Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world cohort of metastatic renal cell cancer (mRCC) patients. Methods: We retrospectively evaluated 43 patients with mRCC who were treated with nivolumab or with nivolumab plus ipilimumab. We considered seven specific classes of irAEs including pulmonary, hepatic, gastrointestinal, cutaneous, endocrine, rheumatological, and renal manifestations. We assessed progression-free survival (PFS) of specific irAEs classes compared to the no-irAEs group. Results: Twenty-nine out of 43 patients (67.4%) experienced a total of 49 irAEs registered. The most frequent irAE was thyroid dysfunction (n = 14). The median PFS after the beginning of therapy was significantly longer in patients with thyroid dysfunction and cutaneous reactions. In multivariate analysis, thyroid dysfunction was an independent factor for favorable outcome [HR: 0.29 (95% CI 0.11–0.77) p = 0.013]. Moreover, experiencing ≥2 irAEs in the same patient correlated in multivariate analysis with better outcome compared with none/one irAE [HR: 0.33 (95% CI 0.13–0.84) p = 0.020]. Conclusions: This retrospective study suggests an association between specific irAES (thyroid dysfunction and skin reaction) and efficacy of ICIs in metastatic RCC. Notably, multiple irAEs in a single patient were associated with better tumor response.

Mutations of the von Hippel–Lindau (VHL) tumor suppressor gene occur frequently in clear cell renal cell carcinoma (RCC), the predominant histology of kidney cancer, and have been associated with its pathogenesis and progression. Alterations of VHL lead to impaired degradation of hypoxia-inducible factor 1α (HIF1α) and HIF2α promoting neoangiogenesis, which is pivotal for cancer growth. As such, targeting the VHL-HIF axis holds relevant potential for therapeutic purposes. Belzutifan, an HIF-2α inhibitor, has been recently indicated for metastatic RCC and other antiangiogenic drugs directed against HIF-2α are currently under investigation. Further, clinical and preclinical studies of combination approaches for metastatic RCC including belzutifan with cyclin-dependent kinase 4–6 inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors achieved promising results or are ongoing. This review aims to summarize the existing evidence regarding the VHL/HIF pathway, and the approved and emerging treatment strategies that target this pivotal molecular axis and their mechanisms of resistance.

Biliary tract cancers (BTCs) are frequently diagnosed in advanced stages and are highly lethal. Immunotherapy may play a role in the treatment of these patients. Promising results come from monothe...

Introduction Avelumab and pembrolizumab are approved immune checkpoint inhibitors (ICIs) for advanced urothelial carcinoma (UC) that are used as maintenance and salvage therapies, respectively. The aim of this study was to highlight patterns of extreme response and support the development of biomarker-driven strategies to optimise patient selection and treatment sequencing. Methods This was a prospective study that included 79 patients with advanced UC treated with avelumab (n = 32) or pembrolizumab (n = 47) following platinum-based chemotherapy. Outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results Avelumab was associated with a DCR of 84.4% and a complete response (CR) rate of 34.4%, while pembrolizumab was associated with a DCR of 55.3% and a CR rate of 12.8%. Progressive disease (PD) occurred in 15.6% and 44.7% of patients, respectively. Despite differences in treatment indications and timing, median PFS and OS in patients with CR and PD were surprisingly comparable across the two agents. Conclusions These findings suggest that extreme responses to ICIs in advanced UC—ranging from complete response to primary progression—may occur irrespective of treatment setting, underscoring the pivotal role of tumour–immune biology. Biomarker-driven strategies are needed to optimise patient selection. Trial Registration OBSERVE-UC study; registration ID: CEAVC 25351.