Purpose

RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer.

Patients and methods

This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48.

Results

Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20).

Conclusion

RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status.

Clinical trial information

NCT02881190.

中文翻译：

---

重组人源化抗 HER2 单克隆抗体-MMAE 偶联物 RC48-ADC 在 HER2 阳性晚期实体瘤患者中的 I 期研究

目的

RC48 包含通过可切割接头与 MMAE 偶联的新型人源化抗 HER2 抗体赫妥珠单抗。启动了一项 I 期研究，以评估 RC48 在 HER2 过度表达的局部晚期或转移性实体癌，特别是胃癌患者中的毒性、MTD、PK 和抗肿瘤活性。

患者和方法

这是一个两部分的第一阶段研究。连续的患者队列接受了递增剂量的 RC48（0.1 mg/kg、0.5 mg/kg、1.0 mg/kg、2.0 mg/kg、2.5 mg/kg 和 3.0 mg/kg）。剂量扩展以 2.0 mg/kg Q2W 的剂量进行。疗效和安全性包括所有接受至少一剂 RC48 的患者。

结果

入组了 57 名患者，由于 3.0 mg/kg 队列的终止，MTD 不可用；2.5 mg/kg Q2W 被宣布为 RP2D。RC48 耐受性良好，最常见的 3 级或更严重的 TRAE 包括中性粒细胞减少 (19.3%)、白细胞减少 (17.5%)、感觉减退 (14.0%) 和结合血胆红素升高 (8.8%)。整个研究期间发生四人死亡，其中三人被认为与 RC48 相关。总体而言，ORR 和 DCR 分别为 21.0% (12/57) 和 49.1% (28/57)。值得注意的是，HER2 IHC2+/FISH- 患者与 IHC2+/FISH+ 和 IHC3+ 患者的反应相似，ORR 分别为 35.7% (5/14)、20% (2/10) 和 13.6% (3/22)，分别。在接受过 HER2 靶向药物预处理的患者中，RC48 也显示出有希望的疗效，ORR 为 15.0%（3/20），DCR 为 45.0%（9/20）。

结论

RC48 耐受性良好，在 HER2 阳性实体瘤（包括 HER2 IHC 2+/FISH- 状态的胃癌）中显示出有希望的抗肿瘤活性。

临床试验信息

NCT02881190。