433?Talimogene laherparepvec (T-VEC) in combination with ipilimumab (IPI) versus IPI alone for advanced melanoma: 4-year interim analysis of a randomized, open-label, phase 2 trial

摘要

Background This is the first randomized trial evaluating an oncolytic virus with an immune checkpoint inhibitor in advanced melanoma. Improved objective response rate (ORR) was observed for T-VEC plus IPI compared to IPI alone (39% vs. 18%; OR 2.9; 95% Cl, 1.5–5.5; P=0.002). 1 At 3-year follow-up, median OS was not reached in either arm (HR, 0.85; 95% CI, 0.55–1.32; P=0.480). 2 Here we present 4-year interim analysis results including BRAF V600 mutation subgroup analysis. Methods Patients with unresectable or metastatic (IIIB-IV) melanoma were randomized 1:1 to receive T-VEC plus IPI or IPI alone. T-VEC was injected day 1, week 1, at 106 PFU/mL, followed by 108 PFU/mL on day 1, week 4, and Q2W thereafter. IPI (3 mg/kg) was given Q3W starting day 1, week 6, up to 4 doses, for T-VEC arm; day 1, week 1 for IPI alone. Response was assessed per immune-related response criteria (irRC) Q12W until disease progression. The primary endpoint was ORR; key secondary endpoints were overall survival (OS), progression-free survival (PFS), durable response rate (DRR), and safety ( NCT01740297 ). Results A total of 198 patients (98 combination, 100 IPI alone) were randomized. As of February 25, 2020, median follow-up was 48.3 months for combination and 35.7 months for IPI alone. DRR improved for combination vs. IPI (33.7% vs. 13.0%; OR 3.4; 95% CI, 1.7–7.0; P=0.001). Median PFS was 13.5 months with combination and 6.4 months with IPI (HR 0.81; 95% Cl, 0.57–1.15; P=0.23). Median OS was not reached for combination and was 50.1 months for IPI (HR 0.82; 95% CI, 0.54–1.25; P=0.36). For combination, 47 (48.0%) patients received subsequent anti-cancer therapy vs. 64 (64.0%) for IPI; median time from randomization to first subsequent therapy was 27.7 months and 8.3 months, respectively. In subgroup analysis, patients without BRAF V600 mutation (63% combination, 60% IPI) improved DRR and PFS for combination vs. IPI alone (DRR: 33.9% vs. 5.0%; median PFS: 18.0 months vs. 4.5 months); BRAF V600 mutation positive patients (36% combination, 34% IPI) were similar between arms (DRR: 34.3% vs. 26.5%; median PFS: 4.2 months vs. 6.4 months). No additional safety signals observed in follow-up. Conclusions The improved PFS and DRR for the combination arm at 4-year follow-up indicates continued benefit of combination therapy. Patients receiving IPI alone were more likely to receive subsequent anti-cancer therapy in a shorter time. Subsequent anticancer therapies may confound OS analysis. The BRAF mutant post-hoc analysis requires further mechanistic investigation. Acknowledgements ? The authors thank the investigators, patients, and study staff who contributed to this study.? The study was sponsored and funded by Amgen Inc. ? Medical writing support was provided by Christopher Nosala (Amgen Inc.). Trial Registration NCT01740297 Ethics Approval The study was approved by all institutional ethics boards.