A phase 1b/2 study of LEE011 in combination with binimetinib (MEK162) in patients with NRAS-mutant melanoma: Early encouraging clinical activity.

Melanoma/Skin Cancers
Session Type and Session Title: 
Clinical Science Symposium, Novel Combination Therapies for Melanoma
Abstract Number: 
J Clin Oncol 32:5s, 2014 (suppl; abstr 9009)
Jeffrey Alan Sosman, Muaiad Kittaneh, Martijn P. J. K. Lolkema, Michael Andrew Postow, Gary Schwartz, Catherine Franklin, Alessandro Matano, Suraj Bhansali, Sudha Parasuraman, Kevin Kim; Vanderbilt University Medical Center, Nashville, TN; Center for Translational Therapeutics, Karmanos Cancer Institute, Detroit, MI; University Medical Center Utrecht, Utrecht, Netherlands; Memorial Sloan Kettering Cancer Center, New York, NY; Columbia University Medical Center, New York, NY; Novartis Institutes for Biomedical Research, Cambridge, MA; Novartis Pharma AG, Basel, Switzerland; Novartis Pharmaceuticals, East Hanover, NJ; Novartis Pharmaceuticals Corporation, East Hanover, NJ; The University of Texas MD Anderson Cancer Center, Houston, TX

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Abstract Disclosures


Background: NRAS-mutant melanoma has poor prognosis with no approved targeted therapies. Enhanced MAPK pathway signaling and cell cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma. Thus, simultaneous inhibition of MEK and CDK4/6 could further suppress pathway activation. The MEK inhibitor binimetinib (MEK162) showed clinical activity in patients (pts) with NRAS-mutant melanoma. In preclinical studies, the selective CDK4/6 inhibitor LEE011 demonstrated tumor growth inhibition, and in combination with binimetinib led to regressions in NRAS-mutant melanoma models, warranting clinical study. Methods: This is a phase 1b/2, open-label study of LEE011 + binimetinib in pts with NRAS-mutant melanoma. The primary objective of the phase 1b part is to estimate the MTD/RP2D of the combination, using a Bayesian logistic regression model (BLRM) with overdose control. Secondary objectives include safety, pharmacokinetics (PK), and preliminary efficacy. LEE011 is administered once daily for 21 days of each 28-day cycle and binimetinib is administered twice daily continuously. Results: As of Dec 20, 2013, 14 pts were enrolled (93% stage M1c; ECOG PS 0/1/2 [43%/50%/7%]; median 2 prior lines) and were treated with LEE011 at 200 mg (dose level [DL] 1, n = 8) or 300 mg (DL 2, n = 6) and with binimetinib 45 mg. DLTs occurred at DL 1 (grade 3 acute renal injury, n = 1) and DL 2 (grade 4 asymptomatic creatine phosphokinase [CPK] elevation and grade 3 edema plus grade 4 atrial fibrillation, 1 pt each). Common treatment-related toxicities included CPK elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. Preliminary PK was consistent with single-agent data for either drug, with no evidence of drug-drug interaction. Six pts achieved partial response (43%; 1 confirmed, 5 unconfirmed) and 6 had stable disease (4 with tumor shrinkage > 20%). Several pts experienced early tumor shrinkage with major symptomatic improvement; 8 pts remain on treatment (duration 2-8 mo). Conclusions: Combined LEE011 + binimetinib shows promising preliminary antitumor activity in pts with NRAS-mutant melanoma. Determination of a phase 2 dose and schedule and PD effects are ongoing. Clinical trial information: NCT01719380.