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      A Retrospective Chart Review Study of Real-World Use of Talimogene Laherparepvec in Unresectable Stage IIIB–IVM1a Melanoma in Four European Countries

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          Abstract

          Introduction

          Talimogene laherparepvec (T-VEC; IMLYGIC ®, Amgen Inc.) is an oncolytic immunotherapy approved in Europe for the treatment of unresectable metastatic melanoma (stage IIIB–IVM1a). This study characterised real-world use of T-VEC in four European countries.

          Methods

          Data on demographics, treatment pattern, safety, and clinical effectiveness were examined in a retrospective chart review of patients with stage IIIB–IVM1a unresectable melanoma treated with T-VEC in surgical (the Netherlands) and medical (Austria, Germany, UK) oncology settings.

          Results

          Overall, 66 patients were included (the Netherlands: n = 31; Austria, Germany, UK: n = 35). The median age was 69 years and 59.1% were female. At the time of T-VEC initiation, 47 patients (71.2%) had stage IIIB/C disease; of these, 30 were from the Netherlands. Although 72.7% patients overall received T-VEC as first-line therapy, this was higher in the Netherlands than the other countries (93.5% vs 54.3%). Of the 47 patients who discontinued T-VEC, 26 (55.3%) had no remaining injectable lesions (potentially indicating complete response); 20/26 of these patients were from the Netherlands. One patient discontinued T-VEC due to toxicity.

          Conclusion

          This study is the first comprehensive multinational evaluation of the use of T-VEC to treat unresectable stage IIIB/C–IVM1a melanoma in real-world clinical practice in Europe. The differences between European countries were apparent, with physicians in the Netherlands using T-VEC in patients with earlier advanced disease stage and in the first-line setting compared with other countries.

          Supplementary Information

          The online version contains supplementary material available at 10.1007/s12325-020-01590-w.

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          Most cited references19

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          Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma.

          Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial.
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            Oncolytic Virotherapy Promotes Intratumoral T Cell Infiltration and Improves Anti-PD-1 Immunotherapy

            Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with talimogene laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with talimogene laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, as well as IFN-γ gene expression on several cell subsets in tumors after talimogene laherparepvec treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-γ signature. These findings suggest that oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment. VIDEO ABSTRACT.
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              A literature review on the representativeness of randomized controlled trial samples and implications for the external validity of trial results

              Randomized controlled trials (RCTs) are conducted under idealized and rigorously controlled conditions that may compromise their external validity. A literature review was conducted of published English language articles that reported the findings of studies assessing external validity by a comparison of the patient sample included in RCTs reporting on pharmaceutical interventions with patients from everyday clinical practice. The review focused on publications in the fields of cardiology, mental health, and oncology. A range of databases were interrogated (MEDLINE; EMBASE; Science Citation Index; Cochrane Methodology Register). Double-abstract review and data extraction were performed as per protocol specifications. Out of 5,456 de-duplicated abstracts, 52 studies met the inclusion criteria (cardiology, n = 20; mental health, n = 17; oncology, n = 15). Studies either performed an analysis of the baseline characteristics (demographic, socioeconomic, and clinical parameters) of RCT-enrolled patients compared with a real-world population, or assessed the proportion of real-world patients who would have been eligible for RCT inclusion following the application of RCT inclusion/exclusion criteria. Many of the included studies concluded that RCT samples are highly selected and have a lower risk profile than real-world populations, with the frequent exclusion of elderly patients and patients with co-morbidities. Calculation of ineligibility rates in individual studies showed that a high proportion of the general disease population was often excluded from trials. The majority of studies (n = 37 [71.2 %]) explicitly concluded that RCT samples were not broadly representative of real-world patients and that this may limit the external validity of the RCT. Authors made a number of recommendations to improve external validity. Findings from this review indicate that there is a need to improve the external validity of RCTs such that physicians treating patients in real-world settings have the appropriate evidence on which to base their clinical decisions. This goal could be achieved by trial design modification to include a more representative patient sample and by supplementing RCT evidence with data generated from observational studies. In general, a thoughtful approach to clinical evidence generation is required in which the trade-offs between internal and external validity are considered in a holistic and balanced manner. Electronic supplementary material The online version of this article (doi:10.1186/s13063-015-1023-4) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                a.v.akkooi@nki.nl
                Journal
                Adv Ther
                Adv Ther
                Advances in Therapy
                Springer Healthcare (Cheshire )
                0741-238X
                1865-8652
                26 December 2020
                26 December 2020
                2021
                : 38
                : 2
                : 1245-1262
                Affiliations
                [1 ]GRID grid.430814.a, Department of Surgical Oncology, , Netherlands Cancer Institute – Antoni van Leeuwenhoek (NKI-AVL), ; Amsterdam, The Netherlands
                [2 ]GRID grid.411941.8, ISNI 0000 0000 9194 7179, Department of Dermatology, , University Hospital Regensburg, ; Regensburg, Germany
                [3 ]GRID grid.420545.2, Department of Medical Oncology, , Guy’s and St. Thomas’ NHS Foundation Trust, ; London, UK
                [4 ]GRID grid.411088.4, ISNI 0000 0004 0578 8220, Department of Dermatology, Venereology and Allergology, , University Hospital Frankfurt, ; Frankfurt am Main, Germany
                [5 ]GRID grid.16149.3b, ISNI 0000 0004 0551 4246, Department of Dermatology, , University Hospital of Muenster, ; Muenster, Germany
                [6 ]GRID grid.6582.9, ISNI 0000 0004 1936 9748, Department of Dermatology and Allergic Diseases, , Ulm University, ; Ulm, Germany
                [7 ]GRID grid.410607.4, Department of Dermatology, , University Medical Center Mainz, ; Mainz, Germany
                [8 ]GRID grid.11598.34, ISNI 0000 0000 8988 2476, Medical University of Graz, ; Graz, Austria
                [9 ]GRID grid.476413.3, Amgen Ltd, ; Cambridge, UK
                [10 ]GRID grid.476152.3, ISNI 0000 0004 0476 2707, Amgen Europe GmbH, ; Rotkreuz, Switzerland
                [11 ]GRID grid.476413.3, Amgen Ltd, ; Uxbridge, UK
                [12 ]Department of Dermatology, Elbe-Klinikum Buxtehude, Buxtehude, Germany
                Article
                1590
                10.1007/s12325-020-01590-w
                7889564
                33368016
                f5bebbc2-a9b4-4a66-8084-d5d0f55f2567
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 9 October 2020
                : 28 November 2020
                Funding
                Funded by: Amgen Ltd
                Categories
                Original Research
                Custom metadata
                © Springer Healthcare Ltd., part of Springer Nature 2021

                immunotherapy,injectable,lesion,melanoma,oncolytic,real-world study,skin cancer,t-vec,talimogene laherparepvec,tumour

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