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First-line therapy-stratified survival in BRAF-mutant melanoma: a retrospective multicenter analysis

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Abstract

Background

Inhibition of the mitogen-activated protein kinase (MAPK) pathway as well as programmed death 1 receptor (PD-1) blockade was shown to prolong overall survival (OS) in patients with advanced B-Raf proto-oncogene (BRAF)-mutant melanoma. However, due to the lack of head-to-head trials, it remains unclear if one of these therapeutic approaches should be preferred in first-line therapy. Here, we present a retrospective analysis comparing anti-PD-1 monotherapy with BRAF/MAPK/ERK kinase (MEK) combined inhibition used as first-line agents in a real-world clinical setting.

Patients and methods

Clinical data, routine blood counts and lactate dehydrogenase (LDH) levels of 301 patients with unresectable or metastatic melanoma harboring an activating mutation in BRAF (V600E/K) were included. Of these, 106 received anti-PD-1 antibodies, while 195 patients were treated with a selective BRAF inhibitor combined with an MEK inhibitor as palliative first-line therapy. Patients were sub-grouped according to previously described predictive and prognostic markers.

Results

OS was significantly longer in patients receiving anti-PD-1 monotherapy compared to patients receiving combined MAPK inhibitors. Subsequent therapies were comparable among these groups. The difference in OS was less pronounced in patients with high LDH levels and visceral metastatic spread.

Conclusion

First-line treatment with a PD-1 blocking antibody might be associated with longer OS than first-line inhibition of the MAPK pathway in patients with advanced melanoma harboring mutant BRAF. These hypothesis-generating data need to be confirmed or rejected in prospective, randomized trials.

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Abbreviations

BRAF:

B-Raf proto-oncogene

BRAFi:

BRAF inhibitors

CI:

Confidence interval

CTLA-4:

Cytolytic T lymphocyte-associated antigen-4

HR:

Hazard ratio

LDH:

Lactate dehydrogenase

MAPK:

Mitogen-activated protein kinase

MAPKi:

MAPK inhibitors

MEK:

MAPK/ERK kinase

MEKi:

MEK inhibitors

NCT:

National Clinical Trial

ORR:

Objective response rate

OS:

Overall survival

PD-1:

Programmed death 1 receptor

PD-L1:

Programmed death ligand 1

ULN:

Upper limit of normal

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Acknowledgements

We thank Giorgos Kyriakakis (First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Greece) for provision of clinical data. We thank Christopher Shipp (The Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany) for proofreading the manuscript.

Funding

No specific funding was received for this study.

Author information

Author notes

  1. Bastian Schilling, Alexander Martens and Marnix H. Geukes Foppen contributed equally.

Authors and Affiliations

  1. Department of Dermatology, University Hospital Würzburg, Würzburg, Germany

    Bastian Schilling & Anja Gesierich

  2. Department of Dermatology, University Medical Center Tübingen, Liebermeisterstr. 25, 72076, Tübingen, Germany

    Alexander Martens, Claus Garbe & Benjamin Weide

  3. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Marnix H. Geukes Foppen, Elisa A. Rozeman & Christian Blank

  4. Department of Dermatology, University Hospital Hamburg-Eppendorf (UKE), Hamburg, Germany

    Christoffer Gebhardt

  5. Department of Dermatology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany

    Christoffer Gebhardt

  6. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Christoffer Gebhardt

  7. Department of Dermatology and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany

    Jessica C. Hassel

  8. Department of Dermatology, Skin Cancer Center, Hannover Medical School, Hannover, Germany

    Ralf Gutzmer

  9. Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany

    Katharina C. Kähler

  10. Department of Dermatology, West German Cancer Center, University Hospital, University Duisburg-Essen, Essen, Germany

    Elisabeth Livingstone & Dirk Schadendorf

  11. First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Panagiotis T. Diamantopoulos & Helen Gogas

  12. Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy

    Gabriele Madonna & Paolo A. Ascierto

  13. Department of Dermatology, University Hospital of Zürich, Zurich, Switzerland

    Simone M. Goldinger & Johanna Mangana

Authors
  1. Bastian Schilling
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  2. Alexander Martens
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  3. Marnix H. Geukes Foppen
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  4. Christoffer Gebhardt
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  5. Jessica C. Hassel
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  6. Elisa A. Rozeman
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  7. Anja Gesierich
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  8. Ralf Gutzmer
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  9. Katharina C. Kähler
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  10. Elisabeth Livingstone
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  11. Panagiotis T. Diamantopoulos
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  12. Helen Gogas
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  14. Paolo A. Ascierto
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  17. Claus Garbe
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  18. Dirk Schadendorf
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  19. Christian Blank
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  20. Benjamin Weide
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Contributions

BS, AM, MHGF, CG, DS, CB and BW designed the study. BS, AM, MHGF and BW analyzed all data and prepared the manuscript. BS, MHGF, CG, JCH, EAR, AG, RG, KCK, EL, PTD, HG, GM, PAA, SMG, JM and BW contributed to patient data acquisition. All authors supported the preparation of the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Benjamin Weide.

Ethics declarations

Conflict of interest

Bastian Schilling reports advisory roles for or has received honoraria from Pierre Fabre Pharmaceuticals, Incyte, Novartis, Roche, Bristol-Myers Squibb (BMS) and Merck Sharp & Dohme (MSD), research funding from BMS, Pierre Fabre Pharmaceuticals and MSD, and travel support from Novartis, Roche, BMS, Pierre Fabre Pharmaceuticals and Amgen. Christoffer Gebhardt reports advisory roles for or has received honoraria from Pierre Fabre Pharmaceuticals, Beiersdorf, BMS, MSD, Novartis, Roche and Sysmex, and travel support from BMS, MSD, Novartis and Roche. Jessica C. Hassel reports advisory roles for Pierre Fabre and Sanofi, and honoraria from BMS, MSD, Novartis, Roche and Pfizer. Anja Gesierich reports advisory roles for BMS, MSD, Novartis, Roche and Pfizer, has received honoraria from MSD and BMS, and travel support from BMS, MSD, Novartis and Roche. Ralf Gutzmer reports advisory roles for Roche, BMS, MSD, Amgen, Almirall, Leo, Pfizer, Novartis, GlaxoSmithKline (GSK), Incyte, Merck and Pierre-Fabre, has received honoraria from Roche, BMS, MSD, GSK, Novartis, Merck, Almirall, Amgen, Galderma, Astra-Zeneca and Pierre-Fabre, research funding from Novartis, Johnson & Johnson and Pfizer, honoraria from Roche, BMS, MSD, GSK, Novartis, Merck, Almirall, Amgen, Galderma, Astra-Zeneca and Pierre-Fabre, and travel support from Roche, BMS, MSD, GSK, Novartis, Merck, Almirall, Amgen, Galderma, Astra-Zeneca and Pierre-Fabre. Elisabeth Livingstone reports advisory roles for Roche, BMS, Novartis and Actelion, has received honoraria from Roche, BMS, MSD, Amgen, Novartis, Boehringer-Ingelheim (BI) and medac, and travel support from Roche, BMS, MSD, Amgen, Novartis, BI and medac. Panagiotis T. Diamantopoulos reports honoraria from Novartis and Roche, and travel support from Roche, Novartis, Janssen and Amgen. Helen Gogas reports honoraria from BMS, Roche, MSD, Novartis, Amgen and Pierre Fabre, and research funding from BMS, Roche, MSD and Novartis. Simone M. Goldinger reports advisory roles for Roche, Novartis, MSD and BMS, and has received travel support from Roche, Novartis, MSD and BMS. Joanna Mangana reports advisory roles for Merck and Pfizer, has received research funding from BMS, and travel support from MSD. Claus Garbe reports advisory roles for Amgen, BMS, MSD, Philogen, Roche and LEO Pharma, has received honoraria from Novartis, Amgen, BMS, MSD, Philogen, Roche and LEO Pharma, and research funding from Novartis, BMS and Roche. Dirk Schadendorf has received honoraria from Roche Pharma, BMS, Novartis, Merck Serono, MSD, Amgen, Incyte, LEO, Pfizer, Pierre Fabre, Array, Astra Zeneca, Regeneron, Philogen, Sanofi and Mologen, and research funding from Novartis and BMS. Christian Blank reports advisory roles for BMS, MSD, Roche, Novartis, GSK, Lilly, Pfizer and Genmab, and has received research funding from Novartis and BMS. Benjamin Weide has received honoraria from Merck/MSD, BMS, Philogen, Curevac, Roche, Novartis and Amgen, research funding from MSD and BMS, and travel support from MSD and BMS. All other authors declare no conflicts of interest.

Ethical approval

Retrospective collection of anonymous patient data was performed during routine clinical care. This study was approved by the Ethics Committee, University of Tübingen (approvals 524/2012BO2 and 234/2015BO2).

Informed consent

For anonymous publication of retrospective data acquired during routine clinical care, individual informed consents were not obtained.

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Schilling, B., Martens, A., Geukes Foppen, M.H. et al. First-line therapy-stratified survival in BRAF-mutant melanoma: a retrospective multicenter analysis. Cancer Immunol Immunother 68, 765–772 (2019). https://doi.org/10.1007/s00262-019-02311-1

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