The purpose of this phase II clinical study is to test the good and bad effects of T-VEC (talimogene laherparepvec) with or without hypofractionated radiotherapy on people with melanoma, Merkel cell carcinoma, or other solid tumors with skin metastasis.

Inclusion Criteria:

• Man or woman ≥ 18 years old

• Life expectancy > 4 months

• Histopathologically confirmed melanoma, Merkel cell carcinoma or other solid tumor malignancy

• Cutaneous subcutaneous soft tissue, or superficial lymphatic metastasis not suitable for surgical resection

• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

• Cutaneous subcutaneous soft tissue, or superficial lymphatic metastasis that is amenable to injection and irradiation and > 10 mm in longest dimension

  ° Cutaneous metastasis in a region of previous radiation therapy is amenable to radiation therapy as part of this protocol if at least 6 months has elapsed since prior radiotherapy and the dose of radiotherapy previously administered did not exceed an equivalent dose of 60 Gy in 2 Gy equivalent fractions at the skin surface (using linear-quadratic modeling with alpha/beta=11.5)

• Metastasis that is > 10 mm in longest dimensionor exhibits radiotracer uptake consistent with metastasis on PET/CT

• Adequate coagulation function (platelet count >50 k/mcL, international normalized ratio of < 1.5)

• Resolution or stabilization of clinically significant adverse events from prior therapy

• Able to provide valid written informed consent

Exclusion Criteria:

• Active herpetic skin lesions or prior complications of HSV-1 infection (such as herpetic keratitis, herpetic encephalitis)

• Receipt of a therapeutic anticoagulant

• Receipt of live vaccine within 28 days of planned first dose of TVEC

• Receipt of another cancer therapy (targeted therapy, chemotherapy, investigational therapy, immunotherapy, radiotherapy or surgery) which is yielding an overall response (by response criteria in this study)

  ° Patients with stable or progressing disease (as determined by at least 2 consecutive assessments at 6-week interval) can continue to receive the same therapy during treatment as part of this protocol

• History of symptomatic autoimmune disease (such as lupus, scleroderma, Crohn's disease, ulcerative colitis) requiring systemic treatment (for example corticosteroids or immunosuppressants); replacement therapy (for example, thyroxine, insulin) is not considered a systemic treatment

• History of high grade (CTCAE ≥ Grade 3) immune mediated adverse event from prior cancer immunotherapy

• History of CTCAE ≥ Grade 2 immune mediated endocrinopathy from prior cancer immunotherapy

• Intermittent or chronic use of oral or intravenous antiherpetic drug (such as acyclovir)

• Active or chronic hepatitis B or C infection

  ° Previously infected, with evidence of immunity and no evidence of active hepatitis is not an exclusion criterion

• Known human immunodeficiency virus (HIV) infection

• Known leukemia or lymphoma

• Common variable immunodeficiency

• Patients requiring chronic high dose immunosuppressants including steroids (prednisone daily equivalent of ≥ 10 mg)

• Known severe congenital or acquired cellular or humoral immunodeficient or immunocompromised patients

• High likelihood of protocol non-compliance (in opinion of investigator)

• Woman of childbearing potential unwilling to use effective contraception during protocol treatment and for 3 months after last dose of Talimogene Laherparepvec

• Woman of childbearing potential that is pregnant or breast-feeding, or planning to become pregnant or breast-feed during protocol treatment and for 3 months after last dose of Talimogene Laherparepvec