Menzer Christian, Dugas-Breit Susanne, Dugas Martin, Blank Christian U, Groen Emma J, Reijers Irene, Schlaak Max, Eckardt Julia, Suijkerbuijk Karijn P M, Zimmer Lisa, Johnson Douglas B, Franklin Cindy, Meiss Frank, Schilling Bastian, Meier Friedegund, Gutzmer Ralf, Thoms Kai-Martin, Haalck Thomas, Müller Marilena, Kopp-Schneider Annette, Carlino Matteo S, Long Georgina V, Menzies Alexander M, van der Veldt Astrid A M, de Groot Jan Willem B, Eigentler Thomas, Stevense-den Boer Marion, Pföhler Claudia, Herbschleb Karin, Hassel Jessica C
Heidelberg University, Medical Faculty Heidelberg, Department of Dermatology and National Center for Tumor Diseases (NCT), NCT Heidelberg, A Partnership Between DKFZ and University Hospital Heidelberg, Heidelberg, Germany.
Institute of Medical Informatics, Heidelberg University Hospital, Heidelberg, Germany.
Eur J Cancer. 2025 Aug 9;228:115703. doi: 10.1016/j.ejca.2025.115703.
While BRAF-/MEK-inhibitor therapy is well established in V600E/K-mutated melanoma, the efficacy in advanced melanoma with rare BRAF mutations remains uncertain. This is an updated analysis of an international data collection including 49 new patients, accompanied by development of a publicly accessible global database.
A retrospective analysis was conducted at 20 international cancer centers, evaluating 143 patients with rare BRAF V600 (V600-nonE/K; 48 %) and non-V600 (52 %) mutations. Treatments included BRAF/MEK inhibitor combination therapy (BRAFi/MEKi) and the respective monotherapies. Clinical outcomes concerning overall response rate (ORR), progression-free (PFS), and overall survival (OS) were collected.
Included patients had a median age of 65 years (range 20-93), 101 (71 %) were male. Most patients (n = 92, 64 %) received BRAFi/MEKi, 42 (29 %) BRAFi monotherapy, and 9 (6 %) MEKi monotherapy. The ORR was 35 % and higher in V600-nonE/K (45 %) than non-V600 melanomas (26 %, p = 0.025). Median duration of response was similar, with 8.2 months (range 2.9-53.1 +) for V600-nonE/K and 7.4 months (range 0.8-73.8 +) for non-V600. Combination therapy achieved best results in both groups, however, differences between V600-nonE/K and non-V600mutation were only found in ORR (51 % vs. 33 %, p = 0,11) and median PFS (6.5 vs. 3.2 months, p = 0.01). Patients with the longest PFS (> 50 months) had V600D/R, V600_K601D/E/N or K601E/N-, L597V/S/R/Q/P/K- mutations. OS was similar in both groups (16.1 vs. 11.7 months, p = 0.96). Of note, in non-V600 melanomas MEKi monotherapy revealed similar response rates as combination treatment (ORR 33 %, PFS 3 months); however, median OS was shorter (6.6 months, p = 0.02).
This updated analysis reinforces the benefit of BRAFi/MEKi therapy in rare BRAF mutations. A database for ongoing data collection was developed and is available at https://www.klinikum.uni-heidelberg.de/en/hautklinik-zentrum/hauttumorzentrum/forschung/datenbank-seltene-braf-mutationen.
虽然BRAF/MEK抑制剂疗法在V600E/K突变型黑色素瘤中已得到充分确立，但在具有罕见BRAF突变的晚期黑色素瘤中的疗效仍不确定。这是一项对国际数据收集的更新分析，纳入了49名新患者，并建立了一个可公开访问的全球数据库。
在20个国际癌症中心进行了一项回顾性分析，评估了143例具有罕见BRAF V600（V600-非E/K；48%）和非V600（52%）突变的患者。治疗方法包括BRAF/MEK抑制剂联合治疗（BRAFi/MEKi）及各自的单药治疗。收集了关于总缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）的临床结果。
纳入患者的中位年龄为65岁（范围20 - 93岁），101例（71%）为男性。大多数患者（n = 92，64%）接受BRAFi/MEKi治疗，4体（29%）接受BRAFi单药治疗，9例（6%）接受MEKi单药治疗。V600-非E/K黑色素瘤的ORR为45%，高于非V600黑色素瘤的26%（p = 0.025）。中位缓解持续时间相似，V600-非E/K为8.2个月（范围2.9 - 53.1+），非V600为7.4个月（范围0.8 - 73.8+）。联合治疗在两组中均取得了最佳效果，然而，V600-非E/K和非V600突变之间仅在ORR（51%对33%，p = 0.11）和中位PFS（6.5对3.2个月，p = 0.01）方面存在差异。PFS最长（>50个月）的患者具有V600D/R、V600_K601D/E/N或K601E/N-、L597V/S/R/Q/P/K-突变。两组的OS相似（16.1对11.7个月，p = 0.96）。值得注意的是，在非V600黑色素瘤中，MEKi单药治疗的缓解率与联合治疗相似（ORR 33%，PFS 3个月）；然而，中位OS较短（6.6个月，p = 0.02）。
这项更新分析强化了BRAFi/MEKi疗法在罕见BRAF突变中的益处。已建立了一个用于持续数据收集的数据库，可在https://www.klinikum.uni-heidelberg.de/en/hautklinik-zentrum/hauttumorzentrum/forschung/datenbank-seltene-braf-mutationen获取。
