Reviewing the Choice of First-Line Combinations for Clear Cell RCC and Other Histologies


During a live virtual event, Ulka N. Vaishampayan, MBBS, discussed the choice of first-line therapy for clear cell renal cell carcinoma and whether the approach to treatment would change with other disease histologies.

Ulka Vaishampayan

Ulka N. Vaishampayan, MBBS

Clinical Professor, Internal Medicine

Director, Phase I Program

Rogel Cancer Center

University of Michigan

Ann Arbor, MI


The patient is a 61-year-old man who is married with 2 grown children and 5 grandchildren who live nearby. He has an active lifestyle including daily walks and golfing regularly. He has a history of metastatic renal cell carcinoma (mRCC) and had a left nephrectomy and adrenalectomy due to clear cell RCC (ccRCC) with metastases in the adrenal​ gland.

Four years later, he has a recurrence of lung nodules with biopsy consistent with ccRCC. In retrospect, this had been present on scans for at least 2 years prior​. He was observed based on low volume and indolency of the disease and patient preference​.

Eighteen months later, there is continued indolent growth on scans, increased total tumor burden, and a new paratracheal lymph node metastasis that is 2.0 x 1.5 cm. He has an ECOG performance status of 0.​

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

Axitinib plus pembrolizumab
Cabozantinib plus nivolumab
Lenvatinib plus pembrolizumab
Nivolumab plus ipilimumab
Single-agent tyrosine kinase inhibitor

If this patient had 2 or more sites of distant metastasis (eg, lung and liver), what first-line therapy would you most likely recommend?

Axitinib plus pembrolizumab
Cabozantinib plus nivolumab
Lenvatinib plus pembrolizumab
Nivolumab plus ipilimumab
Single-agent tyrosine kinase inhibitor


  • Would your choice of therapy change in based on the number of metastases? Why or why not?

MANISH SHETH, MD: I initially chose lenvatinib [Lenvima] plus pembrolizumab [Keytruda] because [the CLEAR study; NCT02811861] had the highest progression-free survival compared with other trials.1 But in my practice, I’ve seen cabozantinib [Cabometyx] plus nivolumab [Opdivo] has been tolerated better than lenvatinib/pembrolizumab, so I usually start patients on cabozantinib/nivolumab. I think that if you look at long-term data on doublet immunotherapy, 30% to 35% of patients still had a good response after many years.2 So, if patient has more organ involvement or more metastatic sites, I decided to change to ipilimumab [Yervoy] plus nivolumab.

ELAINE BEED, MD: I chose the lenvatinib/pembrolizumab [in both cases] because of the recent data, and also because I had a patient on axitinib [Inlyta] plus pembrolizumab who progressed and had lymph node metastases in his neck. I changed to lenvatinib/pembrolizumab, and the lymph node metastases completely went away. The problem I have is he developed all these mouth sores, and so we had to stop it for a while, and I don’t know what’s going to happen. He has had it for 7 years now, so he’s had a lot of these other things that are [difficult]….But, that’s why I chose that [combination], because it worked on this patient that failed the other one, even though the pembrolizumab was the same. But then, on the other hand, I had problems with adverse events with both of those.

ULKA VAISHAMPAYAN, MBBS: What proportion of patients do you typically see with 2 or more sites of metastases?

PRITESH LOHAR, MD: I think maybe 30% to 40% might have widespread [disease]; I’ve seen patients with 2 areas, maybe [in 1 or 2 sites] in the lung and 1 in the adrenal. But, to have extensive liver and lung metastases, would probably be more symptomatic.

VAISHAMPAYAN: Yes, that’s usually [indicative of] more advanced stages.


  • What factors affect your choice of therapy?

SHETH: The data look quite robust [for all 4 regimens]. What is your favorite regimen do you use in your practice, for a patient with favorable risk?

VAISHAMPAYAN: I am split between ipilimumab/nivolumab and cabozantinib/nivolumab or axitinib/pembrolizumab. I put it in my mind as immunotherapy-only regimens versus the TKI [tyrosine kinase inhibitor]/immunotherapy regimens. More and more, I have switched to cabozantinib/nivolumab recently, especially for patients with bulky disease and high disease load, because you need a quick response, and long-term outcomes are pretty similar across the board with all of these agents.

The reason for my preference for dual immunotherapy is more because it was there first. We have much longer, robust follow-up, which we don’t have with these newer regimens, especially the lenvatinib/pembrolizumab. But all of the data look like they are pointing in that similar direction to showing adequate overall survival improvement. But again, it’s early, and that’s the only reason I still use ipilimumab/nivolumab.


  • Should there be any preference for particular agents in patients with different disease histology?

PALLAVI JASTI, MD: I had a recent case for non–clear cell papillary subtype RCC. I would favor cabozantinib up front, with or without immunotherapy combination, as opposed to the other agents.

VAISHAMPAYAN: What would most of you do for sarcomatoid histology?

SHETH: [Dual] immunotherapy.

VAISHAMPAYAN: Yes, I think it needs to be an immunotherapy-based regimen, that much is clear for CheckMate 214 [NCT02231749] and the axitinib/pembrolizumab study, KEYNOTE-426.3,4 They have looked at specifically the sarcomatoid subgroup, similarly, for cabozantinib/nivolumab.5 And across the board, with an immunotherapy-based regimen, the sarcomatoid subgroup does much better.3-5 So, it’s pretty clear that if you see any sarcomatoid histology in the pathology report, you should use an immunotherapy-based regimen.

TAREK SABAGH, MD: Would you use dual immunotherapy or immunotherapy/TKI?

VAISHAMPAYAN: If it’s a controlled setting, where the patient does not have [rapidly growing] disease, yes, I would use dual immunotherapy. But frequently, what I find happens with sarcomatoid histology is they are very sick; they’re sometimes even in the hospital and not doing so well. So typically, I end up having to use a cabozantinib/nivolumab type of regimen to get a quick enough response and be able to deliver the treatment to them quickly. Sarcomatoid can be a pretty aggressive histology, with very symptomatic patients.

SABAGH: Is there advantage for TKI in sarcomatoid histology on top of the immunotherapy benefit?

VAISHAMPAYAN: It’s pretty unknown at this point. But the non-immunotherapy–based regimens, at least, do not do well in sarcomatoid histology. So, if you use a single-agent TKI, you’re not going to get too much mileage. Combination with immunotherapy is critical. You could use dual immunotherapy depending on whether the patient can handle it, or you can use a [TKI-containing] combination.

MARK KNAPP, MD: I once had a chromophobe patient—do you know if there’s any studies that have investigated that histology?

VAISHAMPAYAN: No, those are the toughest to treat. But with that histology, even mTOR inhibitors have been shown to be more beneficial sometimes. For a patient with chromophobe [disease], it would depend on how aggressive their disease is. I would look at the risk characteristics and treat accordingly. [That is], unless you have a specific mutation, like the tuberous sclerosis complex mutations; [in that case], doing NGS [next-generation sequencing] to look at actionable mutations might be a critical piece.

KNAPP: Is that the only histology you would look at NGS?

VAISHAMPAYAN: Upfront, yes. That may change my management.

SHETH: Do you have any preference for patients with a brain metastasis?

VAISHAMPAYAN: I tend to use a TKI-based regimen for brain metastases, because there are some reports of cabozantinib, lenvatinib, etc, showing a response in brain metastases. Ideally, you have to do the surgery, radiotherapy, whatever it takes to get the brain metastases in a semblance of control before you start systemic therapy, for the most part. The few patients to whom I’ve given dual immunotherapy after brain metastases are the ones who’ve been resected completely; [having] 1 or 2 metastases that have been resected, and they are free of disease in the brain afterward.


1. 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

2. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128(11):2085-2097. doi:10.1002/cncr.34180

3. Tannir NM, Signoretti S, Choueiri TK, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res. 2021;27(1):78-86. doi:10.1158/1078-0432.CCR-20-2063

4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): Outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study. J Clin Oncol. 2019;37(15_suppl):4500. doi:10.1200/JCO.2019.37.15_suppl.4500

5. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) versus sunitinib (SUN) for advanced renal cell carcinoma (aRCC): Outcomes by sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. J Clin Oncol. 2021;39(6_suppl):308. doi:10.1200/JCO.2021.39.6_suppl.308

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