Christoffer Gebhardt | PubMed Health

PubMed2026

primary analysis of the RANDOMIZED eortc-2139/columbus-ad trial: Adjuvant encorafenib and binimetinib versus placebo in high-risk stage II BRAF-V600E/K melanoma.

PURPOSE: Stage IIB/IIC melanoma has a high risk of recurrence after resection. Combined BRAF/MEK inhibitor therapy showed benefit in resected high-risk stage III and advanced melanoma. The objective of this study was to investigate its role in stage IIB/IIC. METHODS: Adult patients with resected stage IIB/IIC cutaneous melanoma which had a BRAF V600E/K mutation were randomized 1:1 to receive encorafenib (enco) 450 mg QD + binimetinib (bini) 45 mg BID orally for one year or placebo. The study planned to randomize 815 patients and was designed to demonstrate superiority regarding recurrence-free survival (RFS). Following a premature termination of accrual, the study was amended with safety as the primary endpoint and RFS as secondary endpoint. RESULTS: Between June 9, 2022, and October 9, 2023, 339 patients were screened for a BRAF mutation and 110 randomized. Data cutoff was 19 Nov. 2024, after the last patient discontinued study participation. Among randomized patients, 87 (79%) had a BRAF V600E mutation, and 39 (35%) AJCC8 stage IIC. Median follow-up was 12 and 7 months for enco/bini and placebo arms, respectively. Among 54 patients who initiated enco + bini, grade ≥ 3 treatment-related adverse events (AE) occurred in 13 (24%) patients, and 18 (33%) patients had an AE leading to permanent treatment discontinuation. RFS at 12 months was 86% (95% CI: 65-95%) in the enco + bini and 70% (95% CI: 46-85%) in the placebo arm, distant metastasis-free survival at 12 months was 92% (95% CI: 77-97%) for enco + bini and 82% (95% CI: 55-93%) for placebo. CONCLUSION: EORTC 2139 - Columbus-AD demonstrated a consistent and manageable safety profile and encouraging efficacy results for the combination of enco and bini in resected stage IIB/C BRAF V600E/K-mutated cutaneous melanomas.

Adult↗

PubMed2025

In-depth assessment of BRAF, NRAS, KRAS, EGFR, and PIK3CA mutations on cell-free DNA in the blood of melanoma patients receiving immune checkpoint inhibition.

INTRODUCTION: Circulating tumor DNA (ctDNA) holds promise for guiding immune checkpoint inhibitor (ICI) therapy and stratifying responders from non-responders. While tumor-informed ctDNA detection approaches are sensitive and mutation-inclusive, they require tumor tissue, which limits applicability in real-world settings. Conversely, tumor-agnostic methods often have limited genomic coverage. In this study, we evaluated a tumor-agnostic, broad-panel ctDNA assay in patients with advanced melanoma treated with ICI. METHODS: We conducted a prospective analysis of 241 longitudinal samples from 39 patients with unresectable stage III/IV melanoma using a SYSMEX targeted NGS panel covering 1,114 COSMIC mutations. Plasma samples were collected at baseline and during ICI therapy. The assay's sensitivity reached seven mutant molecules, corresponding to a 0.07% mutation allele frequency (MAF). ctDNA profiles were compared with matched tumor tissue and correlated with clinical features and survival. RESULTS: At baseline, ctDNA was detected in 64.5% of patients. Common mutations included BRAFV600E (43.8%) and NRASG12D (36.4%), followed by KRAS, EGFR, and PIK3CA variants. Overall tissue-plasma concordance was 51.6%, with more extended biopsy-plasma intervals associated with discordance (p = 0.0105). Notably, 12.2% of cases exhibited partial concordance, characterized by shared mutations and additional plasma-only alterations, underscoring the complementary value of blood-based profiling. Persistent or re-emerging ctDNA positivity post-therapy correlated with shorter progression-free survival (PFS, p = 0.003), while ctDNA-negative patients showed significantly improved outcomes. Patients that remained ctDNA-negative had significantly longer progression-free survival (median not reached) compared to those with persistent ctDNA positivity (median 3 months) or those converting to positive (median 7.5 months; p = 0.0073). Early NRAS and KRAS ctDNA levels strongly predicted poor response (p = 0.0069 and p = 0.028). The prognostic impact extended beyond canonical drivers, as non-hotspot variants also correlated with the outcome. Notably, even low-level ctDNA persistence (5-10 MM/mL) carried adverse prognostic implications (p = 0.0054). Concerning a shorter PFS, ctDNA positivity was also associated with elevated S100 levels (p = 0.047). Organ-specific mutation enrichment (e.g., KRASG12D in brain, EGFRG719A in lymph nodes) suggested possible metastatic tropism. CONCLUSION: Broad tumor-agnostic ctDNA analysis effectively identified clinically relevant mutations and predicted outcomes in ICI-treated melanoma patients. This approach enables tissue-independent and real-time ctDNA monitoring and may inform patient selection and therapeutic strategies in future interventional trials.

Humans↗