Protocol amendment V 01 All sections of the protocol including the protocol title that describe the patient population: • Changed the patient population to reflect the inclusion of patients who had progressed on or after prior first-line immunotherapy for metastatic disease. • All section of the protocol were updated with the appropriate visit window exception for the visit occurring 6 weeks after randomization (Study Day 43). The appropriate window is now +3 days • Table 6-6 MEK162-Recommended dose modifications associated with treatment related adverse events •Synopsis, Sections 2.2, 4.1 and 6.6.2 added a stratification factor to stratify patients by first-line immunotherapy (yes versus no) • Synopsis and Section 5.2 added patients who had progressed on or after prior first-line immunotherapy for metastatic disease to inclusion #5 Synopsis and Section 5.3: • Added history of retinal degenerative disease as exclusion #5 • Added patients who have received more than one line of immunotherapy for metastatic melanoma as exclusion #10 • Added patients who have not met the minimal washout requirements for prior metastatic therapy as exclusion #11 • Revised exclusion criterion #12 to exclude prior chemotherapy treatment • Clarified exclusion criterion #13 to not include atrial fibrillation and paroxysmal supraventricular hypertension as exclusionary as significant cardiac arrhythmias • Updated the uncontrolled arterial hypertension exclusion criteria to make it less specific (criterion #14)

Protocol amendment V 02 included: • Update the inclusion and exclusion criteria • New and modify existing safety monitoring • Improvement some operational aspects • Other (clarifications, administrative changes and corrections)

Protocol amendment V 03 included the following updates: • Clarifications of the eligibility criteria • Improvement operational aspects of the trial • Other (clarifications and corrections) Section 1.2.1.2 • Added “For updated clinical safety and efficacy data please refer to the most recent version of the Investigator’s Brochure.” To clinical experience Section 1.2.1.3 • Added results from the food effect study CMEK162A2103 Section 4.1 • Added “using the same IDE test for prescreening that is used in this protocol, and who have consented to utilizing those results for this study” • Added “Regardless of whether additional tumor is needed for the required study analyses, all patients intending to participate in the CMEK162A2301 study must sign both the prescreening and main consents” Section 5.2: • Added “or unknown primary” and “(Uveal and mucosa melanoma are excluded)” to inclusion criterion # 3 • Remove the word “first-line” from inclusion criterion #5 • Reduced the hemoglobin value from 10g/dL to 9g/dL in inclusion criterion # 8 • Added a “triplicate average baseline” to QTcF reading at baseline to the inclusion criterion # 9 Section 5.3: • Removed the word “active” and “(i.e. those with radiographically unresectable, symptomatic lesions)”, “and”, “are eligible if the” from exclusion criterion # 1 • Added the words “untreated” “are eligible if a)” ,“all known CNS lesions have been”, “and b) after treatment” to exclusion criterion # 1 • Removed “non-cutaneous” and Added “Uveal or mucosal ” melanoma to exclusion criterion # 2 • Removed exclusion criterion # 10

Protocol amendment V 04 - The main objectives of this amendment were: • To make mandatory ocular coherence tomography (OCT) assessments at each visit to better characterize retinal events Safety: • To modify the grading criteria and dose modification for retinal events • To clarify the dose modification table for left ventricular systolic dysfunction • To clarify the guidance for monitoring and dose modification for CK elevation • To update and clarify eligibility criteria • To improve operational aspects of the trial • Other (clarifications and corrections)

Protocol amendment V 05 - the purpose of this amendment is to document a change in study sponsorship from Novartis to Array BioPharma. Study design and procedures are not affected.

Protocol amendment V 06 - this protocol amendment decreases the frequency of assessments for those patients continuing to receive binimetinib. In addition, as no further analyses of progression-free survival (PFS) and overall survival (OS) were planned, post-treatment disease follow-up and survival follow-up assessments would not be performed and central review of tumor assessments would be discontinued. Section 4.1 • Efficacy assessments will be performed locally, per standard of care for patients with advanced/metastatic melanoma, and tumor imaging will no longer be sent to the blinded independent review committee (BIRC) • Treatment discontinuation due to disease progression will now be based on Investigator assessment rather than BIRC determination • At the safety follow-up visit, patients will only complete assessment for adverse events (AEs) and serious adverse events (SAEs) and no other follow-up assessments outlined in prior amendments will be completed (i.e. health-related quality of life,survival follow-up) • Definition of study completion was updated Section 4.3 • The definition for the end of study was updated Section 6.2 • The assessment of progressive disease (PD) and discontinuation of study treatment would be based on Investigator assessment Section 6.7.2 • Study drug would no longer be dispensed by Interactive Response Technology (IRT), but would be provided by Fisher and manually assigned to the patients by site personnel.