Dataset Information

Focus on Nintedanib in NSCLC and Other Tumors.

ABSTRACT: Nintedanib is a new triple angiokinase inhibitor that potently blocks the proangiogenic pathways mediated by vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and fibroblast growth factor receptors. Evidence about its efficacy in addition to second-line chemotherapy in non-small cell lung cancer (NSCLC) has been produced by two large randomized phase III clinical trials (LUME-Lung 1 and LUME-Lung 2), conducted in patients with pretreated NSCLC, without major risk factors for bleeding. In the LUME-Lung 1, the addition of nintedanib to docetaxel significantly improved progression-free survival, which was the primary end point of the trial (3.4 vs. 2.7?months, hazard ratio: 0.79; p?=?0.0019). Furthermore, a significant improvement in median overall survival (from 10.3 to 12.6?months) was observed in patients with adenocarcinoma histology, with a greater advantage in patients who progressed within 9?months after start of first-line treatment (from 7.9 to 10.9?months) and in patients who were most refractory to first-line chemotherapy (from 6.3 to 9.8?months). Adverse events were more common in the docetaxel plus nintedanib group, and they included diarrhea and increased liver enzymes, while no statistically significant increase in the incidence of bleeding and hypertension events by the addition of nintedanib was observed. On these bases, the combination of docetaxel and nintedanib can be considered a new option for the second-line treatment for patients with advanced NSCLC with adenocarcinoma histology. Future challenges are the identification of predictive factors to help the decision of using nintedanib in eligible patients.

SUBMITTER: Manzo A

PROVIDER: S-EPMC5165233 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Focus on Nintedanib in NSCLC and Other Tumors.

Manzo Anna A Carillio Guido G Montanino Agnese A Costanzo Raffaele R Sandomenico Claudia C Rocco Gaetano G Morabito Alessandro A

Frontiers in medicine 20161219

Nintedanib is a new triple angiokinase inhibitor that potently blocks the proangiogenic pathways mediated by vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and fibroblast growth factor receptors. Evidence about its efficacy in addition to second-line chemotherapy in non-small cell lung cancer (NSCLC) has been produced by two large randomized phase III clinical trials (LUME-Lung 1 and LUME-Lung 2), conducted in patients with pretreated NSCLC, without major ...[more]

PMID: 28066768

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Project description: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.

Project description:First-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, represented an important addition to the treatment armamentarium for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, all patients inevitably develop acquired resistance to these agents, primarily due to secondary EGFR mutations, molecular aberrations affecting other signaling pathways, or transformation to small-cell histology. It was hypothesized that development of second-generation TKIs with broader inhibitory profiles could confer longer-lasting clinical activity and overcome acquired resistance to first-generation inhibitors. Here, we review the development of afatinib, an irreversible ErbB family blocker that potently inhibits signaling of all homodimers and heterodimers formed by the EGFR, human epidermal growth factor receptor (HER)-2, HER3, and HER4 receptors. In two phase III trials in patients with EGFR mutation-positive NSCLC, first-line afatinib significantly improved progression-free survival (PFS) and health-related quality of life versus standard-of-care chemotherapy. Moreover, in preplanned sub-analyses, afatinib significantly improved overall survival in patients harboring EGFR Del19 mutations. Afatinib has also demonstrated clinical activity in NSCLC patients who had progressed on erlotinib/gefitinib, particularly when combined with cetuximab, and offers 'treatment beyond progression' benefit when combined with paclitaxel versus chemotherapy alone. Furthermore, a recent phase III study demonstrated that PFS was significantly improved with afatinib versus erlotinib for the second-line treatment of patients with squamous cell carcinoma of the lung. The activity of afatinib in both first-line and relapsed/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members. Afatinib has a well-defined safety profile with characteristic gastrointestinal (diarrhea, stomatitis) and cutaneous (rash/acne) adverse events.

Dataset Information

Focus on Nintedanib in NSCLC and Other Tumors.

Publications

Focus on Nintedanib in NSCLC and Other Tumors.

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