Abstract A033: Evaluation of FGFR2b in context of relevant biomarkers supports potential combination of anti-FGFR2b with anti-PD-(L)1 therapy in gastric cancer
Authors: Sharma Khushboo , Schmidt Maike , Hestir Kevin , Mendoza Nerissa , Powers Janine , Hnatyszyn James 
Published: March 2020

Background: Gastric cancer is the third leading cause of global cancer-related death, with 782,685 deaths in 2018 (Jemal, A. et al. 2018). Currently available treatments have limited benefits. Hence there’s a pressing need for more effective treatment strategies. FGFR2 gene amplification or protein overexpression in gastric cancer tumors is associated with poor prognosis (Su et al., 2014, Ahn et al., 2016). Five Prime has developed an FGFR2b-specific first-in-class humanized monoclonal IgG1 antibody, bemarituzumab (FPA144, or bema), that selectively blocks FGFR2b and triggers antibody-dependent cell-mediated cytotoxicity that showed monotherapy efficacy in a phase 1 trial (Lee et al. ASCO 2016, Catenacci et al. ASCO 2017). In this study, we evaluated the expression of FGFR2b in the context of relevant biomarkers for other approved and potential drug combinations. Methods: RNA and IHC analysis were performed using public datasets and procured tumor samples, respectively. 97 tissue samples from gastric cancer patients were assessed for expression of FGFR2b, PD-(L)1, and CD8 by IHC. In addition, TCGA-STAD database was evaluated for the status of FGFR2 overexpression and the expression of relevant targeted combination drug partners, e.g., ERBB2, PD-(L)1 and cytolytic score. For PD-(L)1 and CD8 staining, SP263 and SP57 antibodies were used, and results were reported as percent positive cells. For FGFR2b staining, the FPR2-D antibody was used (Kim, KM. et al. 2016). Staining with intensity greater than 2+ was considered FGFR2b-positive and anything less than or equal to 2 was considered negative for FGFR2b overexpression. We also investigated the literature and past and ongoing clinical trials to assess PD-(L)1 prevalence in gastric cancer and its correlation to efficacy. Results: Based on RNA expression and copy number data from samples in the TCGA-STAD dataset, combination of bemarituzumab and HER2 targeting agents would not be expected to have synergistic activity, as both populations appear mutually exclusive. In contrast, FGFR2 positive/overexpressing tumors showed good representation of high RNA expression levels of PD-(L)1, PD-1 and cytolytic score. Clinical studies using anti-PD-(L)1 therapies such as pembrolizumab indicate that most benefit (higher ORR) was observed in patients that express PD-(L)1 above a predefined threshold, measured either as a combined positive score of immune and tumor cell staining, or tumor cell staining alone (&gt;1 as cutoff). In our dataset, we calculated % positive PD-(L)1 for both tumor cells and immune cells. Both FGFR2b+ and FGFR2b- tumors showed similar distribution of CD8 and PD-(L)1 positive cells. 60% of FGFR2b+ tumors were PD-(L)1 positive using a greater than 1% PD-(L)1 (immune cell + tumor cell) cut off. Conclusion: In our dataset, 60% of FGR2b+ population is also PD-(L)1 positive (&gt;1%) suggesting that a combination of bemarituzumab with checkpoint inhibitors such as anti-PD-(L)1 could potentially benefit patients with FGFR2b+ tumors. Further mechanistic insight and support comes from preclinical studies (Pierce et al. AACR 2016), which showed an increase in efficacy with the combination treatment of bemarituzumab and anti-PD1 in an orthotopic mouse model. Future studies will be performed to evaluate and get a better understanding of the underlying mechanism of action of combination activity, and confirm co-expression in a larger, confirmatory dataset.

Citation Format: Khushboo Sharma, Maike Schmidt, Kevin Hestir, Nerissa Mendoza, Janine Powers, James Hnatyszyn. Evaluation of FGFR2b in context of relevant biomarkers supports potential combination of anti-FGFR2b with anti-PD-(L)1 therapy in gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A033. doi:10.1158/1535-7163.TARG-19-A033