Braftovi (encorafenib)

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.

P2, N=63, Active, not recruiting, Pierre Fabre Medicament | Trial completion date: Sep 2026 --> Dec 2026

P1, N=100, Not yet recruiting, M.D. Anderson Cancer Center

P2, N=16, Active, not recruiting, Gruppo Oncologico del Nord-Ovest | Recruiting --> Active, not recruiting

CDK4/6 and SHP2 emerge as mediators of intrinsic resistance to BRAF/MEK inhibition in Class 2 & 3 BRAF mutant tumors. Therapeutic strategies combining CDK4/6 or SHP2 inhibitors with BRAF/MEK inhibitors in preclinical models show greater efficacy than BRAF/MEK inhibitors alone in these cancers.

A 69-year-old woman with metastatic colorectal cancer (RAS wild-type, microsatellite instability-high, BRAF V600E mutation) receiving encorafenib/binimetinib plus cetuximab developed Grade 2 IR during her first cetuximab infusion (approximately 98 min after initiation)...After discontinuing the infusion, she was treated with oxygen, d-chlorpheniramine, and famotidine, allowing completion at a reduced rate...The generalizability of the findings is limited due to the single-patient design. Prospective validation comparing H1 alone versus combined H1 + H2 premedication, using predefined infusion-rate algorithms, is warranted.

Notable findings include durable survival with pembrolizumab and nivolumab + ipilimumab in MSI-H/dMMR mCRC, efficacy of fruquintinib in refractory disease, and promising early outcomes with SCRT-based immunochemotherapy in LARC. Recent trials support precision oncology in CRC, highlighting durable benefits of targeted and immune therapies. However, heterogeneity in trial designs and underrepresentation of real-world populations limit generalizability.

No new IRRs nor toxic deaths were reported. ENCO-PANI appears to be as safe and effective in pts treated for a BRAFm mCRC unable to continue CET and may represent a valid alternative therapeutic option in this setting.

P2, N=52, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027