Metastatic renal cell carcinoma (mRCC) primary refractory patients to first-line IO-TKI and IO-IO combinations (Meet-URO 33 analysis).
Authors: Bimbatti Davide , Signori Alessio , Buti Sebastiano , Vignani Francesca , Paolieri Federico , Ortega Cinzia , Fratino Lucia , Cocorocchio Emilia , Lolli Cristian , Mucciarini Claudia , Buffoni Martina , Zara Diego , Sardaro Valeria , D'Ausilio Debora , Di Girolamo Stefania , Mosillo Claudia , Galeasso Letizia , Tortorella Anna , Maffezzoli Michele , Rebuzzi Sara Elena 
Published: February 2025

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Background:
Immune-combinations have become the cornerstone of the mRCC treatment scenario, but direct comparisons between the different first-line therapeutic strategies are lacking and few real-world data are available in this setting. In this context, little evidence is available on those patients with disease progression as best response (primary refractory), who have very poor prognosis and lower possibility to receive further therapies compared to the overall population.
Methods:
The Meet-URO 33 study is an Italian retrospective/prospective registry of the first-line setting of mRCC patients from January 2021 (Trial registration: CESC IOV 2023-78, PMID: 38914928) with the aim to answer as many clinical questions as possible. This analysis focused on assessing the baseline clinical characteristics and the survival outcomes of mRCC primary refractory patients to first-line immune-combinations.
Results:
Among 892 patients enrolled from 40 Italian centres, 166 (13%) primary refractory patients were assessed: 37 (31.9%) received IO-IO combination, 68 (58.6%) received IO-TKI combinations and 11 (9.5%) received TKI. After a mFUP of 6.9 months (mo), mPFS was 2.8 mo and mOS 8.2 mo, with no differences in terms of IO-TKI vs IO-IO combinations (HR for PFS = 0.75, p=0.17; HR for OS = 1.06, p=0.81). According to baseline clinical characteristics, compared to other patients, primary refractory patients have a worse IMDC score (favorable-risk: 7.1% vs 23.8%, poor-risk: 36.3% vs 18.6%, p<0.001), Meet-URO score (group 1: 7.5% vs 19.5%, group 5: 12.9% vs 6.4%, p<0.001) and performance status (ECOG PS 2-4: 19.8% vs 7.9, p<0.001); a higher use of steroids pre-first line therapy (11.2% vs 6.2%, p=0.046); a lower percentage of nephrectomy (50% vs 65.3%, p=0.001), clear cell histology (75% vs 83%, p=0.037) and sarcomatoid features (51.7% vs 58.3%, p=0.066); a higher percentage of lung (69% vs 56.1%, p=0.09), lymph node (55.2% vs 43.4%, p=0.018) and bone metastases (38.8% vs 27.8%, p=0.016); a lower percentage of pancreatic metastases (4.3% vs 9.3%, p=0.076). Primary refractory patients received a higher percentage of IO-IO combination (31.9% vs 19.3%) and a lower percentage of TKI (9.% vs 20.6%) compared to the other patients (p<0.001).
Conclusions:
These preliminary analyses of the ongoing Meet-URO 33 study show distinct baseline clinical characteristics of primary refractory mRCC patients to current first-line immune-combinations. No survival differences were recorded according to the type of immune-combination (IO-TKI vs IO-IO). A longer follow-up and further enrolment are needed to examine in depth the different performance of immune-combinations in primary refractory mRCC patients.