دورية أكاديمية
Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with $\textit{BRAF}$V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)
| العنوان: | Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with $\textit{BRAF}$V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i) |
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| المؤلفون: | 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 |
| المصدر: | 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 (2022). Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with $\textit{BRAF}$V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i). Journal for ImmunoTherapy of Cancer, 10(6):e004226. |
| بيانات النشر: | BioMed Central |
| سنة النشر: | 2022 |
| المجموعة: | University of Zurich (UZH): ZORA (Zurich Open Repository and Archive |
| مصطلحات موضوعية: | Dermatology Clinic, 610 Medicine & health, Cancer Research, Pharmacology, Oncology, Molecular Medicine, Immunology, Immunology and Allergy |
| الوصف: | BackgroundThe 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 $\textit{BRAF}$V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn 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; $\textit{BRAF}$V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4$^{+}$/CD8$^{+}$ T-cell ratio via immunophenotyping.ResultsExtensive 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 $\textit{BRAF}$V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4$^{+}$/CD8$^{+}$ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4$^{+}$/CD8$^{+}$ ratio was ... |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2051-1426 |
| العلاقة: | https://www.zora.uzh.ch/id/eprint/220008/1/ZORA_e004226_full.pdfTest; info:pmid/35728875; urn:issn:2051-1426 |
| DOI: | 10.5167/uzh-220008 |
| DOI: | 10.1136/jitc-2021-004226 |
| الإتاحة: | https://doi.org/10.5167/uzh-22000810.1136/jitc-2021-004226Test https://www.zora.uzh.ch/id/eprint/220008Test/ https://www.zora.uzh.ch/id/eprint/220008/1/ZORA_e004226_full.pdfTest |
| حقوق: | info:eu-repo/semantics/openAccess ; Creative Commons: Attribution 4.0 International (CC BY 4.0) ; http://creativecommons.org/licenses/by/4.0Test/ |
| رقم الانضمام: | edsbas.8561DE8 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 20511426 |
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| DOI: | 10.5167/uzh-220008 |