However, its effectiveness and safety in rare variant RCC, in patients with brain metastases, and in the context of immune-related adverse events (irAEs) and steroid use remain less well defined. Our study sought to address these clinically relevant gaps using a real-world cohort treated at a single high-volume tertiary cancer centre.
In this retrospective analysis, we evaluated 154 patients with advanced RCC treated with first-line ipilimumab and nivolumab between 2016 and 2025. Importantly, the cohort included 35 patients with rare variant RCC and 18 patients with brain metastases — populations largely underrepresented in pivotal clinical trials. Median follow-up exceeded 20 months, allowing for mature survival analyses.
Several findings deserve particular attention. First, we observed meaningful clinical activity of ipilimumab and nivolumab not only in ccRCC but also across rare variant RCC. Objective response rates were comparable between histologies (41% in ccRCC and 38% in rare variants), despite a higher prevalence of poor-risk disease in the rare variant cohort. Responses were especially notable in tumors with sarcomatoid differentiation, reinforcing the concept that aggressive histologic features may also confer immunogenicity.
By contrast, outcomes remained poor in SMARCB1-deficient medullary RCC, underscoring the biological heterogeneity within rare variant disease and the need for subtype-specific strategies.
Second, our data provide real-world insight into patients with brain metastases, a group often excluded from landmark trials. Although overall survival in this subgroup was inferior to the broader cohort, a subset achieved durable responses, particularly when local brain-directed therapies preceded systemic treatment. These findings support the feasibility of ipilimumab and nivolumab in selected patients with brain metastases and highlight the importance of multidisciplinary management.
A central focus of our study was the relationship between irAEs, steroid use, and survival — an area of ongoing debate in immuno-oncology. Grade 3–4 irAEs occurred in approximately 28% of patients, a rate somewhat lower than that reported in randomized trials, likely reflecting real-world reporting and early intervention strategies. Notably, the development of severe irAEs was associated with improved overall survival, an association that persisted after adjustment for key prognostic variables and was robust in landmark analyses designed to mitigate immortal-time bias.
Perhaps most clinically provocative was our observation that steroid use for irAE management — including high-dose steroids (≥40 mg prednisone equivalent) — was associated with improved overall survival. This finding contrasts with concerns extrapolated from other tumor types, suggesting that steroids may blunt immunotherapy efficacy. Importantly, our analysis excluded baseline steroids given for cancer-related symptoms or brain metastases and focused specifically on steroids administered for irAEs. We interpret this association not as a protective effect of steroids per se, but rather as a surrogate marker of a vigorous immune response capable of generating both toxicity and durable tumor control.
Our study has limitations inherent to its retrospective, single-centre design and modest sample size, particularly within rare RCC subtypes. Nonetheless, the consistency of data capture and long follow-up strengthens its internal validity. Taken together, our findings support the use of ipilimumab and nivolumab in routine clinical practice across diverse RCC populations and provide reassurance that appropriate steroid management of irAEs does not appear to compromise — and may even reflect — long-term benefit.
Prospective studies and collaborative real-world registries will be essential to validate these observations and to refine treatment strategies for rare RCC variants and patients with brain metastases.
Written by: Tobias Peres and James Larkin
- Division of Medical Oncology, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom