Urologic Oncology Fellow Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, United States
Background: Though ICI use is standard in RCC, these malignancies have an overall paucity of predictive genomic biomarkers, resulting in limited clinical impetus for routine sequencing. In recent landmark decisions, the FDA approved organ-agnostic pembrolizumab treatment based on three explicit biomarkers: MMR deficiency (dMMR), high MSI (MSI-H), and high TMB (TMB-H). Previous work suggests a small but not insignificant fraction of RCCs (~5%) demonstrate these alterations, though the clinical relevance has yet to be determined.
Methods: Our institution’s prospective clinical sequencing database was queried to identify all patients with metastatic RCC who received ICI and had either the primary or metastatic site sequenced with the targeted genomic MSK-IMPACT platform. Deleterious mutations in MMR genes MLH1, MSH2, MSH6, and PMS2 were considered. The threshold for MSI-H was MSIsensor score >10 and for TMB-H it was >10 non-synonymous mutations/Mb. The Kaplan-Meir method was used to compare overall survival (OS) across groups.
Results: Of 653 patients with metastatic RCC who had sequenced tumors and received ICI, 17 (2.6%) demonstrated ≥1/3 investigated biomarkers, with MMRd most common (n=12), then TMB-H (n=8), and lastly MSI-H (n=2). Most of these patients had clear-cell RCC (88%), with solitary cases of chromophobe and unclassified pathology. Most received first-line ICI (82%), while 29% received subsequent lines of systemic therapy following ICI. OS was significantly longer in those with MMRd/MSI-H/TMB-H (HR 0.41, 95% CI 0.17-0.98, p=0.046; Figure 1A). These patients also trended toward enrichment for chromosome 3p21 (BAP1, SETD2, PBRM1) and TP53 mutations (Figure 1B).
Conclusions: RCC patients with MMRd/MSI-H/TMB-H demonstrated improved OS with ICI, despite possible enrichment for mutations typically associated with worse prognosis, such as BAP1 and TP53. This could have implications in selecting systemic therapy regimens and suggest a role for more routine genomic sequencing, though confirmatory studies are required.
