Adaptive BRAF-MEK Inhibitor Therapy for Advanced BRAF Mutant Melanoma

Inclusion Criteria:

• Patients must be 18 years of age or above

• Subjects must have cytologically or histologically-confirmed unresectable melanomathat harbors a BRAF V600E mutation determined by pyrosequencing assay or equivalentgenotyping assay in a Clinical Laboratory Improvement Act (CLIA) certifiedlaboratory, meeting one of the following American Joint Committee on Cancer (AJCC) (8th edition) staging criteria:

• AJCC stage IV

• AJCC stage IIIC or IIID with unresectable nodal/locoregional involvement

• Subjects must have baseline plasma ctDNA >= 0.5 copy/ul at time of study enrollment

• Hemoglobin >= 8.0 g/dL

• Absolute neutrophil count >= 1,500/mcL

• Platelets >= 75,000/mcL

• Total bilirubin =< 2 institutional upper limit of normal (ULN), unless suspectedGilbert's syndrome

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 xinstitutional ULN (in participants with liver metastases =< 5 x ULN)

• Creatinine =< 2.0 institutional ULN

• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance statusof =< 2

• Negative serum pregnancy test within 7 days prior to commencement of dosing inpremenopausal women. Women of non-childbearing potential may be included withoutserum pregnancy test if they are either surgically sterile or have beenpostmenopausal for >= 1 year

• Fertile men and women must use an effective method of contraception during treatmentand for at least 6 months after completion of treatment as directed by theirphysician. (NOTE: Patients must agree to not use hormonal contraceptives, asencorafenib can result in decreased concentration and loss of efficacy.)

• Patients on non-biologic disease modifying agents (e.g. methotrexate) or patients oncorticosteroids =< 10 mg prednisone daily or equivalent are permitted to enroll

• Patients must not have had grade 3 or 4 immune-related adverse events on nivolumabthat required more than 12 weeks of immune suppression with corticosteroids

• No anti-PD-1/PD-L1 or BRAF/MEK inhibitor therapy in the metastatic setting isallowed; these treatments are allowed if given in neoaduvant or adjuvant setting > 24 weeks ago. Prior radiation therapy is permitted. All adverse events associatedwith prior systemic therapy or radiation therapy must have resolved to =< grade 1prior to start of study

• Subjects must have measurable disease as defined by Response Evaluation Criteria inSolid Tumors (RECIST) 1.1

Exclusion Criteria:

• Female subjects who are pregnant, intend to become pregnant or are nursing

• Patients previously treated with BRAF/MEK inhibitor or anti-PD-1/PD-L1 therapy inthe metastatic setting

• Uncontrolled intercurrent illness including, but not limited to, serious infection.Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, must have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, participants must be class 2B or better

• Patients with known human immunodeficiency virus (HIV)-infection are eligibleproviding they are on effective anti-retroviral therapy and have undetectable viralload at their most recent viral load test and within 90 days prior to randomization

• Patients with untreated or uncontrolled brain metastases. Patients with asymptomaticbrain metastases which have been previously treated (with locoregional treatmentsuch as radiation or surgery) and are clinically stable (i.e. not requiringcorticosteroids) at the time of study start will be eligible

• Previous malignancy is not an exclusion provided that the other malignancy isconsidered under control, patient is not on concomitant anti-cancer drug therapy,and target lesions from melanoma are clearly defined for response assessment