A systematic review of immune checkpoint inhibitors (ICI) in non-clear cell renal cell cancer (nccRCC) subtypes.

353 Background: ICI were approved for advanced RCC treatment either alone or combined with another ICI or a tyrosine kinase inhibitor. While most trial data derive from clear cell (cc) histology, the differential activity of ICI in nccRCC subtypes is not entirely known. The aim of this analysis is to summarize the reported activity of ICI-based therapies in ncc-subtypes or in tumors with sarcomatoid/rhabdoid features. Methods: A systematic literature search following PRISMA guidelines was performed. PubMed, GoogleScholars and ASCO Database were searched for the key-words “renal cell cancer” and “immune check point inhibitors” and equivalents. Publications between July 2016 - July 2021 were considered. All original articles reporting outcomes of ICI in at least 5 patients with an advanced nccRCC were eligible. Case reports, reviews, out of scope publications and articles with no full text available were excluded. Results: This study included a total of 14 publications, mostly case series except one phase II and one phase IIIb/IV trial. The table below summarizes the different histological subtypes included in these studies, more frequently papillary (10-88%), chromophobe (0-34%) and unclassified (4-27.5%) RCC. As for first line (L), ICI monotherapy elicited an overall response ratio (ORR) of 5-26.7%, a median progression free survival (mPFS) of 2.2-4.2 months (m) and a median overall survival (mOS) of 16.3-28.9m. ICI combination therapy associated with a higher ORR of 14.2-33%, a mPFS of 2.4-8.3m and a mOS not reached (NR). In ≥2ndL, ICI alone elicited an ORR of 9.4-22.6%, a mPFS of 3.5-7.1m and a mOS of 11.6m-NR. ICI combination therapy was superior, with a reported ORR of 31-44.4%, a mPFS of 4.3-5.6m and a mOS NR. Overall, ICI therapy elicited a higher ORR in papillary tumors (5-50%). Unclassified RCC response was more variable (0-66.7%). Chromophobe tumors had a lower ORR of 0-20%. ICI therapy outcomes among nccRCC with sarcomatoid/rhabdoid features were of an ORR of 0-42.1%, a mPFS of 2.3-6.9m and a mOS of 25.5m–NR. Nonetheless, outcomes were inferior in ncc comparing to cc tumors. Conclusions: The observed activity of ICI-based therapies was heterogenous among nccRCC subtypes. Combination regimens, papillary subtype and sarcomatoid/rhabdoid features were associated with higher responses. These findings might help treatment decisions and require further validation.[Table: see text]