Evolving Evidence Guides Treatment Selection for Favorable-Risk mRCC


During a Targeted Oncology™ Case-Based Roundtable™ event, Rana McKay, MD, moderated a discussion on key takeaways from frontline combination trial data in patients with metastatic renal cell carcinoma. This is the second of 2 articles based on this event.

Rana McKay

Rana McKay, MD

Associate Professor of Medicine

University of California San Diego​

San Diego, CA​


  • What are your key takeaways from the CheckMate 9ER (NCT03141177), KEYNOTE-426 (NCT02853331), and CLEAR (NCT02811861) study data?​
  • When immunotherapy (IO) and tyrosine kinase inhibitor (TKI) is preferred: ​
    • Does your choice of regimen vary based on patient profile? ​
      • What patient factors influence the choice?​
    • Do the updated data change your choice?​

RANA MCKAY, MD: What do you all take away from these data? Do you have an IO/VEGF-TKI combination of choice? If so, what is it and why?

ROBERT YOO, DO: I think they all have survival benefit. They’re equal choices for patients with intermediate or poor risk. I get referrals from neurosurgeons and [these patients] all have brain metastases. For my practice, there has been a dilemma whether I do ipilimumab [Yervoy] plus nivolumab [Opdivo] for patients with intermediate- to poor-risk disease and untreated brain metastases with treatment of stereotactic radiosurgery vs cabozantinib [Cabometyx] plus nivolumab. We have more data of response from cabozantinib from a previous single-arm trial.1 But I’m OK with it either way. I don’t think there’s clear superiority for my practice with the patients predominantly with brain metastases, but cabozantinib/nivolumab seems to be the go-to choice because there are more data for brain metastases. [I am comfortable] with cabozantinib, although I struggle with the 40 mg [dose]. Sometimes I get better luck with 20 mg and most patients tolerate reasonably, unless a patient develops some hepatitis and diarrhea.

MING ZHOU, MD: In the CLEAR study data, was there a reason the third arm [was not included in analyses]?

MCKAY: The predominant reason is that arm was slightly positive for progression-free survival, but had no difference for overall survival [OS]; it trended in the worse direction, so it’s not a viable frontline treatment option.2 A lot of the analyses have left out the interpretation of lenvatinib [Lenvima] plus everolimus [Afinitor] given the lack of an OS benefit.

ZHOU: Based on CheckMate 9ER, because there is no [comparator] arm of single-agent cabozantinib compared with sunitinib [Sutent], do you think the favorable-risk group [benefited] because cabozantinib is a better TKI than sunitinib or is the advantage in PFS and OS because of the combination?

MCKAY: That’s a very good question about the patients with favorable risk. The PFS is substantially better over sunitinib.3 The response rates are also substantially better over sunitinib. The question is, is there a benefit from an OS standpoint? That is a little harder to tease out. These favorable-risk patients do well and will likely go on to receive multiple lines of therapy, which will end up coloring the OS signal. We need to keep in mind that these studies were not powered to do a robust statistical analysis specifically in the subgroup of favorable-risk patients.

Not everybody needs therapy right away; I watch a lot of my patients with favorable risk, and I may do metastasis-directed therapy [such as] stereotactic body radiotherapy. But eventually you come to a point where their burden of disease has increased to the level that they need systemic treatment. A lot of times when I’m instituting therapy, I use IO/VEGF-TKI doublets, or [sometimes] IO/IO doublets even for favorable risk…over sunitinib, because IO therapy does not work as well post VEGF-TKI exposure. We’ve learned that the response rates are much higher in VEGF-naive patients than in VEGF-exposed patients, and [I also tend to use doublet therapy] because of this issue with limitations of the data and being able to tease out OS.

ZHOU: Is there always a value for introducing IO, either as combination IO or IO/TKI in the frontline, even in the favorable-risk [group]?

MCKAY: We [did not yet discuss] the nivolumab/ipilimumab data for favorable risk, but this was presented [recently] with 8-year follow-up data from CheckMate 214 [NCT02231749]. The data for favorable-risk patients look outstanding.4 The thing about the favorable-risk patients is, [often] you have time. You don’t have somebody in visceral crisis before you [in whom] you can’t afford a primary progressive disease rate of [nearly] 20% like with nivolumab/ipilimumab.4 A lot of the favorable-risk patients—it’s not to say you can’t afford that, but you’re not in that position. But you want to try to cure your patient. So there’s that tug of war that happens.

ZHOU: Looking at both [Kaplan-Meier] curves specifically in the favorable-risk group, there is a tail even on sunitinib where they don’t progress.3 I think that we are not there yet, but are there any biomarkers that can guide us to not overtreating all the patients with IO and TKI? Is there a group of patients who you observe or [in whom] even the older TKI can produce that flat line at the tail of the curve? Are there any biomarkers that help you at this time, or are you indiscriminately giving IO/TKI?

MCKAY: I wish we did [but] we don’t at the present time. There has been a lot of work done regarding RNA signatures, angiogenic signatures, and immune signatures, and I think [a reason] why favorable-risk patients tend to do quite well with VEGF inhibition is that a large proportion of those patients have very angiogenic tumors. But there are some patients who have T-effector–high signature that likely do well with IO. But at the present time, these signatures are not something that’s utilized in the clinic for treatment decision making, though, potentially in the future, we can work towards having more biomarkers in this setting.

IMDC [International Metastatic RCC Database Consortium] risk was not designed to predict outcomes of therapy. The IMDC risk groups are prognostic scores; they are not predictive scores by any means. The integration of the IMDC risk [groups] into these studies has created confusion around using the IMDC risks for as predictive markers, which they’re not.

DARSHIL SHAH, MD: Looking at the data, cabozantinib/nivolumab seems to be the go-to for all risk types, but in my experience axitinib [Inlyta] plus pembrolizumab [Keytruda] is better tolerated. All 3 [treatments] are category 1.5 Patient characteristics matter, but for patients with intermediate to poor risk, I would prefer cabozantinib/nivolumab, or lenvatinib plus pembrolizumab if the patient has good performance status because the complete response rate of 18% is encouraging in that population.2 There is not a clear answer; it depends on many variables.

ZHOU: Where I practice…the pathway calls for axitinib/pembrolizumab, but it sounds like cabozantinib/nivolumab may be a better option. What are your thoughts on that?

MCKAY: It’s likely that these combinations are more similar than they are dissimilar. But the lower dose of the cabozantinib makes that an attractive agent combination. The quality of life was a little better with cabozantinib/nivolumab,6,7 the AE profile is very manageable, response rates were robust, and primary progressive disease rates were quite low.3 I think it’s an excellent regimen.

The key is getting a regimen that that you’re comfortable using, that you know how to modulate the dose or titrate the dose. If patients are having toxicity, it’s very easy to titrate cabozantinib, drop them down to 20 mg [daily or] 20 mg every other day. Sometimes you can even adjust the dose on days of the week. I have some patients who [receive] 40 mg 3 times a week, 20 mg the remaining days of the week.

Lenvatinib can sometimes be tricky. Patients start at 20 mg, which is a pretty high dose. Almost 70% of patients need a dose reduction on lenvatinib, and then you drop them down from 20 mg to 14 mg to 10 mg to 8 mg.2 The dosing is interesting. They have to get new pill packs, so there can be a little bit of [difficulty].


1. 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

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

3. Bourlon MT, Escudier B, Burotto M, et al. Nivolumab plus cabozantinib (N+C) vs sunitinib (S) for previously untreated advanced renal cell carcinoma (aRCC): Results from 55-month follow-up of the CheckMate 9ER trial. J Clin Oncol. 2024;42(suppl_4):362. doi:10.1200/JCO.2024.42.4_suppl.36

4. Tannir NM, Escudier B, McDermott DF, et al. Nivolumab plus ipilimumab (NIVO+IPI) vs sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC): Long-term follow-up data from the phase 3 CheckMate 214 trial. J Clin Oncol. 2024;42(suppl_4):363. doi:10.1200/JCO.2024.42.4_suppl.363

5. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 2.2024. Accessed February 7, 2024. http://tinyurl.com/3f4zyez9

6. 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

7. 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

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