medwireNews: Binimetinib could be incorporated into the treatment pathway of patients with advanced melanoma harboring NRAS mutations, say researchers who found a progression-free survival (PFS) benefit with the MEK inhibitor over dacarbazine.
The PFS gain was also observed among patients who had failed prior immunotherapy, “which is currently the guideline-recommended first-line treatment,” the team reports in The Lancet Oncology.
Commenting on the research, Michael Postow and Paul Chapman (both from the Memorial Sloan Kettering Cancer Center, New York, USA) do not discount a role for MEK inhibition in this “under-served patient population,” but they believe that “combining MEK inhibitors with other molecular inhibitors and immunotherapy will likely be necessary to establish MEK inhibition in the treatment of NRAS-mutant melanoma.”
The phase III NEMO (NRAS melanoma and MEK inhibitor) trial randomly assigned patients with stage IIIC or IV locally advanced or metastatic NRAS-mutated melanoma to receive either oral binimetinib 45 mg twice daily or intravenous dacarbazine 1000 mg/m2 once every 3 weeks. Just under a quarter of participants in each treatment arm had received immunotherapy previously.
After a median follow-up of 1.7 months, PFS was a median of 2.8 months for the 269 patients given binimetinib and 1.5 months for the 133 dacarbazine-treated patients, a significant difference giving a hazard ratio of 0.62.
Among participants who had prior immunotherapy, the corresponding median PFS times were 5.5 and 1.6 months, report lead author Reinhard Dummer (University Hospital Zürich Skin Cancer Center, Switzerland) and colleagues.
They also found that a significantly higher proportion of patients in the binimetinib than the dacarbazine group achieved a complete or partial response according to the RECIST criteria, with respective confirmed overall response rates of 15% and 7%.
The commentators urge caution, however, noting that a high proportion of participants in both groups were not assessable for response – 15% and 31% in the binimetinib and dacarbazine treatment arms, respectively. “These patients were counted appropriately as non-responders, but the response might have been underestimated,” they write.
Furthermore, overall survival did not differ significantly between binimetinib- and dacarbazine-treated participants after a median follow-up of 9.2 months. The researchers say that the long-term effects of previous or subsequent immunotherapeutic agents “might have confounded our ability to observe a difference in overall survival.”
Binimetinib-treated patients were more likely than dacarbazine-treated patients to experience grade 3–4 elevations in creatine phosphokinase levels (19 vs 0%) and hypertension (7 vs 2%), whereas hematologic side effects, such as anemia (2 vs 5%) and neutropenia (1 vs 9%), were less common.
Despite the known ocular effects of MEK inhibitors, the rate of severe events was low, with grade 3 retinal pigment epithelial detachment reported in just 1% of binimetinib-treated patients. In light of these results, the study authors question “whether regularly scheduled ophthalmological examinations are necessary in asymptomatic patients.”
Serious adverse events were observed in 34% of participants given binimetinib and 22% of those who received dacarbazine.
Dummer and team say that side effects “were manageable with dose interruption and reduction, when needed,” and describe the MEK inhibitor as “tolerable.”
But the commentators disagree. Highlighting that 61% of patients in the binimetinib group needed a dose reduction and 20% discontinued treatment permanently as a result of drug-related toxicity, they say that “this dose and schedule was not well tolerated.”
Postow and Chapman admit, however, that “[t]his rate of dose reduction might be higher than what could be expected in clinical practice since most dose modifications were due to asymptomatic events detected by frequent protocol mandated evaluations.”
And they conclude: “Additional efforts are needed to improve MEK inhibition through alternative dosing strategies and further molecular studies should be done to define patient populations most likely to benefit.”
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