← Back to Search
Combined BRAF And MEK Inhibition With PD-1 Blockade Immunotherapy In BRAF-mutant Melanoma
A. Ribas, D. Lawrence, V. Atkinson, S. Agarwal, W. Miller, M. Carlino, R. Fisher, G. Long, F. S. Hodi, J. Tsoi, C. Grasso, B. Mookerjee, Qing Zhao, R. Ghori, B. H. Moreno, N. Ibrahim, O. Hamid
Published 2019 · Medicine
Save to my Library
Download PDFAnalyze on Scholarcy
Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year1–3. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity4–6, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab (NCT02130466). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%; 95% confidence interval = 45–92%) had an objective response, and six (40%; 95% confidence interval = 16–68%) continued with a response at a median follow-up of 27 months (range = 10.3–38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.Triple therapy combining BRAF and MEK inhibitors with immune checkpoint blockade may benefit a subset of patients with BRAFV600-mutated metastatic melanoma.
This paper references
Improved overall survival in melanoma with combined dabrafenib and trametinib.
C. Robert (2015)
Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials.
D. Schadendorf (2017)
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma
W. Hugo (2016)
The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer
C. Grasso (2012)
Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006)
J. Schachter (2017)
Dynamic Changes in PD-L1 Expression and Immune Infiltrates Early During Treatment Predict Response to PD-1 Blockade in Melanoma
R. Vilain (2017)
Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma
S. Hu-Lieskovan (2015)
Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma
J. Wolchok (2017)
Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma.
G. Long (2011)
RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors.
Fei Su (2012)
Hepatotoxicity with combination of vemurafenib and ipilimumab.
A. Ribas (2013)
BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma
D. Frederick (2013)
HISAT: a fast spliced aligner with low memory requirements
Daehwan Kim (2015)
MEK Inhibition, Alone or in Combination with BRAF Inhibition, Affects Multiple Functions of Isolated Normal Human Lymphocytes and Dendritic Cells
L. J. Vella (2014)
Human hair follicle bulge cells are biochemically distinct and possess an epithelial stem cell phenotype.
S. Lyle (1999)
Selective BRAF Inhibitors Induce Marked T-cell Infiltration into Human Metastatic Melanoma
J. Wilmott (2011)
Combined vemurafenib and cobimetinib in BRAF-mutated melanoma.
J. Larkin (2014)
Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma.
A. Daud (2016)
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
N. Rizvi (2015)
Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.
H. Shi (2014)
Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma.
A. Ribas (2015)
Genomic Classification of Cutaneous Melanoma
Rehan Akbani (2015)
Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial
A. Hauschild (2012)
IFN-&ggr;–related mRNA profile predicts clinical response to PD-1 blockade
M. Ayers (2017)
Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade.
Pei-ling Chen (2016)
Quantitation of intraepidermal T‐cell subsets in formalin‐fixed, paraffin‐embedded tissue helps in the diagnosis of mycosis fungoides
J. Nuckols (1999)
The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma.
E. V. Van Allen (2014)
Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.
Michael A. Postow (2015)
Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
P. Chapman (2011)
Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma.
G. Long (2014)
Targeting the MAPK and PI3K pathways in combination with PD1 blockade in melanoma
Marcel A. Deken (2016)
Genetic Mechanisms of Immune Evasion in Colorectal Cancer.
C. Grasso (2018)
PD-1 blockade induces responses by inhibiting adaptive immune resistance
P. Tumeh (2014)
Combined treatment with dabrafenib and trametinib with immune-stimulating antibodies for BRAF mutant melanoma
B. Homet Moreno (2016)
HTSeq—a Python framework to work with high-throughput sequencing data
S. Anders (2015)
This paper is referenced by
BRAF+MEKi and ICI triplets show promise in melanoma
David J Killock (2019)
ESMO consensus conference recommendations on the management of metastatic melanoma: under the auspices of the ESMO Guidelines Committee
U. Keilholz (2020)
The concepts of rechallenge and retreatment in melanoma: A proposal for consensus definitions.
C. Gebhardt (2020)
A Closer Look at Immune-Mediated Myocarditis
C. Guo (2019)
Discovery and Validation of a Metastasis-Related Prognostic and Diagnostic Biomarker for Melanoma Based on Single Cell and Gene Expression Datasets
Qi Wan (2020)
Toripalimab for the treatment of melanoma
B. Tang (2020)
Organoid Models of Tumor Immunology
K. Yuki (2020)
The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer
G. Mauri (2021)
Regulation of Cancer Immune Checkpoints: Molecular and Cellular Mechanisms and Therapy
J. Xu (2020)
Mutant BRAF and MEK inhibitors regulate the tumor immune microenvironment via pyroptosis.
Dan A Erkes (2019)
Advances of FDA Approved Drugs that Target PD-1 and PD-L1 for Cancer Immunotherapy
Henrik Zhang (2019)
Comprehensive analysis of cancer hallmarks in cutaneous melanoma and identification of a novel unfolded protein response as a prognostic signature
Qi Wan (2020)
ESMO consensus conference recommendations on the management of locoregional melanoma: the ESMO Guidelines Committee.
O. Michielin (2020)
CARs: Beyond T Cells and T Cell-Derived Signaling Domains
Nico M Sievers (2020)
Autophagy: When to strike?
Shadi Zahedi (2020)
Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study
Sandra Huynh (2020)
Integrating Immunotherapy and Targeted Therapy in Cancer Treatment: Mechanistic Insights and Clinical Implications
J. Bergholz (2020)
Management of V600E and V600K BRAF-Mutant Melanoma
A. Haugh (2019)
Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies
R. J. Walsh (2020)
Immune checkpoint inhibitors in gastrointestinal malignancies: what can we learn from experience with other tumors?
A. Shah (2019)
Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer
M. Ruscetti (2020)
Recent Progress of Potentiating Immune Checkpoint Blockade with External Stimuli—an Industry Perspective
J. Xu (2020)
Chemotherapeutic and targeted agents can modulate the tumor microenvironment and increase the efficacy of immune checkpoint blockades
J. Li (2021)
PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma
A. Ribas (2020)
Translational studies of metastatic melanoma in the era of immunotherapy - from humanized mouse models to clinical trials
H. Jespersen (2020)
RAS: Striking at the Core of the Oncogenic Circuitry
Ryan C Gimple (2019)
Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities.
F. Rambow (2019)
A Novel Cytokine Response Modulatory Function of MEK Inhibitors Mediates Therapeutic Efficacy
Mengyu Xie (2019)
Modulation of Determinant Factors to Improve Therapeutic Combinations with Immune Checkpoint Inhibitors
Magalie Dosset (2020)
Prebiotic-Induced Anti-tumor Immunity Attenuates Tumor Growth
Y. Li (2020)
Antimetastatic dsRNA mimics identified by live imaging of pathogenic neolymphangiogenesis
D. Olmeda (2019)
Is single versus combination therapy problematic in the treatment of cutaneous melanoma?
R. Krattinger (2019)See more