A Phase 2, Randomized, Open-Label Trial Assessing Efficacy And Safety Of Talimogene Laherparepvec (T-Vec) Neoadjuvant Treatment (Tx) Plus Surgery Vs. Surgery For Resectable Stage Iiib-Ivm1a Melanoma

Background: The risk of recurrence and death in patients (pts) with stages IIIB to IVM1a melanoma following resection is high. T-VEC is an HSV-1 derived oncolytic immunotherapy designed to selectively replicate in tumors and produce GM-CSF to enhance systemic antitumor immune responses. In OPTiM, a randomized phase 3 trial of intralesional T-VEC vs subcutaneous GM-CSF in pts with unresected Stage IIIB-IV melanoma, intralesional T-VEC improved durable response rate (DRR; partial response or complete response [CR] lasting continuously for ≥6 months [m]) from 2% to 16% ( P P =0.051) (Kaufman et al, ASCO 2014). By lesion-level tumor response analysis, 64% of injected, 34% of uninjected non-visceral, and 15% of uninjected visceral lesions decreased in size by ≥ 50%, demonstrating systemic antitumor effects of T-VEC (Andtbacka et al, SSO 2014). Therefore, neoadjuvant T-VEC may help to decrease recurrence after resection of melanoma by improving local control through higher rates of tumor-free margin surgical (R0) resection, and decrease distant metastasis through systemic antitumor effects. Methods: This is a phase 2, multicenter, randomized, open-label study designed to estimate the efficacy of neoadjuvant T-VEC followed by surgery compared to surgery alone in pts with resectable stage IIIB, IIIC, or IVM1a melanoma. Key eligibility criteria are age ≥ 18 y old, melanoma stages IIIB/C or IVM1a with at least 1 injectable lesion, and Eastern Cooperative Oncology Group performance status 0 or 1. Prior systemic, regional, and radiation therapies for melanoma must have been completed ≥ 3 m prior to randomization. Primary ocular and mucosal melanoma is excluded. Pts with history or evidence of symptomatic autoimmune disease, immunodeficiency, clinically significant immunosuppression, active herpetic skin lesions or prior complications of HSV-1 infection, intermittent/chronic systemic tx with an antiherpetic drugs, and prior T-VEC or tumor vaccines are excluded. 150 pts are planned to be randomized 1:1 to receive either (A) 6 doses of T-VEC for 12 w followed by resection or (B) immediate resection. T-VEC will be administered intralesionally into injectable cutaneous, subcutaneous, and nodal tumors initially at a dose of 10 6 plaque forming units (PFU)/mL at d1 w1 followed by 10 8 PFU/mL at d1 of w4, 6, 8, 10, and 12, or until all injectable tumors have disappeared or intolerance to T-VEC, whichever is first. Pts experiencing growth in existing tumors or the appearance of new tumors can remain on T-VEC until w12 of therapy unless other tx, including immediate surgery, is warranted per investigator. The primary endpoint is recurrence-free survival (RFS). The primary analysis of the RFS will occur at the later timepoint of either 2 y after the end of randomization or 64 events of recurrence based on assumption of HR 0.6 benefiting T-VEC arm in RFS at 2 y. Additional and the final analyses will occur at 3 and 5 y after the randomization. Secondary endpoints are 2-y, 3-y, 5-y RFS, OS, overall tumor response and tumor response in injected and uninjected lesions (T-VEC arm only), rates of R0 resection and pathological CR, local recurrence and distant metastases-free survival, and safety. Tumors and blood samples will be collected before and after T-VEC tx to investigate the relationship between biomarkers of the immune system and response to tx. Citation Format: Robert HI Andtbacka, Mohamed Shabooti, Ai Li, Michael Chastain, Mark Shilkrut. A phase 2, randomized, open-label trial assessing efficacy and safety of talimogene laherparepvec (T-VEC) neoadjuvant treatment (tx) plus surgery vs. surgery for resectable stage IIIB-IVM1a melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B13.