This study will evaluate the safety, pharmacokinetics, and activity of belvarafenib as a single agent and in combination with either cobimetinib or cobimetinib plus nivolumab in patients with NRAS-mutant advanced melanoma who have received anti-PD-1/PD-L1 therapy.

The study will evaluate three treatment regimens in three arms: a belvarafenib monotherapy arm (Belva arm); a belvarafenib plus cobimetinib arm (Belva + Cobi arm) in an initial dose-finding phase followed by an expansion phase and a belvarafenib plus cobimetinib plus nivolumab arm (Belva + Cobi + Nivo arm) in a run-in phase followed by an expansion phase.

Inclusion Criteria:

• ECOG Performance Status of 0 or 1
• Histologically confirmed, metastatic (recurrent or de novo Stage IV) or unresectable locally advanced (Stage III) cutaneous melanoma, that has progressed on or after treatment with anti-PD-1 or anti-PD-L1 therapy. Patients may have received up to two lines of systemic cancer therapy. Treatment with anti-PD-1/PD-L1 in the adjuvant setting is acceptable. Patients must have progressed disease at study entry
• Documentation of NRAS mutation-positive within 5 years prior to screening
• Tumor specimen availability
• Adequate hematologic and end-organ function
• Measurable disease per RECIST v1.1

Exclusion Criteria:

• Prior treatment with a pan-RAF inhibitor
• Treatment with systemic immunotherapy agents (e.g., anti-CTLA4, anti-PD(L)1, cytokine therapy, investigational therapy, etc.) within 28 days prior to C1D1
• Symptomatic, untreated, or actively progressing CNS metastases
• History or signs/symptoms of clinically significant cardiovascular disease
• Known clinically significant liver disease
• History of autoimmune disease or immune deficiency
• Prior treatment with a MEK inhibitor (cobimetinib arm)
• History of or evidence of retinal pathology on ophthalmologic examination (cobimetinib arm)
• History of immune-related AE attributed to prior anti-PD(L)1 therapy that resulted in permanent discontinuation of anti-PD(L)1 therapy (nivolumab arm)

For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data\_sharing