Abstract
PurposeRC48 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 methodsThis 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.ResultsFifty-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).ConclusionRC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status.Clinical trial informationNCT02881190.
Highlights
20% of metastatic gastric cancer patients have HER2 overexpression or amplification
The primary end point of this study is to evaluate the safety and most tolerated dose (MTD) of RC48 in HER2-positive advanced solid tumors and to explore the recommended phase 2 dose (RP2D) in future studies
Considering there was no trend of improving efficacy after adding the dose to 3.0 mg/kg dose compared with 2.0 mg/kg and 2.5 mg/kg cohorts, and continuing enrolling patients in 3.0 mg/kg group may significantly increase the risk of subjects, after discussion the investigators decided to terminate the enrollment of the 3.0 mg/kg cohort and reported to institutional review board
Summary
20% of metastatic gastric cancer patients have HER2 overexpression or amplification. Extended author information available on the last page of the article use of trastuzumab (trastuzumab beyond progression, TBP) failed to improve PFS in patients with HER2-positive advanced G/GEJ cancer. Several other agents have failed to show efficacy for HER2-positive gastric cancer refractory to trastuzumab, including pertuzumab, lapatinib, and T-DM1 [4,5,6,7,8]. HER2-positive advanced gastric cancer has been found to share some of mechanisms of resistance with breast cancer, and to manifest specific mechanisms of resistance to trastuzumab, including tumor heterogeneity in HER2 positivity, loss of HER2 protein expression, alteration in HER2 downstream signaling, and activation of bypass pathways [9]. The development of new HER2-targeted therapeutic approaches should consider the challenges posed by high levels of heterogeneity and complex mechanisms of resistance
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