Choosing Frontline RCC Therapy After Detecting Metastases in Patient Under Observation


During a Targeted Oncology case-based roundtable event, Sumanta K. Pal, MD, discussed the choice of frontline therapy for a favorable-risk patient with advanced clear cell renal cell carcinoma.

Dr. Sumanta Pal

Sumanta K. Pal, MD (Moderator)

Professor, Department of Medical Oncology & Therapeutics Research

Codirector, Kidney Cancer Program

City of Hope

Duarte, CA


A 61-year-old man with an active lifestyle had a history of low-volume, indolent metastatic clear cell renal cell carcinoma (RCC) and was post‒left nephrectomy and adrenalectomy. He was observed based on low-volume and indolency of disease and patient preference.

Five years after his nephrectomy, there was continued indolent growth on scans, increased total tumor burden, new paratracheal lymph node metastasis (2.0 x 1.5 cm) and greater than 10 pulmonary nodules on a CT scan. A lung biopsy confirms metastatic clear cell RCC. His laboratory results were within normal limits and his ECOG performance status was 0.

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

Axitinib + pembrolizumab
Cabozantinib + nivolumab
Lenvatinib + pembrolizumab
Nivolumab + ipilimumab
Single-agent TKI

SUMANTA K. PAL, MD: I would probably jump into treatment for a scenario like this, getting to that critical juncture when you have measurable nodes. Would you start this patient on axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], lenvatinib [Lenvima] plus pembrolizumab, nivolumab plus ipilimumab [Yervoy], a single-agent tyrosine kinase inhibitor [TKI], or something different? This is probably one of the biggest areas of controversy in RCC.

MIKE MARTIN, MD: I published in JCO Precision Oncology [an article on] the difference in tumor mutational burden [TMB] in lung cancer based on the site of biopsy of metastatic disease, which I understand is different than in RCC.1 For me, it would be important to rebiopsy because if you suddenly biopsied a lung lesion and it had a TMB of 28 mutations/Mb, I would think of that differently than I would if I rebiopsied a lung lesion and it had a TMB of 2 mutations/Mb.

PAL: We can definitely factor elements like that in. If you didn’t have any genomic data or anything like that attached to the biopsy, what would you typically choose for this patient?

JEWRAJ MANESHWARI, MD: I think all the [combination regimens] are right. I don’t think we are using a single-agent TKI in stage IV for patients nowadays. I think this all depends on if somebody is symptomatic. [If] you want quick control in RCC, then I probably going to go with nivolumab/ipilimumab. On the other hand, all 3 [TKI/immunotherapy (IO)] options are acceptable.

MICHAEL HEMPHILL, MD: I think there’s going to be some similarity. It’s going to be nuanced between any differences unless there are head-to-head data, and my hunch is that we’re not going to see head-to-head with dual agents. Then the next part would be non-medical, which is what the patient cost is going to be for the oral TKI part of it.

Outside of all of that, I have most familiarity with axitinib and pembrolizumab. I’ve given that before so [I would] probably [choose] that one. And there are strong data for the lenvatinib/pembrolizumab as well, so I’d have a low threshold for using that. I would be comfortable with any of those, but nivolumab/ipilimumab probably less so than any of the others. Even at the lower dose on the ipilimumab, I would probably reserve that for somebody down the road who failed with just a single IO…I just feel like maybe they’d need exposure to dual IO treatment at some point if we’re running out of options. But I find it to be fairly toxic. In lung cancer, in particular, adding those 2 with the chemotherapy, [based on] the CheckMate 9LA trial [NCT03215706]…it’s a tough regimen, so I don’t like it a ton.

PAL: Yes, that makes sense.

What 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 + pembrolizumab
Cabozantinib + nivolumab
Lenvatinib + pembrolizumab
Nivolumab + ipilimumab
Single-agent TKI

PAL: Let’s say instead of just having this indolent pattern of spread with a couple of paratracheal nodes, what if this patient had more than 2 sites of distant metastases. Let’s say it went to the lungs and the liver more diffusely, what would you recommend in that setting? Does it change your answer? One observation here is it looks as though we have somebody who might shift towards lenvatinib/pembrolizumab in the context of more aggressive disease.

HEMPHILL: I may have come across something where the objective response rates are a little bit higher [for lenvatinib/pembrolizumab in the CLEAR trial (NCT02811861)].2

PAL: You’re absolutely right, very astute.

In terms of the designation of favorable risk, [according to] the NCCN guidelines it’s axitinib/pembrolizumab, cabozantinib/nivolumab, and lenvatinib/pembrolizumab that have category 1 recommendations.3 This would, technically speaking, be a favorable-risk patient. There is long latency from the time of diagnosis to the time of recurrence. This patient did not have any abnormal lab reporting parameters such as clearing calcium, or neutrophils, or platelet counts being elevated, and this patient’s performance status is quite good. So they fall in this favorable-risk category. The one option that is not included there is nivolumab/ipilimumab.


1. Stein MK, Pandey M, Xiu J, et al. Tumor mutational burden is site specific in non-small-cell lung cancer and is highest in lung adenocarcinoma brain metastases. JCO Precis Oncol. 2019;3:1-13. doi:10.1200/PO.18.00376

2. 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

3. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 2.2023. Accessed September 9, 2022.

Related Videos
Video 11 - "Treating Patients With RCC Who Progress Following Adjuvant Therapy"
Related Content