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  1. Article ; Online: Treatment reality of patients with BRAF-mutant advanced/metastatic melanoma in Switzerland in the era of choice.

    Mangana, Joanna / Zihler, Deborah / Bossart, Simon / Brönnimann, Daniel / Zachariah, Ralph / Gérard, Camille Léa

    Melanoma research

    2022  Volume 32, Issue 5, Page(s) 366–372

    Abstract: Cutaneous melanoma represents a major cause of cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15-20% in distant metastatic disease. Evaluating the status quo of treatment standards in advanced melanoma and rationale for ... ...

    Abstract Cutaneous melanoma represents a major cause of cancer death in Europe. Without adequate therapy, the 5-year survival rate is 15-20% in distant metastatic disease. Evaluating the status quo of treatment standards in advanced melanoma and rationale for therapy decisions in Switzerland between January 2016 and September 2018. In this retrospective, anonymized registry, data of male and female patients with unresectable advanced/metastatic BRAF-positive cutaneous melanoma treated in first-, second- and third-line with registered substances were analyzed using descriptive statistics. Forty-one patients (56.1% male) were included providing a total of 70 treatment lines (first-line: n = 41; second-line: n = 18; and third-line: n = 11). Within the patients presenting with stage III or IV melanoma, immunotherapy with checkpoint inhibitors was more frequently administered as first-line treatment than targeted therapy (TT) (70.7% vs. 29.3%). Across all lines, patients received TT in 47.1% (predominantly combined BRAF-MEK-inhibition) and immunotherapy in 52.9% of the cases (anti-PD-1 monotherapy in 62.2% and anti-PD-1/anti-CTLA-4 combinations in 37.8%). Most commonly, the treatment type was switched from TT to immunotherapy or vice versa upon disease progression. The most frequent rationales for prescribing either TT or immunotherapy were physician's preference (40.0%) or remission pressure (28.6%), respectively. Disease progression led to treatment discontinuation more frequently than undesired events. Patients in Switzerland with unresectable advanced or metastatic BRAF-mutant melanoma predominantly receive guideline-recommended treatments. IO was used as predominant front-line therapy, with TT/immunotherapy switch being the predominant treatment principle. Sequencing studies are underway to identify the optimal treatment regimen for those patients. 32: 366-372 Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
    MeSH term(s) Disease Progression ; Female ; Humans ; Male ; Melanoma/drug therapy ; Melanoma/genetics ; Neoplasms, Second Primary/chemically induced ; Programmed Cell Death 1 Receptor ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins B-raf/genetics ; Retrospective Studies ; Skin Neoplasms/chemically induced ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Switzerland ; Melanoma, Cutaneous Malignant
    Chemical Substances Programmed Cell Death 1 Receptor ; Protein Kinase Inhibitors ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2022-07-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1095779-0
    ISSN 1473-5636 ; 0960-8931
    ISSN (online) 1473-5636
    ISSN 0960-8931
    DOI 10.1097/CMR.0000000000000843
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Effects of CTLA-4 Single Nucleotide Polymorphisms on Toxicity of Ipilimumab-Containing Regimens in Patients With Advanced Stage Melanoma.

    de Joode, Karlijn / Mora, Alfonso Rojas / van Schaik, Ron H N / Zippelius, Alfred / van der Veldt, Astrid / Gerard, Camille Léa / Läubli, Heinz / Michielin, Olivier / von Moos, Roger / Joerger, Markus / Levesque, Mitchell P / Aeppli, Stefanie / Mangana, Johanna / Mangas, Cristina / Trost, Nadine / Meyer, Stefan / Parvex, Sandra Leoni / Mathijssen, Ron / Metaxas, Yannis

    Journal of immunotherapy (Hagerstown, Md. : 1997)

    2024  Volume 47, Issue 5, Page(s) 190–194

    Abstract: Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for ... ...

    Abstract Single nucleotide polymorphisms (SNPs) in the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) gene, an inhibitor of T-cell priming, are associated with auto and alloimmunity. Studies implied a role for these SNPs as surrogate markers for immunotherapy-outcome in patients with melanoma. However, no predictive SNPs are defined to date. We analyzed different CTLA-4 SNPs in a large multicenter cohort of patients with ipilimumab-treated melanoma and investigated possible correlations with treatment-related outcomes. Archival blood and/or tumor tissue samples were collected from 361 patients with advanced-stage ipilimumab-treated (±nivolumab) in 6 Swiss and Dutch hospitals. Matrix-assisted laser desorption/ionization-time of flight mass spectrometry based DNA genotyping was performed for 10 different CTLA-4 SNPs: 49A>G, CT60G>A, Jo27T>C, Jo30G>A, Jo31G>T, -658C>T, -1722T>C, -1661A>G, 318C>T, and C>T rs1863800. Associations between different allele genotypes and occurrence of grade ≥3 adverse events (AEs) and survival were tested using univariable logistic regressions or Cox proportional hazard models. 262/361 (73%) patients could be analyzed; 65% of those were males, the median age was 58 years, 39% showed a partial or complete response, and 65% had ≥1 AEs. A TT-genotype of -1722T>C SNP was significantly associated with a lower incidence of grade ≥3 AEs ( P = 0.049), whereas the GG-genotype of CT60G>A correlated with a higher incidence of grade ≥3 AEs ( P = 0.026). The TT-genotype of Jo27T>C SNP ( P = 0.056) and GG-genotype of Jo31G>T ( P = 0.046) were associated with overall survival. CTLA-4 SNPs might predict treatment-related outcomes in patients with melanoma receiving ipilimumab. Confirmatory studies are needed to fully exploit those findings as predictive biomarkers for ipilimumab AEs.
    MeSH term(s) Humans ; Ipilimumab/adverse effects ; Ipilimumab/therapeutic use ; CTLA-4 Antigen/genetics ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/mortality ; Polymorphism, Single Nucleotide ; Male ; Female ; Middle Aged ; Aged ; Neoplasm Staging ; Genotype ; Adult ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Treatment Outcome
    Chemical Substances Ipilimumab ; CTLA-4 Antigen ; CTLA4 protein, human
    Language English
    Publishing date 2024-02-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Multicenter Study
    ZDB-ID 1064067-8
    ISSN 1537-4513 ; 1053-8550 ; 1524-9557
    ISSN (online) 1537-4513
    ISSN 1053-8550 ; 1524-9557
    DOI 10.1097/CJI.0000000000000506
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The features and management of acquired resistance to PD1-based therapy in metastatic melanoma.

    Hepner, Adriana / Versluis, Judith M / Wallace, Roslyn / Allayous, Clara / Brown, Lauren Julia / Trojaniello, Claudia / Gerard, Camille Lea / Jansen, Yanina Jl / Bhave, Prachi / Neyns, Bart / Haydon, Andrew / Michielin, Olivier / Mangana, Joanna / Klein, Oliver / Shoushtari, Alexander N / Warner, Allison Betof / Ascierto, Paolo Antonio / McQuade, Jennifer Leigh / Carlino, Matteo S /
    Zimmer, Lisa / Lebbe, Celeste / Johnson, Douglas B / Sandhu, Shahneen / Atkinson, Victoria / Blank, Christian U / Lo, Serigne N / Long, Georgina V / Menzies, Alexander M

    European journal of cancer (Oxford, England : 1990)

    2023  Volume 196, Page(s) 113441

    Abstract: Background: Anti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience ... ...

    Abstract Background: Anti-PD-1 therapy (PD1) either alone or with anti-CTLA-4 (CTLA4), has high initial response rates, however 20% of patients (pts) with complete response (CR) and 30% with partial response (PR) within 12 months of treatment experience subsequent disease progression by 6 years. The nature and optimal management of this acquired resistance (AR) remains unknown.
    Methods: Pts from 16 centres who responded to PD1-based therapy and who later progressed were examined. Demographics, disease characteristics and subsequent treatments were evaluated.
    Results: 299 melanoma pts were identified, median age 64y, 44% BRAFV600m. 172 (58%) received PD1 alone, 114 (38%) PD1/CTLA4 and 13 (4%) PD1 and an investigational drug. 90 (30%) pts had CR, 209 (70%) PR. Median time to AR was 12.6 mo (95% CI, 11.3, 14.2). Most (N = 193, 65%) progressed in a single organ site, and in a solitary lesion (N = 151, 51%). The most frequent sites were lymph nodes (38%) and brain (25%). Management at AR included systemic therapy (ST, 45%), local therapy (LT) +ST (31%), LT alone (21%), or observation (3%). There was no statistical difference in PFS2 or OS based on management, however, PFS2 was numerically superior for pts treated with ST alone who progressed off PD1 therapy than those who progressed on PD1 (2-year PFS2 42% versus 25%, p = 0.249). mOS from AR was 38.0 months (95% CI, 29.5-NR); longer in single-site versus multi-site progression (2-year OS 70% vs 54%, p < 0·001).
    Conclusions: Acquired resistance to PD1 therapy in melanoma is largely oligometastatic, and pts may have a favorable survival outcome following salvage treatment.
    MeSH term(s) Humans ; Middle Aged ; CTLA-4 Antigen/immunology ; Immunotherapy ; Melanoma/pathology ; Melanoma/therapy ; Retrospective Studies ; Antibodies/therapeutic use
    Chemical Substances CTLA-4 Antigen ; PDCD1 protein, human ; Antibodies
    Language English
    Publishing date 2023-11-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 82061-1
    ISSN 1879-0852 ; 0277-5379 ; 0959-8049 ; 0964-1947
    ISSN (online) 1879-0852
    ISSN 0277-5379 ; 0959-8049 ; 0964-1947
    DOI 10.1016/j.ejca.2023.113441
    Database MEDical Literature Analysis and Retrieval System OnLINE

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