@article{7cff1f5c4f3d44d89640a595b8239974,
title = "Characterization and management of ERK inhibitor associated dermatologic adverse events: analysis from a nonrandomized trial of ulixertinib for advanced cancers",
abstract = "Background Ulixertinib is the first-in-class ERK1/2 kinase inhibitor with encouraging clinical activity in BRAF- and NRAS-mutant cancers. Dermatologic adverse events (dAEs) are common with ulixertinib, so management guidelines like those established for epidermal growth factor receptor inhibitor (EGFRi)-associated dAEs are needed. Patients and Methods This was an open-label, multicenter, phase I dose escalation and expansion trial of ulixertinib evaluating data from 135 patients with advanced malignancies enrolled between March 2013 and July 2017. Histopathological features, management, and dAEs in 34 patients are also reported. Twice daily oral ulixertinib was administered at 10 to 900 mg in the dose escalation cohort (n = 27) and at 600 mg in 21-day cycles in the expansion cohort (n = 108). Results The incidence of ulixertinib-induced dAEs and combined rash were 79% (107/135) and 76% (102/135). The most common dAEs included acneiform rash (45/135, 33%), maculopapular rash (36/135, 27%), and pruritus (34/135, 25%). Grade 3 dAEs were observed in 19% (25/135) of patients; no grade 4 or 5 dAEs were seen. The presence of at least 1 dAE was associated with stable disease (SD) or partial response (PR) (OR = 3.64, 95% CI 1.52–8.72; P =.003). Acneiform rash was associated with a PR (OR = 10.19, 95% CI 2.67–38.91; P <.001). Conclusion The clinical spectrum of ulixertinib-induced dAEs was similar to EGFR and MEK inhibitors; dAEs may serve as a surrogate marker of tumor response. We propose treatment algorithms for common ERK inhibitor-induced dAEs to maintain patients{\textquoteright} quality of life and dose intensity for maximal clinical benefit. Clinical Trial Registration: NCT01781429.",
keywords = "Clinical trial, Dermatologic adverse events, ERK inhibitor, Ulixertinib",
author = "J. Wu and D. Liu and M. Offin and C. Lezcano and Torrisi, {J. M.} and S. Brownstein and Hyman, {D. M.} and Gounder, {M. M.} and W. Abida and A. Drilon and Harding, {J. J.} and Sullivan, {R. J.} and F. Janku and D. Welsch and M. Varterasian and A. Groover and Li, {B. T.} and Lacouture, {M. E.}",
note = "Funding Information: This study was supported in part by the National Institutes of Health/National Cancer Institute Memorial Sloan Kettering Cancer Center Support Grant P30 CA008748. Funding Information: Dr. Wu has nothing to disclose. Dr. Liu reports serving on the Advisory board for Pfizer and Heron Therapeutics. Dr. Offin reports personal fees from PharmaMar, personal fees from Novartis, personal fees from Targeted Oncology, personal fees from Bristol-Myers Squibb, personal fees from Merck Sharp & Dohme, outside the submitted work. Drs. Lezcano, Torrisi, and Brownstein have nothing to disclose. Dr. Hyman owns stock in Fount Therapeutics, has served on advisory boards for ArQule, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, CytomX, Debiopharm, Fount Therapeutics, Genentech, Eli Lilly, Janssen, Jazz Pharma, Pfizer, and Puma Biotechnology, received research funding from AstraZeneca, Bayer, Loxo Oncology, and Puma Biotechnology, and received travel expenses from Chugai Pharma and Genentech; he is currently employed by and holds equity in Loxo Oncology, a subsidiary of Eli Lilly. Dr. Gounder has received honoraria from Bayer and Flatiron Health, served on advisory boards for Bayer, Boehringer Ingelheim, Epizyme, Daiichi Sankyo, Karyopharm, and Springworks Therapeutics, served on a speakers{\textquoteright} bureau for Amgen, and received travel expenses from Epizyme. Dr. Abida reports receiving honoraria from CARET, consulting for Clovis Oncology, Janssen, MORE Health, ORIC Pharmaceuticals, Daiichi Sankyo, research funding from AstraZeneca, Zenith Epigenetics, Clovis Oncology, GlaxoSmithKline, and travel expenses from GlaxoSmithKline, Clovis Oncology, ORIC Pharmaceuticals. Dr. Drilon reports honoraria/advisory board participation from Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Roche, Novartis, EMD Serono, MJH, Faculty RTP, Medendi; associated research paid to the institution from Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; research from Foundation Medicine; royalties from Wolters Kluwer; other support from Merck, Puma, Merus, Boehringer Ingelheim; and CME honoraria from Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD. Dr. Harding reports consulting fees from Bristol Myers Squibb, CytomX, Eli Lilly, Eisai, Exelixis, Imvax, QED, and research funding from Bristol Myers Squibb. Dr. Sullivan reports research funding from Merck, Amgen; and Consulting/Advisory Board Membership with Asana Biosciences, Bristol Myers Squibb, Eisai, Iovance, Merck, Novartis, Pfizer. Dr. Janku has institutional research support from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Synlogic, SpringBank Pharma, Agios, Plexxikon, Deciphera, Piqur, FujiFilm Pharma, Symphogen, Bristol-Myers Squibb, Asana, Astex, Sotio, SQZ, Bicara, JS Innopharm and Proximagen; is or has been on the Scientific Advisory Boards of Guardant Health, IFM Therapeutics, Synlogic, Bicara, Asana, PureTech Health, Synlogic and Deciphera; is a paid consultant for Cardiff Oncology and Immunomet; and has ownership interests in Cardiff Oncology. Dr. Welsch is an employee of ImmunoMet Therapeutics. Dr. Varterasian has nothing to disclose. Dr. Groover is an employee of Biomed Valley Discoveries. Dr. Li is a consultant/advisor at Roche/Genentech, Biosceptre International, Thermo Fisher Scientific, Mersana Therapeutics, Hengrui Therapeutics, and Guardant Health, reports receiving commercial research grants from Roche/Genentech, Daiichi Sankyo, Amgen, Lilly, Hengrui Therapeutics, Illumina, Guardant Health, BioMed Valley Discoveries, AstraZeneca, GRAIL, and MORE Health, and has ownership interest in two institutional patents at Memorial Sloan Kettering Cancer Center (US62/685,057, US62/514,661). Dr. Lacouture reports acting as consultant/advisory role for Legacy Healthcare Services, Apricity Health, LLC, Azitra, Inc., Deciphera, Galderma Research and Development, Johnson and Johnson, NCODA, Novocure Inc., Kyowa Kirin, Inc., Loxo, Merck Sharp and Dohme Corporation, Janssen Research & Development, LLC, Menlo Therapeutics, Novartis Pharmaceuticals Corporation, QED Therapeutics, F. Hoffmann-La Roche AG, Amgen Inc., Astrazeneca Pharmceuticals LP, Genentech, Inc., Seattle Genetics, Lutris, Paxman Coolers, OnQuality Pharmaceuticals Ltd., Takeda Millenium, and research funding from Veloce, US Biotest, Lutris, Paxman. ",
year = "2021",
doi = "10.1007/s10637-020-01035-9",
language = "English (US)",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
}