Phase I Study Finds ERK1/2 Inhibitor Safe and Active in Advanced Solid Tumors

Key Points

  • Phase I study finds ulixertinib has an acceptable safety profile with favorable pharmacokinetics and evidence of clinical activity in NRAS- and BRAF V600– and non–V600-mutant solid tumors.
  • The preliminary efficacy of ulixertinib in a variety of molecularly defined cohorts supports the ongoing development of the drug as a single agent as well as in combination therapies.

Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. Now, a multicenter phase I study investigating its safety and efficacy in the treatment of patients with advanced solid tumors has found that ulixertinib to have an acceptable safety profile with favorable pharmacokinetics and that the therapy showed early evidence of clinical activity in NRAS- and BRAF V600 and non–V600-mutant solid tumors. The preliminary efficacy of ulixertinib supports the ongoing development of the drug as a single agent as well as in combination therapies. The study by Sullivan et al was published in Cancer Discovery.

Study Methodology

Between April 2013 and March 2017, a total of 135 patients at 12 sites were enrolled into this study. Twenty-seven patients were enrolled in the dose-escalation portion and 108 patients were enrolled in the cohort-expansion portion. The median patient age was 62 years. All patients had advanced solid tumors, and more than 65% had BRAF-mutant cancers. Of the patients, 24% had received prior BRAF and/or MEK therapy, and 51% had received prior immunotherapy.

Study Findings

In the dose-escalation phase, the recommended phase II dose of ulixertinib was determined to be 600 mg twice daily. The dose-expansion portion of the trial tested the recommended phase II dose of ulixertinib in six groups of patients whose tumors had BRAF, NRAS, or MEK mutations, the majority of whom were not treated with prior MAPK-targeted therapy.

Partial responses were seen in 12% and 14% of evaluable patients in the dose-escalation and dose-expansion cohorts, respectively. Partial response and/or disease stabilization was seen in all groups, including those with solid tumors with atypical BRAF mutations. Patients treated at the recommended phase II dose had near-complete inhibition of ERK activity.

The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%).

“This study shows that ulixertinib is tolerable and has activity in a subset of patients with mutations in the MAPK pathway,” said Ryan J. Sullivan, MD, Assistant Professor of Hematology/Oncology at Massachusetts General Hospital Cancer Center and lead author of this study, in a statement. “The results of this study can be built upon to develop better treatment regimens for these patients.”

Dr. Sullivan and Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, are the corresponding authors of this study.

This study was funded by BioMed Valley Discoveries. Several authors of this study are or were employed by BioMed. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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