Which first line treatment would you choose for favorable and intermediate risk RCC?


A 61-year-old man with an active lifestyle had a history of metastatic renal cell carcinoma (mRCC), and had nephrectomy and post-left adrenalectomy. He had clear cell RCC (ccRCC) with metastasis to the adrenal gland. Four years later, he had a recurrence of lung nodules with a biopsy consistent with ccRCC. In retrospect, they had been present on the scans for at least 2 years previously. Based on the low volume, the indolence of the disease and the preference of the patient, he was placed under observation. Eighteen months later, there was continued indolent growth on CT scans, increased total tumor burden, and new paratracheal lymph node metastasis (2.0 x 1.5 cm). His ECOG performance score was 0.

Vote in the polls below on what you would have chosen if this was your patient.

The decision was made to initiate systemic treatment. Which first-line treatment are you most likely to choose for this favorable risk patient?

RANA R. MCKAY, MD (moderator): Here’s where we stand on the National Comprehensive Cancer Network [NCCN] kidney cancer guidelines for favorable risk diseases: we have category 1 data for the 3 immuno-oncology [IO] plus VEGF-tyrosine kinase inhibitor [TKI] combinations that have demonstrated improvements in overall survival [OS].1 These include axitinib [Inlyta] more pembrolizumab [Keytruda]cabozantinib [Cabometyx] more nivolumab [Opdivo]and lenvatinib [Lenvima] more pembrolizumab. Then under other recommendations axitinib/avelumab [Bavencio] is listed, cabozantinib alone is listed with a Category 2B designation, nivolumab plus ipilimumab [Yervoy]then TKI as monotherapy.1 These may be options for patients with favorable risk disease.

With combinations of checkpoint inhibitors like nivolumab/ipilimumab, the data supports the long-term durability of the regimen with a five-year long-term PFS of around 30%.2 The Achilles heel of the CheckMate 214 [NCT02231749] the data indicate that the rate of primary progressive disease is 18%.3 Currently, we do not have biomarkers to help us select between IO/IO and IO/VEGF-TKI.

And if this patient had 2 sites of distant metastasis (eg, lung and liver), which first-line treatment would you most likely recommend?

MCKAY: In this context, it seems that not [participants at this roundtable event would] select Single Agent TKI. More people selected nivolumab/ipilimumab as a potential option, and then some continued to select the IO/VEGF-TKI combination.

TIMMY Q. NGUYEN, MD: I changed my treatment from a TKI to a TKI/IO due to the likely more aggressive presentation in the liver as well as the lungs. The cancer is now progressing more and more and is likely to progress [even] After. We will no longer have control of it. Patients need more active treatment.

SIMON VINARSKY, MD: I chose nivolumab/ipilimumab because of liver damage and clear cell morphology. All options, TKI plus nivolumab or pembrolizumab are absolutely acceptable options, but I chose this particular combination because of the aggressive pattern of metastasis and liver injury, which in this setting of RCC tends to be a much more aggressive disease compared to lung involvement.

MCKAY: It is absolutely correct that those with liver metastases may behave more aggressively than those without these sites of metastases.

ROBERT ZAIDEN, MD: I chose lenvatinib plus pembrolizumab based on CLEAR trial data [NCT02811861]. I know it has the longest observed response for any mRCC trial with an objective response rate of 71% [ORR].4 The reason I did not opt ​​for cabozantinib plus nivolumab is that this patient did not have bone metastases and we know that cabozantinib/nivolumab is particularly effective in this subgroup of patients.

MAHENDER YELLU, MD: I chose pembrolizumab/lenvatinib based on complete response rate, faster response, and personal experience. I have a few patients who have been very successful with this combination and having liver disease, it’s probably more aggressive. Also, if the patient is symptomatic, doing a TKI with immunotherapy is probably reasonable.


A 59-year-old black woman was diagnosed with left kidney mass and underwent left radical nephrectomy in December 2019. Her diagnosis was ccRCC, T3aN0Mx, Fuhrman Grade 3. Nine months later, she developed metastatic disease in the liver and retroperitoneal lymph nodes. His radiographic diagnosis was stage IV RCC, with metastases to the liver and retroperitoneum. His Karnofsky performance status was 90%. Her hemoglobin level was 11.1 g/dL and the corrected calcium, neutrophils and platelets were within normal limits.

And if this intermediate-risk patient had 2 sites of distant metastasis (eg, lung and liver), which first-line treatment would you most likely recommend?

MCKAY: A good number of participants would choose nivolumab/ipilimumab, some lenvatinib/pembrolizumab, some nivolumab/cabozantinib. Few people chose pembrolizumab/axitinib or cabozantinib as monotherapy.

And if this patient had 2 sites of distant metastasis (eg, lung and liver), which first-line treatment would you most likely recommend?

MCKAY: In the updated NCCN guidelines for the treatment of patients with low- and intermediate-risk disease, all IO/VEGF-TKI combinations are acceptable, as is nivolumab/ipilimumab.1

[We can compare] granular data regarding OS, progression-free survival, and ORR for the intermediate and low-risk population versus the intent-to-treat population in these trials. I would keep in mind the number of patients with low-risk disease who were recruited into all of these trials, but based on the baseline data, each of these treatment regimens is effective for patients with intermediate and high risk disease.

Looking at the risk report [HR] for OS, with a long-term follow-up of 67.7 months for nivolumab/ipilimumab remains at 0.68 and for pembrolizumab/axitinib at For cabozantinib/nivolumab, the RR for patients at intermediate risk is 0.74; for low-risk patients, it is 0.45.6 Then, similarly for lenvatinib/pembrolizumab, the RR for intermediate risk patients is 0.72 and for low risk patients is 0.39, so these are very effective regimens.seven The ORR in intermediate and high risk patients varies by more than 50% with IO/VEGF combinations and 72% with lenvatinib/pembrolizumab, while for nivolumab/ipilimumab it is 42%.2.5-7


1.NCCN. Clinical practice guidelines in oncology. Kidney cancer, 2.2023. Accessed August 23, 2022. https://bit.ly/2TAx1m3

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

3. 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

4. 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

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

6. Powles T, Choueiri TK, Burotto M, et al. Final analysis of overall survival and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib vs sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(supplement 6):350. doi: 10.1200/JCO.2022.40.6_suppl.350

7. Choueiri TK, Powles T, Porta C, et al. A phase 3 trial comparing lenvatinib plus pembrolizumab with sunitinib as first-line treatment for patients with advanced renal cell carcinoma: follow-up analysis of overall survival (the CLEAR study). Presented at: Kidney Cancer Research Summit 2021; October 7-8, 2021; Philadelphia, PA. Summary E41. Accessed August 23, 2022. https://bit.ly/3yRcxMx

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