A RANDOMIZED, OPEN-LABEL PHASE 3 STUDY IN PATIENTS WITH PREVIOUSLY TREATED UNRESECTABLE OR METASTATIC NRAS MUTANT CUTANEOUS MELANOMA COMPARING THE COMBINATION OF NAPORAFENIB + TRAMETINIB TO PHYSICIAN’S CHOICE OF THERAPY (DACARBAZINE, TEMOZOLOMIDE OR TRAMETINIB MONOTHERAPY) WITH A DOSE OPTIMIZATION LEAD-IN [SEACRAFT-2]

Unresectable or metastatic NRAS mutant cutaneous melanoma

Stage 1 (Dose Optimization) - Analysis of the totality of the safety, pharmacokinetics (PK), and preliminary efficacy data including exposure response relationships for tolerability, safety, and efficacy from Stage 1 and throughout the naporafenib program, Stage 2 (Registration-Enabling Portion) - PFS using RECIST v1.1 per blinded independent central review (BICR), Stage 2 (Registration-Enabling Portion) - OS

Stage 1 (Dose Optimization) - Using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1: • Objective response rate (ORR) • Disease control rate (DCR) • Duration of response (DOR) • Progression-free survival (PFS) • Time to response (TTR), Stage 1 (Dose Optimization) - Safety: incidence and severity of adverse events (AE) and serious adverse events (SAE), changes from baseline in laboratory values, vital signs, and cardiac assessments (electrocardiogram [ECG], echocardiogram [ECHO]/multigated acquisition [MUGA]) Tolerability: AEs leading to dose interruptions, reductions, and permanent discontinuation of study drug(s), Stage 1 (Dose Optimization) - Plasma concentrations of naporafenib and trametinib as combination therapy and plasma concentrations of trametinib as monotherapy obtained via sparse sampling for population PK modeling, Stage 2 (Registration-Enabling Portion) - Using RECIST v1.1, per BICR: • ORR • DOR, Stage 2 (Registration-Enabling Portion) - Safety: Incidence and severity of AEs and SAEs, changes from baseline in laboratory values, vital signs, and cardiac assessments (ECG, ECHO/ MUGA) Tolerability: AEs leading to dose interruptions, reductions, and permanent discontinuation of study drug(s), Stage 2 (Registration-Enabling Portion) - Using RECIST v1.1, per investigator assessment: • PFS • ORR • DOR • DCR • TTR, Stage 2 (Registration-Enabling Portion) - Plasma concentrations of naporafenib and trametinib as combination therapy obtained via sparse sampling for population PK modeling, Stage 2 (Registration-Enabling Portion) - Change from baseline in: • EORTC QLQ-C30 subscales • PRO CTCAE® symptoms Change from baseline to landmark timepoint(s) for one or more of the above measures; specific endpoints of interest will be selected based on data from Stage 1 and prespecified before initiating Stage 2.

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