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Background: Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation.We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel,a small molecule inhibitor of MEK1/2(Ambrosini,CCR 2012).Methods: We conducted a 16 center randomized phase Ⅱ study of hyd-sulfate sel 75 mg BID vs TMZ 150 mg/m2 daily for 5 days in 28-day cycles(or DTIC 1000 mg/m2 q21 days)for patients(pts)with metastatic UM with a Q209 Gq/11 mut who have not received prior TMZ/DTIC.The primary endpoint was progression free survival(PFS).Secondary endpoints included overall survival(OS)and response rate(RR).Select pts underwent tumor biopsies at baseline and after 14(+/-3 days)of sel.Our statistical plan required ≥80 pts randomized and ≥68 events to detect a PFS hazard ratio of 0.6(p=0.1).Randomization was stratified by mut(Gq vs G11),M stage and number of prior therapies(tx).Tumor assessment occurred every 4 weeks(wks)for 8 wks and then every 8 wks using RECIST 1.1.Pts receiving TMZ who progressed could receive sel(TMZ→sel).Results: 80 pts were randomized.Sel(n=39): median age 66(range 32-86),54%male,54%G11 mut,median ECOG PS 0(range 0-1),97%M1c,median prior tx 0(range 0-2).TMZ(n=41): median age 60(range 34-81),63%male,58%G11 mut,median ECOG PS 0(range 0-1),93%M1c,median prior tx 0(range 0-2).11/39(28%)pts on sel experienced grade(gr)3 toxicity(tox)manageable with dose modification(5 CPK elevation,3 LFT elevation,1 rash,1 lymphopenia,1 edema).1/41(2%)pt on TMZ experienced gr 3 tox(neutropenia).No gr 4/5 tox occurred.28 pts on sel underwent paired tumor biopsies with inhibition of pERK and cyclinD1 observed by Western blot at day 14.At interim analysis(9/25/12),55 pts were evaluable with 45 progression events and 16 deaths.Sel(n=27): median PFS 16 wks(95%CI 8-30.9),RR 11%,median OS 11.8 months(95%CI 4.8-not reached).TMZ(n=28): median PFS 4 wks(95%CI 3.7-15),RR 0%,median OS 4.7 months(95%CI 4.3-14.3).TMZ→sel(n=25): median PFS 8.1 wks(95%CI 7-15),RR 0%.Conclusions: Sel is the first drug to ever show improved clinical activity in UM relative to TMZ.Sustained target inhibition is observed with sel.Final results will be presented.