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Article: C–P bond formation of cyclophanyl-, and aryl halides via a UV-induced photo Arbuzov reaction: a versatile portal to phosphonate-grafted scaffolds

Oßwald, Simon / Zippel, Christoph / Hassan, Zahid / Nieger, Martin / Bräse, Stefan

RSC advances. 2022 Jan. 25, v. 12, no. 6

2022

Abstract: A new versatile method for the C–P bond formation of (hetero)aryl halides with trimethyl phosphite ...

Abstract	A new versatile method for the C–P bond formation of (hetero)aryl halides with trimethyl phosphite via a UV-induced photo-Arbuzov reaction, accessing diverse phosphonate-grafted arenes, heteroarenes and co-facially stacked cyclophanes under mild reaction conditions without the need for catalyst, additives, or base is developed. The UV-induced photo-Arbuzov protocol has a wide synthetic scope with large functional group compatibility exemplified by over 30 derivatives. Besides mono-phosphonates, di- and tri-phosphonates are accessible in good to excellent yields. Mild and transition metal-free reaction conditions consolidate this method's potential for synthesizing pharmaceutically relevant compounds and precursors of supramolecular nanostructured materials.
Keywords	additives ; aromatic hydrocarbons ; catalysts ; methodology ; nanomaterials
Language	English
Dates of publication	2022-0125
Size	p. 3309-3312.
Publishing place	The Royal Society of Chemistry
Document type	Article
ISSN	2046-2069
DOI	10.1039/d2ra00094f
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Thio-2 inhibits key signaling pathways required for the development and progression of castration resistant prostate cancer.

Neeb, Antje / Figueiredo, Ines / Bogdan, Denisa / Cato, Laura / Stober, Jutta / Jiménez-Vacas, Juan M / Gourain, Victor / Lee, Irene I / Seeger, Rebecca / Muhle-Goll, Claudia / Gurel, Bora / Welti, Jonathan / Nava Rodrigues, Daniel / Rekowski, Jan / Qiu, Xintao / Jiang, Yija / Di Micco, Patrizio / Mateos, Borja / Bielskutė, Stasė /

Molecular cancer therapeutics

2024

Abstract: Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR that drives transcriptional activity in CRPC remains a challenging ... ...

Abstract	Therapies that abrogate persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) remain an unmet clinical need. The N-terminal domain (NTD) of the AR that drives transcriptional activity in CRPC remains a challenging therapeutic target. Herein we demonstrate that BAG-1 mRNA is highly expressed and associates with signaling pathways, including AR signaling, that are implicated in the development and progression of CRPC. In addition, interrogation of geometric and physiochemical properties of the BAG domain of BAG-1 isoforms identifies it to be a tractable but challenging drug target. Furthermore, through BAG-1 isoform mouse knockout studies we confirm that BAG-1 isoforms regulate hormone physiology and that therapies targeting the BAG domain will be associated with limited 'on-target' toxicity. Importantly, the postulated inhibitor of BAG-1 isoforms, Thio-2, suppressed AR signaling and other important pathways implicated in the development and progression of CRPC to reduce the growth of treatment resistant prostate cancer cell lines and patient derived models. However, the mechanism by which Thio-2 elicits the observed phenotype needs further elucidation since the genomic abrogation of BAG-1 isoforms was unable to recapitulate the Thio-2 mediated phenotype. Overall, these data support the interrogation of related compounds with improved drug-like properties as a novel therapeutic approach in CRPC, and further highlight the clinical potential of treatments that block persistent AR signaling which are currently undergoing clinical evaluation in CRPC.
Language	English
Publishing date	2024-02-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-23-0354
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Article ; Online: Author Correction: Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma.

Váraljai, Renáta / Zimmer, Lisa / Al-Matary, Yahya / Kaptein, Paulien / Albrecht, Lea J / Shannan, Batool / Brase, Jan C / Gusenleitner, Daniel / Amaral, Teresa / Wyss, Nina / Utikal, Jochen / Flatz, Lukas / Rambow, Florian / Reinhardt, Hans Christian / Dick, Jenny / Engel, Daniel R / Horn, Susanne / Ugurel, Selma / Sondermann, Wiebke /

Livingstone, Elisabeth / Sucker, Antje / Paschen, Annette / Zhao, Fang / Placke, Jan M / Klose, Jasmin M / Fendler, Wolfgang P / Thommen, Daniela S / Helfrich, Iris / Schadendorf, Dirk / Roesch, Alexander

Nature cancer

2023 Volume 4, Issue 9, Page(s) 1395

Language	English
Publishing date	2023-08-12
Publishing country	England
Document type	Published Erratum
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-023-00632-w
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Article ; Online: Interleukin 17 signaling supports clinical benefit of dual CTLA-4 and PD-1 checkpoint inhibition in melanoma.

Nature cancer

2023 Volume 4, Issue 9, Page(s) 1292–1308

Abstract: Recent studies suggest that ... ...

Abstract	Recent studies suggest that BRAF
MeSH term(s)	Humans ; Interleukin-17/genetics ; Interleukin-17/therapeutic use ; CTLA-4 Antigen/metabolism ; Programmed Cell Death 1 Receptor/metabolism ; Proto-Oncogene Proteins B-raf/therapeutic use ; Melanoma/drug therapy ; Melanoma/genetics
Chemical Substances	Interleukin-17 ; CTLA-4 Antigen ; Programmed Cell Death 1 Receptor ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
Language	English
Publishing date	2023-07-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-023-00610-2
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Article ; Online: Canakinumab Versus Placebo in Combination With First-Line Pembrolizumab Plus Chemotherapy for Advanced Non-Small-Cell Lung Cancer: Results From the CANOPY-1 Trial.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2023 Volume 42, Issue 2, Page(s) 192–204

Abstract: Purpose: The addition of checkpoint inhibitors to first-line treatment has prolonged survival of patients with non-small-cell lung cancer (NSCLC), but prognosis remains poor, with new treatment options needed. Canakinumab, a human, monoclonal anti- ... ...

Abstract	Purpose: The addition of checkpoint inhibitors to first-line treatment has prolonged survival of patients with non-small-cell lung cancer (NSCLC), but prognosis remains poor, with new treatment options needed. Canakinumab, a human, monoclonal anti-interleukin (IL)-1β antibody, has potential to enhance the activity of PD-L1 inhibitors and chemotherapy (CT) by inhibiting protumor inflammation. Methods: CANOPY-1 was a phase III, randomized, double-blind study comparing canakinumab (200 mg subcutaneously once every 3 weeks) versus placebo, both combined with pembrolizumab (200 mg intravenously once every 3 weeks) and platinum-based doublet CT, as first-line treatment for advanced/metastatic NSCLC without Results: Overall, 643 patients were randomly assigned to canakinumab (n = 320) or placebo (n = 323). With a median study follow-up of 6.5 months, the median PFS was 6.8 months with canakinumab versus 6.8 months with placebo (hazard ratio [HR], 0.85; 95% CI, 0.67 to 1.09; Conclusion: The addition of canakinumab to first-line pembrolizumab and CT did not prolong PFS or OS in patients with NSCLC.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/pathology ; Lung Neoplasms/pathology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/adverse effects
Chemical Substances	pembrolizumab (DPT0O3T46P) ; canakinumab (37CQ2C7X93) ; Antibodies, Monoclonal, Humanized
Language	English
Publishing date	2023-12-01
Publishing country	United States
Document type	Randomized Controlled Trial ; Clinical Trial, Phase III ; Journal Article
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.23.00980
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Article ; Online: Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with

Tawbi, Hussein A / Robert, Caroline / Brase, Jan C / Gusenleitner, Daniel / Gasal, Eduard / Garrett, James / Savchenko, Alexander / Görgün, Güllü / Flaherty, Keith T / Ribas, Antoni / Dummer, Reinhard / Schadendorf, Dirk / Long, Georgina V / Nathan, Paul D / Ascierto, Paolo A

Journal for immunotherapy of cancer

2022 Volume 10, Issue 6

Abstract: Background: The randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) ...

Abstract	Background: The randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic Methods: In COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; Results: Extensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by Conclusions: These results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4 Trial registration number: NCT02967692.
MeSH term(s)	Antibodies, Monoclonal, Humanized ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; B7-H1 Antigen/therapeutic use ; Biomarkers, Tumor/analysis ; Clinical Trials, Phase III as Topic ; Humans ; Imidazoles ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Oximes ; Proto-Oncogene Proteins B-raf/genetics ; Pyridones ; Pyrimidinones ; Randomized Controlled Trials as Topic ; Skin Neoplasms/drug therapy
Chemical Substances	Antibodies, Monoclonal, Humanized ; B7-H1 Antigen ; Biomarkers, Tumor ; Imidazoles ; Oximes ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; dabrafenib (QGP4HA4G1B) ; spartalizumab (QOG25L6Z8Z)
Language	English
Publishing date	2022-06-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2021-004226
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Article ; Online: Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study.

Syeda, Mahrukh M / Wiggins, Jennifer M / Corless, Broderick C / Long, Georgina V / Flaherty, Keith T / Schadendorf, Dirk / Nathan, Paul D / Robert, Caroline / Ribas, Antoni / Davies, Michael A / Grob, Jean Jacques / Gasal, Eduard / Squires, Matthew / Marker, Mahtab / Garrett, James / Brase, Jan C / Polsky, David

The Lancet. Oncology

2021 Volume 22, Issue 3, Page(s) 370–380

Abstract: Background: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large ... ...

Abstract	Background: Melanoma lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Cell-free circulating tumour DNA (ctDNA) is a promising biomarker; however, various detection methods have been used, and, to date, no large studies have examined the association between serial changes in ctDNA and survival after BRAF, MEK, or BRAF plus MEK inhibitor therapy. We aimed to evaluate whether baseline ctDNA concentrations and kinetics could predict survival outcomes. Methods: In this clinical validation study, we used analytically validated droplet digital PCR assays to measure BRAF Findings: In COMBI-d, pretreatment plasma samples were available from 345 (82%) of 423 patients and on-treatment (week 4) plasma samples were available from 224 (53%) of 423 patients. In cohort A of COMBI-MB, pretreatment and on-treatment samples were available from 38 (50%) of 76 patients with intracranial and extracranial metastatic melanoma. ctDNA was detected in pretreatment samples from 320 (93%) of 345 patients (COMBI-d) and 34 (89%) of 38 patients (COMBI-MB). When assessed as a continuous variable, elevated baseline BRAF Interpretation: Pretreatment and on-treatment BRAF Funding: Novartis.
MeSH term(s)	Aged ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Brain Neoplasms/secondary ; Circulating Tumor DNA/analysis ; Circulating Tumor DNA/genetics ; Double-Blind Method ; Female ; Follow-Up Studies ; Humans ; Imidazoles/administration & dosage ; Male ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Middle Aged ; Oximes/administration & dosage ; Prognosis ; Pyridones/administration & dosage ; Pyrimidinones/administration & dosage ; Survival Rate
Chemical Substances	Circulating Tumor DNA ; Imidazoles ; Oximes ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN) ; dabrafenib (QGP4HA4G1B)
Language	English
Publishing date	2021-02-12
Publishing country	England
Document type	Clinical Trial, Phase II ; Clinical Trial, Phase III ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't ; Validation Study
ZDB-ID	2049730-1
ISSN	1474-5488 ; 1470-2045
ISSN (online)	1474-5488
ISSN	1470-2045
DOI	10.1016/S1470-2045(20)30726-9
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Article ; Online: Randomized Phase III Trial Evaluating Spartalizumab Plus Dabrafenib and Trametinib for

Dummer, Reinhard / Long, Georgina V / Robert, Caroline / Tawbi, Hussein A / Flaherty, Keith T / Ascierto, Paolo A / Nathan, Paul D / Rutkowski, Piotr / Leonov, Oleg / Dutriaux, Caroline / Mandalà, Mario / Lorigan, Paul / Ferrucci, Pier Francesco / Grob, Jean Jacques / Meyer, Nicolas / Gogas, Helen / Stroyakovskiy, Daniil / Arance, Ana / Brase, Jan C /

Green, Steven / Haas, Tomas / Masood, Aisha / Gasal, Eduard / Ribas, Antoni / Schadendorf, Dirk

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2022 Volume 40, Issue 13, Page(s) 1428–1438

Abstract: Purpose: Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by ... ...

Abstract	Purpose: Preclinical data suggest the combination of an anti-programmed death receptor 1 antibody plus dabrafenib and trametinib to have superior antitumor activity compared with dabrafenib plus trametinib alone. These observations are supported by translational evidence suggesting that immune checkpoint inhibitors plus targeted therapy may improve treatment outcomes in patients with Methods: Patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily or placebo-DabTram. Participants were age ≥ 18 years with unresectable or metastatic Results: At data cutoff (July 1, 2020), the median progression-free survival was 16.2 months (95% CI, 12.7 to 23.9 months) in the sparta-DabTram arm versus 12.0 months (95% CI, 10.2 to 15.4 months) in the placebo-DabTram arm (hazard ratio, 0.82 [95% CI, 0.66 to 1.03]; Conclusion: The study did not meet its primary end point; broad first-line use of sparta-DabTram is not supported by these results. Further biomarker-driven investigation may identify patient subpopulations who could benefit from checkpoint inhibitor plus targeted therapy combinations.
MeSH term(s)	Adolescent ; Adult ; Antibodies, Monoclonal, Humanized ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Humans ; Imidazoles ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Mutation ; Neoplasms, Second Primary/etiology ; Oximes ; Proto-Oncogene Proteins B-raf/genetics ; Pyridones ; Pyrimidinones ; Receptors, Death Domain ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics
Chemical Substances	Antibodies, Monoclonal, Humanized ; Imidazoles ; Oximes ; Pyridones ; Pyrimidinones ; Receptors, Death Domain ; trametinib (33E86K87QN) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; dabrafenib (QGP4HA4G1B) ; spartalizumab (QOG25L6Z8Z)
Language	English
Publishing date	2022-01-14
Publishing country	United States
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.21.01601
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Article ; Online: microRNA biomarkers in body fluids of prostate cancer patients.

Kuner, Ruprecht / Brase, Jan C / Sültmann, Holger / Wuttig, Daniela

Methods (San Diego, Calif.)

2013 Volume 59, Issue 1, Page(s) 132–137

Abstract: The abundance of miRNAs - small non-coding RNAs involved in posttranscriptional regulation of gene expression - in tissues and body fluids of cancer patients hold great promise to identify specific biomarkers, which may be useful for early diagnosis as ... ...

Abstract	The abundance of miRNAs - small non-coding RNAs involved in posttranscriptional regulation of gene expression - in tissues and body fluids of cancer patients hold great promise to identify specific biomarkers, which may be useful for early diagnosis as well as to predict the clinical outcome and treatment response. For the extraction and quantification of miRNAs from cells and tissues, present technologies for transcriptome analyses like microarrays, quantitative real-time PCR or next generation sequencing can be applied. However, the analyses of miRNAs in body fluids like serum or urine is still a challenge with respect to the nucleic acid recovery from very limited sources of biomaterial, normalization strategies and validation using independent technologies. The presence of specific miRNA patterns in body fluids like serum of cancer patients suggests a promising role of these molecules as surrogate markers. However, the majority of miRNA studies were addressed in relatively small patient cohorts limiting the validity and the clinical application of potential miRNA biomarkers or signatures. We reflect the critical steps to translate miRNA biomarker into clinical routine diagnostics and present future aspects for the fast, robust and standardized quantification of miRNAs in body fluids.
MeSH term(s)	Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Body Fluids/metabolism ; Humans ; Male ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Molecular Diagnostic Techniques ; Prognosis ; Prostatic Neoplasms/diagnosis ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/metabolism ; Transcriptome
Chemical Substances	Biomarkers, Tumor ; MicroRNAs
Language	English
Publishing date	2013-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1066584-5
ISSN	1095-9130 ; 1046-2023
ISSN (online)	1095-9130
ISSN	1046-2023
DOI	10.1016/j.ymeth.2012.05.004
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Article ; Online: Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAF

Dummer, Reinhard / Brase, Jan C / Garrett, James / Campbell, Catarina D / Gasal, Eduard / Squires, Matthew / Gusenleitner, Daniel / Santinami, Mario / Atkinson, Victoria / Mandalà, Mario / Chiarion-Sileni, Vanna / Flaherty, Keith / Larkin, James / Robert, Caroline / Kefford, Richard / Kirkwood, John M / Hauschild, Axel / Schadendorf, Dirk / Long, Georgina V

The Lancet. Oncology

2020 Volume 21, Issue 3, Page(s) 358–372

Abstract: ... Committee on Cancer 7th edition criteria, with a BRAF: Findings: Between Jan 31, 2013, and Dec 11, 2014 ...

Abstract	Background: Adjuvant dabrafenib plus trametinib reduced the risk of relapse versus placebo in patients with resected, BRAF Methods: COMBI-AD is a randomised, double-blind, placebo-controlled, phase 3 trial comparing dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily versus two matched placebos. Study participants were at least 18 years of age and underwent complete resection of stage IIIA (lymph node metastases >1 mm), IIIB, or IIIC cutaneous melanoma, per American Joint Committee on Cancer 7th edition criteria, with a BRAF Findings: Between Jan 31, 2013, and Dec 11, 2014, 870 patients were enrolled in the trial. Median follow-up at data cutoff (April 30, 2018) was 44 months (IQR 38-49) in the dabrafenib plus trametinib group and 42 months (21-49) in the placebo group. Intrinsic tumour genomic features were assessed in 368 patients (DNA sequencing set) and tumour microenvironment characteristics were assessed in 507 patients (NanoString biomarker set). MAPK pathway genomic alterations at baseline did not affect treatment benefit or clinical outcome. An IFNγ gene expression signature higher than the median was prognostic for prolonged relapse-free survival in both treatment groups. Tumour mutational burden was independently prognostic for relapse-free survival in the placebo group (high TMB, top third; hazard ratio [HR] 0·56, 95% CI 0·37-0·85, p=0·0056), but not in the dabrafenib plus trametinib group (0·83, 95% CI 0·53-1·32, p=0·44). Patients with tumour mutational burden in the lower two terciles seem to derive a substantial long-term relapse-free survival benefit from targeted therapy (HR [versus placebo] 0·49, 95% CI 0·35-0·68, p<0·0001). However, patients with high tumour mutational burden seem to have a less pronounced benefit with targeted therapy (HR [versus placebo] 0·75, 95% CI 0·44-1·26, p=0·27), especially if they had an IFNγ signature lower than the median (HR 0·88 [95% CI 0·40-1·93], p=0·74). Interpretation: Tumour mutational burden alone or in combination with IFNγ gene expression signature or other markers for an adaptive immune response might be of relevance for identifying patients with stage III melanoma who might derive clinical benefit from targeted therapy. Further validation in prospective clinical trials is warranted. Funding: Novartis Pharmaceuticals.
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Double-Blind Method ; Drug Resistance, Neoplasm/drug effects ; Female ; Follow-Up Studies ; Humans ; Imidazoles/administration & dosage ; Male ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Middle Aged ; Mutation ; Neoplasm Metastasis ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/genetics ; Neoplasm Recurrence, Local/pathology ; Oximes/administration & dosage ; Prognosis ; Proto-Oncogene Proteins B-raf/genetics ; Pyridones/administration & dosage ; Pyrimidinones/administration & dosage ; Salvage Therapy ; Skin Neoplasms/drug therapy ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Survival Rate ; Young Adult
Chemical Substances	Imidazoles ; Oximes ; Pyridones ; Pyrimidinones ; trametinib (33E86K87QN) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; dabrafenib (QGP4HA4G1B)
Language	English
Publishing date	2020-01-30
Publishing country	England
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2049730-1
ISSN	1474-5488 ; 1470-2045
ISSN (online)	1474-5488
ISSN	1470-2045
DOI	10.1016/S1470-2045(20)30062-0
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