Background: Talimogene laherparepvec (T-VEC) is an oncolytic immunotherapy made from a modified herpes virus expressing granulocyte-macrophage colony-stimulating factor and is FDA approved for the treatment of advanced melanoma. Laboratory studies suggest radiotherapy (RT) may interact with oncolytic immunotherapy to facilitate an immune-mediated anticancer response. We hypothesized that the combination of T-VEC+RT would produce tumor responses in distant (non-irradiated and non-injected) metastases. Methods: A prospective phase II, randomized, Simon two-stage clinical trial of T-VEC with or without RT was conducted with the primary objective of determining if the response rate of the largest non-injected and non-irradiated metastasis was ≥27%. Eligible patients had ≥1 cutaneous metastasis from a solid tumor amenable to T-VEC and RT and 1 measurable metastasis that would not be treated with T-VEC or RT. Using type I and II error probabilities of 10% and 20%, it was calculated that 9 patients would be enrolled in each arm, and if at least 1 of 9 patients subjects exhibited a response, then 6 additional patients would be enrolled in the second stage. Tumor and overall response was assessed using modified World Health Organization (mWHO) and immune related response criteria (irRC). Treatment-emergent and treatment-related adverse events (TEAEs and TRAEs) were characterized using CTCAE v4.0. Results: 19 patients were enrolled and randomized to receive T-VEC alone (n=9) or T-VEC+RT (n=10). One patient in each arm demonstrated a complete response in the largest non-irradiated and non-injected metastasis but progressed in new metastases. The composite response rate in target tumors not injected or irradiated was 13% and 0% in the T-VEC alone and T-VEC+RT arms, respectively. The composite response rate in target tumors treated with T-VEC alone or T-VEC+RT was 7% and 22%, respectively. Because no patient exhibited an overall mWHO or irRC defined response and due to slow accrual, the trial was closed after the first stage of enrollment despite meeting the prespecified response rate to continue enrollment in the second stage. Grade 3-4 TEAEs and TRAEs occurred in 9 and 2 patients, with similar frequencies between study arms. The most common AE was fever and occurred in 47% of patients. Peripheral blood-based immunologic analyses will be presented. Conclusions: The response rate in the largest non-injected or non-irradiated metastasis following T-VEC with or without RT given to a cutaneous metastasis from solid tumor could be ≥27% but was not determined in this trial due to premature closure, in part due to slow accrual rate and no observed mWHO defined overall responses. Cutaneous metastases responded more often after TVEC+RT than T-VEC alone, but the response in non-injected and non-irradiated tumors was more frequent after T-VEC alone. Clinical trial information: NCT02819843.