First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations
Background: We investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations. Methods: This first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 m...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
January 2024
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| In: |
European journal of cancer
Year: 2024, Volume: 196, Pages: 1-9 |
| ISSN: | 1879-0852 |
| DOI: | 10.1016/j.ejca.2023.113458 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ejca.2023.113458 Verlag, lizenzpflichtig, Volltext: https://www.sciencedirect.com/science/article/pii/S0959804923007608?via%3Dihub 
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| Author Notes: | Filip Janku, Tae Min Kim, Gopakumar Iyer, Anna Spreafico, Elena Elez, Maja de Jonge, Noboru Yamamoto, Anthonie J. van der Wekken, Paolo Antonio Ascierto, Michela Maur, Frederik Marme, Jean-Jacques Kiladjian, Sumit Basu, Fabienne Baffert, Amparo Buigues, Chi Chen, Vesselina Cook, Elisa Giorgetti, Jaeyeon Kim, Fiona McCarthy, Michele Moschetta, Reinhard Dummer |
| Summary: | Background: We investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations. Methods: This first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily [QD]) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated nonsmall cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety. Results: A total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/ RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 doselimiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib esca-lation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively. Conclusions: Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation. |
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| Item Description: | Online veröffentlicht: 20. November 2023 Gesehen am 02.08.2024 |
| Physical Description: | Online Resource |
| ISSN: | 1879-0852 |
| DOI: | 10.1016/j.ejca.2023.113458 |