Physicians Debate Role of Metastatic Sites in Treating Favorable-Risk RCC

Peers & Perspectives in OncologyJune 2023
Volume 1
Issue 1
Pages: 48

During a Targeted Oncology™ Case-Based Roundtable™ event, Elizabeth M. Wulff-Burchfield, MD, and participants discussed the choice of frontline options for a patient with favorable-risk clear cell renal cell carcinoma, and how liver or lung metastases affect the decision.

Wulff-Burchfield headshot

Elizabeth M. Wulff-Burchfield, MD (Moderator)

Assistant Professor of Medicine

University of Kansas Medical Center

Kansas City, KS


The patient is a 61-year-old man with an active lifestyle and a history of low-volume, indolent, metastatic clear cell renal cell carcinoma (mRCC). After left nephrectomy and adrenalectomy, he was observed based on his preference as well as on low volume and indolence of disease.

Three years after surgery, continued indolent growth and increased total tumor burden (new paratracheal lymph nodes [2.0 × 1.5 cm] and more than 10 pulmonary nodules) were seen on CT. A lung biopsy confirmed mRCC. Laboratory results were within normal limits, and ECOG performance status was 0.


Armen Asik, MD
Owen Pickus, DO
Jaykumar Thumar, MD
Peter Georges, MD
Philip Brooks, MD
Mark Shparber, MD
Robert Koch, MD
Madhavi Gorusu, MD
Shail Maingi, MD
Prabhsimranjot Singh, MD

polls: frontline therapy


  • Why would you change/not change your approach based on sites of metastases?

WULFF-BURCHFIELD: If you gave 2 different answers, could you share your rationale? What, specifically, drove your decision and what did you change to?

ASIK: I would change from a single-agent TKI [tyrosine kinase inhibitor] to axitinib [Inlyta] plus pembrolizumab [Keytruda]. Initially, it was limited-volume disease with no risk factors, so I would have gone with a single-agent IO [immune-oncology] or single-agent TKI, like axitinib or cabozantinib [Cabometyx]. If there are more than 2 sites of metastases [including] the lung and liver, it is a high disease burden involving vital organs, and that is why I would switch to pembrolizumab plus axitinib.

PICKUS: The reason [I would also] switch is because no one lives with RCC metastatic to the liver for 5 years. It is essentially a death sentence, and the best treatment we have…is ipilimumab [Yervoy] plus nivolumab [Opdivo] or something similar. I would make it clear to the patient that…their chances of living to 66 years with liver metastases with this disease is 0%. I would recommend what I think is the most efficacious treatment.

THUMAR: I would also switch, [although] I know just adding liver metastases won’t change the [risk] score. He still has favorable risk, even with the liver metastasis.


THUMAR: We have been giving TKI with IO in other diseases. Lenvatinib [Lenvima] or cabozantinib are for somebody who has good performance status and is active and enjoying life. I have experience with ipilimumab plus nivolumab, which is very tolerable for most patients. Of course, with the liver metastasis, we want to nudge him to a CR [complete response], so that’s why I would switch to ipilimumab plus nivolumab, which is much more tolerable, in my experience, compared with any IO…[and] TKI combination.

GEORGES: For favorable-risk disease, any combination of IO plus TKI would be reasonable. If the patient has bone metastases, there are more data for a cabozantinib plus nivolumab combination.1 That’s why I favored that combination. Otherwise, [I would decide] based on experience, adverse effects, discussion with the patient, and what the insurance will cover.

WULFF-BURCHFIELD: This patient [would] still have favorable-risk disease despite having liver metastases. Some of my colleagues, like Rana McKay, [MD], who is at UCSD [University of California, San Diego], have advocated for updating the IMDC [International Metastatic RCC Database Consortium] risk criteria to reflect different sites of metastatic disease. But that is not where the trial data are. Would anyone advocate for using the same regimen in both situations?

BROOKS: There are multiple regimens, and they haven’t been compared side-by-side, so it’s hard to compare. I tend to use ipilimumab plus nivolumab. I have a lot of experience with checkpoint inhibitors. I know how to manage the toxicities, and it doesn’t add the toxicities of 2 different kinds of agents.


  • Does risk status influence your first-line decision-making in a patient like this?
  • What about for patients on the borderline, between favorable and intermediate risk?
  • What are the primary factors that drive your selection of first-line therapy for patients with favorable-risk clear cell mRCC?

SHPARBER: All the [ frontline IO/TKI] studies are suspect. They compared the experimental drug with [sunitinib (Sutent),] which nobody uses. The patient population is not the same [across these trials]. Personally, I have a very hard time choosing the [IO/TKI] regimens that these trials use. I am very familiar with ipilimumab plus nivolumab. I think it is a great regimen. I know the toxicities, and that is my primary regimen.

KOCH: If you have a young patient, then you should look at the CR data, as opposed to a patient who is 89 years old, where you look at the PFS [progression-free survival]. The response rates probably play the greatest role in terms of my selection of a regimen.

BROOKS: I feel differently. Balancing OS [overall survival] and toxicity is how I would do it.

GEORGES: I agree with you. I look at OS, and I have been looking at toxicity too.

GORUSU: I would go with OS. No matter what, the patient doesn’t have disseminated disease, and he is still…relatively young. I always see the first chance as a golden chance, rather than thinking of later lines of treatment. It depends on how familiar you are with lenvatinib and pembrolizumab. That has been my recent go-to regimen, but I have tried other combinations too. One picks what they are more comfortable with, and how they manage the toxicities. But, [superior] OS is the golden outcome.

THUMAR: We all try to use scoring, if not on paper, at least in our mind. We are looking at the site of disease and performance status. Everybody does that to some extent. We look at hypercalcemia, lactate dehydrogenase, hemoglobin, [etc]. But at the end of the day, I am clearly looking for the regimen that is going to give my patient a better quality of life [QOL], and hopefully a response. The CR rates didn’t have much difference across the regimens [From the Data2-5]. It’s not that huge of a difference between the TKI plus IO [and]…the IO combination. If you are choosing a regimen based on…CR rate, there isn’t that much of a difference. I think it boils down to performance status and QOL and what your goal is for your patient. But I do risk-stratify all my patients.

data: complete responses in RCC

WULFF-BURCHFIELD: What about if the patient has either liver or brain metastases, or comorbidities? Does that factor into your risk assessment?

I realize that may not fit, necessarily, into IMDC or MSKCC [Memorial Sloan Kettering Cancer Center] risk scores, but is that something you are incorporating into your assessment of…risk for the patient? Or is it more related to your perception of their toxicity experience?

MAINGI: I don’t necessarily [consider those factors]. They could all get through as many lines of therapy. That’s why I’m looking for a response rate and I’m looking at performance status. It is shared decision-making. The problem that I have is the sequencing. If I do ipilimumab plus nivolumab first, am I going to get the same efficacy later when I want to do immunotherapy combined with a TKI?

PICKUS: There has been a lot of discussion about OS. The older the patients are, the more nebulous that term becomes, and PFS becomes the gold standard, not OS, because patients in their 70s and 80s with RCC or other malignancies are likely to die from another disease. Therefore, it makes it less interpretable to determine whether the therapy has or has not been effective when they die from a heart attack, stroke, or from some other…disorder.


  • What are your perspectives on the data from CheckMate 9ER (NCT03141177), KEYNOTE-426 (NCT02853331), and CLEAR (NCT02811861)?
  • When choosing a regimen for favorable-risk disease, what differentiation do you make among these regimens?

THUMAR: I am focusing on the TKI plus IO. I feel the 3 TKIs tend to have similar toxicity. I accept that there is some opinion in the community that axitinib is more tolerable. Cabozantinib at 40 mg is clearly tolerable at least, because I have used it for HCC [hepatocellular carcinoma] and other conditions.

I don’t think anybody can handle cabozantinib 60 mg. I think 40 mg makes sense. But compared with ipilimumab plus nivolumab, a TKI plus IO clearly has more toxicity and requires a lot of frequent follow-ups, supportive care, and dose interruptions.

BROOKS: Can you remind us what the dose of lenvatinib was in this [CLEAR] study?

WULFF-BURCHFIELD: It was 20 mg in the lenvatinib and pembrolizumab arm.

BROOKS: My experience with lenvatinib at that dose has been [poor]. I have had to get patients down to 4 mg, and I’ve had to take them off it. I would be interested in what others think, but 20 mg [in] my limited experience has not been very favorable.


SINGH: I agree…. Lenvatinib at 20 mg is difficult to tolerate. All the trials compared it with sunitinib. TKIs are old drugs. We always need to consider the patient’s adherence, and their co-payment, which can sometimes be a limiting factor. Getting the drug to the patient and keeping them on it sometimes has been an issue, especially in…January, when they are finishing their old payments and…have a big payment to make to meet their deductible.

Otherwise, an IO plus IO combination is reasonable to use in a patient who is not able to tolerate a TKI. But in a fit patient with some tumor disease burden, I try to use a combination of IO and TKI, like nivolumab and cabozantinib, just because of its better durable response and better QOL.


  • Do the toxicity data for these regimens reflect your real-world experience?
  • Based on data from these trials, how likely are you to change the regimen you prescribe for favorable-risk mRCC?

THUMAR: I have yet to find any patient who has handled lenvatinib 20 mg. I don’t even start them on 20 mg. But clinical trial patients tend to have better performance status, even an ECOG performance status of 0. Sometimes [patients] don’t have tolerance to these drugs.

GORUSU: All these regimens are good choices, depending on the patients in front of you and how you work around their doses. I don’t think one answer fits all. We all have a regimen that we want to use, but many times we prefer looking at the patient in front of us.


  • If this patient develops disease progression on first-line cabozantinib plus nivolumab, what are you likely to recommend as next-line therapy?

GEORGES: I would probably go with either lenvatinib as a single agent or, if they are fit, lenvatinib plus everolimus [Afinitor,] and see how they do. A limited option is TKI plus IO. If somebody is young and fit and can tolerate it, it’s worth a try, but I have a low threshold to discontinue one of the drugs if they are not doing too well on the combination.

THUMAR: I might try ipilimumab plus nivolumab as a second regimen, or a clinical trial.

BROOKS: Are there data for ipilimumab plus nivolumab use after nivolumab and a targeted agent?

WULFF-BURCHFIELD: We certainly don’t have any frontline or any second-line trial data. But I hear that it is done, and there were some data presented at ASCO [American Society of Clinical Oncology Annual Meeting] 2021 about [ipilimumab/nivolumab after progression on single-agent nivolumab induction].6


1. Apolo A, Powles T, Bourlon MT, et al. Nivolumab plus cabozantinib vs sunitinib in patients with advanced renal cell carcinoma and bone metastasis: subgroup analysis of the phase 3 CheckMate 9ER trial. Presented at: 2021 International Kidney Cancer Symposium; November 5-6, 2021; Austin, TX. Abstract N22.

2. Motzer R, Tannir N, McDermott D, et al. Conditional survival and 5-year follow-up in CheckMate 214: first-line nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma. Presented at: 2021 European Society for Medical Oncology Congress; September 16-21, 2021; Virtual. Abstract 661P.

3. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470- 2045(20)30436-8

4. 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

5. 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

6. Grimm MO, Esteban E, Barthélémy P, et al. Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC). J Clin Oncol. 2021;39(suppl 15):4576. doi:10.1200/JCO.2021.39.15_suppl.4576

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