitor plus immune checkpoint inhibitor trials for patients with metastatic renal cell carcinoma.

Kilari headshot

Deepak Kilari, MD (Moderator)

Associate Professor

Medical College of Wisconsin

Cancer Center - Froedtert Hospital

Milwaukee, WI


  • What are your perspectives on the CheckMate 9ER (NCT03141177), KEYNOTE-426 (NCT02853331), and CLEAR (NCT02811861) study data?​
  • When you think about the IO/TKI (immunotherapy/tyrosine kinase inhibitor) combination regimens for favorable-risk metastatic renal cell carcinoma (mRCC), what differentiators come to mind?
  • Thinking about each combination, what patient profile comes to mind? ​

DEEPAK KILARI, MD: Each of these trials did a great job in looking at quality-of-life indices. They all had different ways of looking at quality of life [and we] cannot compare 1 trial to another. It’s noteworthy to highlight that the quality of life for the axitinib [Inlyta] plus pembrolizumab [Keytruda] compared with sunitinib [Sutent] was similar.1 But what was interesting to me at least was that cabozantinib [Cabometyx] plus nivolumab [Opdivo] was better than sunitinib when they measured the quality of life using FKSI-19 [Functional assessment of cancer therapy-Kidney Symptom Index] and EQ-5D-3L [European Quality of Life 5 Dimensions 3 Level Version].2 Cross-trial comparison is not to be done but if you look at it, it looks like cabozantinib/nivolumab improved quality of life compared with sunitinib, whereas the combinations in the KEYNOTE-426 and the CLEAR studies had a similar quality of life compared with sunitinib.1,3

JONATHAN S. TREISMAN, MD: With the lenvatinib [Lenvima] data, the risk groups seem to vary a lot in terms of benefit, right?

KILARI: Yes. There was difference in benefit for each of these patients.4

TREISMAN: Does that push you in any way to the different combinations?

KILARI: I don’t think so because they’re subgroups. They’re not planned subgroup analyses. It’s interesting to note where things are, but I would not change my management based on the subgroup analysis because they were not powered to…see [if] this is a better option or not.

TREISMAN: The [Kaplan-Meier] curves for sunitinib seem to vary between the trials significantly. Could you overlap the sunitinib data to see the differences?

KILARI: I think sunitinib probably performed similarly across all 3 trials. We were not surprised by the results of sunitinib by itself, at least in my opinion. To me, if I look at the outcomes with sunitinib and all 3 arms, I don’t think there was 1 trial had a better benefit with sunitinib versus the other.

PAVAN BHAMIDIPATI, MD: I recently had a patient with sarcomatoid differentiation, and [I’ve read that] ipilimumab [Yervoy] plus nivolumab has more data than cabozantinib/nivolumab. Which regimen do you normally pick in these patients with sarcomatoid differentiation? A second question is, what is the role of nephrectomy?

KILARI: For patients with sarcomatoid [differentiation], if I think that they have some wiggle room, I probably will try ipilimumab/nivolumab. [However] if they come in in a wheelchair, I know that I have only one chance…[so] I’d probably try a VEGF-TKI/IO combination and cabozantinib/nivolumab rather than IO/IO.

In terms of your second question as to who is the right candidate for nephrectomy, we all acknowledge that the CARMENA [NCT00930033] and SURTIME [NCT01099423] trials completely [turned] the field upside down. It was what we were doing for all patients when we first started off. Everybody would get nephrectomy. Now nobody gets nephrectomy. I think that’s probably not the right thing to do as well.

There are 2 trials that are trying to answer this question. One of them is the SWOG S1931/PROBE trial [NCT04510597] looking at starting off with systemic treatment and then randomly assigning them to [cytoreductive nephrectomy] versus no surgery. The problem for that trial is there are some patients that don’t like being randomly assigned and…there are some patients who we think are not the right candidates.

There’s a trial [SAMURAI; NCT05327686] that William A. Hall, MD, from our site [at the Medical College of Wisconsin] is leading, looking at radiation therapy instead of surgery and radiating the primary site. That is also a very interesting question, and patients are more interested in radiation therapy rather than surgery because it’s less aggressive.

We don’t know the right answer. If you were to ask me who I would recommend go through a nephrectomy, I would say that…if the disease burden is mostly in the kidney and if they have stable disease or complete response [CR], probably at the 12-month mark, those are the patients whom I will recommend taking out the kidney.

BHAMIDIPATI: That’s very helpful. In the cabozantinib/nivolumab study, it came to my attention that in the subgroup analysis in patients who underwent nephrectomy, there was no benefit.5 Although there is some trend towards improvement it crossed the midline.

KILARI: I think these questions are all hypothesis generating in the sense that they have such small groups, but irrespective of whether they had nephrectomy or no nephrectomy, I’d still offer it.

But you’re right—[should] we come up with a hypothesis based on what the forest plots are? That’s how we ask ourselves the next question, but at this point, for me, it’s been all-comers. I think it’s a reasonable thing to do, and after 12 months or so, if you see good response elsewhere in their disease burden…it’s reasonable to offer it.

We’re trying to do studies to see if we can predict who [gets a CR in their kidney], because sometimes the kidney might still have a mass there and we won’t know if they have a CR. That is another thing that we’re trying to explore and find answers for.


1. Bedke J, Rini BI, Plimack ER, et al. Health-related quality of life analysis from KEYNOTE-426: pembrolizumab plus axitinib versus sunitinib for advanced renal cell carcinoma. Eur Urol. 2022;82(4):427-439. doi:10.1016/j.eururo.2022.06.009

2. Cella D, Motzer RJ, Suarez C, et al. Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(2):292-303. doi:10.1016/S1470-2045(21)00693-8

3. Motzer R, Porta C, Alekseev B, et al. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022;23(6):768-780. doi:10.1016/S1470-2045(22)00212-1

4. 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

5. Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

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