Zheng Qingmei, Chen Dongmei, Wang Xinmei, Yang Yingying, Zhao Shuyong, Dong Xin, Ma Cuicui, Zhang Xin, Duan Huicheng, Sun Yan, Zheng Shansong
Qilu Pharmaceutical Co., Ltd., Jinan, China.
Ann Transl Med. 2022 Jun;10(12):696. doi: 10.21037/atm-22-2780.
To evaluate the safety and therapeutic efficacy of WX-0593, a newly developed potent anaplastic lymphoma kinase (ALK) inhibitor, in combination with an epithelial growth factor receptor (EGFR) monoclonal antibody (QL1203 or Vectibix) for the treatment of xenograft tumors carrying mutant and osimertinib-resistant mutations (/T790M/C797S).
The inhibition of tumor cell proliferation by WX-0593 and Vectibix alone or combined was evaluated in four EGFR triple-mutant cell lines: PC9 ( Del19/T790M/C797S), NCI-H1975 ( L858R/T790M/C797S), Ba/F3 ( L858R/T790M/C797S and Del19/T790M/C797S). The antitumor efficacy of WX-0593 alone or combined with QL1203 or Vectibix was evaluated in xenograft tumor models of BALB/c nude mice developed from H1975 (-Del19/T790M/C797S) and Ba/F3 (-L858R/T790M/C797S) cell lines. Mice were randomized into groups and treated with or without WX-0593, QL1203, Vectibix, or their combination. The tumor volume, mouse body weight, and therapeutic side effects were monitored routinely. Blood samples were obtained from all mice at different time points after the last dosage of treatment to evaluate the pharmacokinetic parameters of the drugs.
WX-0593 and Vectibix showed a strong synergistic inhibitory effect on the proliferation of two triple-mutant Ba/F3 cell lines ( L858R/T790M/C797S and Del19/T790M/C797S), but little synergistic inhibitory effect on the proliferation of NCI-H1975 ( L858R/T790M/C797S) and PC9 ( Del19/T790M/C797S). , WX-0593 (25 mg/kg) showed a modest therapeutic effect when combined with QL1203 or Vectibix, but had no effect on tumor growth as a monotherapy at this dosage. WX-0593 (75 mg/kg) exhibited modest antitumor efficacy that was further enhanced in combination with QL1203 or Vectibix in both tumor models (H1975 and Ba/F3). No significant body weight alteration, any other side effect, or deaths were observed during treatment. Pharmacokinetic analysis showed that the serum level of QL1203 or Vectibix was significantly increased and lasted longer when combined with WX-0593.
WX-0593 exhibited a synergetic effect with an monoclonal antibody on osimertinib-resistant EGFR-mutant non-small cell lung cancer (NSCLC) both and . Their combination showed potent antitumor efficacy and an acceptable safety profile, which may be a promising strategy for the treatment of patients with triple-mutant NSCLC resistant to osimertinib.
评估新开发的强效间变性淋巴瘤激酶（ALK）抑制剂WX-0593与上皮生长因子受体（EGFR）单克隆抗体（QL1203或爱必妥）联合用于治疗携带/ T790M / C797S突变和奥希替尼耐药突变的异种移植肿瘤的安全性和治疗效果。
在四种EGFR三重突变细胞系中评估WX-0593和爱必妥单独或联合使用对肿瘤细胞增殖的抑制作用：PC9（Del19 / T790M / C797S）、NCI-H1975（L858R / T790M / C797S）、Ba / F3（L858R / T790M / C797S和Del19 / T790M / C797S）。在由H1975（-Del19 / T790M / C797S）和Ba / F3（-L858R / T790M / C797S）细胞系建立的BALB / c裸鼠异种移植肿瘤模型中评估WX-0593单独或与QL1203或爱必妥联合使用的抗肿瘤效果。将小鼠随机分组，给予或不给予WX-0593、QL1203、爱必妥或它们的组合进行治疗。定期监测肿瘤体积、小鼠体重和治疗副作用。在最后一次给药治疗后的不同时间点从所有小鼠采集血样，以评估药物的药代动力学参数。
WX-0593和爱必妥对两种三重突变Ba / F3细胞系（L858R / T790M / C797S和Del19 / T790M / C797S）的增殖显示出强烈的协同抑制作用，但对NCI-H1975（L858R / T790M / C797S）和PC9（Del19 / T790M / C797S）的增殖几乎没有协同抑制作用。此外，WX-0593（25 mg / kg）与QL1203或爱必妥联合使用时显示出适度的治疗效果，但在此剂量下单药治疗对肿瘤生长没有影响。WX-0593（75 mg / kg）在两种肿瘤模型（H1975和Ba / F3）中均表现出适度的抗肿瘤效果，与QL1203或爱必妥联合使用时进一步增强。治疗期间未观察到明显的体重变化、任何其他副作用或死亡。药代动力学分析表明，与WX-0593联合使用时，QL1203或爱必妥的血清水平显著升高且持续时间更长。
WX-0593与EGFR单克隆抗体联合使用对奥希替尼耐药的EGFR突变非小细胞肺癌（NSCLC）在体内和体外均表现出协同作用。它们的联合显示出强大的抗肿瘤效果和可接受的安全性，这可能是治疗对奥希替尼耐药的三重突变NSCLC患者的一种有前景的策略。
