Reference Detail

Ref Type

Journal Article

PMID

(27543601)

Authors

Sommer A, Kopitz C, Schatz CA, Nising CF, Mahlert C, Lerchen HG, Stelte-Ludwig B, Hammer S, Greven S, Schuhmacher J, Braun M, Zierz R, Wittemer-Rump S, Harrenga A, Dittmer F, Reetz F, Apeler H, Jautelat R, Huynh H, Ziegelbauer K, Kreft B

Title

Preclinical Efficacy of the Auristatin-Based Antibody-Drug Conjugate BAY 1187982 for the Treatment of FGFR2-Positive Solid Tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	76	21	2016 11 01	6331-6339	Cancer Res

URL

Abstract Text

The fibroblast growth factor receptor FGFR2 is overexpressed in a variety of solid tumors, including breast, gastric, and ovarian tumors, where it offers a potential therapeutic target. In this study, we present evidence of the preclinical efficacy of BAY 1187982, a novel antibody-drug conjugate (ADC). It consists of a fully human FGFR2 monoclonal antibody (mAb BAY 1179470), which binds to the FGFR2 isoforms FGFR2-IIIb and FGFR2-IIIc, conjugated through a noncleavable linker to a novel derivative of the microtubule-disrupting cytotoxic drug auristatin (FGFR2-ADC). In FGFR2-expressing cancer cell lines, this FGFR2-ADC exhibited potency in the low nanomolar to subnanomolar range and was more than 100-fold selective against FGFR2-negative cell lines. High expression levels of FGFR2 in cells correlated with efficient internalization, efficacy, and cytotoxic effects in vitro Pharmacokinetic analyses in mice bearing FGFR2-positive NCI-H716 tumors indicated that the toxophore metabolite of FGFR2-ADC was enriched more than 30-fold in tumors compared with healthy tissues. Efficacy studies demonstrated that FGFR2-ADC treatment leads to a significant tumor growth inhibition or tumor regression of cell line-based or patient-derived xenograft models of human gastric or breast cancer. Furthermore, FGFR2 amplification or mRNA overexpression predicted high efficacy in both of these types of in vivo model systems. Taken together, our results strongly support the clinical evaluation of BAY 1187982 in cancer patients and a phase I study (NCT02368951) has been initiated. Cancer Res; 76(21); 6331-9. ©2016 AACR.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Aprutumab ixadotin	Aprutumab ixadotin	6	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Aprutumab ixadotin		BAY1187982\|FGFR2-ADC	FGFR2 Antibody 3	Aprutumab ixadotin (BAY1187982) is a monoclonal FGFR2 antibody in conjugation with a derivative of auristatin, which may target FGFR2-expressing tumor cells for cytotoxicity (PMID: 27543601).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 dec exp	breast cancer	resistant	Aprutumab ixadotin	Preclinical - Cell culture	Actionable	In a preclinical study, Aprutumab ixadotin (BAY1187982) did not inhibit growth of breast cancer cells with very low Fgfr2 expression level in culture (PMID: 27543601).	27543601
FGFR2 positive	Advanced Solid Tumor	sensitive	Aprutumab ixadotin	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, sensitivity to Aprutumab ixadotin (BAY1187982) positively correlated with Fgfr2 expression level in a variety of cancer cell lines in culture, and in cell line or patient-derived xenograft models (PMID: 27543601).	27543601
FGFR2 amp	ovarian cancer	sensitive	Aprutumab ixadotin	Preclinical - Pdx	Actionable	In a preclinical study, Aprutumab ixadotin (BAY1187982) inhibited tumor growth in patient-derived xenograft models of FGFR2 amplified ovarian cancer (PMID: 27543601).	27543601
FGFR2 over exp	colorectal cancer	sensitive	Aprutumab ixadotin	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Aprutumab ixadotin (BAY1187982) inhibited survival of colorectal cancer cells with over expressing Fgfr2 in culture, and suppressed tumor growth in cell line xenograft models (PMID: 27543601).	27543601
FGFR2 positive	stomach cancer	sensitive	Aprutumab ixadotin	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Aprutumab ixadotin (BAY1187982) inhibited survival of gastric cancer cell lines with elevated Fgfr2 expression level in culture, and suppressed tumor growth in cell line or patient-derived xenograft models (PMID: 27543601).	27543601
FGFR2 positive	breast cancer	sensitive	Aprutumab ixadotin	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, Aprutumab ixadotin (BAY1187982) inhibited survival of Fgfr2 positive breast cancer cell lines in culture, and suppressed tumor growth in both cell line and patient-derived xenograft models (PMID: 27543601).	27543601