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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.

Abstract 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.

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

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.