Reference Detail

Ref Type

Journal Article

PMID

(26916115)

Authors

Waizenegger IC, Baum A, Steurer S, Stadtmüller H, Bader G, Schaaf O, Garin-Chesa P, Schlattl A, Schweifer N, Haslinger C, Colbatzky F, Mousa S, Kalkuhl A, Kraut N, Adolf GR

Title

A Novel RAF Kinase Inhibitor with DFG-Out-Binding Mode: High Efficacy in BRAF-Mutant Tumor Xenograft Models in the Absence of Normal Tissue Hyperproliferation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	3	2016 Mar	354-65	Mol Cancer Ther

URL

Abstract Text

BI 882370 is a highly potent and selective RAF inhibitor that binds to the DFG-out (inactive) conformation of the BRAF kinase. The compound inhibited proliferation of human BRAF-mutant melanoma cells with 100× higher potency (1-10 nmol/L) than vemurafenib, whereas wild-type cells were not affected at 1,000 nmol/L. BI 882370 administered orally was efficacious in multiple mouse models of BRAF-mutant melanomas and colorectal carcinomas, and at 25 mg/kg twice daily showed superior efficacy compared with vemurafenib, dabrafenib, or trametinib (dosed to provide exposures reached in patients). To model drug resistance, A375 melanoma-bearing mice were initially treated with vemurafenib; all tumors responded with regression, but the majority subsequently resumed growth. Trametinib did not show any efficacy in this progressing population. BI 882370 induced tumor regression; however, resistance developed within 3 weeks. BI 882370 in combination with trametinib resulted in more pronounced regressions, and resistance was not observed during 5 weeks of second-line therapy. Importantly, mice treated with BI 882370 did not show any body weight loss or clinical signs of intolerability, and no pathologic changes were observed in several major organs investigated, including skin. Furthermore, a pilot study in rats (up to 60 mg/kg daily for 2 weeks) indicated lack of toxicity in terms of clinical chemistry, hematology, pathology, and toxicogenomics. Our results indicate the feasibility of developing novel compounds that provide an improved therapeutic window compared with first-generation BRAF inhibitors, resulting in more pronounced and long-lasting pathway suppression and thus improved efficacy.

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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
BI 882370	BI 882370	0	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
BI 882370		XP-102\|BI-882370\|BI882370\|XP 102\|XP102	BRAF Inhibitor 25 RAF Inhibitor (Pan) 28	BI 882370 is a Raf kinase inhibitor with potent activity against the inactive conformation of Braf and may result in tumor regression (PMID: 26916115).

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
BRAF V600E	melanoma	sensitive	BI 882370 + Trametinib	Preclinical	Actionable	In a preclinical study, xenograft models of melanoma harboring BRAF V600E treated with the combination of BI 882370 and Mekinist (trametinib) demonstrated tumor regression with no regrowth during the 5 weeks of treatment (PMID: 26916115).	26916115
BRAF V600E	colorectal cancer	sensitive	BI 882370 + Cetuximab	Preclinical	Actionable	In a preclinical study, colorectal cancer cells harboring BRAF V600E were sensitive to the combination of BI 882370 and Erbitux (cetuximab) in xenograft models, resulting in tumor growth inhibition and partial tumor regression (PMID: 26916115).	26916115
BRAF V600E	colorectal cancer	sensitive	BI 882370 + Trametinib	Preclinical	Actionable	In a preclinical study, colorectal cancer cells harboring BRAF V600E were sensitive to the combination of BI 882370 and Mekinist (trametinib) in xenograft models, resulting in tumor growth inhibition and partial tumor regression (PMID: 26916115).	26916115
BRAF V600E	colorectal cancer	sensitive	Afatinib + BI 882370	Preclinical	Actionable	In a preclinical study, colorectal cancer cells harboring BRAF V600E were sensitive to the combination of BI 882370 and Gilotrif (afatinib) in xenograft models, resulting in tumor growth inhibition and partial tumor regression (PMID: 26916115).	26916115