安尼妥单抗ravtansine与帕博利珠单抗联合治疗与单用帕博利珠单抗在间皮瘤中的随机对照试验

Randomized trial of anetumab ravtansine and pembrolizumab compared to pembrolizumab for mesothelioma

LUNG CANCER

影响因子:4.4

分区:医学2区 / 肿瘤学3区呼吸系统3区

发表日期:2024 Sep

作者: Aaron S Mansfield, Jun Vivien Yin, Penelope Bradbury, David J Kwiatkowski, Shiven Patel, Lyudmila A Bazhenova, Patrick Forde, Yanyan Lou, Paul Dizona, Liza C Villaruz, Susanne M Arnold, Maya Khalil, Hedy L Kindler, Marianna Koczywas, Jose Pacheco, Christian Rolfo, Bing Xia, Elizabeth Mikula, Li Chen, Kashish Patel, Katherine E R Smith, Liang Cao, Geoffrey Shapiro, Brian A Costello, Alex Adjei, Elad Sharon, Jeffrey A Moscow, William Zamboni, Raffit Hassan

DOI: 10.1016/j.lungcan.2024.107928

摘要

基于间皮素（mesothelin）广泛表达及在间皮瘤中的活性报告，评估了间皮素靶向抗体药物偶联物安尼妥单抗ravtansine（6.5 mg/kg，静脉每3周一次）联合程序性细胞死亡蛋白-1（PD-1）抑制剂帕博利珠单抗（200 mg，每3周一次）的安全性。此研究为一期安全性试验，随后在美国和加拿大多个中心通过国家癌症研究所的实验性治疗临床试验网络进行二期随机对照试验，将患者随机分入联合组或单用帕博利珠单抗组。符合条件的患者为表达间皮素且曾接受铂类基础化疗的胸膜间皮瘤患者。在一期（n=12）中，仅观察到一例剂量限制性毒性，剂量递减规则未被触发。在二期中，确认反应率在联合组（n=18，2例部分反应，11%）与单用帕博利珠单抗组（n=17，1例部分反应，6%）之间无差异（z=-0.5523，p=0.29116）。两组的无进展生存期（PFS）中位数分别为12.2个月（95% CI 5.1-未评估）与3.9个月（95% CI 2.1-未评估）（HR=0.55，p=0.20）。高基线可溶性间皮素水平患者接受安尼妥单抗ravtansine后，中位PFS为5个月。由于样本量较小，治疗组之间在PFS上的差异未达到统计学显著，建议考虑溶解性间皮素水平在选择是否使用该类靶向治疗中的作用，避免使用被溶解性间皮素中和的疗法。

Abstract

The mesothelin-targeting antibody-drug conjugate anetumab ravtansine was evaluated in combination with the programmed cell death-1 (PD-1) inhibitor pembrolizumab based on the common expression of mesothelin and reports of activity in mesothelioma.A phase 1 safety run-in of the combination of anetumab ravtansine (6.5 mg/kg iv q3weeks) and pembrolizumab (200 mg, IV q3weeks) was conducted, followed by a phase 2 randomization to the combination or pembrolizumab alone at medical centers across the United States and Canada in the National Cancer Institute's Experimental Therapeutics Clinical Trials Network. Patients with pleural mesothelioma that expressed mesothelin and had previously received platinum-based therapy were eligible.In phase 1 (n = 12) only one dose limiting toxicity was observed and the rules for dose reduction were not met. In phase 2, there was no difference in the confirmed response rates between the combination group (n = 18, 2 partial responses [PR], 11 %) and the pembrolizumab group (n = 17, 1 PR, 6 %; z = -0.5523, p = 0.29116). The median PFS was 12.2 months (95 % CI 5.1-not evaluable [NE]) for the combination, and 3.9 months for pembrolizumab (95 % CI 2.1-NE)(HR=0.55, p = 0.20). Patients with high baseline levels of soluble mesothelin who received anetumab ravtansine had a median PFS of 5 months.The numeric difference in PFS between treatment groups was not statistically significant, likely related to a smaller than planned sample size. High levels of soluble mesothelin should potentially be considered to select against the use of mesothelin-targeting therapies in development that are neutralized by soluble mesothelin.