Background: Neoadjuvant systemic treatment with checkpoint inhibitors (ICI) has shown high response rates in patients with resectable metastasized melanoma. In patients with unresectable stage IIIB-IVA melanoma, intralesional treatment with talimogene laherparepvec (T-VEC) has also shown high and durable response rates. In this trial we investigated the safety and efficacy of neoadjuvant treatment with a combination of nivolumab and T-VEC in regionally metastasized melanoma. Methods: In this single arm phase II open-label trial (NCT04330430), 24 patients with resectable stage IIIB-IVA melanoma were included. Inclusion criteria were a RECIST 1.1 measurable lesion of ≥10mm and no prior systemic therapy. Treatment consisted of four doses of intralesional T-VEC (dose in ml according to the size of the lesions) and three doses of nivolumab 240 mg flat dose every two weeks, followed by surgery. The primary endpoint was pathological response rate according to the International Neoadjuvant Melanoma Consortium (INMC) criteria, secondary endpoints were delay or failure to perform surgery, event free survival (EFS) from time of randomization and safety. Results: Baseline characteristics are presented in the table. The overall pathological response rate was 74%, with a major pathological response (MPR = pathologic complete response (pCR) + near-pCR (max 10% viable tumor cells) in 15 patients (65%), a partial response in two patients (9%), a non-response in 4 patients (17%) and progression of disease (PD) in two patients (9%). In one patient the response was not evaluable because surgery was delayed due to a vena cava thrombosis. The two patients with PD had evidence of distant metastasis on preoperative imaging and therefore did not proceed to surgery as planned. Grade 2 treatment related adverse events (trAE) occurred in 7 patients (29%) and grade 3 in 2 (8%). There were no grade 4-5 trAEs. The 1-year EFS was 75% (95%CI 0.55-1). Conclusions: Neoadjuvant combination therapy of nivolumab and T-VEC for patients with regionally metastasized melanoma (satellite/in-transit +/- lymph node metastases) has an acceptable toxicity profile and has shown a significant major pathological response rate of 65%. Clinical trial information: NCT04330430.

*Revision pending.