A phase Ib study of the combination of naporafenib with rineterkib or trametinib in patients with advanced and metastatic KRAS- or BRAF-mutant non-small cell lung cancer
- Author(s)
- Planchard, D; Wolf, J; Solomon, B; Sebastian, M; Wermke, M; Heist, RS; Sun, JM; Min Kim, T; Reguart, N; Sanmamed, MF; Felip, E; Garrido, P; Santoro, A; Bootle, D; Couillebault, XM; Gaur, A; Mueller, C; Poggio, T; Yang, J; Moschetta, M; Dooms, C;
- Journal Title
- Lung Cancer
- Publication Type
- Research article
- Abstract
- BACKGROUND: 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. METHODS: 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. RESULTS: 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 BRAF(non-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. CONCLUSIONS: Both naporafenib combinations had acceptable safety profiles. Antitumor activity was limited in patients with NSCLC, despite the observed on-target pharmacodynamic effect. CLINICALTRIALS: gov identifier: NCT02974725.
- Publisher
- Elsevier
- Keywords
- Humans; *Carcinoma, Non-Small-Cell Lung/drug therapy/genetics/pathology; *Pyridones/administration & dosage/therapeutic use; *Pyrimidinones/administration & dosage/therapeutic use; Female; Middle Aged; *Lung Neoplasms/drug therapy/genetics/pathology; Male; *Antineoplastic Combined Chemotherapy Protocols/therapeutic use/adverse effects; Aged; *Mutation; Adult; *Proto-Oncogene Proteins p21(ras)/genetics; *Proto-Oncogene Proteins B-raf/genetics; Neoplasm Staging; Treatment Outcome; Aged, 80 and over; Neoplasm Metastasis; Aminopyridines; Braf; Kras; Ltt462; Lxh254; Nsclc; Naporafenib; Phase 1; Rineterkib; Trametinib
- Department(s)
- Medical Oncology
- Publisher's Version
- https://doi.org/10.1016/j.lungcan.2024.107964
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2024-12-17 07:00:36
Last Modified: 2024-12-17 07:00:41