Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma.

BACKGROUND: No new agent has improved overall survival in patients with unresectable or metastatic urothelial carcinoma when added to first-line cisplatin-based chemotherapy. METHODS: In this phase 3, multinational, open-label trial, we randomly assigned patients with previously untreated unresectable or metastatic urothelial carcinoma either to receive intravenous nivolumab (at a dose of 360 mg) plus gemcitabine-cisplatin (nivolumab combination) every 3 weeks for up to six cycles, followed by nivolumab (at a dose of 480 mg) every 4 weeks for a maximum of 2 years, or to receive gemcitabine-cisplatin alone every 3 weeks for up to six cycles. The primary outcomes were overall and progression-free survival. The objective response and safety were exploratory outcomes. RESULTS: A total of 608 patients underwent randomization (304 to each group). At a median follow-up of 33.6 months, overall survival was longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for death, 0.78; 95% confidence interval [CI], 0.63 to 0.96; P = 0.02); the median survival was 21.7 months (95% CI, 18.6 to 26.4) as compared with 18.9 months (95% CI, 14.7 to 22.4), respectively. Progression-free survival was also longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for progression or death, 0.72; 95% CI, 0.59 to 0.88; P = 0.001). The median progression-free survival was 7.9 months and 7.6 months, respectively. At 12 months, progression-free survival was 34.2% and 21.8%, respectively. The overall objective response was 57.6% (complete response, 21.7%) with nivolumab-combination therapy and 43.1% (complete response, 11.8%) with gemcitabine-cisplatin alone. The median duration of complete response was 37.1 months with nivolumab-combination therapy and 13.2 months with gemcitabine-cisplatin alone. Grade 3 or higher adverse events occurred in 61.8% and 51.7% of the patients, respectively. CONCLUSIONS: Combination therapy with nivolumab plus gemcitabine-cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma than gemcitabine-cisplatin alone. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 901 ClinicalTrials.gov number, NCT03036098.).

Effect of HLA Genotype on Anti-PD-1 Antibody Treatment for Advanced Renal Cell Carcinoma in the SNiP-RCC Study.

Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.

Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial.

BACKGROUND: Effective adjuvant therapy for patients with resected localised renal cell carcinoma represents an unmet need, with surveillance being the standard of care. We report results from part A of a phase 3, randomised trial that aimed to assess the efficacy and safety of adjuvant nivolumab plus ipilimumab versus placebo. METHODS: The double-blind, randomised, phase 3 CheckMate 914 trial enrolled patients with localised clear cell renal cell carcinoma who were at high risk of relapse after radical or partial nephrectomy between 4-12 weeks before random assignment. Part A, reported herein, was done in 145 hospitals and cancer centres across 20 countries. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks for 12 doses plus ipilimumab (1 mg/kg) intravenously every 6 weeks for four doses, or matching placebo, via an interactive response technology system. The expected treatment period was 24 weeks, and treatment could be continued until week 36, allowing for treatment delays. Randomisation was stratified by TNM stage and nephrectomy (partial vs radical). The primary endpoint was disease-free survival according to masked independent central review; safety was a secondary endpoint. Disease-free survival was analysed in all randomly assigned patients (intention-to-treat population); exposure, safety, and tolerability were analysed in all patients who received at least one dose of study drug (all-treated population). This study is registered with ClinicalTrials.gov, NCT03138512. FINDINGS: Between Aug 28, 2017, and March 16, 2021, 816 patients were randomly assigned to receive either adjuvant nivolumab plus ipilimumab (405 patients) or placebo (411 patients). 580 (71%) of 816 patients were male and 236 (29%) patients were female. With a median follow-up of 37·0 months (IQR 31·3-43·7), median disease-free survival was not reached in the nivolumab plus ipilimumab group and was 50·7 months (95% CI 48·1 to not estimable) in the placebo group (hazard ratio 0·92, 95% CI 0·71-1·19; p=0·53). The number of events required for the planned overall survival interim analysis was not reached at the time of the data cutoff, and only 61 events occurred (33 in the nivolumab plus ipilimumab group and 28 in the placebo group). 155 (38%) of 404 patients who received nivolumab plus ipilimumab and 42 (10%) of 407 patients who received placebo had grade 3-5 adverse events. All-cause adverse events of any grade led to discontinuation of nivolumab plus ipilimumab in 129 (32%) of 404 treated patients and of placebo in nine (2%) of 407 treated patients. Four deaths were attributed to treatment with nivolumab plus ipilimumab and no deaths were attributed to treatment with placebo. INTERPRETATION: Adjuvant therapy with nivolumab plus ipilimumab did not improve disease-free survival versus placebo in patients with localised renal cell carcinoma at high risk of recurrence after nephrectomy. Our study results do not support this regimen for the adjuvant treatment of renal cell carcinoma. FUNDING: Bristol Myers Squibb and Ono Pharmaceutical.

Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.

BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

BACKGROUND: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known. METHODS: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point. RESULTS: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib. CONCLUSIONS: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).

Removal of α1-Microglobulin Using Post-Dilution Online Hemodiafiltration with Polymethylmethacrylate Membrane: An Open-Label, Single-Arm Study.

INTRODUCTION: The removal of low- and medium-molecular-weight proteins has been improved with online hemodiafiltration (OL-HDF) and hemodialysis using high-flux membranes; however, the outcomes of patients with end-stage kidney disease (ESKD) undergoing dialysis treatment are still worse than in the general population. α1-Microglobulin (α1-m), with a molecular weight of 33,000 Da, may contribute to dialysis-related disorders and mortality. However, the removal is insufficient even with current OL-HDF using the polysulfone (PS) membrane, which is common in Japan. Polymethylmethacrylate (PMMA) membranes can remove medium- to high-molecular-weight proteins by adsorption. This study aimed to assess the efficacy of removing medium- to high-molecular-weight proteins, such as α1-m and ß2-microglobulin (ß2-m), through post-dilution OL-HDF with PMMA (Post-PMMA). The assessment was conducted in comparison to pre-dilution OL-HDF with PS (Pre-PS), using an open-label, single-arm study. METHODS: Seven patients with ESKD on Pre-PS underwent Post-PMMA with replacement volume of 30 mL/min (low flow) and 50 mL/min (high flow). Clearance and removal rates of α1-m, ß2-m, small molecules, inflammatory cytokines, and albumin were measured at 60 and 240 min of treatment. RESULTS: Clearance rates of α1-m at 60 min were -2.8 ± 5.2 mL/min with Pre-PS, -0.4 ± 2.6 mL/min with Post-PMMA (low), and 0.6 ± 3.4 mL/min with Post-PMMA (high). The removal rate of α1-m was higher in Post-PMMA than that in Pre-HDF-PS (Post-PMMA [high] 17.7 ± 5.9%, Post-PMMA [low] 15.0 ± 5.6%, and Pre-PS 4.1 ± 5.5%). Adsorption clearance of ß2-m was increased with Post-PMMA. Albumin leakage in Post-PMMA was not higher than that in Pre-PS. CONCLUSION: The removal rate of α1-m with Post-PMMA was higher than that with Pre-PS. The PMMA membrane adsorbed ß2-m, suggesting the removal effect of medium- to high-molecular-weight proteins by the adsorption method. Since Post-PMMA effectively removes α1-m without excessive albumin leakage, it will be useful for patients with ESKD, especially those with a poor nutritional status.

Arteriolar hyalinization at 0-hour biopsy predicts long-term graft function in deceased kidney transplantation.

OBJECTIVES: Regarding the relationship between donor kidney quality and renal graft function after deceased kidney transplantation (KTx) following donation after cardiac death (DCD), the evaluation timing varies depending on the study. Evaluation of histology and changes in long-term renal graft function is limited. METHODS: A retrospective single-center study included 71 recipients who underwent 0-hour biopsy for KTx from DCD. The recipients were divided into two groups to evaluate factors related to renal graft function (study1). The two groups were categorized as stable graft function and poor graft function with the change of estimated glomerular filtration rate (eGFR) after KTx. The recipients were then divided into four groups to assess whether the factors identified in study1 were related to the change in long-term renal graft function (study2). They were categorized as follows: Improved, Stable, Deteriorated, and Primary non-function with the change of eGFR after KTx. RESULTS: In study1, donor age ≥ 50 years (29.5% vs. 65.2%; p = 0.09), banff arteriolar hyalinosis (ah) score (0.66 ± 0.78 vs. 1.2 ± 1.0; p = 0.018), and presence of glomerulosclerosis (43.2% vs. 76.2%; p = 0.017) were significant risk factors for poor long-term graft function. When the recipients were divided into four groups, the severity of ah correlated well with changes in long-term renal function. CONCLUSIONS: We can predict the shift in long-term renal graft function after KTx from DCD according to the severity of ah by 0-hour biopsy.

Real-world outcomes of avelumab plus axitinib as first-line therapy in patients with advanced renal cell carcinoma in Japan: A multicenter, retrospective, observational study (J-DART).

OBJECTIVES: In the phase 3 JAVELIN Renal 101 trial in patients with advanced renal cell carcinoma (aRCC), objective response rate (ORR) and progression-free survival (PFS) were significantly improved in patients treated with first-line avelumab plus axitinib vs sunitinib. Here we evaluate real-world outcomes with first-line avelumab plus axitinib in Japanese patients with aRCC. METHODS: In this multicenter, noninterventional, retrospective study, clinical data from patients with aRCC treated with first-line avelumab plus axitinib between December 2019 and December 2020 in Japan were reviewed. Endpoints included ORR and PFS per investigator assessment, and time to treatment discontinuation (TTD). RESULTS: Data from 48 patients (median age, 69 years) from 12 sites were analyzed. Median follow-up was 10.4 months (range, 2.6-16.5), and median duration of treatment was 7.4 months (range, 0.5-16.5). International Metastatic RCC Database Consortium risk category was favorable, intermediate, or poor in 16.7%, 54.2%, and 29.2% of patients, respectively. The ORR was 48.8% (95% CI, 33.3%-64.5%), including complete response in 3/43 patients (7.0%). Thirteen patients (27.1%) had disease progression or died, and median PFS was 15.3 months (95% CI, 9.7 months - not estimable). At data cutoff, 24 patients (50.0%) were still receiving avelumab plus axitinib, and median TTD was 15.2 months (95% CI, 7.4 months - not estimable). Three patients (6.3%) received high-dose corticosteroid treatment for immune-related adverse events, and 8 (16.7%) received treatment for infusion-related reactions. CONCLUSIONS: We report the first real-world evidence of the effectiveness and tolerability of first-line avelumab plus axitinib in Japanese patients with aRCC. Results were comparable with the JAVELIN Renal 101 trial.

MicroRNAs as Potential Regulators of GSK-3ß in Renal Cell Carcinoma.

The prognosis of patients with advanced renal cell carcinoma (RCC) has improved with newer therapies, including molecular-targeted therapies and immuno-oncology agents. Despite these therapeutic advances, many patients with metastatic disease remain uncured. Inhibition of glycogen synthase kinase-3ß (GSK-3ß) is a promising new therapeutic strategy for RCC; however, the precise regulatory mechanism has not yet been fully elucidated. MicroRNAs (miRNAs) act as post-translational regulators of target genes, and we investigated the potential regulation of miRNAs on GSK-3ß in RCC. We selected nine candidate miRNAs from three databases that could potentially regulate GSK-3ß. Among these, hsa-miR-4465 (miR-4465) was downregulated in RCC cell lines and renal cancer tissues. Furthermore, luciferase assays revealed that miR-4465 directly interacted with the 3' untranslated region of GSK-3ß, and Western blot analysis showed that overexpression of miR-4465 significantly decreased GSK-3ß protein expression. Functional assays showed that miR-4465 overexpression significantly suppressed cell invasion of A498 and Caki-1 cells; however, cell proliferation and migration were suppressed only in Caki-1 and A498 cells, respectively, with no effect on cell cycle and apoptosis. In conclusion, miR-4465 regulates GSK-3ß expression but does not consistently affect RCC cell function as a single molecule. Further comprehensive investigation of regulatory networks is required in this field.

Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial.

BACKGROUND: The standard of care for locoregional renal cell carcinoma is surgery, but many patients experience recurrence. The objective of the current study was to determine if adjuvant atezolizumab (vs placebo) delayed recurrence in patients with an increased risk of recurrence after resection. METHODS: IMmotion010 is a randomised, double-blind, multicentre, phase 3 trial conducted in 215 centres in 28 countries. Eligible patients were patients aged 18 years or older with renal cell carcinoma with a clear cell or sarcomatoid component and increased risk of recurrence. After nephrectomy with or without metastasectomy, patients were randomly assigned (1:1) to receive atezolizumab (1200 mg) or placebo (both intravenous) once every 3 weeks for 16 cycles or 1 year. Randomisation was done with an interactive voice-web response system. Stratification factors were disease stage (T2 or T3a vs T3b-c or T4 or N+ vs M1 no evidence of disease), geographical region (north America [excluding Mexico] vs rest of the world), and PD-L1 status on tumour-infiltrating immune cells (<1% vs ≥1% expression). The primary endpoint was investigator-assessed disease-free survival in the intention-to-treat population, defined as all patients who were randomised, regardless of whether study treatment was received. The safety-evaluable population included all patients randomly assigned to treatment who received any amount of study drug (ie, atezolizumab or placebo), regardless of whether a full or partial dose was received. This trial is registered with ClinicalTrials.gov, NCT03024996, and is closed to further accrual. FINDINGS: Between Jan 3, 2017, and Feb 15, 2019, 778 patients were enrolled; 390 (50%) were assigned to the atezolizumab group and 388 (50%) to the placebo group. At data cutoff (May 3, 2022), the median follow-up duration was 44·7 months (IQR 39·1-51·0). Median investigator-assessed disease-free survival was 57·2 months (95% CI 44·6 to not evaluable) with atezolizumab and 49·5 months (47·4 to not evaluable) with placebo (hazard ratio 0·93, 95% CI 0·75-1·15, p=0·50). The most common grade 3-4 adverse events were hypertension (seven [2%] patients who received atezolizumab vs 15 [4%] patients who received placebo), hyperglycaemia (ten [3%] vs six [2%]), and diarrhoea (two [1%] vs seven [2%]). 69 (18%) patients who received atezolizumab and 46 (12%) patients who received placebo had a serious adverse event. There were no treatment-related deaths. INTERPRETATION: Atezolizumab as adjuvant therapy after resection for patients with renal cell carcinoma with increased risk of recurrence showed no evidence of improved clinical outcomes versus placebo. These study results do not support adjuvant atezolizumab for treatment of renal cell carcinoma. FUNDING: F Hoffmann-La Roche and Genentech, a member of the Roche group.

Avelumab Plus Axitinib as First-Line Therapy for Advanced Renal Cell Carcinoma: Long-Term Results from the JAVELIN Renal 100 Phase Ib Trial.

BACKGROUND: Progression-free survival was significantly longer in patients who received avelumab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma (aRCC) in a randomized phase III trial. We report long-term safety and efficacy of avelumab plus axitinib as first-line treatment for patients with aRCC from the JAVELIN Renal 100 phase Ib trial (NCT02493751). MATERIALS AND METHODS: In this open-label, multicenter, phase Ib study, patients with untreated aRCC received avelumab 10 mg/kg every 2 weeks plus axitinib 5 mg twice daily or with axitinib for 7 days followed by avelumab plus axitinib. Safety and efficacy were assessed in all patients receiving at least one dose of avelumab or axitinib. RESULTS: Overall, 55 patients were enrolled and treated. Median follow-up was 55.7 months (95% CI, 54.5-58.7). Treatment-related adverse events of any grade or grade ≥3 occurred in 54 (98.2%) and 34 (61.8%) patients, respectively. The confirmed objective response rate was 60.0% (95% CI, 45.9-73.0), including complete response in 10.9% of patients. Median duration of response was 35.9 months (95% CI, 12.7-52.9); the probability of response was 65.8% (95% CI, 46.7-79.4) at 2 years. Median progression-free survival was 8.3 months (95% CI, 5.3-32.0). Median overall survival was not reached (95% CI, 40.8-not estimable); the 5-year overall survival rate was 57.3% (95% CI, 41.2-70.5). CONCLUSION: Five-year follow-up for combination treatment with avelumab plus axitinib in previously untreated patients with aRCC showed long-term clinical activity with no new safety signals, supporting use of this regimen within its approved indication in clinical practice (Clinicaltrials.gov NCT02493751).

Effect of genetic polymorphisms on outcomes following nivolumab for advanced renal cell carcinoma in the SNiP-RCC trial.

BACKGROUND: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. METHODS: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. RESULTS: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. CONCLUSION: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.

Treatment of muscle-invasive urothelial cancer with nivolumab (CheckMate 274 study): a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called CheckMate 274. This study looked at a new treatment for muscle-invasive urothelial cancer, a type of cancer found in the urinary tract that has spread from the inner lining of the urinary tract or bladder and into the surrounding muscle wall where it can then spread to other parts of the body. The standard treatment for muscle-invasive urothelial cancer is surgery to remove affected parts of the urinary tract. However, cancer returns in more than half of people after this surgery. Adjuvant therapy is given to people after surgery with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study started, there was no standard adjuvant treatment. WHAT HAPPENED IN THE STUDY?: In the CheckMate 274 study, researchers compared nivolumab with a placebo as an adjuvant treatment for people with muscle-invasive urothelial cancer. The aim of the study was to understand how well nivolumab worked to reduce the chance of the cancer returning after surgery. The study also looked at what side effects (unwanted or unexpected results or conditions that are possibly related to the use of a medication) people had with treatment. WHAT DO THE RESULTS MEAN?: The results showed that people who received nivolumab versus placebo: Survived longer before the cancer was detected again, including people who had programmed death ligand-1 (shortened to PD-L1) on their cancer cells. Survived longer before a secondary cancer outside of the urinary tract was detected. Experienced no differences in health-related quality of life (the impact of the treatment on a person's mental and physical health). Had similar side effects to the people who received nivolumab in other studies. Clinical Trial Registration: NCT02632409 (ClinicalTrials.gov).

The safety profile of nivolumab plus ipilimumab combination therapy in Japanese patients with renal cell carcinoma: results from post-marketing surveillance.

BACKGROUND: Nivolumab and ipilimumab combination therapy is approved in Japan for unresectable or metastatic renal cell carcinoma. Because the clinical trials supporting the approval of nivolumab and ipilimumab combination therapy included relatively few Japanese patients, post-marketing surveillance was implemented to collate further safety data for nivolumab and ipilimumab combination therapy. METHODS: Patients with unresectable or metastatic renal cell carcinoma who started nivolumab and ipilimumab combination therapy between September 2018 and December 2019 were registered in this post-marketing surveillance. The observation period was 13 weeks. Safety data included treatment-related adverse events with a particular emphasis on the gastrointestinal-related (colitis, enteritis, diarrhoea and gastrointestinal perforation) and liver-related (hepatic failure, hepatic function abnormal, hepatitis and cholangitis sclerosing) treatment-related adverse events that are listed in the risk management plan for nivolumab and ipilimumab combination therapy. RESULTS: Of the 203 patients registered, safety data were available for 159 (119 males/40 females) with a median age of 67 years (range 22-88). Seventy-one patients received nivolumab and ipilimumab combination therapy four times per usual clinical therapy, and 33 continued nivolumab monotherapy thereafter. Any-grade treatment-related adverse events were reported in 102 (64.2%) patients and grade ≥ 3 in 63 (39.6%). Hepatic function abnormalities (13.2%), rash (8.8%) and interstitial lung disease (7.5%) were the most common treatment-related adverse events. Five patients died following treatment-related adverse events. Gastrointestinal-related and liver-related treatment-related adverse events occurred in 10 (6.3%; four with grade ≥ 3 treatment-related adverse events) and 27 (17.0%; 19 with grade ≥ 3 treatment-related adverse events) patients, respectively. CONCLUSIONS: This post-marketing surveillance in patients with unresectable or metastatic renal cell carcinoma revealed a safety profile for nivolumab and ipilimumab combination therapy consistent with CheckMate 214. Furthermore, no new safety concerns were identified including gastrointestinal-related and liver-related treatment-related adverse events.

Adjuvant nivolumab versus placebo following radical surgery for high-risk muscle-invasive urothelial carcinoma: a subgroup analysis of Japanese patients enrolled in the phase 3 CheckMate 274 trial.

BACKGROUND: The phase 3 CheckMate 274 trial demonstrated superiority of adjuvant nivolumab over placebo after radical surgery in patients with high-risk muscle-invasive urothelial carcinoma. However, the efficacy and safety of adjuvant nivolumab in Japanese patients with muscle-invasive urothelial carcinoma have not been clarified. METHODS: Patients with muscle-invasive urothelial carcinoma were randomized to adjuvant nivolumab 240 mg or placebo (every 2 weeks via intravenous infusion) up to 120 days after radical surgery in CheckMate 274. RESULTS: Of 49 patients in the Japanese subgroup, 27 and 22 patients were randomized to nivolumab and placebo, respectively. Eleven and 8 patients, respectively, had tumor PD-L1 expression level of 1% or more. The median disease-free survival times in the nivolumab and placebo groups were 29.67 months (95% confidence interval 7.79-not reached) and 9.72 months (95% confidence interval 4.73-not reached), respectively (hazard ratio 0.77, 95% confidence interval 0.35-1.69). The corresponding values in patients with tumor PD-L1 expression level of 1% or more were 29.67 months (95% confidence interval 2.63-not reached) and 25.95 months (95% confidence interval 5.59-not reached) (hazard ratio 1.10, 95% confidence interval 0.31-3.92), respectively. Treatment-related adverse events of Grade 3-4 occurred in 25.9 and 13.6% of patients in the nivolumab and placebo groups, respectively. The most common treatment-related adverse events in the nivolumab group were lipase increased, amylase increased and diarrhea. The changes in quality of life scores from baseline over time were similar in both groups. CONCLUSIONS: The efficacy and safety results in the Japanese subgroup were consistent with the overall population of CheckMate 274.

Hyporesponsiveness against donor's ABO antigens of renal grafts after ABO-incompatible kidney transplantation.

BACKGROUND: ABO antigens expressed on the red blood cells (RBCs) are not identical to those expressed on the renal endothelial cells. The isohemagglutinin assay employing the RBCs is the gold standard for evaluating anti-ABO antibody (Ab) levels. However, it remains unclear whether the anti-ABO Abs detected by the isohemagglutinin assay after ABO-incompatible (ABOi) kidney transplantations (KTx) that are not associated with antibody-mediated rejection can bind to renal graft endothelial cells. METHODS: Ninety plasma samples were collected from patients with stable graft function after ABO-compatible (ABOc) or ABOi KTx. Anti-ABO Ab titers were examined by both the isohemagglutinin assay and the CD31-ABO microarray, which was developed as a mimic of the ABO antigens expressed on the renal endothelial cells. RESULTS: The antibody titers detected by the isohemagglutinin assay and the CD31-ABO microarray after the ABOc KTx relatively correlated with each other. However, the CD31-ABO microarray results showed low antibody levels against donor blood group antigens after ABOi KTx and did not correlate with the isohemagglutinin assay. In contrast, the antibody levels against non-donor blood group antigens after ABOi KTx were comparable to those after the ABOc KTx. Fourteen patients received graft biopsies, and no antibody-mediated rejection was observed in ABOi KTx recipients, except for two patients who had anti-donor-HLA Abs. CONCLUSION: The present study suggested that the anti-ABO Abs detected by the isohemagglutinin assay after ABOi KTx with stable graft function were hyporeactive to the ABO antigen of graft renal endothelial cells.

Final efficacy and safety results and biomarker analysis of a phase 2 study of cabozantinib in Japanese patients with advanced renal cell carcinoma.

BACKGROUND: Cabozantinib was established as the standard of care for the treatment of patients with renal cell carcinoma (RCC) whose disease had progressed after vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy in the global randomized trial METEOR. A phase 2 study was conducted to bridge the findings in METEOR to Japanese patients. Here, we report a biomarker analysis and update the efficacy and safety results of cabozantinib treatment. METHODS: Japanese patients with RCC who received at least one prior VEGFR-TKI were enrolled and received cabozantinib 60 mg orally once daily. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory analyses included the relationship between plasma protein hepatocyte growth factor (HGF) levels and treatment responses. RESULTS: In total, 35 patients were enrolled. The median treatment duration was 58.3 (range 5.1-131.4) weeks. The objective response rate was 25.7% (90% confidence interval [CI] 14.1-40.6). Kaplan-Meier estimate of median progression-free survival was 11.1 months (95% CI 7.4-18.4). The estimated progression-free survival proportion was 73.1% (95% CI 54.6-85.0) at 6 months. Median overall survival was not reached. Adverse events were consistent with those in METEOR and the safety profile was acceptable. Nonresponders to cabozantinib showed relatively higher HGF levels than responders at baseline. CONCLUSIONS: Updated analyses demonstrate the long-term efficacy and safety of cabozantinib in Japanese patients with advanced RCC after at least one VEGFR-TKI therapy. Responders tended to show lower baseline HGF levels ClinicalTrials.gov Identifier: NCT03339219.

Prognostic value of PD-L1 expression in recurrent renal cell carcinoma after nephrectomy: a secondary analysis of the ARCHERY study.

BACKGROUND: Nephrectomy is a curative treatment for localized renal cell carcinoma (RCC), but patients with poor prognostic features may experience relapse. Understanding the prognostic impact of programmed death-ligand 1 (PD-L1) expression in patients who underwent nephrectomy for RCC may aid in future development of adjuvant therapy. METHODS: Of 770 surgical specimens collected from Japanese patients enrolled in the ARCHERY study, only samples obtained from patients with recurrent RCC after nephrectomy were examined for this secondary analysis. Patients were categorized into low- and high-risk groups based on clinical stage and Fuhrman grade. Time to recurrence (TTR) and overall survival (OS) were analyzed. RESULTS: Both TTR and OS were shorter in patients with PD-L1-positive than -negative tumors (median TTR 12.1 vs. 21.9 months [HR 1.46, 95% CI 1.17, 1.81]; median OS, 75.8 vs. 97.7 months [HR 1.32, 95% CI 1.00, 1.75]). TTR and OS were shorter in high-risk patients with PD-L1-positive than -negative tumors (median TTR 7.6 vs. 15.3 months [HR 1.49, 95% CI 1.11, 2.00]; median OS, 55.2 vs. 83.5 months [HR 1.53, 95% CI 1.06, 2.21]) but not in low-risk patients. CONCLUSIONS: This ARCHERY secondary analysis suggests that PD-L1 expression may play a role in predicting OS and risk of recurrence in high-risk patients with localized RCC. CLINICAL TRIAL REGISTRATION: UMIN000034131.

Clinical Practice Guidelines for tuberous sclerosis complex-associated renal angiomyolipoma by the Japanese Urological Association: Summary of the update.

New clinical issues have been raised through an interval of 7 years from the previous version (2016). In this study, we update the "Clinical Practice Guidelines for tuberous sclerosis complex-associated renal angiomyolipoma" as a 2023 version under guidance by the Japanese Urological Association. The present guidelines were cooperatively prepared by the Japanese Urological Association and Japanese Society of Tuberous Sclerosis Complex; committee members belonging to one of the two societies or specializing in the treatment of this disease were selected to prepare the guidelines in accordance with the "Guidance for preparing treatment guidelines" published by Minds (2020 version). The "Introduction" consisted of four sections, "Background Questions (BQ)" consisted of four sections, "Clinical Questions (CQ)" consisted of three sections, and "Future Questions (FQ)" consisted of three sections (total: 14 sections). Concerning CQ, an agreement was confirmed through voting by the committee members based on the direction and strength of recommendation, accuracy of evidence, and recommendation comments. The present guidelines were updated based on the current evidence. We hope that the guidelines will provide guiding principles for the treatment of tuberous sclerosis complex-associated renal angiomyolipoma to many urologists, becoming a foundation for subsequent updating.

Clinical factors for tumor response, progression, and survival in nivolumab for advanced renal cell carcinoma in the SNiP-RCC study.

BACKGROUND: This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. METHODS: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). RESULTS: We included 222 patients. The median age was 69 years (interquartile range 62-74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. CONCLUSION: The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.