Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut) uveal melanoma (UM).

Melanoma/Skin Cancers
Session Type and Session Title: 
Oral Abstract Session, Melanoma/Skin Cancers
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr CRA9003)
Richard D. Carvajal, Jeffrey Alan Sosman, Fernando Quevedo, Mohammed M. Milhem, Anthony Michael Joshua, Ragini Reiney Kudchadkar, Gerald P. Linette, Thomas Gajewski, Jose Lutzky, David H. Lawson, Christopher D. Lao, Patrick J. Flynn, Mark R. Albertini, Takami Sato, Daniel Paucar, Katherine S. Panageas, Mark Andrew Dickson, Jedd D. Wolchok, Paul B. Chapman, Gary K. Schwartz; Memorial Sloan-Kettering Cancer Center, New York, NY; Vanderbilt University Medical Center, Nashville, TN; Mayo Clinic, Rochester, MN; University of Iowa Hospital and Clinics, Iowa City, IA; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Washington University in St. Louis, St. Louis, MO; The University of Chicago, Chicago, IL; Mount Sinai Comprehensive Cancer Center, Miami Beach, FL; Emory University School of Medicine, Atlanta, GA; University of Michigan, Ann Arbor, MI; Metro Minnesota Community Clinical Oncology Program, St. Louis Park, MN; University of Wisconsin, Madison, WI; Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA; Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY

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Abstract Disclosures


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. Clinical trial information: NCT01143402.