Dummer Reinhard, Sandhu Shahneen, Miller Wilson H, Butler Marcus O, Taylor Matthew H, Heinzerling Lucie, Blank Christian U, Muñoz-Couselo Eva, Burris Howard A, Postow Michael A, Chmielowski Bartosz, Middleton Mark R, Berking Carola, Hassel Jessica C, Gesierich Anja Heike, Mauch Cornelia, Kleha Joseph F, Polli Anna, Harney Allison S, di Pietro Alessandra, Ascierto Paolo A
Department of Dermatology, Skin Cancer Unit, University Hospital Zurich, Zurich, Switzerland.
Sir Peter MacCallum Cancer Department of Oncology, University of Melbourne, Melbourne, Australia.
Clin Cancer Res. 2025 Jun 3;31(11):2097-2107. doi: 10.1158/1078-0432.CCR-24-0254.
LOGIC 2 (NCT02159066), a multicenter, open-label, two-part, phase II study, assessed encorafenib plus binimetinib combined with a third targeted agent after tumor progression on encorafenib plus binimetinib in patients with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma.
Adults with locally advanced, unresectable or metastatic BRAFV600-mutant melanoma who were BRAF inhibitor/MEK inhibitor (BRAFi/MEKi) treatment-naïve or pretreated received encorafenib plus binimetinib (part I/run-in). Based on the genomic testing at disease progression following encorafenib plus binimetinib, patients were assigned to one of four treatment arms to receive encorafenib plus binimetinib with an appropriate molecularly targeted agent (ribociclib, infigratinib, capmatinib, or buparlisib; part II). The primary endpoint was best overall response; safety, biomarkers, pharmacokinetics, and other efficacy endpoints were also assessed.
In part I/run-in, 75 BRAFi/MEKi-naïve patients and 83 BRAFi/MEKi-pretreated patients were treated; in part II, 58 patients were treated (ribociclib, n = 38; infigratinib, n = 1; capmatinib, n = 13; buparlisib, n = 6). The overall confirmed response rate was 73.3% [95% confidence interval (CI), 61.9-82.9] in BRAFi/MEKi-naïve patients, 25.3% (95% CI, 16.4-36.0) in pretreated patients, 2.6% (95% CI, 0.1-13.8) in the ribociclib arm, and 0% in the other three arms. Adverse events were manageable and consistent with the known safety profile of each drug.
LOGIC 2 supports the use of encorafenib plus binimetinib for treatment-naïve and previously treated, locally advanced, unresectable or metastatic BRAFV600-mutant melanoma. However, adding a third targeted agent following disease progression did not show meaningful efficacy; further research is needed to identify other therapeutic targets to circumvent resistance.
LOGIC 2（NCT02159066）是一项多中心、开放标签、两部分的II期研究，评估了恩考芬尼联合比美替尼在局部晚期、不可切除或转移性BRAFV600突变黑色素瘤患者中，于恩考芬尼联合比美替尼治疗后肿瘤进展时联合第三种靶向药物的疗效。
局部晚期、不可切除或转移性BRAFV600突变黑色素瘤的成年患者，既往未接受过BRAF抑制剂/MEK抑制剂（BRAFi/MEKi）治疗或接受过治疗，接受恩考芬尼联合比美替尼（第一部分/导入期）。根据恩考芬尼联合比美替尼治疗后疾病进展时的基因检测结果，患者被分配到四个治疗组之一，接受恩考芬尼联合比美替尼及一种合适的分子靶向药物（瑞博西尼、英菲格拉替尼、卡马替尼或布帕利昔布；第二部分）。主要终点为最佳总体缓解率；还评估了安全性、生物标志物、药代动力学和其他疗效终点。
在第一部分/导入期，75例未接受过BRAFi/MEKi治疗的患者和83例接受过BRAFi/MEKi治疗的患者接受了治疗；在第二部分，58例患者接受了治疗（瑞博西尼组，n = 38；英菲格拉替尼组，n = 1；卡马替尼组，n = 13；布帕利昔布组，n = 6）。未接受过BRAFi/MEKi治疗的患者总体确认缓解率为73.3%[95%置信区间（CI），61.9 - 82.
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