Impact of bone target agents on clinical outcomes in patients with metastatic renal cell carcinoma treated with Nivolumab: a sub-analysis of the Meet-URO 15 study

Francesco Pantano¹Andrea Malgeri^1*Ugo De Giorgi²Marco Maruzzo³Giuseppe Fornarini⁴Paolo Zucali^5,6Lucia Fratino⁷Michele Milella⁸Paolo Pedrazzoli⁹Giuseppe Procopio¹⁰Marco Stellato¹⁰Emanuele Naglieri¹¹Hector Soto Parra¹²Marilena Di Napoli¹³Veronica Mollica¹⁴Marianna Tudini¹⁵Stefania Pipitone¹⁶Matteo Santoni¹⁷Riccardo Ricotta¹⁸Giuseppe Luigi Banna^19,20Fabio Catalano⁴Alessia Cavo²¹FRANCESCA VIGNANI²²Cristina Masini²³Chiara Casadei²⁴Luca Galli²⁵Franco Nolè²⁶Sorarù Mariella²⁷Veronica Prati²⁸Stefano Panni²⁹Giandomenico Roviello³⁰Giuseppe Prati²³Franco Morelli³¹Carlo Messina³²Francesco Atzori³³Pasquale Rescigno³⁴Daniele Santini³⁵Sebastiano Buti³⁶Sara Elena Rebuzzi^37,38

• ¹Department of Medical Oncology, Campus Bio-Medico University Hospital, Roma, Italy
• ²Medical Oncology Department, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori', Meldola, Italy
• ³Oncologia 1, Istituto Oncologico Veneto, IOV - IRCCS, Padova, Italy
• ⁴Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, Genova, Italy
• ⁵Department of Oncology, IRCCS, Humanitas Clinical and Research Center, Milano, Italy
• ⁶Department of Biochemical Sciences, Humanitas University, Milano, Italy
• ⁷Department of Medical Oncology, CRO Aviano - Centro di Riferimento Oncologico IRCCS, Aviano, Italy
• ⁸Department of Medical Oncology, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
• ⁹Department of Internal Medicine and Medical Therapy, University of Pavia, Pavia, Italy
• ¹⁰Genitourinary Medical Oncology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milano, Italy
• ¹¹U.O. Oncologia, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
• ¹²Department of Oncology, Medical Oncology, University Hospital Policlinico-San Marco, Catania, Italy
• ¹³Department of Urology and Gynecology, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Napoli, Italy
• ¹⁴Medical Oncology, IRCCS - Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
• ¹⁵Medical Oncology, Ospedale San Salvatore, ASL1 Avezzano Sulmona, L'Aquila, Italy
• ¹⁶Medical Oncology Unit, Department of Oncology and Hemathology, University Hospital of Modena, Modena, Italy
• ¹⁷Oncology Unit, Macerata Hospital, Macerata, Italy
• ¹⁸Oncology Unit, IRCCS MultiMedica Sesto San Giovanni,, Milano, Italy
• ¹⁹Department of Oncology, Portsmouth Hospitals University NHS Trust, Portsmouth, United Kingdom
• ²⁰Faculty of Science and Health, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom
• ²¹Oncology Unit, Villa Scassi Hospital, Genova, Italy
• ²²Division of Medical Oncology, Ordine Mauriziano Hospital, Torino, Italy
• ²³Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
• ²⁴Medical Oncology Department, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
• ²⁵Medical Oncology Unit 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
• ²⁶Medical Oncology Division of Urogenital & Head & Neck Tumors, IEO, European Institute of Oncology IRCCS, Milano, Italy
• ²⁷Medical Oncology, Ospedale Camposampiero, Padova, Italy
• ²⁸Oncology Unit, Ospedale Michele e Pietro Ferrero, Verduno, Italy
• ²⁹Medical Oncology Unit, ASST - Istituti Ospitalieri Cremona Hospital, Cremona, Italy
• ³⁰Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Firenze, Firenze, Italy
• ³¹Medical Oncology Department, Casa Sollievo Della Sofferenza Hospital, IRCCS, San Giovanni Rotondo, Italy
• ³²UOC Oncology, Fondazione Istituto San Raffaele Giglio di Cefalù, Cefalù, Italy
• ³³Medical Oncology Department, University Hospital, University of Cagliari, Cagliari, Italy
• ³⁴Translationsal and Clinical Research Institute, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom
• ³⁵Oncology A, Department of Hematology, Oncology and Dermatology, Umberto I Policlinico di Roma, Rome, Italy
• ³⁶Medical Oncology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy
• ³⁷Medical Oncology Unit, Ospedale San Paolo, Savona, Italy
• ³⁸Department of Internal Medicine and Medical Specialties (Di.M.I.), Universita degli Studi di Genova, Genoa, Italy

Background: Immuno-checkpoint inhibitors have revolutionized the treatment landscape for metastatic renal cell carcinoma (mRCC). However, some patients fail to experience durable benefits, especially those with bone metastases. Objective: This study aims to evaluate the impact of bone-targeted agents (BTAs), specifically Denosumab and Zoledronic acid (ZA), on clinical outcomes in mRCC patients treated with Nivolumab. Methods: The retrospective study analyzed data from the Meet-URO 15 trial on mRCC patients receiving Nivolumab, categorizing them into BTA and non-BTA groups. Survival outcomes were assessed, with Inverse probability of treatment weighting (IPTW) adjustment for confounding variables. Subsequently, the specific impact of different bone-targeted agents on clinical outcomes was explored. Results: Of 203 mRCC patients with bone metastases, 38 received BTAs (BTA-group) while 138 did not (non-BTA group). BTA treatment significantly improved median PFS (291 vs. 117 days, p = 0.005) and OS (960 vs. 397 days, p = 0.008) compared to non-BTA group, with a reduced risk of death (HR 0.57, 95% CI 0.34-0.95; p= 0.031) and progression or death (HR 0.57, 95% CI 0.35-0.92; p = 0.023) at multivariate analyses. IPTW adjustment confirmed these survival benefits, with a reduced risk of death (HR 0.55, 95% CI 0.39-0.76; p <0.001) and progression or death (HR 0.58, 95% CI 0.42-0.79; p <0.001) in BTA patients. Furthermore, Denosumab, compared to ZA and the non-BTA group demonstrated superior OS [1662 vs. 681 vs. 411 days (p <0.001)] and PFS [1101 vs. 242 vs. 132 days (p <0.001)] in the same IPTW-adjusted population. Conclusion: This study suggests a potential beneficial impact of BTAs, especially Denosumab, in the clinical outcome after Nivolumab therapy in mRCC patients with bone metastases. Prospective trials are needed to better define the impact of BTA in mRCC patients.