Abstract 137P
Background
The aim of the present study was to explore the mechanism underlying the poor efficacy of pyrotinib, propose and validate a strategy for pyrotinib-combined therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC).
Methods
Human GC cell lines and patient-derived xenograft (PDX) models were used to evaluate the antitumor activity and mechanisms of pyrotinib. One pyrotinib-refractory PDX model was established to explore the potential mechanisms underlying drug resistance, propose an optimal therapeutic strategy, and further validate in a phase I clinical trial (NCT03480256).
Results
Pyrotinib exerted strong antitumor activity in HER2-positive GC cells and PDX models via suppressing the activation of the AKT/S6 signaling pathway. In addition, dysregulation of the cell cycle, represented by aberrant activation of the CCND1-CDK4/6-Rb axis, was found in the pyrotinib-refractory PDX model compared with the parental model. Then, combination therapy of pyrotinib with a CDK4/6 inhibitor (SHR6390) was proposed and its strong tumor growth inhibition was observed in the pyrotinib refractory-PDX model. Three HER2-positive GC patients after multiline therapies were subsequently enrolled in our clinical trial treatment with pyrotinib (400 mg/d for 28 days per cycle) combined with SHR6390 (100 mg/d for 21 days per cycle). After two cycles of therapy, two patients achieved a partial response (PR) and one patient achieved decreased stable disease (SD) with a progression-free survival of 120, 199, and 110 d, respectively. The common adverse events included leucopenia (grade 2 to 3), neutropenia (grade 2 to 4), anemia (grade 1 to 3), and thrombocytopenia (grade 1).
Conclusions
This representative translational study suggests that a combination treatment of pyrotinib with SHR6390 may serve as a promising strategy for patients with HER2-positive GC after systematic treatment failure. The optimal drug doses and tolerability of this combination treatment will be explored in future studies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Zuhua Chen.
Funding
The National Key Research and Development Program of China (No. 2017YFC1308900, 2017YFC0908400).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
314P - An EGF motif of Del1 inhibits efficient angiogenesis and suppresses tumour growth in vivo
Presenter: Hisataka Kitano
Session: Poster display session
Resources:
Abstract
315P - Inhibition of JAK1 sensitizes human head and neck cancer cells to cetuximab
Presenter: James Bonner
Session: Poster display session
Resources:
Abstract
316TiP - Neoadjuvant and adjuvant pembrolizumab (pembro) plus standard of care (SOC) in patients (pts) with resectable locally advanced (LA) head and neck squamous cell carcinoma (HNSCC): The phase III KEYNOTE-689 study
Presenter: Ezra Cohen
Session: Poster display session
Resources:
Abstract
322P - Three-year overall survival update from the PACIFIC trial
Presenter: Yi-Long Wu
Session: Poster display session
Resources:
Abstract
323P - Novel tumour mutation score versus tumour mutation burden in predicting survival after immunotherapy in pan-cancer from MSK-IMPACT cohort
Presenter: Yuan Li
Session: Poster display session
Resources:
Abstract
324P - A novel anti-PD-1 antibody HLX10 study led to the initiation of combination immunotherapy
Presenter: Tsu Yi Chao
Session: Poster display session
Resources:
Abstract
325P - Association between immune-related adverse events and efficacy of immune checkpoint inhibitors in patients with advanced hepatocellular carcinoma
Presenter: Lawrence Wong
Session: Poster display session
Resources:
Abstract
326P - Autologous V gamma 9 V delta 2 T cell therapy to target Epstein Barr Virus (EBV)-related malignancies
Presenter: Esdy Rozali
Session: Poster display session
Resources:
Abstract
327P - Neoantigen profile of hepatocellular carcinoma reveals its correlation with tumour progression and clonal evolution
Presenter: Xiaolong Liu
Session: Poster display session
Resources:
Abstract
328P - A retrospective analysis of patients with non-small cell lung cancer who developed drug-induced lung disorder by immune checkpoint inhibitors
Presenter: Fumiko Hayashi
Session: Poster display session
Resources:
Abstract