Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma

Abstract

Purpose We evaluated the combination of talimogene laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive talimogene laherparepvec plus ipilimumab or ipilimumab alone. Talimogene laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 10⁶ plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 10⁸ plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to talimogene laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with talimogene laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.

Trial registration: ClinicalTrials.gov NCT01740297.

Fig 1.

Disposition of patients in the study. (*) Of the 76 patients who were not randomly assigned, 57 did not meet eligibility criteria. (†) Ninety-one patients in the talimogene laherparepvec plus ipilimumab arm received at least one dose of both study treatments. (‡) Eight patients were enrolled in the study but did not receive any study medication: talimogene laherparepvec plus ipilimumab (n = 3); ipilimumab alone (n = 5). All but one patient withdrew consent before treatment began; the remaining patient withdrew for insurance reasons. All were included in the intent-to-treat analysis of efficacy.

Fig 2.

Subgroup analysis of objective response rate (A) and disease control rate (B) per immune-related response criteria. LDH, lactate dehydrogenase; OR, odds ratio; SPD, sum of the products of the two longest perpendicular diameters; ULN, upper limit of normal.

Fig 3.

Change in lesion burden from baseline (A) for all lesions, (B) injected lesions, (C) uninjected nonvisceral lesions, and (D) visceral lesions. Per protocol, visceral lesions were not injected. Evaluable patients had baseline and at least one postbaseline evaluation of lesion burden. In panel D, two patients identified as having stage IVM1a disease at baseline had visceral index lesions (one with an adrenal lesion and one with a lung lesion; indicated with (*) and (†), respectively). The remaining patients with stages IIIC and IVM1a disease developed visceral lesions during the study.

Fig 4.

Kaplan-Meier estimate of progression-free survival (PFS). (*) P value is descriptive.

Fig A1.

Study schema for phase II. ECOG, Eastern Cooperative Oncology Group; irRC, immune-related response criteria; IV, intravenous; ORR, objective response rate; OS, overall survival; PD-1, programmed death-1; PFS, progression-free survival; PFU, plaque-forming unit; R, randomization. (*) irRC described in Wolchok et al.