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Immune-related adverse events (irAE) have been described with immune checkpoint inhibitors (ICI), 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 6,528 received an ICI (nivolumab, 1,534; pembrolizumab, 1,522; atezolizumab, 751; and ipilimumab, 2,721) and 4,926 had not. Compared with 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 with 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. Cancer Immunol Res; 5(4); 312–8. ©2017 AACR.

Blockade of the PD1/PD-L1 T cell immune checkpoint yields responses and survival benefits exceeding mTOR blockade alone in metastatic renal cell carcinoma (mRCC). However, predictors of response to anti-PD1/PD-L1 therapy are mostly unknown, and pathways of acquired resistance to immune checkpoint therapy are poorly understood. In this study, we undertook whole exome sequencing and neoantigen analysis of matched “trios” (primary tumor resection, immune-checkpoint-refractory metastasis, and germline tissue) from 3 patients treated with anti-PD1 or anti-PD-L1 therapy for mRCC. Patients RCC-001 and RC-002 received anti-PD1 therapy after VEGF-targeted therapy and patient RCC-003 received anti-PD-L1 first-line for mRCC. All 3 patients experienced tumor regression on immune checkpoint therapy, with treatment durations of 10 months, 2 years, and 3 months, respectively. Progressive disease samples were sequenced for analysis of genomic mechanisms of treatment resistance. Whole transcriptome sequencing was obtained on primary and metastatic tumors from RCC-003. Nonsynonymous mutation load was moderate in all samples (range: 33-46 primary, 36-67 resistant). Alterations in VHL were seen in RCC-001 and RCC-002 before and after treatment. RCC-003 had a frameshift deletion in the tumor suppressor NF2 and a nonsense mutation in the MHCI antigen-processing protein TAP1 in both primary and refractory tumors. Resistance-associated mutations in RCC-002 included a frameshift deletion in MR1, involved in MHC I antigen presentation, and missense mutations in TJP1, implicated in JAK/STAT signaling, and PIAS2, implicated in STAT2 and PTEN regulation. JAK2 amplifications have been found to upregulate PD-L1 expression (Green et al. 2010, Blood), and PTEN loss mediates resistance to T cell-mediated immmunotherapy in vitro (Peng et al. 2016, Cancer Discovery). None of the primary tumors harbored alterations in microsatellite-instability-associated genes, and loss of β2 microglobulin was not observed in any sample. Despite moderate mutational loads, each sample harbored a sizeable number of neoantigens (range: 24-76 primary, 50-104 resistant). Across the 6 samples, 28 to 69% of nonsynonymous mutations were predicted to yield at least one neoantigen, with one alteration yielding a maximum of 12 unique neoantigens. Up to 60% of neoantigens observed in the primary tumor were not seen in the resistant setting (range: 20.8-59.2%). Whole transcriptome sequencing in RCC-003 showed 18/24 predicted neoantigens were expressed in the primary tumor and 24/50 in the refractory sample. 13 neoantigens were shared between the two samples, while 5 were unique to the pre-treatment tumor. Integrated whole exome and whole transcriptome sequencing with matched germline profiling identified 5 neoantigens in RCC-003 that were found exclusively in the primary tumor (lost in the treatment-resistant tumor). This could represent immune evasion via deletion of immunogenic mutations, cytotoxic killing of immunogenic tumor clones, or intrinsic resistance to immune checkpoint therapy in heterogenous tumors. Ongoing in vitro analysis of reactivity of predicted neoantigens from all 3 samples with patient-derived T cells will further clarify the biological significance these putative tumor antigens. Citation Format: Diana Miao, Guillermo De Velasco, Dennis Adeegbe, Craig Norton, Dylan Martini, Stephanie Mullane, Raphael Moreira, Sabina Signoretti, Kwok-Kin Wong, Toni Choueiri, Eliezer Van Allen. Genomic and neoantigen evolution and resistance to immune checkpoint blockade in metastatic renal cell carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A18.