O164: Assessment of standard FLOT chemotherapy drugs and pan-HER family TKIs in models of HER2-low gastric and oesophageal cancer

Abstract

Abstract Background Upper GI cancers have a significant rate of mortality despite advances in treatment. HER2 overexpression is found in 22.3% of gastric and 21% in oesophageal adenocarcinomas (14-32%) with 30% of UGI cancers classed as HER2-low. To examine the potential of pan-HER family inhibition in HER2-low cancers, the effects of pan-HER TKIs neratinib (N) and poziotinib (P) and FLOT chemotherapy ((docetaxel (D), oxaliplatin (O) and 5-Flurouracil (5FU)) were investigated in HER2-low cancer cell lines. Methods HER2-low AGS (gastric) and FLO-1 (oesophageal) cancer cell lines were utilised and acid phosphatase-based proliferation assays were used to examine the effect of both single agents and combinations. Assays were carried out in biological triplicate. IC50 and Combination Index (CI) values were calculated using Calcusyn software. Results Both AGS and FLO-1 cells displayed high sensitivity to neratinib and poziotinib. FLO-1 cells were significantly more sensitive to docetaxel than AGS cells (p = 0.0461), while AGS cells were significantly more sensitive to oxaliplatin (p = 0.0166). PD, NOX, POX and P5FU combinations were synergistic in AGS cells (CI values between 0.24 and 0.64), while ND and N5FU were antagonistic (CI values ≥ 1.47). In FLO-1 cells, POX was synergistic (CI = 0.59), ND and N5FU were additive (CI = 1.07 and 1.09 respectively) and PD, NOX and P5FU were antagonistic (CI values ≥ 1.67). Conclusion Despite the low HER2 expression in AGS and FLO-1, neratinib and poziotinib still show anti-tumour activity. Several combinations of chemotherapy, especially oxaliplatin, with the pan-HER TKIs demonstrated synergy in AGS and FLO-1 cells.