Neoadjuvant Use of Talimogene Laherparepvec and BRAF/MEK Inhibitor for Advanced Nodal BRAF Mutant Melanoma

Inclusion * Age ≥ 18 * Malignant melanoma Stage IIIb-IVM1a patients. * Primary or recurrent disease. * Cutaneous primary melanoma or unknown primary. * Measurable disease as evidenced by: * At least one lesion measuring greater than or equal to 10 mm on CT, ultrasound, or physical exam * A conglomerate of superficial lesions measuring which in aggregate have a total diameter of 10 mm * Injectable disease * Palpable regional metastasis at the time of initial presentation or with regional recurrence * Tumor(s) with BRAF mutation * ECOG 0,1,2 * Life expectancy \> 2 years in the opinion of the investigator * Able to provide written informed consent * Adequate organ function based on most recent labs (according to investigator discretion), defined as follows: * Hematological: Absolute neutrophil count ≥ 1500/mm3 (1.5x109/L); Platelet count ≥ 75,000/mm3 (7.5x109/L); Hemoglobin ≥ 8 g/dL (without need for hematopoietic growth factor or transfusion support) * Renal: Serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR 24-hour creatinine clearance ≥ 60 mL/min for subject with creatinine levels \> 1.5 x ULN. (Note: Creatinine clearance need not be determined if the baseline serum creatinine is ≤ 1.5 x ULN. . Creatinine clearance should be determined per institutional standard). * Hepatic: Serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with total bilirubin level \> 1.5 x ULN; Aspartate aminotransferase (AST) ≤ 2.5 x ULN OR ≤ 5 x ULN, if liver metastases present and injection does not involve a visceral lesion; Alanine aminotransferase (ALT) ≤ 2.5 x ULN OR ≤ 5 x ULN, if liver metastases present and injection does not involve a visceral lesion * Coagulation: International normalization ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN, unless the subject is receiving anticoagulant therapy, in which case PT and partial thromboplastin time (PTT)/ activated PTT (aPTT) must be within therapeutic range of intended use of anticoagulants; PTT or aPTT ≤ 1.5 x ULN, unless the subject is receiving anticoagulant therapy as long as PT and PTT/aPTT is within therapeutic range of intended use of anticoagulants. * Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to enrollment. If urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Exclusion * BRAF wild type tumor * M1b and M1c disease * Clinically active cerebral metastases, bony metastases, visceral metastases * Mucosal or ocular primary disease * Known active central nervous system (CNS) metastases. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids \>10 mg/day of prednisone or equivalent. The exception does not include carcinomatosus meningitis which is excluded regardless of clinical stability. * History or evidence of active autoimmune disease that requires systemic treatment (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. * Evidence of clinically significant immunosuppression such as the following: * Primary immunodeficiency state such as Severe Combined Immunodeficiency Disease. * Concurrent opportunistic infection. * Receiving systemic immunosuppressive therapy (\> 2 weeks) including oral steroid doses \> 10 mg/day of prednisone or equivalent within 7 days prior to enrollment. * Active herpetic skin lesions or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis). * Requires intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (e.g., acyclovir), other than intermittent topical use. * Previous treatment with talimogene laherparepvec or any other oncolytic virus. * Previous treatment with a BRAF or MEK inhibitor * Prior therapy with tumor vaccine. * Received live vaccine within 28 days prior to enrollment. * Prior immunosuppressive, chemotherapy, radiotherapy (in which the field encompassed a planned injection site), biological cancer therapy, or major surgery within 28 days prior to enrollment or has not recovered to CTCAE grade 1 or better from adverse event due to cancer therapy administered more than 28 days prior to enrollment. Adjuvant hormonal therapy is allowed if appropriate for planned study. * Prior radiotherapy in which the field does not overlap the injection sites or non-immunosuppressive targeted therapy within 14 days prior to enrollment or has not recovered to CTCAE grade 1 or better from adverse event due to cancer therapy administered more than 14 days prior to enrollment * Currently receiving treatment with another investigational device or drug study, or \< 28 days since ending treatment with another investigational device or drug study(s). * Other investigational procedures while participating in this study are excluded. * Known to have acute or chronic active hepatitis B infection. * Known to have acute or chronic active hepatitis C infection. * Known to have human immunodeficiency virus (HIV) infection. * History of other malignancy within the past 5 years with the following exceptions: * Adequately treated non melanoma skin cancer without evidence of disease at the time of enrollment * Adequately treated cervical carcinoma in situ without evidence of disease at the time of enrollment * Adequately treated breast ductal carcinoma in situ without evidence of disease at the time of enrollment * Prostatic intraepithelial neoplasia without evidence of prostate cancer at the time of enrollment. * Subject has known sensitivity to talimogene laherparepvec or any of its components to be administered during dosing. * Female subject is pregnant or breast-feeding, or planning to become pregnant during study treatment and through 3 months after the last dose of talimogene laherparepvec. * Sexually active subjects and their partners unwilling to use male or female latex condom to avoid potential viral transmission during sexual contact while on treatment and within 30 days after treatment with talimogene laherparepvec. * Subjects who are unwilling to minimize exposure with his/her blood or other body fluids to individuals who are at higher risks for HSV-1 induced complications such as immunosuppressed individuals, individuals known to have HIV infection, pregnant women, or infants under the age of 3 months, during talimogene laherparepvec treatment and through 30 days after the last dose of talimogene laherparepvec.