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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

Ryan J. Sullivan, Jeffrey R. Infante, Filip Janku, Deborah Jean Lee Wong, Jeffrey A. Sosman, Vicki Keedy, Manish R. Patel, Geoffrey I. Shapiro, James W. Mier, Anthony W. Tolcher, Andrea Wang-Gillam, Mario Sznol, Keith Flaherty, Elizabeth Buchbinder, Richard D. Carvajal, Anna M. Varghese, Mario E. Lacouture, Antoni Ribas, Sapna P. Patel, Gary A. DeCrescenzo, Caroline M. Emery, Anna L. Groover, Saurabh Saha, Mary Varterasian, Dean J. Welsch, David M. Hyman and Bob T. Li
Ryan J. Sullivan
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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  • For correspondence: rsullivan7@mgh.harvard.edu lib1@mskcc.org
Jeffrey R. Infante
2Sarah Cannon Research Institute, Tennessee Oncology, Nashville, Tennessee.
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Filip Janku
3The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Deborah Jean Lee Wong
4University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California.
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Jeffrey A. Sosman
5Vanderbilt University Medical Center, Nashville, Tennessee.
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Vicki Keedy
5Vanderbilt University Medical Center, Nashville, Tennessee.
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Manish R. Patel
6Sarah Cannon Research Institute, Florida Cancer Specialists, Sarasota, Florida.
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Geoffrey I. Shapiro
7Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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James W. Mier
8Beth-Israel Deaconess Medical Center, Boston, Massachusetts.
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Anthony W. Tolcher
9South Texas Accelerated Research Therapeutics, San Antonio, Texas.
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Andrea Wang-Gillam
10Washington University in St. Louis, St. Louis, Missouri.
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Mario Sznol
11Yale University, New Haven, Connecticut.
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Keith Flaherty
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
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Elizabeth Buchbinder
7Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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Richard D. Carvajal
12Memorial Sloan Kettering Cancer Center, New York, New York.
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Anna M. Varghese
12Memorial Sloan Kettering Cancer Center, New York, New York.
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Mario E. Lacouture
12Memorial Sloan Kettering Cancer Center, New York, New York.
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Antoni Ribas
4University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California.
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Sapna P. Patel
3The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Gary A. DeCrescenzo
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Caroline M. Emery
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Anna L. Groover
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Saurabh Saha
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Mary Varterasian
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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Dean J. Welsch
13BioMed Valley Discoveries, Inc., Kansas City, Missouri.
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David M. Hyman
12Memorial Sloan Kettering Cancer Center, New York, New York.
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Bob T. Li
12Memorial Sloan Kettering Cancer Center, New York, New York.
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  • For correspondence: rsullivan7@mgh.harvard.edu lib1@mskcc.org
DOI: 10.1158/2159-8290.CD-17-1119
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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); 1–12. ©2017 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received October 8, 2017.
  • Revision received November 6, 2017.
  • Accepted November 6, 2017.
  • ©2017 American Association for Cancer Research.
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This OnlineFirst version was published on December 15, 2017
doi: 10.1158/2159-8290.CD-17-1119

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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
Ryan J. Sullivan, Jeffrey R. Infante, Filip Janku, Deborah Jean Lee Wong, Jeffrey A. Sosman, Vicki Keedy, Manish R. Patel, Geoffrey I. Shapiro, James W. Mier, Anthony W. Tolcher, Andrea Wang-Gillam, Mario Sznol, Keith Flaherty, Elizabeth Buchbinder, Richard D. Carvajal, Anna M. Varghese, Mario E. Lacouture, Antoni Ribas, Sapna P. Patel, Gary A. DeCrescenzo, Caroline M. Emery, Anna L. Groover, Saurabh Saha, Mary Varterasian, Dean J. Welsch, David M. Hyman and Bob T. Li
Cancer Discov December 15 2017 DOI: 10.1158/2159-8290.CD-17-1119

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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
Ryan J. Sullivan, Jeffrey R. Infante, Filip Janku, Deborah Jean Lee Wong, Jeffrey A. Sosman, Vicki Keedy, Manish R. Patel, Geoffrey I. Shapiro, James W. Mier, Anthony W. Tolcher, Andrea Wang-Gillam, Mario Sznol, Keith Flaherty, Elizabeth Buchbinder, Richard D. Carvajal, Anna M. Varghese, Mario E. Lacouture, Antoni Ribas, Sapna P. Patel, Gary A. DeCrescenzo, Caroline M. Emery, Anna L. Groover, Saurabh Saha, Mary Varterasian, Dean J. Welsch, David M. Hyman and Bob T. Li
Cancer Discov December 15 2017 DOI: 10.1158/2159-8290.CD-17-1119
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