Summary On the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy number, and RNA and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences between clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with chromatin modifier genes or TFE3 gene fusion were present within specific subtypes as well as spanning multiple subtypes. Differences in patient survival and in alteration of specific pathways—including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR—could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.

Immune-related adverse events (irAEs) have been described with immune checkpoint inhibitors (ICIs), but the incidence and relative risk (RR) of irAEs associated with these drugs remains unclear. We selected five key irAEs from treatments with approved cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab or pembrolizumab, and atezolizumab, respectively) to better characterize their safety profile. We performed a meta-analysis of randomized phase II/III immunotherapy trials, with non-ICI control arms, conducted between 1996 and 2016. We calculated the incidence and RR of selected all-grade and high-grade gastrointestinal, liver, skin, endocrine, and pulmonary irAEs across the trials using random-effect models. Twenty-one trials were included, totaling 11,454 patients, of whom 6528 received an ICI (nivolumab, 1534; pembrolizumab, 1522; atezolizumab, 751; and ipilimumab, 2721) and 4926 had not. Compared to non-ICI arms, ICIs were associated with more all-grade colitis (RR 7.66, P < 0.001), aspartate aminotransferase (AST) elevation (RR 1.80; P = 0.020), rash (RR 2.50; P = 0.001), hypothyroidism (RR 6.81; P < 0.001), and pneumonitis (RR 4.14; P = 0.012). Rates of high-grade colitis (RR 5.85; P < 0.001) and AST elevation (RR 2.79; P = 0.014) were higher in the ICI arms. Ipilimumab was associated with a higher risk of all-grade rash (P = 0.006) and high-grade colitis (P = 0.021) compared to PD-1/PD-L1 ICIs. Incidence of fatal irAE was < 1%. This meta-analysis offers substantial evidence that ICIs are associated with a small but significant increase in risk of selected all-grade irAEs and high-grade gastrointestinal and liver toxicities. Although fatal irAEs remain rare, AEs should be recognized promptly as early interventions may alleviate future complications.

Purpose We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC). Experimental Design We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for six months or longer. Non-responders were defined as those with disease progression during the first three months of therapy. Fisher's exact test assessed the association between mutation status in mTOR pathway genes and treatment response. Results Mutations in MTOR, TSC1 or TSC2 were more common in responders, 12 (28%) of 43, than non-responders, 4 (11%) of 36 (p=0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than non-responders, 2(6%), (p=0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1 or TSC2 compared to 4 (11%) of 36 non-responders (p=0.03). Eight additional genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response. Conclusion In this cohort of mRCC patients, mutations in MTOR, TSC1 or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (31 of 43, 72%) had no mTOR pathway mutation identified.