354 results on '"Giuseppe, Procopio"'
Search Results
2. A multicenter phase 2 single arm study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pre-treated with one immune-checkpoint inhibitor: The BREAKPOINT trial (Meet-Uro trial 03)
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Giuseppe Procopio, Mélanie Claps, Chiara Pircher, Luca Porcu, Pierangela Sepe, Valentina Guadalupi, Ugo De Giorgi, Davide Bimbatti, Franco Nolè, Francesco Carrozza, Sebastiano Buti, Roberto Iacovelli, Chiara Ciccarese, Cristina Masini, Cinzia Baldessari, Laura Doni, Antonio Cusmai, Angela Gernone, Sarah Scagliarini, Sandro Pignata, Filippo de Braud, and Elena Verzoni
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Cancer Research ,Oncology ,General Medicine - Abstract
Background: First-line therapies based on immune-checkpoint inhibitors (ICIs) significantly improved survival of metastatic renal cell carcinoma (mRCC) patients. Cabozantinib was shown to target kinases involved in immune-escape and to prolong survival in patients pre-treated with tyrosine-kinase-inhibitors (TKIs). The impact of ICIs combinations in first line on subsequent therapies is still unclear. Methods: This is an open label, multicenter, single arm, phase II study designed to assess activity, safety and efficacy of cabozantinib in mRCC patients progressed after an adjuvant or first line anti-Programmed Death (PD)-1/PD-Ligand (PD-L) 1-based therapy. Primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. Results: 31 patients were included in the analysis. After a median (m) follow-up of 11.9 months, mPFS was 8.3 months (90%CI 3.9-17.4) and mOS was 13.8 months (95%CI 7.7-29.0). ORR was 37.9% with an additional 13 patients achieving disease stability. Grade 3-4 adverse events occurred in 47% of patients, including more frequently creatine phosphokinase (CPK) serum level elevation, neutropenia, hyponatremia, diarrhea, hand-food syndrome, oral mucositis and hypertension. Conclusions: The BREAKPOINT trial met its primary endpoint showing that cabozantinib as second line therapy after ICIs was active in mRCC. Safety profile was manageable. Trial registration number: NCT03463681 - A Study of CaBozantinib in Patients With Advanced or Unresectable Renal cEll cArcinoma (BREAKPOINT) - https://clinicaltrials.gov/ct2/show/NCT03463681
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- 2022
3. Optimal Choice of Adjuvant Treatment for Renal Cell Carcinoma Following Nephrectomy
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Achille Bottiglieri, Pierangela Sepe, Marco Stellato, Chiara Pircher, Giuseppe Fotia, Alberto Giovanni Leone, Valentina Guadalupi, Melanie Claps, Patrizia Giannatempo, Elena Verzoni, and Giuseppe Procopio
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Oncology - Abstract
Renal cell carcinoma (RCC) is the fourteenth most common cancer worldwide. In about 55% of cases, it is diagnosed at a localised and/or locally advanced stage and therefore amenable to a curative approach. Although nephrectomy still represents the cornerstone of non-metastatic RCC (nmRCC) treatment, a relapse is observed in about 25-30% of patients undergoing curative surgery. Prognosis is drastically influenced by lymph nodal involvement. After the first disappointing results with a cytokine-based strategy, tyrosine kinase inhibitors (TKIs) were tested as adjuvant agents. Despite their efficacy in the metastatic setting, results in terms of disease-free survival (DFS) are not unequivocal and the overall survival (OS) benefit has not been demonstrated. Moreover, their toxicity profile induced a remarkable percentage of patients to discontinue the treatment. On the contrary, the KEYNOTE-564 trial showed the benefit of adjuvant pembrolizumab compared with placebo in terms of DFS with promising results in term of OS. Patients included were at intermediate or high risk of relapse, or patients with no evidence of disease after metastasectomy (M1 NED). The updated analysis presented at the American Society of Clinical Oncology Genito-Urinary (ASCO GU) 2022 confirmed the benefit of pembrolizumab versus placebo over time, although OS data are still immature. A longer follow-up and the several ongoing trials with immune checkpoint inhibitors (ICIs) will provide further data about adjuvant immuno-oncology (IO). Furthermore, the patients' selection based on clinical or biological features will be crucial in order to identify who benefits most from treatments.
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- 2022
4. Data from Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA
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Maha Hussain, Elizabeth A. Harrington, Christian Poehlein, Jinyu Kang, Christopher Gresty, Simon Dearden, Kim N. Chi, Neeraj Agarwal, Gero Kramer, Ernesto Korbenfeld, Sebastien J. Hotte, Young Deuk Choi, Michael A. Carducci, Aude Flechon, Robbert van Alphen, Yüksel Ürün, Satoru Kawakami, Giuseppe Procopio, David Olmos, Johann de Bono, and Nobuaki Matsubara
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Purpose:The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment.Patients and Methods:Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A.Results:Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients’ baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47).Conclusions:When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.
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- 2023
5. MP11-16 PROSTATE-SPECIFIC ANTIGEN ANALYSES IN PROPEL: ABIRATERONE AND OLAPARIB VERSUS ABIRATERONE AND PLACEBO AS FIRST-LINE THERAPY FOR METASTATIC CASTRATION-RESISTANT PROSTATE CANCER
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Fred Saad, Andrew J. Armstrong, Antoine Thiery-Vuillemin, Mototsugu Oya, Neal Shore, Giuseppe Procopio, Joao Daniel Guedes, Cagatay Arslan, Niven Mehra, Francis Parnis, Kurralta Park, null Australia, Emma Brown, Friederike Schlürmann, Jae Young Joung, Mikio Sugimoto, A. Oliver Sartor, Christian Poehlein, Elizabeth A. Harrington, Laura Barker, Paula Michelle del Rosario, and Noel Clarke
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Urology - Published
- 2023
6. Effect of systemic therapies or best supportive care after disease progression to both nivolumab and cabozantinib in metastatic renal cell carcinoma: The <scp>Meet‐Uro 19BEYOND</scp> study
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Giandomenico Roviello, Elisabetta Gambale, Roberta Giorgione, Daniele Santini, Marco Stellato, Giuseppe Fornarini, Sara Elena Rebuzzi, Umberto Basso, Davide Bimbatti, Laura Doni, Gabriella Nesi, Melissa Bersanelli, Sebastiano Buti, Ugo De Giorgi, Luca Galli, Andrea Sbrana, Raffaele Conca, Claudia Carella, Emanuele Naglieri, Sandro Pignata, Giuseppe Procopio, and Lorenzo Antonuzzo
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Cancer Research ,Pyridines ,Antineoplastic Agents ,Sorafenib ,fourth-line therapy ,targeted therapy ,metastatic renal cell carcinoma ,Kidney Neoplasms ,immune checkpoint inhibitors ,Nivolumab ,Oncology ,tyrosine kinase inhibitors ,Disease Progression ,Humans ,Anilides ,Radiology, Nuclear Medicine and imaging ,Everolimus ,Carcinoma, Renal Cell ,vascular endothelial growth factor receptor ,Retrospective Studies - Abstract
Nivolumab and cabozantinib are currently approved agents in metastatic renal cell carcinoma (mRCC) but there are no data available for patients progressing to both treatments. The aim of this study was to compare active therapeutic options and best supportive care (BSC) after progression to nivolumab and cabozantinib in mRCC.In this retrospective study, we selected 50 patients from eight Italian centers. The primary endpoint of the study was the overall survival (OS) of patients on active treatment versus BSC. Secondary endpoints were the progression-free survival (PFS) and objective response rate (ORR). The efficacy of active therapy was also investigated.After progression to both nivolumab and cabozantinib, 57.1% of patients were given active treatment (mainly everolimus and sorafenib) while 42.9% received BSC. The median OS was 13 months (95% CI: 4-NR) in actively treated patients and 3 months (95% CI: 2-4) in BSC patients (p = 0.001). Patients treated with sorafenib had better disease control than those treated with everolimus (stable disease: 71.4% vs. 16.7%, progression disease: 14.3% vs. 58.3%; p = 0.03), with no significant differences in PFS (5 and 3 months, 95% CI: 1-6 vs. 2-5; p = 0.6) and OS (12 and 4 months, 95% CI: 3-NR vs. 2-NR; p = 0.2).After treatment with both nivolumab and cabozantinib, the choice of a safe active systemic therapy offered better outcomes than BSC.
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- 2022
7. Hydrodynamic Green functions: paradoxes in unsteady Stokes conditions and infinite propagation velocity in incompressible viscous models
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Massimiliano Giona, Giuseppe Procopio, and Roberto Mauri
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Physics::Fluid Dynamics ,Mechanics of Materials ,Mechanical Engineering ,stokesian paradoxes ,unsteady Stokes flow ,incompressibility ,hydrodynamic Green function ,Condensed Matter Physics - Abstract
We present a simple representation of the hydrodynamic Green functions grounded on the free propagation of a vector field without any constraints (such as incompressibility) coupled with a gradient gauge in order to enforce these constraints. This approach involves the solution of two scalar problems: a couple of Poisson equations in the case of the Stokes regime, and a system of diffusion/Poisson equations for unsteady Stokes flows. The explicit and closed-form expression of the Green function for unsteady Stokes flow is developed. The relevance of this approach resides in its conceptual simplicity and it enables us to focus on the intrinsic singularities (Stokesian paradoxes) associated with the propagation of the stresses in incompressible flows under unsteady Stokes conditions, determining the occurrence of power-law tails in the velocity profile arbitrarily far away from the location of the impulsive force.
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- 2022
8. Immunotherapy and Sonpavde score validation in advanced upper tract urothelial carcinoma: a retrospective study by the Italian Network for Research in Urologic-Oncology (Meet-URO group)
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Marco Stellato, Elena Farè, Sebastiano Buti, Emanuele Naglieri, Marco Maruzzo, Melissa Bersanelli, Francesca Vignani, Sandro Pignata, Giuseppe Luigi Banna, Tania Losanno, Giuseppe Procopio, Ugo De Giorgi, Andrea Necchi, Umberto Basso, Patrizia Giannatempo, Rosa Tambaro, Daniele Raggi, and Giulia Mazzaschi
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Adult ,Male ,Urologic Neoplasms ,medicine.medical_specialty ,Multivariate analysis ,medicine.medical_treatment ,Immunology ,Population ,Urologic Oncology ,Medical Oncology ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,education ,Immune Checkpoint Inhibitors ,Societies, Medical ,Aged ,Retrospective Studies ,Aged, 80 and over ,Chemotherapy ,education.field_of_study ,Performance status ,business.industry ,Reproducibility of Results ,Retrospective cohort study ,Immunotherapy ,Middle Aged ,Survival Analysis ,Treatment Outcome ,Italy ,Oncology ,Upper tract ,Female ,Urothelium ,business ,Follow-Up Studies - Abstract
Background: Few data are available regarding the effectiveness of immune checkpoint inhibitors in advanced upper tract urothelial carcinoma (UTUC) patients. Methods: To provide a real-world experience with anti-PD-1/PD-L1-based therapy in UTUC patients, we involved an Italian network in a multicenter retrospective analysis. Results: A total of 78 UTUC patients were enrolled. The median follow-up was 25.1 months. The median progression-free survival (mPFS) was 2.2 months (95% CI 1.8–2.6), and the median OS (mOS) was 6.0 months (95% CI 3.6–8.4). The Sonpavde score (including performance status > 0, hemoglobin
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- 2022
9. Bitensorial formulation of the singularity method for Stokes flows
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Giuseppe Procopio and Massimiliano Giona
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generalized functions ,bitensor calculus ,Stokes flows ,Applied Mathematics ,hydrodynamics ,singularity method ,Green functions ,Mathematical Physics ,Analysis - Abstract
This paper develops the bitensorial formulation of the system of singularities associated with unbounded and bounded Stokes flows. The motivation for this extension is that Stokesian singularities and hydrodynamic fundamental solutions are multi-point functions, and bitensor calculus provides either the proper geometrical setting, in order to avoid inconsistencies and misunderstandings on the role of the different tensorial indices, or a way for compactly deriving hydrodynamic properties. A first relevant result is to provide a clear definition of the singularities (both bounded and unbounded) in Stokes flow, specifying the associated differential equations and boundary conditions. Using this formalism for bounded flows, we show the existence of an integro-differential operator providing the whole system of hydrodynamic singularities by acting on the unbounded Green function (Stokeslet) at its pole and we derive its explicit representation in terms of moments. In the case of an immersed body in a unbounded fluid, we show that, the operator furnishing the disturbance field of a purely $ n $-th order ambient flow, is a generalized $ n $-th order Faxén operator, i.e., it yields the $ n $-th moment on the body if applied to a generic ambient flow, and that a generic disturbance field can be expressed by a summation of the generalized $ n $-th order Faxén operators. Furthermore, we find that the operator providing the disturbance of an ambient flow coincides with the reflection operator for the Stokes solutions in the same flow geometry. We apply this result to the paradigmatic case of fundamental singularities for the Stokes flow bounded by a plane. In this way, we obtain in an alternative and easy way the image system for the Sourcelet and the Rotlet (already derived in the literature) and for the Source Doublet and the Strainlet (presented here for the first time).
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- 2022
10. Survival by Depth of Response and Efficacy by International Metastatic Renal Cell Carcinoma Database Consortium Subgroup with Lenvatinib Plus Pembrolizumab Versus Sunitinib in Advanced Renal Cell Carcinoma: Analysis of the Phase 3 Randomized CLEAR Study
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Viktor Grünwald, Thomas Powles, Evgeny Kopyltsov, Vadim Kozlov, Teresa Alonso-Gordoa, Masatoshi Eto, Thomas Hutson, Robert Motzer, Eric Winquist, Pablo Maroto, Bhumsuk Keam, Giuseppe Procopio, Shirley Wong, Bohuslav Melichar, Frederic Rolland, Mototsugu Oya, Karla Rodriguez-Lopez, Kenichi Saito, Jodi McKenzie, and Camillo Porta
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Oncology ,Urology ,Radiology, Nuclear Medicine and imaging ,Surgery - Published
- 2023
11. First-line pazopanib in patients with advanced non-clear cell renal carcinoma: An Italian case series
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Orazio Caffo, Giacomo Cartenì, Sebastiano Buti, Melissa Bersanelli, Elena Fea, Umberto Basso, Francesco Massari, Francesco Boccardo, Alfredo Berruti, Fausto Petrelli, Roberto Iacovelli, Gaetano Facchini, Luca Galli, Alessandra Mosca, Gaetano Aurilio, Claudia Caserta, Ugo De Giorgi, Giuseppe Fornarini, Giuseppe Procopio, Camillo Porta, and Emanuele Naglieri
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Tyrosine kinase inhibitors ,Oncology ,medicine.medical_specialty ,Series (stratigraphy) ,Kidney cancer ,Non-clear cell ,Pazopanib ,Renal-cell carcinoma ,Variant histology ,business.industry ,First line ,Cell ,urologic and male genital diseases ,medicine.anatomical_structure ,Retrospective Study ,Internal medicine ,Clear Cell Renal Carcinoma ,medicine ,In patient ,business ,Renal carcinoma ,medicine.drug - Abstract
BACKGROUND Non-clear cell (ncc) metastatic renal-cell carcinoma (RCC) has dismal results with standard systemic therapies and a generally worse prognosis when compared to its clear-cell counterpart. New systemic combination therapies have emerged for metastatic RCC (mRCC), but the pivotal phase III trials excluded patients with nccRCC, which constitute about 30% of metastatic RCC cases. AIM To provide a piece of real-life evidence on the use of pazopanib in this patient subgroup. METHODS The present study is a multicenter retrospective observational analysis aiming to assess the activity, efficacy, and safety of pazopanib as first-line therapy for advanced nccRCC patients treated in a real-life setting. RESULTS Overall, 48 patients were included. At the median follow-up of 40.6 mo, the objective response rate was 27.1%, the disease control rate was 83.3%, and the median progression-free survival and overall survival were 12.3 (95% confidence interval [CI]: 3.6-20.9) and 27.7 (95%CI: 18.2-37.1) mo, respectively. Grade 3 adverse events occurred in 20% of patients, and no grade 4 or 5 toxicities were found. CONCLUSION Pazopanib should be considered as a good first-line option for metastatic RCC with variant histology.
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- 2021
12. BONSAI-2 study: Nivolumab as therapeutic option after cabozantinib failure in metastatic collecting duct carcinoma patients
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Sebastiano Buti, Francesca Trentini, Pierangela Sepe, Melanie Claps, Luca Isella, Elena Verzoni, and Giuseppe Procopio
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Cancer Research ,Oncology ,General Medicine - Abstract
Background: The BONSAI phase II trial recently demonstrated the activity of cabozantinib in metastatic collecting duct patients. The outcomes of patients in this setting treated with immunotherapy as second-line is unknown. The aim of the present report was to describe outcomes of patients enrolled in the BONSAI trial that received nivolumab as second-line treatment. Material and methods: We describe the oncological outcomes in terms of overall response rate, progression-free survival, overall survival and safety. We excluded patients that did not receive any second-line treatment or were treated with agents other than nivolumab. Results: We identified five patients of whom one was excluded due to lack of data. Three patients obtained clinical benefit (one partial response, two stable disease); the second-line progression-free survival (nivolumab) ranged from 2.8 to 19.9 months to and second-line overall survival ranged from 5.1 to 26.5 months. No new safety signals were observed. Conclusions: Nivolumab may be considered as second-line therapy option after cabozantinib failure in selected metastatic collecting duct carcinoma patients.
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- 2022
13. Update on radioligand therapy with 177Lu-PSMA for metastatic castration-resistant prostate cancer: clinical aspects and survival effects
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Marco Maccauro, Valentina Fuoco, Carlo Chiesa, Stefania Mazzaglia, Giovanni Argiroffi, Valentina Guadalupi, Federica Scalorbi, Andrea Franza, Alice Lorenzoni, Giuseppe Procopio, Gianluca Aliberti, and Ettore Seregni
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Cancer Research ,business.industry ,medicine.medical_treatment ,General Medicine ,Castration resistant ,medicine.disease ,Radiation therapy ,Prostate cancer ,Oncology ,Cancer research ,medicine ,Radioligand ,business ,Membrane antigen - Abstract
Objective: To give an updated overview on clinical aspects and survival effects of lutetium-177–prostate-specific membrane antigen (PSMA) (177Lu-PSMA) radioligand therapy (RLT), a novel treatment option for patients with metastatic castration-resistant prostate cancer (mCRPC). Methods: PubMed/MEDLINE database was searched for relevant articles published up to March 2021. The search was restricted to English-language articles. Results: Current evidence from the literature consistently demonstrated the efficacy, safety, and survival benefit of 177Lu-PSMA RLT in mCRPC. However, current data rely predominantly on retrospective analyses, showing heterogeneity of patient population and treatment protocols. More recently, results from the first randomized phase II study (TheraP) demonstrated that 177Lu-PMSA therapy significantly improved prostate-specific antigen response rate (66% vs 37%) and had fewer grade 3/4 adverse events when compared to cabazitaxel in patients with docetaxel-pretreated, progressive mCRPC. This review is intended to provide an updated overview of treatment protocols and responses, toxicity profile, and survival effects of 177Lu-PSMA RLT. Conclusions: 177Lu-PSMA RLT has emerged as a promising targeted treatment in mCRPC. It is currently applied in compassionate use programs and following exhaustion of approved therapies. Crucial for establishing this treatment in routine clinical management will be the results of the phase III VISION trial, which may confirm the encouraging patient outcomes reported to date.
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- 2021
14. Cabozantinib in Pretreated Patients with Metastatic Renal Cell Carcinoma with Sarcomatoid Differentiation: A Real-World Study
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Michele Milella, Orazio Caffo, Giuseppe Procopio, Francesco Carrozza, Nicola Battelli, Sebastiano Buti, Marc R. Matrana, Francesco Massari, Javier Molina-Cerrillo, Lorena Incorvaia, Veronica Mollica, Giuseppe Fornarini, Umberto Basso, Matteo Santoni, Gaetano Aurilio, Fady Farag, Enrique Grande, Mimma Rizzo, Ugo De Giorgi, Roberto Iacovelli, Alessandro Rizzo, Santoni M., Massari F., Grande E., Procopio G., Matrana M.R., Rizzo M., De Giorgi U., Basso U., Milella M., Iacovelli R., Aurilio G., Incorvaia L., Buti S., Caffo O., Fornarini G., Carrozza F., Mollica V., Rizzo A., Farag F., Molina-Cerrillo J., and Battelli N.
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Cabozantinib ,Pyridines ,chemistry.chemical_compound ,Renal cell carcinoma ,Internal medicine ,medicine ,Humans ,Anilides ,Pharmacology (medical) ,Carcinoma, Renal Cell ,Sarcomatoid Differentiation ,Retrospective Studies ,business.industry ,Hazard ratio ,Cell Differentiation ,medicine.disease ,Kidney Neoplasms ,Confidence interval ,chemistry ,Male patient ,Female ,business ,Kidney cancer - Abstract
Background: Renal cell carcinoma with sarcomatoid differentiation is a highly aggressive form of kidney cancer. Objective: We aimed to analyze the outcomes of patients treated with cabozantinib for metastatic renal cell carcinoma with sarcomatoid features. Methods: We retrospectively collected data from 16 worldwide centers. Overall survival and progression-free survival were analyzed using Kaplan–Meier curves. Cox proportional models were used for univariate and multivariate analyses. Results: We collected data from 66 patients with metastatic sarcomatoid renal cell carcinoma receiving cabozantinib as second-line (51%) or third-line (49%) therapy. The median progression-free survival from the start of cabozantinib was 7.59 months (95% confidence interval [CI] 5.75−17.49) and was longer in male patients (8.81 vs 5.95 months, p = 0.042) and in patients without bone metastases (7.59 vs 5.11 months, p = 0.010); the median overall survival was 9.11 months (95% CI 7.13−23.80). At the multivariate analysis, female sex (hazard ratio = 1.81; 95% CI 1.02−3.37,p = 0.046), bone metastases (hazard ratio = 2.62; 95% CI 1.34−5.10, p = 0.005), and International Metastatic Renal Cell Carcinoma Database Consortium criteria (hazard ratio = 3.04; 95% CI 1.54−5.99, p = 0.001) were significant predictors of worse overall survival. Conclusions: Our data show that cabozantinib is active in pretreated patients with sarcomatoid renal cell carcinoma. Biomarkers are needed in this field to select patients for multi-kinase inhibitors or other options.
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- 2021
15. Case report: Metastatic urothelial cancer with an exceptional response to immunotherapy and comprehensive understanding of the tumor and the tumor microenvironment
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Cora N. Sternberg, Nara Shin, Konstantin Chernyshov, Fabio Calabro, Linda Cerbone, Giuseppe Procopio, Natalia Miheecheva, Georgy Sagaradze, Alisa Zaichikova, Naira Samarina, Alexandra Boyko, Jessica H. Brown, Leysan Yunusova, Daniela Guevara, Jyothi Manohar, Michael Sigouros, Majd Al Assaad, Olivier Elemento, and Juan Miguel Mosquera
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Cancer Research ,Oncology - Abstract
Although immune checkpoint inhibitors (ICIs) are increasingly used as second-line treatments for urothelial cancer (UC), only a small proportion of patients respond. Therefore, understanding the mechanisms of response to ICIs is critical to improve clinical outcomes for UC patients. The tumor microenvironment (TME) is recognized as a key player in tumor progression and the response to certain anti-cancer treatments. This study aims to investigate the mechanism of response using integrated genomic and transcriptomic profiling of a UC patient who was part of the KEYNOTE-045 trial and showed an exceptional response to pembrolizumab. Diagnosed in 2014 and receiving first-line chemotherapy without success, the patient took part in the KEYNOTE-045 trial for 2 years. She showed dramatic improvement and has now been free of disease for over 6 years. Recently described by Bagaev et al., the Molecular Functional (MF) Portrait was utilized to dissect genomic and transcriptomic features of the patient’s tumor and TME. The patient’s tumor was characterized as Immune Desert, which is suggestive of a non-inflamed microenvironment. Integrated whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analysis identified an ATM mutation and high TMB level (33.9 mut/mb), which are both positive biomarkers for ICI response. Analysis further revealed the presence of the APOBEC complex, indicating the potential for use of APOBEC signatures as predictive biomarkers for immunotherapy response. Overall, comprehensive characterization of the patient’s tumor and TME with the MF Portrait revealed important insights that could potentially be hypothesis generating to identify clinically useful biomarkers and improve treatment for UC patients.
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- 2022
16. Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2 or ATM Alterations Identified by Testing Circulating Tumor DNA
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Nobuaki Matsubara, Johann de Bono, David Olmos, Giuseppe Procopio, Satoru Kawakami, Yüksel Ürün, Robbert van Alphen, Aude Flechon, Michael A. Carducci, Young Deuk Choi, Sebastien J. Hotte, Ernesto Korbenfeld, Gero Kramer, Neeraj Agarwal, Kim N. Chi, Simon Dearden, Christopher Gresty, Jinyu Kang, Christian Poehlein, Elizabeth A. Harrington, and Maha Hussain
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Cancer Research ,Oncology - Abstract
Purpose: The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment. Patients and Methods: Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A. Results: Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients’ baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47). Conclusions: When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.
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- 2022
17. The prognostic value of the previous nephrectomy in pretreated metastatic renal cell carcinoma receiving immunotherapy: a sub-analysis of the Meet-URO 15 study
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Sara Elena Rebuzzi, Alessio Signori, Giuseppe Luigi Banna, Annalice Gandini, Giuseppe Fornarini, Alessandra Damassi, Marco Maruzzo, Ugo De Giorgi, Umberto Basso, Silvia Chiellino, Luca Galli, Paolo Andrea Zucali, Emanuela Fantinel, Emanuele Naglieri, Giuseppe Procopio, Michele Milella, Francesco Boccardo, Lucia Fratino, Stefania Pipitone, Riccardo Ricotta, Stefano Panni, Veronica Mollica, Mariella Sorarù, Matteo Santoni, Alessio Cortellini, Veronica Prati, Hector Josè Soto Parra, Daniele Santini, Francesco Atzori, Marilena Di Napoli, Orazio Caffo, Marco Messina, Franco Morelli, Giuseppe Prati, Franco Nolè, Francesca Vignani, Alessia Cavo, Giandomenico Roviello, Pasquale Rescigno, and Sebastiano Buti
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Nivolumab ,Cytokines ,Humans ,Immunotherapy ,General Medicine ,Prognosis ,Carcinoma, Renal Cell ,Nephrectomy ,Kidney Neoplasms ,General Biochemistry, Genetics and Molecular Biology ,Retrospective Studies - Abstract
Background Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era. Methods We investigated the Meet-URO-15 study dataset of 571 pretreated mRCC patients receiving nivolumab as second or further lines about the prognostic role of the previous nephrectomy (received in either the localized or metastatic setting) in the overall population and according to the Meet-URO score groups. Results Patients who underwent nephrectomy showed a significantly reduced risk of death (HR 0.44, 95% CI 0.32–0.60, p p = 0.17). It was statistically significant when merging group 1 with 2 and 3 and group 4 with 5 (p = 0.038) and associated with a longer OS for the first three prognostic groups (p p = 0.54). Conclusions Our study suggests an overall positive impact of the previous nephrectomy on the outcome of pretreated mRCC patients receiving immunotherapy. The clinical relevance of cytoreductive nephrectomy, optimal timing and patient selection deserves further investigation, especially for patients with Meet-URO scores of 1 to 3, who are the once deriving benefit in our analyses. However, that benefit is not evident for IMDC poor-risk patients (including the Meet-URO score groups 4 and 5) and a subgroup of IMDC intermediate-risk patients defined as group 4 by the Meet-URO score.
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- 2022
18. Abiraterone and Olaparib for Metastatic Castration-Resistant Prostate Cancer
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Noel W. Clarke, Andrew J. Armstrong, Antoine Thiery-Vuillemin, Mototsugu Oya, Neal Shore, Eugenia Loredo, Giuseppe Procopio, Juliana de Menezes, Gustavo Girotto, Cagatay Arslan, Niven Mehra, Francis Parnis, Emma Brown, Friederike Schlürmann, Jae Y. Joung, Mikio Sugimoto, Juan A. Virizuela, Urban Emmenegger, Jiri Navratil, Gary L. Buchschacher, Christian Poehlein, Elizabeth A. Harrington, Chintu Desai, Jinyu Kang, and Fred Saad
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- 2022
19. Prognostic value of normal sodium levels in patients with metastatic renal cell carcinoma receiving tyrosine kinase inhibitors
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Giandomenico Roviello, Martina Catalano, Ugo De Giorgi, Marco Maruzzo, Sebastiano Buti, Elisabetta Gambale, Giuseppe Procopio, Carlotta Ottanelli, Enrico Caliman, Luca Isella, Pierangela Sepe, Nicole Brighi, Matteo Santoni, Luca Galli, Raffaele Conca, Laura Doni, and Lorenzo Antonuzzo
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Cancer Research ,Oncology - Abstract
BackgroundAlthough serum sodium concentration, particularly hyponatremia, has been shown to be a prognostic marker of survival in metastatic renal cell carcinoma (mRCC), the impact of normal sodium levels has not been investigated. Herein, we investigate the influence of normonatremia in mRCC patients treated with tyrosine kinase inhibitors (TKIs).Materials and methodsFor this retrospective study, the clinical and biochemical data of patients treated with first-line TKIs for mRCC were available from seven Italian cancer centers. We collected natremia levels at baseline and first evaluation after treatment excluding patients with sodium levels outside the normal range (145 mEq/L). The remaining patients were subdivided into two groups according to the median sodium value: natremia patients with n = 132) and baseline natremia patients with ≥140 mEq/L (n = 185). Subsequently, we analyzed the impact of sodium levels on response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). PFS and OS were estimated through the Kaplan–Meier method, and differences between groups were examined by the log-rank test. Univariate and multivariate Cox regression analyses were applied to evaluate the prognostic factors for PFS and OS.ResultsOf the 368 patients, 317 were included in the analysis, 73.1% were men, and the median age was 67 years (range 36–89). When comparing patients with baseline natremia ≥140 mEq/L (n = 185) to patients with natremia n = 132), the PFS was 15 vs. 10 months (p p = 0.02). On the first evaluation, patients with serum sodium ≥140 mEq/L had longer PFS (15 vs. 10 months, p p p p ConclusionsTo the best of our knowledge, this is the first study to investigate the impact of normonatremia in mRCC. We found that serum sodium levels
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- 2022
20. Cultural adaptation of the Italian version of the Patient-Reported Outcomes Common Terminology Criteria for Adverse Event (PRO-CTCAE®)
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Caterina Caminiti, Jane Bryce, Silvia Riva, Diane Ng, Francesca Diodati, Elisa Iezzi, Lucia Sparavigna, Silvia Novello, Camillo Porta, Lucia Del Mastro, Giuseppe Procopio, Saverio Cinieri, Amalia Falzetta, Fabio Calabrò, Vito Lorusso, Alessio Aligi Cogoni, Giampaolo Tortora, Marco Maruzzo, Rodolfo Passalacqua, Francesco Cognetti, Vincenzo Adamo, Enrica Capelletto, Alessandra Ferrari, Michela Bagnalasta, Maurizio Bassi, Annalisa Nicelli, Davide De Persis, Alessia D’Acunti, Elisabetta Iannelli (patient), Francesco Perrone, and Sandra A. Mitchell
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Linguistic validation ,PRO-CTCAE ,cognitive interviewing ,patient-reported outcomes ,symptomatic adverse events ,Cancer Research ,Oncology ,General Medicine - Abstract
Introduction: US National Cancer Institute’s (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE®) is a library of 78 symptom terms and 124 items enabling patient reporting of symptomatic adverse events in cancer trials. This multicenter study used mixed methods to develop an Italian language version of this widely accepted measure, and describe the content validity and reliability in a diverse sample of Italian-speaking patients. Methods: All PRO-CTCAE items were translated in accordance with international guidelines. Subsequently, the content validity of the PRO-CTCAE-Italian was explored and iteratively refined through cognitive debriefing interviews. Participants (n=96; 52% male; median age 64 years; 26% older adults; 18% lower educational attainment) completed a PRO-CTCAE survey and participated in a semi-structured interview to determine if the translation captured the concepts of the original English language PRO-CTCAE, and to evaluate comprehension, clarity and ease of judgement. Test-retest reliability of the finalized measure was explored in a second sample (n=135). Results: Four rounds of cognitive debriefing interviews were conducted. The majority of PRO-CTCAE symptom terms, attributes and associated response choices were well-understood, and respondents found the items easy to judge. To improve comprehension and clarity, the symptom terms for nausea and pain were rephrased and retested in subsequent interview rounds. Test-retest reliability was excellent for 41/49 items (84%); the median intraclass correlation coefficient was 0.83 (range 0.64-0.94). Discussion: Results support the semantic, conceptual and pragmatic equivalence of PRO-CTCAE-Italian to the original English version, and provide preliminary descriptive evidence of content validity and reliability.
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- 2022
21. The amount of circulating DNA and the presence of TP53 mutations in plasma predict clinical outcome of renal cancer patients treated with immunotherapy and VEGFR-TKIs
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Marzia Del Re, Stefania Crucitta, Federico Paolieri, Federico Cucchiara, Elena Verzoni, Francesco Bloise, Raffaele Ciampi, Chiara Mercinelli, Annalisa Capuano, Liberata Sportiello, Giuseppe Procopio, Luca Galli, Camillo Porta, Sergio Bracarda, and Romano Danesi
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Background Despite the increasing treatments options, reliable biomarkers of response are still missing for patients affected by metastatic renal cell carcinoma (mRCC). Methods Patients affected by mRCC undergoing standard first line treatment were enrolled. Twelve ml of blood were drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) analyses were performed on cfDNA using the Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy. Results A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/µl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p=0.001 and p=0.008, respectively). cfDNA amount was also correlated with best response (p=0.006). A further cfDNA cut-point divided patients into short, intermediate and long responders, with a PFS of 4.87 vs 9.13 vs 23.1 months, respectively (pConclusions The present study demonstrates that cfDNA and TP53 may be used as predictive biomarkers of response in mRCC.
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- 2022
22. The amount of DNA combined with TP53 mutations in liquid biopsy is associated with clinical outcome of renal cancer patients treated with immunotherapy and VEGFR-TKIs
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Marzia Del Re, Stefania Crucitta, Federico Paolieri, Federico Cucchiara, Elena Verzoni, Francesco Bloise, Raffaele Ciampi, Chiara Mercinelli, Annalisa Capuano, Liberata Sportiello, Antonia Martinetti, Giuseppe Procopio, Luca Galli, Camillo Porta, Sergio Bracarda, Romano Danesi, Del Re, Marzia, Crucitta, Stefania, Paolieri, Federico, Cucchiara, Federico, Verzoni, Elena, Bloise, Francesco, Ciampi, Raffaele, Mercinelli, Chiara, Capuano, Annalisa, Sportiello, Liberata, Martinetti, Antonia, Procopio, Giuseppe, Galli, Luca, Porta, Camillo, Bracarda, Sergio, and Danesi, Romano
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Tyrosine kinase inhibitors ,Vascular Endothelial Growth Factor A ,Liquid Biopsy ,General Medicine ,Biomarker ,DNA ,General Biochemistry, Genetics and Molecular Biology ,Kidney Neoplasms ,Angiogenesi ,Predictive biomarker ,Receptors, Vascular Endothelial Growth Factor ,Next generation sequencing ,Metastatic clear cell renal cell carcinoma ,Biomarkers, Tumor ,Humans ,TP53 ,Immunotherapy ,Prospective Studies ,Tumor Suppressor Protein p53 ,Circulating free DNA ,Carcinoma, Renal Cell ,Cell-Free Nucleic Acids ,Protein Kinase Inhibitors - Abstract
Background Despite the increasing number of treatment options, reliable prognostic/predictive biomarkers are still missing for patients affected by metastatic clear cell renal cell carcinoma (mccRCC). Methods Patients with mccRCC undergoing standard first line treatment were enrolled. Blood (12 ml) was drawn at treatment baseline and circulating free DNA (cfDNA) was extracted from plasma. Next-generation sequencing (NGS) was performed on cfDNA using the Oncomine Pan-Cancer Cell-Free Assay and clinical outcomes were correlated with liquid biopsy findings. Results A total of 48 patients were enrolled, 12 received immunotherapy and 36 received a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). A cfDNA cut-off of 0.883 ng/μl stratified patients based on progression-free survival (PFS) and overall survival (OS) (p = 0.001 and p = 0.008, respectively). cfDNA amount was also correlated with best response (p = 0.006). Additional cfDNA cut-points divided patients into short, intermediate and long responders, with PFS of 4.87 vs 9.13 vs 23.1 months, respectively (p Conclusions The present study demonstrates that cfDNA and TP53 are potential predictive biomarkers of response in mccRCC to be further explored in larger and/or prospective studies.
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- 2022
23. The Fourfold Way to Gaussianity: Physical Interactions, Distributional Models and Monadic Transformations
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Massimiliano Giona, Chiara Pezzotti, and Giuseppe Procopio
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Algebra and Number Theory ,Logic ,iterated function systems ,stochastic processes ,Geometry and Topology ,Gaussian distributions ,Central Limit Theorem ,Mathematical Physics ,Analysis - Abstract
The Central Limit Theorem stands as a milestone in probability theory and statistical physics, as the privileged, if not the unique, universal route to normal distributions. This article addresses and describes several other alternative routes to Gaussianity, stemming from physical interactions, related to particle-particle and radiative particle–photon elementary processes. The concept of conservative mixing transformations of random ensembles is addressed, as it represents the other main universal distributional route to Gaussianity in classical low-energy physics. Monadic ensemble transformations are introduced, accounting for radiative particle–photon interactions, and are intimately connected with the theory of random Iterated Function Systems. For Monadic transformations, possessing a thermodynamic constraint, Gaussianity represents the equilibrium condition in two limiting cases: in the low radiative-friction limit in any space dimension, and in the high radiative-friction limit, when the dimension of the physical space tends to infinity.
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- 2023
24. Whole-body diffusion-weighted magnetic resonance imaging to assess bone response in patients with hormone-sensitive metastatic prostate cancer randomly assigned to receive androgen deprivation + enzalutamide ± zoledronic acid
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Alberto Dalla Volta, Francesca Valcamonico, Andrea Zivi, Giuseppe Procopio, Pierangela Sepe, Gianluca Del Conte, Nunzia Di Meo, Silvia Foti, Stefania Zamboni, Caterina Messina, Eleonora Lucchini, Anna Rizzi, Marco Ravanelli, Michele Milella, Stefano Calza, Claudio Simeone, Roberto Maroldi, Davide Farina, and Alfredo Berruti
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Cancer Research ,Oncology - Abstract
46 Background: Bone is frequently involved in metastatic hormone sensitive prostate cancer (mHSPC). Whole-body diffusion-weighted magnetic resonance imaging (WB-DW-MRI) is a promising imaging technique for the assessment of bone response in prostate cancer. It is not known whether the addition of antiresorptive agents can improve disease response in bone in mHSPC patients undergoing next generation hormonal agents. Methods: In this multicenter phase II study patients with de novo or relapsed mHSPC and bone metastases at bone scan were randomly allocated with a 1:1 ratio to receive either androgen deprivation therapy (ADT) plus Enzalutamide (E arm) or the same combination with the addition of Zoledronic Acid (EZ arm). The study was designed to observe a significant increase in bone response rate in the experimental arm after 12 months of treatment, as assessed through WB-DW-MRI. WB-DW-MRI was performed centrally at baseline and after 6 and 12 months and images were evaluated by the same radiologist. Results: From February 2018 to June 2021, 126 mHSPC patients were randomized, 64 in EZ arm and 62 in E arm. A total of 111 patients, 54 from E arm and 57 from EZ arm, were eligible for WB-DW-MRI assessment (15 patients were excluded because of the absence of bone target lesions at MRI or specific contraindications to MRI). Bone response at 6 months was observed in 41 patients (76%) in E arm and 41 patients (72%) in EZ arm; the corresponding bone response at 12 months were 44 (82%) and 44 (77%), respectively (OR 0.77; 95%IC 0.30-1.93; p = 0.6). Complete response was the best overall bone response after 12 months in 9 patients (17%) from E arm and in 11 patients (19%) from EZ arm. In the same period, treatment was interrupted due to disease progression in 7 (13%) and 7 (12%) patients in E and EZ arm, respectively. Conclusions: The addition of Zoledronic Acid to Enzalutamide and ADT did not improve bone disease response in patients with mHSPC. WB-DW-MRI was able to detect bone responses in a great proportion of patients. Clinical trial information: NCT03336983 .
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- 2023
25. Prognostic stratification by the Meet-URO score in a real-world elderly population of patients (pts) with metastatic renal cell carcinoma (mRCC) receiving cabozantinib: A subanalysis of the prospective ZEBRA study (Meet-URO 9)
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Alessandra Damassi, Malvina Cremante, Giuseppe Fornarini, Alessio Signori, Sebastiano Buti, Umberto Basso, Giuseppe Procopio, Marco Maruzzo, Mariella Sorarù, Marilena Di Napoli, Lucia Fratino, Daniele Santini, Francesco Grillone, Melissa Ballestrin, Michele Dionese, Veronica Murianni, Fabio Catalano, Giuseppe Luigi L. Banna, Pasquale Rescigno, and Sara Elena Rebuzzi
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Cancer Research ,Oncology - Abstract
637 Background: The combination of neutrophil to lymphocyte (NLR), bone metastases and IMDC score in the novel prognostic Meet-URO score has shown a higher prognostic performance than the IMDC score alone in mRCC pts receiving ≥2nd line nivolumab or cabozantinib in two retrospective analyses and 1st line nivolumab-ipilimumab in a real-world prospective study [http://bit.ly/Meet-URO15_score]. Further validation is needed since this score represents an easy prognostic tool for clinical practice with no additional costs. Methods: A real-world analysis of elderly (≥70 yo) mRCC pts treated with any line cabozantinib was conducted in the multicenter observational prospective Zebra study. Baseline Meet-URO score was assessed. The primary endpoint was overall survival (OS) and the Harrell’s c-index was calculated to compare accuracy of survival prediction of the Meet-URO and IMDC scores. Results: 104 mRCC pts received cabozantinib as 1st (38%), 2nd (20%), 3rd (33%) and 4th (8%) line, with a median follow-up of 11.2 months (mo) and a median overall survival (mOS) of 18.4 mo. According to the IMDC score, favorable- (15%), intermediate- (65%) and poor-risk (19%) pts had a mOS not reached (NR), 15.6 and of 5.7 mo, respectively (p = 0.011). Reclassifying the population according to the Meet-URO score, we observed that group 1 (10%) and group 2 (25%) had both mOS NR, whereas group 3 (33%), group 4 (25%) and group 5 (8%) had a mOS of 13.6, 12.5 and 3.7 mo, respectively (p = 0.001). Moreover, the Meet-URO score maintained its discrimination ability also merging group 1-2 vs 3-4 vs 5 (p < 0.001). NLR < 3.2 was the heaviest component of the score (p < 0.001, mOS 24.8 vs 11.5 mo). The Meet-URO score (using both original with 5 groups and modified with 3 groups) has shown a higher prognostic power than the IMDC score alone (c-index of 0.686 and 0.676 vs 0.622). Conclusions: This analysis confirmed the higher accuracy in survival stratification of the Meet-URO score compared with the IMDC score alone also in a specific population like elderly mRCC pts treated with cabozantinib. NLR was confirmed as a strong prognostic factor with cabozantinib. Further applications of the Meet-URO score in mRCC pts treated with first-line immune-combinations are planned and highly awaited. Clinical trial information: 2018/116/PU .
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- 2023
26. Nivolumab plus ipilimumab for the treatment of post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC): Additional results from the randomized phase 2 CheckMate 650 trial
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Padmanee Sharma, Michael Krainer, Fred Saad, Daniel Castellano, Jens Bedke, Mariusz Kwiatkowski, Akash Patnaik, Giuseppe Procopio, Pawel Wiechno, Samith Thomas Kochuparambil, Christian Thomas, Jose Angel Arranz Arija, Steven L. McCune, Steinbjorn Hansen, Gedske Daugaard, Neha P. Amin, Yumeng Wang, Justin M. David, and Russell Kent Pachynski
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Cancer Research ,Oncology - Abstract
22 Background: In preliminary analyses from the randomized phase 2, open-label CheckMate 650 trial, nivolumab (NIVO) 1 mg/kg (N1) plus ipilimumab (IPI) 3 mg/kg (I3) Q3W × 4 doses showed clinical activity in patients (pts) with post-chemotherapy (post-CT) mCRPC, particularly those with high tumor mutational burden (TMB), but early toxicity contributed to treatment discontinuations. Here, we report results from pts with post-CT mCRPC receiving alternative NIVO+IPI dosing regimens vs IPI alone vs cabazitaxel (CABA) in CheckMate 650. Methods: Newly enrolled pts previously treated with docetaxel for mCRPC were randomized 2:2:1:2 to cohorts D1 (NIVO 3 mg/kg [N3] + IPI 1 mg/kg [I1] Q3W × 4 doses then NIVO 480 mg Q4W), D2 (N1 Q3W × 8 doses + I3 Q6W × 4 doses then NIVO 480 mg Q4W), D3 (I3 Q3W × 4 doses), or D4 (CABA 20 or 25 mg/m2 Q3W + prednisone 10 mg × 10 doses). Crossover from cohorts D3 and D4 to cohort D1 was allowed after radiographic progressive disease. Outcomes included safety, objective response rate (ORR), prostate-specific antigen response rate (PSA-RR; confirmed PSA decline ≥ 50% from baseline), radiographic progression-free survival (rPFS) per blinded independent central review (BICR), and overall survival (OS). Associations between efficacy and TMB were assessed. Results: Overall, 259 pts were randomized (D1, n = 73; D2, n = 74; D3, n = 38; D4, n = 74). Median (range) follow-up for OS was 23.3 (6.0–31.5) months. In the NIVO+IPI cohorts (D1 and D2), median duration of therapy was 2.8 and 2.4 months; the median number of IPI doses received was 4 and 2, and 15% and 26% of pts discontinued due to study drug toxicity, respectively. Two pts died due to study drug toxicity (1 each in cohorts D1 and D2). Key safety and efficacy data are shown. Several pts in cohorts D1 and D2 showed notable reductions (75-100%) in tumor size and PSA. Approximately one-third of pts in cohorts D3 and D4 crossed over to D1. Based on preliminary analyses in small numbers of evaluable pts, there was no clear and consistent association between efficacy and tissue or blood TMB in the NIVO+IPI cohorts (D1 and D2). Conclusions: These results further support the clinical activity of NIVO+IPI in select pts with post-CT mCRPC. Detailed evaluations of the characteristics of responders to NIVO+IPI, including more expansive biomarker analyses, are warranted. Clinical trial information: NCT02985957 . [Table: see text]
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- 2023
27. Real world analysis of peritoneal metastasis from renal cell carcinoma: Meet-Uro 27 study
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Marco Stellato, Sebastiano Buti, Marco Maruzzo, Giuseppe Fotia, Mariella Sorarù, Maria Bassanelli, Brigida Anna Maiorano, Francesco Grillone, Luca Galli, Roberto Filippi, Martina Fanelli, Michele Dionese, Michele Maffezzoli, Bruno Vincenzi, Giuseppe Procopio, and Elena Verzoni
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Cancer Research ,Oncology - Abstract
638 Background: Peritoneal metastases (PM) have been reported in approximately 1% of patients (pts) with metastatic Renal Cell Carcinoma (mRCC). Outcome data are limited due to the rarity of this metastatic site. Therefore, the aim of our study is to describe RCC pts with PM treated as per clinical practice. Methods: Baseline characteristics and outcome data of pts with PM from RCC were retrospectively collected from 12 Italian oncological referral centers adhering to the Meet-Uro group, from January 2016 to September 2022. Results: We collect 91 RCC pts with PM. 87/91 pts received systemic treatment, 4/87 only best supportive care. First line treatment included TKI and ImmuneOncology(IO)-TKI with different Objective Response Rate(ORR) (41% vs 53.8%, respectively) and Disease Control Rate (DCR) (57.1% and 80.7%, respectively) as well as median PFS (9.9 mo (95%CI 4.5-15.4) for TKI and not reached (NR) for IO-TKI (69.7% pts were free from progression at a median follow up of 13.8 months). Primary refractory (PR) pts were 35.7% for TKI and 7.7% for IO-TKI. According to IMDC score, mPFS was consistent among risk categories, 36.8 mo (95%CI 9.6-63.9) for good risk pts, 13.8 mo (95%CI 8.8-18.8) for intermediate pts and 2.9 mo (95%CI 2.2-3.7) for poor risk pts. Synchronous PM was associated to shorter mPFS 11.0 (95%CI 3.1-19.0) compared to patients with metacronous involvement as well as ORR (31.3%) and DCR (43.1%) whereas PR was higher (34.7%). Only 43/87 pts (45.7%) received a second line treatment that was TKI ( ORR 30.7%; DCR 61.5%; or IO (ORR 20.6%; DCR 41.3%). mOS was 21.8 mo (12.0-31.5) for TKI and NR for pts treated with IO-TKI (80.8 alive at 1 yrs). According to IMDC score, mOS was NR for good risk pts, 24.6 (95%CI 15.8-33.3) and 3.4 (95%CI 2.4-4.3) for intermediate and poor risk, respectively. Conclusions: We report one of the largest case series regarding PM from RCC. Poor risk patients according to IMDC score, sarcomatoid feature and liver metastasis were more represented in our population, compared to historical control, suggesting a more aggressive behavior of PM mRCC. Outcome data suggest that TKI-IO as first line treatment, compared to TKI monotherapy, and TKI as second line, compared to IO, are more active treatment for these pts with dismal prognosis. Nevertheless, synchronous PM has been reported in 57% of pts with poorer outcome and lower response rate. [Table: see text]
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- 2023
28. Clinical outcomes of abiraterone acetate (AA) or enzalutamide (E) as first-line therapy (Rx) for men aged ≥75 with metastatic castration-resistant prostate cancer (mCRPC) according to previous use of docetaxel (D) for metastatic castration-sensitive prostate cancer (mCSPC) in a multicenter international registry: A SPARTACUSS – Meet-URO 26 study
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Richard M. Lee-Ying, Calogero Saieva, Pier Vitale Nuzzo, Andrea Malgeri, Giuseppe Fotia, Elisa Zanardi, Sabrina Rossetti, Loana Bueno Valenca, Anna Patrikidou, Mikol Modesti, Thiago Martins Oliveira, Sandro Pignata, Giuseppe Fornarini, Giuseppe Procopio, Daniele Santini, Christopher Sweeney, Daniel Yick Chin Heng, Ugo De Giorgi, Antonio Russo, and Edoardo Francini
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Cancer Research ,Oncology - Abstract
107 Background: The optimal management of mCRPC in men aged ≥75 is challenging, and there is a paucity of clinical data in the literature. Although AA and E are commonly used as 1st line Rx for mCRPC, it is unclear whether use of upfront D for mCSPC may impact their clinical efficacy or safety in this elderly population. Methods: Patients aged ≥75 who started AA or E as 1st line Rx for mCRPC within January 2015 - April 2019 were identified from the IRB approved databases of 10 institutions in Europe, South and North America. Demographic and clinicopathological data were collected from available medical records, including Gleason, prior local therapy, newly diagnosed metastatic disease, disease volume, ECOG, PSA and sites of metastases. Patients were classified by use of upfront D for mCSPC. The primary endpoints were overall survival (OS) from AA/E onset and OS from ADT start and safety of AA/E. The endpoints distributions including median (95% CI) were estimated by Kaplan-Meier method. Results: Of the 337 patients selected, 24 (7.1%) received ADT+D and 313 (92.9%) ADT alone for mCSPC. Patients with ADT+D tended to be younger (78 vs 81, p=0.022) and, albeit not statistically significant, had higher rates of Gleason score >8 (81.0% vs 62.6%, p=0.10), newly diagnosed (83.3% vs 65.6%, p=0.08) and high volume disease (45.8% vs 34.6%, p=0.28), compared to those with ADT alone. Median follow-up was 18.8 months. No significant difference of OS from ADT start or from AA/E onset was observed between the 2 cohorts (see table). Despite OS from ADT start being longer in those having ADT+D, OS from AA/E start was approximately 2 years in both cohorts. Rates of adverse events (AEs) of any grade (58.3% vs 52.1%, p=0.67) and grade ≥3 (12.5% vs 15.7%, p=1.0) did not significantly differ between the 2 cohorts. Conclusions: While limited by small sample size for ADT+D and retrospective study design, patients aged ≥75 having AA/E as 1st line mCRPC Rx showed similar survival outcomes and tolerability regardless of previous use of D for mCSPC. [Table: see text]
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- 2023
29. Final overall survival (OS) in PROpel: Abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC)
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Noel W. Clarke, Andrew J. Armstrong, Antoine Thiery-Vuillemin, Mototsugu Oya, Neal D. Shore, Giuseppe Procopio, João Daniel Cardoso Guedes, Cagatay Arslan, Niven Mehra, Francis Parnis, Emma Brown, Friederike Schlürmann, Jae Young Joung, Mikio Sugimoto, A. Oliver Sartor, Yu-Zhen Liu, Christian Heinrich Poehlein, Laura Barker, Paula Michelle del Rosario, and Fred Saad
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Cancer Research ,Oncology - Abstract
LBA16 Background: PROpel (NCT03732820) met its primary endpoint showing significant investigator-assessed radiographic progression-free survival (rPFS) benefit for patients with mCRPC treated with abi + ola vs abi + pbo in the 1L setting (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81, P< 0.001, data cut-off: 7/30/2021). Sensitivity analysis by blinded independent central review was consistent. A trend toward OS benefit with abi + ola was observed at the time of the primary rPFS analysis (28.6% maturity, HR 0.86, 95% CI 0.66–1.12) and a subsequent interim analysis (40.1% maturity, HR 0.83, 95% CI 0.66–1.03). We report OS and safety from the pre-planned final analysis (data cut-off: 10/12/2022). Methods: PROpel is a randomized, double-blind phase 3 trial of 1L therapy for patients with mCRPC eligible for abiraterone. Patients were prospectively assessed for homologous recombination repair mutation (HRRm) status using tumor tissue (FoundationOne CDx) and/or circulating tumor DNA (ctDNA; FoundationOne Liquid CDx) tests after randomization 1:1 to ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) plus prednisone/prednisolone (5 mg bid). Treatment continued until radiographic disease progression, unacceptable toxicity or withdrawal of consent. OS was a key secondary endpoint (2-sided boundary for significance 0.0377). Aggregate results from tumor tissue and ctDNA tests were used to assign patients to HRRm/BRCAm subgroups. Results: Patient (n = 796) characteristics (including prior docetaxel, site of metastasis, symptom score and HRRm status) were generally balanced. There was a consistent trend toward OS benefit in the intention-to-treat (ITT) population with abi + ola vs abi + pbo (maturity 47.9%, HR 0.81, 95% CI 0.67–1.00, P= 0.0544), with median OS 42.1 months (m) vs 34.7 m, respectively. OS medians and HRs for HRRm, non-HRRm, BRCAm and non-BRCAm subgroups all favored abi + ola vs abi + pbo. In the abi + ola arm the most common Grade ≥3 adverse event was anemia (16.1%). Conclusions: At the prespecified final analysis in PROpel, abi + ola prolonged OS by > 7 m vs standard-of-care abiraterone (abi + pbo) in the ITT population. The median OS of > 42 m is the longest median reported to date in a phase 3 trial in 1L mCRPC. Consistent with rPFS results, a trend toward OS benefit was observed in HRRm, non-HRRm, BRCAm and non-BRCAm subgroups with greatest benefit in the BRCAm subgroup. No new long-term safety issues were identified. These results support the use of abi + ola in 1L mCRPC. Clinical trial information: NCT03732820 . [Table: see text]
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- 2023
30. Phase 2 study of the efficacy and safety of erdafitinib in patients (pts) with intermediate-risk non–muscle-invasive bladder cancer (IR-NMIBC) with FGFR3/2 alterations (alt) in THOR-2: Cohort 3 interim analysis
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Siamak Daneshmand, Renata Zaucha, Benjamin Adam Gartrell, Yair Lotan, Syed A. Hussain, Eugene K. Lee, Giuseppe Procopio, Fernando Galanternik, Vahid Naini, Jenna Carcione, Spyros Triantos, Mahadi Baig, and Jodi K. Maranchie
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Cancer Research ,Oncology - Abstract
504 Background: Current treatments (tx) of papillary NMIBC are not selective. Novel tx can be assessed on measurable disease (eg, a marker lesion) to rapidly and directly assess antitumor efficacy. FGFR inhibitor therapy may improve outcomes for pts with IR-NMIBC with FGFR3/2alt. Erdafitinib (erda) is an oral selective pan-FGFR tyrosine kinase inhibitor approved for locally advanced or metastatic urothelial cancer in adults with FGFR3/2alt who have progressed during or following ≥1 line of platinum-containing chemotherapy. THOR-2 (NCT04172675) is a multicohort phase 2 study of erda in pts with NMIBC. We report results in an exploratory cohort of pts with IR-NMIBC with FGFRalt (Cohort 3). Methods: Inclusion: age ≥18 y, with histologically confirmed NMIBC with FGFR3/2alt (local/central testing) and recurrent IR disease, with all previous tumors being low grade (Gr) (Gr 1-2), Ta/T1, no previous carcinoma in situ, risk of progression 50%. All tumors were removed by transurethral resection of bladder tumor except for a marker lesion (single untouched 5-10 mm lesion). Pts received continuous oral erda 6 mg once daily without uptitration in 28-d cycles. Urine cytology was performed at the time of complete response (CR). Pts with a partial response (PR) or CR ≤3 mos of starting erda continued erda for up to a maximum of 2 y, until progressive disease, intolerable toxicity, withdrawal of consent, investigator decision to discontinue tx, or study closure. Primary exploratory end point: CR rate (CR = disappearance of the marker lesion without any new lesions; if there is a remnant of the marker lesion, no viable tumor should be seen on histopathological examination); key secondary end point: safety. Results: As of the data cutoff (Sep 2022) (median follow-up of 6.2 mos), 10/11 enrolled pts have received erda (enrolled population; median age: 66 y [range 47-77]; 9 Ta, 2 not staged). Pts received erda for a median duration of 2.9 mos (range 1.1-8.4). Efficacy (n=8 evaluable): 6 pts had CR (CR rate, 75.0%; 95% CI, 34.9-96.8%), and 1 had PR. Of 7 pts with CR or PR, median observed duration of response was 2.8 mos. Safety (≥1 dose of erda; n=10): the most common tx-emergent adverse events (TEAEs) were hyperphosphatemia (90.0%; n=9), diarrhea (60.0%; n=6), dry mouth (50.0%; n=5), dry skin (30.0%; n=3), dysgeusia (30.0%; n=3), and constipation (30.0%; n=3). One pt had Gr ≥3 dysuria (10.0%) and 1 (10.0%) had Gr ≥3 tx-related diarrhea. One pt (10.0%) had Gr 1 tx-related central serous chorioretinopathy. No pts had tx-related serious TEAEs or tx-related TEAEs leading to discontinuation. No deaths occurred. Conclusions: Data from Cohort 3 of THOR-2 demonstrate efficacy in adult pts with IR-NMIBC with FGFRalt. Safety data were consistent with the known safety profile of erda. Clinical trial information: NCT04172675 .
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- 2023
31. Efficacy and safety of docetaxel (D) vs androgen-receptor signaling inhibitors (ARSi) as second-line therapy (Rx) after progression on alternative ARSi as first-line Rx for patients who are elderly (≥75 years old) with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter international database: A SPARTACUSS–Meet-URO 26 study
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Vincenzo Gennusa, Calogero Saieva, Richard M. Lee-Ying, Pier Vitale Nuzzo, Gian Paolo Spinelli, Elisa Zanardi, Giuseppe Fotia, Sabrina Rossetti, Loana Bueno Valenca, Anna Patrikidou, Livia Andrade, Ricardo Pereira Mestre, Giuseppe Fornarini, Giuseppe Procopio, Daniele Santini, Christopher Sweeney, Daniel Yick Chin Heng, Ugo De Giorgi, Antonio Russo, and Edoardo Francini
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Cancer Research ,Oncology - Abstract
166 Background: About 2/3 of all prostate cancer (PCa) deaths occur in patients aged ≥75, who are frequently diagnosed with advanced PCa. ARSi abiraterone acetate (AA) and enzalutamide (E) are the most common 1st line Rx for patients with mCRPC. Yet, the optimal treatment sequence for the elderly ≥75 after ARSi failure is still unclear. Methods: Using available medical records, patients aged ≥75 who started ARSi as 1st line Rx for mCRPC within January 2015 - April 2019 and, upon progression, 2nd line alternative ARSi or D were identified from the IRB approved hospital registries of 10 centers in Europe, North and South America. Patients were categorized by type of 2nd line Rx for mCRPC into cohorts AA/E and D. Primary endpoints were overall survival (OS) from 1st line AA/E start, OS and radiographic progression-free survival (rPFS) from 2nd line Rx start, and safety. The Kaplan Meier method was used to calculate endpoint distributions and medians (95% CI). Results: Of the 122 patients identified, 57 (46.7%) had AA/E and 65 (53.3%) D, as 2nd line Rx for mCRPC. Median follow-up was 26.3 months (95% CI, 23.1-27.9 months). Cohort AA/E tended to be older (81 vs 78 years; p=0.001) and with high-volume disease (45.5% vs 25.0%; p=0.022) compared to cohort D. No significant difference in OS from 1st line ARSi onset and OS or rPFS from 2nd line Rx start was found between the 2 cohorts. Cohort AA/E had longer rPFS than cohort D, albeit not significant (18.5 vs 12.0 months; p=0.13). Rates of adverse events (AEs) of any grade (42.1 vs 53.8; p=0.21) and AEs of grade ≥3 (19.3% vs 18.5%; p=1.0) did not show significant differences between the 2 cohorts. Conclusions: Within the limitations of small cohorts and retrospective design, treatment sequences with 2nd line AA/E or D after failure of 1st line alternative ARSi for mCRPC showed similar efficacy and safety in the elderly ≥75 years old.
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- 2023
32. Patient associations and clinical oncology research: how much does a patient’s voice really matter?
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F. Arizio, Celeste Cagnazzo, Giuseppe Procopio, Oriana Nanni, Rosita Cenna, V. Franchina, Nicla La Verde, Stefania Gori, Vincenzo Adamo, Alessandro Di Costanzo, Fabrizio Nicolis, and Angela Maria Elena Frazzetto
- Subjects
associations ,oncology ,Patient ,research ,medicine.medical_specialty ,Biomedical Research ,Patient Empowerment ,education ,Medical Oncology ,03 medical and health sciences ,0302 clinical medicine ,Neoplasms ,Surveys and Questionnaires ,Humans ,Medicine ,Pharmacology (medical) ,030212 general & internal medicine ,Clinical Oncology ,Research ethics ,Italy ,Societies ,Patient Participation ,business.industry ,030503 health policy & services ,Health Policy ,S Voice ,General Medicine ,Clinical research ,Family medicine ,0305 other medical science ,business - Abstract
Background: New trends are emerging in clinical research, such as patient empowerment and an active role in influencing health and research ethics. Patients’ involvement is considered pivotal by st...
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- 2020
33. An Italian, multicenter, real-world, retrospective study of first-line pazopanib in unselected metastatic renal-cell carcinoma patients: the ‘Pamerit’ study
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Francesco Boccardo, Umberto Basso, Camillo Porta, Ugo De Giorgi, Orazio Caffo, Alessandra Mosca, Giacomo Cartenì, Giuseppe Fornarini, Melissa Bersanelli, Luca Galli, Emanuele Naglieri, and Giuseppe Procopio
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Indazoles ,Databases, Factual ,medicine.medical_treatment ,Kaplan-Meier Estimate ,metastatic renal cell carcinoma ,Pazopanib ,first-line therapy ,pazopanib ,real-world effectiveness ,vascular endothelial growth factor receptor tyrosine kinase inhibitors ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,Internal medicine ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,030212 general & internal medicine ,Adverse effect ,Carcinoma, Renal Cell ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Sulfonamides ,business.industry ,Histology ,Retrospective cohort study ,General Medicine ,Immunotherapy ,Middle Aged ,medicine.disease ,Kidney Neoplasms ,Progression-Free Survival ,Clinical trial ,Pyrimidines ,Treatment Outcome ,Italy ,030220 oncology & carcinogenesis ,Female ,business ,Clear cell ,medicine.drug - Abstract
Objective Despite the current immunotherapy era, VEGFR inhibitors maintain effectiveness in metastatic renal cell cancer. Real-world data concerning pazopanib are limited. The aim of this study is to add information about efficacy and safety of pazopanib as first-line treatment in metastatic renal cell cancer patients not enrolled into clinical trials. Methods Retrospective analysis (the PAMERIT study) of first-line pazopanib in real-world metastatic renal cell cancer patients among 39 Centers in Italy. Outcomes were progression-free survival, overall survival, objective response rate and treatment-related adverse events. Kaplan–Meier curves, log-rank test and multivariable Cox’s models were used and adjusted for age, histology, previous renal surgery, International Metastatic RCC Database Consortium score and pazopanib initial dose. Results Among 474 patients, 87.3% had clear cell metastatic renal cell cancer histology. Most of them (84.6%) had upfront renal surgery. Median progression-free survival and overall survival were 15.8 and 34.4 months, respectively, significantly correlating with International Metastatic RCC Database Consortium’s good prognosis (P Conclusions In this real-world study, metastatic renal cell cancer patients treated with first-line pazopanib reached greater progression-free survival and overall survival than in pivotal studies and had high response rates when belonging to International Metastatic RCC Database Consortium’s favorable group, without new toxicities. Pazopanib has been confirmed a valid first-line option for International Metastatic RCC Database Consortium’s good prognosis metastatic renal cell cancer patients who cannot be submitted to immunotherapy.
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- 2020
34. Immunotherapeutic Targets and Therapy for Renal Cell Carcinoma
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Alessia Mennitto, Pierangela Sepe, Francesca Corti, and Giuseppe Procopio
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Oncology ,medicine.medical_specialty ,Cabozantinib ,Mechanism (biology) ,business.industry ,Angiogenesis ,medicine.medical_treatment ,Standard treatment ,Immunology ,Immunotherapy ,urologic and male genital diseases ,medicine.disease ,Targeted therapy ,Unmet needs ,chemistry.chemical_compound ,chemistry ,Renal cell carcinoma ,Internal medicine ,medicine ,Immunology and Allergy ,business - Abstract
Over the last 20 years, different therapies have been considered as the mainstay for the treatment of patients with metastatic renal cell carcinoma (mRCC). Since angiogenesis is a key mechanism in the pathogenesis of renal carcinoma, research is still focusing on the inhibition of new vessel growth through the development of novel and potent tyrosine kinase inhibitors (TKIs), such as cabozantinib. On the other hand, a new therapeutic scenario has opened up in the forefront with immunotherapy. Immune checkpoint inhibitors (ICIs), which already represent a standard treatment option in pretreated mRCC patients, are revolutionizing the frontline therapeutic armamentarium of mRCC. Upfront combination immunotherapy as well as combinations of immunotherapy with targeted agents showed to significantly improved outcomes of mRCC patients compared to single-agent TKIs. ICIs are associated with long-lasting responses. Nonetheless, several unmet needs remain, as a small proportion of patients shows primary refractoriness to immunotherapy. Multiple treatment strategies combining different mechanisms of action or targeting immune escape pathways are emerging with the aim to improve response rates and survival outcomes. This review summarizes current immunotherapeutic targets and therapies approved for mRCC, while examining mechanisms of resistance and future directions, with the aim to address novel treatment strategies and help in improving the management of this tumor.
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- 2020
35. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial
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Thomas Powles, Piotr Tomczak, Se Hoon Park, Balaji Venugopal, Thomas Ferguson, Stefan N Symeonides, Jaroslav Hajek, Howard Gurney, Yen-Hwa Chang, Jae Lyun Lee, Naveed Sarwar, Antoine Thiery-Vuillemin, Marine Gross-Goupil, Mauricio Mahave, Naomi B Haas, Piotr Sawrycki, Joseph E Burgents, Lei Xu, Kentaro Imai, David I Quinn, Toni K Choueiri, Toni Choueiri, Thomas R. Ferguson, Tzu-Ping Lin, Stefan N. Symeonides, Naomi B. Haas, Howard P. Gurney, Christine Chevreau, John M. Burke, Gurjyot Doshi, Bohuslav Melichar, Delphine Topart, Stephane Oudard, Evgeniy Kopyltsov, Hans-Joerg Hammers, David I. Quinn, Ajjai Alva, Juliana de Janoski Menezes, Adriano Goncalves e Silva, Eric W. Winquist, Alketa Hamzaj, Giuseppe Procopio, Boguslawa Karaszewska, Ewa M. Nowakowska-Zajdel, Boris Y. Alekseev, Rustem A. Gafanov, Adel Izmailov, Andrey Semenov, Sergey G. Afanasyev, Oleg N. Lipatov, Thomas B. Powles, Sandy Srinivas, David McDermott, Samith T. Kochuparambil, Ian D. Davis, Katriina Peltola, Roberto Sabbatini, Jinsoo Chung, Michail I. Shkolnik, Vsevolod B. Matveev, Pablo Gajate Borau, Steven McCune, Thomas E. Hutson, Alejandro Dri, Silvio Correia Sales, Carrie Yeung, Carmen Marcela Alcala Castro, Peter Bostrom, Brigitte Laguerre, Consuelo Buttigliero, Ugo de Giorgi, Eugeniy A. Fomin, Yousef Zakharia, Clara Hwang, Eric A. Singer, Jeffrey T. Yorio, David Waterhouse, Ruben Dario Kowalyszyn, Margarita Sonia Alfie, Eduardo Yanez Ruiz, Tomas Buchler, Krista Kankaanranta, Gianluigi Ferretti, Go Kimura, Kazuo Nishimura, Naoya Masumori, Satoshi Tamada, Haruaki Kato, Hiroshi Kitamura, Iwona Danielewicz, Joanna Wojcik-Tomaszewska, Nuria Sala Gonzalez, Kun-Yuan Chiu, Michael B. Atkins, Elisabeth Heath, Gustavo Adolfo Rojas-Uribe, Manuel Enrique Gonzalez Fernandez, Susan Feyerabend, Sandro Pignata, Kazuyuki Numakura, Bozena Cybulska Stopa, Ruslan Zukov, Miguel Angel Climent Duran, Pablo Jose Maroto Rey, Alvaro Montesa Pino, Chao-Hsiang Chang, Salil Vengalil, Tom S. Waddell, Patrick W. Cobb, Ralph Hauke, Daniel M. Anderson, John Sarantopoulos, Theodore Gourdin, Tian Zhang, Gautam Jayram, Luis Enrique Fein, Carole Harris, Patricia Medeiros Milhomem Beato, Francisco Flores, Angela Estay, Juan Andres Rubiano, Jens Bedke, Stefan Hauser, Andreas Neisius, Jonas Busch, Satoshi Anai, Hiroyuki Tsunemori, Dariusz Sawka, Bozena Sikora-Kupis, Jose Angel Arranz, Ignacio Delgado, Chung-Hsin Chen, Elizabeth Gunderson, Scott Tykodi, Alan Koletsky, Kevin Chen, Manish Agrawal, Diego Lucas Kaen, Juan Pablo Sade, Marcelo Daniel Tatangelo, Francis Parnis, Fernando Maciel Barbosa, Genevieve Faucher, Nayyer Iqbal, Daniele Marceau, Jean-Benoit Paradis, Nawar Hanna, Alejandro Acevedo, Carolina Ibanez, Luis Villanueva, Pedro Pablo Galaz, Isabel Cristina Durango, Ray Manneh, Zdenek - Kral, Petra Holeckova, Heikki Hakkarainen, Hanna Ronkainen, Sophie Abadie-Lacourtoisie, Sophie Tartas, Peter J. Goebell, Marc-Oliver Grimm, Thomas Hoefner, Manfred Wirth, Andrej Panic, Wolfgang Schultze-Seemann, Akira Yokomizo, Ryuichi Mizuno, Hirotsugu Uemura, Masatoshi Eto, Masao Tsujihata, Yoshihisa Matsukawa, Yoji Murakami, Miso Kim, Paul Hamberg, Malgorzata Marczewska-Skrodzka, Cezary Szczylik, Alison C. Humphreys, Peter Jiang, Birendra Kumar, Gary Lu, Arpita Desai, Jose Antonio Karam, George Keogh, Mark Fleming, Juan Jose Zarba, Viviana E. Leiva, Guillermo Ariel Mendez, Samuel J. Harris, Stephen J. Brown, Joao Neif Antonio Junior, Rita de Cassia Costamilan, Roberto Odebrecht Rocha, David Muniz, Leandro Brust, Aly-Khan Lalani, Jeffrey Graham, Michael Levesque, Francisco Orlandi, Rostislav Kotasek, Jean L. Deville, Delphine Borchiellini, Axel Merseburger, Michael Rink, Frederik Roos, Ray McDermott, Masafumi Oyama, Yoshiaki Yamamoto, Yoshihiko Tomita, Yuji Miura, Naomasa Ioritani, Hans Westgeest, Tomasz Kubiatowski, Wieslaw Bal, Regina Girones Sarrio, Julie Rowe, Debra M. Prow, Francis Senecal, Neda Hashemi-Sadraei, Scott W. Cole, Stephan D. Kendall, Donald A. Richards, Ian D. Schnadig, and Mukul Gupta
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Adult ,Oncology ,Double-Blind Method ,Antineoplastic Combined Chemotherapy Protocols ,Hypertension ,Humans ,Antibodies, Monoclonal, Humanized ,Carcinoma, Renal Cell ,Nephrectomy ,Kidney Neoplasms ,Follow-Up Studies - Abstract
Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints. Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334. Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7–36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50–0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3–4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (
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- 2022
36. Concomitant Drugs Prognostic Score in Patients With Metastatic Renal Cell Carcinoma Receiving Ipilimumab and Nivolumab in the Compassionate Use Program in Italy: Brief Communication
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Sebastiano Buti, Umberto Basso, Diana Giannarelli, Ugo De Giorgi, Marco Maruzzo, Roberto Iacovelli, Luca Galli, Camillo Porta, Francesco Carrozza, Giuseppe Procopio, Giuseppe Fonarini, Giovanni Lo Re, Matteo Santoni, Roberto Sabbatini, Antonio Cusmai, Paolo Andrea Zucali, Carlo Aschele, Editta Baldini, Elena Zafarana, Adolfo Favaretto, Silvana Leo, Alketa Hamzaj, Rosanna Mirabelli, Franco Nole’, Silvia Zai, Claudio Chini, Cristina Masini, Sonia Fatigoni, Andrea Rocchi, Emiliano Tamburini, Alessio Cortellini, and Melissa Bersanelli
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Pharmacology ,Cancer Research ,Immunology ,Immunology and Allergy - Abstract
A concomitant drug-based score was developed by our group and externally validated for prognostic and predictive purposes in patients with advanced cancer treated with immune checkpoint inhibitors (ICIs). The model considers the use of three classes of drugs within a month before initiating ICI, assigning score 1 for each between proton pump inhibitor and antibiotic administration until a month before immunotherapy initiation and score 2 in case of corticosteroid intake. In the present analysis, the drug score was validated in a prospective population of 305 patients with metastatic renal cell carcinoma treated with ipilimumab plus nivolumab in the first-line setting. The value of the model in predicting overall survival and progression-free survival was statistically significant and clinically meaningful, with an overall survival rate at 12 months of 73% vs. 44% (P0.0001), and median progression-free survival of 11.6 (95% CI: 9.1-14.1) months versus 4.8 (95% CI: 2.7-7.0) months (P=0.002), respectively, for patients belonging to the favorable group (score 0-1) versus the unfavorable (score 2-4). Further development will be represented by the gut microbiome analysis according to the drug-based model classification and to the outcome of patients to ICI therapy to demonstrate the link between drug exposure and immune sensitivity.
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- 2022
37. The emerging role of PARP inhibitors in prostate cancer
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Alessia Mennitto, Giuseppe Procopio, Pierangela Sepe, Giuseppe Tonini, Melanie Claps, Marco Stellato, Elena Verzoni, Emma Zattarin, Riccardo Valdagni, Daniele Santini, Filippo de Braud, and Valentina Guadalupi
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Male ,0301 basic medicine ,DNA Repair ,Veliparib ,Poly ADP ribose polymerase ,Antineoplastic Agents ,Poly(ADP-ribose) Polymerase Inhibitors ,Olaparib ,03 medical and health sciences ,chemistry.chemical_compound ,Prostate cancer ,0302 clinical medicine ,Drug Development ,Animals ,Humans ,Medicine ,Talazoparib ,Pharmacology (medical) ,Rucaparib ,Gene ,business.industry ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,business ,Homologous recombination ,human activities - Abstract
In prostate cancer , there has recently been an emerging interest in mutations in genes belonging to the homologous recombination repair (HRR) pathway and in the inhibition of poly (ADP-ribose) polymerase (PARP) proteins.Mutations in the HRR genes, including BRCA1, BRCA2, and Ataxia-Telangiesctasia mutated (ATM), have been reported in prostate cancer, with different incidence in the localized and advanced settings. The PARP enzyme complex is involved in repair of DNA damage and its inhibition causes the accumulation of DNA mutations in HRR deficient cells. Several PARP inhibitors (PARPi) are under development, such as olaparib, talazoparib, niraparib, rucaparib, and veliparib. In metastatic castration resistant prostate cancer (mCRPC), olaparib has been the most studied and its clinical efficacy has been validated in a phase III clinical trial. Rucaparib and niraparib have also shown promising results in the preliminary analyzes of two phase II trials, while talazoparib is currently under development.PARPi have become part of the treatment of mCRPC. Early results of combination therapy with PARPi and new hormonal therapy are promising and are supported by a strong biological rationale. Current results need to be validated in randomized phase III-controlled trials in order to translate the use of PARPi into real world practice.
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- 2020
38. 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
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Toni K. Choueiri, Howard Gurney, David F. McDermott, Christian Kollmannsberger, Michael A. Carducci, Martin Eduardo Richardet, M. Brent McHenry, Elizabeth R. Plimack, Fabio A.B. Schutz, David Cella, Nizar M. Tannir, Frede Donskov, Bernard Escudier, John Wagstaff, Yoshihiko Tomita, Robert J. Motzer, Satoshi Fukasawa, Shruti Shally Saggi, Saby George, Giuseppe Procopio, Christine Chevreau, Hans J. Hammers, Thomas Gauler, Daniel Castellano, Jeffrey A. Sosman, James Larkin, Ajjai Alva, Sandhya Srinivas, Katriina Peltola, Scott S. Tykodi, and Stéphane Oudard
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CheckMate 025 ,Male ,Oncology ,Cancer Research ,Medizin ,immune checkpoint inhibitor ,DOSE RECOMBINANT INTERLEUKIN-2 ,0302 clinical medicine ,Renal cell carcinoma ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Medicine ,030212 general & internal medicine ,Everolimus/pharmacology ,Hazard ratio ,Kidney Neoplasms ,3. Good health ,Kidney Neoplasms/drug therapy ,Nivolumab ,Treatment Outcome ,Tolerability ,SAFETY ,030220 oncology & carcinogenesis ,SURVIVAL ,Female ,medicine.drug ,medicine.medical_specialty ,Antineoplastic Combined Chemotherapy Protocols/pharmacology ,previously treated ,Article ,03 medical and health sciences ,Nivolumab/pharmacology ,Internal medicine ,Humans ,Everolimus ,Adverse effect ,Carcinoma, Renal Cell ,nivolumab ,business.industry ,everolimus ,medicine.disease ,LIFE ,Carcinoma, Renal Cell/drug therapy ,business ,Kidney cancer ,advanced renal cell carcinoma (aRCC) ,Follow-Up Studies - Abstract
Background: CheckMate 025 has shown superior efficacy for nivolumab over everolimus in patients with advanced renal cell carcinoma (aRCC) along with improved safety and tolerability. This analysis assesses the long-term clinical benefits of nivolumab versus everolimus. Methods: The randomized, open-label, phase 3 CheckMate 025 trial (NCT01668784) included patients with clear cell aRCC previously treated with 1 or 2 antiangiogenic regimens. Patients were randomized to nivolumab (3 mg/kg every 2 weeks) or everolimus (10 mg once a day) until progression or unacceptable toxicity. The primary endpoint was overall survival (OS). The secondary endpoints were the confirmed objective response rate (ORR), progression-free survival (PFS), safety, and health-related quality of life (HRQOL). Results: Eight hundred twenty-one patients were randomized to nivolumab (n = 410) or everolimus (n = 411); 803 patients were treated (406 with nivolumab and 397 with everolimus). With a minimum follow-up of 64 months (median, 72 months), nivolumab maintained an OS benefit in comparison with everolimus (median, 25.8 months [95% CI, 22.2-29.8 months] vs 19.7 months [95% CI, 17.6-22.1 months]; hazard ratio [HR], 0.73; 95% CI, 0.62-0.85) with 5-year OS probabilities of 26% and 18%, respectively. ORR was higher with nivolumab (94 of 410 [23%] vs 17 of 411 [4%]; P
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- 2020
39. Prospective Translational Study Investigating Molecular PrEdictors of Resistance to First-Line PazopanIb in Metastatic reNal CEll Carcinoma (PIPELINE Study)
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Massimo Di Maio, Marco Stellato, Alessia Mennitto, Elena Verzoni, Paolo Grassi, Valentina Guadalupi, Elisa Sottotetti, Alessandra Raimondi, Giuseppe Procopio, Melanie Claps, Pierangela Sepe, Emma Zattarin, and Antonia Martinetti
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Male ,Vascular Endothelial Growth Factor A ,Oncology ,Cancer Research ,circulating angiogenic factors ,Drug Resistance ,Angiogenesis Inhibitors ,Translational Research, Biomedical ,0302 clinical medicine ,Renal cell carcinoma ,pazopanib ,Prospective Studies ,030212 general & internal medicine ,Osteopontin ,Prospective cohort study ,Translational Medical Research ,Sulfonamides ,biology ,Hepatocyte Growth Factor ,circulating biomarkers ,Middle Aged ,TKI ,Kidney Neoplasms ,Progression-Free Survival ,Survival Rate ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,E-Selectin ,medicine.drug ,renal cell carcinoma ,medicine.medical_specialty ,Indazoles ,Antineoplastic Agents ,Aged ,Carcinoma, Renal Cell ,Chemokine CXCL12 ,Humans ,Interleukin-6 ,Interleukin-8 ,Pyrimidines ,Drug Resistance, Neoplasm ,Pazopanib ,03 medical and health sciences ,Internal medicine ,Carcinoma ,medicine ,Progression-free survival ,Survival rate ,business.industry ,Renal Cell ,medicine.disease ,biology.protein ,Neoplasm ,business - Abstract
Objectives Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib. Materials and methods mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared. Results Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017). Conclusion Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.
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- 2020
40. Safety and activity of radium-223 in metastatic castration-resistant prostate cancer: the experience of Istituto Nazionale dei Tumori
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Giovanni Randon, Marco Maccauro, Melanie Claps, Filippo Pagani, Giulia Apollonio, Giorgia Peverelli, Giuseppe Procopio, Gianluca Aliberti, Alessandra Raimondi, Ettore Seregni, Pierangela Sepe, and Elena Verzoni
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Male ,Oncology ,Radium-223 ,Cancer Research ,medicine.medical_specialty ,Castration resistant ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Castration Resistance ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Neoplasm Metastasis ,Aged ,Aged, 80 and over ,Radioisotopes ,business.industry ,General Medicine ,Middle Aged ,Prostate-Specific Antigen ,medicine.disease ,Prostatic Neoplasms, Castration-Resistant ,Treatment Outcome ,030220 oncology & carcinogenesis ,business ,Radium ,medicine.drug - Abstract
Introduction: Therapeutic decision-making in metastatic castration-resistant prostate cancer (mCRPC) represents an open challenge. Radium-223 is approved for patients with symptomatic bone metastases, no visceral involvement, progressing after at least 2 lines of systemic therapy, or ineligible for any other systemic treatment. Methods: We performed a retrospective, observational study on patients with mCRPC treated with radium-223 at our institution outside of clinical trials, to assess the safety and activity in a real-world population. Data regarding baseline patient/disease characteristics and treatment outcomes (number of cycles, treatment-related adverse events [AEs], cause of discontinuation, and best response) were collected. Results: Overall, 41 patients were treated from September 2015 to September 2018. Median age was 73 years; baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0, 1, or 2 in 15%, 80%, and 5% of cases, respectively; and 3%, 41%, 44%, and 12% of patients had 20, and superscan bone lesions, respectively. A median number of 5 cycles (interquartile range 3–6) with median dose 19.52 MBq (interquartile range 12.87–24.83) was received. Treatment schedule was completed in 49% of cases; discontinuations due to AEs, disease-related death, or disease progression occurred in 24%, 33%, and 43% of patients, respectively. Any-grade AEs occurred in 73% and grade 3/4 treatment-related AEs occurred in 29% of patients, mainly anemia, decreased platelet count, and fatigue. No skeletal-related events or treatment-related deaths were recorded. After treatment, 66%, 2%, and 32% of patients had a stable, improved, or deteriorated ECOG PS versus baseline, respectively, and 24%, 61%, and 15% reported a stable, improved, or worsened pain symptom control. Post-treatment versus baseline alkaline phosphatase was reduced or stable in 46% and increased in 54% of patients, whereas prostate-specific antigen was decreased or stable in 83% and increased in 17% of patients. Conclusions: Our study provides clinically useful real-world data on radium-223, highlighting the importance of multidisciplinary patient management to guarantee the best continuum of care for patients with mCRPC.
- Published
- 2020
41. SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)
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Antonio Orlacchio, Carlo Guastoni, Giordano Domenico Beretta, Laura Cosmai, Michele Galluzzo, Stefania Gori, Emanuele Grassedonio, Lorena Incorvaia, Carmelita Marcantoni, Giuseppe Stefano Netti, Matteo Passamonti, Camillo Porta, Giuseppe Procopio, Mimma Rizzo, Silvia Roma, Laura Romanini, Fulvio Stacul, Alice Casinelli, Orlacchio A., Guastoni C., Beretta G.D., Cosmai L., Galluzzo M., Gori S., Grassedonio E., Incorvaia L., Marcantoni C., Netti G.S., Passamonti M., Porta C., Procopio G., Rizzo M., Roma S., Romanini L., Stacul F., and Casinelli A.
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Male ,Consensus ,Contrast Media ,General Medicine ,Acute Kidney Injury ,urologic and male genital diseases ,Kidney ,Medical Oncology ,Oncology ,Settore MED/36 ,Nephrology ,Risk Factors ,Kidney injury ,Humans ,Radiology, Nuclear Medicine and imaging ,Female ,Diagnostic ,Nephrotoxicity ,Radiology - Abstract
The increasing number of examinations and interventional radiological procedures that require the administration of contrast medium (CM) in patients at risk for advanced age and/or comorbidities highlights the problem of CM-induced renal toxicity. A multidisciplinary group consisting of specialists of different disciplines—radiologists, nephrologists and oncologists, members of the respective Italian Scientific Societies—agreed to draw up this position paper, to assist clinicians increasingly facing the challenges posed by CM-related renal dysfunction in their daily clinical practice.The major risk factor for acute renal failure following CM administration (post-CM AKI) is the preexistence of renal failure, particularly when associated with diabetes, heart failure or cancer.In accordance with the recent guidelines ESUR, the present document reaffirms the importance of renal risk assessment through the evaluation of the renal function (eGFR) measured on serum creatinine and defines the renal risk cutoff when the eGFR is The cutoff of renal risk is considered an eGFR Intravenous hydration using either saline or Na bicarbonate solution before and after CM administration represents the most effective preventive measure in patients at risk of post-CM AKI. In the case of urgency, the infusion of 1.4% sodium bicarbonate pre- and post-CM may be more appropriate than the administration of saline.In cancer patients undergoing computed tomography, pre- and post-CM hydration should be performed when the eGFR is In patients with more severe renal risk (i.e., with eGFR In magnetic resonance imaging (MRI) using gadolinium CM, there is a lower risk of AKI than with iodinated CM, particularly if doses 30 ml/min/1.73 m2. Dialysis after MRI is indicated only in patients already undergoing chronic dialysis treatment to reduce the potential risk of systemic nephrogenic fibrosis.
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- 2022
42. The Role of CT Imaging in Characterization of Small Renal Masses
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Maria Vittoria Bazzocchi, Carlotta Zilioli, Vita Ida Gallone, Claudia Commisso, Lorenzo Bertolotti, Francesco Pagnini, Francesco Ziglioli, Umberto Maestroni, Alberto Aliprandi, Sebastiano Buti, Giuseppe Procopio, Giorgio Ascenti, Chiara Martini, and Massimo De Filippo
- Subjects
Clinical Biochemistry - Abstract
Small renal masses (SRM) are increasingly detected incidentally during imaging. They vary widely in histology and aggressiveness, and include benign renal tumors and renal cell carcinomas that can be either indolent or aggressive. Imaging plays a key role in the characterization of these small renal masses. While a confident diagnosis can be made in many cases, some renal masses are indeterminate at imaging and can present as diagnostic dilemmas for both the radiologists and the referring clinicians. This review focuses on CT characterization of small renal masses, perhaps helping us understand small renal masses. The following aspects were considered for the review: (a) assessing the presence of fat, (b) assessing the enhancement, (c) differentiating renal tumor subtype, and (d) identifying valuable CT signs.
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- 2023
43. Pembrolizumab Plus Axitinib for Metastatic Papillary and Chromophobe Renal Cell Carcinoma: NEMESIA (Non Clear MEtaStatic Renal Cell Carcinoma Pembrolizumab Axitinib) Study, a Subgroup Analysis of I-RARE Observational Study (Meet-URO 23a)
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Marco Stellato, Sebastiano Buti, Marco Maruzzo, Melissa Bersanelli, Francesco Pierantoni, Ugo De Giorgi, Marilena Di Napoli, Roberto Iacovelli, Maria Giuseppa Vitale, Paola Ermacora, Andrea Malgeri, Brigida Anna Maiorano, Veronica Prati, Alessia Mennitto, Alessia Cavo, Matteo Santoni, Claudia Carella, Lucia Fratino, Giuseppe Procopio, Elena Verzoni, and Daniele Santini
- Subjects
Inorganic Chemistry ,Organic Chemistry ,General Medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy ,Catalysis ,non-clear renal cell carcinoma ,cromophobe renal cell carcinoma ,papillary renal cell carcinoma ,pembrolizumab ,axitinib ,renal cell carcinoma ,combination ,Computer Science Applications - Abstract
Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous histological group which is 20–25% of those with renal cell carcinoma (RCC). Patients with nccRCC have limited therapeutic options due to their exclusion from phase III randomized trials. The aim of the present study was to investigate the effectiveness and tolerability of pembrolizumabaxitinib combination in chromophobe and papillary metastatic RCC (mRCC) patients enrolled in the I-RARE (Italian Registry on rAre genitor-uRinary nEoplasms) observational ongoing study (Meet-URO 23). Baseline characteristics, objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) and toxicities were retrospectively and prospectively collected from nccRCC patients treated in 14 Italian referral centers adhering to the Meet-Uro group, from December 2020 to April 2022. Only patients with chromophobe and papillary histology were considered eligible for the present pre-specified analysis. There were 32 eligible patients who received pembrolizumab-axitinib as first-line treatment, of whom 13 (40%) had chromophobe histology and 19 (60%) were classified as papillary RCC. The DCR was 78.1% whereas ORR was 43.7% (11 patients achieved stable disease and 14 patients obtained partial response: 9/19 papillary, 5/13 chromophobe). Six patients (18.7%) were primary refractory. Median PFS was 10.8 months (95%CI 1.7–11.5). Eleven patients (34.3%) interrupted the full treatment due to immune-related adverse events (irAEs): G3 hepatitis (n = 5), G3 hypophisitis (n = 1), G3 diarrhea (n = 1), G3 pancreatitis (n = 1), G3 asthenia (n = 1). Twelve patients (37.5%) temporarily interrupted axitinib only due to persistent G2 hand-foot syndrome or G2 hypertension. Pembrolizumab-axitinib combination could be an active and feasible first-line treatment option for patients with papillary or chromophobe mRCC.
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- 2023
44. Clinical outcomes of volume of disease on patients receiving enzalutamide versus abiraterone acetate plus prednisone as first-line therapy for metastatic castration-resistant prostate cancer
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Pier Vitale Nuzzo, Francesco Ravera, Calogero Saieva, Elisa Zanardi, Giuseppe Fotia, Andrea Malgeri, Sabrina Rossetti, Loana Bueno Valença, Thiago Martins Oliveira, Charles Vauchier, Ricardo Pereira Mestre, Mikol Modesti, Anna Patrikidou, Sandro Pignata, Giuseppe Procopio, Giuseppe Fornarini, Ugo De Giorgi, Antonio Russo, and Edoardo Francini
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Oncology - Abstract
Background: Androgen receptor signaling inhibitors (ARSis) abiraterone acetate (AA) plus prednisone and enzalutamide (Enza), are currently the most administered first-line treatments for metastatic castration-resistant prostate cancer (mCRPC). AA and Enza have shown similar overall survival (OS) benefits and there is no consensus upon the best option for mCRPC first-line treatment. Volume of disease may represent a useful biomarker to predict response to therapy in such patients. Objectives: In this study, we seek to evaluate the impact of volume of disease on patients treated with first-line AA versus Enza for mCRPC. Design and methods: We retrospectively evaluated a cohort of consecutive patients with mCRPC categorized by volume of disease [high volume (HV) or low volume (LV) per E3805 criteria] at ARSi onset and treatment type (AA or Enza), assessing OS and radiographic progression-free survival (rPFS), from therapy start, as co-primary endpoints. Results: Of the 420 patients selected, 170 (40.5%) had LV and received AA (LV/AA), 76 (18.1%) LV and had Enza (LV/Enza), 124 (29.5%) HV and were given AA (HV/AA), and 50 (11.9%) HV and received Enza (HV/Enza). Among patients with LV, OS was significantly longer when treated with Enza [57.2 months; 95% confidence interval (CI): 52.1–62.2 months] versus AA (51.6 months; 95% CI, 42.6–60.6 months; p = 0.003). Consistently, those with LV receiving Enza showed increased rPFS (40.3 months; 95 CI, 25.0–55.7 months) than those having AA (22.0 months; 95% CI, 18.1–26.0 months; p = 0.004). No significant difference in OS or rPFS was observed in those with HV treated with AA versus Enza ( p = 0.51 and p = 0.73, respectively). In multivariate analysis of patients with LV, treatment with Enza was independently associated with better prognosis than AA. Conclusion: Within the intrinsic limitations of a retrospective design and small population, our report suggests that volume of disease could be a useful predictive biomarker for patients starting first-line ARSi for mCRPC.
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- 2023
45. Current evidence for second-line treatment in metastatic renal cell carcinoma after progression to immune-based combinations
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Roberto Iacovelli, Chiara Ciccarese, Giuseppe Procopio, Serena Astore, Maria Antonella Cannella, Maria Grazia Maratta, Mimma Rizzo, Elena Verzoni, Camillo Porta, and Giampaolo Tortora
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Oncology ,Humans ,Radiology, Nuclear Medicine and imaging ,General Medicine ,Prospective Studies ,Prognosis ,Carcinoma, Renal Cell ,Kidney Neoplasms ,Retrospective Studies - Abstract
The recent approval of immune checkpoint inhibitor (ICI)-based combinations has redefined the first-line standard of care of metastatic renal cell carcinoma (mRCC) patients. Although the undisputed advantage of these combinations, most patients progressed, requiring subsequent therapies. The change of first-line therapy inevitably led to modification of the all mRCC treatment algorithm; to date, the most appropriate second-line options remain still unclear. The aim of our review was to provide a useful summary of the available evidence in order to overcome the doubts about treatment sequences. Retrospectively, the efficacy of second-line VEGFR-TKIs seems to be greater after failure of a dual ICIs combination rather than after ICIs plus VEGFR-TKIs, nevertheless prospective data of second-line TKIs are limited. Moreover, ICI re-challenge could be an option but, again, most data derived from retrospective series emphasizing the identification of predictive factors of response to select mRCC patients that could benefit from this strategy. Novel molecules and different ICI-based combinations are under evaluation with the aim of implementing the second-line setting. In particular, belzutifan, ciforadenant (CPI-444), and talazoparib achieved encouraging objective response rates (ORR) in phase I/II trials. Phase III trials comparing these new molecules with the standard of care are currently ongoing. The first-line regimen, and the type and duration of response emerged as crucial factors that could influence the efficacy of second-line therapy. Prognostic models that integrate clinical features and molecular biomarkers with a predictive value are warranted to guide clinicians in the decision-making process with the ultimate goal of offering to the patients the most effective therapy in a personalized, precision medicine-based, therapeutic strategy.
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- 2021
46. Biomarker-driven immunotherapy for precision medicine in prostate cancer
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Arianna Ottini, Pierangela Sepe, Teresa Beninato, Mélanie Claps, Valentina Guadalupi, Elena Verzoni, Patrizia Giannatempo, Giulia Baciarello, Filippo de Braud, and Giuseppe Procopio
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Pharmacology ,Male ,Molecular Medicine ,Humans ,Prostatic Neoplasms ,General Medicine ,Immunotherapy ,Precision Medicine ,DNA Mismatch Repair ,Biomarkers - Abstract
Although immunotherapy has recently revolutionized standard of care in different cancer types, prostate cancer has generally failed to show dramatic responses to immune checkpoint inhibitors. As in other tumors, the goal in prostate cancer is now to target treatments more precisely on patient’s individual characteristics through precision medicine. Defects in mismatch repair, mutations in the exonuclease domain of the DNA polymerase epsilon ( POLE), high tumor mutational burden and the presence of biallelic loss of CDK12 among others, are predictive biomarkers of response to immunotherapy. In the present review, we summarize the evolving landscape of immunotherapy in prostate cancer, including precision approaches and strategies to define classes of responsive patients and scale up resistance to immune checkpoint inhibitors.
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- 2021
47. FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy
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Toni K Choueiri, Harriet Kluger, Saby George, Scott S Tykodi, Timothy M Kuzel, Ruth Perets, Suresh Nair, Giuseppe Procopio, Michael A Carducci, Vincent Castonguay, Edmund Folefac, Chung-Han Lee, Sebastien J. Hotte, Wilson H Miller, Shruti Shally Saggi, Chung-Wei Lee, Heshani Desilva, Prabhu Bhagavatheeswaran, Robert J Motzer, and Bernard Escudier
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Pharmacology ,Cancer Research ,Immunology ,Ipilimumab ,B7-H1 Antigen ,Kidney Neoplasms ,Nivolumab ,Treatment Outcome ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Molecular Medicine ,Immunology and Allergy ,Immunotherapy ,Carcinoma, Renal Cell - Abstract
BackgroundThe role and sequencing of combination immuno-oncology (IO) therapy following progression on or after first-line IO therapy has not been well-established. The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology (FRACTION) program is an open-label, phase 2 platform trial designed to evaluate multiple IO combinations in patients with advanced renal cell carcinoma (aRCC) who progressed during or after prior IO therapy. Here, we describe the results for patients treated with nivolumab plus ipilimumab. For enrollment in track 2 (reported here), patients with histologically confirmed clear cell aRCC, Karnofsky performance status ≥70%, and life expectancy ≥3 months who had previously progressed after IO (anti-programmed death 1 (PD-1), anti-programmed death-ligand 1 (PD-L1), or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4)) therapy were eligible. Previous treatment with anti-CTLA-4 therapy plus anti-PD-1/PD-L1 therapy precluded eligibility for enrollment in the nivolumab plus ipilimumab arm. Patients were treated with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses, followed by nivolumab 480 mg every 4 weeks for up to 2 years or until progression, toxicity, or protocol-specified discontinuation. The primary outcome measures were objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Secondary outcomes were safety and tolerability up to 2 years. Overall survival (OS) was a tertiary/exploratory endpoint. Overall, 46 patients were included with a median follow-up of 33.8 months. The ORR was 17.4% (95% CI, 7.8 to 31.4) with eight (17.4%) patients achieving partial response. Stable disease was achieved in 19 (41.3%) patients, while 14 (30.4%) had progressive disease. Median DOR (range) was 16.4 (2.1+ to 27.0+) months. The PFS rate at 24 weeks was 43.2%, and median OS was 23.8 (95% CI, 13.2 to not reached) months. Grade 3–4 immune-mediated adverse events were reported in seven (15.2%) patients. No treatment-related deaths were reported. Patients with aRCC treated with nivolumab plus ipilimumab may derive durable clinical benefit after progression on previous IO therapies, including heavily pretreated patients, with a manageable safety profile that was consistent with previously published safety outcomes. These outcomes contribute to the knowledge of optimal sequencing of IO therapies for patients with aRCC with high unmet needs.Trial registration numberNCT02996110.
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- 2022
48. Pain and health-related quality of life with olaparib versus physician's choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial
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Antoine Thiery-Vuillemin, Johann de Bono, Maha Hussain, Guilhem Roubaud, Giuseppe Procopio, Neal Shore, Karim Fizazi, Gabriel dos Anjos, Gwenaelle Gravis, Jae Young Joung, Nobuaki Matsubara, Daniel Castellano, Arnold Degboe, Chris Gresty, Jinyu Kang, Allison Allen, Christian Poehlein, and Fred Saad
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Adult ,Male ,Prostatic Neoplasms, Castration-Resistant ,Oncology ,Adolescent ,Physicians ,Antineoplastic Combined Chemotherapy Protocols ,Quality of Life ,Humans ,Pain ,Phthalazines ,Recombinational DNA Repair ,Piperazines - Abstract
The PROfound study showed significantly improved radiographical progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes and disease progression on a previous next-generation hormonal drug who received olaparib then those who received control. We aimed to assess pain and patient-centric health-related quality of life (HRQOL) measures in patients in the trial.In this open-label, randomised, phase 3 study, patients (aged ≥18 years) with metastatic castration-resistant prostate cancer and gene alterations to one of 15 genes (BRCA1, BRCA2, or ATM [cohort A] and BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L [cohort B]) and disease progression after a previous next-generation hormonal drug were randomly assigned (2:1) to receive olaparib tablets (300 mg orally twice daily) or a control drug (enzalutamide tablets [160 mg orally once daily] or abiraterone tablets [1000 mg orally once daily] plus prednisone tablets [5 mg orally twice daily]), stratified by previous taxane use and measurable disease. The primary endpoint (radiographical progression-free survival in cohort A) has been previously reported. The prespecified secondary endpoints reported here are on pain, HRQOL, symptomatic skeletal-related events, and time to first opiate use for cancer-related pain in cohort A. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). All endpoints were analysed in patients in cohort A by modified intention-to-treat. The study is registered with ClinicalTrials.gov, NCT02987543.Between Feb 6, 2017, and June 4, 2019, 245 patients were enrolled in cohort A and received study treatment (162 [66%] in the olaparib group and 83 [34%] in the control group). Median duration of follow-up at data cutoff in all patients was 6·2 months (IQR 2·2-10·4) for the olaparib group and 3·5 months (1·7-4·9) for the control group. In cohort A, median time to pain progression was significantly longer with olaparib than with control (median not reached [95% CI not reached-not reached] with olaparib vs 9·92 months [5·39-not reached] with control; HR 0·44 [95% CI 0·22-0·91]; p=0·019). Pain interference scores were also better in the olaparib group (difference in overall adjusted mean change from baseline score -0·85 [95% CI -1·31 to -0·39]; pOlaparib was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations who had disease progression after a previous next-generation hormonal drug. Our findings support the clinical benefit of improved radiographical progression-free survival and overall survival identified in PROfound.AstraZeneca and Merck SharpDohme.
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- 2021
49. Prognostic Value of Thyroid Hormone Ratio in Patients With Advanced Metastatic Renal Cell Carcinoma: Results From the Threefour Study (Meet-URO 14)
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Marco, Maruzzo, Elena, Verzoni, Maria Giuseppa, Vitale, Michele, Dionese, Sebastiano, Buti, Luca, Galli, Andrea, Zivi, Sara, Watutantrige-Fernando, Teresa, Zielli, Elisa, Zanardi, Roberto, Sabbatini, Umberto, Basso, Vittorina, Zagonel, and Giuseppe, Procopio
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renal cell carcinoma ,FT3/FT4 ,Oncology ,tyrosine kinase inhibitors ,immunotherapy ,progression ,survival ,Original Research ,deiodination - Abstract
Background Thyroid hormone impairment, represented as an alteration in levels of thyroid hormones and a lower fT3/fT4 ratio, has been correlated with a worse prognosis for both cancer and non-cancer patients. The role of baseline thyroid function in patients with metastatic renal cell carcinoma (mRCC) however, has not been studied yet. Materials and Methods We recorded clinical data, baseline biochemical results, and oncological outcomes from 10 Oncology Units in Italy. We stratified patients into three groups according to the fT3/fT4 ratio value and subsequently analyzed differences in progression-free survival (PFS) and overall survival (OS) in the three groups. We also performed univariate and multivariate analyses to find prognostic factors for PFS and OS. Results We analyzed 134 patients treated with systemic treatment for mRCC. Median PFS in the low, intermediate, and high fT3/fT4 ratio group were 7.5, 12.1, and 21.7 months respectively (p
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- 2021
50. Update on radioligand therapy with
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Valentina, Fuoco, Giovanni, Argiroffi, Stefania, Mazzaglia, Alice, Lorenzoni, Valentina, Guadalupi, Andrea, Franza, Federica, Scalorbi, Gianluca, Aliberti, Carlo, Chiesa, Giuseppe, Procopio, Ettore, Seregni, and Marco, Maccauro
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Male ,Heterocyclic Compounds, 1-Ring ,Prostatic Neoplasms, Castration-Resistant ,Clinical Trials, Phase II as Topic ,Treatment Outcome ,Humans ,Dipeptides ,Prostate-Specific Antigen ,Randomized Controlled Trials as Topic ,Retrospective Studies - Abstract
To give an updated overview on clinical aspects and survival effects of lutetium-177-prostate-specific membrane antigen (PSMA) (PubMed/MEDLINE database was searched for relevant articles published up to March 2021. The search was restricted to English-language articles.Current evidence from the literature consistently demonstrated the efficacy, safety, and survival benefit of
- Published
- 2021
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