A Systematic Review of Immune Checkpoint Inhibitors in Non-Clear-Cell Renal Cancer

Abstract

BACKGROUND: Immune checkpoint inhibitors (ICI) have emerged as active therapies in the management of advanced RCC. While multiple studies have shown clinical activity of ICIs in clear cell histologies, the evidence to support their use in non-clear cell (ncc) subtypes is based on smaller prospective trials and retrospective analyses. OBJECTIVE: The objective of this review is to summarize the clinical outcomes of ICI-based therapies in ncc-subtypes and in tumors with sarcomatoid/rhabdoid features. METHODS: We performed a systematic literature search using PubMed, Google Scholar and ASCO databases. The keywords “renal cell cancer” and “immune checkpoint inhibitors” and equivalents were used and all original publications between July 2016 and July 2021 were included. RESULTS: We included a total of 14 publications, including two clinical trials and 12 case series. The most frequent histologies were papillary (up to 75-100%), unclassified (up to 34%) and chromophobe (up to 28%). ICI monotherapy showed some activity in both 1st and 2nd line with response rates up to 27%. ICI combination regimens yielded better activity than ICI monotherapy but, overall, a heterogeneous efficacy was noted across histologies. Overall, outcomes of ICIs were superior in tumors with sarcomatoid/rhabdoid features. CONCLUSION: The observed activity of ICI-based therapies was heterogeneous. Combination regimens, papillary subtype and sarcomatoid/rhabdoid features were associated with higher responses. These findings might help treatment decisions and require further validation.

Systemic Treatment for Advanced and Metastatic Non-Clear Cell Renal Cell Carcinoma: Examining Modern Therapeutic Strategies for a Notoriously Challenging Malignancy

“…It is important to note that while sarcomatoid differentiation is not a true histologic classification because it can occur in any RCC histology at variable proportions, sarcomatoid features are correlated with a positive response to immunotherapy, regardless of the formally diagnosed tumor histology ( 13 , 27 , 97 ). Furthermore, because clinical outcomes for ICI-based therapies are superior for this group, compared to treatment with sunitinib ( 98 ), ICIs should be prioritized as first-line treatment for these patients.…”

“…In the past few years, promising clinical trial data have shifted the standard of care for advanced and metastatic RCC toward immune checkpoint inhibitors (ICIs). However, most randomized phase III trials with data supporting the efficacy of ICIs include only patients with clear cell histology ( 11 , 12 ), and only up to one-third of patients with nccRCC respond to ICIs based on small phase II studies ( 13 ). Furthermore, data for the efficacy of other targeted therapies used in RCC, such as tyrosine kinase inhibitors (TKIs) and inhibitors of mammalian target of rapamycin (mTOR), are limited and must be extrapolated from trials of clear cell histology patients ( 14 , 15 ).…”

Immune Checkpoint Inhibitors in Renal Cell Carcinoma: Molecular Basis and Rationale for Their Use in Clinical Practice

“…There are current clinical trials for VISTA and PD-L1 blockade together in advanced cancers (NCT02812875) [ 131 ]. Different results were achieved in patients with non-clear-cell RCC (nccRCC) with ICIs [ 132 , 133 ]. Histology represented one of the main factors affecting the outcomes: better responses were obtained in papillary and sarcomatoid dedifferentiated tumors, whereas poorer responses were found in chromophobe renal cancers.…”

A phase II trial of nivolumab followed by ipilimumab and nivolumab in advanced non‐clear‐cell renal cell carcinoma

“…In the absence of prospective trials, clinicians treating nccRCC patients have historically extrapolated from trials of ccRCC or relied on retrospective datasets [7][8][9][10][11]. nccRCC comprises a biologically and clinically heterogeneous group of neoplasms, and it is difficult to generalize results because of differences among nccRCC histological subtypes [12][13][14]. There is however a strong biological rationale for the use of immune checkpoint inhibitors [15], with multiple trials evaluating immunotherapy strategies in patients with nccRCC [16][17][18][19][20][21].…”