First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study

Cancer Discov. 2018 Feb;8(2):184-195. doi: 10.1158/2159-8290.CD-17-1119.

Ryan J Sullivan ^# ¹, Jeffrey R Infante ^# ², Filip Janku ^# ³, Deborah Jean Lee Wong ⁴, Jeffrey A Sosman ⁵, Vicki Keedy ⁵, Manish R Patel ⁶, Geoffrey I Shapiro ⁷, James W Mier ⁸, Anthony W Tolcher ⁹, Andrea Wang-Gillam ¹⁰, Mario Sznol ¹¹, Keith Flaherty ¹², Elizabeth Buchbinder ⁷, Richard D Carvajal ¹³, Anna M Varghese ¹³, Mario E Lacouture ¹³, Antoni Ribas ⁴, Sapna P Patel ³, Gary A DeCrescenzo ¹⁴, Caroline M Emery ¹⁴, Anna L Groover ¹⁴, Saurabh Saha ¹⁴, Mary Varterasian ¹⁴, Dean J Welsch ¹⁴, David M Hyman ¹³, Bob T Li ¹⁵

Affiliations

1 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. [email protected] [email protected].
2 Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee.
3 The University of Texas MD Anderson Cancer Center, Houston, Texas.
4 University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California.
5 Vanderbilt University Medical Center, Nashville, Tennessee.
6 Sarah Cannon Research Institute, Florida Cancer Specialists, Sarasota, Florida.
7 Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
8 Beth-Israel Deaconess Medical Center, Boston, Massachusetts.
9 South Texas Accelerated Research Therapeutics, San Antonio, Texas.
10 Washington University in St. Louis, St. Louis, Missouri.
11 Yale University, New Haven, Connecticut.
12 Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
13 Memorial Sloan Kettering Cancer Center, New York, New York.
14 BioMed Valley Discoveries, Inc., Kansas City, Missouri.
15 Memorial Sloan Kettering Cancer Center, New York, New York. [email protected] [email protected].
# Contributed equally.

PMID: 29247021 DOI: 10.1158/2159-8290.CD-17-1119

Abstract

Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600-, and non-V600 BRAF-mutant solid tumors.Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600-mutant solid-tumor malignancies. Cancer Discov; 8(2); 184-95. ©2017 AACR.See related commentary by Smalley and Smalley, p. 140This article is highlighted in the In This Issue feature, p. 127.

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