Braftovi (encorafenib)

P1, N=50, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Jul 2026 --> Jul 2027

P3, N=257, Active, not recruiting, Pfizer | Trial completion date: Mar 2026 --> Aug 2026

In real-world clinical practice, triplet and doublet therapies showed comparable survival outcomes, consistent with the BEACON trial. Triplet therapy may provide potential clinical benefit in patients with poor PFs.

Triple therapy with encorafenib, cetuximab, and binimetinib offers meaningful improvements in survival and tumor response in BRAF V600E-mutated CRC, although the toxicity remains substantial. Optimizing patient selection and managing adverse events are critical for broader clinical use.

Although the FDA-approved combination of encorafenib and cetuximab provides clinical benefit in this population, only 22% of patients respond and most eventually develop resistance...Importantly, we demonstrate that addition of TVB3664 to the PLX8394 or encorafenib regimen significantly postpones development of resistance to BRAF-targeted therapy by inhibiting the cell cycle progression via a decrease in pRb (Ser780) and downregulation of E2F transcription factor and Cyclin D1 expression. Consistently, clinical data show that patients with BRAFV600E CRC who have high FASN expression in tumor tissues have higher expression of cell cycle-associated genes, including CDKs, E2F, CCDN1 (Cyclin D1), survivin, and MKI67. Collectively, these findings identify FASN-driven lipid metabolism as a critical mediator of resistance to BRAF-targeted therapy and suggest that incorporation of FASN inhibitors may enhance therapeutic efficacy and delay acquired resistance in BRAFV600E CRC.

Therapeutic targeting of BRAFV600E has led to the approval of dabrafenib plus trametinib for solid tumours [excluding colorectal cancer (CRC)] refractory to standard therapies...In CRC, intrinsic epidermal growth factor receptor (EGFR) activation circumvents BRAF inhibition, necessitating the concurrent use of EGFR inhibitors, whose treatment strategy led to the approval of encorafenib plus cetuximab for BRAF V600E CRC...While noteworthy results have been achieved with BRAFV600E inhibition, further research is needed to optimize BRAF-targeted therapies and address resistance mechanisms. Continued research and innovation are crucial to improving patient outcomes and addressing the complexities of BRAF mutations in human cancers.

Uptake and impact of encorafenib plus cetuximab (EC), since being available in Australia from May 2019, were examined. The COALA study provides the first Australian real-world profile of BRAFV600E-mutated mCRC. These findings underscore the importance of early and effective therapeutic strategies, and identify a novel, disproportionately affected very-young subgroup requiring targeted research and clinical focus.

P1, N=14, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2028 --> Dec 2026

Encorafenib, cetuximab, and binimetinib are targeted therapies developed for metastatic colorectal cancer with a BRAF V600E mutation. The case highlights the potential use of BRAF V600E targeted therapy in BRAF V600E-mutated duodenal cancer and the importance of molecular profiling in rare cancers. Further research is needed on the effect and safety of targeted therapy for small bowel adenocarcinoma.

Interestingly, these so-called NaJa lines displayed distinct differentiation states and responses to the clinically relevant RAF inhibitors (RAFi) encorafenib and exarafenib, thereby resembling the clinical heterogeneity of BRAFV600E-driven CRC. RAFi resistance was overcome by the EGFR-family inhibitor afatinib...Upon re-transplantation into syngeneic mice, all NaJa lines established aggressive tumors with distinct tumor microenvironments matching to their differentiation states. Thus, the NaJa lines provide a unique tool to study tumor heterogeneity, drug resistance and the interplay between tumor, stroma and immune cells in BRAFV600E-driven CRC.

The greatest benefits of encorafenib plus binimetinib were observed in patients with evidence of high TMB and/or tumor immune infiltration, suggesting potential immune contributions to efficacy, which were not observed with vemurafenib. BRAF V600 detectability in ctDNA appears to have utility as a marker of prognosis and response in this population.