Reference Detail

Ref Type

Journal Article

PMID

(30807645)

Authors

Grünewald S, Politz O, Bender S, Héroult M, Lustig K, Thuss U, Kneip C, Kopitz C, Zopf D, Collin MP, Boemer U, Ince S, Ellinghaus P, Mumberg D, Hess-Stumpp H, Ziegelbauer K

Title

Rogaratinib: A potent and selective pan-FGFR inhibitor with broad antitumor activity in FGFR-overexpressing preclinical cancer models.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of cancer	145	5	2019 09 01	1346-1357	Int J Cancer

URL

Abstract Text

Aberrant activation in fibroblast growth factor signaling has been implicated in the development of various cancers, including squamous cell lung cancer, squamous cell head and neck carcinoma, colorectal and bladder cancer. Thus, fibroblast growth factor receptors (FGFRs) present promising targets for novel cancer therapeutics. Here, we evaluated the activity of a novel pan-FGFR inhibitor, rogaratinib, in biochemical, cellular and in vivo efficacy studies in a variety of preclinical cancer models. In vitro kinase activity assays demonstrate that rogaratinib potently and selectively inhibits the activity of FGFRs 1, 2, 3 and 4. In line with this, rogaratinib reduced proliferation in FGFR-addicted cancer cell lines of various cancer types including lung, breast, colon and bladder cancer. FGFR and ERK phosphorylation interruption by rogaratinib treatment in several FGFR-amplified cell lines suggests that the anti-proliferative effects are mediated by FGFR/ERK pathway inhibition. Furthermore, rogaratinib exhibited strong in vivo efficacy in several cell line- and patient-derived xenograft models characterized by FGFR overexpression. The observed efficacy of rogaratinib strongly correlated with FGFR mRNA expression levels. These promising results warrant further development of rogaratinib and clinical trials are currently ongoing (ClinicalTrials.gov Identifiers: NCT01976741, NCT03410693, NCT03473756).

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Molecular Profile	Treatment Approach
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Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role
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Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Rogaratinib	Rogaratinib	23	5

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Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Rogaratinib		BAY 1163877\|BAY-1163877\|BAY1163877	FGFR Inhibitor (Pan) 26	Rogaratinib (BAY 1163877) is a small molecule pan-FGFR inhibitor, which reduces downstream signaling, potentially resulting in decreased tumor cell proliferation (PMID: 27429073, PMID: 29451369, PMID: 30807645, PMID: 31405822).

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Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 over exp	lung cancer	predicted - sensitive	Rogaratinib	Preclinical - Pdx	Actionable	In a preclinical study, a lung cancer patient-derived xenograft (PDX) model with FGFR1 overexpression demonstrated decreased tumor volume when treated with Rogaratinib (BAY 1163877) (PMID: 30807645).	30807645
FGFR1 over exp	lung cancer	predicted - sensitive	Docetaxel + Rogaratinib	Preclinical - Pdx	Actionable	In a preclinical study, the combination of Rogaratinib (BAY 1163877) and Taxotere (docetaxel) resulted in improved inhibition of tumor growth and duration of response, leading to three complete responses and seven partial responses compared to Taxotere (docetaxel) alone, resulting in only six partial responses, in lung cancer patient-derived xenograft models with FGFR1 overexpression (n=10) (PMID: 30807645).	30807645
FGFR1 amp FGFR1 over exp	lung cancer	sensitive	Docetaxel + Rogaratinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, treatment with Rogaratinib (BAY 1163877) and Taxotere (docetaxel) resulted in an increased percentage of partial responses from 40% to 70% and one complete response compared to Taxotere (docetaxel) alone in lung cancer cell line xenograft models with FGFR1 amplification and FGFR1 overexpression (PMID: 30807645).	30807645
FGFR1 amp FGFR1 over exp	lung cancer	sensitive	Rogaratinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, treatment with Rogaratinib (BAY 1163877) in a lung cancer cell line xenograft model with FGFR1 amplification and FGFR1 overexpression resulted in inhibition of tumor growth (PMID: 30807645).	30807645
FGFR1 amp FGFR1 over exp	lung cancer	sensitive	Carboplatin + Paclitaxel + Rogaratinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination therapy of Rogaratinib (BAY 1163877), Paraplatin (carboplatin), and Taxol (paclitaxel) resulted in an increased percentage of partial responses, from 30% to 70%, when compared to chemotherapy alone in lung cancer cell line xenograft models with FGFR1 amplification and FGFR1 overexpression (PMID: 30807645).	30807645
FGFR2 amp FGFR2 over exp	colon cancer	sensitive	Rogaratinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, a colon cancer cell line xenograft model with FGFR2 amplification and FGFR2 overexpression demonstrated antitumor efficacy when treated with Rogaratinib (BAY 1163877), with a partial response in one of eight at one dose and five of eight at a different dose (PMID: 30807645).	30807645
FGFR1 over exp	colon cancer	sensitive	Rogaratinib	Preclinical	Actionable	In a preclinical study, syngeneic colon cancer mouse models with FGFR1 over expression demonstrated antitumor activity when treated with Rogaratinib (BAY 1163877), with a partial response observed in 22% (2/9) and stable disease in one (PMID: 30807645).	30807645

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