The development of the BRAF inhibitor encorafenib (LGX818) and mitogen-activated protein kinase kinase inhibitor binimetinib (MEK162) in patients with metastatic melanoma

Activating mutations in BRAF and NRAS account for 40–50% and 15–25% of mutations in cutaneous melanoma, respectively, and treatment is rapidly evolving with the recent approval of immunotherapies and agents targeting the mitogen-activated protein kinase (MAPK) signalling pathway. Here, a summary of the data supporting clinical development of the BRAF inhibitor encorafenib (LGX818) and the MAPK kinase (MEK) inhibitor binimetinib (MEK162) for the treatment of metastatic cutaneous melanoma will be presented. Encorafenib, a potent, highly selective BRAF inhibitor, has demonstrated phase 1 single-agent clinical activity in BRAF inhibitor-naive patients with BRAF V600-mutant metastatic melanoma [overall response rate (ORR) 65%, 17 of 26; and BRAF inhibitor-pretreated ORR 11%, three of 28]. Common adverse events associated with encorafenib included cutaneous toxicities (palmoplantar erythrodysesthesia syndrome, hyperkeratosis, keratosis pilaris, alopecia, dry skin), arthralgia and fatigue.
Currently, there are no approved specific therapies for patients with NRAS mutant melanoma. In a phase 2 study, the MEK inhibitor binimetinib was the first targeted agent to show clinical activity in the NRAS mutant subset, with 20% of patients with melanoma with NRAS mutations (six of 30) achieving partial response. Adverse events commonly associated with binimetinib included dermatitis acneiform, peripheral oedema, diarrhoea, increased creatine phosphokinase and retinal events.
A phase 3 trial evaluating binimetinib vs. dacarbazine in NRAS mutant melanoma (NEMO; NCT01763164) is currently recruiting worldwide. To increase the duration of patient response to encorafenib monotherapy and potentially improve single-agent safety profiles, the combination of encorafenib and binimetinib in BRAF V600 mutant melanoma was investigated in a phase 1b/2 study. Clinical response was achieved with the combination in both BRAF inhibitor-naive (ORR 89%, eight of nine) and BRAF inhibitor-pretreated patients
(ORR 21%, three of 14). The combination of encorafenib plus binimetinib was well tolerated with no substantial increase in adverse events for the combination compared with single-agent therapy. The combination also mitigated some on-target BRAF inhibitor-associated adverse events, including cutaneous toxicities (hyperkeratosis, keratoacanthoma, squamous cell carcinoma, palmoplantar erythrodysesthesia syndrome), myalgia and arthralgia. Only low incidences of febrile events, photo-sensitivity and rash have been reported in this study to date. A phase 3 trial assessing the combination of encorafenib plus binimetinib or encorafenib alone vs. the BRAF inhibitor vemurafenib in BRAF V600 mutant melanoma (COLUMBUS; NCT01909453) is currently enrolling globally.