Incidence and Impact of Pseudoprogression and Mixed Responses in Metastatic Renal Cell Carcinoma Patients Treated with Ipilimumab/Nivolumab: A Retrospective Analysis

In several tumor types treated with Immune checkpoint inhibitors (ICIs), patients have shown transient tumor size increases or appearance of new lesions due to immune cell infiltrates and edema, followed by subsequent regression or stabilization. This phenomenon, called pseudoprogression (psPD), was first described during the treatment of melanoma with ipilimumab and has subsequently also been documented during ICI treatment in non-small cell lung carcinoma. Another atypical response pattern observed with ICI is mixed response (MR), defined as the increase of some lesions and the response of other lesions.

Our team was the first to publish data on psPD and MR in metastatic clear cell renal carcinoma (m-ccRCC) patients treated with nivolumab in the second or further line. This retrospective analysis of 94 patients showed that atypical responses such as psPD and MR occurred in 8.5 and 11.7% of the patients.

Our most recent study, of 100 patients treated with ipilimumab/nivolumab in first-line, now reports the incidence of psPD (13%) and MR (24%) on double ICIs in m-ccRCC for the first time. The incidence of psPD and MR is numerically higher in comparison to patients treated with nivolumab in monotherapy. This could be a consequence of the higher efficacy of the immunotherapy doublet compared to monotherapy. The figure below shows the comparison of the incidence (%) of subgroups of response between ipilimumab/nivolumab and nivolumab monotherapy.

In these 100 m-ccRCC patients treated with ipilimumab/nivolumab, psPD patients had only slightly inferior TTP and CSS compared to patients displaying PR as best response without a phase of psPD, but superior TTP and CSS compared to patients with SD as best response.

From all patients who presented with RECIST PD at the first CT scan evaluation on therapy (CT1), including 17 patients with unconfirmed PD (uPD) and 23 patients with MR, in 12 (30%) patients, this was a psPD and eventually led to a partial or complete response (PR or CR). Hence, when CT1 shows uPD or MR, the patient still has three chances out of 10 to evolve toward a PR.

For comparison, in m-ccRCC patients treated with nivolumab, in case of uPD or MR at CT1, 14% of patients will not evolve directly to confirmed progressive disease, but to PR or to disease stabilization.

Although the concept of psPD is well known among clinicians treating tumors with ICIs, the present data, for the first time, give a precise idea of the incidence of psPD and clinical outcomes after psPD in m-ccRCC treated with ipilimumab/nivolumab. These findings support clinicians in treating beyond progression on CT1.

Written by: Aaron Caeyman,¹ Giulia Mammone,¹ Lisa Kinget,¹ Marcella Baldewijns,² Liesbeth De Wever,³ Maarten Albersen,⁴ Philip R Debruyne,⁵ Octavie Demeulenaere,⁶ Edward Scott McTaggart,⁷ Saurabh Saraswat,⁶ Charlien Berghen,⁷ Gert De Meerleer,⁷ Stefan Naulaerts,⁷ Abhishek D Garg,⁶ Benoit Beuselinck¹

Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
Department of Pathology, University Hospitals Leuven, Leuven, Belgium.
Department of Radiology, University Hospitals Leuven, Leuven, Belgium.
Department of Urology, University Hospitals Leuven, Leuven, Belgium.
Medical Oncology Department, Kortrijk Cancer Centre, az Groeninge, Kortrijk, Belgium; Medical Technology Research Centre (MTRC), School of Life Sciences, Anglia Ruskin University, Cambridge, UK; School of Nursing & Midwifery, University of Plymouth, Plymouth, UK.
Laboratory of Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium.
Department of Radiotherapy/Oncology, University Hospitals Leuven, Leuven, Belgium.

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