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 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.

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Filip Janku received research support from Astex, Novartis, BioMed Valley Discoveries, Fore Bio, Deciphera, Bristol-Myers Squibb, Asana, Ideaya Biosciences, Sanofi, Merck, F-star, JSI Innopharm, Bioxcel, Lilly, Bicara, PureTech Health, FujiFilm Pharmaceuticals, Piqur, Sotio, Synlogic, NextCure and Hutchinson Medipharma; served on the Scientific Advisory Boards of Ideaya Biosciences, Synlogic, Sotio, Puretech Health, Deciphera, Crown Bioscience, Asana, Fore Bio, Novartis, Bicara and PegaOne; served as a paid consultant for Mersana Therapeutics, Flame Bio, Cardiff Oncology, MedinCell and Immunomet; has ownership interests in Cardiff Oncology and Monte Rosa Therapeutics; and has the leadership position in Monte Rosa Therapeutics. Tae Min Kim received consulting fees or honoraria for lectures from AstraZeneca, IMBDx, Inc., Janssen, Regeneron, Samsung Bioepis, Takeda and Yuhan; had advisory role for AstraZeneca, Janssen, Regeneron and Takeda; and received a research grant from AstraZeneca-KHIDI outside this work. Gopakumar Iyer reports consulting or advisory role for Bayer, Janssen, Mirati Therapeutics, Basilea Pharmaceutica, Flare Therapeutics and Aadi Bioscience; speakers' bureau for Gilead Sciences and Lynx Group; and research funding (to institution) from Mirati Therapeutics, Novartis, Janssen, Seattle Genetics, LOXO at Lilly and Aadi Bioscience. Anna Spreafico has received consulting fees from Merck, Bristol-Myers Squibb, Oncorus, Janssen, and Medison & Immunocore; and funding support for clinical trials paid to the Institution from Novartis, Bristol-Myers Squibb, Symphogen, AstraZeneca/Medimmune, Merck, Bayer, Surface Oncology, Northern Biologics, Janssen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biopharma/Pfizer, GSK, NuBiyota, Oncorus, Treadwell and Amgen. Elena Elez has received personal speaker honoraria from Organon and Novartis; and personal advisory board honoraria from Amgen, Bayer, Hoffman-La Roche, Merck Serono, Sanofi, Pierre Fabre, MSD and Servier. Noboru Yamamoto reports research grants from Astellas, Chugai, Eisai, Taiho, BMS, Pfizer, Novartis, Eli Lilly, AbbVie, Daiichi-Sankyo, Bayer, Boehringer Ingelheim, Kyowa Kirin, Takeda, ONO, Janssen Pharma, MSD, Merck, GSK, Sumitomo Pharma, Chiome Bioscience, Otsuka, Carna Biosciences, Genmab, Shionogi, TORAY, KAKEN, AstraZeneca, Cmic, InventisBio and Rakuten Medical; advisory roles for Eisai, Takeda, Boehringer Ingelheim, Cmic, Chugai, Merck and Healios; and honoraria as a Speaker from ONO, Chugai, Daiichi-Sankyo and Eisai. Anthonie J. van der Wekken reports grants and other support from AstraZeneca, Pfizer, Roche and Takeda; grants from Boehringer Ingelheim; and other support from Agena and Janssen, outside the submitted work. All payments were made to the University Medical Centre Groningen. Paolo Antonio Ascierto has/had a consultant/advisory role for Bristol Myers Squibb, Roche-Genentech, Merck Sharp & Dohme, Novartis, Merck Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Sanofi, Sandoz, Immunocore, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, Medicenna, Bio-Al Health, ValoTX, Replimmune, Bayer and Erasca; received research funding from Bristol Myers Squibb, Roche-Genentech, Pfizer and Sanofi; and travel support from Pfizer, Bio-Al Health and Replimmune. Frederik Marmé reports personal fees from GSK, Roche, Novartis, AstraZeneca, MSD, Vaccibody, Gilead Sciences, Eisai, Pfizer, Myriad, Genomic Health, Seagen, Daiichi Sankyo, Pierre Fabre, Agendia, Lilly and Clovis outside the submitted work. Jean-Jacques Kiladjian reports consulting fees from GSK and Abbvie; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Novartis and AOP Health; participation on a data safety monitoring board or advisory board for Incyte and BMS. Sumit Basu, Fabienne Baffert, Amparo Buigues, Vesselina Cooke and Jaeyeon Kim are employees and stockholders of Novartis. Chi Chen and Elisa Giorgetti are employees of Novartis. Fiona McCarthy is a previous employee and a stockholder of Novartis. Michele Moschetta is a previous employee and a stockholder of Novartis and has submitted a patent application related to LXH254. Reinhard Dummer reports intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, Alligator, T3 Pharma, MaxiVAX SA, Pfizer and touchIME outside the submitted work. Maja de Jonge and Michela Maur report no conflicts of interest.