Background: T-VEC is a herpes simplex virus-1-based intralesional oncolytic immunotherapy that provides durable responses in patients (pts) with advanced melanoma (Andtbacka et al, JCO 2015). Pembrolizumab is a humanized IgG4 high-affinity PD-1 blocking antibody that has been shown to improve survival in melanoma (Robert et al, NEJM 2015). T-VEC and pembrolizumab have favourable and non-overlapping adverse event (AE) profiles and combining them may enhance antitumor effects. We report initial safety data from the phase 1b part of a phase 1b/3 study (NCT02263508) of T-VEC + pembrolizumab in unresectable stage IIIB-IV melanoma.
Methods: The primary objective was to assess dose-limiting toxicities (DLTs) of T-VEC + pembrolizumab. Secondary objectives included evaluation of durable response rate, PFS (per irRC), OS, and treatment- emergent AEs (TEAEs). Pts had stage IIIB-IV melanoma with injectable lesions, no prior systemic therapy and ECOG PS 0−1. T-VEC ([1]4 mL) was injected into cutaneous, subcutaneous, or nodal lesions: 106 PFU/mL day 1, 10 8 PFU/mL day 22 then Q2W. Pembrolizumab was added from day 36 at 200 mg IV Q2W. Treatment was planned until CR or PD (per irRC), no injectable lesions (T-VEC only) or for up to 2yr. DLTs were treatment-related grade (G) 3 (>3 days)/4 non-hematologic AE, G3/4 non-hematologic lab, G3/4 febrile neutropenia, thrombocytopenia with bleeding, or other toxicity leading to permanent discontinuation within 6 wks of first pembrolizumab dose.
Results: 21 pts were enrolled from 12/2014−03/2015. All received
1 dose of both T-VEC and pembrolizumab. Data cutoff was 6 wk after the last pt had their first pembrolizumab dose. Baseline characteristics: median age 58.0 yrs; 62% female; 90% ECOG PS 0; 48% stage IIIB-IVM1a and 52% stage IVb/c melanoma. No DLTs were reported. At time of submission, median treatment duration is 13.1 wk (median 7.0 doses) with T-VEC and 10.1 wk (median 5.0 doses) with pembrolizumab. All 21 pts had a TEAE (treatment-related AE rate was 19%); G3 TEAE rate was 29%, there were no G4 TEAEs. The most common TEAEs were rash (57%), pyrexia (38%), fatigue (29%), chills (24%), nausea (19%), pruritis (19%), diarrhea (19%), vomiting (14%), headache (14%), and arthralgia (14%). The only G3 TEAEs occurring in >1 pt were anemia (n = 2) and rash (n = 2; 1 macular and 1 general rash, both following first pembrolizumab). One pt had G1 cytokine release syndrome (attributed to combination treatment). One pt died of shock related to PD and not to treatment. No pts discontinued therapy due to AEs.
Conclusions: T-VEC in combination with pembrolizumab was well- tolerated at full dose with no DLTs. Efficacy data are not yet available. Phase Ib supported initiation of the randomized phase 3 part of the study, which will evaluate the efficacy and safety of the combination vs pembrolizumab alone.
