Dr. Reinhard Dummer
Binimetinib (MEK162) is an oral, selective ATP-uncompetitive inhibitor of MEK1 and MEK2 that demonstrated clinical activity in metastatic melanoma with an NRAS mutation in a previous phase II study. Prior research found that the mutations may constitutively activate the MAPK pathway, driving cell proliferation and inhibiting apoptosis. According to Dr. Dummer, preclinical studies indicated that melanoma harboring an NRAS mutation is sensitive to MEK inhibition.
There have been no specific therapies for melanoma with an NRAS mutation, and “there is a substantial unmet clinical need, particularly after failure of immunotherapy in these patients,” he said.
The 402 patients in the trial were either previously untreated or had progressed while taking or after immunotherapy. All patients had an Easter Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients were randomly assigned 2:1 to receive 45 mg twice daily of oral binimetinib (269 patients) or 1,000 mg/m2 of intravenous dacarbazine (133 patients) every 3 weeks. The mean duration of exposure was 13 weeks (range, 0 to 73 weeks) with binimetinib and 9 weeks (range, 3 to 57 weeks) with dacarbazine.
Patient stratification was by American Joint Committee on Cancer (AJCC) stage, ECOG performance status, and prior immunotherapy. The primary endpoint was PFS; the key secondary endpoint was overall survival (OS) and other secondary endpoints included objective response rate (ORR) and disease control rate (DCR).
Among patients who had received no prior immunotherapy, PFS was 2.8 months (95% CI [2.7, 2.9]) with binimetinib compared with 1.5 months (95% CI [1.5, 1.7]) with dacarbazine. For patients who had previously received immunotherapy, PFS was 5.5 months (95% CI [2.8, 7.6]) with binimetinib compared with 1.6 months (95% CI [1.5, 2.8]) with dacarbazine.
Dr. Paul B. Chapman
Grade 3/4 adverse events occurred in 68% of patients treated with binimetinib and in 46% treated with dacarbazine. An increase in creatine phosphokinase was the most common grade 3/4 adverse event in the binimetinib group (19%) compared with the dacarbazine group (0%). The safety profile of binimetinib “was consistent with other currently-marketed MEK inhibitors,” Dr. Dummer said.
Discussant Paul B. Chapman, MD, of Memorial Sloan Kettering Cancer Center, noted that there was “no OS benefit” with binimetinib, “although it’s a very early analysis.” Fifty-nine percent of patients had some degree of response to binimetinib, but most response was short-lived, he said.
During his discussion of the Ras/MEK1/2/ERK pathway, he said that drugs that target the pathway have toxicities that limit their therapeutic index.
“The target has to be inhibited almost completely, but probably only needs to be inhibited for a short period of time. It’s very hard to do that by giving the drugs every day because of toxicity,” Dr. Chapman said. “The pathway has to be hit very hard and completely, but not necessarily continuously. Ultimately, we have to continue to measure [progressive disease], but this is more difficult than it seems as we go forward. Not only is collecting samples hard and figuring out when to collect samples, but even the assay we use is fraught with problems. Whether we have a validated assay that really tells us what’s going in a biologic sense is still questionable.”
–Kathy Holliman, MEd