An experimental drug called nintedanib, a small molecule tyrosine kinase inhibitor (TKI) in development by Boehringer Ingelheim, in combination with standard chemotherapy with paclitaxel, causes a total remission of tumors in 50% of patients suffering from early HER-2- negative breast cancer, the most common type of breast cancer. These are the conclusions of the Phase I Clinical Trial, sponsored by the Spanish National Cancer Research Centre (CNIO). The study was published in British Journal of Cancer.

According to Miguel ?ngel Quintela, head of CNIO ?s Breast Cancer Clinical Research Unit: “The drug combination of paclitaxel and nintedanib has turned out to be a complete success, given that it is proved to be safe and that the pathologic complete response [rate of complete recovery] was 50%, which doubles the response compared to patients treated with standard therapy with paclitaxel.” The trial has also included 10 HER-2-negative breast cancer patients, all of them in early stages of the disease.

Based on these results, the CNIO launched a large-scale Phase II Clinical Trial to validate the results in a large group of patients. These results, including biomarker studies that will facilitate advances in personalized medicine, will be released by early 2015.


…if confirmed, this genetic variant, present in 15% of white people, could be used as a reliable biomarker in personalised treatments to select the best suited candidates to receive this drug…


In addition the team at CNIO completed a second Phase I Clinical Trial with a drug of the same family named dovitinib (developed by Novartis), an orally bioavailable lactate salt of a benzimidazole-quinolinone compound with potential antineoplastic activity.

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The study has been tested in metastatic patients with different primary tumors such as breast, colon and lung cancer. The results, still in a preliminary stage, show that patients with a specific variant in the RET gene, a proto-oncogene or cancer driver gene (variant G2071A), could be more sensitive to this drug. This work has been published by Molecular Oncology.

“If these data are confirmed, this genetic variant, present in 15% of white people, could be used as a reliable biomarker in personalised treatments to select the best suited candidates to receive this drug,” Quintela noted.

Suffocating tumor
Recent theories suggest that a possible solution to cancer might be to ‘suffocate the tumour’ by blocking the formation of new blood vessels that surround it. Nintedanib and dovitinib block the formation of new blood vessels, so-called angiogenesis, which can lead to retardation in tumor growth rates and limit its viability.

“Nintedanib [a drug that there is more experimental data on] is an improved antiangiogenic drug compared to previous angiogenesis inhibitors, given that it prevents angiogenesis in a more efficient way and with lower toxicity than its predecessors”, Quintela explained.

Nintedanib, in addition to blocking vascular endothelial growth factor receptors (VEGFR) and platelet derived growth factor receptors (PDGFR), also acts on fibroblast growth factor receptors (FGFR), which makes it different to classical angiogenesis inhibitors. FGFRs work in an aberrant manner in 10-15% of HER-2 negative breast cancers, which could explain a greater the compound’s greater antitumor activity compared to other compounds.

“The clinical trials we are presenting are the first organised by CNIO,” says Quintela. “This wouldn’t have been possible without the fluid collaboration of hospitals from the Spanish National Health System, and the Spanish Breast Cancer Research Group”.

“To test our hypotheses, this type of study is critical”, noted Manuel Hidalgo, an oncologist at CNIO. These studies show that it is possible to create a network of research centres and hospitals to carry out clinical trials with a strong scientific component”.

For more information:
Quintela-Fandino M, Urruticoechea A, Guerra J, Gil M, Gonzalez-Martin A, Marquez R, Hernandez-Agudo E, et al. Phase I clinical trial of nintedanib plus paclitaxel in early HER-2-negative breast cancer (CNIO-BR-01-2010/GEICAM-2010-10 study). Br J Cancer. 2014 Sep 9;111(6):1060-4. doi: 10.1038/bjc.2014.397. Epub 2014 Jul 24. [Article][PubMed]

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