From AVATAR Mice to Patients: RC48-ADC Exerted Promising Efficacy in Advanced Gastric Cancer With HER2 Expression

Abstract

RC48-ADC is a novel humanized antibody specific for human epidermal growth factor receptor 2 (HER2)in conjugation with a microtubule inhibitor via a cleavable linker. This study was to evaluate the antitumor activity and mechanism of RC48-ADC in gastric cancer (GC) and explore the population that may benefit from RC48-ADC treatment. Four human GC cell lines and nine patient-derived xenograft (PDX) models were exploited to evaluate the antitumor effect of RC48-ADC or trastuzumab treatment in vitro and in vivo. The expression and phosphorylation of HER2 were assessed by immunohistochemistry (IHC) staining. Critical molecules of downstream PI3K/AKT and cell cycle and apoptosis signaling pathways were detected and quantified by immunoblotting. Combined with preliminary results of preclinical research, three patients with IHC3+, IHC2+/FISH+, and IHC2+/FISH- of HER2 were enrolled to verify the efficacy of RC48-ADC treatment in advanced GC. In vitro, RC48-ADC had superior antiproliferative effects in a dose-dependent manner on GC cells, especially on HER2-positive cells. In vivo, RC48-ADC exceeded trastuzumab in GC PDX models with HER2 expression, even in models with moderate to low expression of HER2. Further exploration of mechanism showed that RC48-ADC exerted the antitumor effect by inhibiting phosphorylation of HER2, inducing G2/M phase arrest and cell apoptosis in HER2-expressed PDX models. In clinical practice, RC48-ADC had satisfactory efficacy in HER2-positive and HER2 moderately expressed GC patients and demonstrated promising efficacy in HER2-positive patients who have progressed after anti-HER2 therapy. In conclusion, RC48-ADC exerted promising antitumor activity in HER2-positive as well as score of 2+ in IHC and ISH-negative AGC patients after progression of systematic treatment.

Systemic therapy for gastric cancer: Perioperative strategies and beyond

“…Targeting angiogenesis via vascular endothelial growth factor (VEGF) was demonstrated with the development of bevacizumab, which was approved for the treatment of metastatic colorectal cancer in 2004. The efficacy of this humanized monoclonal antibody shown in colorectal cancer was not reproducible in gastric cancer, with AVAGAST and AVATAR trials not demonstrating survival benefit with the addition of bevacizumab to a cytotoxic chemotherapy backbone 50,51 . However, ramucirumab, a recombinant monoclonal antibody of the immunoglobulin G1 class with affinity to the VEGFR‐2, has been used as monotherapy and combined with paclitaxel in two separate Phase III trials in the metastatic gastric cancer setting.…”

“…Specifically, the implementation of ramucirumab and trifluridine/tipiracil have resulted in overall survival improvement for patients with heavily pretreated disease.Targeting angiogenesis via vascular endothelial growth factor (VEGF) was demonstrated with the development of bevacizumab, which was approved for the treatment of metastatic colorectal cancer in 2004. The efficacy of this humanized monoclonal antibody shown in colorectal cancer was not reproducible in gastric cancer, with AVAGAST and AVATAR trials not demonstrating survival benefit with the addition of bevacizumab to a cytotoxic chemotherapy backbone 50,51. However, ramucirumab, a recombinant monoclonal antibody of the immunoglobulin G1 class with affinity to the VEGFR-2, has been used as monotherapy and combined with paclitaxel in two separate Phase III trials in the metastatic gastric cancer setting.The REGARD trial was an international, double blind, placebocontrolled randomized trial comparing ramucirumab monotherapy or placebo for patients with advanced gastric or EGJ adenocarcinoma after progression of disease on first-line fluoropyrimidine or platinum-containing agents 52.…”

Research Progress of Antibody–Drug Conjugate Therapy for Advanced Gastric Cancer

“…It has been confirmed that RC48 can selectively deliver MMAE to the targeted tumor tissue in in-vitro and in-vivo trials. The targeted transport and release of RC48 can reduce systemic side effects and improve antitumor capacities in humans ( 34 ).…”

HER2-targeted advanced metastatic gastric/gastroesophageal junction adenocarcinoma: treatment landscape and future perspectives

“…Recent clinical trials have shown that ADCs, such as DS-8201 and Disitamab vedotin, release intracellular toxins that can exert a killing effect on neighboring cells without target expression. This is termed the bystander effect and allows patients with HER2-low GC to benefit from HER2-targeted therapy [24,25]. Therefore, ADCs may expand the population that can benefit from HER2-targeted therapy and are expected to be a novel option for patients whose tumors have low HER2 expression.…”

“…In June 2021, Disitamab vedotin was approved in China as a second-line treatment for patients with HER2-overexpressing advanced or metastatic G/GEJ adenocarcinoma. Moreover, a recent preclinical study showed that Disitamab vedotin was more efficacious than trastuzumab in HER2-positive GC patient-derived xenografts (PDX) and demonstrated effectiveness in HER2-negative advanced GC [25].…”