Purpose: Mutations in BRAF at codons other than V600 (non-V600) and BRAF fusions confer dependence on RAF-MEK-ERK pathway. BVD-523FB (ulixertinib) is a small molecule that potently inhibits both ERK1 and ERK2 protein kinases in the sub-nanomolar range. Based on the reports of early clinical activity in the phase 1 trial, including in non-V600 BRAF mutations, subprotocol Z1L (EAY131-Z1L) sought to investigate the clinical activity of ulixertinib in patients with tumors harboring these alterations. Methods: 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). BRAF mutation status was determined by an analytically validated assay in a CLIA-certified laboratory for all patients. Results: From August 2019 to July 2020, 35 patients were enrolled and received protocol treatment on the trial. Among the 34 patients who were eligible, median age was 66.5; 50% were female, 88% were white, 9% black, 1% Asian. Performance status was ECOG PS 1 in 74% of patients, with remaining PS 0. Median number of prior therapies was >3.Tumor types included multiple gastrointestinal malignancies (N=16), lung cancer (N=3), and melanoma (N=3), among others. Mutations were centrally confirmed in 26 patients who were deemed analyzable per protocol. Twenty-two patients had a single nucleotide variant (SNV) in BRAF; one patient had an insertion/deletion (indel) in BRAF, and three patients harbored BRAF fusions. 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 1.8 months (90% CI: 1.6, 2.2), 6-month PFS rate was 11% (90% CI: 4%, 22%), and median OS was 4.0 months (90% CI: 2.8, 7.4). Twenty patients (57%) had grade 3 toxicities, and one patient (3%) had grade 4 toxicity; there were no grade 5 toxicities. Most common toxicities include anemia (n=11), diarrhea (n=16), nausea (n=16), vomiting (n=11), fatigue (n=16), increased creatinine (n=12), and acneiform rash (n=14). Conclusion: BVD-523FB (ulixertinib) had no demonstrable evidence of clinical activity in this small, heavily pre-treated population of patients with tumors harboring BRAF fusions, or with non-V600E, non-V600K BRAF mutations
Citation Format: Vivek Subbiah, Fengmin Fengmin, Ragini Kudchadkar, Ryan J. Sullivan, Edith P. Mitchell, John J. Wright, Helen X. Chen, Robert J. Gray, Xin Victoria Wang, Lisa M. McShane, Larry V. Rubinstein, David Patton, P. Mickey Williams, Tilak K. Sundaresan, Barbara A. Conley, Carlos L. Arteaga, Lyndsay N. Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty. BVD-523FB (Ulixertinib) in Patients with Tumors with BRAF Fusions, or with Non-V600E, Non-V600K BRAF Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol EAY131-Z1L [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT160.