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Abstract
Introduction/Background Endometrial cancer (EC) is the most common gynaecological cancer in developed countries. Women with metastatic/recurrent EC have limited treatment options. Immunotherapy alone or in combination with either levantinib or chemotherapy in metastatic or recurrent settings are promising to improve outcomes in a subset of patients. However, there are unmet clinical needs for those women who are not responding to these therapies. Recently, we discovered the FGFR2c splice isoform is associated with poor prognosis in EC patients. The purpose of the study was to evaluate the efficacy of clinically approved FGFR inhibitors in EC ex-vivo and in vivo models via targeting FGFR2c
Methodology Patient-derived xenografts (PDXs) n=21 and matched organoids n=16 were established, propagated, and characterised histologically (H/E, and IHC) and molecularly (WES and WGS). Drug testing for FGFR inhibitors was performed in organoids and the results were validated using matched PDXs either with FGFR inhibitor or in combination with cisplatin
Results We established 21 EC patient-derived xenografts (PDX) and 16 organoids representing the four molecular subtypes with or without FGFR2c. Treatment of 5 EC organoids with infgratinib/BGJ398 showed significant cell death in 3 models with FGFR2c+ but no response in FGFR2c- models (Figure 1). PDXs with high/moderate FGFR2c expression showed significant tumour growth inhibition following 21-day treatment with FGFR inhibitors (BGJ398 or pemigatinib) and significantly prolonged survival in 4/5 models. Pemigatinib + cisplatin combination therapy (n = 5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. All five models treated with cisplatin alone showed de novo resistance and no survival benefit. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206 + M2 macrophages.
Conclusion These data collectively support the evaluation of FGFR inhibitors in a clinical trial either alone or in recombination with immune therapy and this opens a new opportunity for precision therapy in EC patients.
Disclosures All authors declare no conflict of interest.
