尽管抗体-药物偶联物(ADC)显著改善了表达人表皮受体2(HER2)的胃癌或胃食管交界癌(G/GEJ)患者的生存结果,作为单一药物使用的ADC的功效是有限的。因此,有必要研究有效和安全的联合治疗方案。临床前数据表明RC48和程序性细胞死亡蛋白1(PD-1)抑制剂具有协同抗肿瘤作用。我们旨在评估RC48联合toripalimab在HER2表达G/GEJ癌症和其他实体瘤患者中的安全性和有效性。
■这是一个开放标签,多中心,在中国三家医院进行的第一阶段试验。符合条件的患者患有晚期G/GEJ癌症或其他实体瘤,HER2IHC≥1或ISH阳性,并且对至少一种治疗方法难以治疗。或标准治疗对于这些患者是无法耐受或不可用的.本研究遵循“3+3”设计,预定的RC48剂量为2.0mg/kg和2.5mg/kg,加上托里帕利马3mg/kg,每2周一次(q2w)。主要目标是评估安全性并确定推荐的II期剂量(RP2D),次要目标包括评估药代动力学(PK)和初步疗效。这项研究在ClinicalTrials.gov注册,NCT04280341。
■在2020年7月13日至2022年8月30日之间,56名患者,包括30例G/GEJ癌症患者和26例其他实体瘤患者,入选并接受RC48+托里帕利马(对于RC482.0mg/kg,n=7,托里帕利马3毫克/千克,q2w;对于RC482.5mg/kg,n=49,托里帕利马3毫克/千克,q2w)。没有发生剂量限制性毒性作用。RP2D被宣布为RC482.5mg/kg加上托里帕利单抗3mg/kg,q2w.最常见的3级不良事件是中性粒细胞计数减少(n=13),白细胞计数减少(n=7)。完成了52例患者的疗效评估。在G/GEJ癌症患者中(n=30),确认客观缓解率(ORR)为43%(12/28,95%CI25,63),中位无进展生存期(PFS)为6.2个月(95%CI4.0,6.9),中位总生存期(OS)为16.8个月(95%CI7.2,NE).接受RP2D(n=24)的G/GEJ癌症患者的ORR达到50%(11/22,95%CI28,72),中位PFS为5.1个月(95%CI1.4,7.3),中位OS为14.0个月(95%CI6.3,NE)。在接受RP2D的G/GEJ癌症患者中,在HER2阳性和低HER2表达人群中均观察到临床益处,ORR为56%(5/9,95%CI21,86)与46%(6/13,95%CI19,75),中位PFS为7.8个月(95%CI0.9,NE)与5.1个月(95%可信区间1.2,6.9),NE个月的中位OS(95%CI4.3,NE)与14.0个月(95%CI5.1,NE),分别。其他实体瘤也观察到抗肿瘤活性,包括乳腺癌(5/13)和子宫内膜癌(1/1)。
■我们的研究结果表明,RC48联合toripalimab在HER2阳性和低HER2表达G/GEJ癌症的预处理患者中具有可控的安全性,并显示出令人鼓舞的疗效。我们的1期临床试验的结果支持在未来HER2表达G/GEJ癌症和癌症治疗中进一步研究HER2靶向ADC加免疫治疗。
■北京市医学研究院,北京医学研究所(Z200015).
UNASSIGNED: Although the antibody-drug conjugates (ADCs) have significantly improved the survival outcomes of patients with human epidermal receptor 2 (HER2)-expressing gastric or gastroesophageal junction (G/GEJ) cancer, the efficacy of ADC used as a single agent is limited. Therefore, it is necessary to investigate effective and safe combination regimens. Preclinical data indicated a synergetic antitumour effect of RC48 and programmed cell death protein 1 (PD-1) inhibitors. We aimed to evaluate the safety and efficacy of RC48 plus toripalimab in patients with HER2-expressing G/GEJ cancer and other solid tumours.
UNASSIGNED: This was a open-label, multicentre, phase 1 trial performed at three hospitals in China. Eligible patients had advanced G/GEJ cancer or other solid tumours with HER2 IHC≥1 or ISH positivity and were refractory to at least one line of treatment, or standard treatment was intolerable or unavailable for these patients. This study followed a \"3 + 3\" design with predefined RC48 dosages of 2.0 mg/kg and 2.5 mg/kg plus toripalimab 3 mg/kg, once every 2 weeks (q2w). The primary objectives were to evaluate the safety and determine the recommended phase II dose (RP2D), and the secondary objectives included assessing the pharmacokinetics (PK) and preliminary efficacy. This study was registered with ClinicalTrials.gov, NCT04280341.
UNASSIGNED: Between July 13, 2020 and August 30, 2022, 56 patients, including 30 patients with G/GEJ cancer and 26 patients with other solid tumours, were enrolled and received RC48 plus toripalimab (n = 7 for RC48 2.0 mg/kg, toripalimab 3 mg/kg, q2w; n = 49 for RC48 2.5 mg/kg, toripalimab 3 mg/kg, q2w). No dose-limiting toxic effects occurred. The RP2D was declared as RC48 2.5 mg/kg plus toripalimab 3 mg/kg, q2w. The most common grade 3 adverse events were a decreased neutrophil count (n = 13), and a decreased white blood cell count (n = 7). The efficacy assessment was completed for 52 patients. Among patients with G/GEJ cancer (n = 30), the confirmed objective response rate (ORR) was 43% (12/28, 95% CI 25, 63), median progression-free survival (PFS) was 6.2 months (95% CI 4.0, 6.9), median overall survival (OS) was 16.8 months (95% CI 7.2, NE). The ORR of patients with G/GEJ cancer receiving RP2D (n = 24) reached 50% (11/22, 95% CI 28, 72), with median PFS of 5.1 months (95% CI 1.4, 7.3) and median OS of 14.0 months (95% CI 6.3, NE). Among patients with G/GEJ cancer who received RP2D, a clinical benefit was observed in both HER2-positive and low HER2 expressing populations, with an ORR of 56% (5/9, 95% CI 21, 86) vs. 46% (6/13, 95% CI 19, 75), median PFS of 7.8 months (95% CI 0.9, NE) vs. 5.1 months (95% CI 1.2, 6.9), median OS of NE months (95% CI 4.3, NE) vs. 14.0 months (95% CI 5.1, NE), respectively. Antitumour activity was also observed for other solid tumours, including breast cancer (5/13) and endometrial carcinoma (1/1).
UNASSIGNED: Our findings suggested that RC48 plus toripalimab had a manageable safety profile and showed encouraging efficacy in pretreated patients with HER2-positive and low HER2-expressing G/GEJ cancer. The findings of our phase 1 clinical trial support further investigation of HER2-targeted ADC plus immunotherapy in HER2-expressing G/GEJ cancer and pancancer treatment in the future.
UNASSIGNED: Beijing Municipal Medical Research Institutes, Beijing Medical Research Institute (Z200015).