Mektovi (binimetinib) / Ono Pharma, Pierre Fabre, Pfizer, Medison - LARVOL DELTA

Encorafenib plus binimetinib in patients (pts) with previously untreated BRAF V600E-mutant advanced non-small cell lung cancer (NSCLC): An open-label, multicenter phase II trial (IFCT-1904 ENCO-BRAF) (ESMO 2024) - P2 | "Current ESMO guidelines recommend dabrafenib plus trametinib as preferred first-line treatment options or as subsequent treatment for BRAFV600E-mutant advanced NSCLC. In this phase 2 trial with treatment-naïve BRAFV600E-mutant advanced NSCLC, encorafenib plus binimetinib demonstrated robust clinical activity. The safety profile was manageable and consistent with previous studies in lung cancer and melanoma."

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

Efficacy and safety of encorafenib (enco) plus binimetinib (bini) in patients with BRAF V600E-mutant (BRAFV600E) metastatic non-small cell lung cancer (NSCLC) from the phase 2 PHAROS study. (ASCO 2023) - P2 | "Background: The combination of dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, is a current standard of care for patients (pts) with BRAFV600E NSCLC. The combination of enco+bini showed meaningful clinical benefit in treatment-naive and previously treated pts with BRAFV600E metastatic NSCLC. The safety profile of enco+bini was generally consistent with that established for pts with BRAFV600E/K melanoma. ClinicalTrials.gov: NCT03915951."

Clinical • IO biomarker • Metastases • P2 data • Cerebral Hemorrhage • CNS Disorders • Fatigue • Hematological Disorders • Lung Cancer • Melanoma • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BRAF • CDKN2A • CSF1R • KMT2D • MLL2 • SETD2 • SMAD4 • SMARCA4 • TP53

Encorafenib plus binimetinib versus dabrafenib plus trametinib for the first-line treatment of patients with BRAFV600E-mutant metastatic non-small cell lung cancer: a matching-adjusted indirect treatment comparison. (PubMed, ESMO Open) - "This analysis suggests that E + B was associated with statistically significantly longer PFS and fewer SAEs compared with D + T, and may offer an alternative option for the 1L treatment of BRAFV600E-mutant metastatic non-small cell lung cancer."

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

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

Patient-derived extracellular matrix scaffolds enable physiologically relevant ex vivo models of vulvar cancer (ESGO 2026) - "Proteomic analysis further revealed increased expression of laminins and matrix-remodelling enzymes in dhECM cultures. Treatment with gefitinib, afatinib, or binimetinib significantly reduced cancer cell invasion and viability in dhECM organotypics.Conclusion Decellularised human ECM hydrogels provide physiologically relevant, tissue-specific scaffolds for ex vivo modelling of vulvar cancer and enable effective preclinical evaluation of targeted therapies."

Preclinical • Gynecologic Cancers • Oncology • Solid Tumor • Squamous Cell Carcinoma • Vulvar Cancer • COL1A1 • COL1A2 • COL2A1 • COL3A1

Targeting BRAF Fusions with Pan-RAF Inhibitors Highlights Fusion Type–Associated Heterogeneity in Drug Responses and the Need for Combination Therapy with MEK/ERK Inhibitors (IASLC-TTLC 2026) - P1 | "These cell lines were also resistant to the pan-RAS inhibitor RMC-6236 and showed differential sensitivity to pan-RAF inhibitors, with BRAF ex8/9 fusions being the most responsive compared to ex10/11: specifically, average IC50 values for growth inhibition by exarafenib were AGK::BRAFex8: 66nM; AGAP3::BRAFex9: 60nM; TRIM24::BRAFex10: 321nM; SND1::BRAFex11: 1921nM. Similar patterns of sensitivity were observed with other pan-RAF inhibitors (LY3009120, belvarefinib, encorafenib). All CRISPR lines were exquisitely sensitive to MEK1/2 (binimetinib, cobimetinib) and ERK1/2 (ulixertinib) inhibitors, compared to isogenic control cells...We also found that the combination of exarafenib and osimertinib is effective in vivo for EGFR-mutated NSCLC with acquired BRAF fusion. Exarafenib is currently in clinical trials for BRAF- and NRAS-mutant solid tumors (NCT04913285)."

Combination therapy • Heterogeneity • Lung Cancer • Non Small Cell Lung Cancer • Solid Tumor • AGK • BRAF • EML4 • KIAA1549 • MAP2K1 • NRAS • TRIM24

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

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

Phase II study SECOMBIT (sequential combo immuno and target therapy study): 4-years OS data and preliminary biomarkers evaluation (ESMO 2022) - P2 | "We used the combination of encorafenib/binimetinib (E+B) as targeted therapy (T-T) and the combination of ipilimumab/nivolumab (I+N) as immunotherapy (I-O). JAK mutations are associated with long term OS. Further biomarkers evaluations are ongoing."

Biomarker • IO biomarker • Late-breaking abstract • P2 data • Melanoma • Oncology • Solid Tumor • CXCL5 • IFNG

Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial. (PubMed, Nat Commun) - P2 | "BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy."

Biomarker • IO biomarker • Journal • Metastases • P2 data • Melanoma • Oncology • Solid Tumor • BRAF • IFNG

Sequencing of Ipilimumab Plus Nivolumab and Encorafenib Plus Binimetinib for Untreated BRAF-Mutated Metastatic Melanoma (SECOMBIT): A Randomized, Three-Arm, Open-Label Phase II Trial. (PubMed, J Clin Oncol) - P2 | "Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with BRAFV600-mutant melanoma."

IO biomarker • Journal • P2 data • Melanoma • Oncology • Solid Tumor • BRAF

Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma. (PubMed, NEJM Evid) - P2 | "In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases-free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.)."

IO biomarker • Journal • Melanoma • Oncology • Solid Tumor

Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced BRAF-V600E/K-mutated melanoma: The primary analysis of an EORTC randomized phase II study (EBIN). (ASCO 2024) - "The EBIN trial shows there is no difference in PFS between the two treatment arms for unselected patients but supports the hypothesis that patients with very high LDH and those with liver metastases benefit from the sequential approach."

Clinical • IO biomarker • Late-breaking abstract • Metastases • P2 data • Eye Cancer • Melanoma • Oncology • Solid Tumor • Uveal Melanoma • BRAF

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

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

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

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

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

ANCHOR CRC: Results From a Single-Arm, Phase II Study of Encorafenib Plus Binimetinib and Cetuximab in Previously Untreated BRAF-Mutant Metastatic Colorectal Cancer. (PubMed, J Clin Oncol) - P2, P3 | "The ANCHOR CRC study showed that the scientifically driven combination of encorafenib + binimetinib + cetuximab was active in the first-line setting of BRAF-mutated mCRC with a manageable safety profile. Further first-line evaluation is ongoing (ClinicalTrails.gov identifier: NCT04607421)."

Journal • Metastases • P2 data • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

Genomic mechanisms of acquired resistance of patients (pts) with BRAF V600E-mutant (mt) metastatic colorectal cancer (mCRC) treated in the BEACON study (ESMO 2022) - P3 | "Background In the randomized phase III BEACON study (NCT02928224), encorafenib + cetuximab ± binimetinib regimens improved overall survival and objective response rate vs standard of care (control) in pts with previously treated BRAF V600E-mt mCRC. Conclusions ctDNA analyses revealed that MAPK pathway reactivation is a common mechanism of resistance for BRAF V600E-mt mCRC following inhibition of BRAF and EGFR ± MEK inhibition. Acquired mutations in RAS-MEK signaling were more prevalent in the doublet arm, while enhanced receptor signaling was more prevalent in the triplet arm."

Clinical • Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF • EGFR • KRAS • MAP2K1 • MET • NRAS

Quality of life with encorafenib plus cetuximab with or without binimetinib treatment in patients with BRAF V600E-mutant metastatic colorectal cancer: patient-reported outcomes from BEACON CRC. (PubMed, ESMO Open) - P3 | "In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC."

HEOR • Journal • Patient reported outcomes • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BRAF

BREAKWATER safety lead-in (SLI): Encorafenib (E) + cetuximab (C) + chemotherapy (chemo) for BRAFV600E metastatic colorectal cancer (mCRC) (ESMO 2022) - P2, P3 | "In the Ph 2 ANCHOR study (NCT03693170), mPFS was 5.8 mo and ORR was 48% with 1L EC + binimetinib in BRAF V600E mCRC...Pts previously treated with BRAFi/EGFRi or both oxaliplatin and irinotecan were excluded...Conclusions EC + chemo was generally tolerable. Preliminary promising antitumor activity was seen in 1L and 2L BRAF V600E mCRC, supporting the ongoing study."

Clinical • Late-breaking abstract • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor

Pembrolizumab Plus Binimetinib With or Without Chemotherapy for MSS/pMMR Metastatic Colorectal Cancer: Outcomes From KEYNOTE-651 Cohorts A, C, and E. (PubMed, Clin Colorectal Cancer) - "Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E."

Journal • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor