Neoadjuvant toripalimab combined with axitinib in patients with locally advanced clear cell renal cell carcinoma: a single-arm, phase II trial.

BACKGROUND: A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC. METHODS: This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis. RESULTS: A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24-0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1-2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size. CONCLUSION: Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study. TRIAL REGISTRATION NUMBER: clinicaltrials.gov, NCT04118855.

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase-deficient renal cell carcinoma.

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening, and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified 2 tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as excellent plasma biomarkers for early diagnosis. These 2 molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

Effectiveness and safety of immune checkpoint inhibitor monotherapy in advanced upper tract urothelial carcinoma: A multicenter, retrospective, real-world study.

INTRODUCTION: The effectiveness and safety of immune checkpoint inhibitor (ICI) monotherapy in advanced upper tract urothelial carcinoma (UTUC) is less reported. METHODS: In total, 106 consecutive advanced UTUC patients receiving ICI monotherapy were collected from nine high volume centers. Clinical outcomes were analyzed according to multiple parameters (e.g., treatment line, metastatic sites). Objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) were captured after ICI initiation. RESULTS: With a median follow-up of 12.0 months, 25 patients in the first-line group and 15 patients in the second-line group died of UTUC. We reported a median OS of 18.0 months, a median PFS of 5.0 months, and an ORR of 38.6% for patients in the first-line group; a median OS of 10.0 months, a median OS of 4.0 months, and an ORR of 27.8% for patients in the second-line group. Complete response was observed in two patients in the first-line group and one patient in the second-line group with a total complete response rate of 2.8%. In the univariate and multivariate analysis, visceral metastasis with a hazard ratio of 2.4 was associate with poor OS. The most common treatment-related adverse events included fatigue (11.3%), pruritus (10.4%), and diarrhea (6.6%). CONCLUSIONS: This real-world study suggests that ICI monotherapy is active and has acceptable toxic effects for unresectable or metastatic UTUC as first-line therapy in cisplatin-ineligible patients or second-line therapy in platinum-refractory patients.

Genomic Profiling and Response to Immune Checkpoint Inhibition plus Tyrosine Kinase Inhibition in FH-Deficient Renal Cell Carcinoma.

BACKGROUND: FH-deficient renal cell carcinoma (RCC) is a rare and exceptionally aggressive RCC subtype. There is currently limited understanding of the molecular alterations, pathogenesis, survival outcomes, and systemic therapy efficacy for this cancer. OBJECTIVE: To perform a retrospective multicenter analysis of molecular profiling and clinical outcomes for patients with FH-deficient RCC, with an emphasis on treatment response to first-line immune checkpoint inhibitor plus tyrosine kinase inhibitor (ICI/TKI) versus bevacizumab plus erlotinib (Bev/Erlo) combination therapy in patients with advanced disease. DESIGN, SETTING, AND PARTICIPANTS: The study included 77 cases of FH-deficient RCC from 15 centers across China. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Clinical characteristics, molecular correlates, 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging, and treatment outcomes were analyzed. RESULTS AND LIMITATIONS: A total of 77 patients were identified, including 70 cases with a germline FH alteration (hereditary leiomyomatosis RCC syndrome [HLRCC]-associated RCC) and seven patients with somatic FH loss. Recurrent pathogenic alterations were found in NF2 (six/57, 11%), CDH1 (six/57, 11%), PIK3CA (six/57, 11%), and TP53 (five/57, 8.8%). Sixty-seven patients were evaluable for response to first-line systemic therapy with Bev/Erlo (n = 12), TKI monotherapy (n = 29), or ICI/TKI (n = 26). ICI/TKI combination therapy was associated with more favorable overall survival on systemic treatment (hazard ratio [HR] 0.19, 95% confidence interval [CI] 0.04-0.90) and progression-free survival on first-line therapy (HR 0.22, 95% CI 0.07-0.71) compared to Bev/Erlo combination therapy. The main limitation is the retrospective study design. CONCLUSIONS: We described the genomic characteristics of FH-deficient RCC in an Asian population and observed a favorable response to ICI/TKI combinational therapy among patients with advanced disease. PATIENT SUMMARY: This real-world study provides evidence supporting the antitumour activity of combining molecular targeted therapy plus immunotherapy for kidney cancer deficient in fumarate hydratase. Further studies are needed to investigate the efficacy of this combination strategy in this rare cancer.

The efficacy and safety of first-line treatment in cisplatin-ineligible advanced upper tract urothelial carcinoma patients: a comparison of PD-1 inhibitor and carboplatin plus gemcitabine chemotherapy.

Although several programmed cell death (PD)-1 inhibitors are approved for the first-line treatment of advanced urothelial carcinoma, their efficacy remains unknown in cisplatin-ineligible patients with upper tract urothelial carcinoma (UTUC) compared with gemcitabine plus carboplatin. Data for patients with UTUC were retrospectively retrieved from the electronic medical records of nine institutions between 2018 and 2021. Patients considered ineligible for cisplatin who received either PD-1 inhibitors (n = 70) or gemcitabine plus carboplatin (n = 53) were included. Efficacy was assessed using Response Evaluation Criteria in Solid Tumors. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The objective response rate (ORR) was comparable between the PD-1 inhibitor and carboplatin-gemcitabine groups (38.6% versus 41.5%). Median PFS was 5.0 months (95% confidence interval [CI]: 2.0-8.0) in the PD-1 inhibitor group, versus 7.0 months (95% CI: 5.8-8.2) in the carboplatin-gemcitabine group (hazard ratio [HR] = 0.741, 95% CI: 0.485-1.132, p = .166). Median OS was 18 months (95% CI: 4.1-31.9) in the PD-1 inhibitor group, compared with 14 months (95% CI: 12.1-15.9) in the carboplatin-gemcitabine group (HR = 0.731, 95% CI: 0.426-1.256, p = .257). The duration of response was significantly longer in the PD-1 inhibitor group than in the carboplatin-gemcitabine group (not reached vs. 9 months, p < .001). Treatment-related adverse events were less frequent in the PD-1 inhibitor group than in the carboplatin-gemcitabine group (57.1% vs. 77.3%). In conclusion, PD-1 inhibitors displayed promising efficacy with less toxicity and longer DOR in the first-line treatment of UTUC in patients ineligible for cisplatin-based chemotherapy.

Erratum: circPTCH1 promotes invasion and metastasis in renal cell carcinoma via regulating miR-485-5p/MMP14 axis: Erratum.

[This corrects the article DOI: 10.7150/thno.47239.].

Development of a novel gene signature to predict prognosis and response to PD-1 blockade in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common kidney malignancy characterized by a poor prognosis. The treatment efficacy of immune checkpoint inhibitors (ICIs) also varies widely in advanced ccRCC. We aim to construct a robust gene signature to improve the prognostic discrimination and prediction of ICIs for ccRCC patients. In this study, adopting differentially expressed genes from seven ccRCC datasets in GEO (Gene Expression Omnibus), a novel signature (FOXM1&TOP2A) was constructed in TCGA (The Cancer Genome Atlas) database by LASSO and Cox regression. Survival and time-dependent ROC analysis revealed the strong predictive ability of our signature in discovery set, two online validation sets and one tissue microarray (TMA) from our institution. High-risk group based on the signature comprises more high-grade (G3&G4) and advanced pathologic stage (stageIII/IV) tumors and presents hyperactivation of cell cycle process according to the functional analysis. Meanwhile, high-risk tumors demonstrate an immunosuppressive phenotype with more infiltrations of regulatory T cells (Tregs), macrophages and high expressions of genes negatively regulating anti-tumor immunity. Low-risk tumors have an improved response to anti-PD-1 therapy and the predictive ability of our signature is better than other recognized biomarkers in ccRCC. A nomogram containing this signature showed a high predictive accuracy with AUCs of 0.90 and 0.84 at 3 and 5 years. Overall, this robust signature could predict prognosis, evaluate immune microenvironment and response to anti-PD-1 therapy in ccRCC, which is very promising in clinical promotion.

circPTCH1 promotes invasion and metastasis in renal cell carcinoma via regulating miR-485-5p/MMP14 axis.

Background: Circular RNAs (circRNAs) are a new class of non-coding RNAs (ncRNAs) that are derived from exons or introns by special selective shearing. circRNAs have been shown to play critical roles in various human cancers. However, their roles in renal cell carcinoma (RCC) and the underlying mechanisms remain largely unknown. Methods: A novel circRNA-circPTCH1, was identified from a microarray analysis of five paired RCC tissues. Then, we validated its expression and characterization through qRT-PCR, gel electrophoresis, RNase R digestion assays and Sanger sequencing. Functional experiments were performed to determine the effect of circPTCH1 on RCC progression both in vitro and in vivo. The interactions between circPTCH1 and miR-485-5p were clarified by RNA pull-down, luciferase reporter and RNA immunoprecipitation (RIP) assays. Results: We observed that circPTCH1 was up-regulated in RCC cell lines and tumor samples, and higher levels of circPTCH1 were significantly correlated with worse patient survival, advanced Fuhrman grade and greater risk of metastases. Elevated circPTCH1 expression led to increased migration and invasion of RCC cells both in vitro and in vivo whereas silencing circPTCH1 decreased migration and invasion and impeded the epithelial-mesenchymal transition (EMT) of RCC cells. Mechanistically, we elucidated that circPTCH1 could directly bind miR-485-5p and subsequently suppress expression of the target gene MMP14. Conclusion: circPTCH1 promotes RCC metastasis via the miR-485-5p/MMP14 axis and activation of the EMT process. Targeting circPTCH1 may represent a promising therapeutic strategy for metastatic RCC.

Expression of PBRM1 as a prognostic predictor in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitor.

OBJECTIVE: PBRM1, located on 3p21, functions as a tumor suppressor and somatic mutation of PBRM1 is frequent in clear cell renal cell carcinoma (ccRCC). This study aims to determine the influence of PBRM1 expression on the prognosis of patients with mRCC receiving tyrosine kinase inhibitor (TKI) treatment. METHODS: We identified 116 mRCC patients who were administered sunitinib or sorafenib as first-line therapy, between January 2006 and December 2016 at our institution. PBRM1 expression was assessed by immunohistochemistry. The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS), log-rank test was used to compare the survival outcomes between patients with low and high PBRM1 expression levels, and the Cox proportional hazard regression model was used to estimate the prognostic value. Prognostic accuracy was determined using Harrell concordance index, and nomograms were built to evaluate the prognosis of mRCC. RESULTS: Patients with low PBRM1 expression had significantly shorter median PFS (9 vs 26 months, P < 0.001) and OS (21 vs 44 months, P < 0.001) than those with high expression. Multivariate analysis showed that PBRM1 expression was an independent predictor of PFS (HR 1.975, P = 0.013) and OS (HR 2.282, P = 0.007). The model built by the addition of PBRM1 improved the C-index of PFS and OS to 0.72 and 0.82, respectively. CONCLUSIONS: The expression of PBRM1 could be a significant prognostic factor for mRCC patients treated with targeted therapy, and it increases the prognostic accuracy of the established prognostic model.