Current Issues in the Management of Sporadic Non-clear Cell Renal Cell Carcinoma (Non-ccRCC)

Authors

  • Mariam Jafri, MBChB (Hons), MRCP(UK), BMedSc, MSc, Ph.D Assistant Professor, Department of Oncology, Queen’s University, Kingston, Ontario

DOI:

https://doi.org/10.58931/cot.2025.2343

Abstract

Renal cell carcinoma (RCC) is the 10th most common cancer type in Canada. Numerous developments in the management of RCC over the last decade have led to improved outcomes, though these have mostly focused on the ~80% of patients with clear cell renal cell carcinoma (ccRCC). The remaining 20% of cases are labelled non-clear cell renal cell carcinoma (non‑ccRCC) and represent a biologically and clinically heterogeneous group of diseases that are rare entities. Historically, non-ccRCC has been managed similarly to clear cell tumours. Localized non-ccRCC has better outcomes than ccRCC; however, survival of metastatic non-ccRCC is inferior to ccRCC (median overall survival [OS] of metastatic non-ccRCC reported as 39.2 months compared to 81.1 months for ccRCC).

This has led to interest within the RCC scientific and patient communities to further improve outcomes for patients with non-ccRCC. This article describes the current management of patients with non-ccRCC and discusses future areas of interest in the field.

Author Biography

Mariam Jafri, MBChB (Hons), MRCP(UK), BMedSc, MSc, Ph.D, Assistant Professor, Department of Oncology, Queen’s University, Kingston, Ontario

Dr. Mariam Jafri is a medical oncologist and a Senior Investigator at Canadian Cancer Trials Group.  Her clinical and research interests are sarcoma, GU cancers and adolescent and young adult cancers. In addition to her medical degree and specialist training in medical oncology, she has PhD in molecular characteristics of renal cancer and related disorders.

References

Graham J, Ahmad AE, Basappa NS, Bernhard JC, Bhindi B, Bossé D, et al. 2024 CUA-KCRNC Expert Report: Management of non-clear cell renal cell carcinoma. Can Urol Assoc J. 2024;18(11):E371-e86.

Gulati S, Philip E, Salgia S, Pal SK. Evolving treatment paradigm in metastatic non clear cell renal cell carcinoma. Cancer Treat Res Commun. 2020;23:100172.

Urman D, Deshler L, Weise N, Shabaik A, Derweesh I, Bagrodia A, et al. Outcomes of patients with advanced renal cell carcinoma with non-clear cell histology treated with systemic therapy. Clin Genitourin Cancer. 2023;21(6):660-8.e1.

Goswami PR, Singh G, Patel T, Dave R. The WHO 2022 Classification of renal neoplasms (5th Edition): Salient updates. Cureus. 2024;16(4):e58470.

Moch H, Amin MB, Berney DM, Compérat EM, Gill AJ, Hartmann A, et al. The 2022 World Health Organization Classification of tumours of the urinary system and male genital organs—part A: renal, penile, and testicular tumours. Eur Urol. 2022;82(5):458-68.

Cardenas LM, Sigurdson S, Wallis CJD, Lalani A-K, Swaminath A. Advances in the management of renal cell carcinoma. CMAJ. 2024;196(7):E235-E40.

Powles T, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23(9):1133-44.

Gulati S, Tangen C, Ryan CW, Vaishampayan UN, Shuch BM, Barata PC, et al. Adjuvant everolimus in non–clear cell renal cell carcinoma: a secondary analysis of a randomized clinical trial. JAMA Netw Open. 2024;7(8):e2425288-e.

Allaf ME, Kim S-E, Master V, McDermott DF, Harshman LC, Cole SM, et al. Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study. Lancet Oncol 2024;25(8):1038-52.

Pal SK, Tangen C, Thompson IM, Jr., Balzer-Haas N, George DJ, Heng DYC, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703.

Barata P, Tangen C, Plets M, Thompson IM, Narayan V, George DJ, et al. Final Overall survival analysis of S1500: a randomized, phase ii study comparing sunitinib with cabozantinib, crizotinib, and savolitinib in advanced papillary renal cell carcinoma. J Clin Oncol. 2024;42(33):3911-6.

Albiges L, Gurney H, Atduev V, Suarez C, Climent MA, Pook D, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2023;24(8):881-91.

Voss MH, Gurney H, Atduev V, Suarez C, Climent MA, Pook D, et al. First-line pembrolizumab plus lenvatinib for advanced non–clear-cell renal cell carcinoma: updated results from the phase 2 KEYNOTE-B61 trial. Eur Urol. 2025.

McDermott DF, Lee JL, Ziobro M, Suarez C, Langiewicz P, Matveev VB, et al. Open-label, single-arm, phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma. J Clin Oncol. 2021;39(9):1029-39.

Lee C-H, Voss MH, Carlo MI, Chen Y-B, Zucker M, Knezevic A, et al. Phase II trial of cabozantinib plus nivolumab in patients with non–clear-cell renal cell carcinoma and genomic correlates. J Clin Oncol. 2022;40(21):2333-41.

Tykodi SS, Gordan LN, Alter RS, Arrowsmith E, Harrison MR, Percent I, et al. Safety and efficacy of nivolumab plus ipilimumab in patients with advanced non-clear cell renal cell carcinoma: results from the phase 3b/4 CheckMate 920 trial. J Immunother Cancer. 2022;10(2).

Massari F, Mollica V, Kopp RM, Grande E, Fiala O, Kanesvaran R, et al. Immune-based combinations in intermediate-/poor-risk patients with non–clear cell renal cell carcinoma: results from the ARON-1 study. Eur Urol Focus. 2025.

Bergmann L, Albiges L, Ahrens M, Gross-Goupil M, Boleti E, Gravis G, et al. Prospective randomized phase-II trial of ipilimumab/nivolumab versus standard of care in non-clear cell renal cell cancer - results of the SUNNIFORECAST trial. Ann Oncol. 2025;36(7):796-806.

Lebenthal JM, Kontoyiannis PD, Hahn AW, Lim ZD, Rao P, Cheng JP, et al. Clinical Characteristics, Management, and Outcomes of Patients with Renal Medullary Carcinoma: A Single-center Retrospective Analysis of 135 Patients. Eur Urol Oncol. 2025;8(2):315-23.

Suarez C, Marmolejo D, Valdivia A, Morales-Barrera R, Gonzalez M, Mateo J, et al. Update in collecting duct carcinoma: Current aspects of the clinical and molecular characterization of an orphan disease. Front Oncol. 2022;12:970199.

Oudard S, Banu, E, Vieillefond, A, Fournier, L, Priou, F, Medioni, J, Culine, S. Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs Uro-Genitales) Study. J Urol. 2007;177:1698-702.

Srinivasan R, Gurram S, Singer EA, Sidana A, Al Harthy M, Ball MW, et al. Bevacizumab and erlotinib in hereditary and sporadic papillary kidney cancer. N Engl J Med. 2025;392(23):2346-56.

Xu Y, Kong W, Cao M, Wang J, Wang Z, Zheng L, et al. Genomic Profiling and Response to immune checkpoint inhibition plus tyrosine kinase inhibition in FH-deficient renal cell carcinoma. Eur Urol. 2023;83(2):163-72.

Kong W, Wu G, Xu Y, Wang Z, Zhang J. Lenvatinib plus tislelizumab as first-line therapy for advanced fumarate hydratase-deficient renal cell carcinoma: A single-center, single-arm, phase II study. J Clin Oncol. 2025;43(5_suppl):443-.

Oza B, Frangou E, Smith B, Bryant H, Kaplan R, Choodari-Oskooei B, et al. RAMPART: A phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse. Contemp Clin Trials. 2021;108:106482.

Choueiri TK, Xu W, Poole L, Telaranta-Keerie A, Hartmaier R, Powles T. SAMETA: An open-label, three-arm, multicenter, phase III study of savolitinib + durvalumab versus sunitinib and durvalumab monotherapy in patients with MET-driven, unresectable, locally advanced/metastatic papillary renal cell carcinoma (PRCC). J Clin Oncol. 2022;40(16_suppl):TPS4601-TPS.

Maughan BL, Plets M, Pal SK, Ged Y, Tangen C, Vaishampayan UN, et al. SWOG S2200 (PAPMET2): A phase II randomized trial of cabozantinib with or without atezolizumab in patients with advanced papillary renal cell carcinoma (PRCC). J Clin Oncol. 2024;42(4_suppl):TPS493-TPS.

Nepali PR, Eraky A, Okhawere KE, Dogra N, Mehrazin R, Badani K, et al. Molecular and therapeutic landscape of non-clear cell renal carcinoma. Nat Rev Urol. 2025.

Published

2025-11-05

How to Cite

Jafri, M. (2025). Current Issues in the Management of Sporadic Non-clear Cell Renal Cell Carcinoma (Non-ccRCC). Canadian Oncology Today, 2(3), 29–34. https://doi.org/10.58931/cot.2025.2343

Issue

Section

Articles