Purpose: Data on clear-cell renal cell carcinoma (ccRCC) xenografts defined the seleno-L-methionine (SLM) dose and the plasma selenium concentrations associated with the enhancement of hypoxia-inducible factor-1α/2α degradation, stabilization of tumor vasculature, enhanced drug delivery, and efficacy of axitinib. The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC. Patients and Methods: Patients were ≥18 years with histologically and radiologically confirmed advanced or metastatic ccRCC who had received at least one prior systemic therapy, which could include axitinib (last dose ≥6 months prior to enrollment). Escalating dose levels of SLM (2,500, 3,000, and 4,000 μg) were administered orally twice daily for 14 days and then once daily concurrently with axitinib 5 mg twice daily using a 3 + 3 design in phase I. Patients were treated at the 4,000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy. Results: No dose-limiting toxicities occurred at the 4,000 μg SLM dose level. Among the 27 patients treated with 4,000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months. Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1, and stabilization of tumor vasculature by SLM are time dependent. Conclusions: SLM (4,000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy.

Representativeness of Study Participants.

Purpose:Data on clear-cell renal cell carcinoma (ccRCC) xenografts defined the seleno-L-methionine (SLM) dose and the plasma selenium concentrations associated with the enhancement of hypoxia-inducible factor-1α/2α degradation, stabilization of tumor vasculature, enhanced drug delivery, and efficacy of axitinib. The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC.Patients and Methods:Patients were ≥18 years with histologically and radiologically confirmed advanced or metastatic ccRCC who had received at least one prior systemic therapy, which could include axitinib (last dose ≥6 months prior to enrollment). Escalating dose levels of SLM (2,500, 3,000, and 4,000 μg) were administered orally twice daily for 14 days and then once daily concurrently with axitinib 5 mg twice daily using a 3 + 3 design in phase I. Patients were treated at the 4,000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy.Results:No dose-limiting toxicities occurred at the 4,000 μg SLM dose level. Among the 27 patients treated with 4,000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months. Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1, and stabilization of tumor vasculature by SLM are time dependent.Conclusions:SLM (4,000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy.

Metastatic clear cell renal cell carcinoma (ccRCC) remains largely incurable, and the efficacy of pembrolizumab plus axitinib may be limited by hypoxia-associated signaling, immunosuppressive cytokines, and metabolic reprogramming involving the TGF-β1/HIF axis. Seleno-L-methionine (SLM) is a pharmacologic inhibitor of this axis and its downstream effectors, including PD-L1 and VEGF. In a phase I/II pilot study (ClinicalTrials.gov NCT05363631), patients with newly diagnosed metastatic ccRCC received SLM twice daily for 14 days, then once daily with standard-dose axitinib; pembrolizumab was added on day 15. Endpoints included circulating (plasma) TGF-β1, plasma selenium, circulating cytokines, efficacy, and safety. Twelve patients were treated and evaluable for safety (six at 5000 µg, six at 6000 µg SLM); ten were evaluable for response. The objective response rate was 70% (complete response 40%, partial response 30%). Of the four patients with CR, two had favorable and two had intermediate International Metastatic Renal Cell Carcinoma Database Consortium disease. Grade 3 hypertension was documented in 58.3%, about twice the pivotal-trial rate, without treatment discontinuations or new toxicities. SLM increased plasma selenium and produced time-dependent inhibition of TGF-β1 and modulation of immune-related cytokines (CXCL13, IFN-γ, TNF-α, IL-6, IL-8). In this pilot study, SLM combined with axitinib and pembrolizumab showed time-dependent TGF-β1 inhibition, cytokine modulation, and encouraging antitumor activity without treatment-limiting toxicity, supporting further investigation of SLM for targeting the TGF-β1/HIF-driven immunosuppressive microenvironment in ccRCC.

Background: Wilms tumor (WT) is the most common pediatric renal malignancy, but carries a significantly worse prognosis in the adult population. Late recurrence (LR) of a primary WT, defined as disease recurrence five or more years after initial diagnosis, is rare and does not have standardized treatment regimens outside the pediatric population. In this paper we report a LR 32 years after diagnosis, the longest documented disease-free interval ever described. Case presentation: A one-year-old female patient was diagnosed with bilateral, favorable-histology WT and treated with chemotherapy. Biopsies of residual masses after treatment confirmed benign tissue, and she was observed with serial imaging for seventeen years without evidence of recurrence. Thirty-two years after initial diagnosis, she presented with gross hematuria and right-sided abdominal pain. Biopsy demonstrated of the left renal mass was consistent with a LR of WT. She received neoadjuvant chemotherapy followed by left partial nephrectomy, right radical nephrectomy, and adjuvant radiation therapy and remains cancer free without any evidence of tumor recurrence. Conclusion: This case of a 32-year treatment-free interval prior to LR is the longest such case in the medical literature. This case highlights the importance of multidisciplinary management in this rare clinical scenario of LR WT.