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Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis

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Abstract

Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.

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Abbreviations

AE:

Adverse event(s)

AJCC:

American Joint Committee on Cancer

CR:

Complete response

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

ECT:

Electrochemotherapy

ESOPE:

European Standard Operating Procedures for Electrochemotherapy

LDH:

Lactate dehydrogenase

ORR:

Overall response rate

OS:

Overall survival

PD:

Progressive disease

PD-1:

Programmed cell death protein 1

PFS:

Progression-free survival

PR:

Partial response

SD:

Stable disease

T-VEC:

Talimogene laherparepvec

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Acknowledgements

We thank Carla Lingner and Diana Lingk for their support with Fig. 1. Bastian Schilling receives research grants from Bristol-Myers Squibb and MSD Sharp and Dohme.

Author information

Authors and Affiliations

  1. Department of Dermatology and Allergy, Munich University Hospital (LMU), Frauenlobstr. 9-11, 80337, Munich, Germany

    Markus V. Heppt, Fanny Matheis, Julia K. Tietze & Carola Berking

  2. Department of Dermatology, Center for Dermatooncology, University Hospital Tübingen, Liebermeisterstr. 25, 72076, Tübingen, Germany

    Thomas K. Eigentler

  3. Department of Dermatology, University Hospital Schleswig–Holstein, Campus Kiel, Schittenhelmstr. 7, 24105, Kiel, Germany

    Katharina C. Kähler

  4. HELIOS Skin Cancer Center Erfurt, HELIOS Clinic Erfurt, Nordhäuser Str. 74, 99089, Erfurt, Germany

    Rudolf A. Herbst

  5. Department of Dermatology and Venereology, Otto-von-Guericke-University Hospital, Leipziger Str. 44, 39120, Magdeburg, Germany

    Daniela Göppner

  6. Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Gudrunstr. 56, 44791, Bochum, Germany

    Thilo Gambichler

  7. Department of Dermatology, Harzklinikum Dorothea Christiane Erxleben, Ditfurter Weg 24, 06484, Quedlinburg, Germany

    Jens Ulrich

  8. Department of Dermatology, Clinical Center Ludwigshafen, Bremserstr. 79, 67073, Ludwigshafen, Germany

    Edgar Dippel

  9. Department of Dermatology, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Carmen Loquai

  10. Department of Dermatology, SRH Wald-Klinikum Gera GmbH, Str. des Friedens 122, 07548, Gera, Germany

    Beatrice Schell

  11. Department of Dermatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany

    Bastian Schilling

  12. German Cancer Consortium (DKTK), Heidelberg, Germany

    Bastian Schilling

  13. Department of Dermatology and Venereology, University Medical Center Rostock, Strempelstr.13, 18057, Rostock, Germany

    Susanne G. Schäd

  14. Department of Dermatology, General Hospital Nuremberg, Paracelsus Medical University, Prof.-Ernst-Nathan-Str. 1, 90419, Nuremberg, Germany

    Erwin S. Schultz

Authors
  1. Markus V. Heppt
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  2. Thomas K. Eigentler
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  7. Jens Ulrich
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  8. Edgar Dippel
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  14. Fanny Matheis
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  16. Carola Berking
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Corresponding author

Correspondence to Carola Berking.

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Conflict of interest

Beatrice Schell, Edgar Dippel, Fanny Matheis, Markus V. Heppt, Susanne G. Schäd, and Thilo Gambichler declare no conflict of interest. Bastian Schilling: advisory for Roche, M.S.D. Sharp and Dohme, and Bristol-Myers Squibb, travel support from Roche, Bristol-Myers Squibb and Amgen, honoraria from Roche, M.S.D. Sharp and Dohme and Bristol-Myers Squibb. Carola Berking: advisory for Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, M.S.D. Sharp and Dohme, Novartis, Roche, speaker’s honoraria by Bristol-Myers Squibb, GlaxoSmithKline, M.S.D. Sharp and Dohme, Novartis, Roche. Carmen Loquai: advisory for Roche, Amgen, Novartis, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Ribological, speaker’s honoraria from Roche, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis, travel reimbursement from Roche, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis. Daniela Göppner: advisory for Roche, Amgen, Bristol-Myers Squibb and M.S.D. Sharp and Dohme, speaker’s honoraria from Roche and Bristol-Myers Squibb, travel reimbursement from Roche, Amgen and Novartis. Erwin S. Schultz: advisory for Bristol-Myers Squibb and Novartis, speaker’s honoraria for Novartis. Julia K. Tietze: speaker’s honoraria from Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis, Roche. Jens Ulrich: advisory for Roche, speaker’s honoraria from Bristol-Myers Squibb, M.S.D. Sharp and Dohme, GlaxoSmithKline, IGEA, Novartis, Roche, travel reimbursement from Bristol-Myers Squibb, IGEA, Medac, Roche. Katharina C. Kähler: advisory for Roche, Amgen, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, speaker’s honoraria from Roche, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis, travel reimbursement from Roche, Bristol-Myers Squibb, M.S.D. Sharp and Dohme, Novartis. Rudolf A. Herbst: advisory for Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Novartis, Roche, speaker’s honoraria from Bristol-Myers Squibb, GlaxoSmithKline, M.S.D. Sharp and Dohme, Novartis, Roche. Thomas K. Eigentler: advisory for AMGEN, Roche, Bristol-Myers Squibb, travel support from Bristol-Myers Squibb and Novartis, speaker’s honoraria from Roche.

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Heppt, M.V., Eigentler, T.K., Kähler, K.C. et al. Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis. Cancer Immunol Immunother 65, 951–959 (2016). https://doi.org/10.1007/s00262-016-1856-z

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