Risk Groups Vital to Interpreting Results of RCC Immunotherapy Trials


During a Targeted Oncology™ Case-Based Roundtable™ event, Robert J. Motzer, MD, examined the impact of the CheckMate 214 and CheckMate 9ER trials of nivolumab/ipilimumab and nivolumab/cabozantinib in patients with advanced renal cell carcinoma. This is the first of 2 articles based on this event.

Robert Motzer

Robert J. Motzer, MD

Section Head, Kidney Cancer, Genitourinary Oncology Service

Jack and Dorothy Byrne Chair in Clinical Oncology

Memorial Sloan Kettering Cancer Center

New York, NY

Targeted Oncology: What are the recommended regimens for patients with clear cell renal cell carcinoma (RCC)?

ROBERT J. MOTZER, MD: The more recent National Comprehensive Cancer Netowrk guidelines for first-line therapy for clear cell RCC for poor-intermediate risk patients [include] axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], ipilimumab [Yervoy] plus nivolumab, and lenvatinib [Lenvima] plus pembrolizumab as category 1 preferred.1 The difference between poor/intermediate and favorable risk treatment is that ipilimumab/nivolumab has moved over to ‘other recommended regimens’. The reason for that…[is] the primary end point with that trial was in the patients with intermediate- and poor-risk disease. There was some suggestion, particularly with response rate and so forth, that tyrosine kinase inhibitors [TKIs] did better in the favorable-risk population. That’s the difference and it’s based on the IMDC [International Metastatic RCC Database Consortium] risk group. There was originally a risk category that we established at Memorial Sloan Kettering Cancer Center, which divided patients into favorable, intermediate, and poor [risk]. That’s been modified slightly, [and] that’s referred to as the IMDC. That’s the distinction here for whether or not ipilimumab/nivolumab has a similar recommendation as TKI plus IOs [immunotherapies].

Could you describe the design and goals of the phase 3 study of ipilimumab plus nivolumab?

The CheckMate 214 study [NCT02231749], which resulted in an approval for ipilimumab/nivolumab, was open for all patients, but it was primarily directed to intermediate- and poor-risk patients; that was the primary end point. The proportion of patients with favorable risk was capped, so there were some data obtained, but it was not primarily directed at that group. The ipilimumab/nivolumab dosing is standard dosing [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg] with the nivolumab and ipilimumab given together as a doublet every 3 weeks for 4 doses and then nivolumab monotherapy after that. Sunitinib was given as a standard dosing schedule [50 mg once daily] for 4 weeks on, 2 weeks off.

What were the results of CheckMate 214 for patients with RCC?

Sunitinib had been the standard of care since its approval in April 2006. This was the first time that immune combination was compared with sunitinib and showed better results, resulting in a change in paradigm from TKI therapy to immune checkpoint combinations.2 There was an overall survival [OS] benefit that’s associated with ipilimumab/nivolumab, as well as a benefit with progression-free survival [PFS]. [Response data showing a 41% overall response rate with the combination vs 34% with sunitinib] are in the intent-to-treat population, which did include the favorable-risk patients.3 These are not the primary end point results. These are more recent data that we reported with long-term follow-up. One of the advantages of ipilimumab/nivolumab is that there is leveling off of the Kaplan-Meier curve with PFS, suggesting a durable benefit [31% PFS rate at 60 months with the combination vs 11% with sunitinib].3

What led to the approval of cabozantinib plus nivolumab in this population?

The other combination that was approved before lenvatinib/pembrolizumab was cabozantinib and nivolumab. That was approved based on the CheckMate 9ER trial [NCT03141177]. There were similar criteria, all comers for the TKI/IO, [where] patients with clear cell histology were randomly assigned [on a 1:1 basis] to nivolumab/cabozantinib vs the standard dose of sunitinib…. [Nivolumab] was given every 2 weeks in the trial, but most of us now give every 4 weeks. The other thing is the cabozantinib is given at a lower dose than that which is recommended as monotherapy in either first- or second-line therapy, with 40 mg [daily].

What recent data are available from CheckMate 9ER?

The most recent update of that trial hit the primary end point of showing an improvement in PFS.4 This was statistically significant in the primary end point and the median PFS was about doubled with nivolumab/cabozantinib vs sunitinib. There was surely a strong signal for efficacy with CheckMate 9ER. The most recent update was presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium this [January].5 Also, OS benefit showed clear separation of the curves over time for cabozantinib/nivolumab compared with sunitinib.4

What therapies are favored for the risk groups based on these trials?

There’s benefit in PFS for TKI/IO, in this case, cabozantinib/nivolumab, in favorable and in intermediate/poor-risk groups. But there also seems to be an OS benefit in the subset with intermediate/poor, but there isn’t with favorable risk. The favorable-risk group has been the one that’s the most debatable for treatment. Should they get TKI monotherapy; should they get TKI/IO; should they get ipilimumab/nivolumab? The discussion is around the improvement in PFS, but not in OS. In fact, the favorable-risk patients make up a relatively small minority on the [CheckMate 9ER] trial; about 20%. The trials aren’t powered to show a benefit in favorable risk. The favorable-risk patients seem to do well on various therapies. My take on this is, I give TKI/IO in favorable-risk patients in general, because the success rate seems to be the highest. But it’s a little bit of a controversial area.

What adverse events are of most concern in patients receiving nivolumab plus cabozantinib, and which drug is responsible?

[Looking at] those adverse events that occurred more than 20%...for the most part, it reflects the TKI. With cabozantinib, the main ones are diarrhea and skin toxicity, which is no surprise for us. There’s less hypertension than the lenvatinib/pembrolizumab, probably because the cabozantinib is given at a lower dose, but also there’s less hypertension with cabozantinib than lenvatinib and liver toxicity is a known issue that we see with this particular program.6 It’s a different toxicity profile. I think you have to get your own experience with these different programs with your own patient population and reach your own decision in terms of which one you prefer. But I’ve had a fair amount of skin toxicity over time with this particular regimen, and I think that’s an issue.


1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 2.2024. Accessed February 21, 2024. http://tinyurl.com/3f4zyez9

2. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

3. Motzer RJ, Tannir NM, McDermott DF, et al. 661P - Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Ann Oncol. 2021;32(suppl_5):S678-S724. doi:10.1016/annonc/annonc675

4. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl_6):603. doi:10.1200/JCO.2023.41.6_suppl.603

5. 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

6. 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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