ERK1/2 Inhibitor Ulixertinib in Pan-cancer Patients with BRAF Fusions or Non-V600E/K Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1L.

Authors

Vivek Subbiah, Fengmin Zhao, Ragini R Kudchadkar, Ryan J Sullivan, Helen X Chen, Robert J Gray, Victoria Wang, Lisa M McShane, Larry V Rubinstein, David Patton, P Mickey Williams, Stanley R Hamilton, Tilak K Sundaresan, Barbara A Conley, James V Tricoli, Carlos L Arteaga, John J Wright, Lyndsay N Harris, Peter J O'Dwyer, Alice P Chen, Keith T Flaherty

Published in

Clinical cancer research : an official journal of the American Association for Cancer Research. Aug 11, 2026. Epub Aug 11, 2026.

Abstract

Mutations in BRAF at codons other than V600 (non-V600) and BRAF fusions confer dependence on RAF-MEK-ERK pathway. Subprotocol Z1L (EAY131-Z1L) investigated the clinical activity of ulixertinib (ERK1/2 inhibitor) in patients with tumors harboring these alterations.
In this single-arm study, patients with BRAF non-V600 mutation or BRAF fusion were given ulixertinib orally, at a dose of 600 mg twice daily, continuously for each 28-day cycle until progression or intolerability. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS).
Among 34 eligible patients, median age was 66.5; 50% were female, 88% were white, 9% black, 3% Asian. ECOG PS 1 in 74% of patients. Median number of prior therapies was 4. Tumor types included multiple gastrointestinal malignancies (n = 16), lung cancer, melanoma (n = 3 each), among others. No patients achieved CR or PR, resulting in ORR = 0%. Stable disease was the best response in 7/26 centrally confirmed cases. Median PFS was 1.7 months (90% CI: 1.1, 2.2), 6-month PFS rate was 5% (90% CI: 0.6%, 17.7%), and median OS was 3.5 months (90% CI: 1.9, 5.4). Twenty patients (57%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity as their worst toxicity; there were no grade 5 toxicities.
Ulixertinib had no demonstrable evidence of clinical activity in this small, heavily pretreated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations.

PMID:
42578969
Bibliographic data and abstract were imported from PubMed on 11 Aug 2026.

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