Abstract PR09: Phase 1 clinical safety and efficacy of ASN007, a novel oral ERK1/2 inhibitor, in patients with RAS, RAF or MEK mutant advanced solid tumors
Authors: Tolcher Anthony W. , Sullivan Ryan J. , Rasco Drew W. , Eroglu Zeynep , Lakhani Nehal , Kessler Dana , Usansky Helen , Reddy Sanjeeva , Denis Louis J. , Janku Filip 
Published: March 2020

Abstract
Background: The oncogenic mitogen-activated protein kinase (MAPK) pathway is dysregulated in a broad range of cancers through mutations in BRAF, KRAS, NRAS, HRAS and MEK1 genes. ASN007 is a novel, potent and orally bioavailable inhibitor of ERK1/2 kinases (IC50 1-2nM) with a very long target residence time (550 min). Preclinical studies show strong anti-tumor activity in multiple RAS mutant xenograft and PDX models, irrespective of mutation subtype. ASN007 also maintains strong activity in BRAF mutant melanoma PDX models resistant to BRAF and MEK inhibition. Preclinical activity is seen with both intermittent as well as daily dosing. This is the initial report of ASN007 clinical data from this first-in-human Phase 1 Study. Methods: This Phase 1 trial evaluates ASN007 in patients (PS 0-1) with metastatic solid tumors refractory to standard therapies using an accelerated dose titration design for once daily (QD) and once weekly (QW) oral dosing (NCT03415126). Primary objectives in Part A (dose finding) include safety, tolerability, PK and PD to determine the Maximum Tolerated Dose (MTD). Part B (disease specific expansion) will evaluate clinical activity in cohorts of 15 patients each with tumors harboring specific mutations which include NRAS, HRAS, MEK1 and BRAF. Results: To date, 42 eligible patients (pts) were enrolled at dose levels ranging from 10mg to 80mg QD and 80 mg to 350mg QW. The respective MTDs are 40mg QD and 250mg QW. Reversible treatment-related adverse events (TRAEs) at 40mg QD (n=10) included rash ( 90%, Gr3 10%), nausea/vomiting (Gr1 30%), diarrhea (Gr1 30%), fatigue (20%, Gr3 10%) and central serous retinopathy (CSR) (30%, no G3) and at 250mg QW (n=9) included rash (33%, no Gr3), CSR (11%, Gr3 11%), blurred vision (44%, Gr3 11%), nausea/vomiting (33%, Gr3 11%) and diarrhea (33%, no Gr3). Dose limiting toxicities (DLTs) included Gr3 CSR at 60 and 80 QD, Gr3 rash at 80mg QD and Gr3 AST at 350mg QW. Durable clinical benefit was noted for 3 pts treated with QW ASN007 at doses 120 mg to 250 mg: a confirmed partial response (-57%) in a patient with HRAS-mutant salivary gland cancer for 5+ months, stable disease in KRAS mutant ovarian cancer for 9+ months and stable disease in BRAF V600E mutant thyroid cancer for 8+ months. Pharmacokinetic studies demonstrated dose dependent increase in the Cmax and AUC24 with both QD and QW dosing. QW dosing Cmax levels exceed average IC50 values more than &gt;30-fold. Inter-subject variability was moderate (≤ 50%) and the elimination t1/2 was 10-15 hours. Conclusions: ASN007 is a selective oral inhibitor of ERK1/2 with a long target residence time. QD or QW dosing is feasible with expected reversible and manageable AE profile and dose dependent exposure. The dose of 250mg QW was selected for further development due to favorable tolerability and encouraging signs of clinical activity. Part B of the study is open to enroll patients with solid tumors harboring BRAF, MEK1, and RAS mutations. Updated clinical, safety, PK/PD and efficacy data will be presented.
Citation Format: Anthony W. Tolcher, Ryan J. Sullivan, Drew W. Rasco, Zeynep Eroglu, Nehal Lakhani, Dana Kessler, Helen Usansky, Sanjeeva Reddy, Louis J. Denis, Filip Janku. Phase 1 clinical safety and efficacy of ASN007, a novel oral ERK1/2 inhibitor, in patients with RAS, RAF or MEK mutant advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR09. doi:10.1158/1535-7163.TARG-19-PR09