Value through Innovation17 April 2014

Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

88 publications regarding Oncology
  • Author:
    Patwardhan P P; Ivy K S; Giovino N; Schwartz G K
    Title:
    BlBF1120, an investigational triple angiokinase inhibitor, in combination with inhibitors of mTOR signaling shows potent antitumor activity in preclinical models of sarcoma
    Source:
    AACR Annual Meeting 1014, San Diego, CA, USA, Apr 5-9, 2014
  • Author:
    Schumacher D; Boehnke K; Lange M; Welte Y; Davies C; Rivera M; Keil M; Keilholz U; Haybaeck J; Velasco JA; Yaspo ML; Lehrach H; Henderson D; Reinhard C; Hoffmann J; Schaefer R; Regenbrecht CRA
    Title:
    A pipline within the Onco Track project for generating Patient-tumor-derived 3D cell cultures (PT3DCs) and their application for individualized, targeted drug sensitivity assays
    Source:
    AACR, 2014
  • Author:
    Chen L-Z; Rose P; Mao Y; Yong C-L; St George R; Huang F; Latli B; Mandarino D; Li Y
    Title:
    Mass balance and metabolite profiling of steady-state faldaprevir, a hepatitis C virus NS3/4 protease inhibitor, in healthy male subjects
    Source:
    Antimicrob Agents Chemother 58 (4), 2369-2376 (2014)
    Abstract:
    The pharmacokinetics, mass balance, and metabolite profiles of faldaprevir, a selective peptide-mimetic hepatitis C virus NS3/NS4 protease inhibitor, were assessed at steady state in 7 healthy male subjects. Subjects received oral doses of 480 mg faldaprevir on day 1, followed by 240 mg faldaprevir on days 2 to 8 and 10 to 15. [14C]faldaprevir (240 mg containing 100 .Ci) was administered on day 9. Blood, urine, feces, and saliva samples were collected at intervals throughout the study. Metabolite profiling was performed using radiochromatography, and metabolite identification was conducted using liquid chromatography-tandem mass spectrometry. The overall recovery of radioactivity was high (98.8%), with the majority recovered from feces (98.7%). There was minimal radioactivity in urine (0.113%) and saliva. Circulating radioactivity was predominantly confined to plasma with minimal partitioning into red blood cells. The terminal half-life of radioactivity in plasma was approximately 23 h with no evidence of any long-lasting metabolites. Faldaprevir was the predominant circulating form, accounting for 98 to 100% of plasma radioactivity from each subject. Faldaprevir was the only drug-related component detected in urine. Faldaprevir was also the major drug-related component in feces, representing 49.8% of the radioactive dose. The majority of the remainder of radioactivity in feces (41% of the dose) was accounted for in almost equal quantities by 2 hydroxylated metabolites. The most common adverse events were nausea, diarrhea, and constipation, all of which were related to study drug. In conclusion, faldaprevir is predominantly excreted in feces with negligible urinary excretion. Copyright © 2014, American Society for Microbiology. All Rights Reserved.
  • Author:
    Senderowicz AM; Pfaff O
    Title:
    Similarities and differences in the oncology drug approval process between FDA and european union with emphasis on in vitro companion diagnostics
    Source:
    Clin Cancer Res 20 (6), 1445-1452 (2014)
    Abstract:
    Drug approval [U.S. Food and Drug Administration (FDA),or market authorization for the European Union's EuropeanMedicines Agency (EMA)] is the most significant regulatory milestone for any drug, as drugs can only be marketed after marketing approval by a health authority. This article focuses on the main regulatory aspects of the drug approval process in the European Union (EU) and the United States. Although the procedures, requirements, and timelines for drug approvals are different between the EU and the United States, several global harmonization efforts have been developed during the past few years to have more consistent regulatory procedures/outcomes in different parts of the world. One of the most different procedures/requirements among these regions is co-development, also known as in vitro companion diagnostic. In the United States, it is expected that for a drug that requires an in vitro diagnostic test to select the population to be treated, the companion diagnostic should be already/ concomitantly approved by the FDA. In the EU, these requirements are not as stringent as in the United States. However, it is anticipated that in the very near future, legislation changes in the EU will lead to similar requirements for the companion diagnostics for EMA. In summary, although the principles, procedures, and requirements for drug approvals may differ between the United States and EMA, novel efforts to harmonize them are being considered and implemented, thereby leading to simpler global drug development. It is of outmost importance that drug developers understand and appreciate differences in regional regulations. Otherwise, lack of understanding may lead to rejection or delays in drug approvals for useful anticancer agents.© 2014 American Association for Cancer Research.
  • Author:
    Hilberg F
    Title:
    Nintedanib: preclinical and clinical efficacy of a novel triple angiokinase inhibitor
    Source:
    10th International Symposium of Translational Oncology, Barcelona, Spain, Mar 27, 2014
  • Author:
    Modjtahedi H; Cho BC; Michel MC; Solca F
    Title:
    A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer
    Source:
    Naunyn Schmiedebergs Arch Pharmacol Article in Press (2014)
    Abstract:
    Afatinib (also known as BIBW 2992) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. This manuscript comprehensively reviews the preclinical data on afatinib, an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family (ErbB) including EGFR, HER2 and ErbB4. Afatinib covalently binds to cysteine 797 of the EGFR and the corresponding cysteines 805 and 803 in HER2 and ErbB4, respectively. Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors, resulting in reduced auto- and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members. Afatinib inhibits cellular growth and induces apoptosis in a wide range of cells representative for non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network. This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers. Afatinib retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible EGFR inhibitors, such as those exhibiting the T790M mutations. Several combination treatments have been explored to prevent and/or overcome development of resistance to afatinib, the most promising being those with EGFR- or HER2-targeted antibodies, other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules. © 2014 The Author(s).
  • Author:
    Rupp C; Scherzer M; Rudisch A; Unger C; Haslinger C; Schweifer N; Artaker M; Nivarthi H; Moriggl R; Hengstschläger M; Kerjaschki D; Sommergruber W; Dolznig H; Garin-Chesa P
    Title:
    IGFBP7, a novel tumor stroma marker, with growth-promoting effects in colon cancer through a paracrine tumor-stroma interaction
    Source:
    Oncogene Article in Press (2014)
    Abstract:
    The activated tumor stroma participates in many processes that control tumorigenesis, including tumor cell growth, invasion and metastasis. Cancer-associated fibroblasts (CAFs) represent the major cellular component of the stroma and are the main source for connective tissue components of the extracellular matrix and various classes of proteolytic enzymes. The signaling pathways involved in the interactions between tumor and stromal cells and the molecular characteristics that distinguish normal 'resting' fibroblasts from cancer-associated or '-activated' fibroblasts remain poorly defined. Recent studies emphasized the prognostic and therapeutic significance of CAF-related molecular signatures and a number of those genes have been shown to serve as putative therapeutic targets. We have used immuno-laser capture microdissection and whole-genome Affymetrix GeneChip analysis to obtain transcriptional signatures from the activated tumor stroma of colon carcinomas that were compared with normal resting colonic fibroblasts. Several members of the Wnt-signaling pathway and gene sets related to hypoxia, epithelial-to-mesenchymal transition (EMT) and transforming growth factor-. (TGF.) pathway activation were induced in CAFs. The putative TGF.-target IGFBP7 was identified as a tumor stroma marker of epithelial cancers and as a tumor antigen in mesenchyme-derived sarcomas. We show here that in contrast to its tumor-suppressor function in epithelial cells, IGFPB7 can promote anchorage-independent growth in malignant mesenchymal cells and in epithelial cells with an EMT phenotype when IGFBP7 is expressed by the tumor cells themselves and can induce colony formation in colon cancer cells co-cultured with IGFBP7-expressing CAFs by a paracrine tumor-stroma interaction.Oncogene advance online publication, 17 March 2014; doi:10.1038/onc.2014.18.
  • Author:
    Friedbichler K; Hofmann MH; Kroez M; Ostermann E; Lamche HR; Koessl C; Borges E; Pollak MN; Adolf G; Adam P
    Title:
    Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin
    Source:
    Mol Cancer Ther 13 (2), 399-409 (2014)
    Abstract:
    Insulin-like growth factor (IGF) signaling is thought to play a role in the development and progression of multiple cancer types. To date, therapeutic strategies aimed at disrupting IGF signaling have largely focused on antibodies that target the IGF-I receptor (IGF-IR). Here, we describe the pharmacologic profile of BI 836845, a fully human monoclonal antibody that utilizes an alternative approach to IGF signaling inhibition by selectively neutralizing the bioactivity of IGF ligands. Biochemical analyses of BI 836845 demonstrated high affinity tohuman IGF-I and IGF-II, resulting in effective inhibition of IGF-induced activation of both IGF-IR and IR-A in vitro. Cross-reactivity to rodent IGFs has enabled rigorous assessment of the pharmacologic activity of BI 836845 in preclinical models. Pharmacodynamic studies in rats showed potent reduction of serum IGF bioactivity in the absence of metabolic adverse effects, leading to growth inhibition as evidenced by reduced body weight gain and tail length. Moreover, BI 836845 reduced the proliferation of human cell lines derived from different cancer types and enhanced the antitumor efficacy of rapamycin by blocking a rapamycininduced increase in upstream signaling in vitro as well as in human tumor xenograft models in nude mice. Our data suggest that BI 836845 represents a potentially more effective and tolerable approach to the inhibition of IGF signaling compared with agents that target the IGF-I receptor directly, with potential for rational combinations with other targeted agents in clinical studies. Mol Cancer Ther; 13(2); 399-409. © 2014 American Association for Cancer Research.
  • Author:
    Molife LR; Omlin A; Jones RJ; Karavasilis V; Bloomfield D; Lumsden G; Fong PC; Olmos D; O'Sullivan JM; Pedley I; Hickish T; Jenkins P; Thompson E; Oommen N; Wheatley D; Heath C; Temple G; Pelling K; De Bono JS
    Title:
    Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-resistant prostate cancer
    Source:
    Future Oncol 10 (2), 219-231 (2014)
    Abstract:
    Aims: The aim of this article was to evaluate afatinib (BIBW 2992), an ErbB family blocker, and nintedanib (BIBF 1120), a triple angiokinase inhibitor, in castration-resistant prostate cancer patients. Patients & methods: Patients were randomized to receive nintedanib (250 mg twice daily), afatinib (40 mg once daily [q.d.]), or alternating sequential 7-day nintedanib (250 mg twice daily) and afatinib (70 mg q.d. [Combi70]), which was reduced to 40 mg q.d. (Combi40) due to adverse events. The primary end point was progression-free rate at 12 weeks. Results: Of the 85 patients treated 46, 20, 16 and three received nintedanib, afatinib, Combi40 and Combi70, respectively. At 12 weeks, the progression-free rate was 26% (seven out of 27 patients) for nintedanib, and 0% for afatinib and Combi40 groups. Two patients had a .50% decline in PSA (nintedanib and the Combi40 groups). The most common drug-related adverse events were diarrhea, nausea, vomiting and lethargy. Conclusion: Nintedanib and/or afatinib demonstrated limited anti-tumor activity in unselected advanced castration-resistant prostate cancer patients. © 2014 Future Medicine Ltd.
  • Author:
    Reck M; Kaiser R; Mellemgaard A; Douillard J-Y; Orlov S; Krzakowski M; von Pawel J; Gottfried M; Bondarenko I; Liao M; Gann C-N; Barrueco J; Gaschler-Markefski B; Novello S
    Title:
    Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): A phase 3, double-blind, randomised controlled trial
    Source:
    Lancet Oncol 15 (2), 143-145 (2014)
    Abstract:
    Background: The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). Methods: Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m2 by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. Findings: Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7.1 months (IQR 3.8-11.0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3.4 months [95% CI 2.9-3.9] vs 2.7 months [2.6-2.8]; hazard ratio [HR] 0.79 [95% CI 0.68-0.92], p=0.0019). After a median follow-up of 31.7 months (IQR 27.8-36.1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10.9 months [95% CI 8.5-12.6] vs 7.9 months [6.7-9.1]; HR 0.75 [95% CI 0.60-0.92], p=0.0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12.6 months [95% CI 10.6-15.1] vs 10.3 months [95% CI 8.6-12.2]; HR 0.83 [95% CI 0.70-0.99], p=0.0359), but not in the total study population (median 10.1 months [95% CI 8.8-11.2] vs 9.1 months [8.4-10.4]; HR 0.94, 95% CI 0.83-1.05, p=0.2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6.6%] of 652 vs 17 [2.6%] of 655), reversible increases in alanine aminotransferase (51 [7.8%] vs six [0.9%]), and reversible increases in aspartate aminotransferase (22 [3.4%] vs three [0.5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). Interpretation: Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. Funding: Boehringer Ingelheim. © 2014 Elsevier Ltd.
  • Author:
    Wu Y-L; Zhou C; Hu C-P; Feng J; Lu S; Huang Y; Li W; Hou M; Shi JH; Lee KY; Xu C-R; Massey D; Kim M; Shi Y; Geater SL
    Title:
    Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial
    Source:
    Lancet Oncol 15 (2), 213-222 (2014)
    Abstract:
    Background: Afatinib-an oral irreversible ErbB family blocker-improves progression-free survival compared with pemetrexed and cisplatin for first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). We compared afatinib with gemcitabine and cisplatin-a chemotherapy regimen widely used in Asia-for first-line treatment of Asian patients with EGFR mutation-positive advanced NSCLC. Methods: This open-label, randomised phase 3 trial was done at 36 centres in China, Thailand, and South Korea. After central testing for EGFR mutations, treatment-naive patients (stage IIIB or IV cancer [American Joint Committee on Cancer version 6], performance status 0-1) were randomly assigned (2:1) to receive either oral afatinib (40 mg per day) or intravenous gemcitabine 1000 mg/m2 on day 1 and day 8 plus cisplatin 75 mg/m2 on day 1 of a 3-week schedule for up to six cycles. Randomisation was done centrally with a random number-generating system and an interactive internet and voice-response system. Randomisation was stratified by EGFR mutation (Leu858Arg, exon 19 deletions, or other; block size three). Clinicians and patients were not masked to treatment assignment, but the independent central imaging review group were. Treatment continued until disease progression, intolerable toxic effects, or withdrawal of consent. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). This study is registered with ClinicalTrials.gov, NCT01121393. Findings: 910 patients were screened and 364 were randomly assigned (242 to afatinib, 122 to gemcitabine and cisplatin). Median progression-free survival was significantly longer in the afatinib group (11.0 months, 95% CI 9.7-13.7) than in the gemcitabine and cisplatin group (5.6 months, 5.1-6.7; hazard ratio 0.28, 95% CI 0.20-0.39; p<0.0001). The most common treatment-related grade 3 or 4 adverse events in the afatinib group were rash or acne (35 [14.6%] of 239 patients), diarrhoea (13 [5.4%]), and stomatitis or mucositis (13 [5.4%]), compared with neutropenia (30 [26.5%] of 113 patients), vomiting (22 [19.5%]), and leucopenia (17 [15.0%]) in the gemcitabine and cisplatin group. Treatment-related serious adverse events occurred in 15 (6.3%) patients in the afatinib group and nine (8.0%) patients in the gemcitabine and cisplatin group. Interpretation: First-line afatinib significantly improves progression-free survival with a tolerable and manageable safety profile in Asian patients with EGFR mutation-positive advanced lung NSCLC. Afatinib should be considered as a first-line treatment option for this patient population. Funding: Boehringer Ingelheim. © 2014 Elsevier Ltd.
  • Author:
    Wu Y-L; Zhou C; Hu C-P; Feng J; Lu S; Huang Y; Li W; Hou M; Shi JH; Lee KY; Xu C-R; Massey D; Kim M; Shi Y; Geater SL
    Title:
    Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial
    Source:
    Lancet Oncol Article in press (2014)
    Abstract:
    Background: Afatinib-an oral irreversible ErbB family blocker-improves progression-free survival compared with pemetrexed and cisplatin for first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). We compared afatinib with gemcitabine and cisplatin-a chemotherapy regimen widely used in Asia-for first-line treatment of Asian patients with EGFR mutation-positive advanced NSCLC. Methods: This open-label, randomised phase 3 trial was done at 36 centres in China, Thailand, and South Korea. After central testing for EGFR mutations, treatment-naive patients (stage IIIB or IV cancer [American Joint Committee on Cancer version 6], performance status 0-1) were randomly assigned (2:1) to receive either oral afatinib (40 mg per day) or intravenous gemcitabine 1000 mg/m2 on day 1 and day 8 plus cisplatin 75 mg/m2 on day 1 of a 3-week schedule for up to six cycles. Randomisation was done centrally with a random number-generating system and an interactive internet and voice-response system. Randomisation was stratified by EGFR mutation (Leu858Arg, exon 19 deletions, or other; block size three). Clinicians and patients were not masked to treatment assignment, but the independent central imaging review group were. Treatment continued until disease progression, intolerable toxic effects, or withdrawal of consent. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). This study is registered with ClinicalTrials.gov, NCT01121393. Findings: 910 patients were screened and 364 were randomly assigned (242 to afatinib, 122 to gemcitabine and cisplatin). Median progression-free survival was significantly longer in the afatinib group (11.0 months, 95% CI 9.7-13.7) than in the gemcitabine and cisplatin group (5.6 months, 5.1-6.7; hazard ratio 0.28, 95% CI 0.20-0.39; p<0.0001). The most common treatment-related grade 3 or 4 adverse events in the afatinib group were rash or acne (35 [14.6%] of 239 patients), diarrhoea (13 [5.4%]), and stomatitis or mucositis (13 [5.4%]), compared with neutropenia (30 [26.5%] of 113 patients), vomiting (22 [19.5%]), and leucopenia (17 [15.0%]) in the gemcitabine and cisplatin group. Treatment-related serious adverse events occurred in 15 (6.3%) patients in the afatinib group and nine (8.0%) patients in the gemcitabine and cisplatin group. Interpretation: First-line afatinib significantly improves progression-free survival with a tolerable and manageable safety profile in Asian patients with EGFR mutation-positive advanced lung NSCLC. Afatinib should be considered as a first-line treatment option for this patient population. Funding: Boehringer Ingelheim. © 2014 Elsevier Ltd. All rights reserved.
  • Author:
    Reck M; Kaiser R; Mellemgaard A; Douillard J-Y; Orlov S; Krzakowski M; von Pawel J; Gottfried M; Bondarenko I; Liao M; Gann C-N; Barrueco J; Gaschler-Markefski B; Novello S
    Title:
    Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial
    Source:
    Lancet Oncol Article in press (2014)
    Abstract:
    Background: The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). Methods: Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m2 by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194. Findings: Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7.1 months (IQR 3.8-11.0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3.4 months [95% CI 2.9-3.9] vs 2.7 months [2.6-2.8]; hazard ratio [HR] 0.79 [95% CI 0.68-0.92], p=0.0019). After a median follow-up of 31.7 months (IQR 27.8-36.1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10.9 months [95% CI 8.5-12.6] vs 7.9 months [6.7-9.1]; HR 0.75 [95% CI 0.60-0.92], p=0.0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12.6 months [95% CI 10.6-15.1] vs 10.3 months [95% CI 8.6-12.2]; HR 0.83 [95% CI 0.70-0.99], p=0.0359), but not in the total study population (median 10.1 months [95% CI 8.8-11.2] vs 9.1 months [8.4-10.4]; HR 0.94, 95% CI 0.83-1.05, p=0.2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6.6%] of 652 vs 17 [2.6%] of 655), reversible increases in alanine aminotransferase (51 [7.8%] vs six [0.9%]), and reversible increases in aspartate aminotransferase (22 [3.4%] vs three [0.5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). Interpretation: Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. Funding: Boehringer Ingelheim. © 2014 Elsevier Ltd. All rights reserved.
  • Author:
    Lötsch D; Steiner E; Holzmann K; Spiegl-Kreinecker S; Pirker C; Hlavaty J; Petznek H; Hegedus B; Garay T; Mohr T; Sommergruber W; Grusch M; Berger W
    Title:
    Major vault protein supports glioblastoma survival and migration by upregulating the EGFR/PI3K signalling axis
    Source:
    Oncotarget 4 (11), 1904-1918 (2013)
    Abstract:
    Despite their ubiquitous expression and high conservation during evolution, precise cellular functions of vault ribonucleoparticles, mainly built of multiple major vault protein (MVP) copies, are still enigmatic. With regard to cancer, vaults were shown to be upregulated during drug resistance development as well as malignant transformation and progression. Such in a previous study we demonstrated that human astrocytic brain tumours including glioblastoma are generally high in vault levels while MVP expression in normal brain is comparably low. However a direct contribution to the malignant phenotype in general and that of glioblastoma in particular has not been established so far. Thus we address the questions whether MVP itself has a pro-tumorigenic function in glioblastoma. Based on a large tissue collection, we re-confirm strong MVP expression in gliomas as compared to healthy brain. Further, the impact of MVP on human glioblastoma aggressiveness was analysed by using gene transfection, siRNA knock-down and dominant-negative genetic approaches. Our results demonstrate that MVP/vaults significantly support migratory and invasive competence as well as starvation resistance of glioma cells in vitro and in vivo. The enhanced aggressiveness was based on MVP-mediated stabilization of the epidermal growth factor receptor (EGFR)/phosphatidyl-inositol-3-kinase (PI3K) signalling axis. Consequently, MVP overexpression resulted in enhanced growth and brain invasion in human glioblastoma xenograft models. Our study demonstrates, for the first time, that vaults have a tumour-promoting potential by stabilizing EGFR/PI3K-mediated migration and survival pathways in human glioblastoma.
  • Author:
    Stadler WM; Vaughn DJ; Sonpavde G; Vogelzang NJ; Tagawa ST; Petrylak DP; Rosen P; Lin C-C; Mahoney J; Modi S; Lee P; Ernstoff MS; Su W-C; Spira A; Pilz K; Vinisko R; Schloss C; Fritsch H; Zhao C; Carducci MA
    Title:
    An open-label, single-arm, phase 2 trial of the polo-like kinase inhibitor volasertib (BI 6727) in patients with locally advanced or metastatic urothelial cancer
    Source:
    Cancer Article in press (2013)
    Abstract:
    BACKGROUND: Polo-like kinases (Plks) control multiple steps during the cell cycle, and Plk1 is overexpressed in urothelial cancer (UC). Volasertib (BI 6727), a Plk inhibitor, has demonstrated antitumor activity in several malignancies, including UC. In this phase 2 trial, the authors investigated volasertib as a second-line treatment in advanced/metastatic UC. METHODS: Patients who progressed within 2 years of 1 prior chemotherapy regimen received 300 mg volasertib on day 1 every 3 weeks. The dose was escalated to 350 mg in cycle 2 if volasertib was tolerated in cycle 1. The primary endpoint was tumor response, which was assessed every 6 weeks; secondary endpoints were progression-free survival, overall survival, duration of response, safety, and pharmacokinetics. RESULTS: Fifty patients were enrolled, and the median patient age was 68.5 years (range, 52-83 years). All patients had received prior platinum, 94% of patients had relapsed .2 years after prior therapy, 36% had liver metastases, and 54% had lung metastases. The median number of treatment cycles was 2 (range, 1-27 treatment cycles), and 23 patients were dose escalated at cycle 2. Seven patients (14%) had a partial response, 13 (26%) had stable disease, and 30 (60%) progressed within 6 weeks. The median response duration was 41 weeks (range, 29.1-77.3 weeks). The median progression-free survival was 1.4 months, and the median overall survival was 8.5 months. The most frequent grade 3 and 4 adverse events were neutropenia (28%), thrombocytopenia (20%), and anemia (16%). No cumulative toxicity was observed. CONCLUSIONS: Volasertib as second-line treatment for advanced/metastatic UC had an acceptable safety profile but demonstrated insufficient antitumor activity for further evaluation as a monotherapy. © 2013 American Cancer Society.
  • Author:
    Demajo S; Uribesalgo I; Gutiérrez A; Ballaré C; Capdevila S; Roth M; Zuber J; Martín-Caballero J; Di Croce L
    Title:
    ZRF1 controls the retinoic acid pathway and regulates leukemogenic potential in acute myeloid leukemia
    Source:
    Oncogene Article in press (2013)
    Abstract:
    Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in transcriptional regulation, is highly overexpressed in human AML, but it is not known whether it plays a role in leukemia progression. Here, we demonstrate that ZRF1 depletion decreases cell proliferation, induces apoptosis and enhances cell differentiation in human AML cells. Treatment with retinoic acid (RA), a differentiating agent currently used to treat certain AMLs, leads to a functional switch of ZRF1 from a negative regulator to an activator of differentiation. At the molecular level, ZRF1 controls the RA-regulated gene network through its interaction with the RA receptor . (RAR.) and its binding to RA target genes. Our genome-wide expression study reveals that ZRF1 regulates the transcription of nearly half of RA target genes. Consistent with our in vitro observations that ZRF1 regulates proliferation, apoptosis, and differentiation, ZRF1 depletion strongly inhibits leukemia progression in a xenograft mouse model. Finally, ZRF1 knockdown cooperates with RA treatment in leukemia suppression in vivo. Taken together, our data reveal that ZRF1 is a key transcriptional regulator in leukemia progression and suggest that ZRF1 inhibition could be a novel strategy to be explored for AML treatment.Oncogene advance online publication, 2 December 2013; doi:10.1038/onc.2013.501.
  • Author:
    Marijon E; Le Heuzey J-Y; Connolly S; Yang S; Pogue J; Brueckmann M; Eikelboom J; Themeles E; Ezekowitz M; Wallentin L; Yusuf
    Title:
    CYP2B6*6 is associated with increased breast cancer risk
    Source:
    Int J Cancer 134 (2), 426-430 (2013)
    Abstract:
    The cytochrome P450 2B6 (CYP2B6) is involved in the metabolism of testosterone. Functional changes in this enzyme may influence endogenous hormone exposure, which has been associated with risk of breast cancer. To assess potential associations between two functional polymorphisms CYP2B6-516-G>T (rs3745274) and CYP2B6-785-A>G (rs2279343) and breast cancer risk, we established a specific matrix-assisted laser desorption/ionization time-of-flight mass spectrometry assay. The GENICA breast cancer case-control study showed associations between the variant genotypes CYP2B6-516-TT and CYP2B6-785-GG and breast cancer risk with odds ratios (ORs) of 1.34 (p = 0.001) and 1.31 (p = 0.002), respectively. A similar effect was observed for carriers of the CYP2B6-516-T allele in a validation study including four independent studies from Germany, Sweden and USA. In a pooled analysis of all five studies involving 4,638 breast cancer cases and 3,594 controls of European ancestry, carriers of the CYP2B6-516-G and the CYP2B6-785-G variant had an increased breast cancer risk with ORs of 1.10 (p = 0.027) and 1.10 (p = 0.031), respectively. We conclude that the genetic variants CYP2B6-516-G and CYP2B6-785-G (designated CYP2B6 6), which are known to decrease activity of the CYP2B6 enzyme, contribute to an increased breast cancer risk. © 2013 UICC.
  • Author:
    Popp JA; Bogdanffy MS
    Title:
    Evaluation of Potential Carcinogenicity
    Source:
    Nonclinical Safety Assess, 219-254 (2013)
    Abstract:
    The current paradigm for carcinogenicity testing as discussed throughout this chapter has not reached a pinnacle of success for effectively and efficiently determining the potential carcinogenic risk of a drug to humans. This chapter is intended to provide a summary of expected standard approaches in carcinogenicity studies to be used until toxicologists are able to move to more advanced approaches. The ICH Guidelines for carcinogenicity testing provided specific direction on critical aspects of carcinogenicity study design in addition to specific information on when carcinogenicity testing was required for pharmaceuticals. Biotherapeutic drugs, such as monoclonal antibodies, replacement proteins, nanobodies and peptides, present a unique set of considerations when assessing their carcinogenic potential. When to initiate the carcinogenicity studies is frequently a drug development decision rather than a scientific decision. The chapter lists the elements of an effective carcinogenicity protocol review submission. © 2013 John Wiley & Sons, Ltd.
  • Author:
    Kim SM; Yun MR; Hong YK; Solca F; Kim J-H; Kim H-J; Cho BC
    Title:
    Glycolysis inhibition sensitizes non-small cell lung cancer with T790M mutation to irreversible EGFR inhibitors via translational suppression of Mcl-1 by AMPK activation
    Source:
    Mol Cancer Ther 12 (10), 2145-2156 (2013)
    Abstract:
    The secondary EGF receptor (EGFR) T790M is the most common mechanism of resistance to reversible EGFR-tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. Although afatinib (BIBW2992), a second-generation irreversible EGFR-TKI, was expected to overcome the acquired resistance, it showed limited efficacy in a recent phase III clinical study. In this study, we found that the inhibition of glycolysis using 2-deoxy-D-glucose (2DG) improves the efficacy of afatinib in H1975 and PC9-GR NSCLC cells with EGFR T790M. Treatment with the combination of 2DG and afatinib induced intracellular ATP depletion in both H1975 and PC9- GR cells, resulting in activation of AMP-activated protein kinase (AMPK). AMPK activation played a central role in the cytotoxicity of the combined treatment with 2DG and afatinib through the inhibition of mTOR. The alteration of the AMPK/mTOR signaling pathway by the inhibition of glucose metabolism induced specific downregulation of Mcl-1, a member of the antiapoptotic Bcl-2 family, through translational control. The enhancement of afatinib sensitivity by 2DG was confirmed in the in vivo PC9-GR xenograft model. In conclusion, this study examined whether the inhibition of glucose metabolism using 2DG enhances sensitivity to afatinib in NSCLC cells with EGFR T790M through the regulation of the AMPK/mTOR/Mcl-1 signaling pathway. These data suggest that the combined use of an inhibitor of glucose metabolism and afatinib is a potential therapeutic strategy for the treatment of patients with acquired resistance to reversible EGFR-TKIs due to secondary EGFR T790M. ©2013 AACR.
  • Author:
    Roberts SA; Andrews PA; Blanset D; Flagella KM; Gorovits B; Lynch CM; Martin PL; Kramer-Stickland K; Thibault S; Warner G
    Title:
    Considerations for the nonclinical safety evaluation of antibody drug conjugates for oncology
    Source:
    Regul Toxicol Pharmacol Article in press (2013)
    Abstract:
    Antibody drug conjugates (ADCs) include monoclonal antibodies that are linked to cytotoxic small molecules. A number of these agents are currently being developed as anti-cancer agents designed to improve the therapeutic index of the cytotoxin (i.e., cytotoxic small molecule or cytotoxic agent) by specifically delivering it to tumor cells. This paper presents primary considerations for the nonclinical safety evaluation of ADCs and includes strategies for the evaluation of the entire ADC or the various individual components (i.e., antibody, linker or the cytotoxin). Considerations are presented on how to design a nonclinical safety assessment program to identify the on- and off-target toxicities to enable first-in-human (FIH) studies. Specific discussions are also included that provide details as to the need and how to conduct the studies for evaluating ADCs in genetic toxicology, tissue cross-reactivity, safety pharmacology, carcinogenicity, developmental and reproductive toxicology, biotransformation, toxicokinetic monitoring, bioanalytical assays, immunogenicity testing, test article stability and the selection of the FIH dose. Given the complexity of these molecules and our evolving understanding of their properties, there is no single all-encompassing nonclinical strategy. Instead, each ADC should be evaluated on a case-by-case scientifically-based approach that is consistent with ICH and animal research guidelines. © 2013 Elsevier Inc. All rights reserved.
  • Author:
    Ellis PM; Chu QS; Leighl N; Laurie SA; Fritsch H; Gaschler-Markefski B; Gyorffy S; Munzert G
    Title:
    A phase i open-label dose-escalation study of intravenous BI 2536 together with pemetrexed in previously treated patients with non-small-cell lung cancer
    Source:
    Clin Lung Cancer 14 (1), 19-27 (2013)
    Abstract:
    4 (8 cyclopentyl 7 ethyl 5,6,7,8 tetrahydro 5 methyl 6 oxo 2 pteridinylamino) 3 methoxy n (1 methyl 4 piperidinyl)benzamide, pemetrexed; adult, aged, alopecia, anemia, anorexia, article, asthenia, cancer combination chemotherapy, clinical article, clinical trial, diarrhea, dizziness, dose response, drug dose escalation, drug eruption, drug fever, drug induced headache, drug response, drug safety, drug tolerability, dyspnea, fatigue, febrile neutropenia, female, human, injection site reaction, lacrimation, loading drug dose, lung non small cell cancer, male, myalgia, nausea, neutropenia, pruritus, side effect, sore throat, stomatitis, vomiting; Administration, Intravenous, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Cell Cycle Proteins, Disease-Free Survival, Drug Eruptions, Drug Interactions, Enzyme Inhibitors, Fatigue, Female, Glutamates, Guanine, Humans, Lung Neoplasms, Male, Maximum Tolerated Dose, Middle Aged, Nausea, Neutropenia, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Pruritus, Pteridines, Treatment Outcome
  • Author:
    Müller-Tidow C; Bug G; Lübbert M; Krämer A; Krauter J; Valent P; Nachbaur D; Berdel WE; Ottmann OG; Fritsch H; Munzert G; Garin-Chesa P; Fleischer F; Taube T; Döhner H
    Title:
    A randomized, open-label, phase I/II trial to investigate the maximum tolerated dose of the Polo-like kinase inhibitor BI 2536 in elderly patients with refractory/relapsed acute myeloid leukaemia
    Source:
    Br J Haematol 163 (2), 214-222 (2013)
    Abstract:
    Summary: Polo-like kinases (Plks) play an important role in cell cycle checkpoint controls and are over-expressed in acute myeloid leukaemia (AML). BI 2536, a novel Plk inhibitor, induces mitotic arrest and apoptosis. In this phase I/II trial of BI 2536 in 68 elderly patients with relapsed/refractory AML, three schedules were investigated (day 1, days 1-3, and days 1 + 8). Maximum tolerated dose was 350 and 200 mg in the day 1 and days 1 + 8 schedules, respectively. The day 1-3 schedule appeared equivalent to the day 1 schedule and was discontinued early. BI 2536 exhibited multi-compartmental pharmacokinetic behaviour. The majority of patients showed an increase of bone marrow cells in G2/M with a characteristic pattern of mitotic catastrophe. The overall response rate in the day 1 and day 1 + 8 schedules was 9% (5/54) with 2 complete and 3 partial responses. The majority of drug-related adverse events grade .3 were haematological. Taken together, Plk inhibition induced cell cycle arrest in AML blasts in vivo and BI 2536 monotherapy showed modest clinical activity in this poor prognosis patient group. © 2013 John Wiley & Sons Ltd.
  • Author:
    Klimowicz AC; Bose P; Petrillo SK; Magliocco AM; Dort JC; Brockton NT
    Title:
    The prognostic impact of a combined carbonic anhydrase IX and Ki67 signature in oral squamous cell carcinoma
    Source:
    Br J Cancer 109 (7), 1859-1866 (2013)
    Abstract:
    Background:Tumour hypoxia is associated with impaired apoptosis, resistance to therapy and poor prognosis. We previously reported that high stromal expression of the endogenous marker of hypoxia, carbonic anhydrase IX (CAIX), is associated with significantly reduced survival in oral squamous cell carcinoma (OSCC). In addition to hypoxia, CAIX expression is regulated by proliferation-associated signalling. We hypothesised that incorporating Ki67, a proliferation marker, into our existing CAIX-based stratification of OSCC would identify patients with the least favourable prognosis.Methods:Surgically resected tumours from 60 OSCC patients were analysed for CAIX, Ki67 and BAX expression using fluorescence immunohistochemistry and automated quantitative analysis (AQUA).Results:In patients expressing high stromal CAIX (sCAIX), stratification by tumour Ki67 expression revealed significantly distinct survival outcomes (P=0.005). In our OSCC cohort, below-median Ki67 and top-quartile sCAIX expression (Ki67 lo sCAIX hi) were associated with significantly worse disease-specific survival in univariate (HR 7.2 (2.5-20.4), P=0.001) and multivariate (HR 4.2 (1.4-12.8), P=0.011) analyses. Hypoxia is associated with decreased BAX expression; the Ki67 lo sCAIX hi group was more strongly associated with low BAX expression than high sCAIX alone.Conclusion: These data suggest that combined analysis of tumour Ki67 and sCAIX expression may provide a more clinically relevant assessment of tumour hypoxia in OSCC. © 2013 Cancer Research UK.
  • Author:
    Lester JF; Agulnik J; Akerborg O; Chouaid C; De Geer A; Finnern HW; Herder GJM; Lungershausen J; Mitchell PLR; Vansteenkiste J; Ziske C; Goker E
    Title:
    What constitutes best supportive care in the treatment of advanced non-small cell lung cancer patients?-Results from the lung cancer economics and outcomes research (LUCEOR) study
    Source:
    Lung Cancer 82 (1), 128-135 (2013)
    Abstract:
    Background: A significant proportion of advanced non-small cell lung cancer (NSCLC) patients receive supportive treatments to manage disease-related symptoms either separately or combined with systemic anti-cancer therapy (SACT). This supportive treatment is commonly referred to as best supportive care (BSC). Definition of BSC in clinical trials and its description in published comparative and real-life NSCLC studies is limited. The lack of a consensus BSC definition makes detailed evaluations of clinical trials and comparisons between clinical trials problematic. Methods: Data were collected as part of the lung cancer economics and outcomes research (LUCEOR) study. Information on treatment and treatment outcomes from deceased stage IIIb/IV NSCLC patients across ten countries was retrospectively collected from medical records. BSC was defined as the best care available as judged by the attending physicians. Results: A total of 1327 patients' data were analyzed. Of those, 774/1327 (58%), 316/631 (50%), 123/259 (47%), 25/56 (45%) and 15/26 (58%) were administered treatment defined as BSC with first, second, third, fourth and fifth-line SACT respectively. In total, 346/678 (51%), 149/335 (45%), 86/176 (49%), 11/28 (39%) and 13/25 (52%) of patients were administered treatment defined as BSC in the end-of-life setting after finishing first, second, third, fourth and fifth-line SACT respectively. BSC therapies could be grouped into 24 different categories. The most common elements did not vary substantially whether given with SACT (irrespective of treatment line), in the end-of-life setting, or between countries. The commonest categories of BSC were narcotic and non-narcotic analgesics, corticosteroids and gastrointestinal medication. Conclusion: There were no major differences in what constituted BSC. BSC included in all instances narcotic and non-narcotic analgesics, corticosteroids and gastrointestinal medication. To our knowledge this is the first study attempting to describe BSC in routine clinical practice. This study's results could help define a practical, up to date, evidence-based definition of BSC. © 2013 Elsevier Ireland Ltd.
  • Author:
    Kwak EL; Shapiro GI; Cohen SM; Becerra CR; Lenz H-J; Cheng W-F; Su W-C; Robohn M; Le Maulf F; Lobmeyer MT; Chand VK; Iafrate AJ
    Title:
    Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation
    Source:
    cancer 119 (16), 3043-3051 (2013)
    Abstract:
    BACKGROUND The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations. METHODS Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. RESULTS Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. CONCLUSIONS Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging. © 2013 American Cancer Society.
  • Author:
    Krawczyk P; Nico. M; Powrózek T; Mlak R; Sawicki M; Jarosz B; Pajak B; Kucharczyk K; Stencel D; Trojanowski T; Milanowski J
    Title:
    Sensitive methods for the detection of an insertion in exon 20 of the HER2 gene in the metastasis of non-small cell lung cancer to the central nervous system
    Source:
    Oncol Lett 6 (4), 1063-1067 (2013)
    Abstract:
    The HER2 (ErbB2/neu) protein is a member of the HER (ErbB) receptor family (EGFR, HER2, HER3 and HER4) that expresses tyrosine kinase activity in the intracellular domain. EGFR and HER2 overexpression is observed in numerous types of cancer, nevertheless, the susceptibility of patients with non-small cell lung cancer (NSCLC) to therapy with EGFR and HER2 tyrosine kinase inhibitors (TKIs) depends on mutations present in the respective coding genes (driver mutations). In the present study, PCR and amplified DNA fragment length analysis (FLA) were used along with the multi-temperature single-strand conformation polymorphism (MSSCP) technique in order to identify the 12 base pair insertion in exon 20 of the HER2 gene in 143 patients with NSCLC metastasis to the central nervous system. The prevalence of the HER2 gene mutation was correlated with mutations in the EGFR and BRAF genes. The insertion in exon 20 of the HER2 gene was observed in a single 77-year-old, non-smoking male, with poorly-differentiated adenocarcinoma of the lung (1.5% of adenocarcinoma patients). No other genetic abnormalities were identified in this patient. In the therapy of NSCLC patients with HER2 gene mutations, drugs that inhibit the EGFR and HER2 receptors, for example afatinib, may be effective. The identification of other driving mutations in NSCLC cells appears to be key to the appropriate qualification of molecular targeted therapies.
  • Author:
    Müller-Tidow; C Bug G; Lübbert M; Krämer A; Krauter J; Valent P; Nachbaur D; Berdel WE; Ottmann OG; Fritsch H; Munzert G; Garin-Chesa P; Fleischer F; Taube T; Döhner H
    Title:
    A randomized, open-label, phase I/II trial to investigate the maximum tolerated dose of the Polo-like kinase inhibitor BI 2536 in elderly patients with refractory/relapsed acute myeloid leukaemia
    Source:
    Br J Haematol Article in press (2013)
    Abstract:
    Polo-like kinases (Plks) play an important role in cell cycle checkpoint controls and are over-expressed in acute myeloid leukaemia (AML). BI 2536, a novel Plk inhibitor, induces mitotic arrest and apoptosis. In this phase I/II trial of BI 2536 in 68 elderly patients with relapsed/refractory AML, three schedules were investigated (day 1, days 1-3, and days 1 + 8). Maximum tolerated dose was 350 and 200 mg in the day 1 and days 1 + 8 schedules, respectively. The day 1-3 schedule appeared equivalent to the day 1 schedule and was discontinued early. BI 2536 exhibited multi-compartmental pharmacokinetic behaviour. The majority of patients showed an increase of bone marrow cells in G2/M with a characteristic pattern of mitotic catastrophe. The overall response rate in the day 1 and day 1 + 8 schedules was 9% (5/54) with 2 complete and 3 partial responses. The majority of drug-related adverse events grade .3 were haematological. Taken together, Plk inhibition induced cell cycle arrest in AML blasts in vivo and BI 2536 monotherapy showed modest clinical activity in this poor prognosis patient group. © 2013 John Wiley & Sons Ltd.
  • Author:
    Hayes C S; Shicora A; Ashley GossLJ; Van Ryn J; Gilmour S K
    Title:
    Synergistic anti-cancer effects with dabigatran etexilate and Gisplatin or cyclophosphamide
    Source:
    24 th Congress of the International Society on Thrombosis & Hemostasis (ISTH), Amsterdam, Netherlands, Jun 29- Jul 4, 2013
  • Author:
    Lang I; Köhne C-H; Folprecht G; Rougier P; Curran D; Hitre E; Sartorius U; Griebsch 1; Van Cutsem E
    Title:
    Quality of life analysis in patients with KRAS wild-type metastatic colorectal cancer treated first-line with cetuximab plus irinotecan, fluorauraeil and leucovorin
    Source:
    Eur J Cancer 49 (2), 439-448 (2013)
    Abstract:
    Background: ln the CRYSTAL study adding cetuximab to first-line FOLFIRI significantly improved outcome in patients with KRAS wild-type metastatic colorectal cancer. Quality of life (Qol)was assessed, and associations with tumour response and survival were investigated. Patients and methods: The European Organization for Research and Treatment of Cancer Qoql uestionnaire­ core 30 was used, focusing on global health status (GHS)/Qoal nd social functioning scales. Radiological responsewas assessed by an independent review committee. Results: Qowl as evaluable in 627/666 patients (94%) with KRAS wild-type tumours; of these 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. Pattern mixture analysis revealed no significant differences for GHS/Qo(lP = 0.12) and social functioning scores (P = 0.43) between the treatment arms. ln additional analyses: early skin reactions in patients receiving cetuximab Background: ln the CRYSTAL study adding cetuximab to first-line FOLFIRI significantly improved outcome in patients with KRAS wild-type metastatic colorectal cancer. Quality of life (Qol)was assessed, and associations with tumour response and survival were investigated. Patients and methods: The European Organization for Research and Treatment of Cancer Qoql uestionnaire­ core 30 was used, focusing on global health status (GHS)/Qoal nd social functioning scales. Radiological responsewas assessed by an independent review committee. Results: Qowl as evaluable in 627/666 patients (94%) with KRAS wild-type tumours; of these 52% received FOLFIRI, and 48% FOLFIRI plus cetuximab. Pattern mixture analysis revealed no significant differences for GHS/Qo(lP = 0.12) and social functioning scores (P = 0.43) between the treatment arms. ln additional analyses: early skin reactions in patients receiving cetuximab did not significantly affect these Qosl cales, and tumour response was more common (58% versus 40%, P = 0.0002) and survivallonger (Hazard ratio 1.68, P < 0.0001) in asymptomatic compared with symptomatic patients at baseline. Adding cetuximab to FOLFIRI was associated with significantly higher tumour response irrespective of patient baseline symptomatic status, and enhanced symptom relieffrom baseline in those whose tumours had responded. Conclusion: Adding cetuximab to FOLFIRI improved response rate and survival without either improving or negatively impacting on GHS/QoL and social functioning. © 2012 Elsevier Ud. All rights reserved.
  • Author:
    Brixen LM; Bernstein IT; Bülow S; Ehrnrooth E
    Title:
    Survival of patients with Stage III colon cancer is improved in hereditary non-polyposis colorectal cancer compared with sporadic cases. A Danish registry based study
    Source:
    Colorect Dis 15 (7), 816-823 (2013)
    Abstract:
    Aim: Patients with hereditary non-polyposis colorectal cancer (HNPCC) seem to have a better prognosis than those with sporadic colorectal cancer (CRC). The aim was to compare survival after Stage III CC in patients with HNPCC with those having sporadic CC. Method: A total of 230 patients with hereditary cancer from the Danish HNPCC Register and 3557 patients with sporadic CC from the Danish Colorectal Cancer Database, diagnosed during May 2001-December 2008, were included. HNPCC patients were classified according to mismatch repair mutation status and family pedigree. Sporadic cases had no known family history of cancer. Patient characteristics, geographical differences and survival data were analysed. Results: The overall survival (OS) was better in HNPCC patients compared with sporadic CC after stratification for sex and age (P = 0.02; CI 1.04-1.7). The 5-year survival was 70% in HNPCC patients compared with 56% in sporadic CC (P < 0.001). No survival difference was found between HNPCC subgroups but a tendency to better OS was seen in patients with Lynch syndrome. No geographical differences in OS were found. The median follow-up was 3.9 (0-9.5) years for HNPCC vs 3.2 (0-9.6) years for sporadic CC. Conclusion: HNPCC patients with Stage III CC have a better OS compared with sporadic CC. No significant difference in OS was found within HNPCC subgroups. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.
  • Author:
    Chouaid C; Agulnik J; Goker E; Herder GJM; Lester JF; Vansteenkiste J; Finnern HW; Lungershausen J; Eriksson J; Kim K; Mitchell PLR
    Title:
    Health-related quality of life and utility in patients with advanced non-small-cell lung cancer: A prospective cross-sectional patient survey in a real-world setting
    Source:
    J Thorac Oncol 8 (8), 997-1003 (2013)
    Abstract:
    BACKGROUND: Non-small-cell lung cancer (NSCLC) has a significant impact on patients' health-related quality of life (HRQOL). This study aimed to measure health state utility values representing the individual's preferences for specific health-related outcomes in advanced NSCLC patients and to assess predictive parameters. METHODS: We conducted a prospective quality-of-life survey on advanced NSCLC patients in 25 hospitals in Europe, Canada, Australia, and Turkey. HRQOL was assessed using the EuroQol (EQ-5D) questionnaire and EQ-5D utility and EQ-visual analog (EQ-VAS) scores were estimated. RESULTS: Three hundred nineteen patients were recruited of which 263 had evaluable data. Mean utility for progression-free (PF) patients on first-, second-, and third-/fourth-line treatment was 0.71 (SD = 0.24), 0.74 (SD = 0.18), and 0.62 (SD = 0.29), respectively. Mean utility for patients with progressive disease (PD) while on first-, second- and third-/fourth-line treatment was 0.67 (SD = 0.2), 0.59 (SD = 0.34), and 0.46 (SD = 0.38), respectively. Overall, patients with PD had lower mean utility scores than PF patients (0.58 versus 0.70). The results of the EQ-VAS showed that the score decreased with later treatment lines. Patients with PD had a 10-point decrease in VAS scores compared with PF patients (53.7 versus 66.6). The regression analysis revealed that stage IV disease, higher lines of treatment, and health state were significant predictors of utility at the 10% level. CONCLUSION: The results presented indicate a substantial impact of lung cancer on patients' HRQOL, with stage IV disease, line of treatment, and PD, resulting in considerable deterioration of utility. The values obtained here will inform evaluations of cost-utility for NSCLC therapies. © 2013 by the International Association for the Study of Lung Cancer.
  • Author:
    Krämer O
    Title:
    Selection of Compound Subsets for Hit Identification in Cancer Drug Discovery
    Source:
    Frontiers in Medicinal Chemistry, San Francisco, USA, Jun 23-26, 2013
  • Author:
    Mésange P; Poindessous V; Battistella A; Dumont S; Merabtene F; de Gramont A; Larsen A K
    Title:
    Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine VEGF signaling in colorectal cancer models and can be overcome by nintedanib
    Source:
    ESMO GI, Barcelona, Spain, Jul 2013
  • Author:
    Lester JF; Agulnik J; Akerborg O; Chouaid C; De Geer A; Finnern HW; Herder GJM; Lungershausen J; Mitchell PLR; Vansteenkiste J; Ziske C; Goker E
    Title:
    What constitutes best supportive care in the treatment of advanced non-small cell lung cancer patients?-Results from the lung cancer economics and outcomes research (LUCEOR) study
    Source:
    Lung Cancer Article in press (2013)
    Abstract:
    Background: A significant proportion of advanced non-small cell lung cancer (NSCLC) patients receive supportive treatments to manage disease-related symptoms either separately or combined with systemic anti-cancer therapy (SACT). This supportive treatment is commonly referred to as best supportive care (BSC). Definition of BSC in clinical trials and its description in published comparative and real-life NSCLC studies is limited. The lack of a consensus BSC definition makes detailed evaluations of clinical trials and comparisons between clinical trials problematic. Methods: Data were collected as part of the lung cancer economics and outcomes research (LUCEOR) study. Information on treatment and treatment outcomes from deceased stage IIIb/IV NSCLC patients across ten countries was retrospectively collected from medical records. BSC was defined as the best care available as judged by the attending physicians. Results: A total of 1327 patients' data were analyzed. Of those, 774/1327 (58%), 316/631 (50%), 123/259 (47%), 25/56 (45%) and 15/26 (58%) were administered treatment defined as BSC with first, second, third, fourth and fifth-line SACT respectively. In total, 346/678 (51%), 149/335 (45%), 86/176 (49%), 11/28 (39%) and 13/25 (52%) of patients were administered treatment defined as BSC in the end-of-life setting after finishing first, second, third, fourth and fifth-line SACT respectively. BSC therapies could be grouped into 24 different categories. The most common elements did not vary substantially whether given with SACT (irrespective of treatment line), in the end-of-life setting, or between countries. The commonest categories of BSC were narcotic and non-narcotic analgesics, corticosteroids and gastrointestinal medication. Conclusion: There were no major differences in what constituted BSC. BSC included in all instances narcotic and non-narcotic analgesics, corticosteroids and gastrointestinal medication. To our knowledge this is the first study attempting to describe BSC in routine clinical practice. This study's results could help define a practical, up to date, evidence-based definition of BSC. © 2013 Elsevier Ireland Ltd. All rights reserved.
  • Author:
    Choi BD; Kuan CT; Cai M; Archer GE; Mitchell DA; Gedeon PC; Sanchez-Perez L; Pastan I; Bigner DD; Sampson JH.
    Title:
    Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma
    Source:
    Proc Natl Acad Sci USA 110 (1), 270-275 (2012)
    Abstract:
    Bispecific antibodies (bscAbs), particularly those of the bispecific T-cell engager (BiTE) subclass, have been shown to effectively redirect T cells against cancer. Previous efforts to target antigens expressed in both tumors and normal tissues have produced significant toxicity, however. Moreover, like other large molecules, bscAbs may be restricted from entry into the "immunologically privileged" CNS. A tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase not found in normal tissues but frequently expressed in glioblastomas and many other neoplasms. Because it is localized solely to tumor tissue, EGFRvIII presents an ideal target for immunotherapy. Here we report the preclinical evaluation of an EGFRvIII-targeted BiTE, bscEGFRvIIIxCD3. Our results show that bscEGFRvIIIxCD3 activates T cells to mediate potent and antigen-specific lysis of EGFRvIII-expressing gliomas in vitro (P < 0.001) at exceedingly low concentrations (10 ng/mL) and effector-to-target ratios (2.5:1). Treatment with i.v. bscEGFRvIIIxCD3 yielded extended survival in mice with well-established intracerebral tumors (P < 0.05) and achieved durable complete cure at rates up to 75%. Antitumor efficacy was significantly abrogated on blockade of EGFRvIII binding, demonstrating the need for target antigen specificity both in vitro and in vivo. These results demonstrate that BiTEs can be used to elicit functional antitumor immunity in the CNS, and that peptide blockade of BiTE-mediated activity may greatly enhance the safety profile for antibody-redirected T-cell therapies. Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity.
  • Author:
    Soria J; Hollebecque A; Massard C; Deutsch E; Varga A; Morsli N; Kaci M O; Staines H; Marzin K; Bahleda R
    Title:
    PHASE I STUDY OF AFATINIB (BIBW 2992), AN ERBB FAMILY BLOCKER PLUS NINTEDANIB (BIBF 1120), A TRIPLE ANGIOKINASE INHIBITOR, IN PATIENTS (PTS)WITH ADVANCED SOLID TUMOURS.
    Source:
    Ann Oncol 23 (9), 155 (2012)
    Abstract:
    his phase I study evaluated the safety, efficacy, pharmacokinetics (PK) of afatinib, an ErbB family blocker, and nintedanib, a p.o. triple angiokinase inhibitor in 45 patients with advanced solid tumors. Main adverse events were diarrhea, asthenia, nausea, vomiting, creatinine increase, renal failure and transaminase elevation. Efficacy data showed evidence of antitumor activity in patients with advanced solid tumors. Thus, at MTD, the combination of afatinib with nintedanib showed a manageable safety profile and evidence of activity in different heavily pretreated tumor types. (conference abstract: 37th Congress of the European Society for Medical Oncology, ESMO, Vienna, Austria, 28/09/2012-02/10/2012) ABEX Methods 45 Patients (male 26; age range 37-73 yr, median age 56 yr) with heavily pretreated advanced solid tumors were treated with afatinib and nintedanib. Main cancer types included lung (NSCLC), colorectal, breast, melanoma and ovary. This phase I study used a modified 3+3 design to determine the MTD of afatinib, with dose escalating from 10-40 mg every day given in 2 schedules: continuous or intermittent (every other wk), in combination with fixed-dose nintedanib (200 mg b.i.d. reduced to 150 mg b.i.d. after protocol amendment) in a 28-day cycle. Secondary endpoints were safety, efficacy, PK, and circulating tumor cells analysis. Results 2 MTD were established: afatinib 40 mg every day (intermittent) plus nintedanib 150 mg b.i.d. and afatinib 30 mg every day (continuous) plus nintedanib 150 mg b.i.d. Efficacy data showed evidence of antitumor activity with partial responses observed in 2 patients (HER2-negative breast cancer, and head and neck squamous cell carcinoma) and stable disease in 27 patients (lasting >3 mth in 8 patients). Preliminary PK data showed no drug-drug interaction. (N56)
  • Author:
    Senellart H; Bennouna J; Isambert N; De Mont-Serrat H; Squiban P; Tschoepe I; Delord J
    Title:
    PHASE I SAFETY AND TOLERABILITY OF ONCE DAILY ORAL AFATINIB (A) IN COMBINATION WITH DOCETAXEL (D) IN PATIENTS (PTS) WITH RELAPSED OR REFRACTORY ADVANCED SOLID TUMOURS.
    Source:
    Ann Oncol 23 (9), 169 (2012)
    Abstract:
    This phase I study evaluated the safety and tolerability of once-daily p.o. afatinib (AF) in combination with i.v. docetaxel (DC) in 27 patients with relapsed or refractory advanced solid tumors. Adverse events (AE) included diarrhea and asthenia. DLT included diarrhea, febrile neutropenia, hypokalemia, hyponatremia, increase of creatininemia and oral mucositis. Thus, based on the rate of DLT observed at AF 40 mg/day+DC 75 mg/sq.m, the decision was made to evaluate further the AF 30 mg/day+DC 75 mg/sq.m dose regimen in an additional cohort of 12 patients. (conference abstract: 37th Congress of the European Society for Medical Oncology, ESMO, Vienna, Austria, 28/09/2012-02/10/2012) ABEX Methods 27 Patients (female 44.4%; mean age 56.4 yr) with advanced solid tumors received once daily, p.o. dosing of AF with DC, given i.v. on day 1 of every 3 wk cycle. 18 Patients in the escalation phase with AF (30-50 mg/day) and DC (60-75 mg/sq.m), and 9 patients in the expansion phase with AF (40 mg/day) and DC (75 mg/sq.m). Primary objective was to establish the MTD based on the occurrence of DLT observed in cycle 1. Dose escalation was performed with cohorts of 3-6 patients using a 3+3 design. Initial starting dose level was AF 30 mg/day and DC 60 mg/sq.m, escalating upto AF 50 mg/day and DC 75 mg/sq.m until the MTD was reached, and followed by a pharmacokinetic expansion cohort of 12 patients at the MTD level. Results AE were manageable and the MTD was not exceeded in the tested dose range upto AF 50 mg/day and DC 75 mg/sq.m. AE were diarrhea (92.6%) and asthenia (77.8%). Selected dose level for the expansion cohort (AF 40 mg/day with DC 75 mg/sq.m) was based on the potential for diarrhea and rash during later cycles. At this dosage, events qualifying for DLT such as febrile neutropenia (2), diarrhea grade 3, hypokalemia grade 3, hyponatremia grade 3, increase of creatininemia grade 2 and oral mucositis, were observed in 7 patients. (N56)
  • Author:
    Premsrirut P; Fellmann C; Hannon G J; Lowe S W; Zuber J; Elledge S
    Title:
    Proffered Paper: Next Generation RNAi Mouse Models for Drug Discovery and Toxicology Assessment
    Source:
    Eur J Cancer 48 (5), S14-S14 (2012)
    Abstract:
    -
  • Author:
    Ellis PM; Chu QS; Leighl N; Laurie SA; Fritsch H; Gaschler-Markefski B; Gyorffy S; Munzert G
    Title:
    A Phase I Open-Label Dose-Escalation Study of Intravenous BI 2536 Together With Pemetrexed in Previously Treated Patients With Non-Small-Cell Lung Cancer
    Source:
    Clin Lung Cancer 14 (1), 19-27 (2012)
    Abstract:
    This phase I study investigated the maximum tolerated dose, safety, efficacy, and pharmacokinetics of BI 2536 (100-325 mg) IV in combination with standard-dose pemetrexed in 41 patients with previously treated advanced or metastatic non-small-cell lung cancer. BI 2536 200 mg combined with pemetrexed had an acceptable safety profile and encouraging antitumor activity in patients with relapsed non-small-cell lung cancer. Introduction: BI 2536 is a potent, highly selective inhibitor of polo-like kinase (Plk) 1. This open-label, phase I study investigated the maximum tolerated dose (MTD), safety, efficacy, and pharmacokinetics (PK) of BI 2536 IV in combination with standard-dose pemetrexed in previously treated advanced or metastatic non-small-cell lung cancer. Patients and Methods: A standard 3 +/- 3 design was used. The patients received 500 mg/m(2) pemetrexed and escalating doses of BI 2536 on day 1 every 3 weeks. The primary objective was the MTD of BI 2536 combined with pemetrexed. Secondary endpoints were response rate (Response Evaluation Criteria in Solid Tumors), overall safety, and PK. Results: Forty-one patients received BI 2536 (100-325 mg). Two dose-limiting toxicities (DLT) occurred at BI 2536 325 mg (grade 3 pruritus and rash; grade 4 neutropenia). Therefore, the MTD for BI 2536 in combination with pemetrexed was 300 mg. After expanding the MTD dose level, 3 additional patients experienced DLTs, which resulted in expansion of the 250 mg cohort, in which 4 of the 13 additional patients experienced DLTs. Therefore, the recommended dose of BI 2536 was 200 mg. Most frequently reported drug-related adverse events were fatigue (71%), nausea (37%), and rash (34%). Two patients had durable confirmed partial responses; 21 (54%) patients had stable disease after the treatment cycle 2. PK analysis showed that BI 2536 and pemetrexed exposure were not altered when coadministered. Conclusion: BI 2536 200 mg combined with standard-dose pemetrexed has an acceptable safety profile in relapsed non-small-cell lung cancer. The antitumor activity observed is encouraging and supports further investigation of Plk inhibitors. Clinical Lung Cancer, Vol. 14, No. 1, 19-27 (C) 2013 Elsevier Inc. All rights reserved.
  • Author:
    Bogenriedera T; Herlyn M
    Title:
    The molecular pathology of cutaneous melanoma
    Source:
    Transl Pathol of Early Cancer, 267-286 (2012)
    Abstract:
    Cutaneous melanoma is a highly aggressive cancer with still limited, but increasingly efficacious, standard treatment options. Recent preclinical and clinical findings support the notion that cutaneous melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma already has great implications for the management of cutaneous melanoma. Herein, we review our rapidly growing understanding of the molecular biology of cutaneous melanoma, including the pathogenic roles of the mitogenassociated protein kinase (MAPK) pathway, the phosphatidylinositol 3 kinase [PI3K]/phosphatase and tensin homologue deleted on chromosome 10 [PTEN]/Akt/mammalian target of rapamycin [mTOR])PTEN (phosphatase and tensin homolog) pathway, MET (hepatocyte growth factor), Notch signaling, and other key molecules regulating cell cycle progression and apoptosis. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with clinical benefit fromagents that inhibit BRAF(V600E) orMEK (a kinase in theMAPK pathway). Cutaneous melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. These findings suggest that prospective genotyping of patients with melanoma, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, should be used increasingly as we work to develop new and more effective treatments for this devastating disease. © 2012 IOS Press and the authors. All rights reserved.
  • Author:
    Yang JC-H; Reguart N; Barinoff J; Köhler J; Uttenreuther-Fischer M; Stammberger U; O'Brien D; Wolf J; Cohen EE
    Title:
    Diarrhea associated with afatinib: An oral ErbB family blocker
    Source:
    Expert Rev Anticancer Ther 13 (6), 729-736 (2013)
    Abstract:
    Gastrointestinal (GI) adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as HER1 or ErbB1) tyrosine kinase inhibitor therapy. GI AEs are among the most common and most impactful on a patient's quality of life. Severe diarrhea can result in fluid and electrolyte losses, leading to dehydration, electrolyte imbalances and renal insufficiency. Afatinib is an irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to reversible tyrosine kinase inhibitors of EGFR, GI AEs-in particular, diarrhea-have frequently been observed in afatinib-treated patients. This article summarizes current data on afatinib-associated diarrhea and provides strategies for its management. Patient education, early identification, timely management and ongoing assessment will help to prevent aggravation, afatinib dose reductions or therapy discontinuation, encouraging patient compliance and allowing patients to obtain the maximum therapeutic benefit from this agent. © 2013 2013 Expert Reviews Ltd.
  • Author:
    Lacouture ME; Schadendorf D; Chu C-Y; Uttenreuther-Fischer M; Stammberger U; O'Brien D; Hauschild A
    Title:
    Dermatologic adverse events associated with afatinib: An oral ErbB family blocker
    Source:
    Expert Rev Anticancer Ther 13 (6), 721-728 (2013)
    Abstract:
    Dermatologic adverse events (AEs) are frequently observed in patients receiving EGF receptor (EGFR; also known as ErbB1) tyrosine kinase inhibitor therapy. The impact of these AEs goes beyond cosmesis to the discomfort from itching, pain and secondary infections, all of which may significantly impact on patient well-being, adherence and clinical outcomes. Afatinib is a potent, irreversible, oral, ErbB family blocker, inhibiting EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptor kinases. It also inhibits transphosphorylation of ErbB3. Similar to EGFR inhibitors, dermatologic AEs have been frequently observed in patients treated with afatinib. Papulopustular (acneiform) rash, pruritus, xerosis, paronychia and alopecia will require patient education and proactive treatment interventions. This article summarizes current data on the dermatologic AEs associated with afatinib treatment across the clinical trial program, and provides strategies for their effective management. © 2013 2013 Expert Reviews Ltd.
  • Author:
    Feik E; Schweifer N; Baierl A; Sommergruber W; Haslinger C; Hofer P; Maj-Hes A; Madersbacher S; Gsur A
    Title:
    Integrative analysis of prostate cancer aggressiveness
    Source:
    Prostate Article in press (2013)
    Abstract:
    BACKGROUND: Clinical management of prostate cancer (PC) is still highly demanding on the identification of robust biomarkers which will allow a more precise prediction of disease progression. METHODS: We profiled both mRNA expression and DNA copy number alterations (CNAs) from laser capture microdissected cells from 31 PC patients and 17 patients with benign prostatic hyperplasia using Affymetrix GeneChip® technology. PC patients were subdivided into an aggressive (Gleason Score 8 or higher, and/or T3/T4 and/or N+/M+) and non-aggressive (all others) form of PC. Furthermore, we correlated the two datasets, as genes whose varied expression is due to a chromosomal alteration, may suggest a causal implication of these genes in the disease. All statistical analyses were performed in R version 2.15.0 and Bioconductor version 1.8.1., respectively. RESULTS: We confirmed several common altered chromosomal regions as well as recently discovered loci such as deletions on chromosomes 3p14.1-3p13 and 13q13.3-13q14.11 supporting a possible role for RYBP, RGC32, and ELF1 in tumor suppression. Integrative analysis of expression and CN data combined with data retrieved from online databases propose PTP4A3 and ELF1 as possible factors for tumor progression. CONCLUSIONS: Copy number data analysis revealed some significant differences between aggressive and non-aggressive tumors, while gene expression data alone could not define an aggressive group of patients. The assessment of CNA may have diagnostic and prognostic value in PC. © 2013 Wiley Periodicals, Inc.
  • Author:
    Bogenriedera T; Herlyn M
    Title:
    The molecular pathology of cutaneous melanoma The molecular pathology of cutaneous melanoma
    Source:
    Transl Pathol of Early Cancer, 267-286 (2012)
    Abstract:
    Cutaneous melanoma is a highly aggressive cancer with still limited, but increasingly efficacious, standard treatment options. Recent preclinical and clinical findings support the notion that cutaneous melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma already has great implications for the management of cutaneous melanoma. Herein, we review our rapidly growing understanding of the molecular biology of cutaneous melanoma, including the pathogenic roles of the mitogenassociated protein kinase (MAPK) pathway, the phosphatidylinositol 3 kinase [PI3K]/phosphatase and tensin homologue deleted on chromosome 10 [PTEN]/Akt/mammalian target of rapamycin [mTOR])PTEN (phosphatase and tensin homolog) pathway, MET (hepatocyte growth factor), Notch signaling, and other key molecules regulating cell cycle progression and apoptosis. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with clinical benefit fromagents that inhibit BRAF(V600E) orMEK (a kinase in theMAPK pathway). Cutaneous melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. These findings suggest that prospective genotyping of patients with melanoma, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, should be used increasingly as we work to develop new and more effective treatments for this devastating disease. © 2012 IOS Press and the authors. All rights reserved.
  • Author:
    Gordon MS; Mendelson DS; Gross M; Uttenreuther-Fischer M; Ould-Kaci M; Zhao Y; Stopfer P; Agus D
    Title:
    A Phase I, open-label, dose-escalation study of continuous once-daily oral treatment with afatinib in patients with advanced solid tumors
    Source:
    Invest New Drugs 31 (2), 409-416 (2013)
    Abstract:
    Summary: Background This trial evaluated the safety, tolerability and maximum tolerated dose (MTD) of afatinib, a novel ErbB Family Blocker. Methods In this open-label, dose-escalation Phase I study, afatinib was administered continuously, orally, once-daily for 28 days to patients with advanced or metastatic solid tumors. Dose escalation was performed in a 3 + 3 design, with a starting dose of 10 mg/day (d); doses were doubled for each successive cohort until the MTD was defined. The MTD cohort was expanded to a total of 19 patients. Incidence and severity of adverse events (AEs), antitumor activity and pharmacokinetics were assessed. Results Thirty patients received at least one dose of afatinib. Twenty-nine patients were evaluable for response. Dose-limiting toxicities (DLTs) consisting of Grade 3 diarrhea were observed in two out of three patients treated at 60 mg/d. The MTD was determined at 40 mg/d. The most frequent treatment-related AEs were diarrhea and mucosal inflammation reported in 76.7 % and 43.3 % of patients respectively. Five patients had stable disease with a median progression-free survival of 111 days. No objective responses occurred. Pharmacokinetic data showed no deviation from dose-proportionality and steady-state was reached on Day 8 at the latest. Conclusions Afatinib was well tolerated with manageable side effects when administered once-daily, continuously at a dose of 40 mg. © 2012 Springer Science+Business Media New York.
  • Author:
    Kwak EL; Shapiro GI; Cohen SM; Becerra CR; Lenz H-J; Cheng W-F; Su W-C; Robohn M; Maulf FL; Lobmeyer MT; Chand VK; Iafrate AJ
    Title:
    Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation
    Source:
    Cancer Article in press (2013)
    Abstract:
    BACKGROUND: The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations. METHODS: Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety. RESULTS: Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment. CONCLUSIONS: Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging. © 2013 American Cancer Society.
  • Author:
    Waizenegger I C; Baum A; Stadmüllr H; Steurer S; Bader G; Garin-Chesa P; Schweifer N; Bernthaler A; Hasliner C; Schaaf O; Mousa S; Colbatzky F; Adolf G R; Bern
    Title:
    Modeling 1st-and 2nd-line therapy of BRAF mutant melenoma using a novel BRAF inhibitor with DFG-out binding mode
    Source:
    AACR 6.-10. April 2013
  • Author:
    Poindessous V; Mésange P; Batistella A; Afchain A; Forgue-Lafitte M-E; de Gramont A; Larsen A K
    Title:
    Exposure to nintedanib, a triple angiokinase inhibitor, is accompanied by activation of EGFR and other ErbB/HERfamily members in colorectal cancer (CRC) models, providing a rational for combinations of nintedanib with the ErbB family blocker afatinib
    Source:
    Abstract for ESMO 2013 27. September 2013
  • Author:
    Meissner Ch
    Title:
    Exposure to nintedanib, a triple angiokinase inhibitor, is accompanied by activation of EGFR and other ErbB/HERfamily members in colorectal cancer (CRC) models, providing a rational for combinations of nintedanib with the ErbB family blocker afatinib
    Source:
    ESMO 2013 27.09.2013
  • Author:
    Quintela M; Navarro P; Mondejar T; Sanchez J; Garcia E; Gomez G; Gonzalez-Pisano D; Colomer R
    Title:
    Differential luminal breast cancer (LBC) reprogramming in response to BIBF 1120 (BIBF) or bevacizumab (B)
    Source:
    ASCO 2013, Chicago, June 1-4, 2013
  • Author:
    Gianni Dr D
    Title:
    Epigenetic regulators as new drug targets in Oncology: a historical perspective and emerging concepts
    Source:
    Talk at University Maynooth/Dublin, April 9, 2013
  • Author:
    Vermorken J B; Rottey S; Ehmrooth E; Pelling K; Lahogue A; Wind S; Machiels J-P
    Title:
    A phase ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: Cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors
    Source:
    Ann Oncol 24 (5), 1392-1400 mds633 (2013)
    Abstract:
    Background: In this phase Ib, dose-escalation study, the oral irreversible ErbB family blocker afatinib (BIBW 2992) was combined with cisplatin (Cadila Healthcare Ltd, Ahmedabad, India) 50 or 75 mg/m. 2/paclitaxel (Bristol-Myers Squibb Pharmaceuticals Ltd, New York, USA) (Taxol)175 mg/m. 2 (regimen A) or cisplatin 75-100 mg/m. 2/5-fluorouracil 750-1000 mg/m. 2 (regimen B) in patients with advanced solid tumors. Patients and methods: The primary objective was to assess dose-limiting toxicities (DLTs) during cycle 1 for each regimen, from which the maximum tolerated dose (MTD) was determined. Patients received once daily oral afatinib 20, 30, 40 or 50 mg in 21-day cycles (3 + 3 design). Results: The MTD for afatinib in regimens A (n = 26) and B (n = 21) was determined as 20 mg and 30 mg following DLTs in five and four patients in cycle 1, respectively. Most frequent adverse events (AEs, any grade) were diarrhea and nausea. Disease control was observed in 54% and 29% of patients in regimens A and B, respectively. Plasma sampling suggested no relevant pharmacokinetic interaction between afatinib and the chemotherapeutic agents. Conclusions: The MTD of afatinib was 20 mg with cisplatin-paclitaxel and 30 mg with cisplatin-5-fluorouracil. Pre-emptive management of side-effects is important to maintain adequate safety and tolerability. Both combinations showed antitumor activity across tumor types and lines of prior treatment. © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
  • Author:
    Grunt T W; Mariani G L
    Title:
    Novel approaches for molecular targeted therapy of breast cancer: Interfering with PI3K/AKT/mTOR signaling
    Source:
    Curr Cancer Drug Targets 13 (2), 188-204 (2013)
    Abstract:
    Breast cancer is one of the most prevalent and devastating malignant diseases in women worldwide. Fortunately, while breast cancer incidence is still increasing, its death rate is declining. This is mainly due to early diagnosis and potent therapies such as blockade of estrogen receptor- or of ErbB2 (HER2-neu) membrane receptorsignaling. In recent years, the PI3K/AKT/mTOR pathway, which transmits signals from the cell membrane into the nucleus and activates multiple oncogenic programs, has been found to play a crucial role in the regulation of breast cancer cell growth. This pathway is densely interconnected with a multitude of other important regulatory systems for glucose-, lipid- and amino acid-metabolism, for energy balance, and for autophagy. It has been found that PI3K/AKT/mTOR signaling modulates estrogen receptor function. Using transverse and feedback regulatory loops the PI3K/AKT/mTOR cascade can communicate with concurrent and with upstream systems. Thus, PI3K/AKT/mTOR is a crucial element within a complicated signaling network. This pathway is hyperactive in more than 70% of breast tumors. Hence, the protein kinases located along this route represent very attractive and promising drug targets for breast cancer therapy. Currently, numerous small molecular drugs that inhibit PI3K, AKT and/or mTOR are being developed in preclinical and clinical models of breast cancer. Some of these compounds are highly selective blocking only one particular kinase complex, whereas others interfere with two (mTORC1+mTORC2) or even three effectors (PI3K+mTORC1+mTORC2) of the pathway. Due to the many interactions with other regulatory systems, silencing of the pathway can cause unexpected results. Therefore, detailed preclinical and clinical evaluation of these compounds as single drugs and in combination is required to achieve optimal results with maximal clinical benefit and acceptable toxicity. Also, reliable biomarkers for the identification of patient subsets that will maximally benefit from PI3K/AKT/mTOR inhibition need to be developed. Thus, selective silencing of PI3K/AKT/mTOR signaling represents a promising approach for breast cancer and might prove useful when combined with other drugs. Here we review the current preclinical and clinical data and compare the potential benefits of multi- versus single-targeting PI3K/AKT/mTOR drugs. © 2013 Bentham Science Publishers.
  • Author:
    Eisen T; Shparyk Y; Macleod N; Jones R; Wallenstein G; Temple G; Khder Y; Dallinger C; Studeny M; Loembe A B; Bondarenko I
    Title:
    Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study
    Source:
    Invest New Drugs, 1-11 Article in press (2013)
    Abstract:
    Purpose Some targeted anticancer agents are associated with serious ventricular tachyarrhythmias, which may be predicted by electrocardiographic evaluation of drug-related QT prolongation. We studied the effects of nintedanib (BIBF 1120; an oral, triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors) on the QT interval in patients with renal cell carcinoma (RCC) participating in an open-label phase II trial. Methods Treatment-naïve, adult patients with unresectable/metastatic, clear cell RCC received nintedanib 200 mg twice daily. QT intervals were evaluated at baseline (day -1), on day 1 (after the first dose), and on day 15 (steady state) by 12-lead electrocardiograms (ECGs) performed in triplicate. Pharmacokinetic sampling was also undertaken. Results Among 64 evaluable patients, the upper limits of the 2-sided 90 % confidence intervals for the adjusted mean time-matched changes in QTcF interval (corrected for heart rate by Fridericia's method) from baseline to day 1 and 15 (primary ECG endpoint) were well below the regulatory threshold of 10 ms at all times. No relationship between nintedanib exposure and change from baseline in QTcF was seen. Nintedanib was generally well tolerated with no drug-related cardiovascular adverse events. Conclusion Nintedanib administered at 200 mg twice daily was not associated with clinically relevant QT prolongation. © 2013 Springer Science+Business Media New York.
  • Author:
    Herrmann H; Blatt K; Shi J; Gleixner K V; Cemy-Reiterer S; Müllauer L; Vakoc C R; Sperr W R; Homy H P; Bradner J E; Zuber J; Valent P
    Title:
    Small-molecule inhibition of BRD4 as a new potent approach to eliminate leukemic stem- and progenitor cells in acute myeloid leukemia (AML)
    Source:
    Oncotarget 3 (12), 1588-1599 (2012)
    Abstract:
    Acute myeloid leukemia (AML) is a life-threatening stem cell disease characterized by uncontrolled proliferation and accumulation of myeloblasts. Using an advanced RNAi screen-approach in an AML mouse model we have recently identified the epigenetic 'reader' BRD4 as a promising target in AML. In the current study, we asked whether inhibition of BRD4 by a small-molecule inhibitor, JQ1, leads to growth-inhibition and apoptosis in primary human AML stem- and progenitor cells. Primary cell samples were obtained from 37 patients with freshly diagnosed AML (n=23) or refractory AML (n=14). BRD4 was found to be expressed at the mRNA and protein level in unfractionated AML cells as well as in highly enriched CD34+/CD38- and CD34+/CD38+ stem- and progenitor cells in all patients examined. In unfractionated leukemic cells, submicromolar concentrations of JQ1 induced major growth-inhibitory effects (IC50 0.05-0.5 ?M) in most samples, including cells derived from relapsed or refractory patients. In addition, JQ1 was found to induce apoptosis in CD34+/CD38- and CD34+/CD38+ stem-and progenitor cells in all donors examined as evidenced by combined surface/Annexin-V staining. Moreover, we were able to show that JQ1 synergizes with ARA-C in inducing growth inhibition in AML cells. Together, the BRD4-targeting drug JQ1 exerts major anti-leukemic effects in a broad range of human AML subtypes, including relapsed and refractory patients and all relevant stem- and progenitor cell compartments, including CD34+/CD38- and CD34+/CD38+ AML cells. These results characterize BRD4-inhibition as a promising new therapeutic approach in AML which should be further investigated in clinical trials. © Herrmann et al.
  • Author:
    Marshall J; Shapiro G I; Uttenreuther-Fischer M; Ould-Kaci M; Stopfer p; Gordon M S
    Title:
    Phase i dose-escalation study of afatinib, an ErbB family blocker, plus docetaxel in patients with advanced cancer
    Source:
    Future Oncol 9 (2), 271-281 (2013)
    Abstract:
    Aims: To determine the maximum tolerated dose (MTD), safety and anti-tumor activity of afatinib combined with docetaxel in advanced cancer. Patients &amp; methods: The MTD was determined from dose-limiting toxicities in the first cycle. Results: Thirty-one patients received 10, 20 and 30 mg oral afatinib, plus 60 and 75 mg/m2 intravenous docetaxel (six cohorts; 3-week cycles). The MTD of afatinib was 20 mg/day (days 2-21) with 75 mg/m2 docetaxel (day 1). Dose-limiting toxicities were grade 3/4 diarrhea (n = 3) and febrile neutropenia (n = 6). Most frequently occurring adverse events were diarrhea, neutropenia and rash. Disease stabilization occurred in 14 patients. Conclusion: Afatinib 20 mg/day plus docetaxel was suboptimal and the study could not yield Phase II dose recommendations. The combination resulted in a manageable safety profile. © 2013 John Marshall, Geoffrey I Shapiro, Martina Uttenreuther-Fischer, Mahmoud Ould-Kaci, Peter Stopfer &amp; Michael S Gordon.
  • Author:
    SEhi J; Wang E; Zuber J; Rappaport A; Taylor M; Johns C; Lowe S W; Vakoc C R
    Title:
    The Polycomb complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9;Nras G12D acute myeloid leukemia
    Source:
    Oncogene 32 (7), 930-938 (2013)
    Abstract:
    The Trithorax and Polycomb groups of chromatin regulators are critical for cell-lineage specification during normal development; functions that often become deregulated during tumorigenesis. As an example, oncogenic fusions of the Trithorax-related protein mixed lineage leukemia (MLL) can initiate aggressive leukemias by altering the transcriptional circuitry governing hematopoietic cell differentiation, a process that requires multiple epigenetic pathways to implement. Here we used shRNA screening to identify chromatin regulators uniquely required in a mouse model of MLL-fusion acute myeloid leukemia, which revealed a role for the Polycomb repressive complex 2 (PRC2) in maintenance of this disease. shRNA-mediated suppression of PRC2 subunits Eed, Suz12 or Ezh1/Ezh2 led to proliferation arrest and differentiation of leukemia cells, with a minimal impact on growth of several non-transformed hematopoietic cell lines. The requirement for PRC2 in leukemia is partly because of its role in direct transcriptional repression of genes that limit the self-renewal potential of hematopoietic cells, including Cdkn2a. In addition to implicating a role for PRC2 in the pathogenesis of MLL-fusion leukemia, our results suggest, more generally, that Trithorax and Polycomb group proteins can cooperate with one another to maintain aberrant lineage programs in cancer. © 2013 Macmillan Publishers Limited All rights reserved.
  • Author:
    Hirsh Vera; Cadranel Jacques; Cong Xiuyu Julie; Fairclough Diane; Finnern Henrik W; Lorence Robert M; Miller Vice A; Palmer Michael; Yang James C-H
    Title:
    Symptom and Quality of Life Benefit of Afatinib in Advanced Non-Small-Cell Lung Cancer Patients Previously Treated with Erlotinib or Gefitinib
    Source:
    J Thorac Oncol 8 (2), 229-237 (2013)
    Abstract:
    -
  • Author:
    Hirsh V; Cadranel J; Cong X J; Fairclough D; Finnern H W; Lorence R M; Miller V A; Palmer M; Yang J C-H
    Title:
    Symptom and quality of life benefit of afatinib in advanced non-small-cell lung cancer patients previously treated with erlotinib or gefitinib: Results of a randomized phase iib/iii trial (lux-lung 1)
    Source:
    J Thorac Oncol 8 (2), 229-237 (2013)
    Abstract:
    BACKGROUND: Patient-reported symptom and health-related quality of life (HRQoL) benefit of afatinib, a novel, irreversible, ErbB Family Blocker, was investigated in a double-blind, randomized, phase IIb/III trial (LUX-Lung 1). METHODS: Five hundred and eighty-five patients with lung adenocarcinoma (stage IIIb/IV), who had progressed after chemotherapy (1-2 lines) and at least 12 weeks of erlotinib or gefitinib, were randomized (2:1) to receive either afatinib plus best supportive care (BSC) or placebo plus BSC. Symptom and HRQoL benefit were measured using the lung cancer-specific European Organisation for Research and Treatment of Cancer (QLQ-C30/LC13) and EuroQol (EQ-5D) questionnaires. Non-small-cell lung cancer-related symptoms (cough, dyspnea, and pain) were prespecified using three preplanned analyses (percentage of patients improved/worsened/stable, change in scores over time, and time to deterioration of scores). RESULTS: Compared with patients on placebo, a significantly higher proportion of afatinib-treated patients showed an improvement in cough (p < 0.0001), dyspnea (p = 0.006), and pain (p < 0.0001). Afatinib also significantly improved the mean scores over time for cough (p < 0.0001), dyspnea (p = 0.0161), and pain (p = 0.0056); significantly delayed the time to deterioration for cough (p < 0.001); and showed a trend in delaying dyspnea (p = 0.170) and pain (p = 0.287). Consistent with the adverse-event profile of afatinib, a significantly (p < 0.05) higher proportion of afatinib-treated patients showed worsening of diarrhea, sore mouth, dysphagia, and appetite scores. However, compared with placebo, afatinib significantly (p < 0.05) improved QoL assessed with the EQ-5D questionnaire and global health status/QoL, physical functioning, and fatigue, which were assessed with the European Organisation for Research and Treatment of Cancer questionnaires. CONCLUSION: In the LUX-Lung 1 trial, the addition of afatinib to BSC significantly improved non-small-cell lung cancer-related symptoms (cough, dyspnea, and pain), fatigue, physical functioning, and HRQoL and significantly delayed time to deterioration of cough. Copyright © 2012.
  • Author:
    De Geer A; Eriksson J; Finnern HW
    Title:
    A cross-country review of data collected on non-small cell lung cancer (NSCLC) patients in cancer registries, databases, retrospective and non-randomized prospective studies.
    Source:
    J Med Econ 16 (1), 134-149 (2013)
    Abstract:
    Introduction: An increased number of pharmacotherapies exist to treat advanced NSCLC. This necessitates a review of the available information on routine-care treatment patterns, the outcome of treatment, and resource utilization for patients diagnosed and treated with advanced NSCLC that could inform evidence-based treatment decisions and aid decisions on the most costeffective treatment alternatives. Methods: PubMed and the Health Economic Evaluations Database were searched for retrospective or non-randomized prospective studies between January 2000 and May 2012 that included information on treatment patterns, treatment outcomes including health-related quality-of-life (HRQoL), and resource utilization. In addition, registries and databases were identified from retrieved publications and internet searches. Data collected in registries and databases was summarized for eight European countries (Belgium, France, Germany, Italy, Sweden, Turkey, the Netherlands, the UK), Australia, and Canada. Results: The literature search resulted in 410 studies, whereof 87 studies met the study inclusion criteria. In total, 49 were retrospective chart reviews or database analyses, 30 non-randomized prospective studies, and eight HRQoL studies. Two studies compared treatment patterns and/or treatment outcomes across countries. Altogether, 181 cancer registries in the countries studied were identified. Clinical cancer-specific patient registries were identified in Australia and Germany. Databases or linkage systems that enable retrieval of complete information of patient disease history were found in Australia, Canada, the Netherlands, Sweden, and the UK. Cancer registries and databases were found to collect information on NSCLC patient demographics, NSCLC or lung cancer diagnosis, disease stage, performance status, treatment, treatment outcomes, and resource use. Differences existed between country registries and databases in whether information was collected on each of these data points. Conclusion: The literature review revealed few published NSCLC studies on treatment, treatment outcomes, and resource use in routine clinical practice and on HRQoL. Registries and databases were found to collect some of this information, however not systematically. © 2013 Informa UK Ltd.
  • Author:
    Azoulay L; Assimes TL; Yin H; Bartels DB; Schiffrin EL; Suissa S
    Title:
    Long-term use of angiotensin receptor blockers and the risk of cancer.
    Source:
    PLoS ONE 7 (12) art.no.50893 (2012)
  • Author:
    Wong HH; Parkinson C; Ledermann JA; Brenton JD; Merger M; Shaw A; Patterson A; Shafi M; Earl HM
    Title:
    Prolonged response of relapsed high grade serous ovarian carcinoma to the oral angiokinase inhibitor nintedanib in a patient with a germline BRCA1 mutation.
    Source:
    Gynecol Oncol Case Rep 3, 7-10 (2012)
  • Author:
    Awada AH; Dumez H; Hendlisz A; Wolter P; Besse-Hammer T; Uttenreuther-Fischer M; Stopfer P; Fleischer F; Piccart M; Schoeffski P
    Title:
    Phase I study of pulsatile 3-day administration of afatinib (BIBW 2992) in combination with docetaxel in advanced solid tumors.
    Source:
    Invest New Drugs, 1-8 Article in Press (2012)
    Abstract:
    Background A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors. Methods Patients with advanced solid malignancies received docetaxel 75 mg/m 2 intravenously on day 1 and oral afatinib once daily on days 2-4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3-6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed. Results Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m 2 docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2-4) with docetaxel 75 mg/m 2. The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade 52). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease &gt;6 cycles. No pharmacokinetic interaction was observed. Conclusion Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m 2 is the MTD for this treatment schedule and the recommended phase II/phase Ill dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile. © 2012 The Author(s).
  • Author:
    Marshall J; Hwang J; Eskens FALM; Burger H; Malik S; Uttenreuther-Fischer M; Stopfer P; Kaci MO; Cohen RB; Lewis NL
    Title:
    A phase I, open-label, dose escalation study of afatinib, in a 3-week-on/1-week-off schedule in patients with advanced solid tumors.
    Source:
    Invest New Drugs, 1-10 Article in Press (2012)
    Abstract:
    Background A Phase I study to determine the maximum tolerated dose (MTD) and pharmacokinetics of afatinib (BIBW 2992), a novel irreversible ErbB Family Blocker, administered orally once daily in a 3-week-on/1-week-off dosing schedule. Methods Patients with advanced solid tumors received single-agent afatinib at 10, 20, 40, 55 or 65 mg/day. Safety, antitumor activity, pharmacokinetics and pharmacodynamic modulation of biomarkers were assessed. Results: Forty-three patients were enrolled. Dose-limiting toxicities (DLTs) occurred in five patients in the dose escalation phase (1/8 at 40 mg/day; 1/6 at 55 mg/day; 3/6 at 65 mg/day). The MTD was established at 55 mg/day. In the expansion cohort at the MTD, 6 patients experienced a DLT in the first 28-day treatment period. The most frequent DLT was diarrhea. The most common adverse events were diarrhea, rash, nausea, vomiting and fatigue. Overall, the afatinib safety profile in a 3-week-on/1-week-off dose schedule was similar to that of our daily-continuous schedule. Afatinib displayed dose-dependent pharmacokinetics at doses up to and including 55 mg/day, with a terminal half-life suitable for once-daily dosing. Signs of clinical antitumor activity were observed. In biopsies taken from clinically normal forearm skin, afatinib caused a reduced proliferation rate, with a concomitant increase in differentiation of epidermal keratinocytes. Conclusion Afatinib in a 3-week-on/1-week-off schedule showed a good safety profile. The MTD was 55 mg/day, although excess DLTs in the expansion cohort indicated that the 40 mg/day dose would have an acceptable safety profile for future studies. Dose cohorts between 40 and 55 mg/day were not examined in this study. © 2012 Springer Science+Business Media New York.
  • Author:
    George S; Reichardt P; Lechner T; Li S; Cohen DP; Demetri GD
    Title:
    Hypertension as a potential biomarker of efficacy in patients with gastrointestinal stromal tumor treated with sunitinib.
    Source:
    Ann Oncol 23 (12) (art.no.mds179), 3180-3187 (2012)
  • Author:
    MacLeod SH; ElGadi MM; Bossi G; Sankar U; Pisio A; Agopsowicz K; Sharon D; Graham FL; Hitt MM
    Title:
    HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice.
    Source:
  • Author:
    Mross K; Dittrich C; Aulizky WE; Strumberg D; Schutte J; Schmid RM; Hollerbach S; Merger M; Munzert G; Fleischer F; Scheulen ME
    Title:
    A randomised phase II trial of the polo-like kinase inhibitor BI 2536 in chemo-nave patients with unresectable exocrine adenocarcinoma of the pancreas-a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.
    Source:
    Br J Cancer 107 (2), 280-286 (2012)
    Abstract:
    Background: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. Methods: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating =2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control =12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). Results: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). Conclusion: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population
  • Author:
    Arrieta O; Campos-Parra AD; Zuloaga C; Aviles A; Sanchez-Reyes R; Manriquez MEV; Covian-Molina E; Martinez-Barrera L; Meneses A; Cardona A; Borbolla-Escoboza JR
    Title:
    Clinical and pathological characteristics, outcome and mutational profiles regarding non-small-cell lung cancer related to wood-smoke exposure.
    Source:
    J Thorac Oncol 7 (8), 1228-1234 (2012)
    Abstract:
    HYPOTHESIS:: Although smoking is the major risk factor for non-small-cell lung cancer (NSCLC), other factors are also associated with lung carcinogenesis, such as wood-smoke exposure (WSE). This article has been aimed at suggesting that lung cancer related to cigarette smoking and lung cancer related to WSE have different clinical and genetic characteristics. EXPERIMENTAL DESIGN:: A cohort of 914 lung cancer patients was prospectively studied; they had been treated at Mexico's National Cancer Institute between 2007 and 2010. The associations of WSE and cigarette smoking with clinical characteristics, mutation profile, response to chemotherapy, and epidermal growth factor receptor tyrosine kinase inhibitors were analyzed, and overall survival (OS) rate was calculated. The trial was registered with ClinicalTrials.gov: NCT01023828. RESULTS:: Of the lung cancer patients studied, 95.1% were classified as coming within the NSCLC histology subtype; 58% of the patients smoked cigarettes, 35% had a background of WSE (exposure to both cigarette smoke and wood smoke was documented in 12.1% of all patients), and 19.4% patients had no smoke-exposure background. WSE was associated with NSCLC and adenocarcinoma histology, and was also more frequently associated with epidermal growth factor receptor-mutations than cigarette-smoking patients were (50.0% cf. 19.4%), whereas KRAS mutations were less common in WSE patients (6.7%) than in smokers (21%). WSE patients had a higher epidermal growth factor receptor tyrosine kinase inhibitor response rate (39.7%) than smokers (18.8%). The NSCLC patient WSE group's OS was longer (22.7 months) than that for smokers (13.8 months). CONCLUSION:: NSCLC patients who smoked tobacco/cigarettes differed from those having a background of WSE regarding tumor histology, mutation profile, response rate, and OS, indicating that different carcinogenic mechanisms were induced by these two types of smoke exposure.
  • Author:
    Schuler M; Awada A; Harter P; Canon JL; Possinger K; Schmidt M; De Greve J; Neven P; Dirix L; Jonat W; Beckmann MW; Schuette J; Fasching PA; Gottschalk N; Besse-Hammer T; Fleischer F; Wind S; Uttenreuther-Fischer M; Piccart M; Harbeck N
    Title:
    A phase II trial to assess efficacy and safety to afatinib in extensively pretreated patients in HER2-negative metastatic breast cancer.
    Source:
    Breast Cancer Res Treat 134 (3), 1149-1159 (2012)
    Abstract:
    Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for =4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for =4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9-47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract. © 2012 The Author(s).
  • Author:
    Miller VA; Hirsh V; Cadranel J; Chen Y-M; Park K; Kim S-W; Zhou C; Su W-C; Wang M; Sun Y; Heo DS; Crino L; Tan E-H; Chao T-Y; Shahidi M; Cong XJ; Lorence RM; Yang JCH
    Title:
    Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial.
    Source:
    Lancet Oncol 13 (5), 528-538 (2012)
    Abstract:
    Background: Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. Methods: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136. Findings: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group. Interpretation: Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment. Funding: Boehringer Ingelheim Inc. © 2012 Elsevier Ltd. |
  • Author:
    Yang JCH; Shih J-Y; Su W-C; Hsia T-C; Tsai C-M; Ou SHI; Yu C-J; Chang G-C; Ho C-L; Sequist LV; Dudek AZ; Shahidi M; Cong XJ; Lorence RM; Yang P-C; Miller VA
    Title:
    Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): A phase 2 trial.
    Source:
    Lancet Oncol 13 (5), 539-548 (2012)
    Abstract:
    Background: Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations. Methods: In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148. Findings: 129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease). Interpretation: Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC. Funding: Boehringer Ingelheim Inc. © 2012 Elsevier Ltd
  • Author:
    Thomssen C; Gnant M; Harbeck N; Dethling J; Langenfeld M; Mueser M; Muth M; Rieth A; Sperber T; Wilhelm O G; Zaun S
    Title:
    Current research of the pharmaceutical industry.
    Source:
    Breast Care 7 (2), 155-164 (2012)
  • Author:
    Pinn S
    Title:
    New drug therapies, dedicated specialists and desperately-ill patients - but who will fly the flag for service developments in lung cancer as NHS budgets come under pressure?
    Source:
    Source:
    Ecancermedicalscience 5 (1) art.no.209 (2012)
  • Author:
    Doebele R C; Conkling P; Traynor A M; Otterson G A; Zhao Y; Wind S; Stopfer P; Kaiser R; Camidge D R
    Title:
    A phase I, open-label dose-escalation study of continuous treatment with bibf 1120 in combination with paclitaxel and carboplatin as first-line treatment in patients with advanced non-small-cell lung cancer
    Source:
    Ann Oncol 23 (8), 2094-2102 (2012)
    Abstract:
    Abstract Background: BIBF 1120 is an oral potent inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor, the three key receptor families involved in angiogenesis. This phase I, open-label dose-escalation study investigated BIBF 1120 combined with paclitaxel (Taxol) and carboplatin in first-line patients with advanced (IIIB/IV) non-small-cell lung cancer. Patients and methods: Patients received BIBF 1120 (starting dose 50 mg b.i.d.) on days 2-21 and paclitaxel (200 mg/m 2) and carboplatin [area under curve (AUC) = 6 mg/ml/min] on day 1 of each 21-day cycle. Primary end points were safety and BIBF 1120 maximum tolerated dose (MTD) in this combination. Pharmacokinetics (PK) profiles were evaluated. Results: Twenty-six patients were treated (BIBF 1120 50-250 mg b.i.d.). BIBF 1120 MTD was 200 mg b.i.d. in combination with paclitaxel and carboplatin. Six dose-limiting toxicity events occurred during treatment cycle 1 (liver enzyme elevations, thrombocytopenia, abdominal pain, and rash). Best responses included 7 confirmed partial responses (26.9%); 10 patients had stable disease. BIBF 1120 200 mg b.i.d. had no clinically relevant influence on the PK of paclitaxel 200 mg/m 2and carboplatin AUC 6 mg/ml/min and vice versa. Conclusions: BIBF 1120 MTD was 200 mg b.i.d when given with paclitaxel and carboplatin; this combination demonstrated an acceptable safety profile. No relevant changes in PK parameters of the backbone chemotherapeutic agents or BIBF 1120 were observed. © the Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved
  • Author:
    Frost A; Mross K; Steinbild S; Hedborn S; Unger C; Kaiser R; Trommeshauser D; Munzert G
    Title:
    Phase I study of the PK1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumours.
    Source:
    Curr Oncol 19 (1), 28-35 (2012)
  • Author:
    Bridges JFP; Mohamed AF; Finnern AW; Woehl A; Hauber A
    Title:
    Patients' preferences for treatment outcomes for advanced non-small cell lung cancer: A conjoint analysis.
    Source:
    Lung Cancer (Neth) Article in Press (2012)
  • Author:
    Eberl M; Klingler S; Mangelberger D; Loipetzberger A; Damhofer H; Zoidl K; Schnidar H; Hache H; Bauer H-C; Solca F; Hauser-Kronberger C; Ermilov AN; Verhaegen ME; Bichakjian CK; Dlugosz AA; Nietfeld W; Sibilia M; Lehrach H; Wierling C; Aberger F
    Title:
    Hedehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells.
    Source:
    EMBO Mol Med 4 (3), 218-233 (2012)
  • Author:
    Lin NU; Winer EP; Wheatley D; Carey LA; Houston S; Mendelson D; Munster P; Frakes L; Kelly S; Garcia AA; Cleator S; Uttenreuther-Fischer M; Jones H; Wind S; Vinisko R; Hickish T
    Title:
    A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab.
    Source:
    Breast Cancer Res Treat 133 (3), 1057-1065 (2012)
    Abstract:
    Afatinib is an oral, ErbB family blocker, which covalently binds and irreversibly blocks all kinase-compe-tent ErbB family members. This phase II, open-label, singlearm study explored afatinib activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients progressing after trastuzumab treatment. Patients had stage IIIB/IV HER2-positive metastatic breast cancer, with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received 50 mg afatinib once-daily until disease progression. Primary endpoint was objective response rate (Response Evaluation Criteria in Solid Tumors 1.0), with tumor assessments every 8 weeks. Forty-one patients were treated. Patients had received a median of three prior chemotherapy lines (range, 0-15) and 68.3% had received trastuzumab for >1 year.Four patients (10% of 41 treated; 11% of evaluable patients) had partial response. Fifteen patients (37% of 41) had stable disease as best response and 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks (95% confidence interval [CI]: 8.1-16.7); median overall survival was 61.0 weeks (95% CI: 56.7-not evaluable). Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea (24.4%) and rash (9.8%). Afatinib monotherapy was associated with promising clinical activity in extensively pretreated HER2-positive breast cancer patients who had progressed following trastuzumab treatment.
  • Author:
    Shi J; Wang E; Zuber J; Rappaport A; Taylor M; Johns C; Lowe SW; Vakoc CR
    Title:
    The polycomp complex PRC2 supports aberrant self-renewal in a mouse model of MLL-AF9:Nras G12D acute myeloid leukemia.
    Source:
    Oncogene Article in Press (2012)
  • Author:
    Frost A; Mross K; Steinbild S; Hedborn S; Unger C; Kaiser R; Trommeshauser D; Munzert G
    Title:
    Phase I study of the Plk1 inhibitor BI 2536 administered intravenously on three consecutive days in advanced solid tumors.
    Source:
    Curr Oncol 19 (1), 28-35 (2012)
    Abstract:
    Background This open-label phase i study with an accelerated titration design was performed to determine the maximum tolerated dose of BI 2536, a potent, highly selective small-molecule polo-like kinase 1 (Plk1) inhibitor. Methods Patients with advanced solid tumours received a single 60-minute intravenous infusion of BI 2536 (50-70 mg) on days 1-3 of each 21-day treatment course. Recipients without disease progression or untenable toxicity could receive additional treatment courses. The maximum tolerated dose was determined based on dose-limiting toxicities. Other assessments included safety, pharmacokinetic profile, and antitumour activity according to the Response Evaluation Criteria in Solid Tumors. Results The study enrolled 21 patients. The maximum tolerated dose for BI 2536 was determined to be 60 mg for the study schedule. Dose-limiting toxicities included hematologic events, hypertension, elevated liver enzymes, and fatigue. The most frequently reported drug-related adverse events were mild-to-moderate fatigue, leukopenia, constipation, nausea, mucosal inflammation, anorexia, and alopecia. The pharmacokinetics of BI 2536 were linear within the dose range tested. Plasma concentration profiles exhibited multi compartmental pharmacokinetic behaviour, with a terminal elimination half-life of 20-30 hours. Conclusions In the present study, BI 2536 showed an acceptable safety profile warranting further investigation of Plk1 inhibitors in this patient population.
  • Author:
    Glaser SP; Lee EF; Trounson E; Bouillet P; Wei A; Fairlie WD; Izon DJ; Zuber J; Rappaport AR; Herold MJ; Alexander WS; Lowe SW; Robb L; Strasser A
    Title:
    Anti-apoptotic mcl-1 is essential for the development and sustained growth of acute myeloid leukemia.
    Source:
    Genes Dev 26 (2), 120-125 (2012)
    Abstract:
    Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-x L and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-x L, Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML.
  • Author:
    Lavila-Alonso S; Bauer MMT; Abo-Ramadan U; Ristimaeki A; Halavaara J; Desmond RA; Wang D; Escutenaire S; Ahtiainen L; Saksela K; Tatlisumak T; Hemminki A; Pesonen S
    Title:
    Macrophage metalloelastase (MME) as adjuvant for intra-tumoral injection of oncolytic adenovirus and its influence on metastases development.
    Source:
    Cancer Gene Ther 19 (2), 126-134 (2012)
  • Author:
    Adrian C; Zettl M; Christova Y; Freeman M; Taylor M
    Title:
    Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.
    Source:
    Science 335 (6065), 225-228 (2012)
  • Author:
    Murakami H; Tamura T; Takahashi T; Nokihara H; Naito T; Nakamura Y; Nishio K; Seki Y; Sarashina A; Shahidi M; Yamamoto N
    Title:
    Phase I study of contiunous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitnib (LUX-Lung 4).
    Source:
    Cancer Chemother Pharmacol 69 (4), 891-899 (2012)
    Abstract:
    Purpose: This Phase I study determined the maximum-tolerated dose (MTD) of afatinib (Afatinib is an investigational compound and its safety and efficacy have not yet been established) (BIBW 2992; trade name not yet approved by FDA), an irreversible inhibitor of epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER)1 and 2, up to a dose of 50 mg/day in advanced non-small cell lung cancer (NSCLC), to establish the recommended dose for Phase II. Methods: Patients with advanced NSCLC who had received prior platinum-doublet chemotherapy and/or erlotinib/gefitinib therapy, or who were ineligible for, or not amenable to, treatment with established therapies, received oral afatinib once daily. The MTD was determined based on dose-limiting toxicities (DLTs); other assessments included safety, pharmacokinetic profile, antitumour activity according to response evaluation criteria in solid tumours and EGFR/HER1 mutation analysis where possible. Results: Twelve evaluable patients were treated at doses of 20-50 mg/day. One DLT was observed at 50 mg/day in Course 1 (Grade 3 mucositis). The most frequent drug-related adverse events were diarrhoea, dry skin, stomatitis, rash, paronychia and anorexia; most were Grade 1 or 2. Six out of 12 patients had tumour size reductions; durable stable disease was achieved in three patients including one with EGFR/HER1 exon 19 and T790 M mutations. Peak plasma concentrations of afatinib were reached 3-4 h after administration and declined with a half-life of 30-40 h. Afatinib 50 mg/day was well tolerated with an acceptable safety profile during Phase I. Conclusion: Recommended dose for Phase II was defined as 50 mg/day for Japanese patients; the same as for non-Japanese patients.
  • Author:
    Gurtner K; Hessel F; Eicheler W; Doerfler A; Zips D; Heider K-H; Krause M; Baumann M
    Title:
    Combined treatment of the immunoconjgate bivatuzumab mertansine and fractionated irradiation improves local tumour control in vivo.
    Source:
    Radiother Oncol 102 (3), 444-449 (2012)
    Abstract:
    Background and purpose: To test whether BIWI 1 (bivatuzumab mertansine), an immunoconjugate of the humanized anti-CD44v6 monoclonal antibody BIWA 4 and the maytansinoid DM1, given simultaneously to fractionated irradiation improves local tumour control in vivo compared with irradiation alone. Material and methods: For growth delay, FaDu tumours were treated with 5 intravenous injections (daily) of phosphate buffered saline (PBS, control), BIWA 4 (monoclonal antibody against CD44v6) or BIWI 1 (bivatuzumab mertansine) at two different dose levels (50 ?g/kg DM1 and 100 ?g/kg DM1). For local tumour control, FaDu tumours received fractionated irradiation (5f/5d) with simultaneous PBS, BIWA 4 or BIWI 1 (two dose levels). Results: BIWI 1 significantly improved local tumour control after irradiation with 5 fractions already in the lower concentration. The dose modifying factor of 1.9 is substantial compared to the majority of other modifiers of radiation response. Conclusion: Because of the magnitude of the curative effect, this approach is highly promising and should be further evaluated using similar combinations with improved tumour-specificity.
  • Author:
    Lavilla-Alonso S; Bauer MMT; Abo-Ramadan U; Ristimaeki A; Halavaara J; Desmond RA; Wang D; Escutenaire S; Ahtiainen L; Saksela K; Tatlisumak T; Hemminki A; Pesonen S
    Title:
    Macrophage metalloelastase (MME) as adjuvant for intra-tumoral injection of oncolytic adenovirus and its influence on metastases development.
    Source:
    Cancer Gene Ther 19 (2), 126-134 (2012)
    Abstract:
    Oncolytic adenoviruses are a promising treatment alternative for many advanced cancers, including colorectal cancer. However, clinical trials have demonstrated that single-agent therapy in advanced tumor masses is rarely curative. Poor spreading of the virus through tumor tissue is one of the major issues limiting efficacy. As oncolytic viruses kill preferentially cancer cells, high extracellular matrix (ECM) content constitutes potential barriers for viral penetration within tumors. In this study, the ECM-degrading proteases relaxin, hyaluronidase, elastase and macrophage metalloelastase (MME) were tested for their antitumor efficacy alone and in combination with oncolytic adenovirus. MME improved the overall antitumor efficacy of oncolytic adenovirus in subcutaneous HCT116 xenografts. In a liver metastatic colorectal cancer model, intra-tumoral treatment of primary tumors from HT29 cells with MME monotherapy or with oncolytic adenovirus inhibited tumor growth. Combination therapy showed no increased mortality in comparison with either monotherapy alone. Contradictory results of effects of MME on tumorigenesis and metastasis formation have been reported in the literature. This study demonstrates for the first time in a metastatic animal model that MME, as a monotherapy or in combination with oncolytic virus, does not increase tumor invasiveness. Co-administration of MME and oncolytic adenovirus may be a suitable approach for further optimization aiming at clinical applications for metastatic colorectal cancer.
  • Author:
    Schoeffski P; Awada A; Dumez H; Gil T; Bartholomeus S; Wolter P; Toton M; Fritsch A; Glomb P; Munzert G
    Title:
    A phase 1 dose-escalation study of the novel Polo-like kinased inhibitor volasertib (BI 6727) in patients with advanced solid tumours.
    Source:
    Eur J Cancer 48 (2), 179-186 (2012)
    Abstract:
    Background: Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). This phase I dose-escalation study evaluated the maximum tolerated dose (MTD) of volasertib, safety and efficacy, and pharmacokinetic (PK) parameters. Methods: This trial followed an open-label, toxicity-guided dose-titration design. Patients with progressive advanced or metastatic solid tumours received a single 1-h infusion of volasertib every 3 weeks. A total of 65 patients were treated at doses of 12-450 mg. Results: Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3: 8%), neutropenia (15%; grade 3/4: 14%), fatigue (15%; grade 3: 2%), and thrombocytopenia (14%; grade 3/4: 14%) were the most frequent drug-related adverse events. The MTD was 400 mg; however, 300 mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1 year. PK analysis showed no indication of deviation from 'dose-linear PK' behaviour, a large volume of distribution (>4000 l), moderate clearance and a long half-life (?111 h). Conclusion: This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing.
  • Author:
    Birk M; Buerkle A; Pekari K; Maier T; Schmidt M
    Title:
    Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents.
    Source:
    Int J Cancer 130 (4), 798-807 (2012)
    Abstract:
    The mitotic spindle checkpoint (SPC) is a highly regulated mechanism in eukaryotic cells that ensures the even distribution of the duplicated genome between daughter cells. Malfunction of the SPC or deregulated expression of SPC regulatory proteins is frequently associated with a poor response to chemotherapeutic agents. We investigated various approved and investigational mitosis-specific agents, including spindle poisons, an Eg5 kinesin inhibitor, inhibitors of polo-like kinase 1 (Plk1) or Aurora-B kinase, a benzamide class HDAC inhibitor and compounds identified in a chemical genetics screen for their cell cycle-dependent cytotoxicities and for their activities toward SPC deficient (HT29, Caco-2, T47D) and SPC proficient human cell lines (A2780, HCT116, SW480). Using the RKOp27 cell system that allows inducible cell cycle arrest by the tunable expression of the cdk inhibitor p27Kip1, we found an exquisite proliferation-dependent cytotoxicity for all compounds except the aurora kinase inhibitor VX-680. Cytotoxicity of the antimitotic compounds was in general higher on SPC proficient than on deficient cells. We found two exceptions, a benzamide HDAC inhibitor which was effective on SPC proficient and deficient cells and an investigational compound, BYK72767, with a yet unknown mode of action. The degree of increased mitotic index was no predictor of cytotoxicity of the compounds nor was the phosphorylation of BubR1. However, SPC deficient cell lines were able to tolerate mitotic arrest for far longer times than SPC proficient cells. We conclude that targeting of SPC deficient cancers with novel antimitotic principles remains a challenge but certain drug classes may be equally efficacious regardless of SPC status.