Abstract CT003: Activity of the ERK1/2 inhibitor ulixertinib (BVD-523) in patients with BRAF and NRAS mutant melanoma
Authors: Sullivan Ryan J. , Janku Filip , Li Bob T. , Wong Deborah , Sosman Jeffrey , Keedy Vicki , Buchbinder Elizabeth , Tolcher Anthony , Varghese Anna , Hyman David M. , Flaherty Keith T. , Ribas Antoni , Carvajal Richard , Wang-Gillam Andrea , Kluger Harriet , Patel Manish , Langecker Peter , Varterasian Mary , Welsch Dean , Infante Jeffrey 
Published: July 2017

Abstract
Background: Activating mutations of BRAF (50%) or NRAS (25%) are present in over 75% of patients with metastatic melanoma. Inhibitors of BRAF or MEK have been shown to improve survival in patients with specific BRAF-mutations, whereas inhibitors of MEK are associated with responses in over 20% of patients with NRAS mutations. ERK1/2 are serine-threonine kinases downstream of NRAS and BRAF in the MAPK pathway. Ulixertinib is a potent, selective, reversible, ATP-competitive ERK1/2 inhibitor that has demonstrated anti-proliferative effects in cells has been shown to reduce tumor growth and induce tumor regression in BRAF- and RAS-mutant xenograft models.
Methods: Fifty-two patients with metastatic melanoma were enrolled to either the dose escalation (8) or expansion (44) portions of this study (NCT01781429). The dose escalation phase enrolled a total of 27 patients (10-900 mg, BID) and established the recommended phase 2 dose (RP2D) of 600 mg, BID. In cohort expansion, BRAF-mutant melanoma patients without or with prior BRAF/MEK inhibitor therapy, and NRAS-mutant melanoma patients not treated with BRAF /MEK inhibitors were enrolled at the RP2D. Best response was determined by RECIST1.1.
Results: Overall, of the evaluable melanoma patients with BRAF mutations treated in this study (24), 4 had a partial response (PR, [17%]). Among the 8 melanoma patients treated in dose escalation, 6 had BRAFV600 mutations and 3 of these 6 had a partial response (PR), including one patient with PR who was not previously treated with BRAF/MEK inhibitor (all others were). In the expansion phase, only one melanoma patient was enrolled that had not previously received BRAF or MEK inhibitor and had a best response to therapy of stable disease (SD) that lasted over four months. For the 21 melanoma patients enrolled that had prior BRAF/MEK inhibitor therapy, including 20 with BRAFV600 mutation and 1 with a BRAF fusion, 15 were evaluable for response. Of these, 1 had a PR (7%), 6 SD, and 8 with progressive disease (PD). In the NRAS mutant melanoma cohort of 22 patients, including Q61 (17) or G13 (3) or unspecified mutations (2), 17 were evaluable for response; 2 PR (12%), 6 SD, and 9 PD. The most common treatment related adverse events (AEs) were diarrhea (54%), rash (46%), fatigue (42%), nausea (40%), and dermatitis acneiform (31%). 26 treatment-related Grade 3 events occurred in 21 patients, with acneiform rash (3), maculopapular rash (3), diarrhea (3), anemia (3), and fatigue (2) being the only events occurring multiple times. No treatment related grade 4 or 5 events occurred.
Conclusions: Ulixertinib was well tolerated and associated with activity in patients with metastatic melanoma with either a BRAF mutation, in both the BRAF/MEK inhibitor treatment naïve and refractory setting, or NRAS mutation. Further studies, either as single-agent or in combination, to determine the clinical utility of ulixertinib in cancer patients are ongoing.
Citation Format: Ryan J. Sullivan, Filip Janku, Bob T. Li, Deborah Wong, Jeffrey Sosman, Vicki Keedy, Elizabeth Buchbinder, Anthony Tolcher, Anna Varghese, David M. Hyman, Keith T. Flaherty, Antoni Ribas, Richard Carvajal, Andrea Wang-Gillam, Harriet Kluger, Manish Patel, Peter Langecker, Mary Varterasian, Dean Welsch, Jeffrey Infante. Activity of the ERK1/2 inhibitor ulixertinib (BVD-523) in patients with BRAF and NRAS mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT003. doi:10.1158/1538-7445.AM2017-CT003