Tissue-Agnostic Activity of BRAF plus MEK Inhibitor in BRAF V600–Mutant Tumors

Adashek, Jacob J.; Menta, Arjun K.; Reddy, Neha K.; Desai, Aakash; Roszik, Jason; Subbiah, Vivek

doi:10.1158/1535-7163.mct-21-0950

Cited by 29 publications

(23 citation statements)

References 61 publications

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“…In addition, another anti-PD-1 agent, dostarlimab-gxly, has been approved for the same indication ( 12 , 14 ). Subsequently, larotrectinib and entrectinib were approved for solid tumors harboring an NTRK fusion, pembrolizumab was approved for solid tumors with high tumor mutational burden (TMB-H), and more recently, the combination of dabrafenib and trametinib was approved for solid tumors harboring a BRAF V600E mutation ( 13 , 15 , 16 , 18 ). Moreover, therapies seeking such indications have expanded in recent years, beyond immune checkpoint inhibitors and targeted kinase inhibitors, to antibody-drug conjugates ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

Analysis of histology-agnostic targets among soft tissue and bone sarcomas in the AACR GENIE database

Pestana

Serrano

2023

Front. Oncol.

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BackgroundThe development of novel therapies for patients with sarcoma is challenging due to the rarity and diversity of these mesenchymal neoplasms. Hence, histology-agnostic approvals can be of particular interest for the treatment of patients with soft tissue and bone sarcoma.MethodsWe queried the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database Cohort v12.0-Public to investigate the prevalence of currently Food and Drug Administration (FDA)-approved and other potentially actionable histology-agnostic alterations in patients with soft tissue and bone sarcoma. Targets were identified by a literature review by the authors. Results are presented for each cohort identified in the GENIE database, namely: (1) soft tissue sarcoma (STS), (2) gastrointestinal stromal tumor (GIST), (3) bone sarcoma, (4) uterine sarcoma, and (5) breast sarcoma.ResultsWe identified 7,512 samples of 6,955 patients with sarcoma in the AAACR GENIE database v12.0-Public. Molecular alterations that could lead to the clinical use of a currently approved histology-agnostic therapy were identified in 2.1% of sarcomas (2.6% STS, 1.3% GIST, 1.4% bone, 2.7% uterine, and 0% breast). In addition, 2.9% of patients could be eligible for future histology-agnostic approvals. These specific mutations, fusions, and amplifications occurred in multiple histotypes in all cohorts.DiscussionExploring a public large-scale genomic database, we identified that 5% of patients with sarcoma could be eligible for current histology-agnostic FDA-approved drugs or future potential histology-agnostic indications. These actionable alterations were present in a wide variety of histologies in soft tissue and bone sarcomas, highlighting that next-generation sequencing can be considered for patients with advanced sarcoma to guide treatment strategies.

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Section: Introductionmentioning

confidence: 99%

Analysis of histology-agnostic targets among soft tissue and bone sarcomas in the AACR GENIE database

Pestana

Serrano

2023

Front. Oncol.

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“…Beyond melanoma and lung, BRAF V600 is also seen in a variety of tumor types; and although monotherapy with vemurafenib showed responses, resistance quickly emerges and leads to refractory disease progression. 78 With BRAF and MEK combination emerging as standard of care in melanoma tumors, the ROAR (Rare Oncology Agnostic Research) trial (BRF117019; NCT02034110) was designed as a basket trial to investigate the use of combined dabrafenib and trametinib in none different tumor types harboring BRAF V600 alterations. 40 , 41 , 42 , 43 , 56 Given the dramatic responses in ATC, one of the most lethal forms of thyroid cancers, and in an area of huge unmet need, the combination received FDA approval as the first targeted therapy for BRAF V600-mutant anaplastic thyroid carcinoma.…”

Section: Braf -Targeted Combination Therapiesmentioning

confidence: 99%

Precision oncology for BRAF-mutant cancers with BRAF and MEK inhibitors: from melanoma to tissue-agnostic therapy

Gouda¹,

Subbiah²

2023

ESMO Open

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“…Abnormal, disrupted or constitutively activated MAPK pathways are involved in many pediatric cancers, particularly in low-grade gliomas (LGG). Recently, BRAF V600E-mutated tumors in children were eligible for agnostic treatment with BRAF plus MEK inhibitors [ 932 ]. Patients were randomized to receive either dabrafenib plus trametinib or standard chemotherapy.…”

Section: Kinase Inhibitors In Clinical Trialsmentioning

confidence: 99%

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

et al. 2023

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Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases’ functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.

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Tissue-Agnostic Activity of BRAF plus MEK Inhibitor in BRAF V600–Mutant Tumors

Cited by 29 publications

References 61 publications

Analysis of histology-agnostic targets among soft tissue and bone sarcomas in the AACR GENIE database

Analysis of histology-agnostic targets among soft tissue and bone sarcomas in the AACR GENIE database

Precision oncology for BRAF-mutant cancers with BRAF and MEK inhibitors: from melanoma to tissue-agnostic therapy

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

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