Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma

Abstract

Purpose: Combining immunotherapeutic agents with different mechanisms of action may enhance efficacy. We describe the safety and efficacy of talimogene laherparepvec (T-VEC; an oncolytic virus) in combination with ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 checkpoint inhibitor) in patients with advanced melanoma.

Methods: In this open-label, multicenter, phase Ib trial of T-VEC in combination with ipilimumab, T-VEC was administered intratumorally in week 1 (10(6) plaque-forming units/mL), then in week 4 and every 2 weeks thereafter (10(8) plaque-forming units/mL). Ipilimumab (3 mg/kg) was administered intravenously every 3 weeks for four infusions, beginning in week 6. The primary end point was incidence of dose-limiting toxicities. Secondary end points were objective response rate by immune-related response criteria and safety.

Results: Median duration of treatment with T-VEC was 13.3 weeks (range, 2.0 to 95.4 weeks). Median follow-up time for survival analysis was 20.0 months (1.0 to 25.4 months). Nineteen patients were included in the safety analysis. No dose-limiting toxicities occurred, and no new safety signals were detected. Grade 3/4 treatment-related adverse events (AEs) were seen in 26.3% of patients; 15.8% had AEs attributed to T-VEC, and 21.1% had AEs attributed to ipilimumab. The objective response rate was 50%, and 44% of patients had a durable response lasting ≥ 6 months. Eighteen-month progression-free survival was 50%; 18-month overall survival was 67%.

Conclusion: T-VEC with ipilimumab had a tolerable safety profile, and the combination appeared to have greater efficacy than either T-VEC or ipilimumab monotherapy.

Trial registration: ClinicalTrials.gov NCT01740297.

Fig 1.

Maximal change in tumor burden from baseline is shown. Changes in tumor burden are presented at the patient level (A) and at the lesion level (injected lesions in panel B and uninjected lesions in panel C). CR, complete response; irRC, immune-related response criteria; PD, progressive disease; PR, partial response; SD, stable disease. *Patient had a 99.8% reduction in tumor burden. †Patients had a confirmed complete response. ‡Patients had 100% reduction in tumor burden, but response was unconfirmed.

Fig 2.

Changes in tumor burden by disease stage.

Fig 3.

Timing and duration of responses relative to administration of talimogene laherparepvec and ipilimumab. Data are shown for confirmed responders. Administration of talimogene laherparepvec is indicated by light blue vertical lines; the interval from the first to last ipilimumab administration is indicated in yellow; and the bar ends at the first progressive disease if there is progressive disease, otherwise, at the last tumor assessment.

Fig 4.

Kaplan-Meier analysis of (A) progression-free survival (PFS) and (B) overall survival (OS).

Fig A1.

Dosing and assessment schedule. CR, complete response; CTA, clinical tumor assessment; PD, progressive disease; Q2W, once every 2 weeks; Q12W, once every 12 weeks.

Fig A2.

Complete response in patient with stage IVM1b melanoma treated with ipilimumab + talimogene laherparepvec. The initial right scalp lesion was resected in 2010. Recurrence was in scalp, left lower lobe of lung, and left hilar node in 2013 (CT scans on left). Complete response was documented at 24 weeks after initial treatment (CT scans on right). The patient is currently without recurrent disease at over 2 years.

Fig A3.

Changes in subsets of T cells after treatment. Samples were collected at baseline (week 1), after talimogene laherparepvec was given as monotherapy (weeks 4 and 6), and after talimogene laherparepvec was given in combination with ipilimumab (weeks 9 and 15). Data points are overlaid on the box plots. Each box plot shows the range between 25th percentile (q1) and 75th percentile (q3) as a gray box, with a yellow line showing the 50th percentile. The whiskers on each box are q3 ± 1.5 × (q3 − q1). (A) Total and activated CD8⁺ T cells. Activated CD8⁺ T cells are defined as HLA^-DR⁺CD3⁺CD4⁻ cells. (B) Total and ICOS⁺ CD4⁺ T cells. ICOS, inducible T-cell costimulator.

Fig A4.

Changes in subsets of T-cells according to confirmed best response. (A) Changes in activated CD8+ T-cell count after administration of talimogene laherparepvec and talimogene laherparepvec + ipilimumab. (B) Changes in ICOS+ CD4+ T-cell count after administration of talimogene laherparepvec and talimogene laherparepvec + ipilimumab. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.