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Multicenter Study
. 2024 Nov;19(6):893-903.
doi: 10.1007/s11523-024-01096-3. Epub 2024 Sep 17.

Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1)

Daniele Santini  1 , Haoran Li  2 , Giandomenico Roviello  3 , Se Hoon Park  4 , Enrique Grande  5 , Jakub Kucharz  6 , Umberto Basso  7 , Ondrej Fiala  8   9 , Fernando Sabino Marques Monteiro  10   11 , Alexandr Poprach  12   13 , Sebastiano Buti  14 , Javier Molina-Cerrillo  15 , Martina Catalano  3 , Tomas Buchler  16 , Emmanuel Seront  17 , Jawaher Ansari  18 , Zin W Myint  19 , Marwan Ghosn  20 , Fabio Calabrò  21 , Ray Manneh Kopp  22 , Dipen Bhuva  23 , Maria T Bourlon  24 , Michela Roberto  25 , Mattia Alberto Di Civita  25   26 , Veronica Mollica  27 , Andrea Marchetti  27   28 , Andrey Soares  10   29 , Nicola Battelli  30 , Marco Ricci  31 , Ravindran Kanesvaran  32 , Aristotelis Bamias  33 , Camillo Porta  34 , Francesco Massari #  35   36 , Matteo Santoni #  30
Affiliations
Multicenter Study

Real-World Primary Resistance to First-Line Immune-Based Combinations in Patients with Advanced Renal Cell Carcinoma (ARON-1)

Daniele Santini et al. Target Oncol. 2024 Nov.

Abstract

Background: Therapeutic advancements based on immuno-oncology combinations have revolutionized the management of patients with renal cell carcinoma. However, patients who have progressive disease as the best response, "primary refractory" (Pref), face dismal outcomes.

Objective: Our multicenter retrospective real-world study aims to assess the prevalence and clinicopathological characteristics of Pref patients.

Methods: This study collected data from 72 centers across 22 countries (1709 patients), involving patients aged ≥18 years with metastatic clear cell renal cell carcinoma. All patients were treated with first-line immune-oncology combinations. Data included patient demographics, histology, metastatic sites, and treatment responses. Radiological assessments followed Response Evaluation Criteria in Solid Tumors version 1.1. Statistical analyses employed Kaplan-Meier method, Cox proportional hazard models, logistic regression, and the receiver operating characteristic curve.

Results: In our study, the Pref rate was 19%. Nivolumab/ipilimumab showed the highest Pref rate (27%), while pembrolizumab/lenvatinib exhibited the lowest (10%). Primary refactory patients demonstrated significantly lower median overall survival (7.6 months) compared with non-Pref patients (55.7 months), p < 0.001. At the multivariate analysis, nephrectomy, sarcomatoid de-differentiation, intermediate/poor International Metastatic RCC Database Consortium risk, and bone and brain metastases emerged as significant predictors of overall survival for Pref patients with renal cell carcinoma. Logistic regression showed a significant relationship between liver metastases, intermediate/poor International Metastatic RCC Database Consortium risk, and no surgery and an increased risk of Pref. This study presents limitations, mainly because of its retrospective design.

Conclusions: The ARON-1 study provides valuable insights into Pref patients, emphasizing the challenges of this precociously resistant subgroup. Identified predictors could guide risk stratification, aiding clinicians in tailored therapeutic approaches.

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Conflict of interest statement

Declarations Funding No external funding was used in the preparation of this article. Conflicts of Interest/Compting Interests Ondrej Fiala received honoraria from Novartis, Janssen, Merck, BMS, MSD, Pierre Fabre, and Pfizer for consultations and lectures unrelated to this project. Sebastiano Buti has received honoraria for speaking at scientific events and advisory roles from Astra Zeneca, BMS, Ipsen, Merck, Eisai, MSD, Novartis, and Pfizer and research funding from Novartis and Pfizer unrelated to this project. He has also been on the advisory board for Gentili. Francesco Massari has received research support and/or honoraria from Astellas, BMS, Janssen, Ipsen, MSD, and Pfizer outside the submitted work. Enrique Grande has received honoraria for speaker engagements and advisory roles or received funding for continuous medical education from Adacap, Amgen, Angelini, Astellas, Astra Zeneca, Bayer, Blueprint, Bristol Myers Squibb, Caris Life Sciences, Celgene, Clovis-Oncology, Eisai, Eusa Pharma, Genetracer, Guardant Health, HRA-Pharma, Ipsen, ITM-Radiopharma, Janssen, Lexicon, Lilly, Merck KGaA, MSD, Nanostring Technologies, Natera, Novartis, ONCODNA (Biosequence), Palex, Pharmamar, Pierre Fabre, Pfizer, Roche, Sanofi-Genzyme, Servier, Taiho, and Thermo Fisher Scientific and research grants from Pfizer, Astra Zeneca, Astellas, and Lexicon Pharmaceuticals. All of the above are unrelated to the present paper. Alexandr Poprach has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from BMS, Ipsen, Roche, Astellas, Merck, Eisai, MSD, Novartis, and Pfizer, unrelated to this project. Javier Molina-Cerrillo declares consultant, advisory, or speaker roles for Ipsen, Roche, Pfizer, Sanofi, Janssen, and BMS unrelated to this project. Zin W. Myint has received research support from Merck unrelated to the present paper. Ray Manneh Kopp has received research support and/or honoraria from Amgen, Astellas, Astra Zeneca, Bayer, BMS, Eli Lilly, Janssen, MSD, Pfizer, Tecnofarma and Roche, unrelated to this project. Jakub Kucharz has received honoraria from Angelini, Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, IPSEN, Janssen, Merck MSD, Novartis, and Pfizer, and research funding from Novartis, all unrelated to the present paper. Fernando Sabino M. Monteiro has received research support from Janssen and Merck Sharp Dome and honoraria from Janssen, Ipsen, Bristol Myers Squibb, and Merck Sharp Dome, all unrelated to the present paper. Ravindran Kanesvaran has received fees for speaker bureau and advisory board activities from the following companies; Pfizer, MSD, BMS, Eisai, Ipsen, Johnson and Johnson, Merck, Amgen, Astellas, and Bayer, unrelated to this project. Tomáš Büchler has received research support from AstraZeneca, Roche, Bristol Myers Squibb, Exelixis, Merck KGaA, MSD, and Novartis; consulting fees from Bristol Myers Squibb, Astellas, Janssen, and Sanofi/Aventis; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Ipsen, Bristol Myers Squibb, AstraZeneca, Roche, Servier, Accord, MSD, and Pfizer, all unrelated to the present paper. Andrey Soares has received honoraria from Janssen, Pfizer, Bayer, AstraZeneca, Astellas Pharma, Merck Serono, Sanofi, Ipsen, Adium. Consulting or Advisory Role from Astellas Pharma, Janssen, Roche, Bayer, AstraZeneca, MSD, Bristol-Myers Squibb, Adium, Ipsen, and Pfizer, research Funding from Bristol-Myers Squibb (Inst), Astellas (Inst), and AstraZeneca (Inst), travel, accommodations, and expenses from Bayer, Janssen, Ipsen, Adium, MSD, and Merck Serono, and ownership in BIO, Brazilian Information Oncology. All are unrelated to this study. Camillo Porta has received honoraria from Angelini Pharma, AstraZeneca, BMS, Eisai, Exelixis, Genenta, Ipsen, Merck Serono, and MSD and acted as a Protocol Steering Committee Member for Eisai and MSD, unrelated to this project. Matteo Santoni has received research support and honoraria from Janssen, Bristol Myers Squibb, Ipsen, MSD, Astellas, A.A.A. and Bayer, all unrelated to the present paper. Daniele Santini, Haoran Li, Giandomenico Roviello, Se Hoon Park, Umberto Basso, Martina Catalano, Emmanuel Seront, Jawaher Ansari, Marwan Ghosn, Fabio Calabrò, Dipen Bhuva, Maria T. Bourlon, Michela Roberto, Mattia Alberto Di Civita, Veronica Mollica, Andrea Marchetti, Nicola Battelli, Marco Ricci, and Aristotelis Bamias have no conflicts of interest that are directly relevant to the content of this article. Tomas Buchler and Camillo Porta are Editorial Board members of Targeted Oncology. Tomas Buchler and Camillo Porta were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethics Approval The “ARON-1” project obtained approved from the Ethics Committee of the Marche Region (2021-492) and adhered to the principles outlined in the Declaration of Helsinki. Consent to Participate Informed consent was obtained from all individual participants included in the study. Consent for Publication Not applicable. Availability of Data and Material The datasets generated during and/or analyzed in the current study are available from the corresponding author on reasonable request. Code Availability Not applicable. Authors’ Contributions Conception and design: DS, MS, FM; acquisition of data: DS, MS, FM; analysis and interpretation of data: DS, MS, FM; drafting of the manuscript: DS, MS, FM; critical revision of the manuscript for important intellectual content: all authors; statistical analysis: MS; supervision: MS, FM.

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