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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-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.
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| http://dx.doi.org/10.1016/j.lungcan.2024.107964 | DOI Listing |
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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.
Lung Cancer
November 2024
Department of Respiratory Diseases, University Hospitals KU Leuven, Leuven, Belgium; Department of Chronic Diseases and Metabolism, Respiratory Oncology Unit, Laboratory of Respiratory Diseases and Thoracic Surgery, KU Leuven, Leuven, Belgium.
Article Synopsis
- The study focused on pairing naporafenib, a pan-RAF inhibitor, with either rineterkib or trametinib to treat patients with non-small cell lung cancer (NSCLC) and certain genetic mutations.
- Conducted on 216 patients, the research aimed to find safe and effective dosage levels, identifying recommended doses while monitoring for side effects and antitumor activity.
- Results showed dose-limiting toxicities in 16% of patients, with some achieving partial responses; the study established specific dosages that were well-tolerated along with noticeable reductions in certain mRNA levels.