BRAF V600E

P1/2, N=34, Terminated, Pfizer | Active, not recruiting --> Terminated; Study was terminated due to portfolio re-prioritization and strategic considerations. The decision was not based on any safety concerns and/or regulatory interactions

They include larotrectinib/entrectinib/repotrectinib (NTRK fusions), selpercatinib (RET fusions), dabrafenib/trametinib (BRAFV600E mutations), pembrolizumab/dostarlimab (microsatellite instability), pembrolizumab (high tumor mutational burden), and trastuzumab deruxtecan (HER2 3+ expression) (all solid cancers). Pemigatinib is approved for FGFR1-rearranged myeloid/lymphoid neoplasms...For example, BRAFV600E and IDH1/2 mutations; ALK, FGFR, and NTRK fusions; PD-L1 amplification; and CD70 antigens are druggable in both solid and blood malignancies by gene-/immune-targeted therapies/chimeric antigen receptor T cells. Future biomarker-based tissue-agnostic basket studies/approvals should bridge the great divide and include both solid and hematologic cancers.

During a limited 1.5-year follow-up period, neither a confirmed local recurrence nor a distant organ metastasis occurred in this case. We propose that BRAF fusion variations can occur in metastatic EOCC.

This study provides new insights into overcoming resistance to BRAF and MAPK inhibitors, with implications for treating thyroid cancer and potentially other BRAF-mutant tumors. Future efforts will focus on high-throughput screening approaches to explore ANXA7-targeted therapeutic strategies for thyroid cancer.

However, resistance to BRAF pathway inhibitors is inevitable, leading to disease progression, and a well-defined strategy to overcome these resistance mechanisms is lacking. This review aims to explore the critical challenges in the management of BRAF-mutated NSCLC, providing a comprehensive summary of the current evidence and highlighting ongoing clinical trials that aim to address these critical gaps.

Background/Objective: Dabrafenib and trametinib (D + T) have been approved for the treatment of stage III melanoma with BRAF V600E V600K mutations in an adjuvant setting, based on the results from the COMBI-AD trial. Similarly, the median OS was not reached, with OS rates of 96.4% at 12 months and 92.5% at 24 months. D + T achieved an RFS benefit, with effects sustained beyond the treatment period, indicating positive outcomes in this patient population.

After the advent of systemic therapies, a trial of the combination targeted therapy of dabrafenib plus trametinib toward BRAF V600-mutant nodal cutaneous melanoma showed that all 35 patients achieved a pathological response...For those tumours that do recur in-field, there are now competing therapies like Talimogene laherparepvec or T-VEC. Generally, ART is now used at the first recurrence. The challenge now is to find which melanomas are truly radiosensitive if ART is to have any future role in this scenario.

TBC1D12 5'UTR mutations were significantly associated with older age at diagnosis (60 vs. 46 for wild type, p = 0.003), pathological T3/T4 stage (85.7% vs. 37.7%, p = 0.010), and advanced tumor stages (85.7% vs. 32.5%, p = 0.006) in PTC. This preliminary study for the first time showed a high prevalence of TBC1D12 5'UTR mutations in ATC and indicated an association between TBC1D12 mutation and aggressive characteristics of PTC, which needs to be confirmed in large cohort studies.

BRAF mutation analysis can be performed on fixed fine needle aspiration cytology specimens. Although the frequency of the mutation is higher in specimens with higher Bethesda category scores, it could support clinical decision-making in thyroid nodules with intermediate Bethesda category scores.

Both WES and RNAseq results showed gene alterations related to proliferation, cell differentiation, and metabolic processes. These results show that AM share many of the hallmarks of cancer secondary to the presence of oncogenic mutations or activation of oncogenic signaling pathways.

P2, N=40, Recruiting, ImmunityBio, Inc. | Active, not recruiting --> Recruiting | N=147 --> 40

The lack of association between molecular alteration status and recurrence risk prevailed after multivariable adjustment for tumor stage and perioperative treatment (P=0.82 for KRAS G12C mutation and P=0.43 for any other molecular alteration). NSCLC patients with resected tumors that harbor molecular alterations have the same recurrence risk as patients with tumors without molecular alterations if treated with surgery plus chemotherapy when indicated.

This is a case showing improvement of a craniopharyngioma after treatment with BRAF and MEK inhibitor combinations. The role of BRAF and MEK inhibitor combinations continues to evolve in this space.

P1/2, N=58, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2024 --> Nov 2025 | Trial primary completion date: Dec 2024 --> Nov 2025

We also discuss the clinical relevance of biomarkers, emphasizing their alignment with the National Comprehensive Cancer Network® (NCCN®) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) as well as ancillary tests such as BRAF VE1 immunohistochemistry to detect BRAF V600E mutation and molecular techniques such as real-time polymerase chain reaction, matrix-assisted laser desorption ionization-time of flight mass spectrometry and next-generation sequencing. Our proposed standardized minimum criteria for reflex testing prioritize melanomas with Breslow thickness >4 mm or disseminated disease, who will most benefit from enhanced delivery of biomarkers and expedited access to targeted therapies while attempting to balance cost-effectiveness and utilization of public healthcare resources with patient outcomes.

During melanoma development in cdkn2b-/-/tp53-/- frogs, the occurrences of epithelial-to-mesenchymal transition, the reactivation of pigment cell progenitor cell transcriptional states, and the activation in the MAPK, NF-kB, PI3K-Akt, and TGF-β signaling pathways were noted. Overall, cdkn2b-/-/tp53-/- Xenopus tropicalis provides a vertebrate model for investigating the development of CDKN2A germline mutation-induced hereditary melanoma, contributing to the exploration of the pathogenesis of hereditary melanoma in humans.

P1, N=51, Active, not recruiting, Institut de Recherches Internationales Servier | Trial completion date: Jan 2025 --> Jun 2025

P2, N=175, Active, not recruiting, German Cancer Research Center | Recruiting --> Active, not recruiting

Approximately 2% of all CRC cases in this study were CLDN18.2 positive and had unfavorable features (e.g., mucinous or poorly differentiated adenocarcinoma, T3-4 disease, lymphatic invasion, BRAF V600E mutation) and deficient MMR status. CLDN18.2 positivity did not have a significant impact on RFS or OS.

P=N/A, N=1000, Active, not recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

No abstract available

Bethesda III-VI thyroid nodules with isolated RAS mutations have a low rate of aggressive histopathologic features and are unlikely to recur. Thyroid lobectomy may be sufficient treatment for these tumors.

Since BRAF activation occurs in BRAF fusion gene tumors and BRAF mutations, they could share a similar mechanism in tumorigenesis. This case suggests the further expansion of kinase-related spindle cell tumors.

Molecular docking experiments are thoroughly examined to validate the binding interactions of the most active hybrids with the active sites of EGFR and BRAFV600E. The data indicated that the examined compounds can efficiently engage with essential amino acid residues in both kinases.

Importantly, genetic and pharmacological targeting of PI3Kβ phenocopied PREX2 deficiency, sensitizing model systems to therapy. These data reveal a druggable PREX2/RAC1/PI3Kβ signaling axis in BRAF-mutant melanoma that could be exploited clinically.

In this limited case series, two patients were dead at the last follow-up. Whether these findings are consistent within this patient population remains to be addressed as more patient series are published.

Molecular docking demonstrated that Encorafenib inhibits the V600E variant BRAF protein less effectively compared to its wild-type counterpart. Overall, this study highlights the importance of comprehensive molecular screening and bioinformatics in understanding the mutational landscape of CRC in the Saudi population, ultimately improving targeted drug treatments.

The results of ongoing and future trials may define its role in management. Precision oncology is a promising addition to the treatment armamentarium of adult CPs.

In conclusion, PTC in AYA patients differed from PTC in older patients. Particularly, BRAF p.V600E and TERT promoter mutations in AYA with PTC were less frequently observed than in older adults.

Although most PTMC has been widely defined as indolent disease, a non-negligible rate of patients may present one or more biologically aggressive features including nodal involvement. Nonsurgical management should be considered with caution to avoid undertreatment especially in the younger population.

The randomized FIRE-4.5 (AIO KRK0116) trial compared first-line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E-mutant metastatic colorectal cancer (mCRC) patients. Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E-mutated mCRC.

These findings highlight the ongoing difficulties in demonstrating clear clinical utility of CGP tests in Japan, emphasizing the need for broad discussions on its future direction.

Furthermore, iPSC-derived neurons (iNeurons) co-cultured with BRAFV600E/WT iPSC-derived microglia-like cells (iMGL), differentiated from iPSC-derived CD34+ progenitors, exhibit signs of neurodegeneration with neuronal damage and release of neurofilament light chain. In summary, the iPSC-based model described here provides a platform to investigate the effects of BRAFV600E in different hematopoietic cell types and provides a tool to compare and identify novel approaches for the treatment of BRAFV600E-driven diseases.

These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies.

This study delineates a distinct subtype of benign adenoma arising from the esophageal submucosal gland duct, characterised by multiple lobulated cystic proliferation of benign epithelial layers within the submucosa. BRAF V600E mutations were present, similar to in sialadenoma papilliferum. We determined the genetic mutation present in esophageal submucosal gland duct adenoma, providing further evidence that it is an esophageal counterpart of minor salivary gland tumours.

We confirmed a significant gender-based dimorphism in the efficacy of anti-EGFR/BRAF/MEK therapy in patients with advanced-CRC harboring BRAF mutations that warrant further investigation.

These findings suggest rational strategies for combining sequential chemotherapy and BRAF-/EGFR-directed therapy in BRAF-V600E-mutant colon cancer to prevent resistance and improve outcome. The data demonstrate rapid clonal dynamics in response to effective therapies in BRAF-V600E-mutant colon cancer that can be monitored by serial cfDNA analysis. Moreover, in mismatch repair-proficient BRAF-V600E-mutant colon cancers, combined EGFR and BRAF/MEK therapy is not cross-resistant with standard chemotherapy, suggesting new rational combination treatment strategies.

P1, N=36, Recruiting, Transgene | Trial completion date: Mar 2025 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

The 9-gene panel can detect individual cases with gene mutations indicating poor prognosis. The identification of patients with these special gene mutations has certain implications for the clinical management of them.

Our study observed a mean total Gy of 34 (median total 30 Gy) and mean fractionation Gy of 8 (median fractionation 7.5 Gy) with increased frequency of reported abscopal effects with incorporation of modern systemic immunotherapies. The reviewed cases suggest that combining radiation with immunotherapy may enhance systemic tumor control, though further research is required to better understand the underlying mechanisms and improve treatment outcomes.

In vivo studies have shown that BRAFi can enhance human hematopoiesis and erythropoiesis in severe immunodeficient mouse models and alleviate anemia in the Rpl11 haploinsufficiency DBA model, as well as other relevant anemia models. This discovery underscores the role of the MAPK pathway in hematopoiesis and positions BRAFi as a promising therapeutic option for improving hematopoietic reconstitution and treating anemias, including DBA.

To our knowledge, this is the largest retrospective cohort of BRAF-mutated patients reported. The findings confirmed the significant efficacy of D-T in combination with BRAF V600E-mutated metastatic NSCLC in pretreated and untreated patients. These results under real-world conditions are consistent with those of other registered studies.