Pseudoprogression and Mixed Responses in Metastatic Renal Cell Carcinoma Patients Treated With Nivolumab: A Retrospective Analysis

Introduction: Immune checkpoint inhibitors (ICI) are part of the current standard of care for metastatic clear-cell renal cell carcinoma (m-ccRCC). ICI can elicit diverse tumor response, including atypical responses such as pseudoprogression (psPD), mixed responses (MR) and late responses. We aimed to analyze the occurrence and prognostic impact of atypical responses in m-ccRCC patients treated with nivolumab. Materials and methods: A retrospective analysis of m-ccRCC patients treated with nivolumab in first or subsequent therapy line between November 2012 and July 2022 was performed. All radiographic evaluations of eligible patients were analyzed using the iRECIST consensus guideline. Results: We assessed 247 baseline target lesions in 94 eligible patients. MR occurred in 11 (11.7%) patients: in 7 at first CT (computed tomography) evaluation (CT1) and in 4 at second CT evaluation (CT2). In 8 patients (73%), MR evolved to confirmed PD. In 3 patients (27%), MR evolved towards a partial response (PR) and was thus a psPD. psPD occurred in 8 (8.5%) patients: with psPD features at CT1 in 3 patients, with psPD features at CT2 in 2 patients, and with MR features at CT1 in 3 patients. psPD patients had similar progression-free survival and overall survival compared to patients displaying PR as best response without a phase of psPD. 76 patients were treated beyond immune unconfirmed progressive disease (iUPD) at any moment: 12 (16%) of them evolved towards PR or stable disease (SD). Treatment beyond immune confirmed PD (iCPD) in 20 patients did not lead to PR or SD. Conclusion: Atypical responses such as psPD and MR occurred in 8.5% and 11.7% of m-ccRCC patients treated with nivolumab at CT1 and CT2. Patients with psPD had favorable outcomes, while MR most often evolved to progression. Treatment with nivolumab beyond iCPD did not lead to tumor stabilization or regression.