Ryan J. Sullivan, MD
Bob T. Li, MD, MPH
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 has an acceptable safety profile with favorable pharmacokinetics and that the therapy shows 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 Ryan J. Sullivan, MD, of Massachusetts General Hospital and Harvard Medical School, and Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center, and colleagues was published in Cancer Discovery.
Between April 2013 and March 2017, 135 patients at 12 sites were enrolled into this study. A total of 27 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.
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 Dr. Sullivan in a statement. “The results of this study can be built upon to develop better treatment regimens for these patients.” ■