Outcomes with first-line ipilimumab and nivolumab for patients with metastatic renal cell carcinoma by number of doses.

ESMO Clinical Practice Guideline update on the use of immunotherapy in early stage and advanced renal cell carcinoma

Renal cell carcinoma (RCC) is a renal cortical tumor with high clinical incidence. The effect of glutathione peroxidases (GPXs) on RCC and the possible mechanism are still unclear. This study aims to explore the expression level of GPXs gene in RCC and its effect on the clinical prognosis of patients with RCC via bioinformatics analysis. The mRNA expressions of GPXs family genes were obtained from the public data of The Cancer Genome Atlas (TCGA) database. The Kruskal-Wails test was used to analyze the differences in mRNA expression of GPXs family genes between samples from patients with RCC and the normal population. UALAN databases were used to analyze the differences in protein expression of GPXs family genes between samples from patients with renal clear cell carcinoma and the normal population, and to evaluate the role of GPXs family genes in RCC. The Kaplan-Meier Plotter was used to analyze the correlation between different types of RCC and overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS). Kaplan-Meier survival curve was drawn based on the GPX8 gene expression to study the relationship between GPX8 gene expression and prognosis of RCC patients. Based on the results of multivariate Cox regression analysis, a Nomogram scoring model for RCC prediction was established by introducing GPX8 gene. The mRNA expressions of GPX1 and GPX4 were higher in the sample of renal chromophobe cell carcinoma, renal clear cell carcinoma, and renal papillary cell carcinoma than those in the normal population (all P<0.01), and GPX7 and GPX8 were significantly over-expressed in patients with renal papillary cell carcinoma and renal clear cell carcinoma (all P<0.01). Compared with the normal group, the protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in renal clear cell carcinoma (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). The protein expressions of GPX1, GPX2, GPX7, and GPX8 were increased significantly in patients with renal clear cell carcinoma at different tumor grades (all P<0.01), while GPX3 and GPX4 expressions were decreased significantly (both P<0.01). Survival analysis showed that OS, DFS, DSS, and PFS were all decreased in patients with clear cell carcinoma compared with patients with papillary cell carcinoma and chromophobe cell carcinoma. According to the GPX8 level, patients were assigned into the low, medium, and high expression groups. Compared with the low GPX8 level group, the OS (P<0.01), DFS (P=0.03), DSS (P<0.01), and PFS (P=3.18×10-7) were significantly decreased in the high level group. Univariate Cox proportional regression analysis showed that the high level of GPX8 was associated with poor OS of 3 different types of renal cancer. Multifactorial analysis showed that GPX8 was an independent factor affecting the OS of patients with renal papillary cell carcinoma. Race and post tumor node metastasis (pTNM) typing were independent factors influencing the OS of patients with renal clear cell carcinoma. GPX8 and pTMN were independent factors influencing the OS of patients with renal chromophobe cell carcinoma. Based on these variables, the Nomogram risk models of 3 types of cell carcinoma were established, and the discrimination and calibration of the models were evaluated using the Consistency index (C-index) and calibration curves. The C-index of the risk model of renal papillary cell carcinoma was 0.62 (95% CI 0.51 to 1.00, P=0.03). The results of receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) was 0.88. The C-index of the risk model of renal clear cell carcinoma was 0.72 (95% CI 0.52 to 1.00, P=0.03). The results of ROC curve showed that the AUC was 0.90. The C-index of the risk model of chromophobe cell carcinoma of kidney was 0.90 (95% CI 0.85 to 1.00, P<0.01). The results of ROC curve showed that the AUC was 0.59. GPXs family genes, especially GPX8, are potential markers for poor prognosis of RCC, and the occurrence and development of RCC can be predicted in clinical practice based on the expressions of GPXs family genes.

TPS9591 Background: Immunotherapy (IMT) with checkpoint blocking antibodies has led to progress in metastatic melanoma with 3 FDA-approved drugs, including the combination of ipilimumab (IPI), a CTLA-4 antibody, and nivolumab (NIVO), a PD-1 antibody. Although radiotherapy (RT) is primarily used as local palliative therapy in metastatic melanoma, it also possibly affects systemic antitumor immunity. Preclinical data suggest RT alters the tumor microenvironment and renders tumor cells more susceptible to immunologically-mediated disease regression. These preclinical immunologic effects of RT have been shown to vary by RT dose and fractionation. We are now conducting the first clinical trial in patients to evaluate the triple combination of IPI + NIVO + RT using 2 different dose/fractionation schemes of RT. Methods: This ongoing Phase 1, open-label, multicenter study (NCT02659540) evaluates safety, efficacy, and immunologic effects of IPI + NIVO + RT in 18 patients with unresectable stage IV melanoma. Patients must have 1 melanoma metastasis that can be safely irradiated for palliative purposes and at least 1 measurable lesion that will not be irradiated. Patients receive concurrent IPI (3 mg/kg) and NIVO (1 mg/kg) every 3 weeks (Q3W) x 4, followed by NIVO monotherapy (240 mg Q2W), with RT initiated between the first and second doses of IPI + NIVO. In Cohort A, the irradiated metastasis receives a conventionally fractionated low dose of 30 Gy in 10 fractions of 3 Gy each over 2 weeks. If ≤7 of 9 patients (78%) in Cohort A have Grade 3/4 drug- or radiation-related adverse events, safety is deemed acceptable and Cohort B enrollment opens. In Cohort B, the irradiated metastasis receives a hypofractionated high dose of 27 Gy in 3 fractions of 9 Gy each over 2 weeks. The primary endpoint is safety. Secondary endpoints are objective response rate and disease control rate by RECIST and immune-related RECIST measured at Weeks 12 and 18, duration of response, progression-free survival, and overall survival. Exploratory endpoints include correlative studies of immunological effects. Enrollment opened on 05 Aug 2016. As of 31 Dec 2016, 4 patients are enrolled in Cohort A; enrollment is ongoing. Clinical trial information: NCT02659540.

Prognostic Impact of Preoperative Neutrophil-to-Lymphocyte Ratio in Localized Nonclear Cell Renal Cell Carcinoma

e21533 Background: Anti-cytotoxic T lymphocyte-associated antigen 4 inhibitors, such as ipilimumab (IPI), are commonly used in melanoma management. Whilst a clear dose-toxicity relationship exists, and a dose-response relationship is seen with monotherapy in people with anti PD-1 antibody-naïve melanoma, there is no data on the outcomes of patients who progress following low dose IPI and are subsequently treated with standard dose IPI. We conducted a multicentre, retrospective review to assess the efficacy of this strategy. Methods: Patients with resected stage III, unresectable stage III or IV melanoma who received low dose IPI (&lt; 3mg/kg) with an anti-PD1 antibody in the neoadjuvant, adjuvant or metastatic setting with recurrence (neo/adjuvant) or progressive disease (metastatic) as best response, who then received standard dose IPI (3mg/kg, IPI3) alone or in combination with an anti-PD1 antibody were eligible. IPI dose, frequency and best investigator-assessed RECIST response were collected. Progression free survival (PFS) and overall survival (OS) were analysed using the Kaplan Meier method. Results: 36 patients from 8 centres; 27 (75%) male, BRAF V600 mutant (18, 50%). All patients received low dose IPI with an anti-PD1 antibody, 18 (50%) in the neo/adjuvant and 18 (50%) in the metastatic setting; 15 (42%) received IPI 1mg/kg every 6 weeks, 13 (36%) IPI 1mg/kg every 3 weeks, 3 (8%) IPI 50mg every 6 weeks or 100mg every 12 weeks respectively, and 2 (6%) IPI 1mg/kg every 8 weeks. 23 (64%) received &gt;1 intervening line of systemic therapy prior to IPI3. The most common intervening therapy was BRAF/MEK inhibitors; 14/23 (61%) as 2nd line treatment, 4/8 (50%) as 3rd line treatment, and all progressed. All patients received standard dose IPI3 for unresectable stage III or stage IV melanoma; median age 60 (29-78), 18 (50%) had M1d disease, 32 (89%) ECOG 0-1, 18 (50%) normal lactate dehydrogenase. 35 (97%) received IPI3 with nivolumab and 1 received single agent IPI3. 15 (42%) received 4 cycles of IPI3. The most common reason for IPI3 cessation was progressive disease (16, 44%). The response rate to IPI3 following progression on low dose IPI was 9/36 (25%); the disease control rate was 12/36 (33%). After a median follow up of 22 months (95% CI: 15-27 months), the median PFS and OS were not reached in patients who responded;1-year PFS and OS were 73% and 100% respectively. 13/36 (36%) had grade 3-4 immune-related adverse events (irAE). In 3/36 (8%), the same irAE was observed at low dose IPI and IPI3, and 1 patient had the same irAE (rash) at a higher grade with IPI3 compared to low dose IPI. Conclusions: Standard dose IPI3 following progression on low dose IPI has clinical activity.This is a reasonable treatment strategy for patients who progress on low dose IPI and provides further evidence of a dose-response relationship for IPI. Further research is needed to manage resistance to IPI with anti-PD1.

327 Background: This phase 2 randomized discontinuation trial evaluated tivozanib, a potent and selective vascular endothelial growth factor receptor (VEGFR)-1, -2, and -3 kinase inhibitor. Median progression-free survival (PFS) in all pts was 11.8 mo, and the objective response rate (ORR) was 27%. Methods: Pts received 1.5 mg/d tivozanib (3 wk on, 1 wk off = 1 cycle). A retrospective analysis evaluated efficacy and safety by histologic subtype. Response was evaluated by independent radiology review using standard RECIST criteria. Results: 272 pts were enrolled: 70% were male; median age was 56 y (range, 26–79). 226 (83%) pts had clear cell (CC) RCC; 46 had non–clear cell (NCC) RCC, including 11 with papillary RCC. Of pts with CC RCC, 176 (78%) had undergone nephrectomy; of pts with NCC RCC, 23 (50%) had undergone nephrectomy. Median treatment duration was 8.5 mo (range, 0.03– 23.8) as of the data cutoff. Median PFS was 12.5 mo (range, 9.9–17.7) for pts with CC RCC, not yet reached for pts with papillary RCC, and 5.4 mo (range, 3.7–12.0) for pts with other NCC subtypes. ORR and disease control rate (DCR; ORR + stable disease), respectively, were 29% and 85% for pts with CC RCC, 18% and 100% for pts with papillary RCC, and 17% and 74% for pts with other NCC subtypes. For pts with CC RCC, median PFS, ORR, and DCR, respectively, were 14.8 mo, 32%, and 88% for those who had undergone nephrectomy and 8.9 mo, 18%, and 76% for those who had not. Among pts with NCC RCC, median PFS was 6.6 mo for pts who had undergone nephrectomy and 7.2 mo for pts without nephrectomy; ORR was 17% for both NCC subgroups, with a DCR of 78% for pts who had undergone nephrectomy and 83% for pts who had not. Common drug- related adverse events (AEs) for pts with CC and NCC RCC, respectively, included hypertension (49% and 48%), dysphonia (22% and 22%), asthenia (12% and 13%), and diarrhea (13% and 9%). The most common grade ≥3 drug-related AE was hypertension (CC, 8%; NCC, 4%). Conclusions: Disease control was observed for pts with all RCC histologic subtypes. The rate of AEs was similar among patients with CC and NCC RCC and consistent with that of a selective VEGFR inhibitor with minimal off-target toxicities. Tivozanib is currently being tested in a phase 3 trial in pts with CC RCC. [Table: see text]

Background:Disabled homolog 2-interacting protein is a new member of the Ras GTPase superfamily involved in the regulation of cell proliferation, apoptosis, and metastasis. However, the expression of disabled homolog 2-interacting protein in renal cell carcinoma, its correlation with cancer prognosis, and tumor infiltrating lymphocytes remains unclear.Methods:The expression of disabled homolog 2-interacting protein was analyzed by UALCAN database, GEPIA database and the evaluation of disabled homolog 2-interacting protein effects on clinical prognosis. Prognostic factor analysis was used to identify the correlations between disabled homolog 2-interacting protein and cancer immune infiltration via the TIMER database. In addition, COXPRESdb database was used to analyze the enrichment of disabled homolog 2-interacting protein co-expression genes.Results:Compared to the normal tissues, the messenger RNA expression levels of DAB2IP are higher in 8 while lower in 15 types of tumor tissues. Furthermore, disabled homolog 2-interacting protein has high expression in kidney chromophobe and low expression in both kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. The messenger RNA expression levels of disabled homolog 2-interacting protein decrease gradually due to the increasing tumor staging which positively correlates with disease-free survival and overall survival in both kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. The expression levels of disabled homolog 2-interacting protein also positively correlate with the tumor purity of kidney chromophobe, kidney renal clear cell carcinoma, and kidney renal papillary cell carcinoma samples. Besides, the expression of disabled homolog 2-interacting protein in renal cell carcinoma has negative correlation with the immune infiltration, and the immune infiltration of B cells and CD8+ T cells affects the prognosis of kidney renal papillary cell carcinoma. Enrichment analysis of disabled homolog 2-interacting protein co-expressed genes suggested that its biological role was mainly in regulating GTPase activity.Conclusions:These findings suggest that disabled homolog 2-interacting protein functions as a tumor suppressor in the progression of renal cell carcinoma, and the expression of disabled homolog 2-interacting protein is related to the immune infiltrating cells and affects the survival of renal cell carcinoma. Disabled homolog 2-interacting protein can be a novel clinical biomarker for patients with renal cell carcinoma, which also provides new insights for the future treatments of renal cell carcinoma.

Objective To evaluate the efficacy and side effects of targeted therapy in the treatment of metastatic non–clear cell renal cell carcinoma (nccRCC). Methods Data of patients with metastatic renal cell carcinoma (RCC) who received sorafenib (400 mg, twice one day) or sunitinib (50 mg/d, 4 weeks on/2 weeks off) as the first–line targeted therapy from Dec. 2006 to May. 2014 were analyzed retrospectively. Pathological diagnosis indicated 317 clear cell RCC (ccRCC) and 56 nccRCC (29 papillary RCC and 27 other subtypes). Kaplan–Meier method was used to assess overall survival (OS), and log–rank test was performed to compare the difference of median follow–up between the two groups. Side effects were also documented and analyzed in all the patients. Results The follow–up period was 2.7 to 79.9 mon (median: 34.3 mon) in the whole group, among which the median follow–up was 36.6 mon in metastatic ccRCC patients and 18.5 mon in nccRCC patients, respectively. The one, two and three–year survival rate in metastatic ccRCC patients were 90.2%, 47.9% and 24.6%, respectively. The one–year survival rate in metastatic nccRCC patients was 60.7%, and only one patient survived over two years. Compared with ccRCC patients, those with nccRCC showed poorer prognosis (P 0.05). Conclusions Targeted therapy is efficient in the treatment of metastatic nccRCC patients and the side effects are reversible, although the prognosis is poorer compared with ccRCC. Key words: Metastatic renal cell carcinoma; Clear cell renal cell carcinoma; Non–clear cell renal cell carcinoma; Targeted therapy

Objective To explore the clinical characteristics of cardiotoxic reactions induced by nivolumab. Methods CNKI, VIP, Wanfang, PubMed, Web of Science and MEDLINE databases were searched up to September 2018. The literature containing cases on cardiotoxic reactions induced by nivolumab was collected, relevant information was extracted, and the clinical characteristics of cardiotoxic reactions induced by nivolumab were analyzed. Results A total of 22 patients enrolled in the study, including 13 males and 9 females, aged 35-80 years, of them, 70.3% (17 cases) patients were>60 years old. Primary diseases of the patients included malignant melanoma (9 patients), lung adenocarcinoma (6 patients), squamous cell carcinoma of lung (2 patients), type B3 thymoma (1 patient), non-small-cell lung cancer (1 patient), Merkel cell carcinoma (1 patient), uveal melanoma (1 patient), and clear cell renal cell carcinoma (1 patient). There were 6, 1, 1, and 4 patients with history of hypertension, cardiac pacemaker implantation, pseudo bundle branch block syndrome, and targeted therapy with tyrosine kinase inhibitor, respectively. Of the 22 patients, 15 patients received nivolumab monotherapy, 6 patients received combination therapy with nivolumab and ipilimumab, and one patient received 3 months′ ipilimumab before nivolumab. There were 2 patients received nivolumab without reasonable dosage and frequency according to the specifications, and 10 patients with missing information of drug dosage and frequency. Cardiotoxic reactions appeared 47 times totally in the 22 patients, mainly including myocarditis (13 times), heart block (6 times), pericardial effusion (5 times), and etc., and mainly performing as the clinical characteristics of pectoralgia, dyspnea, anhelation, and fatigue. Cardiotoxic reactions first appeared on the 4th day and lastly on the 327th day after the initial dose. After the appearance of cardiotoxic reactions, nivolumab were stopped immediately in 20 patients and after the reactions improved in 1 patient, while intermittent medication was conducted in another 1 patient. Of the 22 patients, 17 received symptomatic treatments, 4 received pacemaker implantation, 18 received high-dose glucocorticoid shock therapy, and 6 received immuno-therapy. Of the 22 patients, 9 (40.9%) died, 12 had improved symptoms, and 1 had unknown prognosis. Conclusions The cardiotoxic reactions induced by nivolumab were characterized by dispersed incubation period and higher mortality. The symptomatic treatments and high-dose glucocorticoid treatment have a certain positive effects. Key words: Immunotherapy; Heart; Drug-related side effects and adverse reactions; Nivolumab

Tailored immunotherapy approach with nivolumab with or without nivolumab plus ipilimumab as immunotherapeutic boost in patients with metastatic renal cell carcinoma (TITAN-RCC): a multicentre, single-arm, phase 2 trial

Objective To analyze the association between hexokinase 2 (HK2) gene expression and clinical pathological characteristics in renal clear cell carcinoma using database and bioinformatics methods. Methods Oncomine database was used to analyze the most significant differentially expressed genes between renal clear cell carcinoma and non-kidney tissue. The expression levels of mRNA and protein were detected by GPEIA and The Human Protein Atlas database. Correlation of HK2 expression level between clinicopathological features and prognosis of renal clear cell carcinoma was analyzed using LinkedOmics and KM-plotter databases, respectively. The STRING database was used to predict the potential protein interaction mechanism. Results The most significant difference protein in renal clear cell carcinoma, i.e. HK2, was found, which was highly expressed in renal clear cell carcinoma tissues, and positively correlated with pathological stage, T stage and N stage of renal cell carcinoma (all P<0.05). The overall survival rate of the renal clear cell carcinoma patients with high expression of HK2 was significantly lower than that of the patients with low expression (P<0.05). Conclusions High expression of HK2 gene may be associated with pathological staging, high T stage, high N stage, and poor prognosis of renal clear cell carcinoma. Key words: Renal clear cell carcinoma; Hexokinase 2; Bioinformatics

582 Background: Kidney injury molecule-1 (KIM-1) is overexpressed in clear cell and papillary renal cell carcinoma (RCC) and in proximal tubular kidney injury. While circulating KIM-1 is a minimally invasive biomarker for RCC, it is unknown whether kidney disease, a common comorbidity among RCC patients, impacts the association of KIM-1 with RCC outcomes. We evaluated the association between KIM-1 and outcomes in metastatic RCC after adjustment for multiple kidney injury biomarkers using plasma proteomics. Methods: Plasma samples from patients with metastatic clear cell and papillary RCC were obtained prior to 1 st line systemic therapy. Samples were analyzed using a high-throughput aptamer-based proteomics assay (SomaLogic), and results were log-transformed for analysis. Clinical and laboratory data, as well as cancer outcomes, were retrospectively curated. Spearman’s ρ was used to evaluate correlations between circulating KIM-1 and kidney injury biomarkers (cystatin C, TNFR1, TNFR2, eGFR). Cox regression analyses were used to evaluate the association between KIM-1 as a continuous variable and overall survival (OS) and progression-free survival (PFS), after adjusting for kidney injury biomarkers. Performance of KIM-1 tertiles versus IMDC risk groups for prognosticating OS was evaluated using the C-index. Results: Among 210 patients, higher baseline KIM-1 was associated with worse PFS (p = 0.004) and OS (p &lt; 0.001) in univariate Cox regression analysis (Table). The prognostic value of KIM-1 was consistent across clear cell and papillary RCC (p-value for interaction = 0.98). KIM-1 remained prognostic for PFS (p = 0.01) and OS (p &lt; 0.001) after multivariable adjustment for kidney injury biomarkers and eGFR (Table). Median follow-up was 22.1 months. Kidney injury biomarkers (cystatin C, TNFR1, TNFR2, eGFR) were correlated with each other but not with plasma KIM-1. KIM-1 tertiles (high/medium/low) were more prognostic for OS than the IMDC risk groups (C-index, KIM-1 0.63 vs. IMDC groups 0.58) and the addition of KIM-1 to the IMDC model improved its performance (C-index, KIM-1 + IMDC groups 0.64). Conclusions: Plasma KIM-1 was associated with PFS and OS in metastatic clear cell and papillary RCC. Plasma KIM-1 was not correlated with kidney injury biomarkers, suggesting that at least in metastatic RCC, circulating KIM-1 derives predominantly from tumor rather than benign kidney. The addition of KIM-1 improves IMDC model performance and may be useful for risk prognostication in RCC. Association of KIM-1 with PFS and OS in metastatic RCC. Multivariable models are adjusted for kidney injury markers (cystatin C, TNFR1, TNFR2) and eGFR. log KIM-1 HR (95% CI) p-value OS (univariate) 1.4 (1.2 – 1.7) &lt;0.001*** PFS (univariate) 1.2 (1.1 – 1.4) 0.004** OS (multivariate) 1.4 (1.2 – 1.6) &lt;0.001*** PFS (multivariate) 1.2 (1.1 – 1.3) 0.01**

The renal sinus is the fatty compartment located within the confines of the kidney not delineated from the renal cortex by a fibrous capsule. Because it contains numerous veins and lymphatics, invasion into this compartment may permit dissemination of a tumor otherwise regarded as renal-limited. Thirty-one consecutive renal carcinomas were studied: 22 clear cell renal cell carcinomas (3 multilocular cystic renal cell carcinomas), 4 chromophobe renal carcinomas, and 5 papillary renal carcinomas. The entire interface between the neoplasm and the sinus was embedded. Seventeen carcinomas did not invade the renal sinus and 16 were pT1 or pT2 tumors. Fourteen carcinomas, 13 clear cell renal cell carcinoma and one chromophobe renal carcinoma, invaded the renal sinus fat, and 9 of 14 invaded the lumen of renal sinus veins (all clear cell renal carcinomas). Although 14 of 22 clear cell renal carcinomas appeared to be renal limited pT1 and pT2 cancers, 6 of 14 carcinomas invaded sinus fat and 4 invaded into the lumen of renal sinus veins. Compared with the nine sinus-negative clear cell renal cell carcinomas, the 13 sinus-positive cancers were larger, exhibited more frequent renal capsule and renal vein involvement, and had higher nuclear grades. Renal sinus invasion was most common in clear cell renal cell carcinomas but was uncommon (one in 12) in 3 more indolent renal cell carcinomas: multilocular cystic renal cell carcinoma, chromophobe renal carcinoma, and papillary renal carcinoma. The follow-up period was short (1-17 months), but metastases developed in four of 31 cases. In three cases with metastases, carcinoma had involved the lumen of sinus veins but not the main renal vein, although two of three had also invaded through the renal capsule. This study shows that in carcinomas which appear to be renal limited (pT1/pT2), seven of 23 (30.4%) had invaded sinus fat and four of 23 (17.4%) had invaded sinus veins. We conclude that renal sinus invasion, especially sinus vein invasion, could identify a patient at risk for metastases even in a putative renal limited tumor, and suggest that all cases be examined for this feature. Renal sinus invasion merits further investigation to establish its prognostic importance and possible incorporation into future revisions of the TNM staging system for renal cell carcinomas.

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

2037 Background: Intracerebral (iCer) administration (admin) of ipilimumab (IPI) and nivolumab (NIVO) plus IV NIVO following resection of recurrent high-grade glioma (rHGG) was well tolerated and showed encouraging overall survival (OS) (J. Duerinck et al. JITC 2021). The safety of additional postoperative (postop) bi-weekly intracavitary (iCav) admin of NIVO or NIVO + IPI (: first in human intracranial CTLA-4 blockade) was investigated in a phase I trial (3+3 design with cohort expansion). Methods: Within 24h prior to surgery, 10 mg NIVO IV was admin, followed by a maximal safe resection and injection of the brain tissue lining the resection cavity with 5 mg IPI + 10 mg NIVO, and positioning of a catheter in the resection cavity connected to an Ommaya reservoir. Only in patients (pts) receiving postop iCav IPI, 10 mg NIVO and 5 mg IPI were admin via the Ommaya at the end of surgery. Postop 1, 5, or 10 mg NIVO was admin iCav as a single agent. In subsequent pts, postop 10 mg iCav NIVO was combined with 1, 5 or 10 mg iCav IPI. All postop iCav admin were combined with NIVO 10 mg IV, and repeated Q2w (&lt; 24w). On-treatment CSF samples were used for cytology, chemical analysis, and measurements of NIVO/IPI concentrations. Results: 43 pts (32 male) initiated treatment, all receiving the predefined pre- and intraop doses of IV and iCer IPI/NIVO. No unexpected AE related to the intraop treatment occurred. Postop treatment was initiated in 39 pts, all receiving 10 mg NIVO IV Q2w. Postop NIVO IV was combined with iCav NIVO 1, 5 or 10 mg in 3, 4, and 9 pts. The median number of postop IV/iCav NIVO admin was 7 (3-7), 4.5 (0-11), and 2 (1-11), resp. Next, postop iCav NIVO 10 mg was combined with iCav IPI 1, 5 or 10 mg in 10, 6, and 11 pts. The median number of postop IV/iCav NIVO + IPI admin was 3 (0-12), 4 (1-11), and 4 (0-12), resp. Dose limiting toxicity consisted of transient grade 3 aseptic neutrophilic pleocytosis with pyrexia and neurological deterioration in 1 and 3 pts treated with 5 and 10 mg IPI iCav, resp. Most frequent TRAEs were fatigue (n=24), headache (n=19), fever (n=17), and bacterial Ommaya colonization (n=11). No grade 5 AE occurred. At database lock, all pts were off study treatment, 1 pt stayed progression-free, and 5 were alive (mFU 80w (31-140)). OS compared favorably against a Belgian historical control cohort (469 pts; log rank p: 0.010) with an improved 1 and 2y OS rate (33 vs. 18.6% and 11.7 vs. 5.7%, resp.). Adding iCav IPI postop did not significantly alter PFS or OS. There was an elevated protein level and lymphocytic pleocytosis in &gt;90% of CSF samples and no evidence for NIVO accumulation in the CSF (IPI under evaluation). Conclusions: In this first in human phase I trial on intracranial CTLA-4/PD-1 blockade in pts with rHGG amenable for resection, intraop iCer and postop iCav admin of NIVO+/- IPI was found to be feasible and safe up to a bi-weekly postop iCav dose of 1 mg IPI + 10 mg NIVO; with encouraging OS results. Clinical trial information: NCT03233152 .