International multicenter real-world REGistry for patients with metastatic renAL cell carcinoma – Meet-URO 33 study (REGAL study)

International multicenter real-world REGistry for patients with metastatic renAL cell carcinoma – Meet-URO 33 study (REGAL study) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol International multicenter real-world REGistry for patients with metastatic renAL cell carcinoma – Meet-URO 33 study (REGAL study) Sara Elena Rebuzzi, Giuseppe Fornarini, Alessio Signori, Sebastiano Buti, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3419200/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 12 You are reading this latest preprint version Abstract Background: Nowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear. Methods: The REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1 st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the Meet-URO score compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile. Discussion: Considering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity. Trial Registration: CESC IOV 2023-78. metastatic renal cell carcinoma first-line immunotherapy immune checkpoint inhibitor clinical practice real-world IMDC score Meet-URO score prospective retrospective Background For decades, the standard treatment of mRCC was based on the inhibition of angiogenesis using the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) [ 1 , 2 ]. Over the past 5 years, immune-checkpoint inhibitors (ICIs) have significantly improved the therapeutic landscape of mRCC [ 3 , 4 ]. In 2015, nivolumab was the first ICI approved for the treatment of mRCC patients progressing to VEGFR-TKIs [ 5 , 6 ]. More recently, ICI-based combinations have become the novel first-line standard of care, according to their superiority in terms of response and survival outcomes compared with sunitinib [ 7 – 12 ]. Based on the results of phase III trials, four combination strategies are now available in Europe for the treatment of mRCC: nivolumab plus ipilimumab for IMDC intermediate and poor risk patients and pembrolizumab plus axitinib, nivolumab plus cabozantinib and pembrolizumab plus lenvatinib regardless of the IMDC risk group. However, the lack of direct comparisons between these ICI-based combinations represents an urgent issue in clinical practice. Nowadays, the regimen choice is based on the toxicity profile, the need for tumor shrinkage and disease control which seems to be better reached with TKI + ICIs combinations, and on the presence of sarcomatoid features, on which TKIs seem to be less effective [ 13 , 14 ]. Furthermore, in favorable risk classes, ICIs + TKIs combinations showed a benefit in progression-free survival (PFS) but not in overall survival (OS), suggesting that some selected categories of patients with indolent disease could still benefit from the TKI monotherapy [ 15 , 16 ]. Given the availability of ICI-based combinations in the first-line, establishing the optimal therapeutic sequence remains undefined [ 17 ]. Cabozantinib monotherapy is the recommended option after failure of immune combinations given its multitarget activity and the efficacy reported by retrospective data [ 18 ]. According to the different first-line combination strategies available and the lack of any direct comparison between these regimens, the identification of clinical and biological prognostic and predictive factors to select patients and help the clinicians’ therapeutic choice is still an unmet clinical need. For this reason, a new prognostic score (Meet-URO score) was developed from a multicentric retrospective Italian study on 571 mRCC patients receiving 2nd line nivolumab [ 19 ]. The Meet-URO score combines the IMDC score with two well-known risk factors, the presence of bone metastases and the neutrophil-to-lymphocyte ratio (NLR). The Meet-URO score demonstrated a higher prognostic accuracy compared with the IMDC score alone, identifying 5 risk groups with different survival outcomes [ 19 ]. The aim of the Meet-URO 33 study (REGAL study) is to set up a large-scale real-world database to identify prognostic and predictive factors to help clinical decision-making, compare the Meet-URO score and the IMDC score, and assess the different response and survival outcomes and toxicity profile of the different immuno-combinations. Methods/design Study design The Meet-URO 33 study (REGAL study) is an international multicentric prospective observational study, which includes patients with a histological diagnosis of RCC and advanced stage treated with first-line systemic therapy in a real-world setting. A retrospective cohort of mRCC patients who underwent first-line systemic therapy from the 1st of January 2021 will also be included. Eighty-four Italian centers are included in the study and a study amendment will be submitted to include about 10 European centers. For its registry nature, this study does not have a maximum limit of patients analyzed. Overall, it is estimated to enrol approximately 200 patients in the retrospective part and over 500 patients in the prospective part. For the prospective part, the enrollment will last about 5 years. Recruitment method Before performing any study procedure, the signature of informed consent is required from each patient. A copy of the consent will be given to the patient. After confirming the presence of all the inclusion criteria and the absence of all exclusion criteria, the patient can be enrolled in the observational study. Eligibility criteria Inclusion criteria Participants meeting all of the following criteria will be considered for enrollment: Age ≥ 18 years old; Histological diagnosis of RCC and advanced stage treated with first-line systemic therapy according to clinical practice, which was started from the 1st of January 2021; Availability of complete oncological and medical records; Written informed consent signed. Exclusion criteria Participants meeting one of the following criteria will be excluded from enrollment in this study: Histological diagnosis of non-RCC (e.g. urothelial carcinoma, sarcoma); mRCC patients in active surveillance; No clinical data available. Treatment In consideration of the non-interventional, descriptive and observational nature, the present study will not influence the current or future therapeutic choices (immuno-combinations or TKI monotherapies). Patients will be treated with different systemic and/or local therapies, as part of normal clinical practice, regardless of study enrollment. Objectives Primary objective The primary objective of the study is the identification of potential prognostic and/or predictive factors of mRCC. Secondary objectives The secondary objectives included: to compare different first-line and subsequent-line oncological treatments according to response and survival outcomes and toxicity profile; to assess the correlation between the clinical and tumor characteristics and the choice of the first line of treatment; To assess the prognostic accuracy of the Meet-URO score compared with the standard IMDC score. Exploratory Objectives Given the observational and prospective nature of the study, further studies will be planned subsequently, both on the entire cohort and particular subgroups (e.g. poor-risk category, elderly, non-clear cell histology). Data collection An international database of mRCC patients undergoing first-line systemic therapy will be established on the RedCap platform. In particular, the subsequent data will be required: name of the center, patient code, sex, date of birth, histology, grading and molecular assessments if available, date of the first diagnosis, date of the metastatic disease diagnosis, data on surgery or locoregional treatments for localized disease if performed, sites of metastatic disease, starting and ending date for each systemic treatment, surgical or locoregional procedures performed for metastatic disease, blood chemistry performed before and during treatment, Eastern Cooperative Oncology Group Performance Status (ECOG PS) before starting systemic therapy, toxicity profile, best radiological response, site and date of progressive disease, last follow-up date, death. Statistical analysis The descriptive statistics will be used to summarize the clinical characteristics of patients and the distribution of possible prognostic factors. All time-to-event endpoints (PFS, OS) will be analyzed using the Kaplan-Meier method, the restricted mean survival time (RMST) and the Cox proportional hazard regression model. The binary endpoints (ORR, DCR) will instead be analyzed through relative frequencies and logistic regression. For all the comparisons between treatments, all causal inference techniques such as propensity scores and marginal structural models will be used. All the steps for a correct target trial emulation strategy will be followed to avoid potential biases deriving from the observational nature of the study. In particular, in comparing the different treatments, the principles of emulating a clinical trial will be applied [ 20 ], developing appropriate ad hoc protocols for each planned comparison. Discussion The treatment landscape of mRCC patients has been revolutionized with the onset of different first-line immuno-combinations in the last few years. No head-to-head comparison data are available and no predictive biomarkers have been identified. Due to these limits, the choice between the different therapeutic regimens is now guided by clinical and tolerability parameters, on regulatory approval and the possible treatment sequence. Recently, several reviews and meta-analyses have been performed comparing the multiple first-line treatments for mRCC [ 7 , 14 , 21 – 23 ]. One of the most recent ones [ 14 ] reported that pembrolizumab plus lenvatinib was associated with the highest probability of providing PFS and OS benefit and yielded the highest probability of being the best treatment in terms of PFS regardless of the IMDC risk group. Moreover, in this meta-analysis nivolumab plus cabozantinib and nivolumab plus ipilimumab had the highest possibility to be the best treatment for the sarcomatoid subgroup. However, these data as the ones from the previous meta-analyses and reviews, may be based on partial and immature data and should be taken with caution since formal comparisons are still urgently awaited. With the institution of a large-scale real-world database on mRCC patients starting first-line therapy, head-to-head comparisons will be performed between the different immune combinations according to response and survival outcomes and toxicity profile. This project is fundamental to identifying the more effective treatment according to clinical and tumoral prognostic and predictive factors. Among them, the Meet-URO score will be assessed in this context and compared with the IMDC score. Moreover, the study will also analyze the different toxicity profiles in a real-world population, providing more data to help clinicians in decision-making. The implementation of the study with ad-hoc sub-analysis on specific patients or tumor subgroups will also be encouraged. In conclusion, this study aims to provide new real-world evidence on the first-line and subsequent therapies in mRCC and answers to the issues still present in clinical practice. Abbreviations mRCC: metastatic Renal Cell-Carcinoma IMDC: International Metastatic RCC Database Consortium Risk Model for Metastatic Renal Cell Carcinoma TKIs: Tyrosine-kinase Inhibitors VEGFR-TKI: Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor ICIs: Immune-checkpoints Inhibitors PFS: Progression-free Survival OS: Overall Survival NLR: Neutrophil-to-Lymphocyte Ratio ECOG PS: Eastern Cooperative Oncology Group Performance Status KM: Kaplan-Meier method RMST: Restricted Mean Survival Time ORR: Overall Response Rate DCR: Disease Control Rate Declarations Ethics approval and consent to participate The study protocol was approved by the ethics committee of Istituto Oncologico Veneto IOV IRCCS of Padua on 1st of June 2023 (Registrational number: CESC IOV 2023-78). The study is conducted in accordance with the Good Clinical Practice (GCP) guidelines, the Helsinki Declaration and the local regulatory requirements for medical research involving human subjects. The documented approval by the local ethic committee will be required for each center as a condition for center recruitment. Investigators must inform the patients about the nature, objectives and aims of the study. All patients alive provide written informed consent before the inclusion into the study. Consent for publication Not applicable. Funding No funding was received for conducting this study. Availability of data and materials The datasets used and/or analysed during the current study will be available from the corresponding author upon reasonable request. Authors’ contributions Conception and design of the study: SER, DB, GF, AS, SB. Coordinator of the study: SER, DB, AM. Revision of the study design and protocol: all authors. Study coordination: SER, DB, GF, UB. Statistical analysis: AS. Obtaining funding and supervision: SER, DB, GF, UB. Drafting the manuscript: SER, DB. Revision and final approval of the manuscript: All authors. Competing interests SER received honoraria as speaker at scientific events and travel accommodation from BMS, Amgen, GSK, Ipsen, Astellas, Janssen and MSD. GF services advisory boards for Astellas, Janssen, Pfizer, Bayer, MSD, Merck and received travel accommodation from Astellas, Janssen, Bayer. DB received honoraria as advisory role by Ipsen, Astellas, Janssen, Novartis, BMS, MSD, Pfizer, Merck and travel accommodation from Ipsen, Janssen, MSD, Merck. UB received honoraria as advisory role by BMS, Novartis, research funding from Ipsen and travel accommodation from BMS, Janssen, Astellas, Ipsen, MSD, Merck, Pfizer, Bayer. SB received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis, Merck, Gentili, Astellas. GP services advisory boards/consulting for Astellas, AstraZeneca, BMS, Janssen, IPSEN, Merk, MSD, Novartis, Pfizer. UDG services as advisory/board member of Astellas, Bayer, BMS, IPSEN, Janssen, Merck, Pfizer, Sanofi, received research grant/funding to the institution from AstraZeneca, Roche, Sanofi and travel/accommodations/expenses from BMS, IPSEN, Janssen, Pfizer. GLB reports personal fees from AstraZeneca and Astellas for speaker bureau. PR services advisory boards for MSD, AstraZeneca and Janssen. The other authors have no conflicts of interest to disclose. Acknowledgements The authors thank the Meet-URO (Italian Network For Research In Urologic-Oncology) and all patients, physicians and study teams participating in this study References Rassy E, Flippot R, Albiges L. Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma. Ther adv Med Oncol 2020; 12: 1758835920907504. Moran M, Nickens D, Adcock K, et al. Sunitinib for metastatic renal cell carcinoma: a systematic review and meta-analysis of real-world and clinical trials data. Target Oncol 2019; 14: 405–416. de Velasco G, Bex A, Albiges L, et al. Sequencing and Combination of Systemic Therapy in Metastatic Renal Cell Carcinoma. Eur Urol Oncol. 2019 Sep;2(5):505-514. doi: 10.1016/j.euo.2019.06.022. Garje R, An J, Greco A, Vaddepally RK, Zakharia Y. The Future of Immunotherapy-Based Combination Therapy in Metastatic Renal Cell Carcinoma. Cancers (Basel). 2020;12(1):143. doi: 10.3390/cancers12010143. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813. Motzer RJ, Escudier B, George S, et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer 2020; 126: 4156–4167. Quhal F, Mori K, Bruchbacher A, et al. First-line Immunotherapy-based Combinations for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. Eur Urol Oncol. 2021;4(5):755-765. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi: 10.1136/esmoopen-2020-001079. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi: 10.1016/S1470-2045(20)30436-8. Rini BI, Plimack ER, Stus V, et al. KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. doi: 10.1056/NEJMoa1816714. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. doi: 10.1016/S1470-2045(22)00290-X. Choueiri TK, Eto M, Motzer R, et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. doi: 10.1016/S1470-2045(23)00049-9. Tran J, Ornstein MC. Clinical Review on the Management of Metastatic Renal Cell Carcinoma. JCO Oncol Pract. 2022;18(3):187-196. Lombardi P, Filetti M, Falcone R, et al. New first-line immunotherapy-based combinations for metastatic renal cell carcinoma: A systematic review and network meta-analysis. Cancer Treat Rev. 2022;106:102377. Ciccarese C, Iacovelli R, Porta C, et al. Efficacy of VEGFR-TKIs plus immune checkpoint inhibitors in metastatic renal cell carcinoma patients with favorable IMDC prognosis. 2021;100:102295 Pan E, Urman D, Malvar C, McKay RR. Managing First-Line Metastatic Renal Cell Carcinoma: Favorable-Risk Disease. Hematol Oncol Clin North Am. 2023;S0889-8588(23)00051-5. Delcuratolo MD, Tucci M, Turco F, et al. Therapeutic sequencing in advanced renal cell carcinoma: How to choose considering clinical and biological factors. Crit Rev Oncol Hematol 2023;181:103881. McGregor BA, Lalani AA, Xie W, et al. Activity of cabozantinib after immune checkpoint blockade in metastatic clear-cell renal cell carcinoma. Eur J Cancer 2020 Aug;135:203-210 Rebuzzi SE, Signori A, Banna GL, et al. Inflammatory indices and clinical factors in metastatic renal cell carcinoma patients treated with nivolumab: the development of a novel prognostic score (Meet-URO 15 study). Ther Adv Med Oncol. 2021;13:17588359211019642. Matthews AA, Danaei G, Islam N, Kurth T. Target trial emulation: applying principles of randomised trials to observational studies. BMJ. 2022;378:e071108. Powles T, [email protected] EGCommitteeE address: Recent eUpdate to the ESMO Clinical Practice Guidelines on renal cell carcinoma on cabozantinib and nivolumab for first-line clear cell renal cancer: Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021;32: 422–3. https://doi.org/10.1016/j.annonc.2020.11.016 Mori K, Mostafaei H, Miura N, Karakiewicz PI, Luzzago S, Schmidinger M, et al. Systemic therapy for metastatic renal cell carcinoma in the first-line setting: a systematic review and network meta-analysis. Cancer Immunol Immunother 2021; 70(2):265–73. https://doi.org/10.1007/s00262-020-02684-8. Massari F, Rizzo A, Mollica V, Rosellini M, Marchetti A, Ardizzoni A, et al. Immune-based combinations for the treatment of metastatic renal cell carcinoma: a meta-analysis of randomised clinical trials. Eur J Cancer 2021;154:120–7. https://doi. org/10.1016/j.ejca.2021.06.015 Additional Declarations Competing interest reported. SER received honoraria as speaker at scientific events and travel accommodation from BMS, Amgen, GSK, Ipsen, Astellas, Janssen and MSD. GF services advisory boards for Astellas, Janssen, Pfizer, Bayer, MSD, Merck and received travel accommodation from Astellas, Janssen, Bayer. DB received honoraria as advisory role by Ipsen, Astellas, Janssen, Novartis, BMS, MSD, Pfizer, Merck and travel accommodation from Ipsen, Janssen, MSD, Merck. UB received honoraria as advisory role by BMS, Novartis, research funding from Ipsen and travel accommodation from BMS, Janssen, Astellas, Ipsen, MSD, Merck, Pfizer, Bayer. SB received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis, Merck, Gentili, Astellas. GP services advisory boards/consulting for Astellas, AstraZeneca, BMS, Janssen, IPSEN, Merk, MSD, Novartis, Pfizer. UDG services as advisory/board member of Astellas, Bayer, BMS, IPSEN, Janssen, Merck, Pfizer, Sanofi, received research grant/funding to the institution from AstraZeneca, Roche, Sanofi and travel/accommodations/expenses from BMS, IPSEN, Janssen, Pfizer. GLB reports personal fees from AstraZeneca and Astellas for speaker bureau. PR services advisory boards for MSD, AstraZeneca and Janssen. The other authors have no conflicts of interest to disclose. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 23 Apr, 2024 Reviews received at journal 22 Feb, 2024 Reviewers agreed at journal 15 Feb, 2024 Reviewers agreed at journal 12 Jan, 2024 Reviews received at journal 24 Nov, 2023 Reviewers agreed at journal 09 Nov, 2023 Reviewers agreed at journal 07 Nov, 2023 Reviewers invited by journal 10 Oct, 2023 Editor assigned by journal 09 Oct, 2023 Editor invited by journal 08 Oct, 2023 Submission checks completed at journal 08 Oct, 2023 First submitted to journal 07 Oct, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3419200","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":238632434,"identity":"065fe828-72e7-4ff8-aacb-76876690f031","order_by":0,"name":"Sara Elena Rebuzzi","email":"","orcid":"","institution":"Ospedale San Paolo","correspondingAuthor":false,"prefix":"","firstName":"Sara","middleName":"Elena","lastName":"Rebuzzi","suffix":""},{"id":238632436,"identity":"e399acc9-3c4b-444d-8143-92da77254967","order_by":1,"name":"Giuseppe Fornarini","email":"","orcid":"","institution":"IRCCS Ospedale Policlinico San Martino","correspondingAuthor":false,"prefix":"","firstName":"Giuseppe","middleName":"","lastName":"Fornarini","suffix":""},{"id":238632437,"identity":"7dcf43a7-9384-47bc-aa7e-513f2156554b","order_by":2,"name":"Alessio Signori","email":"","orcid":"","institution":"University of Genova","correspondingAuthor":false,"prefix":"","firstName":"Alessio","middleName":"","lastName":"Signori","suffix":""},{"id":238632439,"identity":"4547dd3a-dd07-449b-bba5-929b7f8d52c9","order_by":3,"name":"Sebastiano Buti","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYFACHgZmEMnPztgG5rMRqcWAR7IZpoWwHogWBoPDMPMJaZFv7z34ubDtj4zxYea2Bx/32DDwyTfg12Jw5lyy9Mw2Ax6zw4zthjOepRF2mIFEjoE0L0RLmzTPgcOEtcjPf2P8G6TFGOh96T/EaGG4wWMGtsWAGaiFgRgtBmfy0qxnnDPmkQD5pedAGg8bWwIBh7WfPXy7oEzOnr+9/dmDHwds5OSbDxByGRrgIVH9KBgFo2AUjAJsAADufzfCDZtRjgAAAABJRU5ErkJggg==","orcid":"","institution":"University Hospital of Parma","correspondingAuthor":true,"prefix":"","firstName":"Sebastiano","middleName":"","lastName":"Buti","suffix":""},{"id":238632440,"identity":"004cdb2d-b3a6-4b1f-9210-27108e5486e6","order_by":4,"name":"Giuseppe Procopio","email":"","orcid":"","institution":"Fondazione IRCCS – Istituto Nazionale dei Tumori","correspondingAuthor":false,"prefix":"","firstName":"Giuseppe","middleName":"","lastName":"Procopio","suffix":""},{"id":238632442,"identity":"90720d8e-2e70-45ac-a143-fc392e461c26","order_by":5,"name":"Ugo De Giorgi","email":"","orcid":"","institution":"IRCCS Istituto Romagnolo per lo studio dei tumori (IRST) “Dino Amadori”","correspondingAuthor":false,"prefix":"","firstName":"Ugo","middleName":"","lastName":"De Giorgi","suffix":""},{"id":238632444,"identity":"9635979c-7fce-4f8f-8584-53e793799088","order_by":6,"name":"Sandro Pignata","email":"","orcid":"","institution":"Istituto Nazionale Tumori IRCCS Fondazione G. 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SER received honoraria as speaker at scientific events and travel accommodation from BMS, Amgen, GSK, Ipsen, Astellas, Janssen and MSD. GF services advisory boards for Astellas, Janssen, Pfizer, Bayer, MSD, Merck and received travel accommodation from Astellas, Janssen, Bayer. DB received honoraria as advisory role by Ipsen, Astellas, Janssen, Novartis, BMS, MSD, Pfizer, Merck and travel accommodation from Ipsen, Janssen, MSD, Merck. UB received honoraria as advisory role by BMS, Novartis, research funding from Ipsen and travel accommodation from BMS, Janssen, Astellas, Ipsen, MSD, Merck, Pfizer, Bayer. SB received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis, Merck, Gentili, Astellas. GP services advisory boards/consulting for Astellas, AstraZeneca, BMS, Janssen, IPSEN, Merk, MSD, Novartis, Pfizer. UDG services as advisory/board member of Astellas, Bayer, BMS, IPSEN, Janssen, Merck, Pfizer, Sanofi, received research grant/funding to the institution from AstraZeneca, Roche, Sanofi and travel/accommodations/expenses from BMS, IPSEN, Janssen, Pfizer. GLB reports personal fees from AstraZeneca and Astellas for speaker bureau. PR services advisory boards for MSD, AstraZeneca and Janssen. \nThe other authors have no conflicts of interest to disclose.","formattedTitle":"\u003cp\u003e International multicenter real-world REGistry for patients with metastatic renAL cell carcinoma – Meet-URO 33 study (REGAL study)\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eFor decades, the standard treatment of mRCC was based on the inhibition of angiogenesis using the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Over the past 5 years, immune-checkpoint inhibitors (ICIs) have significantly improved the therapeutic landscape of mRCC [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In 2015, nivolumab was the first ICI approved for the treatment of mRCC patients progressing to VEGFR-TKIs [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMore recently, ICI-based combinations have become the novel first-line standard of care, according to their superiority in terms of response and survival outcomes compared with sunitinib [\u003cspan additionalcitationids=\"CR8 CR9 CR10 CR11\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Based on the results of phase III trials, four combination strategies are now available in Europe for the treatment of mRCC: nivolumab plus ipilimumab for IMDC intermediate and poor risk patients and pembrolizumab plus axitinib, nivolumab plus cabozantinib and pembrolizumab plus lenvatinib regardless of the IMDC risk group.\u003c/p\u003e \u003cp\u003eHowever, the lack of direct comparisons between these ICI-based combinations represents an urgent issue in clinical practice. Nowadays, the regimen choice is based on the toxicity profile, the need for tumor shrinkage and disease control which seems to be better reached with TKI\u0026thinsp;+\u0026thinsp;ICIs combinations, and on the presence of sarcomatoid features, on which TKIs seem to be less effective [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, in favorable risk classes, ICIs\u0026thinsp;+\u0026thinsp;TKIs combinations showed a benefit in progression-free survival (PFS) but not in overall survival (OS), suggesting that some selected categories of patients with indolent disease could still benefit from the TKI monotherapy [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGiven the availability of ICI-based combinations in the first-line, establishing the optimal therapeutic sequence remains undefined [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Cabozantinib monotherapy is the recommended option after failure of immune combinations given its multitarget activity and the efficacy reported by retrospective data [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to the different first-line combination strategies available and the lack of any direct comparison between these regimens, the identification of clinical and biological prognostic and predictive factors to select patients and help the clinicians\u0026rsquo; therapeutic choice is still an unmet clinical need. For this reason, a new prognostic score (Meet-URO score) was developed from a multicentric retrospective Italian study on 571 mRCC patients receiving 2nd line nivolumab [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The Meet-URO score combines the IMDC score with two well-known risk factors, the presence of bone metastases and the neutrophil-to-lymphocyte ratio (NLR). The Meet-URO score demonstrated a higher prognostic accuracy compared with the IMDC score alone, identifying 5 risk groups with different survival outcomes [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe aim of the Meet-URO 33 study (REGAL study) is to set up a large-scale real-world database to identify prognostic and predictive factors to help clinical decision-making, compare the Meet-URO score and the IMDC score, and assess the different response and survival outcomes and toxicity profile of the different immuno-combinations.\u003c/p\u003e"},{"header":"Methods/design","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThe Meet-URO 33 study (REGAL study) is an international multicentric prospective observational study, which includes patients with a histological diagnosis of RCC and advanced stage treated with first-line systemic therapy in a real-world setting. A retrospective cohort of mRCC patients who underwent first-line systemic therapy from the 1st of January 2021 will also be included.\u003c/p\u003e \u003cp\u003eEighty-four Italian centers are included in the study and a study amendment will be submitted to include about 10 European centers.\u003c/p\u003e \u003cp\u003eFor its registry nature, this study does not have a maximum limit of patients analyzed. Overall, it is estimated to enrol approximately 200 patients in the retrospective part and over 500 patients in the prospective part. For the prospective part, the enrollment will last about 5 years.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eRecruitment method\u003c/h2\u003e \u003cp\u003eBefore performing any study procedure, the signature of informed consent is required from each patient. A copy of the consent will be given to the patient. After confirming the presence of all the inclusion criteria and the absence of all exclusion criteria, the patient can be enrolled in the observational study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEligibility criteria\u003c/h2\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003eInclusion criteria\u003c/h2\u003e \u003cp\u003eParticipants meeting all of the following criteria will be considered for enrollment:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;18 years old;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eHistological diagnosis of RCC and advanced stage treated with first-line systemic therapy according to clinical practice, which was started from the 1st of January 2021;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAvailability of complete oncological and medical records;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eWritten informed consent signed.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003eExclusion criteria\u003c/h2\u003e \u003cp\u003eParticipants meeting one of the following criteria will be excluded from enrollment in this study:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eHistological diagnosis of non-RCC (e.g. urothelial carcinoma, sarcoma);\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003emRCC patients in active surveillance;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eNo clinical data available.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003eIn consideration of the non-interventional, descriptive and observational nature, the present study will not influence the current or future therapeutic choices (immuno-combinations or TKI monotherapies). Patients will be treated with different systemic and/or local therapies, as part of normal clinical practice, regardless of study enrollment.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eObjectives\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section4\"\u003e \u003ch2\u003ePrimary objective\u003c/h2\u003e \u003cp\u003eThe primary objective of the study is the identification of potential prognostic and/or predictive factors of mRCC.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSecondary objectives\u003c/h2\u003e \u003cp\u003eThe secondary objectives included:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eto compare different first-line and subsequent-line oncological treatments according to response and survival outcomes and toxicity profile;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eto assess the correlation between the clinical and tumor characteristics and the choice of the first line of treatment;\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eTo assess the prognostic accuracy of the Meet-URO score compared with the standard IMDC score.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eExploratory Objectives\u003c/h2\u003e \u003cp\u003eGiven the observational and prospective nature of the study, further studies will be planned subsequently, both on the entire cohort and particular subgroups (e.g. poor-risk category, elderly, non-clear cell histology).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eData collection\u003c/h2\u003e \u003cp\u003eAn international database of mRCC patients undergoing first-line systemic therapy will be established on the RedCap platform. In particular, the subsequent data will be required: name of the center, patient code, sex, date of birth, histology, grading and molecular assessments if available, date of the first diagnosis, date of the metastatic disease diagnosis, data on surgery or locoregional treatments for localized disease if performed, sites of metastatic disease, starting and ending date for each systemic treatment, surgical or locoregional procedures performed for metastatic disease, blood chemistry performed before and during treatment, Eastern Cooperative Oncology Group Performance Status (ECOG PS) before starting systemic therapy, toxicity profile, best radiological response, site and date of progressive disease, last follow-up date, death.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe descriptive statistics will be used to summarize the clinical characteristics of patients and the distribution of possible prognostic factors. All time-to-event endpoints (PFS, OS) will be analyzed using the Kaplan-Meier method, the restricted mean survival time (RMST) and the Cox proportional hazard regression model. The binary endpoints (ORR, DCR) will instead be analyzed through relative frequencies and logistic regression.\u003c/p\u003e \u003cp\u003eFor all the comparisons between treatments, all causal inference techniques such as propensity scores and marginal structural models will be used. All the steps for a correct target trial emulation strategy will be followed to avoid potential biases deriving from the observational nature of the study.\u003c/p\u003e \u003cp\u003eIn particular, in comparing the different treatments, the principles of emulating a clinical trial will be applied [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], developing appropriate ad hoc protocols for each planned comparison.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe treatment landscape of mRCC patients has been revolutionized with the onset of different first-line immuno-combinations in the last few years. No head-to-head comparison data are available and no predictive biomarkers have been identified. Due to these limits, the choice between the different therapeutic regimens is now guided by clinical and tolerability parameters, on regulatory approval and the possible treatment sequence.\u003c/p\u003e \u003cp\u003eRecently, several reviews and meta-analyses have been performed comparing the multiple first-line treatments for mRCC [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. One of the most recent ones [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] reported that pembrolizumab plus lenvatinib was associated with the highest probability of providing PFS and OS benefit and yielded the highest probability of being the best treatment in terms of PFS regardless of the IMDC risk group. Moreover, in this meta-analysis nivolumab plus cabozantinib and nivolumab plus ipilimumab had the highest possibility to be the best treatment for the sarcomatoid subgroup. However, these data as the ones from the previous meta-analyses and reviews, may be based on partial and immature data and should be taken with caution since formal comparisons are still urgently awaited.\u003c/p\u003e \u003cp\u003eWith the institution of a large-scale real-world database on mRCC patients starting first-line therapy, head-to-head comparisons will be performed between the different immune combinations according to response and survival outcomes and toxicity profile. This project is fundamental to identifying the more effective treatment according to clinical and tumoral prognostic and predictive factors. Among them, the Meet-URO score will be assessed in this context and compared with the IMDC score.\u003c/p\u003e \u003cp\u003eMoreover, the study will also analyze the different toxicity profiles in a real-world population, providing more data to help clinicians in decision-making. The implementation of the study with ad-hoc sub-analysis on specific patients or tumor subgroups will also be encouraged.\u003c/p\u003e \u003cp\u003eIn conclusion, this study aims to provide new real-world evidence on the first-line and subsequent therapies in mRCC and answers to the issues still present in clinical practice.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003emRCC: metastatic Renal Cell-Carcinoma\u003c/li\u003e\n \u003cli\u003eIMDC: International Metastatic RCC Database Consortium Risk Model for Metastatic Renal Cell Carcinoma\u003c/li\u003e\n \u003cli\u003eTKIs: Tyrosine-kinase Inhibitors\u003c/li\u003e\n \u003cli\u003eVEGFR-TKI: Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor\u003c/li\u003e\n \u003cli\u003eICIs: Immune-checkpoints Inhibitors\u003c/li\u003e\n \u003cli\u003ePFS: Progression-free Survival\u003c/li\u003e\n \u003cli\u003eOS: Overall Survival\u003c/li\u003e\n \u003cli\u003eNLR: Neutrophil-to-Lymphocyte Ratio\u003c/li\u003e\n \u003cli\u003eECOG PS: Eastern Cooperative Oncology Group Performance Status\u003c/li\u003e\n \u003cli\u003eKM: Kaplan-Meier method\u003c/li\u003e\n \u003cli\u003eRMST: Restricted Mean Survival Time\u003c/li\u003e\n \u003cli\u003eORR: Overall Response Rate\u003c/li\u003e\n \u003cli\u003eDCR: Disease Control Rate\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the ethics committee of Istituto Oncologico Veneto IOV IRCCS of Padua on 1st of June 2023 (Registrational number: CESC IOV 2023-78).\u003c/p\u003e\n\u003cp\u003eThe study is conducted in accordance with the Good Clinical Practice (GCP) guidelines, the Helsinki Declaration and the local regulatory requirements for medical research involving human subjects.\u003c/p\u003e\n\u003cp\u003eThe documented approval by the local ethic committee will be required for each center as a condition for center recruitment.\u003c/p\u003e\n\u003cp\u003eInvestigators must inform the patients about the nature, objectives and aims of the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients alive provide written informed consent before the inclusion into the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for conducting this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study will be available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design of the study: SER, DB, GF, AS, SB. Coordinator of the study: SER, DB, AM. Revision of the study design and protocol: all authors. Study coordination: SER, DB, GF, UB. Statistical analysis: AS. Obtaining funding and supervision: SER, DB, GF, UB. Drafting the manuscript: SER, DB. Revision and final approval of the manuscript: All authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSER received honoraria as speaker at scientific events and travel accommodation from BMS, Amgen, GSK, Ipsen, Astellas, Janssen and MSD. GF services advisory boards for Astellas, Janssen, Pfizer, Bayer, MSD, Merck and received travel accommodation from Astellas, Janssen, Bayer. DB received honoraria as advisory role by Ipsen, Astellas, Janssen, Novartis, BMS, MSD, Pfizer, Merck and travel accommodation from Ipsen, Janssen, MSD, Merck. UB received honoraria as advisory role by BMS, Novartis, research funding from Ipsen and travel accommodation from BMS, Janssen, Astellas, Ipsen, MSD, Merck, Pfizer, Bayer. SB received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis, Merck, Gentili, Astellas. GP services advisory boards/consulting for Astellas, AstraZeneca, BMS, Janssen, IPSEN, Merk, MSD, Novartis, Pfizer. UDG services as advisory/board member of Astellas, Bayer, BMS, IPSEN, Janssen, Merck, Pfizer, Sanofi, received research grant/funding to the institution from AstraZeneca, Roche, Sanofi and travel/accommodations/expenses from BMS, IPSEN, Janssen, Pfizer. GLB reports personal fees from AstraZeneca and Astellas for speaker bureau. PR services advisory boards for MSD, AstraZeneca and Janssen.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe other authors have no conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the Meet-URO (Italian Network For Research In Urologic-Oncology) and all patients, physicians and study teams participating in this study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRassy E, Flippot R, Albiges L. Tyrosine kinase inhibitors and immunotherapy combinations in renal cell carcinoma. Ther adv Med Oncol 2020; 12: 1758835920907504.\u003c/li\u003e\n\u003cli\u003eMoran M, Nickens D, Adcock K, et al. Sunitinib for metastatic renal cell carcinoma: a systematic review and meta-analysis of real-world and clinical trials data. Target Oncol 2019; 14: 405\u0026ndash;416.\u003c/li\u003e\n\u003cli\u003ede Velasco G, Bex A, Albiges L, et al. Sequencing and Combination of Systemic Therapy in Metastatic Renal Cell Carcinoma. Eur Urol Oncol. 2019 Sep;2(5):505-514. doi: 10.1016/j.euo.2019.06.022. \u003c/li\u003e\n\u003cli\u003eGarje R, An J, Greco A, Vaddepally RK, Zakharia Y. The Future of Immunotherapy-Based Combination Therapy in Metastatic Renal Cell Carcinoma. Cancers (Basel). 2020;12(1):143. doi: 10.3390/cancers12010143. \u003c/li\u003e\n\u003cli\u003eMotzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med. 2015;373(19):1803-1813. \u003c/li\u003e\n\u003cli\u003eMotzer RJ, Escudier B, George S, et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. \u003cem\u003eCancer \u003c/em\u003e2020; 126: 4156\u0026ndash;4167. \u003c/li\u003e\n\u003cli\u003eQuhal F, Mori K, Bruchbacher A, et al. First-line Immunotherapy-based Combinations for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. Eur Urol Oncol. 2021;4(5):755-765.\u003c/li\u003e\n\u003cli\u003eAlbiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi: 10.1136/esmoopen-2020-001079. \u003c/li\u003e\n\u003cli\u003ePowles T, Plimack ER, Souli\u0026egrave;res D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi: 10.1016/S1470-2045(20)30436-8. \u003c/li\u003e\n\u003cli\u003eRini BI, Plimack ER, Stus V, et al. KEYNOTE-426 Investigators. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019 Mar 21;380(12):1116-1127. doi: 10.1056/NEJMoa1816714. \u003c/li\u003e\n\u003cli\u003eMotzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022 Jul;23(7):888-898. doi: 10.1016/S1470-2045(22)00290-X. \u003c/li\u003e\n\u003cli\u003eChoueiri TK, Eto M, Motzer R, et al. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. doi: 10.1016/S1470-2045(23)00049-9. \u003c/li\u003e\n\u003cli\u003eTran J, Ornstein MC. Clinical Review on the Management of Metastatic Renal Cell Carcinoma. JCO Oncol Pract. 2022;18(3):187-196.\u003c/li\u003e\n\u003cli\u003eLombardi P, Filetti M, Falcone R, et al. New first-line immunotherapy-based combinations for metastatic renal cell carcinoma: A systematic review and network meta-analysis. Cancer Treat Rev. 2022;106:102377. \u003c/li\u003e\n\u003cli\u003eCiccarese C, Iacovelli R, Porta C, et al. Efficacy of VEGFR-TKIs plus immune checkpoint inhibitors in metastatic renal cell carcinoma patients with favorable IMDC prognosis. 2021;100:102295\u003c/li\u003e\n\u003cli\u003ePan E, Urman D, Malvar C, McKay RR. Managing First-Line Metastatic Renal Cell Carcinoma: Favorable-Risk Disease. \u003cem\u003eHematol Oncol Clin North Am.\u003c/em\u003e 2023;S0889-8588(23)00051-5. \u003c/li\u003e\n\u003cli\u003eDelcuratolo MD, Tucci M, Turco F, et al. Therapeutic sequencing in advanced renal cell carcinoma: How to choose considering clinical and biological factors. Crit Rev Oncol Hematol 2023;181:103881.\u003c/li\u003e\n\u003cli\u003eMcGregor BA, Lalani AA, Xie W, et al. Activity of cabozantinib after immune checkpoint blockade in metastatic clear-cell renal cell carcinoma. Eur J Cancer 2020 Aug;135:203-210\u003c/li\u003e\n\u003cli\u003eRebuzzi SE, Signori A, Banna GL, et al. Inflammatory indices and clinical factors in metastatic renal cell carcinoma patients treated with nivolumab: the development of a novel prognostic score (Meet-URO 15 study). Ther Adv Med Oncol. 2021;13:17588359211019642. \u003c/li\u003e\n\u003cli\u003eMatthews AA, Danaei G, Islam N, Kurth T. Target trial emulation: applying principles of randomised trials to observational studies. BMJ. 2022;378:e071108.\u003c/li\u003e\n\u003cli\u003ePowles T, [email protected] EGCommitteeE address: Recent eUpdate to the ESMO Clinical Practice Guidelines on renal cell carcinoma on cabozantinib and nivolumab for first-line clear cell renal cancer: Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021;32: 422\u0026ndash;3. https://doi.org/10.1016/j.annonc.2020.11.016\u003c/li\u003e\n\u003cli\u003eMori K, Mostafaei H, Miura N, Karakiewicz PI, Luzzago S, Schmidinger M, et al. Systemic therapy for metastatic renal cell carcinoma in the first-line setting: a systematic review and network meta-analysis. Cancer Immunol Immunother 2021; 70(2):265\u0026ndash;73. https://doi.org/10.1007/s00262-020-02684-8.\u003c/li\u003e\n\u003cli\u003eMassari F, Rizzo A, Mollica V, Rosellini M, Marchetti A, Ardizzoni A, et al. Immune-based combinations for the treatment of metastatic renal cell carcinoma: a meta-analysis of randomised clinical trials. Eur J Cancer 2021;154:120\u0026ndash;7. https://doi. org/10.1016/j.ejca.2021.06.015\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"metastatic renal cell carcinoma, first-line, immunotherapy, immune checkpoint inhibitor, clinical practice, real-world, IMDC score, Meet-URO score, prospective, retrospective","lastPublishedDoi":"10.21203/rs.3.rs-3419200/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3419200/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eNowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1\u003csup\u003est\u003c/sup\u003e of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the Meet-URO score compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion: \u003c/strong\u003eConsidering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial Registration: \u003c/strong\u003eCESC IOV 2023-78.\u003c/p\u003e","manuscriptTitle":"International multicenter real-world REGistry for patients with metastatic renAL cell carcinoma – Meet-URO 33 study (REGAL study)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-11 16:14:14","doi":"10.21203/rs.3.rs-3419200/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-04-23T16:06:52+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-22T18:54:09+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"4aa6d0da-7642-418f-9e91-faf4885e32e3","date":"2024-02-15T08:42:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"d9077dd2-3af8-4834-bc24-cd91b423f6ec","date":"2024-01-12T17:20:10+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-11-24T16:56:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"c314ff30-bc7e-4807-b93b-3c4f8e9633bb","date":"2023-11-09T19:55:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"b14a0867-32dd-4dce-9ade-49446a2eebb7","date":"2023-11-07T19:50:58+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-10-10T11:31:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-10-09T07:31:53+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2023-10-08T16:23:55+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-10-08T16:22:50+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Cancer","date":"2023-10-07T13:26:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bcan","sideBox":"Learn more about [BMC Cancer](http://bmccancer.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bcan/default.aspx","title":"BMC Cancer","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"8817b17d-efe7-4387-aad1-9b31d89d199a","owner":[],"postedDate":"October 11th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-04-29T16:16:25+00:00","versionOfRecord":[],"versionCreatedAt":"2023-10-11 16:14:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3419200","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3419200","identity":"rs-3419200","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}