Phase I and Clinical Pharmacology
Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors
T.A.Y. and L.V. contributed equally to this work.
Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy.
Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state.
Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non–small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting ≥ 6 months.
The ErbB receptor tyrosine kinase family, which comprises epidermal growth factor receptor (ErbB1; EGFR; HER1) and human epidermal growth factor receptor 2 to 4 (HER2 to 4), as well as their ligands, are often dysregulated by cancer cells and are a validated target for anticancer therapeutics.1 These receptors homo- and/or heterodimerize, leading to their activation by tyrosine kinase phosphorylation.2 Small molecule reversible inhibitors specific for EGFR have resulted in clinical benefit in some trials, resulting in their regulatory approval.3–6 A broader-spectrum reversible small molecule inhibitor, lapatinib, has also demonstrated activity in HER2-overexpressing breast cancer.7 Resistance to these inhibitors may be a result of insufficient or nonsustained target modulation, narrow receptor specificity and receptor heterodimerization, or the emergence of acquired mutations and alternative signaling pathways.8–10
BIBW 2992 (Appendix Fig A1, Appendix Table A1, online only), an anilino-quinazoline derivative, is a novel, highly selective, potent, and irreversible inhibitor of both EGFR and HER2 kinases.11 The 50% inhibitory concentration (IC50) of BIBW 2992 for the EGFR and HER2 kinases is 0.5 nmol/L and 14 nmol/L, respectively.12 BIBW 2992 has preclinical antitumor activity in several in vivo models.12,13 Irreversible tyrosine kinase blockade may result in longer suppression of ErbB signaling than that resulting from reversible inhibitors.14 Furthermore, because of covalent binding to the tyrosine kinase active site, BIBW 2992 shows potent inhibitory activity in a variety of EGFR mutants including T790M point mutations,12 known to be resistant to first-generation EGFR tyrosine kinase inhibitors (TKIs).
Promising preclinical antitumor activity and toxicology studies led to a phase I dose-escalation study of BIBW 2992 in patients with advanced solid tumors. The primary objectives were to evaluate safety and tolerability, and define dose-limiting toxicities (DLTs) and the maximum-tolerated dose (MTD) of BIBW 2992 when administered in a continuous, once-daily dosing schedule. Previous phase I trials investigating different schedules had shown that BIBW 2992 was well-tolerated.11,15,16 However, the safety of continuous dosing had not been formally assessed. Secondary objectives included pharmacokinetic (PK) evaluation of BIBW 2992, including food-effect studies of this oral agent, and preliminary assessment of antitumor efficacy. The molecular genetic characteristics of responding patients were also explored.
This was a phase I, open-label, dose-escalation study of continuous once-daily oral treatment with BIBW 2992 conducted at two centers (the Royal Marsden NHS Foundation Trust, Sutton and Newcastle General Hospital, Newcastle) in the United Kingdom. Patients with pathologically confirmed solid tumors known to have a high likelihood of expressing EGFR and/or HER2 for whom no proven therapy existed or who were not amenable to established treatments, were eligible. Other eligibility criteria included written informed consent; age ≥ 18 years; Eastern Cooperative Oncology Group performance status ≤ 217; life expectancy ≥ 12 weeks; recovery from previous therapy-related adverse effects to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) grade ≤ 1; adequate bone marrow, renal, and hepatic function and left ventricular ejection fraction (LVEF); no concomitant anticancer or investigational drug; completion of anticancer therapy ≥ 4 weeks before study entry (8 weeks for monoclonal antibodies [eg, trastuzumab]). Patients were excluded if they had an active disorder that could interfere with study drug absorption; untreated or symptomatic brain metastasis; were sexually active and unwilling to use medically acceptable contraception; pregnant or breastfeeding. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guideline and approved by relevant regulatory and independent ethics committees.
BIBW 2992 (Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany) was administered once daily, continuously, in 28-day cycles to fasted patients as 5-mg and 20-mg tablets. The starting dose level was 10 mg/d and subsequently escalated at 100% increments until study drug-related adverse event (AE) of grade ≥ 2, when escalation steps of 50% were employed. Dose escalation followed a standard 3 + 3 design. Cohort expansion to six patients was required if one DLT was reported, and dose escalation would stop if two DLTs were observed in those six patients. The preceding MTD cohort would then be expanded to include ≥ six further patients. Food-effect PK studies were planned for higher doses, with an expansion at the MTD level to further evaluate safety and antitumor activity. Treatment continued until disease progression, patient's withdrawal of consent, patient refusal, ≥ 4 missed doses in a cycle, or treatment delay of longer than 14 days.
The MTD was defined as the highest dose at which ≤ one (17%) of six patients experience DLT during the first 28-day treatment period. A DLT was defined as grade 4 hematologic AE; grade 3/4 nonhematologic AE, including diarrhea, nausea, or vomiting—despite supportive care—of ≥ grade 3, or ≥ grade 2 if longer than 7 days, and worsening left ventricular cardiac or renal function of ≥ grade 2.
Safety evaluations were conducted at baseline, days 1, 2, 8, 15, 22, 27, and 28 of cycle 1, and weekly subsequently. All patients had a history, physical examination, hematology and chemistry profile, ECGs, and urine analyses. All AEs and laboratory variables were assessed using CTCAE version 3.0.
Blood samples were collected for PK analysis at 0.05 hours before and 0.5, 1, 2, 3, 4, 5, 7, 9, and 24 hours after drug administration on day 1 and directly before drug administration on days 8, 15, and 22. An additional 24-hour PK profile was performed in the fourth week of treatment at the same time points. Patients who received repeated treatment cycles had blood samples for determination of trough levels taken directly before drug administration on days 15 and 28.
The effect of food on the PK characteristics of BIBW 2992 was investigated in a cohort of patients. Patients participating in the food-effect part of the study were given BIBW 2992 either after fasting or directly after receiving a high-fat, high-calorific breakfast meal (based on the US Food and Drug Administration guidance for industry food-effect bioavailability and fed bioequivalence studies). PK sampling then took place on day −14 and day 1, to allow a wash-out period of 14 days. The PK sampling times were 0.05 hours before, and 0.5, 1, 2, 3, 4, 5, 7, 9, 24, 32, and 48 hours after drug administration. If patients received repeated treatment cycles, samples for trough levels were taken before drug administration on days 15 and 28.
Plasma samples were stored at −20°C. Plasma concentrations of BIBW 2992 were analyzed by validated high-performance liquid chromatography– tandem mass spectrometry methods at Boehringer Ingelheim Pharma GmbH & Co. KG. No interference from endogenous compounds was observed. Validation data documented adequate accuracy, precision and specificity of the high-performance liquid chromatography–tandem mass spectrometry assay employed for the study.
Standard noncompartmental methods were used to calculate the PK parameters using WINNonlin (Scientific Consultant, Apex, NC; version 4.1, Pharsight, Mountainview, CA). A comparison of PK parameters (maximum measured concentration of the analyte in plasma [Cmax] and area under the time concentration curve [AUC] 0-∞) was assessed using analysis of variance with data from BIBW 2992 administered under fed and fasted conditions.
Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) every two cycles.18 As appropriate, additional disease evaluations involving serum cancer antigen 125 (CA125) and prostate-specific antigen were assessed according to Gynecologic Cancer Intergroup and Prostate-Specific Antigen Working Group criteria, respectively.19,20 Paraffin-fixed archival tumor material was obtained from all patients achieving a confirmed partial response (PR) for EGFR mutation analysis. DNA was extracted from formalin-fixed paraffin-embedded sections after deparaffinisation after standard protocols. Briefly, individual kinase domain exons were amplified and sequenced using capillary sequencing as previously described.21 Sequencing chromatograms were inspected manually for the presence of mutations.
Fifty-three patients entered the dose-escalation study between November 2004 and March 2007 and all were included in the safety analysis. Dose levels studied were 10 mg/d (n = 3), 20 mg/d (n = 4), 30 mg/d (n = 7), 40 mg/d (n = 26), and 50 mg/d (n = 13). The 40 mg/d dose level included 13 patients enrolled in the food-effect study. Patient characteristics are shown in Table 1.
|Median age, years||56.0|
|ECOG PS at screening|
|All prior therapies†|
Abbreviation: ECOG PS, Eastern Cooperative Oncology Group performance status.
*Patient also had a second primary malignancy of non–small-cell lung carcinoma.
†Includes chemotherapy, radiotherapy, hormone therapy and immunotherapies.
Three DLTs occurred in course 1 of treatment, one each at dose levels of 30, 40, and 50 mg/d. At 30 mg/d, a 56-year-old patient with breast cancer developed CTCAE grade 3 respiratory failure associated with reversible pneumonitis and radiographic infiltrates, which resolved 11 days after drug withdrawal. A 46-year-old patient with non–small-cell lung carcinoma (NSCLC) developed a grade 3 rash at 40 mg/d BIBW 2992, which fully resolved after 71 days of drug discontinuation. In the 50 mg/d cohort, a 56-year-old patient with colorectal cancer developed a grade 3 acneiform rash, which resolved afterdose reduction to 40 mg/d. Although only one DLT in course 1 was reported in the 50 mg/d cohort, no further dose escalation was undertaken in this study. This decision was based on the overall toxicity profile reported, for both course 1 and subsequent courses, in this trial and in other BIBW 2992 phase I trials which had pursued dose levels exceeding 50 mg.11,15,16 An assessment of overall safety data from four BIBW 2992 phase I trials including this study led to the recommended phase II dose (RP2D) of 50 mg/d.
Overall, BIBW 2992 was well-tolerated, with mainly grade 1 to 2 AEs and no grade 4 to 5 AEs observed. Fifty-two patients (98.1%) experienced ≥ one AEs irrespective of relationship to study drug, while 44 patients (83.0%) experienced ≥ one drug-related AEs. Table 2 summarizes all treatment-related AEs observed in the first 28-day cycle and in all treatment cycles by dose level and CTCAE grade. There were 44 patients with 122 drug-related AEs, including gastrointestinal disorders (n = 37 [69.8%]), skin and subcutaneous tissue disorders (n = 39 [73.6%]), and general disorders and administration site conditions (eg, mucosal inflammation and fatigue; n = 15 [28.3%]).
|AEs||Dosage (mg/d) by Grade|
|10 ||20 ||30 ||40 ||50|
|1 ||2 ||1 ||2 ||3 ||1 ||2 ||1 ||2 ||3 ||1 ||2 ||3|
|Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses||Course 1.||All Courses|
|Skin and subcutaneous tissue|
NOTE. No treatment-related grade 3 AEs were observed in the 10- or 30-mg dose cohorts and no treatment-related grade 4-5 AEs were observed during this study.
Abbreviation: AE, adverse event.
Treatment-related diarrhea was reported by 34 patients (64.2%), vomiting by six (11.3%), and nausea by five patients (9.4%), but were generally self-limiting or effectively controlled with antidiarrhea or antiemetic medications. Thirty-nine patients (73.6%) experienced mild drug-related skin AEs (mainly grade 1 to 2). These events included rash (36 [67.9%] patients), dry skin (8 [15.1%]), palmar-planter disorders (4 [7.5%]), and dermatitis acneiform (4 [7.5%]). Of the other drug-related AEs, 10 patients (18.9%) reported grade 1 to 2 mucosal inflammation and four (7.5%) reported fatigue, which was mild in three patients.
A patient with pleural and pericardial effusions experienced a transient and reversible decline in LVEF at the end of treatment cycle 1. This decline in LVEF was not considered drug-associated by the investigators and treatment with BIBW 2992 was not affected.
Geometric mean BIBW 2992 plasma concentration–time profiles after single and multiple dosing are shown in Figure 1. No deviation from dose-proportional behavior was observed over the evaluated dose range. Across doses, the terminal half-life of BIBW 2992 ranged between 21.3 to 27.7 hours on day 1 and 22.3 to 67.0 hours on day 27. Steady-state was reached after 7 days of initiating continuous BIBW 2992 dosing, with no evidence of further drug accumulation or decrease through subsequent cycles. The poor association between apparent total body clearance and both weight and body-surface area justified the fixed oral dosing of BIBW 2992 (Appendix Fig A2, online only). Table 3 summarizes the PK parameters of BIBW 2992 on days 1 and 27 (steady-state) after single and multiple doses, and Appendix Table A2 (online only) presents the PK parameters of drug under fed and fasted conditions. High-fat food intake before single oral BIBW 2992 doses of 40 mg/d significantly altered and decreased drug disposition. Under fed conditions, mean tmax was prolonged (6.90 hours fed; 3.02 hours fasted), Cmax decreased (12.2 ng/mL fed; 24.9 ng/mL fasted), and AUC0-∞ was reduced (414 ng×h/mL fed; 676 ng×h/mL fasted).
|BIBW 2992 Once Daily||Dosage (mg)|
|10 ||20 ||30 ||40 ||50|
|gMean||gCV (%)||gMean||gCV (%)||gMean||gCV (%)||gMean||gCV (%)||gMean||gCV (%)|
|Single dose (days 1 to 2)|
|AUC0-∞, ng × h/mL||109||80.8||208||53.7||263||47.0||662||177||762||94.0|
|Median tmax, h||3.04||2.51||3.00||5.49||5.08|
|Steady state (days 27 to 28)|
|Median tmax,ss, h||3.05||4.17||3.00||2.50||5.00|
|AUCτ,ss, ng × h/mL||66.1||110||360||62.2||438||67.6||968||61.1||598||47.3|
Abbreviations: ss, steady state; gMean, geometric mean; gCV, geometric mean of the coefficient of variation; Cmax, maximum measured concentration of the analyte in plasma; AUC, area under the time concentration curve; tmax, time from dosing to the maximum concentration of the analyte in plasma; t1/2, terminal half-life of the analyte in plasma; Cpre, pre-dose concentration of the analyte in plasma immediately before administration of next dose; Vz/F, apparent volume of distribution during the terminal phase λz after an extravascular dose; CL/F, apparent clearance of the analyte in plasma after extravascular administration.
*n = 4.
†n = 2.
Thirty-four patients had measurable disease by RECIST; five experienced RECIST PRs (three confirmed, two unconfirmed), including four patients with NSCLC and one with esophageal cancer (Fig 2). Three of the patients with NSCLC (1003, 1020, and 1054) had confirmed and sustained PRs to treatment lasting 24, 18, and 34 months, respectively. Two of these patients (1003 and 1020) were female ex-smokers, and their tumors were found to have activating in-frame deletion mutations in the EGFR domain (exon 19). Patient 1003 was a 55-year-old white female ex-smoker with NSCLC who had previously experienced treatment failure with gemcitabine and carboplatin. This patient had an initial confirmed PR with more than 50% tumor regression at the lowest dose level of 10 mg/d of BIBW 2992 (Fig 3A), but relapsed after 14 months with brain metastases. The patient refused radiotherapy to avoid alopecia; therefore, after acquiring local ethics committee permission, she was treated at a higher dose of 40 mg/d of BIBW 2992. After this, the patient experienced a PR of her brain metastases (Fig 3B) and a further PR of her thoracic disease, and received a further 10 months of BIBW 2992. She finally developed progressive disease in her brain again after a total of 24 months on treatment. Patient 1020 was a 67-year-old white ex-smoker with squamous cell carcinoma of the lung who had experienced treatment failure with multiple chemotherapy regimens, including carboplatin, cisplatin, gemcitabine, and vinorelbine. This patient responded to 40 mg/d of BIBW 2992 for 18 months, with a maximum tumor shrinkage of 75.3%. The third NSCLC patient (1054) with a confirmed PR was a 38-year-old male never-smoker with a p.E746_S752>V mutation. He had previously progressed on carboplatin and gemcitabine chemotherapies. This patient responded (61.8% shrinkage) to 40 mg/d of BIBW 2992 and remained on trial for 34 months.
Two patients experienced PRs which were not confirmed by subsequent scans. A white male with esophageal cancer who was treated with 50 mg/d of BIBW 2992, achieved a PR after 4 months, but no further confirmatory tumor assessments were carried out. The second patient with an unconfirmed PR was an Asian female with NSCLC, treated with 40 mg/d BIBW 2992. This patient had a PR after 2 months, but subsequent scans showed RECIST stable disease (SD). This patient remained on treatment for 19 months.
RECIST SD for ≥ 6 months was the best response in seven patients, including patients with advanced mesothelioma, breast, colorectal (n = 2), cervical, and thyroid carcinomas, and adenocarcinoma of unknown primary.
Small molecule (ie, gefitinib, erlotinib, lapatinib) and antibody (eg, trastuzumab, cetuximab, panitumumab) therapeutics directed against ErbB receptors have obtained regulatory approval for the treatment of breast, colorectal, lung, and head and neck squamous cell cancers. Nonetheless, both preclinical and clinical studies support a continued need to develop improved inhibitors of this receptor family. Emerging data indicate that despite disease progression on established ErbB blockers, a population of patients with cancer may still benefit from treatment with novel, improved, ErbB receptor inhibitors. This suggests a continued dependence on, or addiction to, this signaling pathway in these cancers and supports the development of more effective ErbB inhibitors. Specifically, resistance to the first generation small molecule EGFR inhibitors (ie, erlotinib and gefitinib) is associated with the presence of the T790M EGFR mutation, and improved efficacy in the treatment of patients with NSCLC may be achieved with an irreversible kinase inhibitor active against this EGFR mutant. We describe a phase I trial of the continuous, oral administration of an irreversible inhibitor of EGFR and HER2, BIBW 2992, which has been shown in vitro to demonstrate potent growth inhibition in tumors harboring the T790M EGFR mutation.14 This study indicates that this agent is well-tolerated in patients with advanced cancer with satisfactory pharmacologic properties. Importantly, we report durable antitumor activity in different tumor types, including multiple patients with NSCLC, supporting the development of this small molecule in phase III trials in this disease.
The most common AEs observed with continuous oral dosing of BIBW 2992 were gastrointestinal (eg, diarrhea, nausea and vomiting), fatigue, and rash. DLTs were rash in two patients, and reversible dyspnea in another. The most frequent AEs observed are consistent with those associated with first-generation EGFR-specific drugs (eg, erlotinib and gefitinib).22–26 Rash was effectively controlled with systemic antibiotics and topical steroids where necessary, and diarrhea with loperamide. Despite the known expression of HER2 on cardiac myocytes,27 no significant decline in ejection fraction was seen.
Four phase I trials assessing the safety of BIBW 2992 utilizing different schedules were started at the same time.11,15,16 BIBW 2992 was escalated up to 100-mg daily with discontinuous schedules. An increased frequency and severity of drug-related AEs were observed at doses of BIBW 2992 higher than 50-mg daily. These included fatigue, rash, stomatitis/mucositis, nausea, and diarrhea. Dose escalation of BIBW 2992 beyond 50-mg daily in this trial was therefore not pursued and the RP2D was established at 50-mg daily.
PK analysis suggested a dose-proportional relationship over the dose range tested. Trough BIBW 2992 concentrations at steady-state were above concentrations known to inhibit EGFR and HER2 in vitro.12 All PK parameters displayed moderate to high variability within the expected range for orally administered EGFR TKIs (eg, lapatinib,28 erlotinib,29 and gefitinib).30 The terminal elimination half-life of BIBW 2992 determined was suitable for once-daily dosing. The poor association of drug clearance parameters with weight and surface area supports fixed drug dose administration. There was reduced drug absorption with food intake, suggesting that BIBW 2992 is best administered under fasting conditions.
Robust evidence of antitumor activity was reported, including four patients with NSCLC and another with esophageal cancer. Sequencing of tumor DNA for two of the NSCLC responders revealed in-frame exon 19 EGFR deletion mutations in each. These tyrosine kinase domain mutations have previously been described, and are associated with response to the first-generation EGFR inhibitors erlotinib and gefitinib.31 Although none of the patients treated in this study were resistant to erlotinib or displayed the T790M mutation, acquired resistance to first-generation EGFR inhibitors in NSCLC is commonly associated with the emergence of a T790M missense mutation,32 which is detectable in a subpopulation of cells in some tumors even before treatment with an EGFR inhibitor.33 The ability of BIBW 2992 to inhibit the growth of cells exhibiting the T790M mutant EGFR, 12 indicates that this agent deserves further evaluation in this disease setting in both EGFR inhibitor–naive and –resistant patients. Preliminary reports indicate that BIBW 2992 has promising antitumor activity in patients with EGFR mutation–positive, EGFR inhibitor–naive NSCLC.34 Pivotal phase III trials of BIBW 2992 are now ongoing for the treatment of patients with NSCLC.
In conclusion, BIBW 2992 is well-tolerated when administered orally, once-daily continuously at the RP2D of 50 mg, with promising antitumor activity in multiple tumor types. Further studies evaluating this agent's antitumor activity are ongoing in multiple disease types, including clinical trials in NSCLC patients experiencing treatment failure with reversible EGFR TKIs and in patients with tumors harboring EGFR-activating mutations.
Supported by Boehringer Ingelheim; the Drug Development Unit of the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research is supported in part by a program grant from Cancer Research UK. Support was also provided by the Experimental Cancer Medicine Centre (to The Institute of Cancer Research) and the National Institute for Health Research Biomedical Research Centre (jointly to the Royal Marsden NHS Foundation Trust and The Institute of Cancer Research). Northern Institute for Cancer Research, Newcastle University is supported by programmatic grant funding from Cancer Research UK and is an Experimental Cancer Medicine Centre.
Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006; and at the Annual Meeting of the American Association for Cancer Research, National Cancer Institute, European Organisation for the Research and Treatment of Cancer, November 7-10, 2006, Prague, Czech Republic.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Graham Temple, Boehringer Ingelheim (C); Susan Bell, Boehringer Ingelheim (C); Mehdi Shahidi, Boehringer Ingelheim (C); Martina Uttenreuther-Fischer, Boehringer Ingelheim (C); Peter Stopfer, Boehringer Ingelheim (C) Consultant or Advisory Role: James Spicer, Boehringer Ingelheim (C); Johann S. de Bono, Boehringer Ingleheim (C), AstraZeneca (C), OSI Pharmaceuticals (C), Genentech (C), Roche (C) Stock Ownership: None Honoraria: James Spicer, Boehringer Ingelheim; Johann S. de Bono, Boehringer Ingelheim, AstraZeneca Research Funding: None Expert Testimony: None Other Remuneration: None
Conception and design: Timothy A. Yap, Laura Vidal, Graham Temple, Susan Bell, Mehdi Shahidi, Peter Stopfer, Johann S. de Bono
Administrative support: Graham Temple, Susan Bell
Provision of study materials or patients: Timothy A. Yap, Laura Vidal, Jan Adam, Peter Stephens, James Spicer, Heather Shaw, Jooern Ang, Graham Temple, Susan Bell, Hilary Calvert, Johann S. de Bono, Ruth Plummer
Collection and assembly of data: Timothy A. Yap, Laura Vidal, Graham Temple, Susan Bell, Martina Uttenreuther-Fischer, Peter Stopfer, Andrew Futreal, Johann S. de Bono, Ruth Plummer
Data analysis and interpretation: Timothy A. Yap, Laura Vidal, Mehdi Shahidi, Martina Uttenreuther-Fischer, Peter Stopfer, Andrew Futreal, Johann S. de Bono, Ruth Plummer
Manuscript writing: Timothy A. Yap, Laura Vidal, James Spicer, Jooern Ang, Graham Temple, Susan Bell, Peter Stopfer, Johann S. de Bono, Ruth Plummer
Final approval of manuscript: Timothy A. Yap, Laura Vidal, Jan Adam, Peter Stephens, James Spicer, Heather Shaw, Jooern Ang, Graham Temple, Susan Bell, Mehdi Shahidi, Martina Uttenreuther-Fischer, Peter Stopfer, Andrew Futreal, Hilary Calvert, Johann S. de Bono, Ruth Plummer
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|Protein Kinases||IC50 Selectivity (nM)|
NOTE. Data adapted.12
Abbreviations: EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; InsRK, insulin receptor kinase; HGFR, hepatocyte growth factor receptor; VEGFR-2, vascular endothelial growth factor receptor-2; IC50, 50% inhibitory concentration.
|BIBW 2992||40-mg Fed (n = 13) ||40-mg Fasted (n = 13) ||Adjusted gMean ratio (fasted/fed) [%]||Two-Sided 90% CI||Intraindividual gCV (%)||P for Ratio Outside Interval (0.8-1.25)|
|gMean||gCV (%)||gMean||gCV (%)|
|Cmax, ng/mL||12.2||82.6||24.9||50.5||201.95||146.73 to 277.97||47.6||.9896|
|AUC0-∞, ng × h/mL||414||62.8||676||62.3||163.48||132.66 to 201.46||30.2||.9793|
Abbreviations: BS, base; Cmax, maximum measured concentration of the analyte in plasma; AUC, area under the time concentration curve; gMean, geometric mean; gCV, geometric mean of the coefficient of variation; tmax, time from dosing to the maximum concentration of the analyte in plasma.