Using Risk Stratification to Determine Frontline Treatment for ccRCC


During a live virtual event, Robert J. Motzer, MD, discussed the role of risk assessment in treating a patient with clear cell renal cell carcinoma. This is the first of 2 articles based on this event.


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


A 59-year-old African-American woman received a diagnosis of clear cell renal cell carcinoma (RCC)​. She underwent left radical nephrectomy, but 9 months later, she developed metastatic disease to both lungs, mediastinum (35 x 38 mm), and retroperitoneal lymph nodes​. She received a diagnosis of stage IV clear cell RCC, with metastases to lungs and retroperitoneum​. Her Karnofsky performance status was 90%; hemoglobin level was 11.1 g/dL; and corrected calcium, neutrophils, and platelets were within normal limits.


  • How do you assess patient risk? ​Does risk status influence your frontline decision making for a patient like this?​
  • Would you initiate systemic therapy at this point? ​

ROBERT J. MOTZER, MD: Do you find the IMDC [International Metastatic RCC Database Consortium] Group risk system to be helpful in your own management of patients?

KASHIF ALI, MD: I’m from Maryland Oncology, one of the large private practice groups in the area. We see quite a lot of patients with RCC. We’ve also had a few large clinical trials that we’ve been part of for these patients. I can tell you…80% of people that are going to present to you are going to have intermediate or poor risk, so it makes a difference. In fact, it’s hard for me to find a favorable-risk patient these days. I get very few favorable-risk patients in a whole year. I might get 15 intermediate or poor risk before I get 1 with favorable risk…. Everybody has some degree of anemia, and it doesn’t take much to find 1 risk factor in most of my patients. It helps from a prognostic standpoint, but it may not help that much from a treatment standpoint because my first line generally is ipilimumab [Yervoy] plus nivolumab [Opdivo]. That’s been my go-to for a very long time, partly because we are part of some of the ipilimumab/nivolumab trials. It’s helpful but doesn’t change my treatment [plan] much.

MOTZER: Right, it’s a part of your evaluation but it has limited usefulness. I think that’s a pretty good assessment. One of the other points about kidney cancer is whether all patients need to be started on systemic therapy immediately at diagnosis or whether, in some patients, active surveillance can be utilized or is initially part of your treatment plan. Do you start therapy on all patients immediately or, [for] some patients, do you perform active surveillance?

ARIF HUSSAIN, MD: This is Dr Hussain from the University of Maryland Greenbaum Cancer Center. I was part of a couple of papers that were published with Daniel A. George, MD’s group, the MaRCC [Metastatic Renal Cell Carcinoma] Registry.1 This is a question that was asked in terms of time to treatment initiation, and I do [observation] in my practice—I’m in an academic environment—but it’s not a kneejerk that you need to start patients right away on systemic therapy. Certainly, risk stratification does help, and in our practice we also generally see patients who are more intermediate to advanced. But, certainly, this concept of not necessarily starting right away is out there and that was part of this registry that we published.

MOTZER: I’m aware of that. That’s a high-quality registry that you published with Dr George from the real-world data. One of the things that has always distinguished RCC is a variable natural history that is different than many other cancers, like pancreas cancer and so forth. Some patients have very indolent, slow-growing disease, and so…back when there was a lack of systemic therapy, rather than giving them cytokines, particularly high-dose interleukin-2, they would be watched, and certainly a subset will do well for a long time and delay the toxicities to treatment. I still think…not everybody needs to start systemic therapy. Some patients can have a delayed approach, and I think it also is impacted by the patient’s comorbidities. There’s more of a tendency to hold off on systemic therapy unless the tumor is becoming aggressive. For this patient though, they have relatively rapidly growing disease, multiple sites, and it is fairly bulky.

A decision was made to initiate systemic therapy. What frontline therapy are you most likely to choose for this patient?


MOTZER: [In the poll], there’s a split between ipilimumab/nivolumab and the tyrosine kinase inhibitor [TKI] plus immunotherapy [IO] regimens, with axitinib [Inlyta] plus pembrolizumab [Keytruda] being the predominant one. I think that’s a very good distribution.

[Looking at the] National Comprehensive Cancer Network [NCCN] guidelines, for favorable-risk patients, the preferred category 1 are the TKI/IOs, and they’re all there: axitinib/pembrolizumab, cabozantinib [Cabometyx] plus nivolumab, lenvatinib [Lenvima] plus pembrolizumab.2 One of the differences for using the risk group to direct therapy is that the CheckMate 214 trial [NCT02231749] with ipilimumab/nivolumab versus sunitinib reached positive outcomes in the poor/intermediate group, which was the primary group that was studied in that trial.3 So the label for ipilimumab/nivolumab is for poor- and intermediate-risk patients.

One way to distinguish treatment would be that ipilimumab/nivolumab is a good option in poor/intermediate patients and probably doesn’t have the same level or the same strength in those with favorable risk. The NCCN helps to guide us in choosing therapy for our patients. Now, for poor and intermediate risk, all the TKI/IOs are listed as category 1 as well.3 The exception is axitinib plus avelumab [Bavencio], which reached its primary end point of PFS, but there was no OS benefit.4 And so it has not been considered to have the high level of efficacy that the anti–PD-1/TKI combinations have.


1. Costello BA, Bhavsar NA, Zakharia Y, et al. A Prospective Multicenter Evaluation of Initial Treatment Choice in Metastatic Renal Cell Carcinoma Prior to the Immunotherapy Era: The MaRCC Registry Experience. Clin Genitourin Cancer. 2022;20(1):1-10. doi:10.1016/j.clgc.2021.07.002

2. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 2.2023. Accessed September 21, 2022.

3. Motzer RJ, Tannir NM, McDermott DF, et al. 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):S685-S687. doi:10.1016/j.annonc.2021.08.057

4. Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31(8):1030-1039. doi:10.1016/j.annonc.2020.04.010

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