Tafinlar (dabrafenib)

Using high-throughput screening, we established that combining p38 inhibitors with the BRAF inhibitor dabrafenib showed strong synergy in vitro, including in cells resistant to dabrafenib and trametinib that had acquired a secondary TP53 mutation. Overall, our findings suggest an oncogenic link between the MAPK and p38/MAPK14 pathways and that combining p38 pathway inhibitors with dabrafenib-targeted therapy could improve treatment outcomes for aggressive thyroid cancers. However, more specific and effective p38 inhibitors are required to fully harness this potential.

Multigene testing is underutilized in this population. While many targeted therapies carry a high risk of pneumonitis, sotorasib appeared relatively safe. Despite the risks, identifying and treating actionable oncogenic drivers may improve survival.

P1/2, N=75, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

Both patients were treated with dabrafenib and trametinib and monitored through clinical assessments, magnetic resonance imaging (MRI), and repeat CSF analyses. In one case, follow-up CSF analysis 3 months post-treatment initiation was negative for BRAF V600E, indicating a potential role for liquid biopsy in monitoring treatment response. No significant toxicity was observed.

Our findings provide new insights for combination therapy including Bcl-xL degradation for melanoma treatment.

P4, N=165, Recruiting, Novartis Pharmaceuticals | Active, not recruiting --> Recruiting | Trial completion date: Jul 2026 --> Nov 2026

The postoperative pathology review revealed a pathological complete response (pCR). This case illustrates that BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor therapy may represent a viable option for neoadjuvant therapy in locally advanced BRAF V600E mutant NSCLC.

After 6 months, he achieved complete remission of liver metastases, experiencing only mild adverse events, including grade 1 pyrexia and diarrhea. This case report demonstrates that dabrafenib-trametinib combination therapy is an effective and well-tolerated treatment option for BRAF-mutated metastatic melanoma in advanced-age patients.

These data confirm the efficacy and safety of first line D/T in BRAF V600E-mutated pts in the real-world setting consistently with prior studies, suggesting a differential activity among key clinical-molecular subgroups.

No treatment-related deaths were reported. In pediatric patients with relapsed orrefractory BRAF V600-mutated HGG, dabrafenib exhibited sustained objective tumor responses and a manageable safety profile.

Combining targeted therapies with immune checkpoint inhibitors showed promising results in 2 patients with advanced BTC driven by specific genetic mutations. Significant tumor reduction and successful surgeries suggest this approach may improve resectability and outcomes. These cases highlight the potential of personalized treatment guided by genetic profiling. Further research is needed to confirm these findings and explore broader applications for this strategy.

Among the derivatives, compound 3k showed the highest binding affinity for VEGFR-2 (- 8.18 kcal/mol) and BRAF (- 8.64 kcal/mol), surpassing the control drugs etoposide (- 8.00 kcal/mol) and dabrafenib (- 8.15 kcal/mol) respectively. ADMET analysis confirmed good intestinal absorption, limited blood-brain barrier penetration, non-toxicity, acceptable total clearance, and compliance with Lipinski's rule. Overall, the study suggests that pyrazole-modified catalpol derivatives, especially compound 3k, are promising multi-target inhibitors for pancreatic and esophageal cancers, justify further in-vitro and in-vivo studies.