Targeted Drug Binimetinib Slows Disease Progression in NRAS-Mutated Melanoma

The experimental targeted drug binimetinib reduced the risk of progression or death by 38 percent compared with the chemotherapy dacarbazine in patients with NRAS-mutant metastatic melanoma, according to findings from the phase 3 NEMO study presented at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO), a gathering of 30,000 oncology professionals in Chicago.

Binimetinib is a MEK inhibitor that slows down the activity of enzymes that have become overactive, causing out-of-control cell growth that develops into cancer. NRAS mutations, which help drive melanoma, are thought to be present in 15 percent or more of patients who have the disease, but there are no approved drugs to target this mutation. Dacarbazine has been the approved chemotherapy for melanoma since 1975, but has been used with limited success.

In the open-label trial, median progression-free survival (PFS) with binimetinib was 2.8 versus 1.5 months with dacarbazine. The objective response rate (ORR) with binimetinib was 15 percent, including one complete response, compared with 7 percent for dacarbazine.

Intriguingly, median PFS was greater in patients treated with prior immunotherapy. In those pretreated with immunotherapy, the median PFS was 5.5 months with binimetinib versus 1.6 months with dacarbazine. Array BioPharma, the company developing the MEK inhibitor, plans to submit these data to the U.S. Food and Drug Administration later this month, according to a statement from the company.

"Binimetinib is a new treatment option in patients with NRAS-mutated melanoma who failed immunotherapy," said lead investigator Reinhard Dummer, a professor in the Department of Dermatology at the University of Zurich Hospital. "Binimetinib significantly prolonged progression-free survival and improved response rates versus dacarbazine. It is important to see how this therapy works in patients treated with prior immunotherapy."

In the NEMO study, 402 patients were randomized in a 2:1 ratio to receive 45 mg of binimetinib twice daily (269 patients) or 1,000 mg/m2 of dacarbazine every three weeks (133 patients). Patients in the study had stage 3c, 4M1a, and 4M1b NRAS Q61-mutant melanoma, and may have received prior treatment with immunotherapy. Patients with untreated central nervous system metastases and those who had received a prior MEK inhibitor were excluded from the trial.

In the binimetinib and dacarbazine arms, respectively, patients were a median age of 65 and 62 years, and most were male (62 percent and 64 percent). The most common ECOG performance status in both arms was 0 (72 percent), meaning that the patients’ ability to carry out daily activities was not compromised by their disease. LDH levels were greater than the upper limit of normal for a quarter of patients in each arm, indicating cell damage. Twenty-one percent of patients had received prior immunotherapy, primarily Yervoy (ipilimumab) (13 percent).

The primary endpoint of the study was PFS by blinded independent review. Secondary outcome measures focused on overall survival (OS), ORR and safety.

When adding those with stable disease to ORR, the disease control rate was 58 percent with the targeted therapy versus 25 percent with dacarbazine. The median duration of response was 6.9 months with binimetinib and was not evaluated with dacarbazine.

The median OS with binimetinib was 11.0 months compared with 10.1 months with dacarbazine; however, these data were still being fully analyzed, explained Dummer. Following the trial, 46 percent of those in the binimetinib arm and 44 percent of patients in the dacarbazine arm went on to receive immunotherapy, which was most commonly Yervoy.

"This study was done between 2013 and 2015, and there were many open expanded access programs that allowed access to immunotherapy, and many of these patients have gone on to another therapy that affected this dataset [for OS]," said Dummer.

The PFS benefits associated with binimetinib versus dacarbazine were observed across patient populations, except for those with ECOG performance status 1 and those without visceral disease. The greatest benefit was seen for those with metastases in three or more organs. Patients treated with other frontline therapies besides immunotherapy experienced a median PFS that was similar to that seen in the full trial (2.8 vs 1.5 months).

All patients in the binimetinib arm experienced side effects compared with 91 percent of those in the dacarbazine group. Grade 3/4 (serious or severe) side effects were experienced by 68 percent of those in the targeted therapy arm versus 46 percent in the dacarbazine group.

The most common all-grade side effects with binimetinib were CPK elevation, indicating damage to brain, lungs, heart or muscle from disease (42 percent), diarrhea (40 percent), accumulation of liquid in the limbs, causing swelling (36 percent), rash (35 percent), nausea (29 percent), fatigue (22 percent), vomiting (21 percent) and weakness (18 percent). Side effects leading to discontinuation occurred in 25 percent of patients in the binimetinib arm, and included ejection fraction decrease, a heart-pumping problem (4 percent), blood CPK increase (2 percent) and a blockage of veins in the eye (2 percent). Side effects led to discontinuation for 8 percent of those in the dacarbazine arm.

"The safety profile was absolutely in the range that you would expect for this type of therapy," said Dummer. “The safety of binimetinib was consistent with other currently marketed MEK inhibitors.”

In addition to NRAS-mutated tumors, binimetinib is also under exploration as a treatment for BRAF-mutant melanoma. The phase 3 COLUMBUS trial is exploring the combination of binimetinib and the BRAF inhibitor encorafenib compared with the BRAF inhibitor vemurafenib alone or encorafenib alone. The trial has fully enrolled approximately 900 participants, and results are anticipated in 2016.