Talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone for advanced melanoma: 5-year final analysis of a multicenter, randomized, open-label, phase II trial

Abstract

Talimogene laherparepvec (T-VEC) plus ipilimumab has demonstrated greater antitumor activity versus ipilimumab alone, without additional toxicity, in patients with advanced melanoma. Here, we report the 5-year outcomes from a randomized phase II study. These data provide the longest efficacy and safety follow-up for patients with melanoma treated with a combination of an oncolytic virus and a checkpoint inhibitor.Eligible patients with unresectable stage IIIB‒IV melanoma were randomized 1:1 to receive T-VEC plus ipilimumab or ipilimumab alone. T-VEC was administered intralesionally at 10⁶ plaque-forming units (PFU)/mL in week 1, followed by 10⁸ PFU/mL in week 4 and every 2 weeks thereafter. Ipilimumab (3 mg/kg every 3 weeks; ≤4 doses) was administered intravenously starting at week 1 in the ipilimumab arm and week 6 in the combination arm. The primary end point was investigator-assessed objective response rate (ORR) per immune-related response criteria; key secondary end points included durable response rate (DRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Overall, 198 patients were randomized to receive the combination (n=98) or ipilimumab (n=100). The combination improved the ORR versus ipilimumab (35.7% vs 16.0%; OR 2.9; 95% CI 1.5 to 5.7; p=0.003). DRR was 33.7% and 13.0% (unadjusted OR 3.4; 95% CI 1.7 to 7.0; descriptive p=0.001), respectively. Among the objective responders, the median DOR was 69.2 months (95% CI 38.5 to not estimable) with the combination and was not reached with ipilimumab. Median PFS was 13.5 months with the combination and 6.4 months with ipilimumab (HR 0.78; 95% CI 0.55 to 1.09; descriptive p=0.14). Estimated 5-year OS was 54.7% (95% CI 43.9 to 64.2) in the combination arm and 48.4% (95% CI 37.9 to 58.1) in the ipilimumab arm. Forty-seven (48.0%) and 65 (65.0%) patients in the combination and ipilimumab arms, respectively, received subsequent therapies. No new safety signals were reported.At the 5-year follow-up, the improved response rates observed with T-VEC plus ipilimumab were durable. This is the first randomized controlled study of the combination of an oncolytic virus and a checkpoint inhibitor that meets its primary end point.Trial registration number: NCT01740297.

Keywords: immunotherapy; melanoma; oncolytic virotherapy; oncolytic viruses.

Figure 1

(A) Kaplan-Meier estimate of PFS in the intent-to-treat population. (B) Forest plot for PFS in subgroups. *p value is descriptive. Vertical lines indicate censoring. LCL and UCL denote the lower and upper limits of 95% CI, respectively. The intent-to-treat analysis set included all randomized patients regardless of whether they received study treatment. PFS was defined as the time from randomization to the first confirmed disease progression per modified immune-related response criteria, or death, whichever occurred earlier. Patients without documented death or disease progression were censored at their last evaluable tumor assessment date. CRF, case report form; LCL, lower confidence limit; LDH, lactate dehydrogenase; NE, not estimable; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; SPD, sum of the products of the two largest perpendicular diameters; T-VEC, talimogene laherparepvec; UCL, upper confidence limit; ULN, upper limit of normal.

Figure 2

(A) Kaplan-Meier estimate of OS in the intent-to-treat population. (B) Forest plot for OS in subgroups. *p value is descriptive. Vertical lines indicate censoring. LCL and UCL denote the lower and upper limits of 95% CI, respectively. The intent-to-treat analysis set included all randomized patients regardless of whether they received study treatment. OS was defined as the time from randomization to death from any cause. Patients without documented death at the time of analysis were censored on the date that they were last known to have been alive. One month=365.25/12 days. CRF, case report form; LCL, lower confidence limit; LDH, lactate dehydrogenase; NE, not estimable; OS, overall survival; PD-1, programmed cell death-1; PD-L1, programmed death-ligand 1; SPD, sum of the products of the two largest perpendicular diameters; T-VEC, talimogene laherparepvec; UCL, upper confidence limit; ULN, upper limit of normal.