Phase Ib/Ii Study of Lee011 (Cdk4/6 Inhibitor) and Lgx818 (Braf Inhibitor) in Braf-Mutant Melanoma

Abstract

ABSTRACT Aim: Despite improvements in BRAF-mutant melanoma therapy, resistance is problematic. The cyclin D–CDK4/6–INK4A–Rb pathway is frequently dysregulated in melanoma and is associated with reduced BRAF inhibitor (BRAFi) response. LGX818 and LEE011 selectively inhibit BRAF and CDK4/6, respectively. In preclinical models, adding LEE011 to LGX818 delayed BRAFi resistance. This study investigates safety and efficacy of LEE011 and LGX818 in pts with BRAF-mutant locally advanced or metastatic, BRAFi-naïve or BRAFi-pretreated melanoma. Methods: Pts receive once-daily LEE011 (3-weeks-on/1-week-off) and LGX818 (continuously). Dose escalation is guided by Bayesian Logistic Regression Model with overdose control principle and real-time PK. Primary objective: MTD and/or RP2D determination. Secondary objectives: safety, PK, and efficacy. Results: As of April 8, 2014, 18 pts received LEE011 and LGX818: 6 at 200/300; 7 at 300/200; 3 at 400/100; 2 at 400 mg LEE011/200 mg LGX818. Median age: 64 (23–81) yrs; median 3 prior regimens: 78% prior BRAFi therapy; 44% prior MEKi therapy (all of whom received prior BRAFi). Two DLTs reported, both at the 200/300 dose (G3 myalgia and G3 conjugated hyperbilirubinemia). Study-drug related (SDR) all-grade AEs (>25%; N = 11): palmar–plantar hyperkeratosis (PPH; 46%); flushing (36%); pruritus (36%); rash (36%); alopecia, dry skin, dysgeusia, fatigue, myalgia, and nausea (27% each). SDR G3/4 AEs observed in 1 pt: PPH, rash, myalgia, and blood bilirubin increase. At steady-state, exposure of LGX818 was increased 1.5-fold and 2- to 3-fold at the 200/300 and 300/200 doses, respectively, compared with single agent (SA). Exposure of LEE011 was unaltered at the 200/300 dose and decreased 0.5-fold compared with SA at the 300/200 dose. Of 9 pts evaluable for response, 2 had PRs (1 BRAFi naive and 1 BRAFi pretreated) and 6 had SD (4 ongoing ≥ 4 cycles, 2 BRAFi naïve, 2 BRAFi pretreated). 9 pts remain on treatment. Conclusions: At the 200/300 dose DLTs were observed. At the 300/200 dose, a 2- to 3-fold increase in blood levels of LGX818 compared with historic levels was observed. In latter cohorts, reduced LGX818 and increased LEE011 doses are being tested and appear better tolerated. Clinical signs of activity were observed even in BRAFi-pretreated pts. Dose escalation continues. Disclosure: M. Taylor: has served on a paid advisory board for Onyx. No other conflicts; M.S. Carlino: has received honoraria from Novartis; W. Miller: has worked in a consultancy capacity or on advisory boards for Novartis, Roche, GSK, and BMS; A. Marino: is an employee of Novartis Pharma AG; V. Zhang: is an employee of and holds shares in Novartis Pharma AG; S.G. Bhansali: is an employee of and holds shares in Novartis Pharmaceuticals Corporation; S. Parasuraman: is an employee of and holds shares in Novartis Pharma AG.All other authors have declared no conflicts of interest.