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.

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

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.

Informations de copyright

Copyright © 2024 Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest David Planchard reports consulting, advisory role or lectures for AstraZeneca, Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Janssen, Pfizer, Roche, Pierre-fabre, Takeda, ArriVent, Mirati and Seagen; clinical trials research as principal investigator or co-investigator (institutional financial interests) for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo, Abbvie, Janssen, Pierre-fabre, Takeda, ArriVent, Mirati and Seagen; and travel, accommodation and expenses from AstraZeneca, Roche, Novartis and Pfizer. Jürgen Wolf reports grants from BMS, Janssen, Pharmaceutica, Novartis and Pfizer (payment to institution); and consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and/or travel, and participation on a data safety monitoring board or advisory board from Amgen,  AstraZeneca, Bayer, BluePrint, BMS, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre-Fabre, Roche, Seattle Genetics, Takeda and Turning Point. Benjamin Solomon reports fees for advisory boards from Pfizer, AstraZeneca, Janssen, Takeda, Bristol Myers Squibb, Meck, Roche-Genentech, Beigene and Amgen; payment or honoraria for lectures and presentations from AstraZeneca, Pfizer, Glaxo Smith Klein, Merck and Roche; and is a board director of Thoracic Oncology Group of Australasia, Cancer Council Victoria and International Association for the Study of Lung Cancer. Martin Sebastian reports grants or contracts to institution from AstraZeneca; consulting fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer lngelheim, Amgen, Takeda, Merck-Serono, Pfizer, Pierre-Fabre and DaiIchi- Sankyo; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Lilly, Roche, Boehringer lngelheim, Amgen, Takeda, Merck, GSK, Daiichi and Pfizer; and support for attending meetings and/or travel from Pfizer, Merck and BMS. Martin Wermke reports research funding for institution from Roche; consulting fees from Bristol Myers Squibb, Novartis, Lilly, Boehringer Ingelheim, Immatics, Bayer and ImCheck Therapeutics; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Lilly, Boehringer Ingelheim, SNYLAB, Merck Serono, GWT, Amgen and Novartis; support for attending meetings and/or travel from Pfizer, Bristol Myers Squibb, AstraZeneca, Amgen, GEMoaB, Sanofi/Aventis, Immatics and Merck Serono; and participation on a data safety monitoring board or advisory board for ISA Pharmaceuticals. Rebecca S. Heist reports grants to institution from Abbvie, Agios, Daichii Sankyo, Lilly, Novartis, Mythic, Mirati, Symphogen, Turning Point and Erasca; consulting fees from Novartis, EMD Serono, Daichii Sankyo, Abbvie, Regeneron, Sanofi, Lilly, Claim Therapeutics, AstraZeneca, Amgen and Gilead; and receiving medical writing services from Daichii Sankyo, Novartis, Lilly and Mirati. Jong-Mu Sun has no conflicts of interest to declare. Tae Min Kim reports consulting fees from AstraZeneca, Janssen, Regeneron, Samsung Bioepis, Takeda and Yuhan; participation on Advisory Board for AstraZeneca/Medimmune, Janssen and Regeneron; and other financial or non-financial interests received by the institution from ABBVIE, AstraZeneca, Bayer, Black Diamond Therapeutics, Blueprint Medicines, Boryung, Bristol Myers Squibb, Celgene, F. Hoffmann-La Roche Ltd/Genentech, Inc, Hanmi, Janssen, Novartis, Regeneron, Sanofi, Takeda and Yuhan. Noemi Reguart has received speaker’s honoraria or sponsorship to attend international scientific meetings from Bayer, MSD, BMS, Roche, Boehringer Ingelheim, Janssen, Pfizer, AbbVie, Novartis, Astrazeneca, Lilly, Takeda, Amgen and Merck; and research grants from Novartis, MSD and Pfizer (all for Institution). Miguel F. Sanmamed received research grants from Roche; consulting fees from Numab; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD; support for attending meetings and/or travel from Roche; and participation on advisory board for Numab. Enriqueta Felip reports consulting fees from Abbvie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point and Daiichi Sankyo; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda and Touch Oncology; and support for attending meetings and/or travel from AstraZeneca, Janssen and Roche. Pilar Garrido received personal fees for lectures, presentations, speakers bureaus or educational events from Janssen, MSD, Novartis, Medscape, Takeda, TouchTime and Medscape; support for attending meetings and/or travel from Astra Zeneca, Roche and Janssen; personal fees for advisory role from Abbvie, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda, and personal fees for steering committee from Novartis and IO Biotech IO102-Janssen. Armando Santoro received consultancy fees from Sanofi and Incyte; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Takeda, BMS, Roche, Abbvie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayer, MSD and BeiGene; and participation on a data safety monitoring board or advisory board for BMS, Servier, Gilead, Pfizer, Eisai, Bayer and MSD. Douglas Bootle is a Novartis employee. Xuân-Mai Couillebault is a Novartis employee. Anil Gaur is a Novartis employee. Christina Mueller is a Novartis employee and Novartis stockholder. Teresa Poggio is a Novartis employee. Jie Yang is a Novartis employee and Novartis stockholder. Michele Moschetta is a previous Novartis employee, Novartis stockholder and has one patent issued relating to naporafenib. Christophe Dooms has no conflicts of interest to declare. All authors received medical writing support funded by Novartis Pharmaceuticals Corporation.