Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors

Yingying Xu, Yakun Wang, Jifang Gong, Xiaotian Zhang, Zhi Peng, Xinan Sheng, Chenyu Mao, Qingxia Fan, Yuxian Bai, Yi Ba, Da Jiang, Fen Yang, Changsong Qi, Jian Li, Xicheng Wang, Jun Zhou, Ming Lu, Yanshuo Cao, Jiajia Yuan, Dan Liu, Zhenghang Wang, Jianmin Fang, Lin Shen, Yingying Xu, Yakun Wang, Jifang Gong, Xiaotian Zhang, Zhi Peng, Xinan Sheng, Chenyu Mao, Qingxia Fan, Yuxian Bai, Yi Ba, Da Jiang, Fen Yang, Changsong Qi, Jian Li, Xicheng Wang, Jun Zhou, Ming Lu, Yanshuo Cao, Jiajia Yuan, Dan Liu, Zhenghang Wang, Jianmin Fang, Lin Shen

Abstract

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.

Keywords: Gastric cancer; HER2; RC48-ADC; Solid tumors.

Conflict of interest statement

None of the authors declare any conflict of interest.

Figures

Fig. 1
Fig. 1
The process of dose escalation and expansion
Fig. 2
Fig. 2
Best percentage change to date from baseline in sum of diameters in target lesions. Maximal change of tumor size from baseline assessed by investigator per RECIST v1.1 from all patients with baseline and at least one post-treatment radiographic evaluation (N = 48)

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Source: PubMed

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