Immune checkpoint inhibitor therapy in metastatic renal cell carcinoma: tumour response and immune-related renal vasculitis following cytoreductive nephrectomy.

Objective: Therapeutic landscape of metastatic renal cell carcinoma (mRCC) has transformed over the last 2 decades, particularly with the advent of immune checkpoint inhibitors (ICI). While ICI offer therapeutic benefits, they can also provoke immune-related adverse events (iRAEs). Vasculitis as a clinical iRAE from ICI is rare in association with RCC treatment. Methods: This study included patients treated at our institution with ICI for mRCC (2019-2024). We collected clinicopathologic data and type and duration of immunotherapy. Histologic sections of tumors were re-reviewed by two pathologists to determine pathologic response and features of ICI-related renal injuries. Results: We identified 8 patients (median age 61.5 years) of which six (75%) presented with metastases at multiple sites, while two had recurrent oligometastatic disease post-partial nephrectomy. All patients were treated with ICI for a duration ranging from 6 to 20 months; 7 patients received combination therapy (CT) [iplimumab & nivolumab (n = 3), pembrolizumab & lenvatinib (n = 2), nivolumab & carbozantinib (n = 1), pembrolizumab & axitinib (n = 1)], while one received monotherapy (MT) (pembrolizumab). Patients were poor surgical candidates at diagnosis (25% Stage 3, 75% stage 4). Six (75%) patients had clear cell RCC (CCRCC), 2 patients had RCC with papillary and eosinophilic features. Tumor necrosis was noted in 75% of cases. Partial tumor response occurred in 7 (87.5%) patients, with 3 (37.5%) achieving tumor downstaging. One patient showed stable primary disease despite resolution of metastatic burden and none of the patients achieved complete response. Three patients (37.5%) had histopathological confirmed renal iRAEs. Two (25%) patients displayed vascular lymphocytic infiltrates, consistent with medium vessels vasculitis; they received CT for 6 months. One patient, who received CT for 20 months, showed a non-necrotizing granuloma. Conclusions: This study highlights the potential of ICIs for tumor downstaging and disease control in mRCC, though further investigation is warranted to optimize management of iRAEs and long-term outcomes. ICI-associated renal vasculitis is likely underrecognized and underreported highlighting the need for thorough pathological evaluation of non-neoplastic renal tissue in patients receiving ICI.