Non-clear cell renal cell carcinoma in the immune checkpoint era: A retrospective study on survival and treatment approaches.
Authors: Yildirim Ahmet , Liu Yuan , Marra Angelo , Suh Lauren , Choi Yujin , Martini Dylan J. , Hartman Caitlin , McClintock Greta Russler , Zhuang Tony Zibo , Harris Wayne B. , Ciuro Jordan Alana , Berchuck Jacob E , Brown Jacqueline T , Nazha Bassel , Carthon Bradley Curtis , Kucuk Omer , Master Viraj A. , Bilen Mehmet Asim 
Published: February 2025

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Background:
Non-clear cell renal cell carcinoma (nccRCC) includes several molecularly distinct subtypes of renal carcinoma. Due to their rarity, nccRCC subtypes have been understudied, and treatment options are often adapted from clear cell RCC therapies. Trials investigating immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy and survival benefits in certain nccRCC histologies. This report aims to present our experience with nccRCC, focusing on patient characteristics, treatment choices, and survival outcomes in the era of ICIs.
Methods:
A retrospective analysis was conducted on adult patients with metastatic RCC treated at the Emory Winship Cancer Institute between 2018 and 2024. nccRCC histologies were identified and confirmed through pathology reports. An objective response is defined as a complete or partial response by RECIST v1.1. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method with SAS 9.4 software to calculate survival probabilities.
Results:
We identified 69 patients with various nccRCC histologies, with papillary RCC (pRCC) being the most common (36.2%), followed by unclassified RCC (24.6%). The median age was 63 years. 59.4 of the patients were male, and 75.4% of the patients had an ECOG PS of 0 or 1. 53.6% of the patients were White, while 40.6% were African American or Black. Nephrectomy was performed in 44 patients (63.8%). The median follow-up time was 24 months. ICI-based treatments were used as the first-line option in 52% of patients, with 88% of unclassified RCC patients receiving ICI-based regimens as first-line. The mOS was longest in patients with chromophobe RCC at 21 months (4, NA), followed by patients with unclassified RCC at 19 months (6, NA). Among pRCC patients, there was no significant difference in mOS between African American or Black patients (12 months) and White patients (10.5 months; p=0.61). mOS was similar across ICI monotherapy, dual ICI therapy, and ICI+TKI combinations. 12-month survival rates were 50%, 57%, and 33% (p=0.21), and objective response rates (ORR) were 11%, 14%, and 11% for ICI monotherapy, dual ICI, and ICI+TKI combinations, respectively.
Conclusions:
Our study highlights the heterogeneity of non-clear cell RCC subtypes. The rare nature of nccRCC and the small patient cohort in our study limited its statistical power, emphasizing the importance of larger studies and expanded clinical trials to better understand and optimize treatment strategies for this understudied group of renal carcinomas.

Histology
n
White
African American or Black
12 Months OS Rate
12 Months PFS Rate
ORR

Papillary
25
12
12
46% (25, 64)
44% (7, 78)
12%

Unclassified
17
10
6
63% (35, 81)
43% (10, 73)
35%

Translocation
9
4
3
67% (21, 91)
36% (17, 56)
0%

Collecting Duct
7
4
3
43% (10, 73)
0% (NA)
14%

Chromophobe
6
6
-
67% (20, 90)
34% (12, 58)
0%