Pembrolizumab and Trametinib with or without Dabrafenib in Treating Patients with Melanoma That Is Metastatic or Cannot Be Removed by Surgery

Inclusion Criteria

• Participants must have histologically confirmed metastatic or unresectable melanoma
• Participants must have BRAFV600-mutation status known (molecularly confirmed using validated, commercially available assay performed in a Clinical Laboratory Improvement Act [CLIA] approved laboratory) * If test at CLIA-certified lab used a non-Food and Drug Administration (FDA) approved method, information about the assay must be provided; (FDA approved tests for BRAF V600 mutations in melanoma include: THxID BRAF Detection Kit and Cobas 4800 BRAF V600 Mutation Test)
• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Life expectancy of greater than three months in the opinion of the investigator
• Leukocytes (white blood cell [WBC]) >= 3,000/uL
• Absolute neutrophil count >= 1,500 uL
• Platelets >= 100,000/uL
• Total bilirubin =< 1.5 X institutional upper limits of normal; total bilirubin > 1.5 X above institutional upper limits of normal will be allowed if direct bilirubin is within normal limits or if patients has a documented history of Gilbert’s disease
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
• Creatinine within normal institutional limits or creatinine clearance (estimated glomerular filtration rate [eGFR]) >= 60 mL/min/1.73 m^2 for subjects with creatinine levels about institutional normal
• Participants must have disease amenable to and be willing to undergo serial core or excisional biopsies of a tumor lesion(s)
• Because both dabrafenib and trametinib are class D agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with either dabrafenib and trametinib; breastfeeding should be discontinued if the mother is treated with either dabrafenib, trametinib, or the combination of dabrafenib and trametinib; female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication or 14 days prior to the initiation of study medication for oral contraceptives; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; male subjects with partners of childbearing potential should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy; if there is any question that a subject of childbearing potential will not reliably comply with the requirements for contraception, that subject should not be entered into the study
• Ability to understand and the willingness to sign a written informed consent document
• Ability to swallow and retain oral medication

Exclusion Criteria

• Participants with any clinically significant gastrointestinal abnormalities that may alter absorption
• Participants treated with prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to the prior chemotherapy, targeted small molecule therapy, and radiation therapy * Note: Subjects with =< grade 2 neuropathy and/or alopecia are an exception to this criterion and may qualify for the study * Note: If subject received major surgery, they must have had the surgery > 2 weeks prior to study day 1 and recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Participants previously treated with BRAF inhibitors (vemurafenib, dabrafenib, encorafenib), MEK inhibitors (selumetinib, trametinib, binimetinib, cobimetinib), and/or anti-PD1/PDL1 monoclonal antibodies for metastatic or unresectable disease; any other prior therapy will be allowed (including ipilimumab, adjuvant anti-PD1 therapy, high-dose IL-2)
• Participants with any prior >= grade 3 immune-related adverse event (irAE) which began while receiving immunotherapy
• Participants with any unresolved immune-related adverse event (irAE) at time of study entry * Note: Subjects with =< grade 2 thyroiditis and/or hypophysitis are an exception to this criterion and may qualify for the study
• Participants who have had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• Patients may not be receiving any other anti-neoplastic agents
• Participants with symptomatic brain metastases will be excluded from this clinical trial; subjects with asymptomatic, stable brain metastases and subjects who, if they have been previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll; brain metastasis must be stable with verification by imaging (brain magnetic resonance imaging [MRI] completed at screening demonstrating no current evidence of progressive brain metastases); if asymptomatic brain metastasis are first identified on the required pre-study scans, another set of scans must be completed to confirm that they are stable
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment; corticosteroids to prevent contrast reactions is allowable
• Pregnant women are excluded from this study because both dabrafenib and trametinib are class D agents with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with either dabrafenib and trametinib; breastfeeding should be discontinued if the mother is treated with either dabrafenib, trametinib, or the combination of dabrafenib and trametinib
• Participants known to be human immunodeficiency virus (HIV)-positive and on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with either dabrafenib or trametinib; appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
• Has a known history of active TB (Bacillus tuberculosis)
• Known hypersensitivity to pembrolizumab or any of its excipients
• Symptomatic or untreated leptomeningeal disease
• Participants are not permitted to receive enzyme inducing anti-epileptic drugs
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Has a history of non-infectious pneumonitis that required steroids or has current/active pneumonitis
• History of or current evidence of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED): * History of RVO or RPED * Current evidence of visible retinal pathology as assessed by pre-study ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of visual field defects, and/or intraocular pressure > 21 mm Hg
• Uncontrolled intercurrent illness including, but not limited to: * Ongoing or active infection * Left ventricular ejection fraction (LVEF) < 50% as determined by either multigated acquisition (MUGA) scan or echocardiogram (Echo) * Edema > grade 1 * Documented myocardial infarction or unstable/uncontrolled cardiac disease (e.g., unstable angina, severe arrhythmias, congestive heart failure [New York Heart Association [NYHA] > class II]) within 6 months of study entry * Arterial thrombosis or vascular ischemic events, such as transient ischemic attack, cerebral infarction, within 6 months prior to study entry * Serious or non-healing wound * History of any medical condition including cardiovascular disease or chronic obstructive pulmonary disease (COPD), that in the opinion of the investigator, may increase the risks associated with study participation or study treatments or may interfere with the conduct of the study or interpretation of study results * Psychiatric illness/social situations that, in the opinion of the investigator, would limit compliance with study requirements
• Individuals with a history of a different malignancy are ineligible except for the following circumstances: * Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy * Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ and basal cell or squamous cell carcinoma of the skin
• Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
• Has received a live vaccine within 30 days of planned start of study therapy