Research Papers:

The efficacy of re-challenge with BRAF inhibitors after previous progression to BRAF inhibitors in melanoma: A retrospective multicenter study

Julia K. Tietze _, Andrea Forschner, Carmen Loquai, Heidrun Mitzel-Rink, Lisa Zimmer, Frank Meiss, David Rafei-Shamsabadi, Jochen Utikal, Maike Bergmann, Friedegund Meier, Nicole Kreuzberg, Max Schlaak, Carsten Weishaupt, Claudia Pföhler, Mirjana Ziemer, Michael Fluck, Jessica Rainer, Markus V. Heppt and Carola Berking

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Oncotarget. 2018; 9:34336-34346. https://doi.org/10.18632/oncotarget.26149

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Julia K. Tietze1, Andrea Forschner2, Carmen Loquai3, Heidrun Mitzel-Rink3, Lisa Zimmer4, Frank Meiss5, David Rafei-Shamsabadi5, Jochen Utikal6, Maike Bergmann7, Friedegund Meier7, Nicole Kreuzberg8, Max Schlaak8, Carsten Weishaupt9, Claudia Pföhler10, Mirjana Ziemer11, Michael Fluck12, Jessica Rainer13, Markus V. Heppt1 and Carola Berking1

1Department of Dermatology and Allergy, University Hospital Munich (LMU), 80337 Munich, Germany

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

3Department of Dermatology, University Medical Center Mainz, 55131 Mainz, Germany

4Department of Dermatology, University Hospital Essen, University of Essen, 45147 Essen, Germany

5Department of Dermatology and Venereology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany

6Skin Cancer Unit, German Cancer Research Center (DKFZ) and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, 68167 Mannheim, Germany

7Department of Dermatology, Skin Cancer Center, National Center for Tumor Diseases, Medical Faculty and University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany

8Department of Dermatology, University of Cologne, 50937 Cologne, Germany

9Department of Dermatology, University of Münster, 48149 Münster, Germany

10Department of Dermatology, Saarland University Medical Center, 66421 Homburg/Saar, Germany

11Department of Dermatology, Venereology, and Allergology, University Hospital Leipzig, 04103 Leipzig, Germany

12Department of Internal Medical Oncology, Clinic Hornheide, 48157 Münster, Germany

13Deparment of Dermatology, Klinikum Süd, 86179 Augsburg, Germany

Correspondence to:

Julia K. Tietze, email: [email protected]

Keywords: melanoma; BRAF-inhibition; MEK-inhibition; re-challenge; BRAFV600 mutation

Received: February 28, 2018     Accepted: August 20, 2018     Published: September 28, 2018


BRAF and MEK inhibition is efficient in patients with BRAF V600-mutated metastatic melanoma, but due to acquired resistance the duration of response (DoR) is often only short-lived. In this retrospective multicenter study with 60 patients suffering from inoperable or metastatic melanoma we evaluated the efficacy of re-challenge with a BRAF inhibitor (BRAF2) with or without MEK-inhibition after progressive disease upon previous treatment with a BRAF inhibitor (BRAF1) with or without MEK inhibition.

Treatment with BRAF1 led to a disease control rate (DCR) of 90% with 12% complete responses (CR), 58% partial responses (PR) and 20% stable diseases (SD), the median progression-free survival (PFS) was 9.9 and DoR 10.7 months. BRAF2 with (68%) or without (32%) additional MEK inhibition was initiated after a median interval of 3.4 months. DCR after re-challenge with BRAF2 was 57%, 8% CR, 20% PR and 28% SD, median PFS was 5.0 and DoR 14.0 months. The duration of the treatment interval or the treatment in the interval did not influence the DCR or PFS to BRAF2. The only predictive factor for response to BRAF2 was previous response to BRAF1; all patients with CR to BRAF1 achieved disease control with BRAF2, but only 60% of the patients with PR to BRAF1 (p=0.002). Addition of MEK inhibition to BRAF2 after treatment with BRAF1 as monotherapy did not significantly increase the DCR or PFS compared to patients treated solely with mono- or combination therapy.

In conclusion re-challenge with a BRAF inhibitor is a meaningful therapeutic option for patients with BRAF V600-mutated metastatic melanoma.

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