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Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study

1
Department of Dermatology, University Medical Center Mainz, 55131 Mainz, Germany
2
Department of Dermatology, Elbe Kliniken Buxtehude, 21614 Buxtehude, Germany
3
Skin Cancer Center at the University Cancer Center Dresden and National Center for Tumor Diseases, 01307 Dresden, Germany
4
Department of Dermatology, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
5
Department of Dermatology, University Hospital Essen, 45122 Essen, Germany
6
Department of Dermatology, Helios-Hospital Erfurt, 99089 Erfurt, Germany
7
Department of Dermatology, Saarland University Medical Center, 66421 Homburg/Saar, Germany
8
Department of Dermatology, Campus Kiel, University Hospital of Schleswig-Holstein Hospital, 24105 Kiel, Germany
9
Department of Dermatology, Allergology, and Venereology, University of Lübeck, 23538 Lübeck, Germany
10
Department of Dermatology, Hospital Dortmund, 44137 Dortmund, Germany
11
Department of Dermatology, Paracelsus Medical University Nuremberg, City Hospital of Nuremberg, 90408 Nuremberg, Germany
12
Department of Dermatology, Wald-Klinikum Gera, 07548 Gera, Germany
13
Department of Dermatology, DRK Krankenhaus Rabenstein, 09117 Chemnitz, Germany
14
Department of Dermatology, University Hospital Regensburg, 93053 Regensburg, Germany
15
Department of Dermatology, University Hospital Tübingen, 72076 Tübingen, Germany
16
Department of Dermatology, Venereology and Allergology, Helios St. Elisabeth Klinik Oberhausen, University Witten-Herdecke, 46045 Oberhausen, Germany
17
Department of Dermatology, Klinikum Quedlinburg, 06484 Quedlinburg, Germany
18
Department of Dermatology, Venereology and Allergy, Johann Wolfgang Goethe University, 60590 Frankfurt/Main, Germany
*
Author to whom correspondence should be addressed.
These authors have contributed equally to this work.
These authors have contributed equally to this work.
Academic Editor: David Wong
Cancers 2021, 13(10), 2312; https://doi.org/10.3390/cancers13102312
Received: 17 April 2021 / Revised: 5 May 2021 / Accepted: 6 May 2021 / Published: 12 May 2021
(This article belongs to the Special Issue Therapeutic Strategies for Metastatic Melanomas)
The introduction of BRAF/MEK-directed targeted therapy (TT) has significantly improved the management of patients with advanced BRAF-V600-mutant melanoma. Although resistance occurs, there is a subgroup of patients showing a complete response (CR) to TT and who maintain durable disease control. For these patients with durable CR, it is not clear whether it is safe to cease therapy. In this retrospective, multicenter study we have analyzed 37 patients who received TT and achieved a CR upon treatment. We identified 15 patients with a durable CR to TT. Overall, patients who discontinued TT (n = 26) were at higher risk of tumor progression compared to patients receiving ongoing TT. Sustained CR was however not restricted to patients with ongoing TT (n = 11) but was also found in patients who ceased TT (n = 4). Finally, our analysis indicated which patients with an initial CR might be most likely to maintain durable CR upon discontinuation of TT.
The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progression-free (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment (p < 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary real-world cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT. View Full-Text
Keywords: targeted therapy; complete response; advanced melanoma; discontinuation; disease progression; second-line immunotherapy targeted therapy; complete response; advanced melanoma; discontinuation; disease progression; second-line immunotherapy
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Figure 1

MDPI and ACS Style

Stege, H.; Haist, M.; Schultheis, M.; Fleischer, M.I.; Mohr, P.; Meier, F.; Schadendorf, D.; Ugurel, S.; Livingstone, E.; Zimmer, L.; Herbst, R.; Pföhler, C.; Kähler, K.; Weichenthal, M.; Terheyden, P.; Nashan, D.; Debus, D.; Kaatz, M.; Ziller, F.; Haferkamp, S.; Forschner, A.; Leiter, U.; Kreuter, A.; Ulrich, J.; Kleemann, J.; Bradfisch, F.; Grabbe, S.; Loquai, C. Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study. Cancers 2021, 13, 2312. https://doi.org/10.3390/cancers13102312

AMA Style

Stege H, Haist M, Schultheis M, Fleischer MI, Mohr P, Meier F, Schadendorf D, Ugurel S, Livingstone E, Zimmer L, Herbst R, Pföhler C, Kähler K, Weichenthal M, Terheyden P, Nashan D, Debus D, Kaatz M, Ziller F, Haferkamp S, Forschner A, Leiter U, Kreuter A, Ulrich J, Kleemann J, Bradfisch F, Grabbe S, Loquai C. Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study. Cancers. 2021; 13(10):2312. https://doi.org/10.3390/cancers13102312

Chicago/Turabian Style

Stege, Henner, Maximilian Haist, Michael Schultheis, Maria Isabel Fleischer, Peter Mohr, Friedegund Meier, Dirk Schadendorf, Selma Ugurel, Elisabeth Livingstone, Lisa Zimmer, Rudolf Herbst, Claudia Pföhler, Katharina Kähler, Michael Weichenthal, Patrick Terheyden, Dorothée Nashan, Dirk Debus, Martin Kaatz, Fabian Ziller, Sebastian Haferkamp, Andrea Forschner, Ulrike Leiter, Alexander Kreuter, Jens Ulrich, Johannes Kleemann, Fabienne Bradfisch, Stephan Grabbe, and Carmen Loquai. 2021. "Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study" Cancers 13, no. 10: 2312. https://doi.org/10.3390/cancers13102312

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