激活 MAPK 通路的基因改变在非小细胞肺癌 (NSCLC) 中很常见。 NSCLC 患者可能会受益于泛 RAF 抑制剂纳波非尼 (LXH254) 加 ERK1/2 抑制剂 rineterkib (LTT462) 或 MEK1/2 抑制剂曲美替尼 (trametinib) 的治疗。这项首例人体 1b 期剂量递增/剂量扩展研究研究了纳拉非尼（50-350 mg 每天一次 [QD] 或 300-600 mg 每天两次 [BID]）与rineterkib（100-300 mg QD）联合治疗 KRAS-/BRAF 突变 NSCLC 和纳拉非尼（200 mg BID 或 400 mg BID）与曲美替尼（0.5 mg QD、1 mg QD 或 1 mg QD，2 周用药/2 周停药）治疗 KRAS/BRAF 突变 NSCLC 和 NRAS 突变黑色素瘤患者。主要目标是确定扩张推荐剂量 (RDE) 并评估耐受性和安全性。次要目标包括抗肿瘤活性和药效学。总体而言，216 名患者接受了纳波非尼加 rineterkib（NSCLC：n = 101）或纳波非尼加曲美替尼（NSCLC：n = 79；黑色素瘤：n = 36）治疗。总共 62 名患者中有 10 名 (16%) 经历了至少一种剂量限制性毒性。 RDE 确定为纳波拉非尼 400 mg BID 加 rineterkib 200 mg QD、纳波拉非尼 200 mg BID 加曲美替尼 1 mg QD 和纳波拉非尼 400 mg BID 加曲美替尼 0.5 mg QD。最常见的 ≥ 3 级治疗相关不良事件是纳波非尼加rineterkib 的脂肪酶升高（8/101 [7.9%] 患者）和纳波拉非尼加曲美替尼的皮疹（22/115 [19.1%] 患者）。在 NSCLC 患者中，三名患者（一名患有 KRAS 突变型，两名患有 BRAFnon-V600 突变型 NSCLC）接受纳波非尼加rineterkib 治疗，两名患者（均为 KRAS 突变型 NSCLC）接受纳拉非尼加曲美替尼治疗，观察到部分缓解。纳帕拉非尼加rineterkib或trametinib治疗时DUSP6 mRNA水平相对于基线的中位降低分别为45.5%和76.1%。两种纳波非尼组合均具有可接受的安全性。尽管观察到了靶向药效学效应，但 NSCLC 患者的抗肿瘤活性有限。gov 标识符：NCT02974725。版权所有 © 2024 Elsevier B.V。保留所有权利。

Genetic alterations activating the MAPK pathway are common in non-small cell lung cancer (NSCLC). Patients with NSCLC may benefit from treatment with the pan-RAF inhibitor naporafenib (LXH254) plus the ERK1/2 inhibitor rineterkib (LTT462) or MEK1/2 inhibitor trametinib.This first-in-human phase 1b dose-escalation/dose-expansion study investigated the combinations of naporafenib (50-350 mg once daily [QD] or 300-600 mg twice daily [BID]) with rineterkib (100-300 mg QD) in patients with KRAS-/BRAF-mutant NSCLC and naporafenib (200 mg BID or 400 mg BID) with trametinib (0.5 mg QD, 1 mg QD or 1 mg QD 2 weeks on/2 weeks off) in patients with KRAS-/BRAF-mutant NSCLC and NRAS-mutant melanoma. The primary objectives were to identify the recommended dose for expansion (RDE) and evaluate tolerability and safety. Secondary objectives included antitumor activity and pharmacodynamics.Overall, 216 patients were treated with naporafenib plus rineterkib (NSCLC: n = 101) or naporafenib plus trametinib (NSCLC: n = 79; melanoma: n = 36). In total, 10 of 62 (16%) patients experienced at least one dose-limiting toxicity. The RDEs were established as naporafenib 400 mg BID plus rineterkib 200 mg QD, naporafenib 200 mg BID plus trametinib 1 mg QD and naporafenib 400 mg BID plus trametinib 0.5 mg QD. The most frequent grade ≥ 3 treatment-related adverse event was increased lipase (8/101 [7.9%] patients) for naporafenib plus rineterkib and rash (22/115 [19.1%] patients) for naporafenib plus trametinib. Among patients with NSCLC, partial response was observed in three patients (one with KRAS-mutant, two with BRAFnon-V600-mutant NSCLC) treated with naporafenib plus rineterkib and two patients (both with KRAS-mutant NSCLC) treated with naporafenib plus trametinib. On-treatment median reductions in DUSP6 mRNA levels from baseline were 45.5% and 76.1% with naporafenib plus rineterkib or trametinib, respectively.Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect.gov identifier: NCT02974725.Copyright © 2024 Elsevier B.V. All rights reserved.