Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study

医学 曲美替尼 皮疹 神经母细胞瘤RAS病毒癌基因同源物 内科学 不利影响 黑色素瘤 克拉斯 耐受性 胃肠病学 肿瘤科 肺癌 威罗菲尼 癌症 激酶 癌症研究 结直肠癌 MAPK/ERK通路 转移性黑色素瘤 生物 细胞生物学
作者
Filippo de Braud,Christophe Dooms,Rebecca S. Heist,Célèste Lebbé,Martin Wermke,Anas Gazzah,Dirk Schadendorf,Piotr Rutkowski,Jürgen Wolf,Paolo A. Ascierto,Ignacio Gil-Bazo,Shumei Kato,Maria Wolodarski,Meredith McKean,Eva Muñoz-Couselo,Martin Sebastian,Armando Santoro,Vesselina G. Cooke,Luca Manganelli,Kitty Wan,Anil Gaur,Jaeyeon Kim,Giordano Caponigro,Xuân-Mai Couillebault,Helen H. Evans,Catarina D. Campbell,Sumit Basu,Michele Moschetta,Adil Daud
出处
期刊:Journal of Clinical Oncology [Lippincott Williams & Wilkins]
卷期号:41 (14): 2651-2660 被引量:20
标识
DOI:10.1200/jco.22.02018
摘要

No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available.In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms).Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily.Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.
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