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

Phase 1/2 trial of encorafenib, cetuximab, and nivolumab in microsatellite stable BRAFV600E metastatic colorectal cancer. (PubMed, Cancer Cell) - P1/2 | "On serial evRNA profiling, decreased MAPK signature and increased interferon gamma response signature associate with sustained treatment benefit. MSS BRAFV600E mCRC with baseline MAPK activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation."

Journal • P1/2 data • Colorectal Cancer • Oncology • Solid Tumor • IFNG

Updated overall survival analysis from the phase II PHAROS study of encorafenib plus binimetinib in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC) (ESMO 2025) - P2 | "Conclusions In this analysis after a median of approximately 4 years of follow-up, enco+bini showed prolonged mOS of approximately 4 years in treatment-naïve pts, which is the longest mOS reported to date with targeted therapies in this patient population from pivotal trials. Long-term safety was consistent with prior analyses, with no new safety signals observed."

Clinical • Metastases • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF

Real-world outcomes of encorafenib, cetuximab ± binimetinib for BRAF‑mutated metastatic colorectal cancer: The BEETS (JACCRO CC‑18) study. (PubMed, Oncologist) - P=N/A | "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."

Journal • Real-world evidence • Colorectal Cancer • Oncology • Solid Tumor • BRAF • CRP

Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. (PubMed, N Engl J Med) - P3 | "This trial showed significantly longer progression-free survival and overall survival with first-line treatment with EC+mFOLFOX6 than with standard care among patients with BRAF V600E-mutated metastatic colorectal cancer. (Funded by Pfizer and others; BREAKWATER ClinicalTrials.gov number, NCT04607421.)."

Journal • Colorectal Cancer • Oncology • 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

A Randomized Trial of Encorafenib and Cetuximab Versus Irinotecan/Cetuximab or FOLFIRI/Cetuximab in Chinese Patients With BRAFV600E Mutant Metastatic Colorectal Cancer: The NAUTICAL Study. (PubMed, Cancer Med) - P2 | "This NAUTICAL CRC Phase II study showed that the combination of encorafenib and cetuximab offers significant clinical benefits, improving PFS and OS, while providing manageable safety and important QoL advantages, making it a valuable treatment option for Chinese patients with previously treated BRAFV600E mutant mCRC."

Clinical • Journal • Colorectal Cancer • Oncology • Solid Tumor

Population pharmacokinetics of encorafenib and binimetinib in real-world patients with BRAFV600E/K-mutant metastatic melanoma. (PubMed, Cancer Chemother Pharmacol) - No abstract available

Journal • PK/PD data • Real-world evidence • Melanoma • Oncology • Solid Tumor

Subsequent therapies in the phase III BREAKWATER study of first-line encorafenib + cetuximab + mFOLFOX6 in patients with BRAF V600E-mutant metastatic colorectal cancer (ESMO 2025) - P3 | "Background BREAKWATER (NCT04607421) is an ongoing, open-label, global, randomized, phase III study evaluating first-line (1L) encorafenib + cetuximab (EC) ± mFOLFOX6 vs chemotherapy ± bevacizumab (control) in BRAF V600E-mutant metastatic colorectal cancer (mCRC)...Table: 751P Patients, n (%) EC n=158 EC+mFOLFOX6 n=236 Control n=243 Discontinued study treatment 146 (92.4) 169 (71.6) 227 (93.4) Any subsequent systemic anticancer treatment 107 (67.7) 108 (45.8) 139 (57.2) BRAF inhibitor ± combination 21 (13.3) 19 (8.1) 100 (41.2) EC ± combination 14 (8.9) 15 (6.4) 77 (31.7) EC 4 (2.5) 9 (3.8) 62 (25.5) EP ± combination 0 1 (0.4) 4 (1.6) EP 0 0 4 (1.6) First subsequent BRAF inhibitor ± combination 2L 8 (5.1) 10 (4.2) 83 (34.2) 3L 8 (5.1) 8 (3.4) 14 (5.8) 4L 4 (2.5) 0 2 (0.8) 5L 1 (0.6) 1 (0.4) 1 (0.4) BRAF inhibitor ± combination in >1 subsequent line 3 (1.9) 3 (1.3) 6 (2.5) EP, encorafenib + panitumumab...Of these, most received..."

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

BREAKWATER: Primary analysis of first-line (1L) encorafenib + cetuximab (EC) + FOLFIRI in BRAF V600E-mutant metastatic colorectal cancer (mCRC). (ASCO-GI 2026) - P3 | "Background: Leucovorin/5-FU in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are common chemotherapies used in 1L mCRC. In patients (pts) with BRAF V600E-mutant mCRC, the Phase 3 portion of BREAKWATER (NCT04607421) demonstrated clinically meaningful and statistically significantly improved ORR by blinded independent central review (BICR), PFS by BICR, and OS with 1L EC + mFOLFOX6 vs chemotherapy ± bevacizumab (bev) (Kopetz Nat Med 2025; Elez N Engl J Med 2025)... BREAKWATER Cohort 3 demonstrated a clinically meaningful and statistically significant improved response rate that was rapid and durable with EC+FOLFIRI vs control in 1L BRAF V600E-mutant mCRC, with manageable toxicities and no new safety signals. These data support EC+FOLFIRI as a potential new standard of care in BRAF V600E-mutant mCRC. aBy BICR."

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

Proteomic analysis of BRAF-V600E mutant metastatic colorectal cancer FFPE tissues reveals potential involvement of WEE1 expression in therapeutic resistance (AACR 2026) - "Although targeted therapies such as encorafenib plus cetuximab with or without binimetinib (BEACON regimen) have been developed for this subtype, clinical outcomes remain poor, and overcoming therapeutic resistance represents a critical unmet need. Our proteomic analysis identified WEE1 expression as a potential biomarker associated with poor clinical outcomes in patients with BRAF-V600E mutant mCRC treated with the BEACON regimen. These findings suggest a context-dependent resistance mechanism as a promising therapeutic target warranting further investigation in preclinical and clinical settings."

Metastases • Omic analysis • Colorectal Cancer • Oncology • Solid Tumor • BRAF • WEE1

Novel Bcl-2/Bcl-xL inhibitor, LP-118, enhances apoptosis induction by the CDK2/9 inhibitor, fadraciclib, in BRAF(V600E) human colorectal cancer cells (AACR 2026) - "LP-118 synergistically enhanced the antitumor activity of fadraciclib plus encorafenib in BRAFV600E human CRC cells, and to a greater extent than did venetoclax. Mechanistically, targeting Bcl-2/Bcl-xL concurrent with inhibition of MCL-1 and CDK2/9 by fadraciclib potently induced apoptosis and suppressed tumor cell growth. These findings suggest a novel and effective therapeutic strategy for BRAFV600E human CRCs."

IO biomarker • Colorectal Cancer • Oncology • Solid Tumor • ANXA5 • BCL2 • BCL2L1 • BRAF • CASP3

Circulating tumour (ct) DNA analysis of BRAF V600E dynamics and changes in genomic landscape in patients (pts) with first-line (1L) BRAF V600E-mutant metastatic colorectal cancer (mCRC) treated in BREAKWATER (ESMO 2025) - P3 | "Background The randomized phase III BREAKWATER study (NCT04607421) demonstrated statistically significant and clinically meaningful improvements in ORR with encorafenib + cetuximab (EC) + mFOLFOX6 vs chemotherapy ± bevacizumab (control) in 1L BRAF V600E-mutant mCRC (Kopetz et al 2025)...Table: 729MO BRAF V600E VAF-high at BL BRAF V600E VAF-low at BL EC (n=61) EC + mFOLFOX6 (n=95) Control (n=91) EC (n=62) EC + mFOLFOX6 (n=96) Control (n=89) ORR, % (95% CI) 49 (36, 62) 75 (65, 83) 42 (32, 53) 40 (28, 54) 63 (52, 72) 40 (30, 51) OS HR (95% CI) 0.76 (0.52, 1.13) 0.50 (0.35, 0.73) – 0.66 (0.41, 1.06) 0.39 (0.24, 0.64) – ORR, objective response rate; OS, overall survival. Conclusions Clinical benefit across BRAF V600E subgroups and differential patterns of acquired resistance mutations support EC+mFOLFOX6 as a SOC for pts with BRAF V600E-mutant mCRC."

Clinical • Metastases • Colorectal Cancer • Oncology • Solid Tumor • BRAF • KRAS • MAP2K1 • NRAS

Triple-targeted therapy with encorafenib, binimetinib and osimertinib in BRAF- and EGFR-co-mutated non-small cell lung cancer: A single-center experience (ELCC 2026) - "While case series reported activity with dabrafenib, trametinib, and osimertinib, there are no published data on the combination of encorafenib, binimetinib, and osimertinib (E+B+O) in this population. E+B+O may be considered in select patients following informed discussion, with close response assessment and monitoring for GI toxicity. Larger prospective studies are needed to validate these findings and optimize patient selection."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • EGFR

Phase 1 dose escalation results of the WEE1 inhibitor, azenosertib (A), in combination with encorafenib (E) and cetuximab (C) in patients (pts) with previously treated BRAF V600E mutant metastatic colorectal cancer (mCRC). (ASCO 2025) - P1 | "The combination of A+E+C was well tolerated at the MTD and yielded response rates in BRAFi-naïve mCRC pts which exceeded the historical data from the E+C doublet."

Clinical • Combination therapy • Metastases • P1 data • Atrial Fibrillation • Cardiovascular • Colorectal Cancer • Fatigue • Neutropenia • Oncology • Solid Tumor • BRAF • CYP2C19 • CYP3A4

STARBOARD: A Clinical Trial of Three Study Medicines (Encorafenib, Binimetinib, and Pembrolizumab) in Patients With Advanced or Metastatic Melanoma (clinicaltrials.gov) - P3 | N=257 | Active, not recruiting | Sponsor: Pfizer | Trial completion date: Mar 2026 ➔ Aug 2026

Trial completion date • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

PORTSIDE: A Study Comparing 3 Study Medicines (Encorafenib, Binimetinib, Pembrolizumab) to 2 Study Medicines (Ipilimumab and Nivolumab) in Patients With Advanced Melanoma (clinicaltrials.gov) - P2 | N=38 | Terminated | Sponsor: Pfizer | Active, not recruiting ➔ Terminated; Study terminated due to inability to recruit the target number of patients. There were no safety and/or efficacy concerns involved in the decision to stop enrollment.

IO biomarker • Trial termination • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

A randomized phase 2 trial of encorafenib + binimetinib + nivolumab vs ipilimumab + nivolumab in BRAFV600-mutant melanoma brain metastases: SWOG S2000 (NCT04511013). (ASCO 2025) - P2 | "Steroids up to 8 mg of dexamethasone/day (or equivalent), leptomeningeal spread, and prior local therapy (radiation or surgery) for MBM were permitted, if there was at least one measurable, progressing MBM ≥ 0.5 cm. S2000 is the first randomized trial in patients with symptomatic melanoma brain metastases. A first-line triplet regimen of enco/bini/nivo demonstrated a statistically significant improvement in PFS as compared to ipi/nivo, with a HR of 0.51. Both regimens also had toxicity rates consistent with their known profiles."

Clinical • IO biomarker • Late-breaking abstract • P2 data • Melanoma • Oncology • Solid Tumor

BREAKWATER phase 3: Post hoc subgroup analyses by age in patients (pts) with BRAF V600E-mutant metastatic colorectal cancer (mCRC). (ASCO-GI 2026) - P3 | "BREAKWATER (Phase 3; NCT04607421) demonstrated statistically significant and clinically meaningful improvements in ORR, PFS by blinded independent central review (BICR), and OS with encorafenib + cetuximab (EC)+mFOLFOX6 vs control (chemotherapy±bevacizumab) in 1L BRAF V600E-mutant mCRC, making EC+mFOLFOX6 a new standard of care... All pts with BRAF V600E-mutant mCRC receiving 1L EC+mFOLFOX6, including EOCRC pts, showed improved ORR, PFS, and OS vs control. The safety profile of EC+mFOLFOX6 was similar for both age groups. NE, not estimable."

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

CAF-secreted periostin promotes tumor aggressiveness in BRAF-mutant papillary thyroid carcinoma by upregulating MMP1 (AACR 2026) - "Animal experiments further confirmed that the combination of a BRAF inhibitor (encorafenib) with knockdown of POSTN in CAFs most effectively suppressed lung metastasis of PTC and prolonged mouse survival. This study uncovers a novel signaling axi—BRAF mutation/IL-1β/CAFs/POSTN/MMP1—that plays a critical role in enhancing the aggressiveness of PTC. Thus, a combined therapeutic strategy targeting BRAF and inhibiting CAF-secreted POSTN represents a promising strategy to improve the prognosis of aggressive BRAF-mutant PTC."

Oncology • Solid Tumor • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • BRAF • CAFs • IL1B • MMP1 • POSTN

Cotargeting B-Raf and ACLY in Ras mutant cells leads to synergistic loss of cell viability and apoptosis (AACR 2026) - "B-Raf inhibitors Vemurafenib, Dabrafenib and Encorafenib are used clinically in combination with MEK inhibitors Trametinib, Cobimetinib and Binimetinib. All four Ras mutant cell lines showed increased expression of cleaved PARP and the activation of the ER stress pathway regulator ATF4. Finally, the apoptosis stimulated by the combination was shown to be dependent on Caspase-3 activity using Annexin V analysis of HCT116 cells treated with Vemurafenib plus NDI-091143."

Breast Cancer • Colon Cancer • Colorectal Cancer • Melanoma • Oncology • Pancreatic Cancer • Solid Tumor • ACLY • ANXA5 • ATF4 • BRAF • CASP3 • RAS

Investigating the combined inhibition of RAF, MEK, and FAK in melanoma molecular subtypes (AACR 2026) - P1/2 | "These findings support an ongoing clinical trial evaluating the efficacy of avutometinib and the FAK inhibitor defactinib, with or without encorafenib, in patients with brain metastases from cutaneous melanoma (DETERMINE; NCT06194929). Additionally, in melanoma models harboring RAS mutations or NF1 loss, the combination of VS-4718 and avutometinib significantly reduced melanoma cell growth and viability in vitro, delayed tumor progression in autochthonous mouse models, and inhibited tumor growth in patient-derived xenografts driven by these alterations. Lastly, we are investigating the non-canonical roles of FAK in modulating the tumor microenvironment to determine whether this treatment strategy alters immune cell composition, chemokine and cytokine production, and enhances the efficacy of immune checkpoint inhibition."

IO biomarker • Brain Cancer • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • NF1 • NRAS

Off-target activation of GCN2 by BRAFV600inhibitors attenuates melanoma outgrowth (AACR 2026) - "Herein, we define an off-target effect in which several clinical BRAFV600 inhibitors, including the widely used dabrafenib and encorafenib, interact directly with GCN2 to activate the Integrated Stress Response and ATF4...This result is mirrored in PC9 lung cancer cells treated with erlotinib, an EGFR inhibitor, that shares the same off-target activation of GCN2...We further describe the activation of GCN2 signaling in melanoma patient-derived xenograft models treated with dabrafenib and trametinib, and observe a significant decrease in disease-free survival in a cohort of human melanoma patients with altered GCN2 pathway components. Finally, we describe the benefits of combining the next-generation "paradox breaker" RAF inhibitor naporafenib with a GCN2 activator, HC-7366, in A375 melanoma cells. Thus, GCN2 is emerging as a promising cotreatment candidate in melanoma and potentially beyond."

Lung Cancer • Melanoma • Oncology • Solid Tumor • ATF4

PRAC adopted an extension of indication for BRAFTOVI (encorafenib) in combination with cetuximab and FOLFOX for first-line treatment of adults with metastatic colorectal cancer harbouring a BRAF V600E mutation, based on interim Phase III BREAKWATER (C4221015) results. SmPC sections 4.1, 4.2, 4.4, 4.8, 5.1 and 5.2 and the Package Leaflet were updated accordingly, and RMP version 3.1 was submitted. (European Medicines Agency) - Pharmacovigilance Risk Assessment Committee (PRAC) Minutes of meeting on 12 – 15 Jan 2026: [AI generated summary]

PRAC • Colorectal Cancer • Gastrointestinal Cancer • Oncology

Severe Ileocolitis Associated with Encorafenib/Binimetinib Therapy (USCAP 2026) - "Multifocal ileal and colonic ulcerations with active ileitis/colitis pattern of injury can occur in patients treated with encorafenib/binimetinib. Although most patients had prior ICI treatment, crypt apoptosis and chronic injury were rare, suggesting the findings are specific to this therapy. Despite a low incidence, severe ileocolitis can lead to significant clinical consequences, highlighting the need for recognizing these histopathologic features for timely intervention and management."

IO biomarker • Crohn's disease • Cytomegalovirus Infection • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammatory Bowel Disease • Melanoma • Solid Tumor • BRAF

BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. (ASCO-GI 2025) - P3 | "BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating 1L EC with or without chemo vs standard of care (SOC; chemo with or without bevacizumab). Reported here are the primary analysis of objective response rate by blinded independent central review (ORR by BICR; dual primary endpoint [EP]), the first interim analysis of overall survival (OS; key secondary EP), other secondary EPs, and safety for the EC+FOLFOX (oxaliplatin, leucovorin, and 5-FU) vs SOC arms... BREAKWATER demonstrated a substantially improved response rate that was rapid and durable with EC+FOLFOX in BRAF V600E-mutant mCRC with manageable toxicities and no new safety signals. aOne-sided α=0.001.NE, not estimable."

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