Abstract 558: M6123, a selective FGFR1 antagonist, demonstrates anti-tumor activity as monotherapy and in combination with chemotherapy in mesothelioma models

Abstract

Abstract Malignant pleural mesothelioma is an aggressive, asbestos-related cancer most commonly arising from the mesothelial cells lining the pleural cavity surrounding the lung. Despite the poor prognosis and increasing incidence of this disease, the combination of pemetrexed with cisplatin currently remains the only available treatment option to patients. Molecular characterization of mesothelioma tumors indicates a potential dependency on autocrine FGF-FGFR signaling. Based on this information, the therapeutic activity of M6123, a potent and selective, monovalent antagonist of FGFR1, was investigated in preclinical mesothelioma models in vitro and in vivo. In a panel of mesothelioma cell lines, M6123 mediated cellular growth reduction was clearly correlated with the level of endogenous FGF2 ligand. M6123 monotherapy significantly inhibited FGFR1 signal transduction and tumor growth in a cell line derived mesothelioma model. Furthermore, combination benefit was observed for M6123 with standard of care (SoC) chemotherapy. In a panel of nine mesothelioma patient derived xenograft (PDX) models, 66% (6/9) were sensitive to the combination of M6123 plus pemetrexed/cisplatin compared to 33% (3/9) for chemotherapy alone. The expression of a focused set of FGF-FGFR pathway genes was examined in PDX models to elucidate potential predictive biomarkers of sensitivity to M6123. Sprouty homolog 2 (SPRY2), a negative regulator of FGFR1 signaling, was upregulated in non-sensitive PDX models, whilst positive regulators of FGFR1 signaling including the ligand FGF5, the coreceptor FGFRL1 (FGFR5) and the downstream transcription factor ELK3 were elevated in sensitive models. In summary, M6123 showed favorable anti-tumor activity in preclinical models of mesothelioma, in particular in combination with standard of care chemotherapy. Further preclinical testing is warranted to confirm a predictive biomarker signature for selection of mesothelioma patients that may benefit from addition of M6123. Citation Format: Christina Esdar, Edith Ross, Michael Sanderson, Astrid Zimmermann. M6123, a selective FGFR1 antagonist, demonstrates anti-tumor activity as monotherapy and in combination with chemotherapy in mesothelioma models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 558.