Impact of initial local therapy (LT) in the combination treatment era for metastatic renal cell carcinoma (mRCC): Subgroup analysis from ProPaxi study.
Authors: Guida Annalisa , Gili Alessio , Mosillo Claudia , Maruzzo Marco , Lai Eleonora , Pierantoni Francesco , Bimbatti Davide , Basso Umberto , Fornarini Giuseppe , Rebuzzi Sara Elena , Calabrò Fabio , Cerbone Linda , Sirgiovanni Grazia , Mammarella Alex , Serafin Debora , Caffo Orazio , Scagliarini Sarah , Bracarda Sergio 
Published: February 2025

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Background:
Local therapy for managing metastatic sites may be a beneficial frontline approach for patients with mRCC. However, existing data are limited to retrospective studies involving patients treated mainly with tyrosine kinase inhibitors (TKIs). This study aims to characterize the initial LT approach prior to the initiation of immuno-TKI combinations.
Methods:
ProPaxi is a prospective observational study that enrolled pts treated with the Pembrolizumab/Axitinib (Paxi) combination as first-line therapy. We conducted a retrospective analysis of pts characteristics and outcomes when LT was used as a frontline approach.
Results:
From December 2020 to September 2023 ProPaxi study enrolled 170 pts, of whome 56 (33%) received LT as frontline therapeutic approach. The majority had clear-cell histology (86%). Approximately half of pts (46%) had synchronous metastasis and nephrectomy was performed in 60% of cases. Stratifying by IMDC criteria at the time of the start of systemic treatment, 11 pts (20%) were classified as favorable-risk, 32(59%) as intermediate-risk, and 12 (21%) as poor-risk. Additionally, around half of pts (52%) had time-to-treatment start longer than 1 year as prognostic factors; this was the only prognostic factor in 18% of cases. Bone was the most commonly treated metastatic site, accounting for 50% of cases, followed by the lung (14%) and brain (13%). The types of LT administered were as follows: radiotherapy (46%), surgery (43%), and other (11%). The objectives of treatment included: pain control (30%), curative treatment for local complications (29%), prevention of local complications (29%), and achieving complete response or delaying systemic treatment (30%). In one-fifth of patients (21%), there were multiple objectives for the local therapy. Radiotherapy was the most frequently used treatment for pain control, applied in 94% of cases. For managing local complications, surgery and radiotherapy were also common, accounting for 31% and 38%, respectively. Both treatments were equally utilized (38%) for the prevention of local complications. Surgery was the predominant approach for achieving complete response or delaying systemic treatment, used in 88% of cases. The mean time from metastasis diagnosis to treatment start was 7.9 months (95% CI: 4.1–11.2) for patients who received LT versus 2.5 months (95% CI: 1.9–3.1) for those who did not (p < 0.001). No significant differences were observed in progression-free survival (PFS) or overall survival (OS).
Conclusions:
This analysis describes for the first time the current approach to implementing LT for the management of mRCC. Thus, LT emerges as a valid and established option even in the era of immuno-TKI combinations. The objective of therapy appears to be the key factor in determining the choice of treatment in clinical practice.