Randomized, Double-Blind, Placebo-Controlled, Global Phase III Trial of Talimogene Laherparepvec Combined With Pembrolizumab for Advanced Melanoma

Abstract

Purpose: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma.

Methods: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 10⁶ plaque-forming unit (PFU) followed by ≤ 4 × 10⁸ PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis.

Results: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm.

Conclusion: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.

Trial registration: ClinicalTrials.gov NCT02263508.

FIG 1.

CONSORT diagram. T-VEC, talimogene laherparepvec.

FIG 2.

(A) Kaplan-Meier estimate of PFS in the intention-to treat population. Vertical lines indicate censoring. (B) Forest plots for PFS in subgroups. HRs are shown for subgroups as defined by baseline patient and tumor characteristics. BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HSV, herpes simplex virus; IVRS, interactive voice response system; LDH, lactate dehydrogenase; PFS, progression-free survival; SLD, sum of lesion diameters; T-VEC, talimogene laherparepvec; ULN, upper limit of normal.

FIG 3.

(A) Kaplan-Meier estimate of OS in the intention-to treat population. Vertical lines indicate censoring. (B) Forest plots for OS in subgroups. HRs are shown for subgroups as defined by baseline patient and tumor characteristics. BICR, blinded independent central review; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; HSV, herpes simplex virus; IVRS, interactive voice response system; LDH, lactate dehydrogenase; NE, not estimable; OS, overall survival; SLD, sum of lesion diameters; T-VEC, talimogene laherparepvec; ULN, upper limit of normal.