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Peter Stopfer – One of the best experts on this subject based on the ideXlab platform.

  • Clinical Pharmacokinetics and Pharmacodynamics of Afatinib
    Clinical Pharmacokinetics, 2017
    Co-Authors: Sven Wind, David Schnell, Matthias Freiwald, Thomas Ebner, Peter Stopfer
    Abstract:

    Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily Afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of Afatinib are reached approximately 2–5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to Afatinib. Over the clinical dose range of 20–50 mg, Afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug Afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration–time curve (AUC) after multiple dosing. The pharmacokinetic profile of Afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on Afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to Afatinib. Renal function is correlated with Afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in Afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug–drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycglycoprotein transporter can affect the pharmacokinetics of Afatinib. At a dose of 50 mg, Afatinib does not have proarrhythmic potential.

  • Pharmacokinetics of Afatinib in subjects with mild or moderate hepatic impairment
    Cancer Chemotherapy and Pharmacology, 2014
    Co-Authors: David Schnell, Susanne Buschke, Holger Fuchs, Dietmar Gansser, Rainer-georg Goeldner, Martina Uttenreuther-fischer, Peter Stopfer, Sven Wind, Marc Petersen-sylla, Atef Halabi
    Abstract:

    Afatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-hepatic system. This trial assessed whether mild or moderate hepatic impairment influences the pharmacokinetics of Afatinib. This was an open-label single-dose study. Pharmacokinetic parameters after Afatinib 50 mg were investigated in subjects with mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh A and B) and healthy controls (n = 16) matched for age, weight and gender. Plasma and urine samples for pharmacokinetic assessment were collected before and up to 10 days after dosing. Additional blood samples were drawn to determine ex vivo plasma protproteinding of Afatinib. Primary endpoints were comparisons of Afatinib C max and AUC0–∞ between subjects with hepatic impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and C max of Afatinib. Afatinib pharmacokinetic profiles and plasma protproteinding were similar in subjects with impaired liver function and healthy controls. Compared with matched controls, the Afatinib-adjusted geometric mean ratio for AUC0–∞ was 92.6 % (90 % CI 68.0–126.3 %) and C max was 109.5 % (90 % CI 82.7–144.9 %) for subjects with mild hepatic impairment, and 94.9 % (90 % CI 72.3–124.5 %) and 126.9 % (90 % CI 86.0–187.2 %), respectively, for subjects with moderate hepatic impairment. For all parameters, the 90 % CI included 100 %. Afatinib was generally well tolerated with no serious adverse events reported. Mild to moderate hepatic impairment had no clinically relevant effect on the pharmacokinetics of a single 50 mg dose of Afatinib, implying that adjustments to the starting dose of Afatinib are not considered necessary in this patient population.

  • Pharmacokinetic Drug Interactions of Afatinib with Rifampicin and Ritonavir
    Clinical Drug Investigation, 2014
    Co-Authors: Sven Wind, Dietmar Gansser, Thomas Giessmann, Arvid Jungnik, Tobias Brand, Kristell Marzin, Julia Bertulis, Julia Hocke, Peter Stopfer
    Abstract:

    Background and Objective Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of advanced non-small cell lung cancer, metastatic head and neck cancer, and other solid tumours. As Afatinib is a substrate for the P-glycglycoprotein (P-gp) pump transporter the three studies presented here investigated the pharmacokinetics of Afatinib in the presence of a potent inhibitor (ritonavir) or inducer [rifampicin (rifampin)] of P-gp. Methods We conducted phase I, open-label, single-centre studies in healthy male volunteers who received a single once-daily oral dose of Afatinib (20 or 40 mg) together with either ritonavir or rifampicin; two studies had a randomised, two- and three-way crossover design and the third was a non-randomised, two-period sequential study. Results When Afatinib 20 mg was administered 1 h after ritonavir, Afatinib geometric mean (gMean) maximum plasma concentration ( C _max) and area under the plasma concentration–time curve from time zero to infinity (AUC_∞) increased by 38.5 and 47.6 %, respectively. Coadministration of ritonavir either simultaneously or 6 h later than Afatinib 40 mg resulted in minimal increase in the Afatinib gMean C _max and AUC_∞ (4.1 and 18.6 % for simultaneous administration with AUC_∞ not completely within the bioequivalence limits; 5.1 and 10.8 % for timed administration within the bioequivalence limits). Administration of Afatinib 40 mg in the presence of rifampicin led to reduction in C _max and AUC_∞ by 21.6 and 33.8 %, respectively. In all studies, P-gp modulation mainly affected the extent of absorption of Afatinib; there was no change in the terminal elimination half-life. The overall safety profile of Afatinib was acceptable. Conclusion Coadministration of potent P-gp modulators had no clinically relevant effect on Afatinib exposure. Effects of potent P-gp inhibitors were minimal at higher Afatinib doses and can be readily managed by the timing of concomitant therapy. As Afatinib is not a relevant modulator or substrate of cytochrome P450 enzymes, the drug–drug interaction potential is considered to be low.

James Chih-hsin Yang – One of the best experts on this subject based on the ideXlab platform.

  • First-line Afatinib for the treatment of mutation-positive non-small-cell lung cancer in the ‘real-world’ clinical setting
    SAGE Publishing, 2019
    Co-Authors: Keunchil Park, Darren Wan-teck Lim, Isamu Okamoto, James Chih-hsin Yang
    Abstract:

    Afatinib is an ErbB family blocker that is approved for the treatment of epidermal growth factor receptor ( EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Pivotal randomized clinical studies demonstrated that Afatinib significantly prolonged progression-free survival compared with platinum-based chemotherapy (LUX-Lung 3, LUX-Lung 6), and with gefitinib (LUX-Lung 7), with manageable side effects. However, these results were derived from controlled studies conducted in selected patients and are not necessarily representative of real-world use of Afatinib. To gain a broader understanding of the effectiveness and safety of first-line Afatinib, we have undertaken a literature review of real-world studies that have assessed its use in a variety of patient populations. We focused on patients with uncommon EGFR mutations, brain metastases, or those of advanced age, as these patients are often excluded from clinical studies but are regularly seen in routine clinical practice. The available real-world studies suggest that Afatinib has clinical activity, and is tolerable, in diverse patient populations in an everyday clinical practice setting. Moreover, consistent with LUX-Lung 7, several real-world comparative studies indicate that Afatinib might confer better efficacy than first-generation EGFR tyrosine kinase inhibitors. Tolerability-guided dose adjustment, undertaken in 21–68% of patients in clinical practice, did not appear to reduce the efficacy of Afatinib. Taken together, these findings provide further support for the use of Afatinib as a treatment option in patients with EGFR mutation-positive NSCLC

  • Afatinib versus gefitinib in patients with egfr mutation positive advanced non small cell lung cancer overall survival data from the phase iib lux lung 7 trial
    Annals of Oncology, 2017
    Co-Authors: L Pazares, Vera Hirsh, Ki Hyeong Lee, James Chih-hsin Yang, Kenneth J Obyrne, Tony Mok, Eng Huat Tan, Li Zhang, Michael Boyer, Yuankai Shi
    Abstract:

    ABSTRACT Background In LUX-Lung 7, the irreversible ErbB family blocker, Afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data. Patients and methods LUX-Lung 7 assessed Afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naive patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases. Results Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (Afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (Afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (Afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of Afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with Afatinib. Conclusion In LUX-Lung 7, there was no significant difference in OS with Afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with Afatinib. Clinicaltrials.gov identifier NCT01466660.

  • Novel EGFR Inhibitors in Non-small Cell Lung Cancer: Current Status of Afatinib.
    Current oncology reports, 2017
    Co-Authors: Bin-chi Liao, Chia-chi Lin, James Chih-hsin Yang
    Abstract:

    Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been approved worldwide as a first-line treatment for advanced non-small cell lung cancer (NSCLC) that harbors activating EGFR mutations. Here, we have reviewed the recent clinical developments in the treatment of lung cancer using Afatinib. Emerging data have revealed the overall survival benefit of first-line Afatinib therapy in patients with advanced EGFR del19-positive NSCLC. Phase III studies of Afatinib have shown the effectiveness of Afatinib as a second-line treatment for advanced lung squamous cell carcinoma, as well as the benefit of continuing Afatinib therapy in combination with cytotoxic chemotherapy for advanced NSCLC after the occurrence of disease progprogression in patients who are receiving Afatinib monotherapy. Therapeutic benefits of Afatinib have also been reported in studies of patients with central nervous system metastasis and patients with HER2 mutation. The utility of Afatinib-based combination therapies is being investigated in ongoing research.

Sok Ching Cheong – One of the best experts on this subject based on the ideXlab platform.

  • Synergistic Growth Inhibition by Afatinib and Trametinib in Preclinical Oral Squamous Cell Carcinoma Models
    Targeted Oncology, 2019
    Co-Authors: Pei San Yee, Nur Syafinaz Zainal, Chai Phei Gan, Bernard K. B. Lee, Kein Seong Mun, Mannil Thomas Abraham, Siti Mazlipah Ismail, Zainal Ariff Abdul Rahman, Vyomesh Patel, Sok Ching Cheong
    Abstract:

    BackgroundGiven that aberrant activation of epidermal growth factor recereceptor family receptors (ErbB) is a common event in oral squamous cell carcinoma, and that high expression of these receptor proteins is often associated with poor prognosis, this rationalizes the approach of targeting ErbB signaling pathways to improve the survival of patients with oral squamous cell carcinoma. However, monotherapy with the ErbB blocker Afatinib has shown limited survival benefits.ObjectivesThis study was performed to identify mechanisms of Afatinib resistance and to explore potential Afatinib-based combination treatments with other targeted inhibitors in oral squamous cell carcinoma.MethodsWe determined the anti-proliferative effects of Afatinib on a panel of oral squamous cell carcinoma cell lines using a crystal violetgrowth inhibition assay, click-iT 5-ethynyl-2′-deoxyuridine staining, and cell-cyclcycle analysis. Biochemical assays were performed to study the underlying mechanism of drug treatment as a single agent or in combination with the MEK inhiinhibitor trametinib. We further evaluated and compared the anti-tumor effects of single agent and combined treatment by using oral squamous cell carcinoma xenograft models.ResultsIn this study, we showed that Afatinib inhibited oral squamous cell carcinoma cell proliferation via cell-cycle arrest at the G0/G1 phase, and inhibited tumor growth in xenograft mouse models. Interestingly, we demonstrated reactivation of the mitogen-activated protein kinase (ERK1/2) pathway in vitro, which possibly reduced the effects of ErbB inhibition. Concomitant treatment of oral squamous cell carcinoma cells with Afatinib and trametinib synergized the anti-tumor effects in oral squamous cell carcinoma-bearing mouse models.ConclusionsOur findings provide insight into the molecular mechanism of resistance to Afatinib and support further clinical evaluation into the combination of Afatinib and MEK inhibition in the treatment of oral squamous cell carcinoma.

Sven Wind – One of the best experts on this subject based on the ideXlab platform.

  • Clinical Pharmacokinetics and Pharmacodynamics of Afatinib
    Clinical Pharmacokinetics, 2017
    Co-Authors: Sven Wind, David Schnell, Matthias Freiwald, Thomas Ebner, Peter Stopfer
    Abstract:

    Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily Afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of Afatinib are reached approximately 2–5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to Afatinib. Over the clinical dose range of 20–50 mg, Afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug Afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5- to 3.4-fold based on area under the plasma concentration–time curve (AUC) after multiple dosing. The pharmacokinetic profile of Afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on Afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to Afatinib. Renal function is correlated with Afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in Afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug–drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of Afatinib. At a dose of 50 mg, Afatinib does not have proarrhythmic potential.

  • A phase II study of Afatinib, an irreversible ErbB family blocker, added to letrozole in patients with estrogen receptor-positive hormone-refractory metastatic breast cancer progressing on letrozole
    SpringerPlus, 2016
    Co-Authors: Katharina Gunzer, Martina Uttenreuther-fischer, Sven Wind, Helene De Mont-serrat, Florence Joly, Jean-marc Ferrero, Joseph Gligorov, Katy Pelling, Guilhem Bousquet, Jean-louis Misset
    Abstract:

    Phase II, open‑label study assessing the efficacy and safety of the ErbB family blocker Afatinib combined with letrozole in estrogen receptor‑positive metastatic breast cancer (MBC) patients who had progressed on letrozole monotherapy. Adult females (N = 28) received oral Afatinib (50 [n = 7], 40 [n = 13] or 30 [n = 8] mg/day) plus letrozole 2.5 mg/day in 28‑day cycles until disease progprogression. Primary endpoint was the progression‑free rate at or after 16 weeks of Afatinib. At 16 weeks, four patients remained on Afatinib without progression; two of these were HER2 negative. Fifteen (54 %) patients had a best response of stable disease according to Response Evaluation Criteria in Solid Tumors. Median progression‑free survival was 60, 107 and 79 days with 50, 40 and 30 mg/day Afatinib, respectively. Diarrhea, asthe‑ nia, rash, mucosal inflammation and nausea were the most frequent adverse events. In this small, exploratory study, Afatinib combined with letrozole was able to induce disease stabilization in 54 % of hormone‑refractory MBC patients previously progressing on letrozole.

  • Pharmacokinetics of Afatinib in subjects with mild or moderate hepatic impairment
    Cancer Chemotherapy and Pharmacology, 2014
    Co-Authors: David Schnell, Susanne Buschke, Holger Fuchs, Dietmar Gansser, Rainer-georg Goeldner, Martina Uttenreuther-fischer, Peter Stopfer, Sven Wind, Marc Petersen-sylla, Atef Halabi
    Abstract:

    Afatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-hepatic system. This trial assessed whether mild or moderate hepatic impairment influences the pharmacokinetics of Afatinib. This was an open-label single-dose study. Pharmacokinetic parameters after Afatinib 50 mg were investigated in subjects with mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh A and B) and healthy controls (n = 16) matched for age, weight and gender. Plasma and urine samples for pharmacokinetic assessment were collected before and up to 10 days after dosing. Additional blood samples were drawn to determine ex vivo plasma protein binding of Afatinib. Primary endpoints were comparisons of Afatinib C max and AUC0–∞ between subjects with hepatic impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and C max of Afatinib. Afatinib pharmacokinetic profiles and plasma protein binding were similar in subjects with impaired liver function and healthy controls. Compared with matched controls, the Afatinib-adjusted geometric mean ratio for AUC0–∞ was 92.6 % (90 % CI 68.0–126.3 %) and C max was 109.5 % (90 % CI 82.7–144.9 %) for subjects with mild hepatic impairment, and 94.9 % (90 % CI 72.3–124.5 %) and 126.9 % (90 % CI 86.0–187.2 %), respectively, for subjects with moderate hepatic impairment. For all parameters, the 90 % CI included 100 %. Afatinib was generally well tolerated with no serious adverse events reported. Mild to moderate hepatic impairment had no clinically relevant effect on the pharmacokinetics of a single 50 mg dose of Afatinib, implying that adjustments to the starting dose of Afatinib are not considered necessary in this patient population.

Ezra E.w. Cohen – One of the best experts on this subject based on the ideXlab platform.

  • Afatinib versus methotrexate in older patients with second line recurrent and or metastatic head and neck squamous cell carcinoma subgroup analysis of the lux head neck 1 trial
    Annals of Oncology, 2016
    Co-Authors: Paul Clement, Ezra E.w. Cohen, T Gauler, Jp Machiels, Robert I Haddad, Jerome Fayette, Lisa Licitra, Makoto Tahara, Didier Cupissol, Juan J Grau
    Abstract:

    Author(s): Clement, PM; Gauler, T; Machiels, JP; Haddad, RI; Fayette, J; Licitra, LF; Tahara, M; Cohen, EEW; Cupissol, D; Grau, JJ; Guigay, J; Caponigro, F; de Castro, G; de Souza Viana, L; Keilholz, U; Del Campo, JM; Cong, XJ; Ehrnrooth, E; Vermorken, JB; LUX-HN Neck 1 (LHN1) trial, Afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates Afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and l65 years.Patients and methodsPatients were randomized (2:1) to 40 mg/day oral Afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed.ResultsOf 483 randomized patients, 27% (83 Afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 Afatinib; 116 methotrexate) l65 years (younger) at study entry. Similar PFS benefit with Afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with Afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with Afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with Afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with Afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with Afatinib was observed in both subgroups.ConclusionsAdvancing age (≥65 years) did not adversely affect clinical outcomes or safety with Afatinib versus methotrexate in second-line R/M HNSCC patients.Clinical trial registrationNCT01345682 (ClinicalTrials.gov).

  • Afatinib efficacy against squamous cell carcinoma of the head and neck cell lines in vitro and in vivo
    Targeted oncology, 2015
    Co-Authors: Natalie R. Young, Christian Soneru, Jing Liu, Tatyana A. Grushko, Ashley Hardeman, Olufunmilayo I. Olopade, Anke Baum, Flavio Solca, Ezra E.w. Cohen
    Abstract:

    Epidermal growth factor receptor (EGFR) inhibitors have demonstrated efficacy in squamous cell carcinoma of the head and neck (SCCHN). In addition to EGFR, other ErbB family members are expressed and activated in SCCHN. Afatinib is an ErbB family blocker that has been approved for treating patients with EGFR-mutated nonsmall cell lung cancer. We sought to determine the efficacy of Afatinib in preclinical models and compare this to other EGFR-targeted agents. Afatinib efficacy was characterized in a panel of ten SCCHN cell lines and found to be most effective against cell lines amplified for EGFR. Afatinib had lower IC50 values than did gefitinib against the same panel. Two EGFR-amplified cell lines that are resistant to gefitinib are sensitive to Afatinib. Cetuximab was not found to have a synergistic effect with Afatinib either in vitro or in vivo. Both Afatinib and cetuximab were effective in tumor xenoxenograft model. Afatinib is an effective agent in SCCHN especially in models with EGFR amplification.