First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations Journal Article
| Authors: | Janku, F.; Kim, T. M.; Iyer, G.; Spreafico, A.; Elez, E.; de Jonge, M.; Yamamoto, N.; van der Wekken, A. J.; Ascierto, P. A.; Maur, M.; Marmé, F.; Kiladjian, J. J.; Basu, S.; Baffert, F.; Buigues, A.; Chen, C.; Cooke, V.; Giorgetti, E.; Kim, J.; McCarthy, F.; Moschetta, M.; Dummer, R. |
| Article Title: | First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations |
| Abstract: | 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 non-small 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 dose-limiting 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 escalation, 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. © 2023 Elsevier Ltd |
| Keywords: | signal transduction; mitogen activated protein kinase; adult; controlled study; protein expression; aged; cancer surgery; major clinical study; genetics; clinical trial; drug tolerability; fatigue; advanced cancer; drug dose reduction; drug safety; recommended drug dose; side effect; comparative study; antineoplastic agent; neoplasm; neoplasms; cancer immunotherapy; melanoma; controlled clinical trial; ovary cancer; sensory neuropathy; mitogen activated protein kinase inhibitor; protein kinase inhibitor; nausea; vomiting; carcinoma, non-small-cell lung; lung neoplasms; myalgia; peripheral neuropathy; incidence; tumor biopsy; antineoplastic activity; asthenia; drug dose escalation; fever; pruritus; rash; protein kinase inhibitors; lung tumor; bilirubin; hyponatremia; maculopapular rash; messenger rna; head and neck cancer; acne; dermatitis; drug bioavailability; maximum tolerated dose; phase 1 clinical trial; kras; k ras protein; crossover procedure; protein p21; proto-oncogene proteins p21(ras); bilirubin blood level; platelet count; exanthema; neuralgia; non small cell lung cancer; nsclc; pharmacokinetic parameters; decreased appetite; oncogene n ras; mapk pathway; nras; overall response rate; immune checkpoint inhibitor; response evaluation criteria in solid tumors; dual specificity phosphatase 6; mapk signaling; humans; human; male; female; article; patient history of radiotherapy; patient history of surgery; solid malignant neoplasm; pharmacodynamic parameters; mrna expression level; spartalizumab; first in human study; lxh254; naporafenib |
| Journal Title: | European Journal of Cancer |
| Volume: | 196 |
| ISSN: | 0959-8049 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2024-01-01 |
| Start Page: | 113458 |
| Language: | English |
| DOI: | 10.1016/j.ejca.2023.113458 |
| PUBMED: | 38039779 |
| PROVIDER: | scopus |
| PMCID: | PMC11380116 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
