A lead-in safety study followed by a phase 2 clinical trial of dabrafenib, trametinib and hydroxychloroquine in advanced BRAFV600 mutant melanoma patients previously treated with BRAF-/MEK-inhibitors and immune checkpoint inhibitors

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Samenvatting

Patients with advanced v-Raf murine sarcoma viral oncogene homolog B V600 (BRAFV600) mutant melanoma who progressed on prior treatment with v-Raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen-activated protein kinase kinase (MEK) inhibitors and programmed cell death 1 or cytotoxic T-lymphocyte-associated antigen 4 immune checkpoint inhibitors can benefit from retreatment with the combination of a BRAF- and a MEK-inhibitor ('rechallenge'). Hydroxychloroquine can prevent autophagy-driven resistance and improve the efficacy of BRAF-/MEK-inhibitors in preclinical melanoma models. This clinical trial investigated the use of combined BRAF-/MEK-inhibition with dabrafenib and trametinib plus hydroxychloroquine in patients with advanced BRAFV600 mutant melanoma who previously progressed on prior treatment with BRAF-/MEK-inhibitors and immune checkpoint inhibitors. Following a safety lead-in phase, patients were randomized in the phase 2 part of the trial between upfront treatment with dabrafenib, trametinib and hydroxychloroquine (experimental arm), or dabrafenib and trametinib, with the possibility to add-on hydroxychloroquine at the time of documented tumor progression (contemporary control arm). Ten and four patients were recruited to the experimental and contemporary control arm, respectively. The objective response rate was 20.0% and the disease control rate was 50.0% in the experimental arm, whereas no responses were observed before or after adding hydroxychloroquine in the contemporary control arm. No new safety signals were observed for dabrafenib and trametinib. Hydroxychloroquine was suspected of causing an anxiety/psychotic disorder in one patient. Based on an early negative evaluation of the risk/benefit ratio for adding hydroxychloroquine to dabrafenib and trametinib when 'rechallenging' BRAFV600mutant melanoma patients, recruitment to the trial was closed prematurely.

Originele taal-2English
Pagina's (van-tot)183-191
Aantal pagina's9
TijdschriftMelanoma Research
Volume32
Nummer van het tijdschrift3
Vroegere onlinedatum2022
DOI's
StatusPublished - 1 jun 2022

Bibliografische nota

Funding Information:
G.A. reports nonfinancial support from MSD, Astellas and Novartis; personal fees from Novartis; institutional research grants from Kom op tegen Kanker, Stichting tegen Kanker and Novartis. J.K.S. reports nonfinancial support from MSD and Amgen; institutional research grants from Kom op tegen Kanker and Stichting tegen Kanker. B.N. reports personal fees from Roche, Bristol-Myers Squibb, MSD, Novartis, AstraZeneca for public speaking, consultancy and participation in advisory board meetings; institutional research grants from Pfizer, Novartis, Roche, Merck-Serono. For the remaining authors, there are no conflicts of interest.

Funding Information:
The authors would like to thank all patients and their families for their participation; our data nurse Katrien Van Den Bossche and our financial manager Isalien Deleu for the logistic and financial management of the trial. This study was financially supported by a grant from Kom op tegen Kanker

Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.

Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.

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