Altering Adjuvant Therapy Based on Pathologic Response to Neoadjuvant Dabrafenib and Trametinib (ALTER-PATH NeoDT)

• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

• Patients must have histologically or cytologically confirmed clinically detected, node involved Stage IIIB/C/D melanoma by American Joint Committee on Cancer (AJCC) version 8 and surgically resectable disease. The definition of resectability can be determined by the patient's surgical oncologist and verified via discussion at multidisciplinary tumor conference attended by melanoma medical and surgical oncology staff. Resectable tumors are defined as having no significant vascular, neural or bony involvement that would preclude complete resection or necessitate the use of adjuvant radiation. Only cases where a complete surgical resection with tumor- free margins can safely be achieved are defined as resectable

• BRAF mutation-positive melanoma (V600E or V600K) based on report from a Clinical Laboratory Improvement Act (CLIA) certified laboratory

• Patients must have measurable disease, defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

• Patients who have been previously treated in the adjuvant setting with ipilimumab or interferon alpha or investigational vaccines for melanoma will be eligible for treatment after a 28 day wash-out period

• Patients who have previously received anti PD-1 in the adjuvant setting will be allowed if it has been six months or longer since previous drug exposure

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Women of childbearing potential, defined as all women physiologically capable of becoming pregnant will be required to use highly effective methods of contraception during dosing and for 150-days after stopping treatment with spartalizumab. Highly effective contraception methods include:

‣ Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

⁃ Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.

⁃ Male sterilization (at least 6 months prior to screening). The vasectomized male partner should be the sole partner for that subject

⁃ Placement of a non-hormonal intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year

⁃ Notes:

• Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository) are not considered highly effective methods of contraception.

∙ Hormonal-based methods (e.g., oral contraceptives) are not considered as highly effective methods of contraception due to potential drug-drug interactions with dabrafenib.

• Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of childbearing potential

• Sexually active males must use a condom during intercourse while on treatment and for 150 days after stopping treatment with spartalizumab and should not father a child in this period. A condom is required to be used by vasectomized men as well during intercourse in order to prevent delivery of the drug via semen

• Absolute neutrophil count (ANC) \>= 1500/uL

• Platelets \>= 100,000/uL

• Hemoglobin \>= 9.0 g/dL or \>= 5.6 mmol/L

‣ Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks

• Creatinine =\< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate \[GFR\] can also be used in place of creatinine or creatinine clearance \[CrCl\]) \>= 30 mL/min for participant with creatinine levels \> 1.5 x institutional ULN

‣ Creatinine clearance (CrCl) should be calculated per institutional standard

• Total bilirubin =\< 1.5 x ULN OR direct bilirubin =\< ULN for participants with total bilirubin levels \> 1.5 x ULN

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 2.5 x ULN

• International normalized ratio (INR) OR prothrombin time (PT) =\<1.5 x ULN unless participant is receiving anticoagulant therapy as long as prothrombin time (PT) or partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants

• Activated partial thromboplastin time (aPTT) =\< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants