Primary analysis of MASTERKEY-265 phase 1b study of talimogene laherparepvec (T-VEC) and pembrolizumab (pembro) for unresectable stage IIIB-IV melanoma

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Background: T-VEC is a herpes simplex virus-1 -based oncolytic immunotherapy designed to selectively replicate in tumors, pro- duce GM-CSF, and stimulate antitumor immune responses. T-VEC significantly improved durable response rate (DRR; primary end- point) in the T-VEC arm vs GM-CSF in OPTiM (Andtbacka et al. JCO 2015) and is approved in the US for local treatment of unresect- able cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent after initial surgery. Pembro is a PD-1 block- ing antibody approved for the treatment of advanced metastatic or unresectable melanoma and has demonstrated superiority over the CTLA-4-blocking antibody ipilimumab in patients with stage III or IV melanoma (Robert et al. NEJM 2015). Both drugs have toler- able and non-overlapping adverse event (AE) profiles, and combin- ing them may enhance antitumor efficacy. Safety and preliminary efficacy data from the phase 1b primary analysis of a phase 1b/3 study of T-VEC + pembro in unresectable stage IIIB-IV melanoma (NCT02263508) are reported. Materials and methods: The primary endpoint is incidence of dose- limiting toxicities (DLT). Key secondary endpoints are objective response, survival, and AEs. Patients had stage IIIB-IV melanoma with injectable lesions, no prior systemic therapy, and ECOG PS 0-1. T-VEC was given ≤4 mL injected into (sub)cutaneous/nodal lesions 106 PFU/ mL d1, 108 PFU/mL d22 then Q2W. Pembro was given IV 200 mg d36 then Q2W. Treatment (tx) continues until. CR, all injectable tumors have disappeared (for T-VEC), confirmed PD per modified immune-related response criteria, intolerance of study treatment, 24 months from the date of the first dose of pembro or end of study, whichever occurs first. Results: 21 patients were enrolled Dec 2014-Mar 2015 with data cut- off of Jun 2015. Patient characteristics: median age 58 year; 48 % stage IIIB-IVM1a, 52 % stage IVM1b/c melanoma; 81 % PD-L1+; 76 % HSV+. Median follow-up time was 18.7 w. No DLTs were reported. All 21 patients had an AE: 29 % G3, no G4, and one G5 (not attributed to tx). Most common AEs were fatigue 52 %, pyrexia 48 %, chills 43 %, and rash 38 %. Of 16 patients ≥12 w after first pembro tx and with evalu- able response assessment, unconfirmed response rate per investigator was 56 %; disease control rate was 69 % (12.5 % CR, 44 % PR, 12.5 % SD, 31 % PD). Conclusions: T-VEC+ pembro can be given at full doses with no unexpected safety signals. Responses were seen in over half of eval- uable patients in this early efficacy analysis. A randomized phase 3 trial comparing T-VEC+ pembro vs T-VEC placebo + pembro is planned.

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