Abstract 4766: Pharmacodynamic and stratification biomarker for the anti-FGFR2 antibody (BAY1179470) and the FGFR2-ADC

Abstract

We are developing a novel fibroblast growth factor receptor 2 (FGFR2) directed antibody (BAY 1179470) as well as an FGFR2-antibody drug conjugate (FGFR2-ADC) for cancer therapy. FGFR2 is expressed in a range of tumor types such as gastric, breast, HNSCC, pancreatic and ovarian cancers. FGFR2 has been described to promote tumor growth and survival and play a role in chemotherapy resistance. In this study, we aim to identify stratification and pharmacodynamic biomarkers for two antibody-based anti-FGFR2 therapies in preclinical models. As potential biomarkers, FGFR2 antigen expression levels were investigated in tumors by FGFR2 immunohistochemistry (IHC), FGFR2 gene amplification by FISH, FGFR2 mRNA by RNAscope, and FGFR2 protein by mass spectrometry. Furthermore, FGFR2 levels in xenograft tumors were compared to those in clinical samples of human tumors. Efficacy of BAY 1179470 in gastric cancer tumor models with high FGFR2 expression levels was generally higher compared to models with low FGFR2 expression. SNU-16 and GC10-0608, which are characterized by high expression levels of FGFR2, had T/C values of 0.13 and 0.55 when treated with 5 mg/kg BAY 1179470. Tumor growth was not inhibited by BAY 1179470 in MKN-45 and T47D, which had no detectable FGFR2 expression. MFM-223 and NCI-H716 with high FGFR2 expression levels did not respond to BAY1179470 suggesting that they were not dependent on FGFR2 signaling. In contrast, all three established tumor models SNU-16, MFM-223, and NCI-H716 were highly responsive to FGFR2-ADC. Analysis and scoring of FGFR2 expression by IHC using human tumor samples (gastric, breast, HNSCC, pancreatic and ovarian cancer, respectively) demonstrated that tumor cell FGFR2 expression varied both within and between tumor types. IHC scoring revealed that 54% of gastric cancers, 73% of triple negative breast cancers, 90% of HNSCC, 43% of pancreatic cancers, and 43% of ovarian cancer investigated were FGFR2 positive. Within the tumor indications investigated patients showed FGFR2 expression of score 0, 1, 2 or 3 respectively.In the SNU-16 gastric cancer xenograft model, total and phospho-FGFR2 were reduced upon treatment with BAY 1179470. Depending on dose, total FGFR2 levels showed the lowest level 1-4 days after treatment and returned to baseline after 21 days. Suppression of the downstream signaling pathway component phospho-RPS6 signaling was also shown. In summary, these results demonstrate that FGFR2-directed therapies are effective in xenograft models with high FGFR2 expression. FGFR2 expression as assessed by IHC and FGFR2 gene amplifications are therefore candidate biomarkers for stratification of the FGFR2-directed studies. The anti-FGFR2 antibody BAY 1179470 is currently in Phase I testing (NCT01881217). Citation Format: Christoph A. Schatz, Charlotte Kopitz, Sabine Wittemer-Rump, Anette Sommer, Lars Lindbom, Motonobu Osada, Hiroshi Yamanouchi, Hung Huynh, Thomas Krahn, Khusru Asadullah. Pharmacodynamic and stratification biomarker for the anti-FGFR2 antibody (BAY1179470) and the FGFR2-ADC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4766. doi:10.1158/1538-7445.AM2014-4766

Fibroblast Growth Factor Receptors (FGFRs): Structures and Small Molecule Inhibitors

“…The dominant strategy to target FGFR ectodomains is using monoclonal antibody/antibody-drug conjugate [93]. Several anti-FGFR monoclonal antibodies have been developed, and some of them are in clinical trials [94,95,96,97,98]. In addition, efforts have been made in the development of small molecule inhibitor targeting FGFR ectodomains.…”

Molecular and clinical significance of fibroblast growth factor 2 (FGF2 /bFGF) in malignancies of solid and hematological cancers for personalized therapies

“…Similarly, BAY 1179470 (developed by Bayer) is a human anti-FGFR2 monoclonal antibody. BAY 1179470 showed antitumor activity in gastric cancer xenograft models with high FGFR2 expression [100]. The anti-FGFR2 antibody BAY 1179470 is currently in Phase I testing in subjects with advanced, refractory solid tumors (Tables 5 and 6)…”

Current biologics for treatment of biliary tract cancers

“…Preclinical and phase I studies have suggested that these compounds have potent and selective anti-tumor activity against FGFRmutated cancers (80)(81)(82)(83). A recently developed monoclonal antibody against FGFR2 (BAY1179470) showed tumor suppressive potential in tumors with high FGFR2 expression (84). Phase I testing of this antibody just recently completed (NCT01881217).…”