Inclusion Criteria:

• Male or female must be ≥ 12 years.
• For adolescent participants only (12-17 years):  body weight > 40kg.
• Histologically confirmed unresectable or metastatic cutaneous melanoma.
• Documentation of BRAFV600 or NRAS mutation in tumor tissue prior to study treatment as determined by local assay or as determined by central pre-screening assessment performed at a Novartis designated laboratory.
• Previously treated for unresectable or metastatic melanoma.

Participants with NRAS mutation

• Participants must have received prior systemic therapy for unresectable or metastatic melanoma with an anti-PD-1/PD-L1 checkpoint inhibitor as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy, or locally-directed anti-neoplastic agents.
• Prior checkpoint inhibitor therapy in the unresectable or metastatic setting is not required for participants who have progressed on or within 6 months of adjuvant therapy with a checkpoint inhibitor.
• Prior therapy with T-VEC (talimogene laherparepvec) is allowed and will not be counted as a prior line of systemic therapy.
• A maximum of two prior lines of systemic CPI-containing immunotherapy for unresectable or metastatic melanoma are allowed.  Additional agents administered with a CPI are permitted.
• To rule out pseudo-progression, participants must have documented progressive disease as per iRECIST v1.1 while on/after treatment of with checkpoint inhibitor therapy.  Confirmation is not required for patients who remained on treatment > 6 months.

Patients with BRAFV600 mutant disease

• Participants must have received prior systemic therapy for unresectable or metastatic melanoma with a checkpoint inhibitor (CPI) either/and anti-PD-1/anti-PD-L1 as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy or locally-directed anti-neoplastic agents.  Additionally, participants must have received targeted therapy with a RAFi as a single agent or in combination with a MEKi (+/- CPI allowed) as the last prior therapy. 
• Prior checkpoint inhibitor therapy in the unresectable or metastatic setting is not required for participants who have progressed on or within 6 months of adjuvant checkpoint inhibitors.
• Prior therapy with T-VEC (talimogene laherparepvec) is allowed and will not be counted as a prior line of systemic therapy.
• A maximum of two prior lines of CPI-containing systemic therapy for unresectable or metastatic melanoma are allowed.  Additional agents with CPI are permitted.
• A maximum of one line of targeted therapy is allowed, and it must be most recent line of therapy.
• If a participant discontinued targeted therapy for reasons other than disease progression, a switch to another targeted therapy regimen is allowed.
• Participants must have documented progressive disease as per RECIST v1.1 while on/after treatment with targeted therapy. 
• Participants must have a site of disease amenable to repeated biopsies and must be willing to undergo a new tumor biopsy at baseline and during treatment according to the treating institution’s own guidelines and requirements for such procedure. For screening biopsy, exceptions may be made for patients who have undergone a fresh tumor biopsy out of the screening window and have received no intervening therapy, after discussion with the Novartis medical monitor.  Bone metastases are not acceptable as a site for biopsy.

Exclusion Criteria:

• All primary central nervous system (CNS) tumors or symptomatic CNS metastases that are neurologically unstable.
• Insufficent bone marrow, hepatic renal function at the screening visit.
• Abnormal ECG as determined by the mean of a triple ECG and assessed locally.
• Cardiac disease or cardiac repolarization abnormality.
• Presence of ≥ CTCAE grade 2 toxicity (except alopecia) due to prior anti-cancer therapy.  Grade 2 endocrinopathies being treated with replacement therapy and are no longer symptomatic.
• History of current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).

Eligibility last updated 10/14/21. Questions regarding updates should be directed to the study team contact.