Pharmacodynamic activity of selumetinib to predict radiographic response in advanced uveal melanoma.

Abstract

8598 Background: Functionally activating mutations (mut) in Gnaq or Gna11, genes that encode for widely expressed G-protein alpha subunits, are early oncogenic events in uveal melanoma (UM) development and result in activation of the MAPK pathway. We previously demonstrated effective pathway inhibition with selumetinib (AZD6244, ARRY-142866) in UM cell lines, with decreased viability associated with pERK and cyclinD1 suppression (Ambrosini, AACR 2010). Methods: Using paired metastatic tumor biopsies from patients (pts) with radiographically progressing UM treated with selumetinib 75 mg BID on a phase II trial (NCT01143402), we correlated MAPK pathway inhibition with radiographic tumor regression and clinical benefit. Biopsies were performed at baseline and after 14 +/-1 days of treatment. Western blotting was performed for pERK and cyclinD1, and quantitated by densitometry. Response (RECIST 1.1) was assessed at baseline, week (wk) 4, wk 8, and q8wks subsequently. Radiographic regression was defined as greatest percentage shrinkage from baseline. Clinical benefit was defined as RECIST response or stable disease ≥16wks. Results: Paired tumor biopsies were assayed from 18 pts: median age 60 (range 47-81), M:F 11:7, median 1 prior therapy (range 0-2), 17 with liver involvement, Gnaq mut:Gna11 mut:wild-type 8:9:1. Radiographic regression was observed in 5 pts, with 2 achieving partial responses. 4 pts were on study ≥16wks (16+, 20, 25, 31 wks), with one currently on study at 11+ wks. Median pERK and cyclinD1 as measured by densitometry decreased by 48% (p=.03) and 76% (p=.03), respectively. Radiographic regression correlated with suppression of pERK (Spearmen’s rank correlation; p=0.04) but not cyclinD1 (p=0.38). A trend towards pERK suppression correlating with clinical benefit was observed (p=.07) with each of the 5 pts achieving PR or SD ≥16wks having a decrease of ≥30% in pERK from baseline. Conclusions: Selumetinib can inhibit pERK and cyclinD1 in UM and can result in tumor shrinkage. Sustained inhibition of pERK inhibition at day 14 may be predictive of benefit. Further evaluation of MEK inhibition in this disease is warranted.