Efficacy and safety of recombinant human lymphotoxin‐α derivative with cisplatin and fluorouracil in patients with metastatic esophageal squamous cell carcinoma: A randomized, multicenter, open‐label, controlled, phase 2b trial

• Published in: Cancer 2017-10, Vol.123 (20), p.3986-3994
• Main Authors: Wang, Feng‐hua, Wang, Yun, Sun, Guo‐ping, Chen, Jian‐hua, Lin, Ying‐cheng, Liu, Wei, Zheng, Rong‐sheng, Chen, Jia, Zhang, He‐long, Lan, Hai‐tao, Qi, Jun, Liu, Yang‐qing, Deng, Yan‐ming, Zhao, Heng, Xiong, Jian‐ping, Xu, Qing, Jiang, Wen‐qi, Li, Yu‐hong
• Format: Article
• Language: English
• Subjects: 5‐fluorouracil; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - secondary; China; cisplatin; Cisplatin - administration & dosage; Disease-Free Survival; esophageal cancer; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Female; Fluorouracil - administration & dosage; Humans; lymphotoxin α; Lymphotoxin-alpha - adverse effects; Lymphotoxin-alpha - therapeutic use; Male; metastases; Middle Aged; Receptors, Tumor Necrosis Factor, Type II - blood; Recombinant Proteins - adverse effects; Recombinant Proteins - therapeutic use
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.30845

BACKGROUND Recombinant human lymphotoxin‐α derivative (rhLTα‐Da) is a lymphotoxin‐α derivative that is missing 27 N‐terminal amino acid residues. Previous studies indicated a benefit from the addition of rhLTα‐Da to cisplatin‐based treatment in patients with metastatic esophageal squamous cell carcinoma. The current study was conducted to evaluate the efficacy and safety of rhLTα‐Da plus cisplatin and fluorouracil (PF) in patients with mESCC. METHODS Patients from 15 centers in China were randomly assigned (1:1:1) to 3 arms (arm A, PF plus 10 μg/m2 daily rhLTα‐Da; arm B, PF plus 20 μg/m2 daily rhLTα‐Da; arm C, PF alone). The primary endpoints included progression‐free survival (PFS) and the confirmed overall response rate (ORR). An exploratory analysis was performed to evaluate the role of serum tumor necrosis factor receptor II (TNFR II) in predicting the efficacy of rhLTα‐Da. RESULTS Between September 2010 and May 2013, 150 patients were enrolled. No significant differences in either PFS or ORR were observed between the 3 arms. However, in a small subset of patients who had low serum TNFR II levels, the median PFS was significantly longer for those in arm B than for these in other 2 arms (7.2 months [95% confidence interval, 5.1‐8.6 months] for arm B vs 3.5 months [95% confidence interval, 1.7‐5.5 months] for arm A [P = .022] and 4.0 months [95% confidence interval, 3.2‐6.3 months] for arm C [P = .027]). The addition of rhLTα‐Da significantly increased the incidence of chills (P < .001). CONCLUSIONS rhLTα‐Da combined with the PF regimen failed to improve PFS and ORR in patients with mESCC, except in a small subset that had low serum TNFR II concentrations. Cancer 2017;123:3986‐94. © 2017 American Cancer Society. Combined recombinant human lymphotoxin‐α derivative (rhLTα‐Da) with cisplatin and fluorouracil failed to improve the progression‐free survival and overall response rate in patients with metastatic esophageal squamous cell carcinoma, but only in a small subset with low levels of serum tumor necrosis factor receptor II. Derivatives that target membrane receptors only and eliminate the interference of serum receptors could be more promising for antitumor reconstructed lymphotoxin.