BRAF G469V

Despite the clinical success of BRAF/MEK inhibitors for the treatment of advanced melanoma, dabrafenib and vemurafenib have limited intracranial overall response rates of 42-50% and median progression-free survival of 3.6-5.5 months...KIN-7136 showed improved rodent brain exposure compared to conventional agents; the brain-to-plasma concentration ratio (Kp) of KIN-7136 was >1.0, much higher than comparators binimetinib and mirdametinib...In vivo, daily oral treatment with KIN-7136 was well tolerated and produced a significant extension of overall survival compared to the vehicle control (p=0.0289, log-rank test) in the A375 intracranial tumor model in athymic mice. These preclinical data confirm activity of KIN-7136 in BRAF-mutant melanoma brain metastases models and support further research to advance its clinical progression.

D594A mutant CRC exhibited lower aggressiveness and immune-activated phenotype. ATF3-THBS1-CXCL9/CXCL10 axis mediated functional CD8 T cells infiltration into the microenvironment of D594A mutant CRC. Our present study is helpful to define this mutation in CRC and provide important insights in designing effective immunotherapeutic strategies in clinic.

Introduction: Treatment with neoadjuvant nivolumab plus chemotherapy has demonstrated high efficacy in patients with locally advanced non-small-cell lung cancer (NSCLC)... Our data suggest that BRAF pathogenic variants may be a good prognostic factor in locally advance NSCLC patients treated with neoadjuvant chemo-immunotherapy.

In 10% of cases, an increase in the number of copies of the EGFR and KRAS genes was found, and in 10% of cases, a fusion gene (RNA) MET- MET.M13M15, TMPRSS2-ERG.The identified genome changes were processed by the server through the FDA, NCCN, EMA, ESMO registries to search for the most appropriate therapy options that exist in world practice for a specific type and localization of the established mutation.ConclusionConclusion. For personalized prescription of targeted drugs, it is more efficient to use multigene diagnostics for a comprehensive study of the mutational status of a tumor.

C+Vdemonstrated evidence of anti-tumor activity in pts with advanced solid tumors with BRAF V600E and other muts.

The study's findings would support the development of more effective treatment strategies for skin melanoma. Communicated by Ramaswamy H. Sarma.

"In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of VUS more likely to be oncogenic drivers. Our data indicate certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide treatment for BRAF-mutant NSCLC."

Of 30 V600E-mutated patients who received anti-BRAF therapy during the course of disease, median PFS of vemurafenib, dabrafenib, and dabrafenib plus trametinib was 7.8, 5.8, and 6.0 months, respectively (P = 0.970). Our data demonstrated the clinical benefit of anti-BRAF targeted therapy in Chinese NSCLC patients harboring BRAF-V600E mutation. The value of immunotherapy and treatment selection among non-V600E population needs further study.

Of 30 V600E-mutated patients who received anti-BRAF therapy during the course of disease, the median PFS of vemurafenib, dabrafenib, and dabrafenib plus trametinib was 7.8 months, 5.8 months and 6.0 months, respectively (P = 0.970). Our data demonstrated the clinical benefit of anti-BRAF targeted therapy in Chinese NSCLC patients harboring BRAF-V600E mutation. The value of immunotherapy and treatment selection among non-V600E population needs further study. Research Funding: None