Binimetinib plus LEE011 shows early promise against NRAS-mutant melanoma, for which no effective therapies currently exist. By simultaneously inhibiting MEK1/2 and CDK4/6, thereby inducing apoptosis and blocking cell proliferation, the drug combination better mimics direct inhibition of RAS.

Melanoma is a complex cancer, driven by a diffuse spectrum of mutations across tumors and even within a single lesion. The notoriety of BRAF mutations in melanoma is well established, and BRAF inhibitors are now approved by the FDA. However, effective therapies have yet to be found for the nearly 20% of patients with melanomas harboring NRAS mutations. NRAS and BRAF mutations are mutually exclusive, with NRAS-mutant tumors often more aggressive.

Unlike the development of drugs to inhibit BRAF, attempts to pharmacologically target RAS remain unsuccessful. RAS binds tightly to GDP in its “off” state and to GTP when turned “on,” making its enzymatic function very difficult to block directly, said Jeffrey Sosman, MD, director of the melanoma program at Vanderbilt-Ingram Cancer Center in Nashville, TN.

Early data from a phase Ib/II study now show that combining the MEK1/2 inhibitor binimetinib (MEK162; Array BioPharma) with the CDK4/6 inhibitor LEE011 (Novartis)—a drug that halts the cell cycle at the G1 phase—produces promising antitumor activity in patients with NRAS-mutant melanoma. Sosman reported the findings on June 1 at the American Society of Clinical Oncology's Annual Meeting in Chicago, IL.

The rationale for this ongoing study came from a 2012 systems biology analysis showing that MEK inhibition triggered apoptosis but not cell-cycle arrest. Network modeling pinpointed CDK4 as the key driver of this differential effect.

“To better mimic direct RAS inhibition, cell proliferation has to be blocked alongside inducing apoptosis,” Sosman said. “Because many NRAS-mutant melanomas also exhibit defective cell-cycle regulators, including CDKN2A, CDK4, and cyclin D1, we had a strong case for combining LEE011 with binimetinib.”

At the time of Sosman's presentation, 21 patients had been given the drug combination. Seven had partial tumor shrinkage with major symptomatic improvement, and 11 more saw their diseases stabilize. Notably, one patient rebounded from substantial weight loss and had an 8-month reprieve from gastric mass bleeding. Another with progressive disease despite adjuvant ipilimumab (Yervoy; Bristol-Myers Squibb) and pembrolizumab (MK-3475; Merck) experienced rapid regression of liver metastases.

A recommended phase II dose and an optimal dosing schedule are being defined; meanwhile, the combination's pharmacokinetics suggest LEE011 and binimetinib do not interact. The primary toxicities were elevated creatine phosphokinase levels and acneiform dermatitis, both known side effects of MEK inhibitors.

“MEK inhibitors make a good treatment backbone, but the transient clinical responses achieved so far indicate that additional reinforcements are required,” said Michael Davies, MD, PhD, a melanoma specialist at The University of Texas MD Anderson Cancer Center in Houston, who was not involved with the study. “Clearly, there's a rationale for identifying which drug combinations make sense to move forward and, in parallel, determining the appropriate patients for each.”

“Our observations with this study are early but promising,” said Sosman. “This is one combinatorial strategy for NRAS-mutant melanoma that should be explored further.”