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

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

Primary analysis of the EORTC-2139-MG/Columbus-AD trial: A randomized trial of adjuvant encorafenib and binimetinib versus placebo in high-risk stage II melanoma with a BRAF-V600E/K mutation. (ASCO 2025) - P3 | "EORTC 2139 - Columbus-AD demonstrated a consistent safety profile for enco+bini. Descriptive analyses of efficacy show encouraging results of the combination of enco+bini for adjuvant treatment of stage IIB/C BRAF V600E/K cutaneous melanoma."

Clinical • IO biomarker • Late-breaking abstract • Cutaneous Melanoma • Melanoma • Oncology • Solid Tumor • BRAF

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

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

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

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

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

Adaptive BRAF-MEK Inhibitor Therapy for Advanced BRAF Mutant Melanoma (clinicaltrials.gov) - P1 | N=14 | Active, not recruiting | Sponsor: H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Dec 2028 ➔ Dec 2026

Trial completion date • Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor

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) - No abstract available

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

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

First-line encorafenib + cetuximab + mFOLFOX6 in BRAF V600E-mutant metastatic colorectal cancer (BREAKWATER): Progression-free survival and updated overall survival analyses. (ASCO 2025) - P3 | "Funded by Pfizer Clinical Trial Registration Number: NCT04607421 Background: BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating first-line (1L) encorafenib + cetuximab (EC) ± chemotherapy (chemo) vs standard of care (SOC; chemo ± bevacizumab) in BRAF V600E-mutant metastatic colorectal cancer (mCRC)... BREAKWATER demonstrated clinically meaningful and statistically significant PFS and OS improvements with EC+mFOLFOX6 vs SOC and manageable toxicities. EC+mFOLFOX6 is potentially practice changing as the new SOC. a1-sided stratified log rank test."

Clinical • Late-breaking abstract • Metastases • 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

Updated results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with EC-naïve metastatic BRAF V600E colorectal cancer (CRC) in the phase 1b/2 HERKULES-3 study. (ASCO 2024) - P1/2 | "ERAS-007 100 mg BID-QW in combination with EC was safe and well tolerated with preliminary evidence of promising clinical activity. These results support continued evaluation of this combination in EC naïve pts with BRAF V600E CRC."

Clinical • Metastases • P1/2 data • Anemia • Colorectal Cancer • Constipation • Dermatitis • Dermatology • Fatigue • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Hematological Disorders • Immunology • Oncology • Pain • Respiratory Diseases • Solid Tumor • BRAF

SEAMARK: Randomized phase 2 study of pembrolizumab + encorafenib + cetuximab versus pembrolizumab alone for first-line treatment of BRAF V600E-mutant and microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC). (ASCO 2022) - P2 | "Secondary endpoints include safety and tolerability, overall survival, objective response rate, duration of response, and quality of life. Enrollment will begin in April 2022."

Clinical • IO biomarker • Mismatch repair • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Immune Modulation • Inflammation • Oncology • Solid Tumor • BRAF • MSI

Dr. @skopetz of @MDAndersonNews discusses unexpected response patterns with encorafenib, cetuximab, and chemotherapy in #BRAF-mutant #ColorectalCancer, plus other key updates from the pivotal #BREAKWATER trial: https://buff.ly/kCDCsmc

Clinical

BREAKWATER safety lead-in (SLI): Encorafenib (E) + cetuximab (C) + chemotherapy for BRAFV600E metastatic colorectal cancer (mCRC). (ASCO-GI 2023) - P2, P3 | "In the phase 2 ANCHOR study (NCT03693170), mPFS was 5.8 mo and ORR was 48% for 1L EC + binimetinib in BRAFV600E mCRC...Pts received E 300 mg daily + C 500 mg/m2 every 2 weeks (Q2W) + either mFOLFOX6 Q2W (n=27) or FOLFIRI Q2W (n=30) in 28-day cycles until disease progression or unacceptable toxicity...Expected conclusions will be included in the final abstract. Clinical trial information: NCT04607421."

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

Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. (PubMed, Nat Med) - P3 | "BREAKWATER demonstrated a significantly improved response rate that was durable for first-line EC+mFOLFOX6 versus SOC in patients with BRAF V600E mCRC. ClinicalTrials.gov identifier: NCT04607421 ."

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

Remission of metastatic duodenal cancer after treatment with BRAF inhibitor (PubMed, Ugeskr Laeger) - "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."

Journal • Colorectal Cancer • Oncology • Small Intestinal Carcinoma • Solid Tumor • BRAF

Encorafenib + cetuximab (EC) + FOLFIRI for BRAF V600E-mutant metastatic colorectal cancer (mCRC): Updated results from the BREAKWATER safety lead-in (SLI) (ESMO 2024) - P3 | "Pts received E 300 mg once a day + C 500 mg/m2 intravenously (IV) every 2 weeks (Q2W) + FOLFIRI/mFOLFOX6 IV Q2W in 28-day cycles... EC + FOLFIRI was generally tolerable, with no new safety signals identified. The antitumor activity reported is encouraging. These results support the continued evaluation of EC + chemo in cohort 3."

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

Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable (MSS), BRAFV600E metastatic colorectal cancer. (ASCO 2022) - P1/2 | "E + C + N appears to be effective and well-tolerated for pts with MSS, BRAFV600E metastatic CRC. Ex vivo analysis of pretreatment tissue predicted eventual clinical response in matched patients. A follow-up randomized phase II trial (SWOG 2107) to evaluate encorafenib/cetuximab with or without nivolumab in pts with MSS, BRAFV600E metastatic CRC will activate in 2022."

Clinical • P1/2 data • Cardiovascular • Colorectal Cancer • Gastroenterology • Gastrointestinal Cancer • Gastrointestinal Disorder • Immunology • Inflammation • Myositis • Oncology • Solid Tumor • MSI

A first-in-human, phase 1 study of the SHP2 inhibitor PF-07284892 as monotherapy and in combination with different targeted therapies in oncogene-driven, treatment-resistant solid tumors. (ASCO 2023) - P1 | "In the absence of dose limiting toxicity (DLT), matched targeted therapy (lorlatinib for ALK/ROS1 fusion+ cancers, encorafenib + cetuximab for BRAFV600E colorectal cancers, and binimetinib for MAPK-mutant cancers) could be added after 6 weeks of monotherapy at the discretion of the investigator. PF-07284892 was generally well tolerated alone and in combination with rational targeted therapies. This study design enabled combination therapy rescue of disease progression on PF-07284892 monotherapy with 3 pts achieving confirmed PR. Clinical trial information: NCT04800822."

Combination therapy • Monotherapy • P1 data • Anemia • Colorectal Cancer • Gastrointestinal Cancer • Hematological Disorders • Oncology • Solid Tumor • Thrombocytopenia • ALK • ROS1

Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial. (PubMed, Nat Med) - P3 | "The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. These findings support treatment with Enco+Cetux±Bini for patients with BRAF-V600E-mutant mCRC and provide insights into the biology of response and resistance to MAPK-pathway-targeted therapy. ClinicalTrials.gov registration: NCT02928224."

Journal • Metastases • P3 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • MAP2K1 • MET • TP53

COLONTOWN DocTalk (Facebook) - "Join us for BREAKWATER: 2026 Update! Hear about the much awaited results of the FOLFIRI + Encorafenib + Cetuximab arm of this 1L trial for patients with BRAF V600E - mutated metastatic colorectal cancer."

Live event

Evaluating age as a factor for survival and quality of life in patients with BRAF V600E-mutant metastatic colorectal cancer treated with encorafenib + cetuximab ± binimetinib: subanalysis of BEACON CRC (ESMO-GI 2022) - "Methods BEACON CRC was a randomized, open-label, phase 3 study comparing enco+cetux±bini and investigator's choice of irinotecan+cetux or FOLFIRI+cetux (control) in patients with previously treated BRAF V600E-mutant mCRC...This subanalysis is limited by the low number of patients. Further analyses are warranted to compare these age groups when treated with targeted therapies for mCRC."

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