UofL Health-Brown Cancer Center, University of Louisville, Louisville, KY.
Jonsson Comprehensive Cancer Center at the University of California Los Angeles, Los Angeles, CA.
J Clin Oncol. 2023 Jan 20;41(3):528-540. doi: 10.1200/JCO.22.00343. Epub 2022 Aug 23.
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.
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 × 10 plaque-forming unit (PFU) followed by ≤ 4 × 10 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.
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; = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; = .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.
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.
在一项 Ib 期研究中，晚期黑色素瘤患者联合使用替莫唑胺拉帕替尼（T-VEC）和派姆单抗显示出可接受的安全性和令人鼓舞的完全缓解率（CRR）。我们报告了一项 III 期、随机、双盲、多中心、国际 T-VEC 联合派姆单抗（T-VEC-派姆单抗）与安慰剂联合派姆单抗（安慰剂-派姆单抗）治疗晚期黑色素瘤患者的疗效和安全性。
IIIb-IVM1c 期不可切除的黑色素瘤患者，对程序性细胞死亡蛋白-1 治疗无经验，以 1:1 的比例随机分配接受 T-VEC-派姆单抗或安慰剂-派姆单抗治疗。T-VEC 以 ≤ 4×10 噬斑形成单位（PFU）的剂量给药，然后在 3 周后给予 ≤ 4×10 PFU，此后每 2 周给予一次，直至剂量 5，然后每 3 周给予一次。派姆单抗静脉注射 200mg，每 3 周一次。主要终点是盲法独立中心评估的改良 RECIST 1.1 下的无进展生存期（PFS）和总生存期（OS）。次要终点包括基于 mRECIST 的客观缓解率（ORR）、CRR 和安全性。在此，我们报告了 PFS 的主要分析、OS 的第二次预先计划的中期分析和最终分析。
总体而言，692 名患者被随机分配（T-VEC-派姆单抗 346 例，安慰剂-派姆单抗 346 例）。与安慰剂-派姆单抗相比，T-VEC-派姆单抗并未显著改善 PFS（风险比，0.86；95%CI，0.71 至 1.04；=0.13）或 OS（风险比，0.96；95%CI，0.76 至 1.22；=0.74）。T-VEC-派姆单抗的客观缓解率为 48.6%（CRR 为 17.9%），安慰剂-派姆单抗的客观缓解率为 41.3%（CRR 为 11.6%）；分别为 42.2%和 34.1%。T-VEC-派姆单抗组有 20.7%的患者发生≥3 级治疗相关不良事件，安慰剂-派姆单抗组有 19.5%的患者发生≥3 级治疗相关不良事件。
与安慰剂-派姆单抗相比，T-VEC-派姆单抗并未显著改善 PFS 或 OS。T-VEC-派姆单抗联合治疗的安全性结果与每种药物单独使用的安全性一致。
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