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First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of

Ryan J Sullivan1, Jeffrey R Infante2, Filip Janku3

  • 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts. rsullivan7@mgh.harvard.edu lib1@mskcc.org.

Cancer Discovery
|December 17, 2017
PubMed

Insights

Ulixertinib, an ERK1/2 inhibitor, demonstrated an acceptable safety profile and early clinical activity in patients with advanced solid tumors harboring BRAF or RAS mutations. The recommended phase II dose was established, showing promising results for targeted cancer therapy.

Area of Science:

  • Oncology
  • Pharmacology
  • Clinical Trials

Background:

  • Targeted therapies are crucial for treating solid tumors with specific genetic mutations.
  • ERK1/2 pathway dysregulation is implicated in various cancers, making it a therapeutic target.
  • Ulixertinib is an ERK1/2 kinase inhibitor with demonstrated preclinical efficacy.

Purpose of the Study:

  • To evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ulixertinib in patients with advanced solid tumors.
  • To determine the recommended phase II dose (RP2D) of ulixertinib.
  • To explore clinical activity in patients with BRAF- and RAS-mutant solid tumors.

Main Methods:

  • A multicenter, phase I, dose-escalation and dose-expansion study (NCT01781429).
  • Patients received ulixertinib orally, with dose escalation from 10 to 900 mg twice daily.
  • Recommended phase II dose (RP2D) established at 600 mg twice daily.

Main Results:

  • The RP2D of 600 mg twice daily was established, achieving near-complete ERK inhibition.
  • Common adverse events included diarrhea (48%), fatigue (42%), and nausea (41%).
  • Partial responses were observed in 17% of patients at or above the maximum tolerated dose and in 14% of evaluable patients in dose expansion, including those with NRAS and BRAF mutations.

Conclusions:

  • Ulixertinib exhibits an acceptable safety profile and favorable pharmacokinetics in patients with advanced solid tumors.
  • Early clinical activity was observed in patients with NRAS-mutant and BRAF-mutant (V600 and non-V600) solid tumors.
  • Ulixertinib represents a potential targeted therapy for a range of solid tumor malignancies.

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