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      Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program

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          Abstract

          Background

          The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with metastatic renal cell carcinoma (mRCC) prior to regulatory approval.

          Methods

          Pts with previously treated advanced or mRCC were eligible to receive nivolumab 3 mg/kg every 2 weeks. Pts included in the analysis had received ≥1 dose of nivolumab and were monitored for drug-related adverse events (drAEs) using CTCAE v.4.0. Immune-related (ir) AEs were defined as AEs displaying a certain, likely or possible correlation with immunotherapy (cutaneous, endocrine, hepatic, gastro-intestinal and pulmonary). The association between overall survival (OS) and irAEs was assessed, and associations between variables were evaluated with a logistic regression model.

          Results

          A total of 389 pts were enrolled between July 2015 and April 2016. Overall, the objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7–6.2) and the 12-month overall survival rate was 63%. Any grade and grade 3–4 drAEs were reported in 124 (32%) and 27 (7%) of pts, respectively, and there were no treatment-related deaths. Any grade irAEs occurred in 76 (20%) of patients, 8% cutaneous, 4% endocrine, 2% hepatic, 5% gastro-intestinal and 1% pulmonary. Of the 22 drAEs inducing treatment discontinuation, 10 (45%) were irAEs. Pts with drAEs had a significantly longer survival than those without drAEs (median OS 22.5 versus 16.4 months, p = 0.01). Pts with irAEs versus without irAEs had a more significant survival benefit (median OS not reached versus 16.8 months, p = 0.002), confirmed at the landmark analysis at 6 weeks. The occurrence of irAEs displayed a strong association with OS in univariable (HR 0.48, p = 0.003) and multivariable (HR 0.57, p = 0.02) analysis.

          Conclusions

          The appearance of irAEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with nivolumab.

          Electronic supplementary material

          The online version of this article (10.1186/s40425-019-0579-z) contains supplementary material, which is available to authorized users.

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          Most cited references10

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          Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis.

          Vitiligo-like depigmentation in patients with melanoma may be associated with more favorable clinical outcome. We conducted a systematic review of patients with stage III to IV melanoma treated with immunotherapy to determine the cumulative incidence of vitiligo-like depigmentation and the prognostic value of vitiligo development on survival.
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            Early Immune-Related Adverse Events and Association with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study.

            Retrospective studies have shown immune-related adverse events (irAEs) to be associated with better prognosis. However, no prospective clinical trials have been conducted, and little is known regarding the association between irAEs and the outcome of patients with NSCLC after treatment with immunotherapy.
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              The Price of Tumor Control: An Analysis of Rare Side Effects of Anti-CTLA-4 Therapy in Metastatic Melanoma from the Ipilimumab Network

              Background Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.
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                Author and article information

                Contributors
                +39 02 2390 4449 , elena.verzoni@istitutotumori.mi.it
                cartenigiacomo@gmail.com
                enrico.cortesi@uniroma1.it
                diana.giannarelli@gmail.com
                degio1989@gmail.com
                sabbrob@unimore.it
                sebabuti@libero.it
                sabrinarossetti@virgilio.it
                francesco.cognetti@ifo.gov.it
                fraraste@gmail.com
                alberto.sobrero@hsanmartino.it
                d.turci@ausl.ra.it
                csternberg@scamilloforlanini.rm.it
                camillo.porta@gmail.com
                f.cappuzzo@gmail.com
                giampaolo.tortora@univr.it
                davide.tassinari@auslromagna.it
                s.panni@asst-cremona.it
                antonio.pazzola@aousassari.it
                oncologia.polecce@ausl.le.it
                alessandra.raimondi@istitutotumori.mi.it
                ugo.degiorgi@irst.emr.it
                giuseppe.procopio@istitutotumori.mi.it
                Journal
                J Immunother Cancer
                J Immunother Cancer
                Journal for Immunotherapy of Cancer
                BioMed Central (London )
                2051-1426
                3 April 2019
                3 April 2019
                2019
                : 7
                : 99
                Affiliations
                [1 ]ISNI 0000 0001 0807 2568, GRID grid.417893.0, Medical Oncology-Genitourinary Unit, , Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, ; Via Venezian 1, 20133 Milan, Italy
                [2 ]GRID grid.413172.2, Oncology Unit, , A. Cardarelli Hospital, ; Naples, Italy
                [3 ]GRID grid.417007.5, Radiology, Oncology and Pathology, , Policlinico Umberto I, ; Rome, Italy
                [4 ]ISNI 0000 0004 1760 5276, GRID grid.417520.5, Biostatistical Unit, , Regina Elena National Cancer Institute – IRCCS, ; Rome, Italy
                [5 ]ISNI 0000 0004 1760 672X, GRID grid.416377.0, Medical Oncology, , Azienda Ospedaliera Santa Maria, ; Terni, Italy
                [6 ]ISNI 0000 0004 1769 5275, GRID grid.413363.0, Oncology and Hematology Department, , Azienda Ospedaliero-Universitaria Policlinico di Modena, ; Modena, Italy
                [7 ]GRID grid.411482.a, Medical Oncology, , Azienda Ospedaliera di Parma, ; Parma, Italy
                [8 ]Urology and Gynecology, Istituto Nazionale Tumori – IRCCS – Fondazione Pascale, Naples, Italy
                [9 ]ISNI 0000 0004 1760 5276, GRID grid.417520.5, Medical Oncology, , Regina Elena National Cancer Institute – IRCCS, ; Rome, Italy
                [10 ]Medical Oncology, UOC Oncologia Area Vasta 4, Fermo, Italy
                [11 ]ISNI 0000 0004 1756 7871, GRID grid.410345.7, Medical Oncology, , San Martino Hospital, ; Genoa, Italy
                [12 ]ISNI 0000 0004 1760 3756, GRID grid.415207.5, Medical Oncology, , Ospedale Santa Maria delle Croci, ; Ravenna, Italy
                [13 ]Medical Oncology, Azienda Ospedaliera S. Camillo Forlanini, Rome, Italy
                [14 ]ISNI 0000 0004 1762 5736, GRID grid.8982.b, Department of Internal Medicine, , University of Pavia and Division of Translational Oncology, IRCCS Istituti Clinici Scientifici Maugeri, ; Pavia, Italy
                [15 ]Medical Oncology, Ospedale Umberto I (AUSL Romagna), Lugo, Italy
                [16 ]Medical Oncology, AOU Integrata Verona “Borgo Roma”, Verona, Italy
                [17 ]GRID grid.414614.2, Oncology, , Ospedale Infermi, ; Rimini, Italy
                [18 ]GRID grid.419450.d, Medical Oncology, , Istituti Ospitalieri di Cremona, ; Cremona, Italy
                [19 ]Medical Oncology, Ospedale Civile SS Annunziata, Sassari, Italy
                [20 ]ISNI 0000 0004 1769 6825, GRID grid.417011.2, Medical Oncology, , Ospedale Vito Fazzi, ; Lecce, Italy
                [21 ]ISNI 0000 0004 1755 9177, GRID grid.419563.c, Urologic-Gynecologic Unit, , Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), ; Meldola, Italy
                Article
                579
                10.1186/s40425-019-0579-z
                6448290
                30944023
                21738f59-6f6c-44f4-84ed-e87900624a27
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 14 November 2018
                : 26 March 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100002491, Bristol-Myers Squibb;
                Award ID: not applicable
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2019

                immunotherapy,adverse events,renal cell carcinoma,expanded access trials

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