Expanding the Benefit: Dabrafenib/Trametinib as Tissue-Agnostic Therapy for BRAF V600E–Positive Adult and Pediatric Solid Tumors

American Society of Clinical Oncology Educational Book, Journal Year: 2023, Volume and Issue: 43

Published: May 1, 2023

The recent US Food and Drug Administration (FDA) approval of the dabrafenib/trametinib combination as a tissue-agnostic treatment for solid tumors with BRAF V600E mutation is result more than 20 years extensive research into mutations in human cancer, underlying biological mechanisms that drive BRAF-mediated tumor growth, clinical testing refinement selective RAF MEK kinase inhibitors. Such marks significant achievement field oncology represents major step forward our ability to treat cancer. Early evidence supported use melanoma, non–small-cell lung anaplastic thyroid Furthermore, data from basket trials have demonstrated consistently good response rates various tumors, including biliary tract low-grade glioma, high-grade hairy cell leukemia, multiple other malignancies, which has been basis FDA indication adult pediatric patients V600E–positive tumors. From standpoint, review delves efficacy tumors: examining rationale its use, evaluating latest on potential benefits, discussing possible associated adverse effects strategies minimize their impact. Additionally, we explore resistance future landscape BRAF-targeted therapies.

Language: Английский

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The evolving landscape of tissue‐agnostic therapies in precision oncology

CA A Cancer Journal for Clinicians, Journal Year: 2024, Volume and Issue: 74(5), P. 433 - 452

Published: May 30, 2024

Tumor-agnostic therapies represent a paradigm shift in oncology by altering the traditional means of characterizing tumors based on their origin or location. Instead, they zero specific genetic anomalies responsible for fueling malignant growth. The watershed moment tumor-agnostic arrived 2017, with US Food and Drug Administration's historic approval pembrolizumab, an immune checkpoint inhibitor. This milestone marked marriage genomics immunology fields, as immunotherapeutic agent gained genomic biomarkers, specifically, microsatellite instability-high mismatch repair deficiency (dMMR). Subsequently, NTRK inhibitors, designed to combat gene fusions prevalent various tumor types, including pediatric cancers adult solid tumors, further underscored potential therapies. Administration approvals targeted (BRAF V600E, RET fusion), immunotherapies (tumor mutational burden ≥10 mutations per megabase, dMMR) antibody-drug conjugate (Her2-positive-immunohistochemistry 3+ expression) pan-cancer efficacy have continued, offering newfound hope patients grappling advanced that harbor particular biomarkers. In this comprehensive review, authors delve into expansive landscape tissue-agnostic targets drugs, shedding light rationale underpinning approach, hurdles it faces, presently approved therapies, voices from patient advocacy perspective, tantalizing prospects horizon. is welcome advance transcends boundaries histology location provide personalized options.

Language: Английский

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Molecular Frontiers in Melanoma: Pathogenesis, Diagnosis, and Therapeutic Advances

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(5), P. 2984 - 2984

Published: March 4, 2024

Melanoma, a highly aggressive skin cancer, is characterized by rapid progression and high mortality. Recent advances in molecular pathogenesis have shed light on genetic epigenetic changes that drive melanoma development. This review provides an overview of these developments, focusing mechanisms genesis. It highlights how mutations, particularly the BRAF, NRAS, c-KIT, GNAQ/GNA11 genes, affect critical signaling pathways. The evolution diagnostic techniques, such as genomics, transcriptomics, liquid biopsies, biomarkers for early detection prognosis, also discussed. therapeutic landscape has transformed with targeted therapies immunotherapies, improving patient outcomes. paper examines efficacy, challenges, prospects treatments, including recent clinical trials emerging strategies. potential novel treatment strategies, neoantigen vaccines, adoptive cell transfer, microbiome interactions, nanoparticle-based combination therapy, explored. These emphasize challenges therapy resistance importance personalized medicine. underlines necessity evidence-based selection managing increasing global incidence melanoma.

Language: Английский

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Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical Implications

Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 29(15), P. 2753 - 2760

Published: April 6, 2023

Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored, which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers obtained FDA approval for targeted therapies immunotherapies. Those include BRAFV600E mutations, RET fusions, NTRK high mutation burden (TMB), deficient mismatch repair/high microsatellite instability (dMMR/MSI-High). Herein, we used data from AACR project GENIE explore the clinico-genomic landscape these alterations. is publicly accessible registry genomic multiple collaborating centers. Current database (version 13.0) includes sequencing 168,423 samples collected patients different cancers. We were able identify BRAFV600E, TMB in 2.9%, 1.6%, 1.5%, 15.2% samples, respectively. In this article, describe distribution those among types. addition, summarize current prospect on biology alterations evidence approved drugs, including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, dabrafenib/trametinib combination.

Language: Английский

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Molecular Targeting of the BRAF Proto-Oncogene/Mitogen-Activated Protein Kinase (MAPK) Pathway across Cancers

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(1), P. 624 - 624

Published: Jan. 3, 2024

The mitogen-activated protein kinase (MAPK) pathway is essential for cellular proliferation, growth, and survival. Constitutive activation of this by BRAF mutations can cause downstream kinases, leading to uncontrolled growth carcinogenesis. Therefore, inhibition the substrate MEK has been shown be effective in controlling tumor proliferation. Over last decade, several inhibitors have investigated, ranging from primarily melanoma various cancer types with alterations. This subsequently led Food Drug Administration (FDA) approvals BRAF/MEK melanoma, non-small cell lung cancer, anaplastic thyroid colorectal histiocytosis neoplasms, finally, tumor-agnostic indications. Here, comprehensive review will cover developments melanomas indications, novel drugs, challenges, future directions, importance those drugs personalized medicine.

Language: Английский

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Cardiovascular Considerations Before Cancer Therapy

JACC CardioOncology, Journal Year: 2024, Volume and Issue: 6(5), P. 631 - 654

Published: Sept. 24, 2024

Language: Английский

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Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial

EClinicalMedicine, Journal Year: 2024, Volume and Issue: 69, P. 102447 - 102447

Published: Feb. 2, 2024

BackgroundBRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the of with BRAF V600E/R or non-V600 mutations.MethodsBetween October 1, 2019, June 2022, at least 50 patients measurable seven without diseases examined were enrolled a subcohort (NCCH1901, jRCTs031190104). mutated tumour cases other than V600E colorectal cancer, non-small cell cancer included. Patients received (150 mg) twice daily (2 once until disease progression intolerable toxicity was observed. primary endpoint overall response rate (ORR), secondary endpoints included progression-free survival (PFS), 6-month PFS, (OS). Bayesian analysis performed using prior distribution 30% expected [Beta (0.6, 1.4)].FindingsFourty-seven disease, mainly mutation (94%), three others non-V600E (V600R, G466A, N486_P490del) enrolled. sites thyroid gland, central nervous system, liver, bile ducts, colorectum, pancreas. confirmed ORR 28.0%; value posterior (14.6, 37.4)] 28.1%, although achieved, not exceeding an unexpectedly high 60% obtained analysis. control (DCR) 84.0%. median PFS 6.5 months (95% confidence interval [CI]; 4.2–7.2 months, 87.8% 6 months). Responses observed types. Median OS 9.7 CI, 7.5–12.2 Additional had 4.5 months. Adverse events (AEs) consistent previous reports, 45.6% experiencing grade ≥3 AEs.InterpretationThis study reported promising against V600-mutant tumours. Dabrafenib would offer new therapeutic option rare such as high-grade gliomas, biliary tract cancer.FundingThis funded by Japan Agency Medical Research Development (22ck0106622h0003) Health Labour Sciences Grant (19EA1008).

Language: Английский

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Revolutionizing cancer drug development: Harnessing the potential of basket trials

Cancer, Journal Year: 2023, Volume and Issue: 130(2), P. 186 - 200

Published: Nov. 7, 2023

Abstract The landscape of cancer therapy has been transformed by advances in clinical next‐generation sequencing, genomically targeted therapies, and immunotherapies. Well designed trials efficient trial conduct are crucial for advancing our understanding cancer, improving patient outcomes, identifying personalized treatments. Basket have emerged as one the modern designs that evaluate efficacy these therapies across multiple types based on specific molecular alterations or biomarkers, irrespective histology anatomic location. This review delves into evolution basket drug development, highlighting their potential prospects current obstacles. design involves screening patients biomarkers enrolling them to receive under investigation. Statistical considerations play a role design, analysis, interpretation trials. Several notable examples led US Food Drug Administration approval uncommon (e.g., NTRK fusions, BRAF mutations, RET FGFR1 alterations) discussed, including LOXO‐TRK (ClinicalTrials.gov identifier NCT02122913)/SCOUT NCT02637687)/NAVIGATE NCT02576431)/STARTRK identifiers NT02097810, NT02568267), VE‐BASKET NCT01524978), ROAR NCT02034110), LIBRETTO‐001 NCT03157128), ARROW NCT03037385), FIGHT‐203 NCT03011372), National Cancer Institute‐Molecular Analysis Therapy Choice NCT02465060). revolutionize treatment effective rather than traditional histology‐based approaches. Plain Language Summary To gain more knowledge about improve discover treatments, it is efficiently. One type called . In trials, new treatments tested various regardless location body; instead, researchers focus abnormalities cells. offer hope we can find each individual battling cancer.

Language: Английский

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Heterogeneous pathogenesis of melanoma: BRAF mutations and beyond

Critical Reviews in Oncology/Hematology, Journal Year: 2024, Volume and Issue: 201, P. 104435 - 104435

Published: July 6, 2024

Melanoma pathogenesis, conventionally perceived as a linear accumulation of molecular changes, discloses substantial heterogeneity driven by non-linear biological processes, including the direct transformation melanocyte stem cells. This manifests in diverse phenotypes and developmental states, influencing variable responses to treatments. Unveiling aberrant mechanisms steering melanoma initiation, progression, metastasis is imperative. Beyond mutations oncogenic tumor suppressor genes, involvement distinct pathways assumes pivotal role pathogenesis. Ultraviolet (UV) radiations, principal factor etiology, categorizes melanomas based on cumulative sun damage (CSD). The genomic landscape lesions correlates with UV exposure, impacting mutational load spectrum mutations. World Health Organization's 2018 classification underscores interplay between exposure characteristics, distinguishing associated CSD from those unrelated CSD. elucidates features such burden copy number alterations different subtypes. significance mutated BRAF gene its pathway, notably BRAFV600 variants, paramount. mutations, prevalent across cancer types, present therapeutic avenues, clinical trials validating efficacy targeted therapies immunotherapy. Additional driver oncogenes further characterize specific pathways, behavior. While histopathological examination remains pivotal, challenges persist molecularly classifying melanocytic tumors. In this review, we went through all characterization that aid discriminating common ambiguous lesions. Integration highly sensitive diagnostic tests into workflow becomes indispensable, particularly instances where histology alone fails achieve conclusive diagnosis. A algorithm inferred various studies here proposed.

Language: Английский

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The ERK5 pathway in BRAFV600E melanoma cells plays a role in development of acquired resistance to dabrafenib but not vemurafenib

FEBS Letters, Journal Year: 2024, Volume and Issue: 598(16), P. 2011 - 2027

Published: July 8, 2024

Malignant melanoma, an aggressive skin cancer with a poor prognosis, frequently features BRAFV600E mutation resulting in activation of the MAPK pathway and melanocyte proliferation survival. inhibitors like vemurafenib dabrafenib have enhanced patient survival, yet drug resistance remains significant challenge. We investigated role ERK5 melanoma cells acquired to PLX4720 (vemurafenib) dabrafenib. In inhibition minimally affected viability compared ERK1/2 inhibition. vemurafenib-resistant cells, alone didn't impact or restore sensitivity vemurafenib. However, dabrafenib-resistant reduced anti-proliferative effect MEK1/2 Targeting may represent therapeutic opportunity melanoma.

Language: Английский

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