Comparison the anti-tumor effect of pyrotinib, afatinb and T-DM1 in lung cancer organoids and PDX models with HER2 mutation.

e24281 Background: Targeted therapy for patients of NSCLC with HER2 mutations is still on unmet need in clinical setting. Pyrotinib, a HER2 and EGFR tyrosine kinase inhibitor, has showed encouraging anti-tumor effect with a ORR of 54.5% (6/11) in our preliminary data of phase 2 trial. This study aimed to investigate the anti-cancer effect and the potential different mechanism of pyrotinib in organoids and PDX models with HER2 mutation, compared with the other anti-HER2 drugs, afatinib and T-DM1. Methods: Organoids and PDX models were established from the therapeutic naïve patient with HER2-mutant lung cancer. Anti-tumor efficacy,and downstream signaling pathways inhibition were analyzed and compared in afatinb, T-DM1 and different dose of pyrotinib groups in both the organoids and PDX models. Results: Patient-derived organoids and xenografts were established from a 42-year-old female with HER2-A775_G776YVMA-inserted advanced lung adenocarcinoma. When the organoids were treated with afatinib and pyrotinib, at 29nM and 180nM respectively(adopted from the plasma concentrations of previous phase 1 clinical trials) , pyrotinib significantly inhibited the cell growth compared with afatinib(p = 0.0038). The in vivo PDX model study showed that pyrotinib(mouse,80mg/kg,adopted from clinical trial recommended dose) showed a significantly superior anti-cancer effect than afatinib of 15 mg/kg (p = 0.0471), T-DM1 of 10 mg/kg (p = 0.0138) and lower dose of pyrotinib 5 mg/kg(p = 0.0001) and 20 mg/kg(p < 0.0001). Pyrotinib(80mg/kg) also showed a robust ability to inhibit pHER2, pERK and pAkt both in the IHC and western blot analysis. Meanwhile, the body weight of PDX model mice receiving afatinib of 15mg/kg showed a significantly decrease compared with pyrotinib of 80mg/kg(p < 0.0001). Conclusions: Pyrotinib, afatinb and T-DM1 all showed the ability to inhibit HER2 in lung cancer models, while pyrotinib showed a significantly better tolerance and anti-cancer effect than afatinib and T-DM1, which might contribute the encouraging results of our previous phase 2 trial.