Randomized phase II study of nintedanib in metastatic castration-resistant prostate cancer postdocetaxel

Droz, Jean‐Pierre; Medioni, J.; Chevreau, Christine; Mont-Serrat, H. de; Merger, Michael; Stopfer, Peter; Kaiser, Rolf; Oudard, Stéphane

doi:10.1097/cad.0000000000000131

Cited by 13 publications

(10 citation statements)

References 46 publications

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“…Moreover, 68.4% of Nintedanib treated patients showed decreased serum levels of prostate specific antigen (PSA) [30]. Recent studies have shown the efficiency of Nintedanib on castration-resistant prostate cancer, the most challenging type of prostate cancer [31, 32]. …”

Section: Discussionmentioning

confidence: 99%

Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP)

et al. 2017

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BackgroundIn recent times, anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation. One such drug is Nintedanib; the present study evaluated the effectiveness of Nintedanib treatment against in vitro proliferation of human prostate cancer (PCa) cell lines, and growth and progression of different grades of PCa lesions in pre-clinical PCa transgenic adenocarcinoma for the mouse prostate (TRAMP) model.MethodsBoth androgen-independent (LNCaP) and androgen-dependent (PC3) PCa cell lines were treated with a range of Nintedanib doses for 72 h, and effect on cell growth and expression of angiogenesis associated VEGF receptors was analyzed. In pre-clinical efficacy evaluation, male TRAMP mice starting at 8 and 12 weeks of age were orally-fed with vehicle control (10% Tween 20) or Nintedanib (10 mg/Kg/day in vehicle control) for 4 weeks, and sacrificed immediately after 4 weeks of drug treatment or sacrificed 6–10 weeks after stopping drug treatments. At the end of treatment schedule, mice were sacrificed and ventral lobe of prostate was excised along with essential metabolic organ liver, and subjected to histopathological and extensive molecular evaluations.ResultsThe total cell number decreased by 56–80% in LNCaP and 45–93% in PC3 cells after 72 h of Nintedanib treatment at 2.5–25 μM concentrations. In pre-clinical TRAMP studies, Nintedanib led to a delay in tumor progression in all treatment groups; the effect was more pronounced when treatment was given at the beginning of the glandular lesion development and continued till study end. A decreased microvessel density and VEGF immunolocalization was observed, besides decreased expression of Androgen Receptor (AR), VEGFR-1 and FGFR-3 in some of the treated groups. No changes were observed in the histological liver analysis.ConclusionsNintedanib treatment was able to significantly decrease the growth of PCa cell lines and also delay growth and progression of PCa lesions to higher grades of malignancy (without inducing any hepatotoxic effects) in TRAMP mice. Furthermore, it was observed that Nintedanib intervention is more effective when administered during the early stages of neoplastic development, although the drug is capable of reducing cell proliferation even after treatment interruption.

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Section: Discussionmentioning

confidence: 99%

Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP)

et al. 2017

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“…Two doses of nintedanib (150 and 250 mg, bid) were evaluated in a randomized Phase II study in metastatic castration-resistant prostate cancer patients after progression with docetaxel. 73 The primary endpoint, prostate-specific antigen (PSA) response rate (≥20% decline in PSA from baseline), was 0% in the nintedanib 150 mg group and 11.1% in the nintedanib 250 mg group ( P =0.12). However, nintedanib at 250 mg showed at least 50% PSA reduction in 5.6% patients and the rate of PSA increase in this group was significantly decelerated on treatment vs before treatment ( P =0.002).…”

Section: Introductionmentioning

confidence: 99%

Profile of nintedanib in the treatment of solid tumors: the evidence to date

Awasthi¹,

Schwarz²

2015

OTT

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Angiogenesis is an essential process for tumor growth and metastasis, and remains a promising therapeutic target process in cancer treatment for several cancer types. Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF), was the first antiangiogenic agent approved for cancer therapy. Novel antiangiogenic agents, such as sunitinib, sorafenib, pazopanib, or vandetanib that target additional proangiogenic signaling pathways beyond VEGF, have also been approved for the treatment of various malignant diseases. While most of these agents are approved in combination with cytotoxic chemotherapy for indications including metastatic colorectal cancer, non-small-cell lung cancer, breast cancer, renal cell carcinoma (RCC), and gastric cancer, some are used as approved monotherapy for advanced RCC, hepatocellular carcinoma and medullary thyroid cancer. Major challenges to the success of antiangiogenic therapy include associated toxicity risks, limitation of efficacy through the possible development of resistance and induction or promotion of metastatic progression. Nintedanib (formally known as BIBF 1120) is a triple angiokinase inhibitor of VEGF, fibroblast growth factor, platelet-derived growth factor signaling with lesser activity against RET, Flt-3, and Src. Through this unique targeting profile nintedanib has demonstrated significant antitumor activity in several tumor types in preclinical studies. Nintedanib has also shown promising clinical efficacy in combination with docetaxel and has been approved for treating patients with locally advanced and metastatic non-small-cell lung cancer in Europe. Nintedanib has also been found to be clinically promising in terms of efficacy and safety in several other solid tumors including ovarian cancer (Phase III), RCC (Phase II), and prostate cancer (Phase II). This review article provides a comprehensive summary of the preclinical and clinical efficacy of nintedanib in the treatment of solid tumors.

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“…Nintedanib (formerly known as BIBF 1120) is also an angiokinase inhibitor that is highly active against VEGFR1–3, FGFR1–3, and PDGFRα/β with IC 50 values of 13–34, 37–108, and 59–65 nmol/L, respectively . This agent has also shown promise in clinical trials for patients with various solid tumors including NSCLC, renal cell cancer, ovarian cancer, and prostate cancer …”

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FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib

Hibi

Kaneda²,

Tanizaki³

et al. 2016

Cancer Science

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Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non‐small cell lung cancer. We have now applied next‐generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG‐positive LSCC cell lines in association with attenuation of the FGFR1–ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.

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Randomized phase II study of nintedanib in metastatic castration-resistant prostate cancer postdocetaxel

Cited by 13 publications

References 46 publications

Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP)

Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP)

Profile of nintedanib in the treatment of solid tumors: the evidence to date

FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib

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