Updated clinical outcomes from ULI-EAP-100, an intermediate expanded access program for ulixertinib (BVD-523).
Authors: Stuhlmiller Timothy Joseph , Cohen Stacey , Jain Sharad K. , Nair Suresh , Weinberg Benjamin Adam , Ginn Sarah , Wood Alayna , Knoerzer Deb , Box Jessica A. , Federowicz Bryan , Kesari Santosh 
Published: June 2022

e15101

Background: Ulixertinib is a first-in-class selective small molecule inhibitor of ERK1/2 with demonstrated clinical efficacy in patients with solid tumors harboring MAPK pathway alterations in BRAF and NRAS. Emerging clinical data suggest improved efficacy for certain patient populations when MEK/ERK inhibitors are combined with inhibitors of autophagy (hydroxychloroquine), CDK4/6 (palbociclib), or EGFR/BRAF (cetuximab/encorafenib). Methods: ULI-EAP-100 (NCT04566393) is an ongoing intermediate expanded access protocol (EAP) that offers ulixertinib to US patients with advanced solid tumors harboring MAPK pathway alterations including but not limited to KRAS, BRAF, NRAS, MEK1/2, and ERK1/2, who have exhausted or not tolerated standard-of-care. Combinations with approved agents are permitted at the discretion of the treating physician and approval. Clinical data is collected and structured in a 21 CFR Part 11-compliant database according to XCELSIOR (NCT03793088), a real-world observational registry. Results: As of February 1st, 2022, 48 patients (pts) across 17 sites have been treated with ulixertinib under ULI-EAP-100 including pts with colorectal cancer (CRC) (21), melanoma (8), pancreatic ductal adenocarcinoma (PDAC) (6), lung cancer (5), cholangiocarcinoma (4), glioblastoma (2), and appendiceal cancer (2). Qualifying alterations were mutations in KRAS (21 pts), BRAF (13), NRAS (3), MAP2K1 (1), multiple genes (7), and overexpression of MAPK1 (1). Regimens included ulixertinib monotherapy (28 pts), ulixertinib + hydroxychloroquine (12), ulixertinib + encorafenib + EGFRi (cetuximab, panitumumab) (5), ulixertinib + palbociclib (2), and ulixertinib + encorafenib + atezolizumab (1). Thirty-nine (39) pts have discontinued ulixertinib for reasons including progression (25), AEs (9), and patient choice including hospice (5). Most common AEs (any grade/relatedness) were acneiform rash (29%), fatigue (25%), diarrhea (19%), abdominal pain (15%), and anorexia (15%). Grade 3/4 SAEs occurred in 15 pts (31%). Nine pts (19%) expired while on protocol, all attributed to disease progression. Four pts attained clinical benefit including BRAF V600E PDAC and glioblastoma pts on monotherapy for 413 and 128 days, respectively. A BRAF D594G melanoma pt’s tumor rapidly shrunk with monotherapy permitting surgery and rendering pt with no evidence of disease and a BRAF V600E CRC pt experienced a complete response following ulixertinib + encorafenib + cetuximab combination therapy. Conclusions: ULI-EAP-100 is a unique EAP permitting monotherapy and personalized combination regimens at treating physicians’ discretion. Safety of ulixertinib in this program is consistent with previous experience and all grade 5 AEs were attributed to disease progression. Multiple patients who exhausted prior therapies gained significant clinical benefit from ulixertinib under ULI-EAP-100. Clinical trial information: NCT04566393.