Pauline Tétu1, Laetitia Vercellino2, Coralie Reger de Moura3, Barouyr Baroudjian1, Nicolas Dumaz4, Samia Mourah4,5, Céleste Lebbé1. 1. APHP Dermatology, Department of Dermatology, Paris 7 Diderot University, INSERM U976, Hôpital Saint-Louis. 2. Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Nuclear Medecine. 3. Laboratory of Pharmacogenomics, Hôpital Saint-Louis, AP-HP. 4. Université de Paris, INSERM UMR-S 976, Team 1, Human Immunology Pathophysiology & Immunotherapy (HIPI). 5. Department of Pharmacology and Solid Tumor Genomics, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Paris, France.
Abstract
PURPOSE OF REVIEW: Although targeted therapy provides a high response rate and rapid disease control in advanced melanoma, most patients experience disease progression due to acquired resistance mechanisms leading to reactivation of mitogen-activated protein kinase pathway. The purpose of this article is to review the recently published data on the impact of an intermittent versus continuous dosing schedule of BRAF and MEK inhibition in advanced melanoma to determine the best approach in clinical practice. RECENT FINDINGS: Some preclinical studies have highlighted the concept that drug-resistant cells may also display drug dependency, such that intermittent dosing of targeted therapy may prevent the emergence of lethal drug resistance. Moreover, clinical observations have suggested that repeated treatment after a break or an intervening therapy may provide clinical benefit. However, recent preclinical and clinical studies have also failed to demonstrate an advantage of intermittent dosing and showed a similar efficacy of the intermittent versus continuous regimens of BRAF and MEK inhibitors in mice models and phase 2 clinical trial. SUMMARY: Owing to these discordant results, continuous dosing of BRAF and MEK inhibitors remains the optimal therapeutic approach until additional clinical data demonstrate the superiority of another combination or dosing regimen.
PURPOSE OF REVIEW: Although targeted therapy provides a high response rate and rapid disease control in advanced melanoma, most patients experience disease progression due to acquired resistance mechanisms leading to reactivation of mitogen-activated protein kinase pathway. The purpose of this article is to review the recently published data on the impact of an intermittent versus continuous dosing schedule of BRAF and MEK inhibition in advanced melanoma to determine the best approach in clinical practice. RECENT FINDINGS: Some preclinical studies have highlighted the concept that drug-resistant cells may also display drug dependency, such that intermittent dosing of targeted therapy may prevent the emergence of lethal drug resistance. Moreover, clinical observations have suggested that repeated treatment after a break or an intervening therapy may provide clinical benefit. However, recent preclinical and clinical studies have also failed to demonstrate an advantage of intermittent dosing and showed a similar efficacy of the intermittent versus continuous regimens of BRAF and MEK inhibitors in mice models and phase 2 clinical trial. SUMMARY: Owing to these discordant results, continuous dosing of BRAF and MEK inhibitors remains the optimal therapeutic approach until additional clinical data demonstrate the superiority of another combination or dosing regimen.
Authors: Andrew J Kavran; Scott A Stuart; Kristyn R Hayashi; Joel M Basken; Barbara J Brandhuber; Natalie G Ahn Journal: Proc Natl Acad Sci U S A Date: 2022-03-15 Impact factor: 12.779