Braftovi (encorafenib)

P4, N=0, Withdrawn, SRH Wald-Klinikum Gera GmbH | N=101 --> 0 | Not yet recruiting --> Withdrawn

P2, N=25, Active, not recruiting, Fondazione Policlinico Universitario Agostino Gemelli IRCCS | Recruiting --> Active, not recruiting

KSR1 knockdown did not substantially affect ppERK responses to Type I½ RAF inhibitor (Encorafenib) in both cell types, whereas ppERK sensitivity slightly decreased for Type II RAFi (TAK-632) in MCF7 cells, aligning with simulations. The efficacy of MEKi (Cobimetinib) slightly increased in MCF7 cells following KSR1 knockdown but slightly decreased in PSN1 cells where higher MEKi concentrations were required to suppress ERK signaling, as predicted by the model. Our computational models predict, and experiments validate that in RAS-mutant cells, two conformation-specific RAF inhibitors used in combination suppress the ERK pathway more effectively than a combination of MEK and RAF inhibitors irrespective of KSR1 levels.

P2, N=24, Active, not recruiting, Providence Health & Services | Trial completion date: Jan 2027 --> Dec 2028 | Trial primary completion date: Jan 2026 --> Dec 2027

P=N/A, N=50, Active, not recruiting, Pierre Fabre Ltd | Recruiting --> Active, not recruiting

In the absence of head-to-head trials comparing 1L nivolumab plus relatlimab (NIVO+RELA) to BRAF/MEK inhibitors, we compared its efficacy to dabrafenib+trametinib (DAB+TRAM), encorafenib+binimetinib (ENCO+BINI), vemurafenib+cobimetinib (VEM+COBI) and atezolizumab (ATEZO)+VEM+COBI using matching-adjusted indirect comparisons (MAICs)...These MAICs suggest that 1L dual IO therapy with NIVO+RELA confers a long-term OS advantage in BRAF-mutant advanced melanoma compared with BRAF/MEK inhibitor combinations despite lower ORR, consistent with prior evidence for 1L NIVO+IPI in this setting. As unanchored analyses, potential residual confounding remains, and results should be interpreted cautiously.

CheckMate 577 reported mature overall survival (OS) data for adjuvant nivolumab in esophageal/GEJ cancer; however, OS benefit was not statistically significant in the intent-to-treat population and appeared restricted to PD-L1-positive tumors. MATTERHORN demonstrated significant improvements in event-free survival and OS with perioperative durvalumab plus FLOT in gastric/GEJ cancer. In stage III dMMR colon cancer, ATOMIC supported adjuvant atezolizumab plus chemotherapy, though questions persist about chemotherapy necessity and neoadjuvant immunotherapy. For advanced disease, BREAKWATER established encorafenib-based triplet therapy as first-line standard for BRAF V600E-mutant metastatic colorectal cancer, while DESTINY-Gastric04 confirmed trastuzumab deruxtecan as superior second-line therapy for HER2-positive gastric cancer, mandating re-biopsy. Given the great interest in circulating tumor DNA, we integrate the ESMO 2025 DYNAMIC-III trial, demonstrating ctDNA-guided de-escalation reduces toxicity with outcomes approaching standard care. These advances mandate comprehensive biomarker testing while highlighting persistent evidence gaps.

We report here a patient on encorafenib who developed numerous new pigmented lesions within 3 weeks of therapy...This case underscores that BRAF inhibition may enhance PRAME expression in benign melanocytic nevi, potentially through mechanisms involving mitogen-activated protein kinase (MAPK) activation, altered Erk phosphorylation, or disruption of retinoic acid (RA) signaling. This case also brings awareness to the potential of medication-induced PRAME expression and encourages both dermatologists and dermatopathologists to avoid overdiagnosis as PRAME continues to gain prominence as a diagnostic biomarker.

Targeted inhibition with the oral BRAF inhibitor encorafenib, combined with intravenous cetuximab targeting epithelial growth factor receptor (EGFR) and standard chemotherapy FOLFOX, has improved outcomes and received FDA approval in 2025 based on results from the phase III BREAKWATER trial...This case demonstrates that rectal and nasogastric administration of encorafenib is feasible, achieves therapeutic plasma concentrations, and induces objective and clinical remission in context of FOLFOX+EC. Short-term safety appeared manageable, though increased infection risk cannot be excluded.

Trastuzumab-based combinations and HER2-selective tyrosine kinase inhibitors such as tucatinib have demonstrated durable responses and favorable safety profiles in heavily pretreated patients. This review summarizes current evidence from pivotal phase II and III clinical trials, translational studies, and real-world data evaluating EGFR-, BRAF-, and HER2-directed therapies in colorectal cancer. Particular emphasis is placed on biomarker-guided patient selection, mechanisms of resistance, and emerging combination strategies that continue to refine precision oncology approaches in mCRC.