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

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 treatmentrelated 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 fi rst-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profi le 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);

Phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF‐mutated melanoma and other advanced malignancies

“…This compares favorably with previously published response rates of 11% to 18% in chemotherapy‐naive patients with metastatic melanoma treated with carboplatin and paclitaxel and with some published results for targeted treatment strategies for patients with BRAF ‐mutated melanoma previously treated with BRAF inhibitors . For instance, the first‐in‐class extracellular signal‐regulated kinase inhibitor ulixertinib demonstrated a PR/CR rate of 16% (3 of 19) in patients with advanced BRAF V600 ‐mutated melanoma previously treated with BRAF and/or MEK inhibitors . However, the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in patients with advanced BRAF V600 ‐mutated melanoma previously treated until progression with a BRAF inhibitor without or with an MEK inhibitor followed by a treatment break demonstrated CR/PR rates of 32% to 37% .…”

“…12,13,22 For instance, the first-in-class extracellular signal-regulated kinase inhibitor ulixertinib demonstrated a PR/CR rate of 16% (3 of 19) in patients with advanced BRAF V600 -mutated melanoma previously treated with BRAF and/or MEK inhibitors. 23 However, the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in patients with advanced BRAF V600 -mutated melanoma previously treated until progression with a BRAF inhibitor without or with an MEK inhibitor followed by a treatment break demonstrated CR/PR rates of 32% to 37%. 24,25 This relatively high CR/PR rate can be explained by a suppression of resistance clones after discontinuation of a BRAF inhibitor.…”

Effects of ATP‐competitive and function‐selective ERK inhibitors on airway smooth muscle cell proliferation

“…Several potent ATP-competitive or catalytic site inhibitors of ERK1/2 have been developed and are being tested for the treatment of cancer (24)(25)(26)(27). Given the large number of ERK1/2 substrates and their capacity to regulate numerous cellular signaling pathways and functions, we have identified substrate-selective ERK1/2 inhibitors with the goal of inhibiting specific kinase functions associated with disease while preserving other ERK1/2 functions needed for normal cell functions (28)(29)(30).…”

Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies

“…A total of 105 patients, a subset of the total number of patients enrolled in this phase 1 study [1], were included in the analysis (Table 1). In Part 1, 24 patients who qualified for the ECG assessment were enrolled; six patients were in the low-dose group.…”

“…Ulixertinib inhibits growth and survival of cancer cells in cultured cell lines, including melanoma, colorectal, and pancreatic cell lines harboring BRAF or RAS mutations, as well as in animal models. Tumor response was assessed in 101 patients treated with ≥ 600 mg twice daily (BID) ulixertinib, of whom 14 had a partial response per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria [1]. While ulixertinib modestly inhibited (IC 50 , 3.4 µM) the human ether-á-go-go-related gene, it did not significantly prolong the cardiac action potentials recorded from dog Purkinje fibers at concentrations of up to 10 µg/mL.…”