MEK Inhibitor Misses Mark in Phase III Ovarian Cancer Study

Victor Sandor, MD

The MEK inhibitor binimetinib (MEK162) failed to improve progression-free survival (PFS) compared with physician's choice of chemotherapy for patients with low-grade serous ovarian cancer, according to early findings from the phase III MILO study that were released by the drug's developer, Array BioPharma.

Results from MILO were not anticipated until 2017; however, a planned interim analysis revealed that the hazard ratio for PFS had crossed a predefined futility boundary. The study has now been discontinued, which will allow patients in the binimetinib arm to cross over to receive chemotherapy.

In the study, patients had recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. Physician's choice of chemotherapy included liposomal doxorubicin, paclitaxel, and topotecan. The primary endpoint was PFS. The study had not yet fully accrued participants at the time of its discontinuation.

“While we are disappointed by this outcome, the findings from MILO have no impact on the other studies of binimetinib, including the NEMO trial, which has already met its primary endpoint, and the COLUMBUS trial, which is designed to test a highly precedented combination of mechanisms in patients with BRAF-mutant melanoma," Victor Sandor, MD, chief medical officer of Array, said in a statement.

Array noted that it planned to work with investigators to conclude the study. Results from the study will be prepared for presentation at a future medical meeting. Other trials exploring binimetinib include the phase III COLUMBUS study in BRAF-mutant melanoma and the phase III NEMO trial in NRAS-mutant melanoma, which has already reported top-line success.

In top-line findings from the NEMO trial that were released in December 2015, binimetinib reduced the risk of progression or death by 38% versus dacarbazine in NRAS-mutant melanoma (HR, 0.62; 95% CI, 0.47-0.80; P <.0001). Median PFS with binimetinib was 2.8 versus 1.5 months with dacarbazine.

In the study, 402 patients were randomized in a 2:1 ratio to receive 45 mg of binimetinib twice daily or 1,000 mg/m² of dacarbazine every 3 weeks. Patients in the study had stage IIIC, IVM1a, and IVM1b NRAS Q61-mutant melanoma, and may have received prior treatment with immunotherapy. Patients with untreated CNS metastases and those who received a prior MEK inhibitor were excluded from the trial.

Array BioPharma plans to submit data from NEMO to the FDA in the first half of 2016. Full findings from the study, including outcomes based on prior immunotherapy, will be presented at a medical meeting in 2016, according to Array BioPharma.

Overall, NRAS mutations occur in approximately 15% to 20% of patients with melanoma and normally do not coexist with BRAF alterations. In general, alterations in NRAS are associated with a poor prognosis, with an overall survival of 8.5 months from the time of diagnosis.

“The presence of an NRAS mutation is a poor prognostic indicator for patients with advanced melanoma,” Keith T. Flaherty, MD, associate professor, Medicine, Harvard Medical School and Director of Developmental Therapeutics, Cancer Center, Massachusetts General Hospital, said in a statement when the findings were announced. “I am encouraged the NEMO trial met its primary endpoint and look forward to sharing the full results soon.”

The phase III COLUMBUS trial is currently exploring the combination binimetinib and the BRAF inhibitor encorafenib for patients with BRAF-mutant melanoma. In the trial, the combination will be compared with the BRAF inhibitor vemurafenib alone or with encorafenib alone. The trial has fully enrolled approximately 900 participants, and results are anticipated in June 2016.

A preceding phase II study that was presented at the 2015 European Cancer Congress showed promising signs of efficacy and a low occurrence of rash and photosensitivity with encorafenib plus binimetinib. Patients with BRAF inhibitor-naive melanoma experienced an objective response rate of 68% with the combination. After a median of 6 months, the PFS rate was 79%.