Braftovi (encorafenib) / Ono Pharma, Pierre Fabre, Pfizer, Medison, Nerviano Medical Sciences - LARVOL DELTA

Phase 2 trial of encorafenib plus binimetinib for patients with BRAF V600 mutated relapsed/refractory hairy cell leukemia (ASH 2025) - "Background : Hairy cell leukemia (HCL) is an indolent B-cell leukemia characterized by durable completeremissions to purine analogs cladribine or pentostatin, but repeated relapses and cumulative toxicity torepeated purine analog courses...Vemurafenib was combined with rituximab,achieving 57% MRD-free CRs... Encorafenib-binimetinib is highly effective in relapsed/refractory HCL and was well toleratedwhen dose reductions occurred as needed. Compared to dabrafenib-trametinib, the lower incidence offever (11% vs 58%, p<0.0001) is a major advantage. The CR rate of 93% without rituximab isunprecedented for BRAF inhibition in HCL."

Clinical • P2 data • Hairy Cell Leukemia • Hematological Malignancies • Leukemia • Melanoma • Musculoskeletal Pain • Pancreatitis • Retinal Disorders • Solid Tumor • BRAF

First-line (1L) encorafenib + cetuximab + mFOLFOX6 in East Asian patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC): Results from the phase III BREAKWATER study (ESMO Asia 2025) - P3 | "Background: The randomized phase 3 BREAKWATER study (NCT04607421) demonstrated statistically significant and clinically meaningful improvements in ORR by blinded independent central review (BICR), PFS by BICR, and OS with encorafenib + cetuximab (EC) + mFOLFOX6 vs control (chemotherapy ± bevacizumab) in 1L BRAF V600E-mutant mCRC (Kopetz, Nat Med 2025; Elez, N Engl J Med 2025)... Consistent with the global study results, East Asian pts with untreated BRAF V600E-mutant mCRC attained clinically significantly improved ORR, PFS, and OS with EC+mFOLFOX6 vs control therapy. The treatment safety profiles in East Asian pts were consistent with those observed in the overall population and as expected for each agent."

Clinical • Metastases • P3 data • Colorectal Cancer • Oncology • Solid Tumor • BRAF

Eruptive Verrucous Keratoses and Melanocytic Nevi Induced by Encorafenib Plus Cetuximab in a Patient With Metastatic Colorectal Cancer. (PubMed, Actas Dermosifiliogr) - No abstract available

Journal • Colorectal Cancer • Oncology • Solid Tumor

BREAKWATER: Primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). (ASCO-GI 2026) - P3 | "Funded by Pfizer Clinical Trial Registration Number: NCT04607421 The full, final text of this abstract will be available on Jan 05 at 05:00 PM EST."

Clinical • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

Efficacy of Small Molecule Kinase Inhibitors in Histiocytic Neoplasms with Non-BRAFV600E Mutations: Concordance of Pre-Clinical Predictions to Clinical Responses (ASH 2024) - "Preclinical studies suggest class I, but not classes II-III, BRAF mutations are sensitive to RAF monomer inhibitors (dabrafenib, encorafenib, vemurafenib) while classes I-II, but not class III, BRAF mutations are sensitive to MEK inhibitors (Yaeger R, Cancer Discovery 2019). In contrast, RAF-regulated MAP2K1 mutants have variable sensitivities to allosteric MEK inhibitors (binimetinib, cobimetinib, selumetinib, trametinib) while RAF-dependent and RAF-independent MAP2K1 mutations are resistant...Among those with BRAF class II mutations, 2 received vemurafenib and had NR, while 9 received MEK inhibitors (binimetinib, cobimetinib, trametinib) and most responded (3 CRs, 5 PRs)...There was concordance of efficacy in the setting of BRAF classes I-III and MAP2K1 RAF-regulated mutations. However, we found discordant findings in patients harboring RAF-dependent and RAF-independent MAP2K1 mutations as well as KRAS mutations as most responded to allosteric MEK inhibitors."

Discordant • Preclinical • Langerhans Cell Histiocytosis • Rare Diseases • BRAF • KRAS • MAP2K1 • NRAS

The safety and efficacy of encorafenib plus binimetinib for brain metastases: a systematic review and meta-analysis. (PubMed, Discov Oncol) - No abstract available

Journal • Retrospective data • Review • Oncology • Solid Tumor

Experts Unpack the Most Notable NCCN Guideline Changes Heading Into 2026 (OncLive) - "'[During 2025], adjuvant therapy regimens from the [phase 3] ATOMIC trial [NCT02912559]—FOLFOX or CAPEOX in combination with atezolizumab—were added in stage III dMMR/MSI-H colon cancer. This change represents the addition of checkpoint inhibitor therapies at earlier points of the patient journey.' Al B. Benson, III, MD...said in a statement to OncLive."

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CA209-73R: Encorafenib and Binimetinib With or Without Nivolumab in Treating Patients With Metastatic Radioiodine Refractory BRAF V600 Mutant Thyroid Cancer (clinicaltrials.gov) - P2 | N=24 | Active, not recruiting | Sponsor: Providence Health & Services | Trial completion date: Oct 2027 ➔ Jan 2027 | Trial primary completion date: Oct 2025 ➔ Jan 2026

Trial completion date • Trial primary completion date • Oncology • Solid Tumor • Thyroid Gland Carcinoma • BRAF

Mosperafenib, a novel paradox breaker BRAF inhibitor with potent preclinical activity in BRAF mutated colorectal cancer. (PubMed, Mol Cancer Ther) - "The therapeutic benefit of the combination of the first generation BRAFi encorafenib and the EGFR blocking antibody cetuximab in second line metastatic colorectal cancers (CRC) harboring BRAF V600E mutations remains limited and short lived...Additional combination studies of mosperafenib with FOLFOX resulted in tumor regression and superior activity compared to the same combination with encorafenib. Collectively these data provide a strong preclinical rationale for the potentially transformative activity of mosperafenib as monotherapy and as a preferred backbone BRAFi for combinatorial regimen for BRAF mutated CRC."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor

BRAF V600E-MUTATED GASTROINTESTINAL STROMAL TUMORS: A CASE SERIES AND ANALYSIS OF IMMUNE TUMOR INFILTRATE (CTOS 2025) - "Patient A received vemurafenib for 21 months achieving an initial response, followed by gradual progression. He subsequently received dabrafenib/trametinib for 8 months with stable disease initially followed by slow progression. Ipilimumab/nivolumab was initiated and achieved a durable complete response, remaining disease-free for 6.5 years off therapy. Patient B received binimetinib/encorafenib for 26 months showing an initial mixed response with regression of the primary tumor but progression of hepatic metastases... BRAF mutant GISTs are rare with variable responses to BRAF/MEK inhibition. A durable complete response to ICI was observed in one patient. Preliminary immune profiling supports further investigation of immunotherapy in selected cases with immune-infiltrated microenvironments."

Clinical • IO biomarker • Stroma • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Hepatocellular Cancer • Oncology • Sarcoma • BRAF • CD20 • CD8 • EP300 • FLT4 • JAK3 • LAG3 • NF1 • PD-1 • PD-L1 • RB1 • TSC2

Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer (clinicaltrials.gov) - P1/2 | N=38 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2025 ➔ Dec 2027 | Trial primary completion date: Dec 2025 ➔ Dec 2027

Trial completion date • Trial primary completion date • Colon Adenocarcinoma • Colon Cancer • Colorectal Adenocarcinoma • Colorectal Cancer • Oncology • Rectal Adenocarcinoma • Solid Tumor • BRAF

Intracranial antitumor efficacy of combination treatment with encorafenib plus binimetinib in BRAF V600E-mutated anaplastic thyroid carcinoma. (PubMed, Auris Nasus Larynx) - "The patient was initially diagnosed with T4bN1bM1 and experienced disease progression following surgery and lenvatinib treatment. This possibility is supported by reliable evidence for the use of BRAF plus MEK inhibitor for brain metastasis from BRAF-mutated malignant melanoma. We conclude that encorafenib plus binimetinib treatment for brain metastasis from BRAF-mutated thyroid cancer is a safe and effective treatment choice."

Journal • Infectious Disease • Melanoma • Novel Coronavirus Disease • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • BRAF

Turning the Tables: How Encorafenib and Binimetinib are Reshaping NSCLC Treatment. (PubMed, Cancer Invest) - No abstract available

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

ENCEFALO (GEM2301) clinical trial: Encorafenib and binimetinib followed by cemiplimab and fianlimab in BRAF-mutant melanoma and symptomatic brain metastases (ESMO-IO 2025) - P2 | "If among the first 18 pts, ≥4 had icPD at 6m or sooner, the study will stop. Accrual started in May 2025 and five patients were included by Sep 2025.Clinical trial identification EudraCT: 2024-513375-40-00; NCT06887088.Legal entity responsible for the study Grupo Español Multidisciplinar de Melanoma (GEM)."

Clinical • IO biomarker • Melanoma • Oncology • Solid Tumor • BRAF

Trends of adverse event reports associated with BRAF and MEK inhibitors and combinations: a retrospective disproportionality analysis using the FDA adverse event reporting system database from 2012 to 2021. (PubMed, Melanoma Res) - "Study drugs included BRAF/MEK inhibitors (dabrafenib, trametinib, vemurafenib, cobimetinib, encorafenib, and binimetinib). AE reports associated with melanoma therapies are sizable and significant. Healthcare professionals should be aware of the AE profiles attributable to the melanoma treatment and management."

Adverse events • Journal • Retrospective data • Fatigue • Melanoma • Musculoskeletal Pain • Oncology • Solid Tumor

Rapid response to encorafenib and binimetinib (Enc/Bini) in a patient with recurrent ganglioglioma with leptomeningeal spread (SNO 2025) - "Initial treatment included surgical resection, followed by concurrent radiation and temozolomide (TMZ). She initiated anti-BRAFV600E therapy with dabrafenib and trametinib but was intolerant due to intractable flu-like symptoms including fever, rash and fatigue...Ocular and generalized seizures resolved with targeted treatment and transition to lacosamide...Prior studies in patients with primary CNS tumors and brain metastases have demonstrated encouraging responses and overall tolerability with this regimen. To our knowledge, this represents the first documented case of a rapid and durable (four months to date) clinical and radiographic response to systemic BRAF-targeted therapy in a patient with recurrent-AGG and leptomeningeal spread."

Clinical • Brain Cancer • CNS Disorders • CNS Tumor • Epilepsy • Ganglioglioma • Glioma • Mood Disorders • Ophthalmology • Otorhinolaryngology • Solid Tumor • APC • CDKN2A • CDKN2B

A phase II clinical trial of regorafenib (REGO) combined with BRAF-/MEK-inhibitors in advanced pretreated BRAFV600-mutant (mut) melanoma (RegoMel) (ESMO 2025) - P2 | "REGO was added to encorafenib/binimetinib (E/B) and dabrafenib/trametinib (D/T) in 10 and 8 pts respectively. Conclusions This phase 2 trial of REGO + BRAF/MEKi in BRAF V600 mut melanoma pts progressing on BRAF/MEKi failed to meet its predefined primary efficacy endpoint but demonstrated activity (incl. in the brain) in a subset of patients, with manageable toxicity."

Clinical • Metastases • P2 data • Melanoma • Oncology • Solid Tumor

Rapid response to encorafenib and binimetinib (Enc/Bini) in a patient with recurrent ganglioglioma with leptomeningeal spread (WFNOS 2025) - "Initial treatment included surgical resection, followed by concurrent radiation and temozolomide (TMZ). She initiated anti-BRAFV600E therapy with dabrafenib and trametinib but was intolerant due to intractable flu-like symptoms including fever, rash and fatigue...Ocular and generalized seizures resolved with targeted treatment and transition to lacosamide...Prior studies in patients with primary CNS tumors and brain metastases have demonstrated encouraging responses and overall tolerability with this regimen. To our knowledge, this represents the first documented case of a rapid and durable (four months to date) clinical and radiographic response to systemic BRAF-targeted therapy in a patient with recurrent-AGG and leptomeningeal spread."

Clinical • Brain Cancer • CNS Disorders • Epilepsy • Ganglioglioma • Glioma • Mood Disorders • Oncology • Ophthalmology • Otorhinolaryngology • Psychiatry • Solid Tumor • APC • CDKN2A • CDKN2B

Development and validation of a quick and sensitive UPLC-MS/MS method for measuring ensartinib in HLMs: investigation of structural alerts associated with metabolic lability and in silico toxicity. (PubMed, Analyst) - "EST and Encorafenib (ECB as the internal standard) were differentiated using an isocratic mobile phase system on a reversed stationary phase (Eclipse Plus C18) column. In silico data proposed that minor structural modifications to the dichlorophenyl moiety or the piperazine ring during drug design may enhance the safety profile and metabolic stability relative to the properties of EST. Evaluating the EST metabolic stability and in silico ADME characteristics is essential for advancing innovative therapeutic research focused on improving metabolic stability."

Journal • Leukemia • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • ALK • AXL • MET • ROS1

Defining the Prognostic Significance of BRAF V600E in Early-Stage Colon Cancer: A Systematic Review and Meta-Analysis. (PubMed, Curr Oncol) - "BRAF V600E is associated with inferior prognoses compared to BRAF WT in early-stage CC. This finding will help optimize trial design for this population."

Clinical • Journal • Retrospective data • Review • Colon Cancer • Colorectal Cancer • Microsatellite Instability • Oncology • Solid Tumor • BRAF • MSI

Myasthenia gravis induced by encorafenib and binimetinib for metastatic melanoma. (PubMed, Ann Dermatol Venereol) - No abstract available

Journal • CNS Disorders • Melanoma • Myasthenia Gravis • Oncology • Solid Tumor

Developing and validating a sensitive and fast UPLC-MS/MS method for estimating the in vitro metabolic stability of crenolanib in HLMs: identification of structural alarms related to the in silico toxicity and metabolic lability. (PubMed, Anal Methods) - "CLB and encorafenib (EFB as the internal standard, IS) were separated utilizing an isocratic mobile phase method on a reversed-phase (SB-C18) column. The intrinsic clearance of CLB was computed to be 26.79 mL min-1 kg-1, while the in vitro half-life was estimated to be 30.27 min. In silico analysis indicated that slight structural changes to the piperidin-4-amine moiety (99%) during drug design may increase the metabolic stability and improve the safety compared to the case with CLB."

Journal • Preclinical

Using Structure-Based Modeling to Identify Effective Drug Combinations in RAS-Mutant Acute Myeloid Leukemia (ASH 2024) - "Mice were then treated with vehicle, lifirafenib (LIF; 10 mg/kg, p.o.), encorafenib (ENCO; 20 mg/kg, p.o.), SB590885 (SB; 25 mg/kg, IP), or either drug combination (LIF + ENCO or LIF + SB). Conclusions We used a structural biology and in silico computational modelling approach to identify novel, non-obvious kinase inhibitor combinations. Computational approaches were notably validated by the high efficacy of well-tolerated treatments in a pre-clinical mouse model, suggesting potential translatability for treating RAS-mutant AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Solid Tumor • AFDN • KMT2A • KRAS • NRAS • PTPRC • RAS

BREAKWATER Phase III: results for encorafenib and cetuximab plus mFOLFOX6 in first-line BRAF V600E-mutant metastatic colorectal cancer. (PubMed, Future Oncol) - P3 | "The BREAKWATER Phase III study investigated encorafenib and cetuximab plus mFOLFOX6 versus chemotherapy with or without bevacizumab for the treatment of patients with previously untreated BRAF V600E - mutant metastatic colorectal cancer...This paradigm shift in metastatic colorectal cancer highlights the importance for early genomic testing to identify patients who would benefit from this new treatment option. We discuss the results from BREAKWATER - including progression-free survival by blinded independent central review, overall survival, objective response rate by blinded independent central review in all participants, and safety - and the meaning of these results for clinical practice as a new treatment option and the need for earlier genomic testing.Clinical Trial Registration: www.clinicaltrials.gov identifier is NCT04607421."

Journal • P3 data • Colorectal Cancer • Oncology • Solid Tumor • BRAF

Noninvasive Therapeutic Monitoring of Circulating Tumor DNA in BRAF-Mutant Metastatic Colon Cancer Using Droplet Digital PCR, Next-Generation Sequencing, and Fragmentomics. (PubMed, Case Rep Oncol Med) - "A 40-year-old man diagnosed with metastatic BRAFV600E mutant sigmoid adenocarcinoma received multiple lines of treatment, including first-line chemotherapy + bevacizumab and targeted therapy of cetuximab, encorafenib ± binimetinib. This case demonstrates the potential application of ctDNA and fragmentomics biomarkers, molecular analyses, and drug testing in noninvasive therapeutic monitoring of BRAFV600E mutant mCRC. These illustrate the potential application of such noninvasive therapeutic monitoring in larger scale cohorts of patients."

Biomarker • Circulating tumor DNA • Journal • Next-generation sequencing • Colon Cancer • Colorectal Cancer • Oncology • Solid Tumor • BRAF