Inclusion Criteria:

- locally advanced or metastatic melanoma

- confirmed BRAF V600 mutation

- patients naïve to a selective BRAF inhibitor

- fresh tumor biopsy at baseline, and patient agrees for a mandatory biopsy at the time
of relapse

- life expectancy ≥ 3 months

- World Health Organization (WHO) Performance Status ≤ 2.

Exclusion Criteria:

- Previous treatment with RAF-inhibitor

- Symptomatic or untreated leptomeningeal disease

- Symptomatic brain metastases.

- Known acute or chronic pancreatitis

- Clinically significant cardiac disease

- AST/SGOT and ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of oral interventional drug

- Previous or concurrent malignancy.

- Other severe, acute, or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation

Specific exclusion criteria for each treatment arm:

LGX818/MEK162:

History or current evidence of retinal disease History of Gilbert's syndrome.

LGX818/BKM120:

Patients with diabetes mellitus requiring insulin treatment Patient has mood disorders

LGX818/BGJ398:

History and/or current evidence of ectopic mineralization/ calcification Current evidence
of corneal disorder/ keratopathy Patients with current evidence of endocrine alteration of
calcium/phosphate homeostasis.

History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade ≥ 3 Ionized (i)
calcium (Ca) > ULN Serum inorganic phosphorus (Pi) > ULN

LGX818/LEE011 History of congenital long QT- syndrome and/or hypokalaemia CTCAE Grade ≥ 3