Binimetinib

Binimetinib (MEK162; ARRY-438162) is a potent, adenosine triphosphate-uncompetitive, highly selective allosteric inhibitor of MEK1/2 with demonstrated on-target activity in vitro and in vivo, including models of cancer [...] In vivo, binimetinib displays broad anti-tumour activity in xenograft models derived from melanoma, colorectal cancer, non-small cell lung cancer (NSCLC), fibrosarcoma, cholangiocarcinoma, and pancreatic cancer. These non-clinical data support the use of binimetinib in a wide variety of tumour types, with a priority in tumours with aberrantly activated MAPK pathway signalling.

Binimetinib improved progression-free survival compared with dacarbazine and was tolerable. Binimetinib might represent a new treatment option for patients with NRAS-mutant melanoma after failure of immunotherapy.

Under development are binimetinib, a MEK inhibitor being studied in patients with NRAS-mutant melanoma, and encorafinib, a BRAF inhibitor being used in combination with binimetinib for patients with BRAF-mutant melanoma.

The initial report of the phase I/II combination trial of encorafenib and binimetinib reported on 9 BRAF inhibitor naive and 14 BRAF inhibitor pretreated patients with metastatic BRAF mutant melanoma across a range of doses.

Binimetinib is an oral reversible inhibitor of mitogen-activated extracellular signal-regulated kinase (MEK) 1/2. [...] Binimetinib inhibits MEK 1/2 downstream from BRAF and halts cancer cell signaling and survival. [...] Binimetinib is approved in combination with encorafenib, a BRAF inhibitor, for the treatment of unresectable or metastatic melanoma with a BRAF V600E/K mutation, as detected by an FDA-approved test.

Special Considerations [...] 7. Monitor patients for an increased risk of new primary cancers, both cutaneous and non-cutaneous, while on therapy and for up to 6 months following the last dose of binimetinib. [...] 10. Baseline and periodic CPK levels while on therapy, as rhabdomyolysis has been observed with binimetinib therapy.

Binimetinib is given in combination with encorafenib as each drug targets a different kinase in the RAS/RAF/MEK/ERK pathway to stop malignant cell proliferation and to tell the cells to die (undergo apoptosis). [...] Terminal half-life of binimetinib is 3.5 hours. [...] No clinically significant changes in binimetinib exposure were seen in patients with severe renal impairment.