Method for treating gefitinib resistant cancer (2024)

Title:

Method for treating gefitinib resistant cancer

United States Patent 10603314


Abstract:

The present invention is directed to methods for the treatment of gefitinib and/or erlotinib resistant cancer. An individual with cancer is monitored for cancer progression following treatment with gefitinib and/or erlotinib. Progression of the cancer is indicative that the cancer is resistant to gefitinib and/or erlotinib. Once progression of cancer is noted, the subject is administered a pharmaceutical composition comprising an irreversible epidermal growth factor receptor (EGFR) inhibitor. In preferred embodiments, the irreversible EGFR inhibitor is EKB-569, HKI-272 and HKI-357.


Inventors:

Haber, Daniel A. (Chestnut Hill, MA, US)
Bell, Daphne Winifred (Chevy Chase, MD, US)
Settleman, Jeffrey E. (Newton, MA, US)
Sordella, Raffaella (Cold Spring Harbor, NY, US)
Godin-heymann, Nadia G. (Stanmore, GB)
Kwak, Eunice L. (Marlborough, MA, US)
Rabindran, Sridhar Krishna (Eagleville, PA, US)

Application Number:

11/883474

Publication Date:

03/31/2020

Filing Date:

02/02/2006

Export Citation:

Click for automatic bibliography generation

Assignee:

The General Hospital Corporation (Boston, MA, US)
Wyeth LLC (New York, NY, US)

International Classes:

A61K31/4709; A61K31/17; A61K31/4706; A61K38/17

View Patent Images:

Download PDF 10603314

US Patent References:

9630946Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof2017-04-25Lu et al.
9511063Antineoplastic combinations containing HKI-272 and vinorelbine2016-12-06Zacharchuk
20160310482METHOD FOR TREATING GEFITINIB RESISTANT CANCER2016-10-27Haber
9139558Maleate salts of (E)-N-{4-[3-Chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof2015-09-22Lu et al.
8790708Coated tablet formulations and uses thereof2014-07-29Asraf et al.
20140171384ANTINEOPLASTIC COMBINATIONS OF 4-ANILINO-3-CYANOQUINOLINES AND CAPECITABINE2014-06-19Zacharchuk et al.
8669273Antineoplastic combinations of 4-anilino-3-cyanoquinolines and capecitabine2014-03-11Zacharchuk et al.
20140050721Antineoplastic Combinations with mTOR Inhibitor, Trastuzumab and/or HKI-2722014-02-20Moore et al.
20140004203COATED DRUG SPHEROIDS AND USES THEREOF FOR ELIMINATING OR REDUCING CONDITIONS SUCH AS EMESIS AND DIARRHEA2014-01-02Rao et al.
20130316935METHOD TO DETERMINE RESPONSIVENESS OF CANCER TO EPIDERMAL GROWTH FACTOR RECEPTOR TARGETING TREATMENTS2013-11-28Bell et al.506/16
20130281488MALEATE SALTS OF (E)-N--4-(DIMETHYLAMINO)-2-BUTENAMIDE AND CRYSTALLINE FORMS THEREOF2013-10-24Lu et al.
8524281Coated drug spheroids and uses thereof for eliminating or reducing conditions such as emesis and diarrhea2013-09-03Venkata et al.
8518446Coated tablet formulations and uses thereof2013-08-27Asraf et al.
20130189274PHOSPHATIDYLINOSITOL-3-KINASE PATHWAY BIOMARKERS2013-07-25Berkenblit et al.
8465916Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments2013-06-18Bell et al.435/6.1
8394959Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl)-4-(dimethylamino)-2-buteramide and crystalline forms thereof2013-03-12Lu et al.
8338456Cut-point in PTEN protein expression that accurately identifies tumors and is predictive of drug response to a pan-ErbB inhibitor2012-12-25Coughlin et al.
20120308560Antineoplastic Combinations with mTOR Inhibitor, Trastuzumab and/or HKI-2722012-12-06Moore et al.
20120270896Antineoplastic Combinations Containing HKI-272 and Vinorelbine2012-10-25Zacharchuk
8173817Stereoselective synthesis of benzimidazole sulfoxides2012-05-08Reddy et al.
8173814Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof2012-05-08Lu et al.
20120071507TREATMENT REGIMEN UTILIZING NERATINIB FOR BREAST CANCER2012-03-22Berkenblit et al.
8105769Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments2012-01-31Bell et al.435/6.11
8022216Maleate salts of (E)-N-{4-[3-chloro-4-(2-pyridinylmethoxy)anilino]-3-cyano-7-ethoxy-6-quinolinyl}-4-(dimethylamino)-2-butenamide and crystalline forms thereof2011-09-20Lu et al.
7982043Protein tyrosine kinase enzyme inhibitors2011-07-19Wissner et al.
20110165257COATED DRUG SPHEROIDS AND USES THEREOF FOR ELIMINATING OR REDUCING CONDITIONS SUCH AS EMESIS AND DIARRHEA2011-07-07Rao et al.
7964349Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments2011-06-21Bell et al.435/6.11
20110129456Sequential Administration of Chemotherapeutic Agents for Treatment of Cancer2011-06-02Wang et al.
7943778Antioxidant inflammation modulators: C-17 hom*ologated oleanolic acid derivatives2011-05-17Jiang et al.
20110112180NOVEL STAT3 PATHWAY INHIBITORS AND CANCER STEM CELL INHIBITORS2011-05-12Jiang et al.
20110111018COATED TABLET FORMULATIONS AND USES THEREOF2011-05-12Asraf et al.
20110104256METHODS FOR TREATING OR PREVENTING COLORECTAL CANCER2011-05-05Wang et al.
20110097340FULLY HUMAN ANTI-VEGF ANTIBODIES AND METHODS OF USING2011-04-28Ramachandra et al.
20110091524BIOMARKERS FOR SENSITIVITY TO ANTI-IGF1R THERAPY2011-04-21Wang et al.
20110091421Methods of Novel Therapeutic Candidate Identification Through Gene Expression Analysis in Vascular-Related Diseases2011-04-21Mann
7915402Antioxidant inflammation modulators: oleanolic acid derivatives with saturation in the C-ring2011-03-29Anderson et al.
20110052570METHOD TO PROGNOSE RESPONSE TO ANTI-EGFR THERAPEUTICS2011-03-03Klagsbrun et al.
7897159Parapoxviruses in combination with classical cytotoxic chemotherapeutic agents as biochemotherapy for the treatment of cancer2011-03-01Weber
20110045459Molecular determinants of EGFR kinase inhibitor response in glioblastoma2011-02-24Mischel et al.
20110014117ANTI-IGF1R2011-01-20Wang et al.
20100310503NOVEL COMPOSITIONS AND METHODS FOR CANCER TREATMENT2010-12-09Li et al.
7846936Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis2010-12-07Hilberg et al.
20100298760METHODS, KITS, AND COMPOSITIONS FOR ADMINISTERING PHARMACEUTICAL COMPOUNDS2010-11-25Olle et al.
20100297118Therapeutic Cancer Treatments2010-11-25Macdougall et al.
20100226943SURFACE TOPOGRAPHIES FOR NON-TOXIC BIOADHESION CONTROL2010-09-09Brennan et al.
201001897735-CYANO-4- (PYRROLO [2,3] PYRIDINE-3-YL) -PYRIMIDINE DERIVATIVES USEFUL AS PROTEIN KINASE INHIBITORS2010-07-29Mortimore et al.
20100166744USE OF ANTI-EGFR ANTIBODIES IN TREATMENT OF EGFR MUTANT MEDIATED DISEASE2010-07-01Wong
20100143350COMBINATION OF A PURINE-BASED CDK INHIBITOR WITH A TYROSINE KINASE INHIBITOR AND USE THEREOF IN THE TREATMENT OF PROLIFERATIVE DISORDERS2010-06-10Green et al.
20100143340METHODS AND COMPOSITIONS FOR TREATING CANCER2010-06-10Kolhe et al.
20100120768METHODS, KITS, AND COMPOSITIONS FOR GENERATING NEW HAIR FOLLICLES AND GROWING HAIR2010-05-13Steinberg et al.
20100120072DETECTION OF ELEVATED LEVELS OF HER-2/NEU PROTEIN FROM NON-ISOLATED CIRCULATING CANCER CELLS AND TREATMENT2010-05-13Lorence et al.
20100113474Antineoplastic Combinations of 4-Anilino-3-Cyanoquinolines and Capecitabine2010-05-06Zacharchuk et al.
20100105031METHOD FOR PREDICTION OF THE EFFICACY OF VASCULARIZATION INHIBITOR2010-04-29Matsui et al.
20100092490METHOD FOR ASSAY ON THE EFFECT OF VASCULARIZATION INHIBITOR2010-04-15Uenaka et al.
20100087482Method for Treating Gefitinib Resistant Cancer2010-04-08Haber et al.
20100081632High-content and high throughput assays for identification of lipid-regulating pathways, and novel therapeutic agents for lipid disorders2010-04-01Oksenberg et al.
20100069340PHARMACEUTICAL COMPOSITIONS OF AN SRC KINASE INHIBITOR AND AN AROMATASE INHIBITOR2010-03-18Zacharchuk et al.
20100056777ANTIOXIDANT INFLAMMATION MODULATORS: OLEANOLIC ACID DERIVATIVES WITH SATURATION IN THE C-RING2010-03-04Anderson et al.
20100048892ANTIOXIDANT INFLAMMATION MODULATORS: OLEANOLIC ACID DERIVATIVES WITH AMINO AND OTHER MODIFICATIONS AT C-172010-02-25Anderson et al.
20100048540Heterocyclic N-Oxides as Hypoxic Selective Protein Kinase Inhibitors2010-02-25Boyle et al.
20100041904ANTIOXIDANT INFLAMMATION MODULATORS: C-17 hom*oLOGATED OLEANOLIC ACID DERIVATIVES2010-02-18Jiang et al.
20090325877Combination Product of Receptor Tyrosine Kinase Inhibitor and Fatty Acid Synthase Inhibitor for Treating Cancer2009-12-31Grunt et al.
20090318480METHOD FOR TREATING CANCER HARBORING EGFR MUTATIONS2009-12-24Solca
20090317456USE OF ONCOLYTIC VIRUSES AND ANTIANGIOGENIC AGENTS IN THE TREATMENT OF CANCER2009-12-24Karrasch et al.
20090312360Antineoplastic Combinations Containing HKI-272 and Vinorelbine2009-12-17Zacharchuk
20090306101COMBINATION TREATMENT OF CANCER COMPRISING EGFR/HER2 INHIBITORS2009-12-10Solca et al.
20090297519ANTINEOPLASTIC COMBINATIONS WITH mTOR INHIBITOR, TRASTUZUMAB, AND/OR HKI-2722009-12-03Moore et al.
20090246198MAPK/ERK KINASE INHIBITORS AND METHODS OF USE THEREOF2009-10-01Dong et al.
20090203709Pharmaceutical Dosage Form For Oral Administration Of Tyrosine Kinase Inhibitor2009-08-13Steinberg et al.
20090176827MALEATE SALTS OF (E)-N--4-(DIMETHYLAMINO)-2-BUTENAMIDE AND CRYSTALLINE FORMS THEREOF2009-07-09Lu et al.
20090060873Novel synthetic triterpenoids and methods of use in the treatment and prevention of multiple scleroris2009-03-05Sp*rn et al.
20090047278Novel Combinational Use of Sulfonamide Compound2009-02-19Owa et al.
20090035269PARAPOXVIRUSES IN COMBINATION WITH CLASSICAL CYTOTOXIC CHEMOTHERAPEUTIC AGENTS AS BIOCHEMOTHERAPY FOR THE TREATMENT OF CANCER2009-02-05Weber
20080286785Method to predict or monitor the response of a patient to an erbb receptor drug2008-11-20Nishio et al.
20080286771Method of Predicting the Responsiveness of a Tumour to Erbb Receptor Drugs2008-11-20Hudson et al.
20080268034Solid Oral Dosage Forms of Ziprasidone Containing Colloidal Silicone Dioxide2008-10-30Karanth et al.
20080254040COMBINATIONS FOR THE TREATMENT OF DISEASES INVOLVING CELL PROLIFERATION, MIGRATION OR APOPTOSIS OF MYELOMA CELLS OR ANGIOGENESIS2008-10-16Stefanie et al.
20080234264Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments2008-09-25Bell et al.
20080207615Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments2008-08-28Bell et al.
20080193448Combinations and Methods of Using an Indolinone Compound2008-08-14Baum
7399865Protein tyrosine kinase enzyme inhibitors2008-07-15Wissner et al.
20080166359Methods of using MEK inhibitors2008-07-10Lamb
RE40418Treatment of neoplasms with CCI-779/EKB-569 combination2008-07-01Rabindran et al.
20080112888IGFBP2 BIOMARKER2008-05-15Wang
20080096212Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments2008-04-24Bell et al.
7306801Methods of therapy for cancers characterized by overexpression of the HER2 receptor protein2007-12-11Caligiuri et al.
20070281932Method of preparing 4-halogenated quinoline intermediates2007-12-06Bernier et al.
7297795Process for preparation of 4-amino-3-quinolinecarbonitriles2007-11-20Sutherland et al.
7294468Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments2007-11-13Bell et al.
7235564Vinorelbine derivatives2007-06-26Scott et al.
20070105887Antineoplastic combinations of temsirolimus and sunitinib malate2007-05-10Moore
20070104721Antineoplastic combinations with mTOR inhibitor,herceptin, and/or hki-2722007-05-10Moore et al.
7189735Use of CCI-779 as an antineoplastic agent2007-03-13Dukart et al.
20070048754Epidermal growth factor receptor mutations2007-03-01Freeman et al.
20070014859Highly bioavailable oral delayed release dosage forms of O-desmethylvenlafaxine succinate2007-01-18Shah et al.
20060270669Method of preparing 3-cyano-quinolines and intermediates made thereby2006-11-30Chew et al.
20060270668Methods of synthesizing substituted 3-cyanoquinolines and intermediates thereof2006-11-30Chew et al.
7126025Synthesis of 4-(amino)-2-butenoyl chlorides and their use in the preparation of 3-cyano quinolines2006-10-24Considine et al.
20060235046Use of an epidermal growth factor receptor kinase inhibitor (EGFR) in gefitinib resistant patients2006-10-19Zacharchuk et al.514/313
7091213Phosphorus-containing compounds and uses thereof2006-08-15Metcalf et al.
20060178387Combined treatment with capecitabine and an epidermal growth factor receptor kinase inhibitor2006-08-10Fujimoto-Ouchi et al.
20060147959Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments2006-07-06Bell et al.435/6
20060128793Analogs of 17-hydroxywortmannin as P13K inhibitors2006-06-15Zask et al.
20060094674Combination of mtor inhibitor and a tyrosine kinase inhibitor for the treatment of neoplasms2006-05-04Neel et al.
20060084666Combined treatment with radiation and an epidermal growth factor receptor kinase inhibitor2006-04-20Harari514/263.34
20060079515Method for the treatment of polycystic kidney disease2006-04-13Frost
7026330Methods for treatment of acute lymphocytic leukemia2006-04-11Grupp et al.
20060058311Combinations for the treatment of diseases involving cell proliferation2006-03-16Munzert et al.
20060035904Antineoplastic combinations2006-02-16Gibbons et al.
20060030547Antineoplastic combinations2006-02-09Dukart et al.
20050272758Antineoplastic combinations of CCI-779 and rituximab2005-12-08Bayever et al.
20050272083EGFR mutations2005-12-08Seshagiri435/6
20050187184Antineoplastic combinations2005-08-25Gibbons, Jr. et al.
20050136063Anti-IGFR antibody therapeutic combinations2005-06-23Wang et al.
20050129761Pantoprazole multiparticulate formulations2005-06-16Venkata et al.
20050059678Protein tyrosine kinase enzyme inhibitors2005-03-17Wissner et al.
20050043233Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis2005-02-24Stefanie et al.
20050038080Fluoro substituted omega-carboxyaryl diphenyl urea for the treatment and prevention of diseases and conditions2005-02-17Boyer et al.
20050032825Phosphorus-containing compounds and uses thereof2005-02-10Metcalf et al.
20050025825Tranexamic acid formulations with reduced adverse effects2005-02-03Heasley et al.
20040258662Antineoplastic agents2004-12-23Gibbons et al.
68219883-cyanoquinolines as inhibitors of EGF-R and HER2 kinases2004-11-23Wissner et al.
6821515Protein formulation2004-11-23Cleland et al.
20040209930Synergistic methods and compositions for treating cancer2004-10-21Carboni et al.
20040176339Antineoplastic combinations2004-09-09Sherman et al.
6780996Process for the preparation of 7-substituted-3 quinolinecarbonitriles2004-08-24Boschelli et al.
20040162442Synthesis of 4-(amino)-2-butenoyl chlorides and their use in the preparation of 3-cyano quinolines2004-08-19Considine et al.
20040096436Methods for inhibiting protein kinases in cancer cells2004-05-20Carson424/94.4
20040039010Methods for treatment of acute lymphocytic leukemia2004-02-26Grupp et al.
6617333Antineoplastic combinations comprising2003-09-09Rabindran et al.
20030153593Use of CCI-779 as an antineoplastic agent2003-08-14Dukart et al.
200301490563-cyanoquinolines as inhibitors of EGF-R and HER2 kinases2003-08-07Wissner et al.
20030144252Combination product comprising a non-steroidal antiandrogen and an egfr tyrosine kinase inhibitor2003-07-31Furr
6511986Method of treating estrogen receptor positive carcinoma2003-01-28Zhang et al.
20020198137Antineoplastic combinations2002-12-26Dukart et al.
20020183240Antineoplastic combinations2002-12-05Gibbons et al.
20020183239Antineoplastic combinations2002-12-05Gibbons, Jr. et al.
6432979Method of treating or inhibiting colonic polyps and colorectal cancer2002-08-13Frost et al.
6399063Monoclonal antibodies directed to the HER2 receptor2002-06-04Hudziak et al.
6387371Monoclonal antibodies directed to the HER2 receptor2002-05-14Hudziak et al.
6384051Method of treating or inhibiting colonic polyps2002-05-07Frost et al.
20020002162Synergistic methods and compositions for treating cancer2002-01-03Lee
6297258Substituted 3-cyanoquinolines2001-10-02Wissner et al.
6288082Substituted 3-cyanoquinolines2001-09-11Wissner et al.
6277983Regioselective synthesis of rapamycin derivatives2001-08-21Shaw et al.
6251912Substituted quinazoline derivatives2001-06-26Wissner et al.
6143764Quinoline and quinazoline derivatives inhibiting platelet-derived growth factor receptor autophosphorylation and pharmaceutical compositions containing the same2000-11-07Kubo et al.
6002008Substituted 3-cyano quinolines1999-12-14Wissner et al.
57600414-aminoquinazoline EGFR Inhibitors1998-06-02Wissner et al.
5715151Control and protection system for AC-DC conversion system1998-02-03Moriura
5476932Process for producing N4-acyl-5'-deoxy-5-fluorocytidine derivatives1995-12-19Brinkman et al.
5472949N4 -(substituted-oxycarbonyl)-5'-deoxy-5-fluorocytidine compounds, compositions and methods of using same1995-12-05Arasaki et al.
5453497Process for producing N4 -acyl-5'-deoxy-5-fluorocytidine compounds1995-09-26Kamiya et al.
5362718Rapamycin hydroxyesters1994-11-08Skotnicki et al.
4966891Fluorocytidine derivatives1990-10-30Fujiu et al.

Foreign References:

CN1437942A2003-08-27Vinorebin powder injection and preparation method
CN101185633A2008-05-28Neratinib sustained-release implant for treating solid tumor
EP06932851996-01-24Pharmaceutical compositions containing a bisphosphonate and an anti-resorptive agent for inhibiting bone loss
EP14485312007-08-153-CYANOQUINOLINES AS INHIBITORS OF EGF-R AND HER2 KINASES
EP16639782007-11-28FLUORO SUBSTITUTED OMEGA-CARBOXYARYL DIPHENYL UREA FOR THE TREATMENT AND PREVENTION OF DISEASES AND CONDITIONS
EP18544632007-11-14RELEASE-CONTROL COMPOSITION
EP19781062008-10-08Detection of ESR1 amplification in endometrium cancer and ovary cancer
EP19512742009-12-02PARAPOXVIRUSES IN COMBINATION WITH CLASSICAL CYTOTOXIC CHEMOTHERAPEUTIC AGENTS AS BIOCHEMOTHERAPY FOR THE TREATMENT OF CANCER
EP18484142011-04-06METHOD FOR TREATING GEFITINIB RESISTANT CANCER
EP18597932011-04-20NOVEL COMBINATIONAL USE OF A SULFONAMIDE COMPOUND IN THE TREATMENT OF CANCER
EP26568442013-10-30Antineoplastic combinations containing HKI-272 and vinorelbine
JP2003519698A2003-06-24多様な固体形態のハイスループットでの形成、同定および分析
JP2007145745A2007-06-14LUNG CANCER MEDICINE CONTAINING SRC FAMILY TYROSINE KINASE INHIBITOR FOR INHIBITING VARIANT EGFR DOWNSTREAM SIGNAL AND UTILIZATION THEREOF
WO1992022653A11992-12-23METHOD FOR MAKING HUMANIZED ANTIBODIES
WO1995028406A11995-10-26RAPAMYCIN HYDROXYESTERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO1996033978A11996-10-31QUINAZOLINE DERIVATIVE
WO1996033980A11996-10-31QUINAZOLINE DERIVATIVES
WO1998043960A11998-10-08SUBSTITUTED 3-CYANO QUINOLINES
WO2000018761A12000-04-06SUBSTITUTED 3-CYANOQUINOLINES AS PROTEIN TYROSINE KINASES INHIBITORS
WO2001023395A22001-04-05REGIOSELECTIVE SYNTHESIS OF RAPAMYCIN DERIVATIVES
WO2001051919A22001-07-19HIGH-THROUGHPUT FORMATION, IDENTIFICATION, AND ANALYSIS OF DIVERSE SOLID-FORMS
WO2002080975A12002-10-17ANTINEOPLASTIC COMBINATIONS SUCH AS RAPAMYCIN TOGETHER WITH GEMCITABINE OR FLUOROURACIL
WO2002102976A22002-12-27MUTATIONS IN THE BCR-ABL TYROSINE KINASE ASSOCIATED WITH RESISTANCE TO STI-571
WO2002098416A22002-12-12ANTINEOPLASTIC COMBINATIONS
WO2003050090A12003-06-193-CYANOQUINOLINES AS INHIBITORS OF EGF-R AND HER2 KINASES
WO/2003/103676December, 2003METHOD OF TREATING CANCER USING KINASE INHIBITORS
WO2003103676A22003-12-18METHOD OF TREATING CANCER USING KINASE INHIBITORS
WO2004004644A22004-01-15COMBINATION OF MTOR INHIBITOR AND A TYROSINE KINASE INHIBITOR FOR THE TREATMENT OF NEOPLASMS
WO2004066919A22004-08-12SYNTHESIS OF 4AMINO-2-BUTENOYL CHLORIDES AND THEIR USE IN THE PREPARATION OF 3-CYANO QUINOLINES
WO2004078133A22004-09-16ANTINEOPLASTIC COMBINATIONS COMPRISING A RAPAMYCIN DDERIOVATIVE AND AN AROMATSE INHIBITOR
WO2004093854A22004-11-04ANTINEOPLASTIC COMBINATIONS
WO2004096224A22004-11-11COMBINATIONS FOR THE TREATMENT OF DISEASES INVOLVING CELL PROLIFERATION, MIGRATION OR APOPTOSIS OF MYELOMA CELLS, OR ANGIOGENESIS
WO2005018677A22005-03-03USE OF COMBINATION OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR AND CYTOTOXIC AGENTS FOR TREATMENT AND INHIBITION OF CANCER
WO2005032513A22005-04-14PANTOPRAZOLE MULTIPARTICULATE FORMULATIONS
WO2005034955A12005-04-21SUBSTITUTED QUINOLINES AS PROTEIN TYROSINE KINASE ENZYME INHIBITORS
WO2005037287A12005-04-28ORAL ADMINISTRATION OF [2-(8,9-DIOXO-2,6-DIAZABICYCLO[5.2.0]NON-1(7)­ EN-2-YL)ALKYL]PHOSPHONIC ACID AND DERIVATIVES
WO2005044091A22005-05-19DIAGNOSTIC AND THERAPEUTIC METHODS AND COMPOSITIONS INVOLVING PTEN AND BREAST CANCER
WO2005049021A12005-06-02MATERIALS AND METHODS FOR INHIBITING NEOINTIMAL HYPERPLASIA
WO2005087265A12005-09-22ANTINEOPLASTIC COMBINATIONS OF CCI-779 AND RITUXIMAB
WO2005094357A22005-10-13METHOD TO DETERMINE RESPONSIVENESS OF CANCER TO EPIDERMAL GROWTH FACTOR RECEPTOR TARGETING TREATMENTS
WO2006044453A12006-04-27ANALOGS OF 17-HYDROXYWORTMANNIN AS PI3K INHIBITORS
WO2006044748A22006-04-27RESPONSE PREDICTORS FOR ErbB PATHWAY-SPECIFIC DRUGS
WO2006081985A12006-08-10COMBINED TREATMENT WITH AN N4-(SUBSTITUTED-OXYCARBONYL)-5’-DEOXY-5-FLUOROCYTIDINE DERIVATIVE AND AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR
WO2006084058A22006-08-10METHOD FOR TREATING GEFITINIB RESISTANT CANCER
WO2006095185A12006-09-1439-DESMETHOXY DERIVATIVES OF RAPAMYCIN
WO2006098978A12006-09-21DIAGNOSTICS METHOD FOR IDENTIFYING CANDIDATE PATIENTS FOR THE TREATMENT WITH TRASTUZUMAB
WO2006113151A22006-10-26USE OF AN EPIDERMAL GROWTH FACTOR RECEPTOR KINASE INHIBITOR (EGFR) IN GEFITINIB RESISTANT PATIENTS
WO2006113304A22006-10-26COMBINATIONS, METHODS AND COMPOSITIONS FOR TREATING CANCER
WO2006116514A22006-11-02MICRONIZED TANAPROGET, COMPOSITIONS, AND METHODS OF PREPARING THE SAME
WO2006120557A12006-11-16ANTICANCER COMBINATION THERAPY USING SUNITINIB MALATE
WO2006120573A22006-11-16HETEROCYCLIC N-OXIDES AS HYPOXIC SELECTIVE PROTEIN KINASE INHIBITORS
WO2006127205A22006-11-30METHODS OF PREPARING 3-CYANO-QUINOLINES AND INTERMEDIATES MADE THEREBY
WO2006127207A12006-11-30METHODS OF SYNTHESIZING SUBSTITUTED 3-CYANOQUINOLINES AND INTERMEDIATES THEREOF
WO2007000234A12007-01-04MOXIFLOXACIN THERAPEUTIC USE FOR TREATING IMMUNE SYSTEM FUNCTIONAL DISTURBANCES
WO2007011619A22007-01-25HIGHLY BIOAVAILABLE ORAL DELAYED RELEASE DOSAGE FORMS OF O-DESMETHYLVENLAFAXINE SUCCINATE
WO2007056118A12007-05-18ANTINEOPLASTIC COMBINATIONS WITH MTOR INHIBITOR, HERCEPTIN, AND/OR HKI-272
WO2007075794A22007-07-05ORAL FORMULATIONS COMPRISING TIGECYCLINE
WO2007095038A22007-08-23MUTATIONS AND POLYMORPHISMS OF ERBB2
WO2007116025A22007-10-18USE OF C-SRC INHIBITORS IN COMBINATION WITH A PYRIMIDYLAMINOBENZAMIDE COMPOUND FOR THE TREATMENT OF LEUKEMIA
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Other References:

Kobayashi et al. (N. Engl. J. Med. Feb. 24, 2005, 352: 786-792).
Dorland's Medical Dictionary for Healthcare Consumers (carcinoma 2007).
Discafani et al. (Biohcemical Pharmacology 1999, 57:917-925).
Smaill et al. (J. Med. Chem. 2001 44: 429-440).
Cross et al. (Cancer Discovery Jun. 3, 2014, 4:1046-1061) (Year: 2014).
Tan et al. (J. Thoracic Oncology Jul. 2016 11(7): 946-963) (Year: 2016).
Arteaga, Exp Cell Res., 284:122-30 (2003).
Baselga et al., J. Clin. Onc. 20:4292-4302 (2002).
Cappuzzo et al., J. Clin. Oncol. 21:2658-2663 (2003).
Cohen et al., Clin. Cancer Res. 10:1212-1218 (2004).
de Bono et al., Trends in Molecular Medicine 8(4):S19-S26 (2002).
Druker et al., N. Engl. J. Med. 344:1031-1037 (2001).
Fitch et al., Genes & Dev 17:214-22 (2003).
Fry, Pharmacology and Therapeutics, Elsevier, GB 82(2/03):207-218 (1999).
f*ckuoka et al., J. Clin. Oncol. 21:2237-2246 (2003).
Giaccone et al., J. Clin. Oncol. 22:777-784 (2004).
Greenberger et al., Nov. 7-10, 2000, Abstract 388, vol. 6 Supplement, Nov. 2000, ISSN 1078-0432.
Gullick et al., Cancer Research 46:285-292 (1986).
Harris et al., Int. J. Biol. Markers 14:8-15(1999).
Herbst et al., J. Clin. Oncol. 22:785-794 (2004).
Herbst et al., J. Clin. Oncol. 20:3815-3825 (2002).
Holbro et al., Rev. Pharm. Tox. 44:195-217 (2004).
Jorissen et al., Exp. Cell. Res. 284:31-53 (2003).
Kris et al., JAMA 290:2149-2158 (2003).
Kwak et al., Prceedings of the Nainal Academy of Sciences of the Unitd States of Amerca 102(21):7665-7670 (2005).
Luetteke et al., Genes Dev. 8:399-413 (1994).
Lynch et al., 350:2129-2139 (2004).
Mendelsohn et al., Oncogene, 19:6550-6565 (2000).
Nicholson et al. Eur. J. Cancer 37:S9-S15 (2001).
Oh et al., Clin. Cancer Res., 6:4760-4763 (2000).
Rabindran et al., Cancer Res. 64, 3958-3965 (2004).
Rewcastle et al., Current Organic Chemistry, Hilversum, NL 4(7):679-706 (2000).
Rich et al., J. Clin. Oncol. 22:133-142 (2004).
Schiller et al. N. Engl. J. Med. 346:92-98 (2002).
Tejpar et al., J. Clin. Oncol. ASCO Annual Meeting Proc. 22(14S):3579 (2004).
Tsou et al. J. Med. Chem. 48:1107-1131 (2005).
Coldren, C., et al., “Baseline Gene Expression Predicts Sensitivity to Gefitinib in Non-Small Cell Lung Cancer Cell Lines,” Mol Cancer Res (2006); 4(8) pp. 1-8.
Heymach, J., et al., “Epidermal Growth Factor Receptor Inhibitors in Development for the Treatment of Non-Small cell Lung Cancer,” Clin Cancer Res 2006; 12(14 Suppl), pp. 4441s-4445s.
Mitsudomi, T., et al., “Biological and clinical implications of EGFR mutations in lung cancer,” Int J Clin Oncol (2006) vol. 11, pp. 190-198.
Ulrich A. et al., Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells, Nature 309:418-425 (1984).
Blencke, S. et al. Mutation of Threonine 786 in the Epidermal Growth Factor Receptor Reveals a Hotspot for Resistance Formation against Selective Kinase Inhibitors, The Journal of Biological Chemistry, 278(17):15435-15440 (2003).
Choong, N.W. et al., Gefitinib response of erlotinib-refractory lung cancer involving meninges—role of EGFR mutation, Nature Clinical Practice Oncology, 3(1):50-57 (2006).
Greulich, H. et al., Oncogenic Transformation by Inhibitor-Sensitive and -Resistant EGFR Mutants, PLOS Medicine 2(11) e313: 1167-1176 (2005).
Rabindran, S.K., Antitumor of HKI-272, an Orally Active, Irreversible Inhibitor of the HER-2 Tyrosine Kinase, Cancer Research 64:3958-3965 (2004).
Blanke, C. D.; Journal of Clinical Oncology; Gefitinib in Colorectal Cancer: If Wishes Were Horses; (2005) 23:24; 5446-5449.
Camp E. R., et al.; Clin. Cancer Res.; Molecular Mechanisms of Resistance to Therapies Targeting the Epidermal Growth Factor Receptor; (2005) 11:397-405.
Einhorn, L.; Lung Cancer; Perspective on the Development of New Agents in Thoracic Cancers; (2005) 50, Suppl 1, S27-8.
Frederick, B. A., et al.; Mol. Cancer Ther.; Epithelial to Mesenchymal Transition Predicts Gefitinib Resistance in Cell Lines of Head and Neck Squamous Cell Carcinoma and Non-small Cell Lung Carcinoma; (2007) 6:1683-1691.
Katakami, N. et al.; J. Clin Oncol.; LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non-Small-Cell Lung Cancer Who Progressed During Prior Treatment with Erlotinib, Gefitinib, or Both; (2013) 31:3335-3341.
Nakagawa, T., et al.; Mol. Cancer Ther.; Combined Therapy with Mutant-Selective EGFR Inhibitor and Met Kinase inhibitor for Overcoming Erlotinib Resistance in EGFR-Mutant Lung Cancer; (2012) 11:2149-2157.
Therasse, P., et al.; J. Natl. Cancer Inst.; New Guidelines to Evaluate the Response to Treatment in Solid Tumors; (2000) 92:3; 205-16.
Van Schaeybroeck, S., et al.; Clin. Cancer Res.; Epidermal Growth Factor Receptor Activity Determines Response of Colorectal Cancer Cells to Gefitinib Alone and in Combination with Chemotherapy; (2005) 11:7480-7489.
Vincent, P. W., et al.; Cancer Chemother Pharmacol.; Anticancer Efficacy of the Irreversible EGFr Tyrosine Kinase Inhibitor PD 0169414 against Human Tumor Xenografts; (2000) 45:231-8.
Ware, K. E., et al.; Oncogenesis; A Mechanism of Resistance to Gefitinib Mediated by Cellular Reprogramming and the Acquisition of an FGF2-FGFR1 Autocrine Growth Loop; (2013) 2:1-9.
Yoshimura, N., et al.; Lung Cancer; EKB-569, A New Irreversible Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, with Clinical Activity in Patients with Non-Small Cell Lung Cancer with Acquired Resistance to Gefitinib; (2006) 51:363-8.
Zhou, W., et al.; Nature; Novel Mutant-Selective EGFR Kinase Inhibitors Against EGFR T790M; (2009) 462(7276): 1070-1074.
Campos et al., “A phase 2, single agent study of CI-1033 administered at two doses in ovarian cancer patients who failed platinum therapy,” J. Clin. Oncol. (ASCO Annual Meeting Proceedings) 22(14S):5054 (2004).
Carmi et al., “Clinical perspectives for irreversible tyrosine kinase inhibitors in cancer,” Biochem. Pharmacol. 84(11):1388-1399 (2012) (Epub Aug. 4, 2012).
Casado et al., “A phase I/IIA pharmaco*kinetic (PK) and serial skin and tumor pharmacodynamic (PD) study of the EGFR irreversible tyrosine kinase inhibitor EKB-569 in combination with 5-fluorouracil (5FU), leucovorin (LV) and irinotecan (CPT-11) (FOLFIRI regimen) in patients (pts) with advanced colorectal cancer (ACC),” J. Clin. Oncol., 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). vol. 22, No. 14S (Jul. 15 Supplement), 2004:3543.
Clovis Oncology, Inc. publication on Rociletinib: “Study to Evaluate Safety, Pharmaco*kinetics, and Efficacy of Rociletinib (CO-1686) in Previously Treated Mutant Epidermal Growth Factor Receptor (EGFR) in Non-Small Cell Lung Cancer (NSCLC) Patients.” ClinicalTrials.gov Identifier: NCT01526928; verified Feb. 2015 by Clovis Oncology, Inc.
Comments by the President of the European Patent Office re: Case G 1/12—Invitation to comment under Article 9 of the Rules of Procedure of the Enlarged Board of Appeal dated Jun. 25, 2012 (9 pages).
Costa et al., “The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial,” Clin. Cancer Res. 20:2001-2010 (2014).
Declaration by Dr. Leena Gandhi, MD, Ph.D., dated Feb. 13, 2015 (6 pages).
Declaration by Thomas C. Harding, Ph.D., executed Oct. 1, 2014 (15 pages).
Desai et al., “EGFR pharmacogenomics: the story continues to mutate and evolve,” Am. J. Pharmacogenomics 5(2):137-139 (2005).
Dowell et al., “Chasing mutations in the epidermal growth factor in lung cancer,” N. Engl. J. Med. 352(8):830-832 (2005).
Dua et al., “EGFR over-expression and activation in high HER2, ER negative breast cancer cell line induces trastuzumab resistance,” Breast Cancer Res. Treat. 122(3):685-697 (2010) (Epub 2009 Oct. 27).
Hidalgo et al., “Phase 1 trial of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor (EGFR), in patients with advanced solid tumors,” ASCO Annual Meeting Proceedings, 21:17a; Abstr. 65 (2002).
Irwin et al., “Small Molecule ErbB Inhibitors Decrease Proliferative Signaling and Promote Apoptosis in Philadelphia Chromosome—Positive Acute Lymphoblastic Leukemia” PLoS One 8(8): e70608 (2013).
Kobayashi et al. “Gefitinib resistance caused by a secondary mutation of the epidermal growth factor receptor,” Proc. Amer. Assoc. Cancer Res. 46:620; Abstr. 2637 (2005).
Laheru et al., “A phase I study of EKB-569, an irreversible inhibitor of epidermal growth factor receptor, in combination with capecitabine in patients with advanced colorectal cancer: Preliminary report,” Clin. Cancer Res. 9: 6091s-6092s; Abstr. 93 (2003).
Message from ATCC to Roland Graf of Jones Day Jan. 22, 2015 (1 page).
Miller et al., “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 ,” Lancet Oncol. 13:528-538 (2012).
Modjtahedi et al., “A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer,” Naunyn Schmiedebergs Arch. Pharmacol. 2014 Jun.;387(6):505-521 (2014) (Epub Mar. 19, 2014).
Morgan et al., “Preliminary report of a phase 1 study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor (EGFR), given in combination with gemcitabine to patients with advanced pancreatic cancer,” ASCO Annual Meeting Proceedings, 22(Abstr. 788):197 (2003).
Nagasawa et al., “Novel HER2 selective tyrosine kinase inhibitor, TAK-165, inhibits bladder, kidney and androgen-independent prostate cancer in vitro and in vivo,” Int. J. Urol. 13(5):587-592 (2006).
Nemunaitis et al., “Phase 1 clinical and pharmaco*kinetics evaluation of oral CI-1033 in patients with refractory cancer,” Clin. Cancer Res. 11(10):3846-3853 (2005).
Pao et al., “Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain,” PLoS Med. 2(3):e73 (2005) (Epub Feb. 22, 2005).
Pao et al., “KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib,” PLoS Med. 2(1):e17 (2005) (Epub Jan. 25, 2005).
Salazar et al., “Preliminary report of a phase I/IIA open-label study of EKB-569 in combination with 5-fluorouracil, leucovorin. irinotecan in patients with advanced colorectal cancer,” Clin. Cancer Res. 9(16):6099S-6100S; Abstr. 125 (2003).
Schuler et al., “An interim analysis of the LUX-Lung 5 trial: Afatinib monotherapy in metastatic NSCLC following progressionon chemotherapy and erlotinib/gefitinib,” J. Clin. Oncol. (ASCO Annual Meeting Abstracts) 2012;(Suppl):7557.
Schuler et al., “Continuation of afatinib beyond progression: Results of a randomized, open-label, phase III trial of afatinib plus pacl*taxel (P) versus investigator's choice chemotherapy (CT) in patients (pts) with metastatic non-small cell lung cancer (NSCLC) progressed on erlotinib/gefitinib (E/G) and afatinib—Lux-Lung 5 (LL5),” J. Clin. Oncol. 32:5s, 2014 (suppl; abstr. 8019).
Sequist et al., “Neratinib, an Irreversible Pan-ErbB Receptor Tyrosine Kinase Inhibitor: Results of a Phase II Trial in Patients With Advanced Non-Small-Cell Lung Cancer,” J. Clin. Oncol. 28:1-8 (2010).
Su et al., “Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer,” J. Clin. Oncol. 30(4):433-440 (2012) (Epub Jan. 3, 2012).
Allen et al., “Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer,” Semin. Oncol. 29(3 Suppl 11):11-21 (2002).
Avizienyte et al., “Comparison of the EGFR resistance mutation profiles generated by EGFR-targeted tyrosine kinase inhibitors and the impact of drug combinations,” Biochem. J. 415(2):197-206 (2008).
Erjala et al., “Concomitant chemoirradiation with vinorelbine and gefitinib induces additive effect in head and neck squamous cell carcinoma cell lines in vitro,” Radiother. Oncol. 85(1):138-145 (2007).
Gilmer et al., “Impact of common epidermal growth factor receptor and HER2 variants on receptor activity and inhibition by lapatinib,” Cancer Res. 68(2):571-579 (2008).
Goldhirsch et al., “2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an 3pen-label, randomised control trail,” Lancet 382:1021-1028 (2013).
Intellectual Property Office of Singapore Examination Report for Singapore Patent Application No. 2013046099 (dated Jan. 21, 2016).
Intellectual Property Office of Singapore Written Opinion for Singapore Patent Application No. 2013046099 (dated Jun. 4, 2015).
Kulke et al., “Capecitabine Plus Erlotinib in Gemcitabine-Refractory Advanced Pancreatic Cancer,” J. Clin. Oncol. 25 (30):4787-4792 (2007).
McNeil et al., “Two targets, one drug for new EGFR inhibitors,” J. Natl. Cancer Inst. 98(16):1102-1103 (2006).
Okumura et al., “Induction of Noxa Sensitizes Human Colorectal Cancer Cells Expressing Mcl-1 to the Small-Molecule Bcl-2/Bcl-xL Inhibitor, ABT-737,” Clin. Cancer Res. 14(24):8132-8142 (2008).
Ross et al., “The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine,” Oncologist 14:320-368 (2009).
Stockler et al., “Chemotherapy for advanced breast cancer—how long should it continue?” Breast Cancer Res. Treat. 81(Suppl. 1):S49-S52 (2003).
Vengerovsky, “Farmacologicheskaya nesovmestimost,” Bulleten' sibirskoi medicini 3:49-56 (2003). (English translation of Abstract provided).
Zhang et al., “Targeting cancer with small molecule kinase inhibitors,” Nature 9:28-39 (2009).
“Trastuzumab.” Wikipedia: Wikipedia: The Free Encyclopedia. Wikimedia Foundation, Inc. Retrieved from the Internet Aug. 14, 2009. URL:http://en.wikipedia.org/wiki/Herceptin.
“Vinorelbine” Wikipedia: The Free Encyclopedia. Wikimedia Foundation, Inc. Retrieved from the Internet Jan. 28, 2013. URL:http://en.wikipedia.org/wiki/Vinorelbine.
Abbas et al., “A Drug Interaction Study to Evaluate the Effect of Ketoconazole on the Pharmaco*kinetics (PK) of Neratinib in Healthy Subjects,” Clin. Pharmacol. Therapeutics 85:s44 (2009).
Abbas et al., “Evaluation of Neratinib (HKI-272) and Pacl*taxel Pharmaco*kinetics (PK) in Asian and Caucasian Patients with Erbb2+ Breast Cancer: a Phase 1/2 Study of Neratinib in Combination with Pacl*taxel,” Ann. Oncol. 21:101 (2010).
Abbas et al., “Pharmaco*kinetics of Oral Neratinib During Co-Administration of Ketoconazole in Healthy Subjects,” Br. J. Clin. Pharmacol. 71(4):522-527 (2011).
Abbas-Borhan et al., “A Clinical Study to Characterize the Occurrence of Mild-To-Moderate Diarrhea After Administration of Neratinib Either Once Daily or Twice Daily for 14 Days,” EJC Suppl. 8:143 (2010).
Abbas-Borhan et al., “An Open-Label Study to Assess the Mass Balance and Metabolic Disposition of an Orally Administered Single Dose of 14C-Labeled Neratinib, an Irreversible pan-ErbB inhibitor, in Healthy Subjects,” Drug Metab. Rev. 42:S1, 216 Abstr. P330 (2010).
Abrams et al., “Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with ”standard of care“ therapeutic agents for the treatment of breast cancer,” Mol. Cancer Ther. 2(10):1011-1021 (2003).
Abramson and Arteaga, “New Strategies in HER2-Overexpressing Breast Cancer: Many Combinations of Targeted Drugs Available,” Clin. Cancer Res. 17:952-958 (2011).
Adelaide et al., “Integrated Profiling of Basal and Luminal Breast Cancers,” Cancer Res. 67(24):11565-11575 (2007).
Al-Dasooqi et al., “HER2 Targeted Therapies for Cancer and the Gastrointestinal Tract,” Curr. Drug Targets 10(6):537-542 (2009).
Ali et al., “Mutational Spectra of PTEN/MMAC1 Gene: a Tumor Suppressor with Lipid Phosphatase Activity,” J. Natl. Cancer Inst. 91(22):1922-1932 (1999).
Allegra et al., “American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy,” J. Clin. Oncol. 27(12):2091-2096 (2009).
Al-Muhammed et al., “In-Vivo Studies on Dexamethasone Sodium Phosphate Liposomes,” J. Microencapsul. 13(3):293-306 (1996).
Alvarez et al., “Emerging Targeted Therapies for Breast Cancer,” J. Clin. Oncol. 28(20):3366-3379 (2010).
Alvarez, “Present and Future Evolution of Advanced Breast Cancer Therapy,” Breast Cancer Res. 12(Suppl 2):S1 (2010).
Amslinger, “The tunable functionality of alpha,beta-unsaturated carbonyl compounds enables their differential application in biological systems,” ChemMedChem. 5(3):351-356 (2010).
Andre and Diniz, “Targeted regimes without cytotoxics—are they ready for prime time?” EJC Suppl. 7:49 Abst. 191 (2009).
Andre et al., “Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial,” Lancet Oncol. 15(6):580-591 (2014) (Epub Apr. 14, 2014).
Anonymous, “Trastuzumab”, Wikipedia, Retrieved from the Internet Nov. 21, 2014. URL:http://en.wikipedia.org/wiki/Trastuzumab?oldid=634842165.
Anonymous: “Meeting Archives of Chemotherapy Foundation Symposium XXIV, Nov. 7-10, 2007”, The Chemotherapy Foundation, Nov. 8, 2007, Retrieved from the Internet Jan. 13, 2010: URL:http://www.chemotherapyfoundationsymposium.org/meeting_archives/meetingarchives_tcf2007_main.html.
Anonymous: “Anticancer Agent—neratinib”, Manufacturing Chemist, Dec. 2010/Jan. 2011, p27.
Awada and Piccart-Gebhart, “Management of HER-2/Neu-Positive Metastatic Breast Cancer,” Eur. J. Cancer (Suppl. 6):2-9 (2008).
Awada et al., “Safety and Efficacy of Neratinib (HKI-272) in Combination with Vinorelbine in ErbB2+ Metastatic Breast Cancer,” Cancer Res. 69:24(Suppl 3) Abstr. 5095 (2009).
Awada et al., “Safety and Efficacy of Neratinib (HKI-272) in Combination with Vinorelbine in ErbB2+ Metastatic Breast Cancer (MBC),” Ann. Oncol. 21(Suppl. 4):iv62-iv63 Abstr. 145P (2010).
Awada et al., “Safety and efficacy of neratinib (HKI-272) plus vinorelbine in the treatment of patients with ErbB2-positive metastatic breast cancer pretreated with anti-HER2 therapy,” Ann. Oncol. 24(1):109-116 (2013) (Epub Sep. 11, 2012).
Azria et al., “[Radiotherapy and inhibitors of epidermal growth factor receptor: preclinical findings and preliminary clinical trials],” Bull Cancer. 90 Spec No:5202-S212 (2003). (Abstract only).
Badache and Goncalves, “The ErbB2 signaling network as a target for breast cancer therapy,” J. Mammary Gland Biol. Neoplasia 11(1):13-25 (2006).
Barton et al., “Predictive molecular markers of response to epidermal growth factor receptor(EGFR) family-targeted therapies,” Curr. Cancer Drug Targets 10(8):799-812 (2010).
Baselga and Swain, “Novel anticancer targets: revisiting ERBB2 and discovering ERBB3,” Nat. Rev. Cancer 9(7):463-475 (2009) (Epub Jun. 18, 2009).
Baselga, “Is there a role for the irreversible epidermal growth factor receptor inhibitor EKB-569 in the treatment of cancer? a mutation-driven question,” J. Clin. Oncol. 24(15):2225-2226 (2006).
Baselga, “Novel agents in the era of targeted therapy: what have we learned and how has our practice changed?” Ann. Oncol. 19(Suppl 7):vii281-vii288 (2008).
Baselga, “Treatment of HER2-Overexpressing Breast Cancer,” Ann. Oncol. (Suppl 7):vii36-vii40 (2010).
Bayes et al., “Gateways to clinical trials,” Methods Find. Exp. Clin. Pharmacol. 28(9):657-678 (2006).
Bedard et al., “Beyond trastuzumab: overcoming resistance to targeted HER-2 therapy in breast cancer,” Curr. Cancer Drug Targets 9(2):148-162 (2009).
Bedard et al., “Stemming resistance to HER-2 targeted therapy,” J. Mammary Gland Biol. Neoplasia 14(1):55-66 (2009) (Epub Mar. 4, 2009).
Belani, “The role of irreversible EGFR inhibitors in the treatment of non-small cell lung cancer: overcoming resistance to reversible EGFR inhibitors,” Cancer Invest. 28(4):413-423 (2010).
Bell and Haber, “A blood-based test for epidermal growth factor receptor mutations in lung cancer,” Clin. Cancer Res. 12(13):3875-3877 (2006).
Berns et al., “A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer,” Cancer Cell 12(4):395-402 (2007).
Berz and Wanebo, “Targeting the growth factors and angiogenesis pathways: small molecules in solid tumors,” J. Surg. Oncol. 103(6):574-586 (2011).
Besse et al., “Neratinib (HKI-272), an irreversible pan-ErbB receptor tyrosine kinase inhibitor: preliminary results of a phase 2 trial in patients with advanced non-small cell lung cancer,” Eur. J. Cancer (Suppl.):23 Abstr. 203 (2008).
Besse et al., “Targeted therapies in lung cancer,” Ann. Oncol. 18(Suppl. 9):ix135-ix142 (2007).
Bettendorf et al., “Chromosomal imbalances, loss of heterozygosity, and immunohistochemical expression of TP53, RB1, and PTEN in intraductal cancer, intraepithelial neoplasia, and invasive adenocarcinoma of the prostate,” Genes Chromosomes Cancer 47(7):565-572 (2008).
Bischoff and Ignatov, “The Role of Targeted Agents in the Treatment of Metastatic Breast Cancer,” Breast Care (Basel) 5(3):134-141 (2010) (Epub Jun. 16, 2010).
Blanco-Aparicio et al., “PTEN, More Than the AKT Pathway,” Carcinogenesis 28(7):1379-1386 (2007) (Epub Mar. 6, 2007).
Board et al., “Multiplexed assays for detection of mutations in PIK3CA,” Clin. Chem 54(4):757-760 (2008).
Bonanno et al., “Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors and new therapeutic perspectives in non small cell lung cancer,” Curr. Drug Targets 12(6):922-933 (2011).
Boschelli et al., “Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia,” Eur. J. Cancer. 46(10):1781-1789 (2010).
Boschelli, “4-Anilino-3-quinolinecarbonitriles: An Emerging Class of Kinase Inhibitors—An Update,” Med. Chem Rev. Online 1:457-463 (2004).
Bose and Ozer, “Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non-small cell lung cancer,” Expert Opin. Investig. Drugs 18(11):1735-1751 (2009).
Bose et al., “Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas,” Oncogene 17(1):123-127 (1998).
Bose et al., “Reduced expression of PTEN correlates with breast cancer progression,” Hum. Pathol. 33(4):405-409 (2002).
Boyce et al., “Requirement of pp60c-src expression for osteoclasts to form ruffled borders and resorb bone in mice,” J. Clin. Invest. 90(4):1622-1627 (1992).
Boyd et al., “Lapatanib: Oncolytic Dual EFGR and erbB-2 Inhibitor,” Drugs Future 30(12):1225-1239 (2005).
Brackstone et al., “Canadian initiatives for locally advanced breast cancer research and treatment: inaugural meeting of the Canadian Consortium for LABC,” Curr. Oncol. 18(3):139-144 (2011).
Bridges, “Current Progress Towards the Development of Tyrosine Kinase Inhibitors as Anticancer Agents,” Expert Opin. Emerg. Drugs. 3:279-292 (1998).
Brittain, Harry G. (Eds), “Polymorphism in Pharmaceutical Solids”, Chapters 1 and 5, Marcel Dekker, Inc., New York (1999).
Brook et al., “Management of transitional cell carcinoma by targeting the epidermal growth factor receptor,” Therapy 3(3):407-416 (2006).
Browne et al., “HER-2 Signaling and Inhibition in Breast Cancer,” Curr. Cancer Drug Targets 9(3):419-438 (2009).
Broxterman and Georgopapadakou, “Anticancer therapeutics: a surge of new developments increasingly target tumor and stroma,” Drug Resist. Updat. 10(4-5):182-193 (2007) (Epub Sep. 12, 2007).
Buerger et al., “Allelic length of a CA dinucleotide repeat in the egfr gene correlates with the frequency of amplifications of this sequence—first results of an inter-ethnic breast cancer study,” J. Pathol. 203(1):545-550 (2004).
Bullard Dunn et al., “Evolving Therapies and FAK Inhibitors for the Treatment of Cancer,” Anticancer Agents Med. Chem. 10(10):722-734 (2010).
Burstein et al., “Gastrointestinal and Cardiovascular Safety Profiles of Neratinib Monotherapy in Patients with Advanced Erbb2-Positive Breast Cancer,” Cancer Res. 69:Abst 5096 (2009).
Burstein et al., “HKI-272, an irreversible pan ErbB receptor tyrosine kinase inhibitor: preliminary phase 2 results in patients with advanced breast cancer,” Breast Cancer Res. Treat. 106(Suppl. 1):S268 Abstr. 6061 (2007).
Burstein et al., “Neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor: phase 2 results in patients with advanced HER2+ breast cancer,” Cancer Res. 69(2 Suppl.) Abstr. 37 (2009).
Burstein et al., “Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer,” J. Clin. Oncol. 28(8):1301-1307 (2010).
Burstein, “The Distinctive Nature of HER2-Positive Breast Cancers,” N. Engl. J. Med. 353(16):1652-1654 (2005).
Byrn et al., “Pharmaceutical solids: a strategic approach to regulatory considerations,” Pharm. Res. 12(7):945-954 (1995).
Callahan and Hurwitz, “Human epidermal growth factor receptor-2-positive breast cancer: Current management of early, advanced, and recurrent disease,” Curr. Opin. Obstet. Gynecol. 23(1):3743 (2011).
Campas et al., “Bibw-2992. Dual EGFR/HER2 Inhibitor Oncolytic;Tovok™,” Drugs Future 33(8):649-654 (2008).
Campbel et al., “Gefitinib for the Treatment of Non-Small-Cell Lung Cancer,” Expert Opin. Pharmacother. 11(8):1343-1357 (2010).
Cao et al., “Epidermal Growth Factor Receptor as a Target for Anti-Cancer Agent Design,” Anticancer Agents Med. Chem. 10(6):491-503 (2010).
Cappuzzo et al., “Surrogate predictive biomarkers for response to anti-EGFR agents: state of the art and challenges,” Int. J. Biol. Markers 22(1 Suppl 4):S10-S23 (2007).
Cardoso et al., “Locally Recurrent or Metastatic Breast Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up,” Ann. Oncol. 21(5):v15-v19 (2010).
Carney et al., “HER-2/neu diagnostics in breast cancer,” Breast Cancer Res. 9(3):207 (2007).
Carter et al., “Small-Molecule Inhibitors of the Human Epidermal Receptor Family,” Expert Opin. Investig. Drugs 18(12):1829-1842 (2009).
Cascone et al., “Epidermal Growth Factor Receptor Inhibitors in Non-Small-Cell Lung Cancer,” Expert Opin. Drug Discov. 2(3):335-348 (2007).
Centre de Lutte Contre le Cancer Georges-Francois Leclerc (Fumoleau P. Study chair): “Lapatinib and Vinorelbine in Treating Women With HER2-Overexpressing Locally Advanced or Metastatic Breast Cancer” Clinical Trials Aug. 6, 2007 Retrieved from the Internet: URL:http://clinicaltrials.gov/ct2/show/NCT00513058?term=lapatinib+and+vinorelbine&rank=1 [dated Jan. 13, 2010].
Chan and Giaccia, “Harnessing Synthetic Lethal Interactions in Anticancer Drug Discovery,” Nat. Rev. Drug Discov. 10(5):351-364 (2011).
Chan, “A review of the use of trastuzumab (Herceptin®) plus vinorelbine in metastatic breast cancer,” Ann. Onco1.18(7):1152-1158 (2007) (Epub Jan. 29, 2007) Review.
Chandrasekaran et al., “Reversible Covalent Binding of Neratinib to Human Serum Albumin in Vitro,” Drug Metab. Left. 4(4):220-227 (2010).
Chen et al., “Epidermal growth factor receptor inhibitors: current status and future directions,” Curr. Probl. Cancer 33(4):245-294 (2009).
Chenoweth, “Can single-patient investigational new drug studies hurry slow trains to the fast track?” Drug Discov. Today 11(5-6):185-186 (2006).
Cheung and Paterson, “American Chemical Society—226th National Meeting. Pain and Oncology,” Idrugs 6(10):935-936 (2003).
Chew, H. K. et al., EGFR Inhibition with Lapatinib in Combination with Vinorelbine: a Phase I Study, Chemotherapy Foundation Symposium XXV, Chemotherapy Foundation, 2007, [dated Aug. 30, H-25 (2013)], obtained from the Internet, URL, http://chemotherapyfoundationsymposium.org/CMS/2007-archives-main.
Chew, Helen K., MD (University of California, Davis): “Lapatinib and Vinorelbine in Treating Patients With Advanced Solid Tumors” ClinicalTrials, Oct. 18, 2006, Retrieved from the Internet: URL:http//clinicaltrials.gov/ct2/show/NCT00389922?term=lapatinib+and+vinorelnine&rank=2 [dated Jan. 13, 2010].
Chien and Rugo, “The Cardiac Safety of Trastuzumab in the Treatment of Breast Cancer,” Expert Opin. Drug Saf. 9(2):335-346 (2010).
Chirieac and Dacic, “Targeted Therapies in Lung Cancer,” Surg. Pathol. Clin. 3(1):71-82 (2010).
Chmielecki et al. Selection for the EGFR T790M gatekeeper resistance mutation may vary among different small molecule EGFR TKIs [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; Apr. 17-21, 2010; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1774.
Cho et al., “Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab,” Nature 421(6924):756-760 (2003).
Chonn et al., “Recent Advances in Liposomal Drug-Delivery Systems,” Curr. Opin. Biotechnol. 6(6):698-708 (1995).
Chow et al., “Safety and efficacy of neratinib (HKI-272) in combination with pacl*taxel in ErbB2+ metastatic breast cancer,” Cancer Res. (Meeting Abstracts) 69:S5081 (2009).
Chow et al., “Safety and efficacy of neratinib (HKI-272) in combination with pacl*taxel in patients with solid tumors,” J. Clin. Oncol. (Meeting Abstracts) 27(155):3557 (2009).
Chow et al., “Safety and efficacy of neratinib (HKI-272) in combination with pacl*taxel in ERBB2+ metastatic breast cancer (MBC),” Ann. Oncol. 21(Suppl 4):iv62 Abstr. 144P (2010).
Cicenas, “The Potential Role of the EGFR/ERBB2 Heterodimer in Breast Cancer,” Expert Opin. Ther. Patents 17(6):607-616 (2007).
Clouser et al., “Biomarker Targets and Novel Therapeutics,” Cancer Treat. Res. 149:85-105 (2009).
Cobleigh et al., “Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease,” J. Clin. Oncol. 17(9):2639-2648 (1999).
Collins et al., “Lapatinib: a competitor or companion to trastuzumab?” Cancer Treat. Rev. 35(7):574- 581 (2009).
Colombo et al., “HER2 targeting as a two-sided strategy for breast cancer diagnosis and treatment: Outlook and recent implications in nanomedical approaches,” Pharmacol. Res. 62(2):150-165 (2010) (Epub Feb. 1, 2010).
Cooper and Cohen, “Mechanisms of resistance to EGFR inhibitors in head and neck cancer,” Head Neck 31(8):1086-1094 (2009).
Correspondence from Chilean associate regarding a First Office Action issued in corresponding Chilean Patent Application No. 2961-2006 in 2009-2010.
Correspondence from Israeli associate regarding a First Office Action issued in corresponding Israeli Patent Application No. 190805 in 2010.
Correspondence from Peruvian associate regarding an Opposition filed against corresponding Peruvian Patent Application No. 001 342-2006/QIN in 2007.
Cortes-Funes et al., “Neratinib, an Irreversible Pan Erb Receptor Tyrosine Kinase Inhibitor Active for Advanced HER2+ Breast Cancer,” Breast Cancer Res. 11 Suppl 1:S19 (2009).
Coughlin et al., “Approaches and limitations of phosphatidylinositol-3-kinase pathway activation status as a predictive biomarker in the clinical development of targeted therapy,” Breast Cancer Res. Treat. 124(1):1-11 (2010) (Epub Aug. 28, 2010).
Cox, “Regression Models and Life Tables (With Discussion),” Journal of the Royal Statistical Society. Series B (Methodological), vol. 34, No. 2. (1972), pp. 187-220.
Da Cunha Santos et al., “EGFR Mutations and Lung Cancer,” Ann. Rev. Pathol. 6:49-69 (2011).
Damia and D'Incalci, “Contemporary pre-clinical development of anticancer agents—what are the optimal preclinical models?” Eur. J. Cancer 45(16):2768-2781 (2009) (Epub Sep. 15, 2009).
Dancey, “Epidermal growth factor receptor inhibitors in non-small cell lung cancer,” Drugs 67(8):1125-1138 (2007).
Dang et al.,“The safety of dose-dense doxorubicin and cyclophosphamide followed by pacl*taxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer,” J. Clin. Oncol. 26(8):1216-1222 (2008).
Daniele and Sapino, “Anti-HER2 treatment and breast cancer: state of the art, recent patents, and new strategies,” Recent Pat. Anticancer Drug Discov. 4(1):9-18 (2009).
Davidian, M. (2006) Introduction to statistical population modeling and analysis for pharmaco*kinetic data. Invited white paper for the International Workshop on Uncertainty and Variability in Physiologically Based Pharmaco*kinetic (PBPK) Models. Retrieved from the Internet: URL:http://www.epa.gov/nect/uvpkm/files/Calibration_PreMeeting_Draft.pdf (89 pages) [dated Jan. 29, 2014].
Davidson, “HER2-Targeted Therapies: How Far We've Come-And Where We're Headed,” Oncology . (Williston Park) 25(5):425-426 (2011).
Davoli et al., “Progression and Treatment of HER2-Positive Breast Cancer,” Cancer Chemother. Pharmacol. 65(4):611-623 (2010) (Epub Dec. 20, 2009).
De Luca and Normanno, “Predictive biomarkers to tyrosine kinase inhibitors for the epidermal growth factor receptor in non-small-cell lung cancer,” Curr. Drug Targets 11(7):851-864 (2010).
De Maio et al., “Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a single-centre phase 2 trial,” BMC Cancer. 7:50 (2007).
De Seranno and Meuwissen, “Progress and Applications of Mouse Models for Human Lung Cancer,” Eur. Respir. J. 5(2):426-443 (2010).
Dempke and Heinemann, “Resistance to EGF-R (erbB-1) and VEGF-R modulating agents,” Eur. J. Cancer 45(7):1117-1128 (2009) (Epub Jan. 3, 2009).
Depowski et al., “Loss of expression of the PTEN gene protein product is associated with poor outcome in breast cancer,” Mod. Pathol. 14(7):672-676 (2001).
Di Cosimo and Baselga, “Management of breast cancer with targeted agents: importance of heterogeneity. [corrected].” Nat. Rev. Clin. Oncol. 7(3):139-147 (2010) (Epub Feb. 2, 2010).
Di Cosimo and Baselga, “Targeted Therapies in Breast Cancer: Where Are We Now?” Eur. J. Cancer 44(18):2781-2790 (2008) (Epub Nov. 14, 2008).
Di Maio et al., “New drugs in advanced non-small-cell lung cancer: searching for the correct clinical development,” Expert Opin. Investig. Drugs 19(12):1503-1514 (2010) (Epub Nov. 4, 2010).
Dickler, “Updates on Therapeutic Approaches in HER2-Positive Disease,” Clin. Adv. Hematol. Oncol. 8(2):105-107 (2010).
Dinh et al., “Trastuzumab for early breast cancer: current status and future directions,” Clin. Adv. Hematol. Oncol. 5(9):707-717 (2007).
Dirix et al., “Neratinib Monotherapy in Patients with Advanced ERBB2-Positive Breast Cancer: Gastrointestinal and Cardiovascular Safety Profiles,” Ann. Oncol. 21(Suppl 4):iv61-iv62 Abstr. 141P (2010).
Doebele et al., “New strategies to overcome limitations of reversible EGFR tyrosine kinase inhibitor therapy in non-small cell lung cancer,” Lung Cancer 69(1):1-12 (2010) (Epub Jan. 25, 2010).
Dowsett and Dunbier, “Emerging Biomarkers and New Understanding of Traditional Markers in Personalized Therapy for Breast Cancer,” Clin. Cancer Res. 14(24):8019-8026 (2008).
Eck and Yun, “Structural and Mechanistic Underpinnings of the Differential Drug Sensitivity of EGFR Mutations in Non-Small Cell Lung Cancer,” Biochim. Biophys. Acta 1804(3):559-566 (2010).
Egloff and Grandis, “Targeting epidermal growth factor receptor and SRC pathways in head and neck cancer,” Semin. Oncol. 35(3):286-297 (2008).
Eichhorn et al., “Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235,” Cancer Res. 68(22):9221-9230 (2008).
Einhorn et al., “Summary Report 7th Annual Targeted Therapies of the Treatment of Lung Cancer,” J. Thorac. Oncol. 3(5):545-555 (2008).
Ellis and Crowder, “PIKing” the winner for phosphatidylinositol 3-kinase inhibitors in ErbB2-positive breast cancer: let's not “PTENed” it's easy! Clin. Cancer Res. 13(19):5661-5662 (2007).
Engelman and Settleman, “Acquired Resistance to Tyrosine Kinase Inhibitors During Cancer Therapy,” Curr. Opin. Genet. Dev. 18(1):73-79 (2008) (Epub Mar. 5, 2008).
Engelman, “Targeting PI3K Signalling in Cancer: Opportunities, Challenges and Limitations,” Nat. Rev. Cancer 9(8):550-562 (2009).
Engleman and Jänne, “Mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer,” Clin. Cancer Res. 14(10):2895-2899 (2008).
English Translation of an Opposition filed against corresponding Ecuador Patent Application No. SP-08-8423 in 2008.
Ercan et al., “Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor,” Oncogene. 29(16):2346-2356 (2010) (Epub Feb. 1, 2010).
Esteva et al., “Molecular predictors of response to trastuzumab and lapatinib in breast cancer,” Nat. Rev. Clin. Oncol. 7(2):98-107 (2010) (Epub Dec. 22, 2009).
Ettinger et al., “Antiemesis,” J. Natl. Compr. Canc. Netw. 10(4):456-485 (2012).
Eyles et al., “Oral delivery and fate of poly(lactic acid) microsphere-encapsulated interferon in rats,” J. Pharm. Pharmacol. 49(7):669-674 (1997).
Farley and Birrer, “Novel Therapeutic Targets,” Cancer Treat. Res.149:63-84 (2009).
Felip et al., “Emerging Drugs for Non-Small-Cell Lung Cancer,” Expert Opin. Emerg. Drugs 12(3):449-460 (2007).
Ferron et al., “Oral bioavailability of pantoprazole suspended in sodium bicarbonate solution,” Am. J. Health Syst. Pharm. 60(13):1324-1329 (2003).
Ferté et al., “Molecular circuits of solid tumors: prognostic and predictive tools for bedside use,” Nat. Rev. Clin. Oncol. 7(7):367-380 (2010) (Epub Jun. 15, 2010).
Fleming et al., “Nitrile-containing pharmaceuticals: efficacious roles of the nitrile pharmacophore,” J. Med. Chem. 53(22)7902-7917 (2010) (Epub Aug. 30, 2010).
Fleming et al., “Phase II trial of temsirolimus in patients with metastatic breast cancer,” Breast Cancer Res. Treat. 136(2):355-363 (2012) (Epub Jan. 13, 2012).
Folkman, “Angiogenesis in cancer, vascular, rheumatoid and other disease,” Nat. Med. 1(1):27-31 (1995).
Früh, “The search for improved systemic therapy of non-small cell lung cancer—what are today's options?” Lung Cancer 72(3):265-270 (2011) (Epub Apr. 14, 2011).
Gadji et al., “EGF receptor inhibitors in the treatment of glioblastoma multiform: old clinical allies and newly emerging therapeutic concepts,” Eur. J. Pharmacol. 625(1-3):23-30 (2009) (Epub Oct. 18, 2009).
Gajria and Chandarlapaty, “HER2-amplified breast cancer: mechanisms of trastuzumab resistance and novel targeted therapies,” Expert Rev. Anticancer Ther. 11(2):263-275 (2011).
Gajria et al., “Tolerability and Efficacy of Targeting Both mTOR and HER2 Signaling in Trastuzumab-Refractory HER2+ Metastatic Breast Cancer,” San Antonio Breast cancer Symposium. Abstract P5-18-04 (2010).
Gao et al., “Controlled Release of a Contraceptive Steroid From Biodegradable and Injectable Gel Formulations: in Vitro Evaluation,” Pharm. Res. 12:857-863 (1995).
Garcia et al., “Promoter Methylation of the PTEN Gene Is a Common Molecular Change in Breast Cancer,” Genes Chromosomes Cancer 41(2):117-127 (2004).
Garrett and Arteaga, “Resistance to HER2-directed antibodies and tyrosine kinase inhibitors: mechanisms and clinical implications,” Cancer Biol. Ther. 11(9):793-800 (2011) (Epub May 1, 2011).
Gatzemeier, “Second-Generation EGFR Inhibitors and Combinations,” J. Thorac Oncol. 4(9): S121 (2009).
Gazdar, “Activating and Resistance Mutations of EGFR in Non-Small-Cell Lung Cancer: Role in Clinical Response to EGFR Tyrosine Kinase Inhibitors,” Oncogene 28:S24-S31 (2009).
Genentech, Herceptino®-Product Literature, www.Genetech.com, Sep. 1998 Revised (Jun. 2014), pp, 1-35.
Gennaro (Ed.), Remington's Pharmaceutical Sciences, 17th Edition, Alfonso R. Gennaro, Mack Publishing Company, Easton, PA (1985).
Geuna et al., “Hitting multiple targets in HER2-positive breast cancer: proof of principle or therapeutic opportunity?” Expert Opin. Pharmacother. 12(4):549-565 (2011) (Epub Jan. 6, 2011).
Geyer et al., “Lapatinib plus capecitabine for HER2-positive advanced breast cancer,” N. Engl. J. Med. 355(26):2733-2743 (2006).
Ghayad and Cohen, “Inhibitors of the PI3K/Akt/mTOR pathway: new hope for breast cancer patients,” Recent Pat. Anticancer Drug Discov. 5(1):29-57 (2010).
Giamas et al., “Kinases as Targets in the Treatment of Solid Tumors,” Cell. Signal. 22(7):984-1002 (2010) (Epub Jan. 21, 2010).
Glaxosmithkline, Tykerb Prescription Label, 2010, pp. 1-25.
Glück, “Chemotherapy Regimens in Metastatic Breast Cancer,” Clin. Adv. Hematol. Oncol. 9(1)47-48 (2011).
Godin-Heymann et al., “Oncogenic activity of epidermal growth factor receptor kinase mutant alleles is enhanced by the T790M drug resistance mutation,” Cancer Res. 67(15):7319-7326 (2007).
Godin-Heymann et al., “The T790M ”gatekeeper“ mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor,” Mol. Cancer Ther. 7(4):874-879 (2008).
Good, “A Comparison of Contact Angle Interpretations,” J. Colloid Interface Sci. 44(1):63-71 (1973).
Govindan, “A review of epidermal growth factor receptor/HER2 inhibitors in the treatment of patients with non-small-cell lung cancer,” Clin. Lung Cancer 11(1):8-12 (2010).
Gridelli et al., “Erlotinib in the Treatment of Non-small Cell Lung Cancer: Current Status and Future Developments,” Anticancer Res. 30:1301-1310 (2010).
Grimm et al., “Diagnostic and Therapeutic Use of Membrane Proteins in Cancer Cells,” Curr. Med. Chem. 18(2):176-190 (2011).
Guarneri et al., “Anti-HER2 neoadjuvant and adjuvant therapies in HER2 positive breast cancer,” Cancer Treat. Rev. 36 Suppl 3:S62-S66 (2010).
Guertin et al., “Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1,” Dev. Cell. 11(6):859871 (2006).
Hager et al., “PTEN expression in renal cell carcinoma and oncocytoma and prognosis,” Pathology 39(5):482-485 (2007) (Abstract Only).
Hammerman et al., “Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer,” Clin. Cancer Res. 15(24):7502-7509 (2009).
Hasselblatt, “Ependymal Tumors,” Recent Results Cancer Res. 171:51-66 (2009).
Hawkins and Grunberg, “Chemotherapy-Induced Nausea and Vomiting: Challenges and Opportunities for Improved Patient Outcomes,” Clin. J. Oncol. Nurs. 13(1):54-64 (2009).
Hegedus et al., “Interaction of ABC multidrug transporters with anticancer protein kinase inhibitors: substrates and/or inhibitors?” Curr. Cancer Drug Targets 9(3):252-272 (2009).
Heigener and Reck, “Mutations in the epidermal growth factor receptor gene in non-small cell lung cancer: Impact on treatment beyond gefitinib and erlotinib,” Adv. Ther. 28(2):126-133 (2011) (Epub Dec. 16, 2010).
Heigener, “Non-Small Cell Lung Cancer in Never-Smokers: a New Disease Entity?” Onkologie 34(4):202-207 (2011) (Epub Mar. 18, 2011).
Heist et al., “A phase II study of oxaliplatin, pemetrexed, and bevacizumab in previously treated advanced non-small cell lung cancer,” J. Thorac. Oncol. 3(10):1153-1158 (2008).
Higa et al., “Biological considerations and clinical applications of new HER2-targeted agents,” Expert Rev. Anticancer Ther. 10(9):1497-1509 (2010).
Ho and Laskin, “EGFR-directed therapies to treat non-small-cell lung cancer,” Expert Opin. Investig. Drugs 18(8):1133-1145 (2009).
Holodov and Yakovlev, Clinical Pharmaco*kinetics, Moscow, Medicine, (1985), pp. 83-98, 134- 138, 160, 378-380 (English translation not available).
Hookes and Lakeram, “American Chemical Society—235th National Meeting. Part 2: EGFR kinaseinhibitors and (33-lactamases under investigation by Wyeth” Idrugs 11(6):391-393 (2008).
Horn and Sandler, “Epidermal growth factor receptor inhibitors and antiangiogenic agents for the treatment of non-small cell lung cancer,” Clin. Cancer Res. 15(16):5040-5048 (2009) (Epub Aug. 11, 2009).
Hou and Kumamoto, “Flavonoids as protein kinase inhibitors for cancer chemoprevention: direct binding and molecular modeling,” Antioxid. Redox Signal. 13(5):691-719 (2010).
Huang et al., “Up-regulation of miR-21 by HER2/neu signaling promotes cell invasion,” J. Biol. Chem. 284(27):18515-18524 (2009) (Epub May 6, 2009).
Hubalek et al., “Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment,” Wien. Med. Wochenschr. 160(1920):506-512 (2010) (Epub Oct. 26, 2010).
Huber et al., “Pharmaco*kinetics of pantoprazole in man,” Int. J. Clin. Pharmacol. Ther. 34(5):185-194 (1996).
Hug et al., “A single-dose, crossover, placebo- and moxifloxacin-controlled study to assess the effects of neratinib (HKI-272) on cardiac repolarization in healthy adult subjects,” Clin. Cancer Res. 16(15):4016-4023 (2010) (Epub Jul. 20, 2010).
Hung and Lau, “Basic Science of HER-2/neu: a review,” Semin. Oncol. 26(4 Suppl 12):51-59 (1999).
Hungarian Intellectual Property Office Search Report for Hungarian Patent Application No. 201002712-6 (dated Aug. 4, 2011).
Hynes and Lane, “ERBB Receptors and Cancer: the Complexity of Targeted Inhibitors,” Nat. Rev. Cancer 5(5):341-354 (2005).
Ich Expert Working Group: Impurities in New Drug Substances Q3A (R2), “International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use” (Online) 2006.
Ikediobi, “Somatic Pharmacogenomics in Cancer,” Pharmacogenomics J. 8(5):305-314 (2008) (Epub Aug. 5, 2008).
Ikezoe et al., “Effect of SU11248 on gastrointestinal stromal tumor-T1 cells: enhancement of growth inhibition via inhibition of 3-kinase/Akt/mammalian target of rapamycin signaling,” Cancer Sci. 97(9):945-951 (2006).
Ikezoe et al., “The Anti-Tumor Effects of SU11248, a Class III Receptor Tyrosine Kinase Inhibitor, Against a Variety of Human Hematological Malignancies,” Blood (ASH Annual Meeting Abstracts) 106: Abstract 2795 (2005).
Ilango et al., “Investigation of Colon Specificity of Novel Polysaccharide-Okra Mucilage-Film Coated with Enteric Materials,” Int. J. Pharma. Bio. Sci. 3(2):52-62 (2012).
Iliadis et al., “APIS: a software for model identification, simulation and dosage regimen calculations in clinical and experimental pharmaco*kinetics,” Computer Methods Programs Biomed. 38(4):227-239 (1992).
International Preliminary Report on Patentability Chapter 1 for International Application No. PCT/US2009/047643 dated Dec. 18, 2010.
International Search Report for International Application No. PCT/US2008/080130, dated Apr. 5, 2009.
International Search Report for International Patent Application No. PCT/US2009/047643, dated Jan. 28, 2010.
Isakoff and Baselga, “Trastuzumab-DM1: building a chemotherapy-free road in the treatment of human epidermal growth factor receptor 2-positive breast cancer,” J. Clin. Oncol. 29(4):351-354 (2011) (Epub Dec. 20, 2010).
Ito et al., “A Phase 1 Study of Neratinib (HKI-272) in Combination with Pacl*taxel in Japanese Patients with Solid Tumors,” Ann. Oncol. 21 (Suppl 8):viii103 Abstr. 298P (2010).
Ito et al., “Tolerability and safety of oral neratinib (HKI-272) in Japanese patients with advanced solid tumors,” J. Clin. Oncol. 27:(suppl; abstr. e14505) (2009).
Jackisch, “Challenges in the treatment of ErbB2 (HER2)-positive breast cancer,” EJC Suppl. 6(5):7- 14 (2008).
Jahanzeb et al., “Phase II trial of weekly vinorelbine and trastuzumab as first-line therapy in patients with HER2+ metastatic breast cancer,” Oncologist 7(5):410-417 (2002).
Jallal et al., “A Src/Abl kinase inhibitor, SKI-606, blocks breast cancer invasion, growth, and metastasis in vitro and in vivo,” Cancer Res. 67(4):1580-1588 (2007).
Janczuk and Bialopiotrowicz, “Surface Free-Energy Components of Liquids and Low Energy . Solids and Contact Angles,” J. Colloid Interface Sci. 127(1):189-204 (1989).
Jänne et al., “Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors,” Clin. Cancer Res. 17(5):1131-1139 (2011) (Epub Jan. 10, 2011).
Jänne, “Challenges of detecting EGFR T790M in gefitinib/erlotinib-resistant tumours,” Lung Cancer 60 Suppl 2:S3-S9 (2008).
Japanese Official Action for Corresponding Japanese Patent Application No. 2010-258729, dated Apr. 12, 2013.
Japanese Official Action dated Sep. 17, 2013, for Japanese Patent Application No. 2011-289220.
Jasper, “The Surface Tension of Pure Liquid Compounds,” J. Phys. Chem. Ref. Data 1:841 (1972).
Jelliffe et al., “Adaptive control of drug dosage regimens: basic foundations, relevant issues, and . clinical examples,” Int. J. Biomed. Comput. 36(1-2):1-23 (1994).
Ji et al., “Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors,” Proc. Natl. Acad. Sci. U.S.A. 103(20):7817-7822 (2006) (Epub May 3, 2006).
Ji et al., “The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to Egfr-targeted therapies,” Cancer Cell. 9(6):485-495 (2006) (Epub May 25, 2006).
Jimeno and Hidalgo, “Pharmacogenomics of epidermal growth factor receptor (EGFR) tyrosine kinaseinhibitors,” Biochim. Biophys. Acta 1766(2):217-229 (2006) (Epub Sep. 12, 2006).
Johnson et al., “Cisplatin and Its Analogues,” Cancer Principles & Practice of Oncology, 6th Edition, Ed. Devita, V.T., Hellman, S., Rosenberg, S.A, Lippincott Williams & Wilkins. Philadelphia, 2001, pp. 376-388.
Johnson et al., “Impact of EGFR mutations on treatment of non-small cell lung cancer,” Cancer Chemother. Pharmacol. 58(Supp11): s5-s9 (2006).
Johnson et al., “Strategies for discovering and derisking covalent, irreversible enzyme inhibitors,” Future Med. Chem. 2(6):949-964 (2010).
Johnson, “Biomarkers of Lung Cancer Response to EGFR-TKI,” EJC Suppl. 5(8):14-15 Abstr. S23 (2007).
Johnson, “Protein kinase inhibitors: contributions from structure to clinical compounds,” Q. Rev. Biophys. 42(1):1-40 (2009) (Epub Mar. 19, 2009).
Jones and Buzdar, “Evolving Novel Anti-HER2 Strategies,” Lancet Oncol. 10(12):1179-1187 (2009).
Jones, “Adaptive trials receive boost,” Nat. Rev. Drug Discov. 9(5):345-348 (2010) (Epub Apr. 23, 2010).
Jones, “HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer,” J. Mammary Gland Biol. Neoplasia 13(2):247-258 (2008) (Epub May 13, 2008).
Joshi and Kucherlapati, “Pharmacogenomics of lung cancer: with a view to address EGFR-targeted therapies,” Pharmacogenomics 8(9):1211-1220 (2007).
Kamath and Buolamwini, “Targeting EGFR and HER-2 receptor tyrosine kinases for cancer drug discovery and development,” Med. Res. Rev. 26(5):569-594 (2006).
Kane, “Cancer Therapies Targeted to the Epidermal Growth Factor Receptor and Its Family Members,” Expert Opin. Ther. Pat. 16(2):147-164 (2006).
Kaplan and Meier, “Nonparametric Estimation From Incomplete Observations,” J. Am. Stat. Assoc. 53:457-481 (1958).
Katzel et al., “Recent advances of novel targeted therapy in non-small cell lung cancer,” .J Hematol. Oncool. 2:2 (2009).
Kennedy et al., “Novel Agents in the Management of Lung Cancer,” Curr. Med. Chem. 17(35):4291- 4325 (2010).
Kim et al., “Chasing targets for EGFR tyrosine kinase inhibitors in non-small-cell lung cancer: Asian perspectives,” Expert Rev. Mol. Diagn.7(6):821-836 (2007).
Kim et al., “The role of HER-2 oncoprotein in drug-sensitivity in breast cancer (Review),” Oncol. Rep. 9(1):3-9 (2002).
Klein and Levitzki, “Targeting the EGFR and the PKB Pathway in Cancer,” Curr. Opin. Cell. Biol. 21(2):185-193 (2009) (Epub Feb. 11, 2009).
Klüter et al., “Characterization of irreversible kinase inhibitors by directly detecting covalent bond formation: a tool for dissecting kinase drug resistance,” ChemBioChem 11(18):2557-2566 (2010).
Kotteas et al., “Targeted therapy for nonsmall cell lung cancer: focusing on angiogenesis, the epidermal growth factor receptor and multikinase inhibitors,” Anticancer Drugs 21(2):151-168 (2010).
Krop, “Managing Trastuzumab-resistant Breast Cancer,” Clin. Adv. Hematol. Oncol. 7(2):108-110 (2009).
Kuznar, “New Small Molecule Added to Trastuzumab Improves Survival in Metastatic Disease,” Am. Health Drug Benefits 2(5):27 (2009).
La Motta et al., “Computational studies of epidermal growth factor receptor: docking reliability, three-dimensional quantitative structure-activity relationship analysis, and virtual screening studies,” J. Med. Chem. 52(4):964-975 (2009).
Laack et al., “Lessons learnt from gefitinib and erlotinib: Key insights into small-molecule EGFR-targeted kinase inhibitors in non-small cell lung cancer,” Lung Cancer 69(3):259-264 (2010) (Epub Jun. 19, 2010).
Lam and Mok, “Targeted Therapy: an Evolving World of Lung Cancer,” Respirology 16(1):13-21 (2011) (Epub Aug. 16, 2010).
Langdon et al., “Pertuzumab—Humanized anti-HER2 monoclonal antibody HER dimerization inhibitor oncolytic,” Drugs Future 33(2):123-130 (2008).
Langer and Soria, “The role of anti-epidermal growth factor receptor and anti-vascular endothelial growth factor therapies in the treatment of non-small-cell lung cancer,” Clin. Lung Cancer 11(2):82-90 (2010).
Langlois et al., “Application of a modification of the Polonovski reaction to the synthesis of vinblastine-type alkaloids,” J. Am. Chem. Soc. 98(22):7017-7024 (1976).
Lapatinib and Vinorelbine in Treating Patients with Advanced Solid Tumors, clinicaltrials.gov, [Online], U.S. National Institutes of Health, May 26, 2008, [Retrieved Aug. 30, H-25 (2013)], obtained from the Internet, URL, http://clinic altrials .gov/archive/NCT00389922/2008_05_26.
Lapatinib and Vinorelbine in Treating Women With HER2-Overexpressing Locally Advanced or Metastatic Breast Cancer, http://clinicaltrials.gov, [Online], U.S. National Institutes of Health, May 26, 2008, [Retrieved Aug. 30, H-25 (2013)], obtained from the Internet, URL, http://clinicaltrials.gov/archive/NCT00513058/2008_05_26.
Lee et al., “Lung Cancer in Never Smokers: Change of a Mindset in the Molecular Era,” Lung Cancer 72(1):9-15 (2011) (Epub Jan. 26, 2011).
Lee et al., “Phase II Study of Vinorelbine Plus Trastuzumab in HER2 Overexpressing Metastatic Breast Cancer Pretreated with Anthracyclines and Taxanes,” J. Breast Cancer 14(2):140-146 (2011).
Leone and Dudek, “Enzyme replacement therapy for Gaucher's disease in patient treated for non-small cell lung cancer,” Anticancer Res. 28(6B):3937-3939 (2008).
Levitzki and Mishani, “Tyrphostins and other tyrosine kinase inhibitors,” Annu. Rev. Biochem. 75:93-109 (2006).
Li and Perez-Soler, “Skin toxicities associated with epidermal growth factor receptor inhibitors,” Target. Oncol. 4(2):107-119 (2009) (Epub May 19, 2009).
Li and Sun, “PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells,” Proc. Natl. Acad. Sci. U.S.A. 95(26):15406-15411 (1998).
Li and Sun, “TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factorβ” Cancer Res. 57(11):2124-2129 (1997).
Li et al., “BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models,” Oncogene 27(34):4702-4711 (2008) (Epub Apr. 14, 2008).
Li et al., “Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy,” Cancer Cell 12(1):81-93 (2007).
Li et al., “PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer,” Science 275(5308):1943-1947 (1997).
Ligibel and Winer, “Trastuzumab/chemotherapy combinations in metastatic breast cancer,” Semin. Oncol. 29(3 Suppl 11):38-43 (2002).
Limentani et al., “Safety and Efficacy of Neratinib (HKI-272) in Combination with Vinorelbine in Patients with Solid Tumors,” J. Clin. Oncol. (Meeting Abstracts) 27(15S):e14554 (2009).
Lin and Winer, “Chemotherapy agents in human epidermal growth factor receptor 2-positive breast cancer: time to step out of the limelight,” J. Clin. Oncol. 29(3):251-253 (2011) (Epub Dec. 13, 2010).
Lin and Yang, “Epidermal growth factor receptor tyrosine kinase inhibitors in elderly or poor performance status patients with advanced non-small cell lung cancer,” Target. Oncol. 4(1):37-44 (2009) (Epub Jan. 20, 2009).
Linardou et al., “Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC,” Nat. Rev. Clin. Oncol. 6(6):352-366 (2009).
Little, “Molecular Tests, Targets and Therapies for Cancer,” EPC (DIA 43rd Annual Meeting Edition) pp. 98 (2007).
Liu et al., “Targeting epidermal growth factor receptor in lung cancer: Perspective from the Asia—Pacific region,” Asia-Pac. J. Clin. Oncol. 2:22-31 (2006).
Locker et al., “ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer,” J. Clin. Oncol. 24(33):5313-5327 (2006) (Epub Oct. 23, 2006).
Loew et al., “The epidermal growth factor receptor as a therapeutic target in glioblastoma multiforme and other malignant neoplasms,” Anticancer Agents Med. Chem. 9(6):703-715 (2009).
Loke, “Drug-drug interactions—bridging the gulf between the bench and the bedside?” Br. J. Clin. Pharmacol. 71(4):485-486 (2011).
LoPiccolo et al., “Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations,” Drug Resist. Updat. 11(1-2):32-50 (2008) (Epub Dec. 31, 2007).
Loriot et al., “Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy,” Nat. Clin. Pract. Oncol. 5(5):268-278 (2008) (Epub Mar. 18, 2008).
Loriot et al., “Pemetrexed-induced pneumonitis: a case report,” Clin. Lung Cancer 10(5):364-366 (2009).
Lorusso and Eder, “Therapeutic potential of novel selective-spectrum kinase inhibitors in oncology,” Expert Opin. Investig. Drugs 17(7):1013-1028 (2008).
Lou et al., “Progress in Target Therapy for Breast Cancer,” J. Oncology 15(9):788-795 (2009). (English Abstract).
Lu and Ku, “Preformulation stability study of the EGFR inhibitor HKI-272 (Neratinib) and mechanism of degradation,” Drug Dcv. Ind. Pharm. 1-7 (2011).
Lu et al., “The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells,” Oncogene 18(50):7034-7045 (1999).
Lynch et al., “Novel Agents in theTreatment of Lung Cancer: Fourth Cambridge Conference,” Clin. Cancer Res. 13(15 Suppl.):4583s-4588s (2007).
Lynch et al., “Summary statement novel agents in the treatment of lung cancer: Fifth Cambridge Conference assessing opportunities for combination therapy,” J. Thorac. Oncol. 3(6 Suppl 2):S107-S112 (2008).
Lynch, “Molecular Staging of NSCLC: 2006,” EJC (Suppl 4):24-25 Abstr. S55 (2006).
Ma et al., “PIK3CA as an oncogene in cervical cancer,” Oncogene 19(23):2739-2744 (2000).
Macrinici and Romond, “Clinical updates on EGFR/HER targeted agents in early-stage breast cancer,” Clin. Breast Cancer 10 Suppl 1:E38-E46 (2010).
Maehama et al., “A sensitive assay for phosphoinositide phosphatases,” Anal. Biochem. 279(2):248- 250 (2000).
Maehama et al., “PTEN and myotubularin: novel phosphoinositide phosphatases,” Annu. Rev. Biochem. 70:247-279 (2001).
Maehama, “PTEN: its deregulation and tumorigenesis,” Biol. Pharm. Bull. 30(9):1624-1627 (2007).
Mallon et al., “Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor,” . Clm. Cancer Res. 17(10):3193-3203 (2011) (Epub Feb. 15, 2011).
Man et al., “New and established targets for the treatment of breast cancer,” Adv. Breast Cancer 7(3):10-13 (2010).
Mangeney et al., “5'-Nor anhydrovinblastine: Prototype of a new class of vinblastine derivatives,” Tetrahedron 35(18):2175-2179 (1979).
Mantel and Haenszel, “Statistical aspects of the analysis of data from retrospective studies of disease,” J. Natl. Cancer Inst. 22(4):719-748 (1959).
Martinez-Garcia et al., “Tyrosine Kinase Inhibitors in Breast Cancer: Present Status and Perspectives,” Cancer Chemother. Rev. 186-194 (2010).
Mattsson and Clowes, “Current concepts in restenosis following balloon angioplasty,” Trends Cardiovasc. Med. 5(5):200-204 (1995).
Mauriz and Gonzalez-Gallego, “Antiangiogenic drugs: current knowledge and new approaches to cancer therapy,” J. Pharm. Sci. 97(10):4129-4154 (2008).
Mayer, “Treatment of HER2-positive metastatic breast cancer following initial progression,” Clin. Breast Cancer 9 Suppl 2:S50-S57 (2009).
McDermott et al., “Acquired resistance of non-small cell lung cancer cells to MET kinase inhibition is mediated by a switch to epidermal growth factor receptor dependency,” Cancer Res. 70(4):1625-1634 (2010) (Epub Feb. 2, 2010).
McDermott et al., “High-throughput lung cancer cell line screening for genotype-correlated sensitivity to an EGFR kinase inhibitor,” Methods Enzymol. 438:331-341 (2008).
McDermott et al., “Identification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profiling,” Proc. Natl. Acad. Sci. U.S.A. 104(50):19936-19941 (2007) (Epub Dec. 6, 2007).
Mehta and Osipo, “Trastuzumab resistance: role for Notch signaling,” ScientificWorldJournal 9:1438-1448 (2009).
Mendoza, “Targeted therapies in the treatment of advanced non-small-cell lung cancer: update,” Klin. Onkol. 22(4):131-138 (2009).
Meng et al., “MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer,” Gastroenterology 133(2):647-658 (2007) (Epub May 21, 2007).
Metro and Cappuzzo, “New targeted therapies for non-small-cell lung cancer,” Therapy 6(3):335- 350 (2009).
Metzger-Filho et al., “Management of metastatic HER2-positive breast cancer progression after adjuvant trastuzumab therapy-current evidence and future trends,” Expert Opin. Investig. Drugs 19 Suppl 1:S31-S39 (2010).
Metzger-Filho et al., “Molecular targeted therapy in prevalent tumors: learning from the past and future perspectives,” Current Clin. Pharmacol. 5(3):166-177 (2010).
Meyerhardt et al., “Phase II study of capecitabine, oxaliplatin, and erlotinib in previously treated patients with metastastic colorectal cancer,” J. Clin. Oncol. 24(12):1892-1897 (2006).
Minami et al., “The major lung cancer-derived mutants of ERBB2 are oncogenic and are associated with sensitivity to the irreversible EGFR/ERBB2 inhibitor HKI-272,” Oncogene 26(34):5023-5027 (2007) (Epub Feb. 19, 2007).
Minkovsky and Berezov, “BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors,” Curr. Opin. Investig. Drugs 9(12):1336-1346 (2008).
Moasser, “Targeting the function of the HER2 oncogene in human cancer therapeutics,” Oncogene 26(46):6577-6592 (2007) (Epub 2007 May 7).
Morabito et al., “Methodological Issues of Clinical Research with EGFR Inhibitors,” Curr. Cancer Ther. Rev. 3(4):292-302 (2007).
Moreno-Aspitia and Perez, “Treatment options for breast cancer resistant to anthracycline and taxane,” Mayo Clin. Proc. 84(6):533-545 (2009).
Morozova et al., “System-level analysis of neuroblastoma tumor-initiating cells implicates AURKB as a novel drug target for neuroblastoma,” Clin. Cancer Res. 16(18):4572-4582 (2010) (Epub Jul. 22, 2010).
Morris and Hudis, “Personalizing therapy for metastatic breast cancer,” Expert Rev. Anticancer Ther. 9(9):1223-1226 (2009).
Morrow et al., “Recent advances in systemic therapy: Advances in systemic therapy for HER2-positive metastatic breast cancer,” Breast Cancer Res. 11(4):207 (2009) (Epub Jul. 15, 2009).
Mukai, “Targeted therapy in breast cancer: current status and future directions,” Jpn. J. Clin. Oncol. 40(8):711-716 (2010) (Epub Apr. 8, 2010).
Mukai, “Treatment strategy for HER2-positive breast cancer,” Int. J. Clin. Oncol. 15(4):335-340 (2010) (Epub Jul. 15, 2010).
Mukherji and Spicer, “Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer,” Expert Opin. Investig. Drugs 18(3):293-301 (2009).
Mullard, “2010 in Reflection,” Nat. Rev. Drug Discov. 10:7-9 (2011).
Munagala et al., “Promising molecular targeted therapies in breast cancer,” Indian J. Pharmacol. 43(3):236-245 (2011).
Mundhenke et al., “Significance of Tyrosine Kinase Inhibitors in the Treatment of Metastatic Breast Cancer,” Breast Care (Basel) 4(6):373-378 (2009) (Epub Nov. 16, 2009).
Murphy and Fornier, “HER2-positive breast cancer: beyond trastuzumab,” Oncology (Williston Park) 24(5):410-415 (2010).
Muthuswamy, “Trastuzumab resistance: all roads lead to Src,” Nat. Med. 17(4):416-418 (2011).
Nagata et al., “PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients,” Cancer Cell vol. 6(2):117-127 (2004).
Nahta and O'Regan, “Evolving strategies for overcoming resistance to HER2-directed therapy: targeting the PI3K/AKT/mTOR pathway,” Clin. Breast Cancer 10 Suppl 3:S72-S78 (2010).
Natoli et al., “Tyrosine kinase inhibitors,” Curr. Cancer Drug Targets 10(5):462-483 (2010).
Nguyen et al., “Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway,” Clin. Lung Cancer 10(4):281-289(2009).
Nielsen et al., “HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors,” Cancer Treat Rev. 35(2):121-136 (2009) (Epub Nov. 12, 2008).
Nitz, “Perspectives: Other ErbB2-Targeted Therapies,” Breast Care (Basel) 5(s1):25-27 (2010) (Epub Apr. 26, 2010).
Nolè et al., “Dose-finding and pharmaco*kinetic study of an all-oral combination regimen of oral vinorelbine and capecitabine for patients with metastatic breast cancer,” Ann. Oncol. 17(2):322-329 (2006) (Epub Nov. 22, 2005).
O'Brien et al., “Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib,” Mol. Cancer Ther. 9(6):1489-1502 (2010) (Epub May 25, 2010).
Ocaña and Amir, “Irreversible pan-ErbB tyrosine kinase inhibitors and breast cancer: current status and future directions,” Cancer Treat. Rev. 35(8):685-691 (2009) (Epub Sep. 4, 2009).
Ocaña and Pandiella, “Identifying breast cancer druggable oncogenic alterations: lessons learned and future targeted options,” Clin. Cancer Res. 14(4):961-970 (2008).
Ocaña et al., “New Targeted Therapies in Head and Neck Cancer,” Cancer Chemo. Rev. 4:35-43 (2009).
Ocaña et al., “Novel tyrosine kinase inhibitors in the treatment of cancer,” Curr. Drug Targets 10(6):575-576 (2009).
Ocaña et al., “Preclinical development of molecular-targeted agents for cancer,” Nat. Rev. Clin. Oncol. 8:200-209 (2011).
Office Action dated May 26, 2010 issued in corresponding European Patent Application No. 06836862.0.
Office Action dated Oct. 28, 2013 issued in corresponding Japanese Patent Application No. 2012- 179873.
Official Action from corresponding Japanese Application Jp 2012-279650, dated Apr. 22, 2014 [along with an English Translation, received Jul. 16, 2014].
Office Action issued in corresponding Pakistan Patent Application No. 1456/2006 in 2007.
Official Action and Search Report with English Translation, dated Jun. 18, 2013, for corresponding Chinese Application No. 201210328133.2.
O'Hare et al., “Bcr-Abl kinase domain mutations and the unsettled problem of Bcr-AblT315I: looking into the future of controlling drug resistance in chronic myeloid leukemia,” Clin. Lymphoma Myeloma 7 Suppl 3:S120-S130 (2007).
Omuro et al., “Lessons learned in the development of targeted therapy for malignant gliomas,” Mol. Cancer Ther. 6(7):1909-1919 (2007).
O'Neil et al., (ed.). The Merck Index—An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th . Edition, Whitehouse Station, Nj: Merck and Co., Inc., 2001., pp. 1454-1455.
Oshima, “Crystallization of Polymorphs and Pseudo-Polymorphs and Its Control,” Pharm. Stage 6(10):48-53 (2007). [English Translation Not Available].
Ostro and Cullis, “Use of liposomes as injectable-drug delivery systems,” Am. J. Hosp. Pharm. 46(8):1576-1587 (1989).
Ouchi et al., “Antitumor activity of erlotinib in combination with capecitabine in human tumor xenograft models,” Cancer Chemother. Pharmacol. 57(5):693-702 (2006).
Pal et al., “Targeted therapies for non-small cell lung cancer: an evolving landscape,” Mol. Cancer Ther. 9(7):1931-1944 (2010) (Epub Jun. 22, 2010).
Pallis et al., “Targeted therapies in the treatment of advanced/metastatic NSCLC,” Eur. J. Cancer 45(14):2473-2487 (2009).
Pantuck et al., “Prognostic relevance of the mTOR pathway in renal cell carcinoma: implications for molecular patient selection for targeted therapy,” Cancer 109(11):2257-2267 (2007).
Pao and Chmielecki, “Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer,” Nat. Rev. Cancer 10(11):760-774 (2010) (Epub Oct. 22, 2010).
Pao, “Defining clinically relevant molecular subsets of lung cancer,” Cancer Chemother. Pharmacol. 58(Suppl 1):s11-s15 (2006).
Papaldo et al., “A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease,” Ann. Oncol. 17(4):630-636 (2006) (Epub Jan. 12, 2006).
Parideans et al., “Neratinib (HKI-272), an irreversible pan-ErbB receptor tyrosine kinase inhibitor: Phase 2 results in patients with ErbB2+ advanced breast cancer,” Ann. Oncol. 20(Suppl 2):ii61-ii62 Abstr. 186P (2009).
Parkin and Fernández, “Use of statistics to assess the global burden of breast cancer,” Breast J. 12(Suppl 1):570-580 (2006).
Pegram et al., “Expert roundtable: emerging questions in ErbB2-positive breast cancer; Feb. 22, 2007,” Clin. Breast Cancer 8(Suppl 3):5131-5141 (2008).
Pegram et al., “The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer,” Cancer Treat. Res. 103:57-75 (2000).
Perez et al., “Updated Results of the Combined Analysis of NCCTG N9831 and NSABP B-31 Adjuvant Chemotherapy With/Without Trastuzumab in Patients with HER2-Positive Breast Cancer,” J. Clin. Oncol. ASCO Annual Meeting Proc. 25(18S):512 (2007).
Pérez-Soler, “Individualized therapy in non-small-cell lung cancer: future versus current clinical practice,” Oncogene 28(Suppl 1):S38-S45 (2009).
Pérez-Tenorio et al., “PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer,” Clin. Cancer Res. 13(12):3577-3584 (2007).
Perren et al “Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast,” Am. J. Pathol. 155(4):1253-1260 (1999).
Petter et al., “A novel small-molecule drug platform to silence cancer targets-application to the panErbB kinases,” in: Proceedings of the 100th Annual Meeting of the American Association for Cancer Research; Apr. 18-22, 2009; Denver, Co. Abstr. 3746 (2009).
Pfister et al., “American Society of Clinical Oncology Clinical Practice Guideline for the Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer,” J. Clin. Oncol. 24(22):36933704 (2006) (Epub Jul. 10, 2006).
Piccart et al., “Beyond trastuzumab: new anti-HER2 agents,” Breast 20(Suppl 1):S1-52 Abstr. S02 (2011).
Piccart, “Circumventing de novo and acquired resistance to trastuzumab: new hope for the care of ErbB2-positive breast cancer,” Clin. Breast Cancer 8(Suppl 3):S100-S113 (2008).
Plati et al., “Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities,” J. Cell. Biochem. 104(4):1124-1149 (2008).
Plosker and Keam, “Trastuzumab: a review of its use in the management of HER2-positive metastatic and early-stage breast cancer,” Drugs 66(4):449-475 (2006).
Ponz-Sarvisé et al., “Epidermal growth factor receptor inhibitors in colorectal cancer treatment: what's new?” World J. Gastroenterol. 13(44):5877-5887 (2007).
Potashman and Duggan, “Covalent modifiers: an orthogonal approach to drug design,” J. Med. Chem. 52(5):1231-1246 (2009).
Rabindran, “Antitumor activity of HER-2 inhibitors,” Cancer Lett. 227(1):9-23 (2005) (Epub Dec. 15, 2004).
Raines and Ross, “Multiple growth factors are associated with lesions of atherosclerosis: specificity or redundancy?” Bioessays 18(4):271-282 (1996).
Rampaul et al., “Clinical value of epidermal growth factor receptor expression in primary breast cancer,” Adv. Anat. Pathol. 12(5):271-273 (2005).
Rana and Swaby, “Targeted Therapies for HER2 Breast Cancer: A View of the Landscape,” Curr. Breast Cancer Rep. 3:55-62 (2011).
Ranganathan and Muneer, “Highlights from: The 24th Annual Meeting of the American Association for Cancer Research; Los Angeles, Ca; Apr. 14-18, 2007,” Clin. Lung Cancer 8(6):359363 (2007).
Rao, “Recent developments of collagen-based materials for medical applications and drug delivery systems,” J. Biomater Sci. Polym. Ed. 7(7):623-645 (1995).
Ray et al., “Lung cancer therapeutics that target signaling pathways: an update,” Expert Rev. Respir. Med. 4(5):631-645 (2010).
Ray et al., “The role of EGFR inhibition in the treatment of non-small cell lung cancer,” Oncologist 14(11):1116-1130 (2009) (Epub Nov. 5, 2009).
Redon et al., “A simple specific pattern of chromosomal aberrations at early stages of head and neck squamous cell carcinomas: PIK3CA but not p63 gene as a likely target of 3q26-qter gains,” Cancer Res. 61(10):4122-4129 (2001).
Reid et al., “Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu),” Eur. J. Cancer 43(3):481-489 (2007) (Epub Jan. 8, 2007).
Response filed by Applicant Apr. 30, 2009 to Office Action dated Jul. 18, 2008, in corresponding European Patent Application No. 06836862.0.
Rexer et al., “Overcoming resistance to tyrosine kinase inhibitors: lessons learned from cancer cells treated with EGFR antagonists,” Cell Cycle 8(1):18-22 (2009) (Epub Jan. 30, 2009).
Riely et al., “Update on epidermal growth factor receptor mutations in non-small cell lung cancer,” . Clm. Cancer Res. 12(24):7232-7241 (2006).
Riely, “Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer,” J. Thorac. Oncol. 3(6 Suppl 2):5146-5149 (2008).
Rosell et al., “Age-related genetic abnormalities: the Achilles' heel for customizing therapy in elderly lung cancer patients,” Personalized Medicine 4(1):59-72 (2007).
Rosell et al., “Screening for epidermal growth factor receptor mutations in lung cancer,” N. Engl. J. Med. 361(10):958-967 (2009) (Epub Aug. 19, 2009).
Rosell et al., “Treatment of non-small-cell lung cancer and pharmacogenomics: where we are and where we are going,” Curr. Opin. Oncol. 18(2):135-143 (2006).
Rosen et al., “Targeting signal transduction pathways in metastatic breast cancer: a comprehensive review,” Oncologist 15(3):216-235 (2010) (Epub Mar. 3, 2010).
Rotella, “Medicinal Chemistry—XXth International Symposium. Lead finding strategies and kinase selectivity,” IDrugs 11(11):774-778 (2008).
Roukos, “Trastuzumab and beyond: sequencing cancer genomes and predicting molecular networks,” Pharmacogenomics J. 11(2):81-92 (2011) (Epub Oct. 26, 2010).
Roy and Perez, “Beyond trastuzumab: small molecule tyrosine kinase inhibitors in HER-2-positive breast cancer,” Oncologist 14(11):1061-1069 (2009) (Epub Nov. 3, 2009).
Rubin et al., “10q23.3 loss of heterozygosity is higher in lymph node-positive (pT2-3,N+) versus lymph node-negative (pT2-3,N0) prostate cancer,” Hum. Pathol. 31(4):504-508 (2000).
Rudloff and Samuels, “A growing family: adding mutated Erbb4 as a novel cancer target,” Cell Cycle. 9(8):1487-1503 (2010) (Epub Apr. 15, 2010).
Saal et al., “PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma,” Cancer Res. 65(7):2554-2559 (2005).
Sakamoto et al., “Su-11248 Sugen,” Curr. Opin. Investig. Drugs 5(12):1329-1339 (2004).
Salvesen et al., “Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation,” Proc. Natl. Acad. Sci. U.S.A. 106(12):4834-4839 (2009) (Epub Mar. 4, 2009).
Samuels and Ericson, “Oncogenic PI3K and its role in cancer,” Curr. Opin. Oncol. 18(1):77-82 (2006).
Sanchez-Martin and Pandiella, “Differential action of ErbB kinase inhibitors on receptor oligomerization,” EJC Suppl. 8:107 Abstr. 337 (2010).
Santarpia et al., “Tyrosine kinase inhibitors for non-small-cell lung cancer: finding patients who will be responsive,” Expert Rev. Respir. Med. (3):413-424 (2011).
Sartore-Bianchi et al., “Rationale and clinical results of multi-target treatments in oncology,” Int. J. Biol. Markers 22(1 Suppl 4):S77-S87 (2007).
Sathornsumetee et al., “Malignant glioma drug discovery—targeting protein kinases,” Expert . Opm. Drug Discov. 2(1):1-17 (2007).
Sattler et al., “EGFR-targeted therapeutics: focus on SCCHN and NSCLC,” ScientificWorldJournal 8:909-919 (2008).
Saura et al., “Safety of Neratinib (HKI-272) in Combination with Capecitabine in Patients with Solid Tumors: a Phase 1/2 Study,” Cancer Res. 69(24 Suppl) Abstr. 5108 (2009).
Saura et al., “The safety of Neratinib (HKI-272) in Combination with Capecitabine in Patients with Solid Tumors: A Phase 1/2 Study,” Ann. Oncol. 21(Suppl 4):iv63 Abstr. 147P (2010).
Saura et al., (Dec. 2011). Safety and Efficacy of Neratinib in Combination with Capecitabine in Patients with ErbB2-Positive Breast Cancer. Poster presented at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, San Antonio, Texas.
Scaltriti et al., “Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer,” J. Natl. Cancer Inst. 99(8):628-638 (2007).
Scott and Salgia, “Biomarkers in lung cancer: from early detection to novel therapeutics and decision making,” Biomark. Med. 2(6):577-586 (2008).
Sebastian et al., “The complexity of targeting EGFR signalling in cancer: from expression to turnover,” Biochim. Biophys. Acta. 1766(1):120-139 (2006) (Epub Jun. 23, 2006).
Sequist and Dziadziuszko, “Update on epidermal growth factor receptor inhibitor development in lung cancer,” J. Thorac. Oncol. 1(7):740-743 (2006).
Sequist et al., “Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase Ii trial in patients with advanced non-small-cell lung cancer,” J. Clin. Oncol. 28(18):3076-3083 (2010) (Epub May 17, 2010).
Sequist, “Second-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer,” Oncologist 12(3):325-330 (2007).
Settleman and Kurie, “Drugging the bad ”AKT-TOR“ to overcome TKI-resistant lung cancer,” Cancer Cell 12(1):6-8 (2007).
Seyhan et al., “A genome-wide RNAi screen identifies novel targets of neratinib sensitivity leading to neratinib and pacl*taxel combination drug treatments,” Mol. Biosyst. 7(6):1974-1989 (2011) (Epub Apr. 12, 2011).
Sharma and Jayanth, “Neratinib, an irreversible erbB receptor tyrosine Kinase inhibitor, in patients with advanced erbB2-positive breast cancer,” [commentary] Adv. Breast Cancer 7(1):21 (2010).
Sharma and Settleman, “Oncogene addiction: setting the stage for molecularly targeted cancer therapy,” Genes Dev. 21(24):3214-3231 (2007).
Sharma et al., “Epidermal growth factor receptor mutations in lung cancer,” Nat. Rev. Cancer7(3):169-181 (2007).
Sharma et al., “Receptor tyrosine kinase inhibitors as potent weapons in war against cancers,” Curr. Pharm. Des. 15(7):758-776 (2009).
Shaw et al., “Pharmacological Inhibition of Restenosis: Learning From Experience,” Trends Pharmacol. Sci. 16(12):401-404 (1995).
Shawver et al., “Receptor Tyrosine Kinases as Targets for Inhibition of Angiogenesis,” Drug Discov. Today 2(2):50-63 (1997).
Shayesteh et al., “PIK3CA is implicated as an oncogene in ovarian cancer,” Nat. Genet. 21(1):99- 102 (1999).
Shimamura and Shapiro, “Heat shock protein 90 inhibition in lung cancer,” J. Thorac. Oncol. 3(6 Suppl 2):5152-5159 (2008).
Shimamura et al., “Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance,” Cancer Res. 68(14):5827-5838 (2008).
Shimamura et al., “on-small-cell lung cancer and Ba/F3 transformed cells harboring the ERBB2 G776insV_G/C mutation are sensitive to the dual-specific epidermal growth factor receptor and ERBB2 inhibitor HKI-272,” Cancer Res. 66(13):6487-6491 (2006).
Sibilia et al., “The epidermal growth factor receptor: from development to tumorigenesis,” Differentiation 75(9):770-787 (2007).
Sigal, “Basic science for the clinician 48: tyrosine kinases in disease: the potential for inhibitors in the treatment of immunologic diseases,” J. Clin. Rheumatol. 14(1):45-48 (2008).
Simon et al., “By 1023/SK&F 96022: biochemistry of a novel (H+ + K+)-ATPase inhibitor,” Biochem Pharmacol. 39(11):1799-1806 (1990).
Singh et al., “Targeted covalent drugs of the kinase family,” Curr. Opin. Chem. Biol. 14(4):475-480 (2010) (Epub Jul. 6, 2010).
Singh et al., “The resurgence of covalent drugs,” Nat. Rev. Drug Discov. 10(4):307-317 (2011).
Slamon et al., “BCIRG 006: 2nd interim analysis phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC-T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early breast cancer patients,” In: San Antonio breast cancer symposium; 2006 [abstract 52].
Slamon et al., “Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene,” Science 235(4785):177-182 (1987).
Smith et al. “2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline,”J. Clin. Oncol. 24(19):3187-3205 (2006) (Epub May 8, 2006).
Smith et al., “2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial.” Lancet 369(9555):29-36 (2007).
Smith, “Goals of Treatment of Patients with Metastatic Breast Cancer,” Semin. Oncol. 33:S2-S5 (2006).
Solca et al., “Beyond Trastuzumab: Second-Generation Targeted Therapies for HER-2-Positive Breast Cancer,” Drugs for HER-2-positive Breast Cancer, Milestones in Drug Therapy, 2011 pp. 91-107 (2011).
Specht and Gralow, “Neoadjuvant chemotherapy for locally advanced breast cancer,” Semin. Radiat. Oncol. 9(4):222-228 (2009).
Spector et al., “Small Molecule HER-2 Tyrosine Kinase Inhibitors,” Breast Cancer Res. 9(2):205 (2007).
Spector, “Treatment of metastatic ErbB2-positive breast cancer: options after progression on trastuzumab,” Clin. Breast Cancer 8 Suppl 3:S94-S99 (2008).
Spicer and Rudman, “EGFR inhibitors in non-small cell lung cancer (NSCLC): the emerging role of the dual irreversible EGFR/HER2 inhibitor BIBW 2992,” Target Oncol. 5(4):245-255 (2010) (Epub Jun. 24, 2010).
Srivastava et al., “Synthesis and structure-activity relationships of potent antitumor active quinoline and naphthyridine derivatives,” Anticancer Agents Med. Chem. 7(6):685-709 (2007).
Staroslawska et al. (Dec. 2012). Safety and Efficacy of Neratinib (HKI-272) Plus Vinorelbine in the Treatment of Patients With ErbB2+ Metastatic Breast Cancer Pretreated With Anti-Her2 Therapy. Poster presented at teh 33rd Annual San Antonio Breast Cancer Symposium, San Antonio, Texas.
Stebbing et al., “Lemur tyrosine kinase-3 (LMTK3) in cancer and evolution,” Oncotarget 2(6):428- 429 (2011).
Steck et al., “Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers,” Nat. Genet. 15(4):356-362 (1997).
Steins et al., “Targeting the epidermal growth factor receptor in non-small cell lung cancer,” Onkologie 33(12):704-709 (2010) (Epub Nov. 26, 2010).
Stemke-Hale et al., “An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer,” Cancer Res. 68(15):6084-6091 (2008).
Stokoe et al., “Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B,” Science 277(5325):567-570 (1997).
Sugiyama, “Drug Transporters: Roles in New Drug Discovery and Development,” Drug Metab. Rev. 42(S1):1-323 (2010).
Suzuki et al., “Combination of trastuzumab and vinorelbine in metastatic breast cancer,” Jpn. J. Clin. Oncol. 33(10):514-517 (2003).
Swaby et al., “Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase I/II study,” J. Clin. Oncol. 27:15s(suppl; abstr 1004) (2009).
Tagliabue et al., “HER2 as a target for breast cancer therapy,” Expert Opin. Biol. Ther. 10(5):711-724 (2010).
Takada, “API Form Screening and Selection in Drug Discovery Stage,” Pharm Stage 6(10):20-25 (2007). [English Translation Not Available].
Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products; Pharmaceutical Affairs Bureau Notification No. 568; 2001 [English Translation Not Available].
Tjin Tham Sjin et al., “Design of a novel covalent EGFR mutant-selective inhibitor,” EJC Suppl. 8(7):31 Abstr. 73 (2010).
Toffoli et al., “Pharmacology of epidermal growth factor inhibitors,” Int. J. Biol. Markers 22(1 Suppl 4):524-539 (2007).
Tolaney and Krop, “Mechanisms of trastuzumab resistance in breast cancer,” Anticancer Agents Med. Chem. 9(3):348-355 (2009).
Tolaney et al., “HER2-Positive Breast Cancer,” JCOM 14(7):395-403 (2007).
Tomillero and Moral, “Gateways to Clinical Trials,” Methods Find. Exp. Clin. Pharmacol. 31(3):183-226 (2009).
Tomillero and Moral, “Gateways to Clinical Trials,” Methods Find. Exp. Clin. Pharmacol. 31(10):661-700 (2009).
Tookman and Roylance, “New Drugs for Breast Cancer,” Br. Med. Bull. 96:111-129 (2010) (Epub Sep. 23, 2010).
Torres and Harris, “Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities,” J. Intern. Med. 261(1):17-31 (2007).
Traxler, “Tyrosine kinase inhibitors in cancer treatment (Part II),” Exp. Opin. Ther. Patents 8(12):1599-1625 (1998).
Tsou, “American Chemical Society—226th National Meeting. Novel Substituted 4-Anilinoquinoline-3-carbonitriles as orally active, irreversible binding inhibitors of HER-2 Kinase,” (abstr. 14) 2003.
Twelves et al., “Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: a dose-escalation study,” Eur. J. Cancer 44(3):419-426 (2008) (Epub Jan. 30, 2008).
Ullrich et al., “Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells,” Nature 309(5967):418-425 (1984).
Untch, “Targeted Therapy for Early and Locally Advanced Breast Cancer,” Breast Care (Basel) 5(3):144-152 (2010) (Epub Jun. 16, 2010).
Upeslacis, Janis, Meeting At Mcgill University, Canada, Evolution of Kinase Inhibitors At Wyeth, Oct. 16, 2002.
Van Arnum, “Evaluating late-stage pipelines and potential: will 2011 be a more promising year for new molecular entities? A review of Big Pharma's late-stage pipeline shows what might lie ahead.” Pharmaceutical Technology 35.2 (2011): 52+. Expanded Academic ASAP. Web. Jul. 18, 2011.
Vasudevan et al., “AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer,” Cancer Cell 16(1):21-32 (2009).
Vazquez et al., “HER2-Positive Breast Cancer: Analysis of Efficacy in Different Groups,” Cancer Chemother. Rev. 4(4):224-240 (2009).
Vivanco and Mellinghoff, “Epidermal growth factor receptor inhibitors in oncology,” Curr. Opin. Oncol. 22(6):573-578 (2010).
Von Eyben, “Epidermal growth factor receptor inhibition and non-small cell lung cancer,” Crit. Rev. Clin. Lab. Sci. 43(4):291-323 (2006).
Vora et al., “Novel Therapeutics in Breast Cancer—Looking to the Future,” Update on Cancer Therapeutics 3:189-205 (2009).
Wagner and Kaufmann, “Prospects for the Use of ATR Inhibitors to Treat Cancer,” Pharmaceuticals 3:1311-1334 (2010).
Walko and Lindley, “Capecitabine: a review,” Clin. Ther. 27(1):23-44 (2005).
Wang et al., “Characterization of HKI-272 covalent binding to human serum albumin,” Drug Metab. Dispos. 38(7):1083-1093 (2010) (Epub Apr. 16, 2010).
Weber, “Toward a molecular classification of cancer,” Toxicology Dec. 5, 2010;278(2):195-198 (2010) (Epub Oct. 24, 2009).
Wen and Drappatz, “Novel therapies for meningiomas,” Expert Rev. Neurother. 6(10):1447-1464 (2006).
Wheatley-Price and Shepherd, “Epidermal growth factor receptor inhibitors in the treatment of lung cancer: reality and hopes,” Curr. Opin. Oncol. 20(2):162-175 (2008).
Whenham et al., “HER2-positive breast cancer: from trastuzumab to innovatory anti-HER2 strategies,” Clin. Breast Cancer 8(1):38-49 (2008).
Wickham, “Evolving treatment paradigms for chemotherapy-induced nausea and vomiting,” Cancer Control 19(2 Suppl):3-9 (2012).
Widakowich et al., “HER-2 positive breast cancer: what else beyond trastuzumab-based therapy?” Anticancer Agents Med. Chem. 8(5):488-496 (2008).
Widakowich et al., “Molecular targeted therapies in breast cancer: where are we now?” Int. J. Biochem. Cell. Biol. 2007;39(7-8):1375-1387 (2007) (Epub May 4, 2007).
Wissner and Mansour, “The development of HKI-272 and related compounds for the treatment of cancer,” Arch. Pharm. (Weinheim) 341(8):465-477 (2008).
Wissner et al., “Dual irreversible kinase inhibitors: quinazoline-based inhibitors incorporating two independent reactive centers with each targeting different cysteine residues in the kinase domains of EGFR and VEGFR-2,” Bioorg. Med. Chem. 15(11):3635-4368 (2007) (Epub Mar. 23, 2007).
Woenckhaus et al., “Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer,” Virchows Arch. 450(4):387-395 (2007) (Epub Feb. 15, 2007).
Wondrak, “Redox-directed cancer therapeutics: molecular mechanisms and opportunities,” Antioxid. Redox Signal. 11(12):3013-3069 (2009).
Wong et al., “A phase I study with neratinib (HKI-272), an irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors,” Clin. Cancer Res. 15(7):2552-2558 (2009) (Epub Mar. 24, 2009).
Wong et al., “HKI-272, an irreversible pan ErbB receptor tyrosine kinase inhibitory: Preliminary phase 1 results in patients with solid tumors,” J. Clin. Oncol. 24(18S):125s Abstr. 3018 (2006).
Wong, “HKI-272 in non small cell lung cancer,” Clin. Cancer Res. 13(15 Pt 2):4593s-4596s (2007).
Wong, “Searching for a magic bullet in NSCLC: the role of epidermal growth factor receptor mutations and tyrosine kinase inhibitors,” Lung Cancer 60(Suppl 2):S10-S18 (2008).
World Health Organization (2008). Fact Sheet—Cancer, No. 297, 2008. Retrieved from http://www.who.int/mediacentre/factsheets/fs297/en/.
World Health Organization (2008). World Health Statistics, 2008. Retrieved from http://www.who.int/gho/publications/world_health_statistics/EN_WHS08_Full.pdf?ua=1.
Written Opinion of the International Searching Authority for International Application No. PCT/US2009/047643 dated Dec. 17, 2010.
Wu et al., “Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and Michael acceptor group for maximal potency,” J. Med. Chem. 53(20):7316-7326 (2010).
Wu et al., “Somatic mutation and gain of copy number of PIK3CA in human breast cancer,” Breast Cancer Res. 7(5):R609-R616 (2005) (Epub May 31, 2005).
Wu et al., “TAK-285, a Novel HER2/EGFR Inhibitor, Penetrates the CNS in Rats with an Intact Blood Brain Barrier (BBB),”Cancer Res. 69(24 Suppl): Abstr. 5098 (2009).
Wu et al., “Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors,” J. Clin. Endocrinol. Metab. 90(8):4688-4693 (2005) (Epub May 31, 2005).
Wykosky et al., “Therapeutic targeting of epidermal growth factor receptor in human cancer: successes and limitations,” Chin. J. Cancer 30(1):5-12 (2011).
Xia et al., “Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016,” Oncogene 23(3):646-653 (2004).
Xu et al., “Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib,” Cancer Biol. Ther. 9(8):572-582 (2010) (Epub Apr. 26, 2010).
Yamano, “Approach to Crystal Polymorph in Process Research of New Drug,” Journal of Synthetic Organic Chemistry, Japan, 65(9):907-913 (2007). [English Translation Not Available].
Yang et al., “MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN,” Cancer Res. 68(2):425-433 (2008).
Yano et al., “HGF-MET in Resistance to EGFR Tyrosine Kinase Inhibitors in Lung Cancer,” Curr. Signal Transduct. Ther. 6(2):228-233 (2011).
Yim et al., “Rak functions as a tumor suppressor by regulating PTEN protein stability and function,” Cancer Cell 15(4):304-314 (2009).
Yoshida et al., “Targeting epidermal growth factor receptor: central signaling kinase in lung cancer,” Biochem. Pharmacol. 80(5):613-623 (2010) (Epub May 24, 2010).
Yuan and Cantley, “PI3K pathway alterations in cancer: variations on a theme,” Oncogene 27(41):5497-5510 (2008).
Yun et al., “The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP,” Proc. Natl. Acad. Sci. U.S.A. 105(6):2070-2075 (2008) (Epub Jan. 28, 2008).
Yuza et al., “Allele-dependent variation in the relative cellular potency of distinct EGFR inhibitors,” Cancer Biol. Ther. 6(5):661-667 (2007) (Epub Feb. 13, 2007).
Zaczek et al., “The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches,” Histol. Histopathol. 20(3):1005-1015 (2005).
Zagrekova et al., “Drug Treatment of Breast Cancer,” Rossijskij Medicinskij Zhurnal 14:605 (2002). (English Translation Not Available).
Zahnow, “ErbB receptors and their ligands in the breast,” Expert Rev. Mol. Med. 8(23):1-21 (2006).
Zhang et al. Xenograft Models of Breast Cancer: the Link between Characteristics of Biomarker Expression and the Anti-tumor Effect of the Representative Therapies [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; Apr. 17-21, 2010; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 647.
Zhang et al., “Advances in preclinical small molecules for the treatment of NSCLC,” Expert Opin. Ther. Pat. 19(6):731-751 (2009).
Zhao et al., “Neratinib Reverses ATP-Binding Cassette B1-Mediaed Chemotherapeutic Drug Resistance in Vitro, in Vivo, and Ex-Vivo,” Mol. Pharmacal. 82: 47-58 (2012).
Zhou et al., “Activation of the PTEN/Mtor/STAT3 Pathway in Breast Cancer Stem-Like Cells Is Required for Viability and Maintenance,” Proc. Natl. Acad. Sci. U.S.A. 104:16158-16163 (2007).
Zhou et al., “EGFR Intron I Polymorphism in Asian Populations and Its Correlation with EGFR Gene Expression and Amplification in Breast Tumor Tissues,” Cancer Biol. Ther. 5(11):1445-1449 (2006).
Anzensei shiken gaidorain (Guidelines for safety testing), Pharmaceutical Affairs Bureau Notification No. 0603001, Jun. 3, 2003; Notification Date: Oct. 19, 2017. (English translation attached).
AstraZeneca Press Release, “TAGRISSO™(osimertinib) (AZD9291) approved by the US FDA as treatment for patients with EGFR T790M mutation-positive metastatic non-small cell lung cancer,” published Nov. 13, 2015. [Obtained from the Internet on Mar. 7, 2017].
Blackwell et al., “Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer,” J. Clin. Oncol. 28(7):1124-1130 (2010).
Chan et al., “Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial,” 17(3):367-377 (2016) (Epub Feb. 10, 2016).
Chan, “Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer,”Br. J. Cancer. 91(8):1420-1424 (2004).
Chew et al., “Phase II study of lapatinib in combination with vinorelbine, as first or second-line therapy in women with HER2 overexpressing metastatic breast cancer,” SpringerPlus 3:108 (2014).
Ciardiello et al., “The role of EGFR inhibitors in nonsmall cell lung cancer,” Curr. Opin. Oncol. 16(2):130-135 (2004).
Coldren et al., “Baseline gene expression predicts sensitivity to gefitinib in non-small cell lung cancer cell lines,” Mol. Cancer Res. 4(8):521-528 (Aug. 2006).
Conte et al., “Evolving nonendocrine therapeutic options for metastatic breast cancer: how adjuvant chemotherapy influences treatment,” Clin. Breast Cancer 7(11):841-849 (2007).
Cybulska-Stopa et al., “Evaluation of vinorelbine-based chemotherapy as the second or further-line treatment in patients with metastatic breast cancer,” Wspalczesna Onkol. 17(1):78-82 (2013).
Davies et al., “OSI-774 and vinorelbine in advanced solid tumors (with emphasis on non-small cell lung cancer, NSCLC): A phase I study,” Proc. Am. Soc. Clin. Oncol. 22: 2003 (abstr 996). 2003 ASCO Annual Meeting.
Degardin et al., “Vinorelbine (navelbine) as a salvage treatment for advanced breast cancer,” Ann. Oncol. 5(5):423-426 (1994).
Depierre et al., “Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: a randomized trial,” Ann. Oncol. 5(1):37-42 (1994).
EMEA: Committee for Medicinal Products for Human Use (CHMP). Guideline on the Evaluation of Anticancer Medicinal Products in Man. London, Dec. 14, 2005.
Firoozinia et al., “PIK3CA gene amplification and PI3K p110α protein expression in breast carcinoma,” Int. J. Med. Sci. 11(6):620-625 (2014).
Fry et al., “Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor,” Proc. Natl. Acad. Sci. U.S.A. 95(20):12022-12027 (1998).
Gandhi et al., “Phase I Study of Neratinib in Combination With Temsirolimus in Patients With Human Epidermal Growth Factor Receptor 2—Dependent and Other Solid Tumors,” J. Clin. Oncol. 32(2):68-75 (2014) (Epub Dec. 9, 2013).
Hegde et al., “Delineation of molecular mechanisms of sensitivity to lapatinib in breast cancer cell lines using global gene expression profiles,” Mol. Cancer Ther. 6(5):1629-1640 (2007).
Herbst, “Review of epidermal growth factor receptor biology,” Int. J. Radiat. Oncol. Biol. Phys.59(2 Suppl):21-26 (2004).
Ich Expert Working Group: Impurities in New Drug Substances Q3A (R), “International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use” (Online) 2006, URL: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3B_R2/Step4/Q3B_R2_Guideline.pdf
Mondesire et al., “Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells,” Clin. Cancer Res. 10(20):7031-7042 (2004).
Normanno et al., “Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs):Simple Drugs With a Complex Mechanism of Action?” J. Cell. Physiol. 194:13-19 (2002).
Pegram et al., “Rational Combinations of Trastuzumab with Chemotherapeutic Drugs Used in the Treatment of Breast Cancer,” J. Natl. Cancer Inst. 96(10):739-749 (2004).
“Progress of Research on Therapeutic Drugs and Molecular Pharmacology”, edited by Zhou Hong et al., Sichuan University Press, published in Mar. 2004, pp. 46-47. (English translation attached).
Qiu et al., “Mechanism of Activation and Inhibition of the HER4/ErbB4 Kinase,” Structure 16(3):460-467 (2008).
Schedule of Presentations—Chemotherapy Foundation Symposium XXV—Nov. 6, 2007.
Scholl et al., “Targeting HER2 in other tumor types,” Ann. Oncol. 12(Suppl. 1): S81-S87 (2001).
Smaill et al., “Tyrosine kinase inhibitors. 15. 4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine actylamides as irreversible inhibitors of the ATP binding site of the epidermal growth factor receptor,” J. Med. Chem. 42(10):1803-1815 (1999).
State Intellectual Property Office of the People's Republic of China Search Report for Chinese Patent Application No. 201210069340.0 (dated Dec. 11, 2015).
State Intellectual Property Office of the People's Republic of China Office Action for Chinese Patent Application No. 201210069340.0 (dated Dec. 21, 2015).
Tsou et al., “6-Substituted-4-(3-bromophenylamino)quinazolines as putative irreversible inhibitors of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor (HER-2) tyrosine kinases with enhanced antitumor activity,” J. Med. Chem. 44(17):2719-2734 (2001).
U.S. National Institutes of Health, “View of NCT00389922 on May 26, 2008”.
U.S. National Institutes of Health, “View of NCT00513058 on May 26, 2008”.
U.S. National Institutes of Health, “View of NCT00706030 on Apr. 26, 2008”.
Wikipedia, “Neoplasm” [retrieved from internet on Sep. 12, 2016] URL:http://en.wikipedia.org/wiki/Neoplasm published Aug. 17, 2016.
Wissner et al., “Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2),” J. Med. Chem. 46(1):49-63 (2003).
Wyeth: “Study Evaluating HKI-272 in Combination With Vinorelbine in Subjects With Solid Tumors and Metastatic Breast Cancer,” ClinicalTrials, Jun. 25, 2008. Retrieved from the Internet: URL: http://clinicaltrials.govict2/show/NCT00706030?term=vinorelbine+hki-272&rank=1 [dated Jan. 13, 2010].
Wyeth: “Study evaluating Neratinib in Combination With Vinorelbine in Subjects With Advanced or Metastatic Solid Tumors,” ClinicalTrials, Aug. 5, 2009. Retrieved from the Internet: URL: http://clinicaltrials.gov/ct2/show/NCT/00958724?term=vinorelbine+hki-272&rank=2 [dated Jan. 13, 2010].
Yap et al., “Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises,” Curr. Opin. Pharmacol. 8:393-412 (2008).
Extended European Search Report dated Nov. 17, 2016 for European Application No. EP 16193659.6.
United States Patent and Trademark Office Final Office Action for U.S. Appl. No. 12/534,895, dated May 2, 2013 (20 pages).
United States Patent and Trademark Office Final Office Action for U.S. Appl. No. 12/940,797, dated Mar. 29, 2012 (11 pages).
United States Patent and Trademark Office Non-Final Office Action for U.S. Appl. No. 12/534,895, dated Nov. 1, 2011 (23 pages).
United States Patent and Trademark Office Non-Final Office Action for U.S. Appl. No. 12/940,797, dated Sep. 30, 2011 (15 pages).
United States Patent and Trademark Office Non-Final Office Action for U.S. Appl. No. 12/940,797, dated Sep. 13, 2012 (20 pages).
United States Patent and Trademark Office Notice of Allowance for U.S. Appl. No. 12/534,895, dated Sep. 12, 2013 (6 pages).
United States Patent and Trademark Office Notice of Allowance for U.S. Appl. No. 12/940,797, dated May 3, 2013 (12 pages).
Written Opinion of the International Searching Authority for International Application No. PCT/US2010/054934 dated May 10, 2011.
Written Opinion of the International Searching Authority for International Application No. PCT/US2011/020080 dated Feb. 28, 2011.

Primary Examiner:

REDDIG, PETER J

Attorney, Agent or Firm:

Jones Day (New York, NY, US)

Parent Case Data:

This application is a 371 National Phase Entry Application of co-pending International Application PCT/US2006/003717, filed Feb. 2, 2006, which designated the U.S. and claims the benefit under 35 U.S.C. §119(e) of U.S. provisional Patent Application No. 60/649,483, filed Feb. 3, 2005, and U.S. Provisional Application No. 60/671,989, Filed Apr. 15, 2005, the entire contents of which are incorporated herein by reference.

Claims:

The invention claimed is:

1.

A method for treating gefitinib and/or erlotinib resistant non-small cell lung cancer in a patient in need thereof, comprising administering daily to the patient having gefitinib and/or erlotinib resistant non-small cell lung cancer a pharmaceutical composition comprising a unit dosage of an irreversible epidermal growth factor receptor (EGFR) inhibitor that covalently binds to cysteine 773 residue in the ligand-binding pocket of EGFR or cysteine 805 residue in the ligand-binding pocket of erb-B2.

2.

The method of claim 1, wherein the irreversible EGFR inhibitor is EKB-569 or HKI-357.

3.

The method of claim 1, wherein the irreversible EGFR inhibitor covalently binds to cysteine 773 residue of EGFR.

4.

The method of claim 1, wherein the irreversible EGFR inhibitor covalently binds to cysteine 805 residue of erb-B2.

5.

The method of claim 1, wherein the method further comprises administering at least one other tyrosine kinase inhibitor.

6.

The method of claim 1, wherein the method further comprises administering radiation.

7.

The method of claim 1, wherein the route of administering is intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, intrapleural, intrauterine, rectal, vagin*l, topical, or intratumor.

8.

The method of claim 1, wherein the route of administering is transmucosal or transdermal.

9.

The method of claim 1, wherein the route of administering is oral.

Description:

This application is a 371 National Phase Entry Application of co-pending International Application PCT/US2006/003717, filed Feb. 2, 2006, which designated the U.S. and claims the benefit under 35 U.S.C. §119(e) of U.S. provisional Patent Application No. 60/649,483, filed Feb. 3, 2005, and U.S. Provisional Application No. 60/671,989, Filed Apr. 15, 2005, the entire contents of which are incorporated herein by reference.

This application incorporates by reference in its entirety the Computer Readable Form (CRF) of a Sequence Listing in ASCII text format submitted via EFS-Web. The Sequence Listing text file submitted via EFS-Web, entitled 13120-004-999 SUB SEQ LISTING.txt, was created on Dec. 16, 2019, and is 27,589 bytes in size.

Epithelial cell cancers, for example, prostate cancer, breast cancer, colon cancer, lung cancer, pancreatic cancer, ovarian cancer, cancer of the spleen, testicular cancer, cancer of the thymus, etc., are diseases characterized by abnormal, accelerated growth of epithelial cells. This accelerated growth initially causes a tumor to form. Eventually, metastasis to different organ sites can also occur. Although progress has been made in the diagnosis and treatment of various cancers, these diseases still result in significant mortality.

Lung cancer remains the leading cause of cancer death in industrialized countries. Cancers that begin in the lungs are divided into two major types, non-small cell lung cancer and small cell lung cancer, depending on how the cells appear under a microscope. Non-small cell lung cancer (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) generally spreads to other organs more slowly than does small cell lung cancer. About 75 percent of lung cancer cases are categorized as non-small cell lung cancer (e.g., adenocarcinomas), and the other 25 percent are small cell lung cancer. Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States, Japan and Western Europe. For patients with advanced disease, chemotherapy provides a modest benefit in survival, but at the cost of significant toxicity, underscoring the need for therapeutic agents that are specifically targeted to the critical genetic lesions that direct tumor growth (Schiller J H et al., N Engl J Med, 346: 92-98, 2002).

Epidermal growth factor receptor (EGFR) is a 170 kilodalton (kDa) membrane-bound protein expressed on the surface of epithelial cells. EGFR is a member of the growth factor receptor family of protein tyrosine kinases, a class of cell cycle regulatory molecules. (W. J. Gullick et al., 1986, Cancer Res., 46:285-292). EGFR is activated when its ligand (either EGF or TGF-α) binds to the extracellular domain, resulting in autophosphorylation of the receptor's intracellular tyrosine kinase domain (S. Cohen et al., 1980, J. Biol. Chem., 255:4834-4842; A. B. Schreiber et al., 1983, J. Biol. Chem., 258:846-853).

EGFR is the protein product of a growth promoting oncogene, erbB or ErbB1, that is but one member of a family, i.e., the ERBB family of protooncogenes, believed to play pivotal roles in the development and progression of many human cancers. In particular, increased expression of EGFR has been observed in breast, bladder, lung, head, neck and stomach cancer as well as glioblastomas. The ERBB family of oncogenes encodes four, structurally-related transmembrane receptors, namely, EGFR, HER-2/neu (erbB2), HER-3 (erbB3) and HER-4 (erbB4). Clinically, ERBB oncogene amplification and/or receptor overexpression in tumors have been reported to correlate with disease recurrence and poor patient prognosis, as well as with responsiveness in therapy. (L. Harris et al., 1999, Int. J. Biol. Markers, 14:8-15; and J. Mendelsohn and J. Baselga, 2000, Oncogene, 19:6550-6565).

EGFR is composed of three principal domains, namely, the extracellular domain (ECD), which is glycosylated and contains the ligand-binding pocket with two cysteine-rich regions; a short transmembrane domain, and an intracellular domain that has intrinsic tyrosine kinase activity. The transmembrane region joins the ligand-binding domain to the intracellular domain. Amino acid and DNA sequence analysis, as well as studies of nonglycosylated forms of EGFR, indicate that the protein backbone of EGFR has a mass of 132 kDa, with 1186 amino acid residues (A. L. Ullrich et al., 1984, Nature, 309:418-425; J. Downward et al., 1984, Nature, 307:521-527; C. R. Carlin et al., 1986, Mol. Cell. Biol., 6:257-264; and F. L. V. Mayes and M. D. Waterfield, 1984, The EMBO J., 3:531-537).

The binding of EGF or TGF-α to EGFR activates a signal transduction pathway and results in cell proliferation. The dimerization, conformational changes and internalization of EGFR molecules function to transmit intracellular signals leading to cell growth regulation (G. Carpenter and S. Cohen, 1979, Ann. Rev. Biochem., 48:193-216). Genetic alterations that affect the regulation of growth factor receptor function, or lead to overexpression of receptor and/or ligand, result in cell proliferation. In addition, EGFR has been determined to play a role in cell differentiation, enhancement of cell motility, protein secretion, neovascularization, invasion, metastasis and resistance of cancer cells to chemotherapeutic agents and radiation. (M.-J. Oh et al., 2000, Clin. Cancer Res., 6:4760-4763).

A variety of inhibitors of EGFR have been identified, including a number already undergoing clinical trials for treatment of various cancers. For a recent summary, see de Bono, J. S. and Rowinsky, E. K. (2002), “The ErbB Receptor Family: A Therapeutic Target For Cancer”, Trends in Molecular Medicine, 8, S19-26.

A promising set of targets for therapeutic intervention in the treatment of cancer includes the members of the HER-kinase axis. They are frequently upregulated in solid epithelial tumors of, by way of example, the prostate, lung and breast, and are also upregulated in glioblastoma tumors. Epidermal growth factor receptor (EGFR) is a member of the HER-kinase axis, and has been the target of choice for the development of several different cancer therapies. EGFR tyrosine kinase inhibitors (EGFR-TKIs) are among these therapies, since the reversible phosphorylation of tyrosine residues is required for activation of the EGFR pathway. In other words, EGFR-TKIs block a cell surface receptor responsible for triggering and/or maintaining the cell signaling pathway that induces tumor cell growth and division. Specifically, it is believed that these inhibitors interfere with the EGFR kinase domain, referred to as HER-1. Among the more promising EGFR-TKIs are three series of compounds: quinazolines, pyridopyrimidines and pyrrolopyrimidines.

Two of the more advanced compounds in clinical development include Gefitinib (compound ZD1839 developed by AstraZeneca UK Ltd.; available under the tradename IRESSA; hereinafter “IRESSA”) and Erlotinib (compound OSI-774 developed by Genentech, Inc. and OSI Pharmaceuticals, Inc.; available under the tradename TARCEVA; hereinafter “TARCEVA”); both have generated encouraging clinical results. Conventional cancer treatment with both IRESSA and TARCEVA involves the daily, oral administration of no more than 500 mg of the respective compounds. In May, 2003, IRESSA became the first of these products to reach the United States market, when it was approved for the treatment of advanced non-small cell lung cancer patients.

IRESSA is an orally active quinazoline that functions by directly inhibiting tyrosine kinase phosphorylation on the EGFR molecule. It competes for the adenosine triphosphate (ATP) binding site, leading to suppression of the HER-kinase axis. The exact mechanism of the IRESSA response is not completely understood, however, studies suggest that the presence of EGFR is a necessary prerequisite for its action.

A significant limitation in using these compounds is that recipients thereof may develop a resistance to their therapeutic effects after they initially respond to therapy, or they may not respond to EGFR-TKIs to any measurable degree at all. The response rate to EGFR-TKIs varies between different ethnic groups. At the low end of EGFR-TKI responders, in some populations, only 10-15 percent of advanced non-small cell lung cancer patients respond to EGFR kinase inhibitors. Thus, a better understanding of the molecular mechanisms underlying sensitivity to IRESSA and TARCEVA would be extremely beneficial in targeting therapy to those individuals whom are most likely to benefit from such therapy.

There is a significant need in the art for a satisfactory treatment of cancer, and specifically epithelial cell cancers such as lung, ovarian, breast, brain, colon and prostate cancers, which incorporates the benefits of TKI therapy and overcoming the non-responsiveness exhibited by patients. Such a treatment could have a dramatic impact on the health of individuals, and especially older individuals, among whom cancer is especially common.

The inventors of the present invention have surprisingly discovered that irreversible EGFR inhibitors are effective in the treatment of cancer in subjects who are no longer responding to gefitinib and/or erlotinib therapies. Thus, in one embodiment, the present invention provides a method for the treatment of gefitinib and/or erlotinib resistant cancer. In this embodiment, progression of cancer in a subject is monitored at a time point after the subject has initiated gefitinib and/or erlotinib treatment. Progression of the cancer is indicative of cancer that is resistant to gefitinib and/or erlotinib treatment and the subject is administered a pharmaceutical composition comprising an irreversible epidermal growth factor receptor (EGFR) inhibitor.

In preferred embodiments, the irreversible EGFR inhibitor EKB-569, HKI-272 or HKI-357. Alternatively, the irreversible EGFR inhibitor may be any compound which binds to cysteine 773 of EGFR (SEQ ID NO: 1).

The progression of cancer may be monitored by methods well known to those of skill in the art. For example, the progression may be monitored by way of visual inspection of the cancer, such as, by means of X-ray, CT scan or MRI. Alternatively, the progression may be monitored by way of tumor biomarker detection.

In one embodiment, the patient is monitored at various time points throughout the treatment of the cancer. For example, the progression of a cancer may be monitored by analyzing the progression of cancer at a second time point and comparing this analysis to an analysis at a first time point. The first time point may be before or after initiation of gefitinib and/or erlotinib treatment and the second time point is after the first. An increased growth of the cancer indicates progression of the cancer.

In one embodiment, the progression of cancer is monitored by analyzing the size of the cancer. In one embodiment, the size of the cancer is analyzed via visual inspection of the cancer by means of X-ray, CT scan or MRI. In one embodiment, the size of the cancer is monitored by way of tumor biomarker detection.

In one embodiment, the cancer is epithelial cell cancer. In one embodiment, the cancer is gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, esophageal cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

In one embodiment, the size of the cancer is monitored at additional time points, and the additional time points are after the second time point.

In one embodiment, the later time point is at least 2 months after the preceding time point. In one embodiment, the later time point is at least 6 months after preceding time point. In one embodiment, the later time point is at least 10 months after preceding time point. In one embodiment, the later time point is at least one year after preceding time point.

In another embodiment, the present invention provides a method of treating cancer, comprising administering to a subject having a mutation in EGFR, namely, a substitution of a methionine for a threonine at position 790 (T790M) of SEQ ID. No. 1, a pharmaceutical composition comprising an irreversible EGFR inhibitor. The T790M mutation confers resistance to gefitinib and/or erlotinib treatment.

FIGS. 1A-1B show EGFR sequence analysis in recurrent metastatic lesions from two NSCLC patients with acquired gefitinib resistance. FIG. 1A shows sequence analysis for Case 1. The T790M mutation in EGFR is present in a recurrent liver lesion after the development of clinical gefitinib resistance. (Left) The mutation was not detected in the primary lung lesion at the time of diagnosis. (Right) Both the primary lung tumor and the recurrent liver lesion harbor the L858R gefitinib-sensitizing mutation. Of note, the L858R mutation is present in the expected ratio for a heterozygous mutation in both primary and recurrent lesions, whereas T790M is detectable at low levels compared with the wild-type allele. A polymorphism (G/A) is shown in the same tracing to demonstrate equivalent representation of the two alleles in the uncloned PCR product (SEQ ID NOS 3 & 4 disclosed respectively, in order of appearance). FIG. 1B shows sequence analysis for Case 2. The T790M mutation is present within a small minority of gefitinib-resistant cells. (Left) The T790M mutation was undetectable either in the lung primary tumor or in eight recurrent liver lesions from this case by sequencing uncloned PCR products. Heterozygosity at an adjacent polymorphism (G/A) confirms amplification of both EGFR alleles from these specimens. The heterozygous gefitinib-sensitizing mutation, L861 Q, was detected at the expected ratio within the primary lung tumor as well as each of the eight recurrent liver lesions (SEQ ID NOS 3 & 5 disclosed respectively, in order of appearance).

FIGS. 2A-2C show acquired resistance to gefitinib in bronchoalveolar cancer cell lines and persistent sensitivity to irreversible ERBB family inhibitors. FIG. 2A shows inhibition by tyrosine kinase inhibitors of proliferation of bronchoalveolar cancer cell lines with wild-type EGFR (NCI-H1666), the activating de1E746-A750 mutation in EGFR (NCI-H1650), or two representative gefitinib-resistant subclones of NCI-H1650 (G7 and C11). The effect of the reversible inhibitor gefitinib is compared with that of the irreversible inhibitor HKI-357. Comparable results were observed with the other irreversible inhibitors. Cell numbers were measured by crystal violet staining, after culture in 5% FCS, with 100 ng/ml EGFR, at 72 h after exposure to indicated drug concentrations. Each data point represents the mean of four samples. FIG. 2B shows the chemical structure of gefitinib, a reversible inhibitor of EGFR; EKB-569, an irreversible inhibitor of EGFR; and HKI-272 and HKI-357, two irreversible dual inhibitors of EGFR and ERBB2. FIG. 2C shows generation of drug-resistant NCI-H1650 cells after treatment with varying concentrations of gefitinib or the irreversible ERBB inhibitor EKB-569. Colonies were stained after 12 days in culture in the presence of inhibitors.

FIGS. 3A-3D show persistent dependence on EGFR and ERBB2 signaling in gefitinib-resistant cells, and altered receptor trafficking. FIG. 3A shows cell viability after siRNA-mediated knockdown of EGFR and ERBB2 in bronchoalveolar cell lines with wild-type EGFR (NCI-H1666), compared with cells with the activating de1E746-A750 mutation in EGFR (NCI-H1650) and two gefitinib-resistant derivatives (G7 and C11). Viable cells were counted 72 h after treatment with double-stranded RNA and are shown as a fraction relative to cells treated with nonspecific siRNA, with standard deviations based on triplicate samples. FIG. 3B shows inhibition of EGFR autophosphorylation (Y1068) and phosphorylation of downstream effectors AKT and MAPK (ERK) in cells treated with increasing concentrations of gefitinib or the irreversible inhibitor HKI-357, followed by a 2-h pulse with EGF. The parental cell line NCI-H1650 is compared with a representative gefitinib-resistant line, G7. Total AKT and MAPK are shown as controls; tubulin is used as loading control for total EGFR levels, which are at the lower limit of detection in these cells. FIG. 3C shows altered EGFR internalization in gefitinib-resistant NCI-H1650 (G7) cells, compared with the sensitive NCI-H1650 parental cell line. Rhodamine-tagged EGF is used to label EGFR at 5 and 20 min, after addition of ligand. The increased internalization of EGFR in NCI-H1650 (G7) cells is most evident at 20 min. (Zeiss microscope, ×63 magnification). FIG. 3D shows immunoblotting of internalized EGFR from NCI-H1650 parental cells and the resistant derivative G7 after pulse labeling of cell surface proteins by biotinylation and chase over 20 min. The increased intracellular EGFR in NCI-H1650 (G7) cells is compared with the unaltered transferrin receptor (TR) internalization.

FIGS. 4A-4B show Effectiveness of irreversible ERBB inhibitors in suppressing the T790M EGFR mutant. FIG. 4A shows comparison of gefitinib and two irreversible inhibitors, HKI-357 and HKI-272, in their ability to suppress EGFR autophosphorylation (Y1068) and phosphorylation of downstream effectors AKT and MAPK (ERK) in the NCI-H1975 bronchoalveolar cell line, harboring both a sensitizing mutation (L858R) and the resistance-associated mutation (T790M). Total EGFR, AKT, and MAPK are shown as loading controls. FIG. 4B shows suppression of proliferation in NCI-H1975 cells harboring the L858R and T790M mutations by the three irreversible ERBB family inhibitors, compared with gefitinib.

FIG. 5 shows the nucleotide sequence (SEQ ID NO: 2) and the amino acid sequence (SEQ ID NO: 1) of EGFR.

FIG. 6 shows that like gefitinib, HKI 357 and EKB 569 (labeled “Wyeth”) demonstrated increased cell killing of NSCLC cells harboring an EGFR mutation, but unlike gefitinib, clones resistant to these drugs were not readily generated in vitro and they retained their effectiveness against gefitinib-resistant clones.

Gefitinib and Erlotinib Resistant Cancers

Gefitinib (compound ZD1839 developed by AstraZeneca UK Ltd.; available under the tradename IRESSA) and erlotinib (compound OSI-774 developed by Genentech, Inc. and OSI Pharmaceuticals, Inc.; available under the trade name TARCEVA) induce dramatic clinical responses in cases of non-small cell lung cancers (NSCLCs) harboring activating mutations in the EGF receptor (EGFR) (1-3), which is targeted by these competitive inhibitors of ATP binding (4, 5). The effectiveness of these tyrosine kinase inhibitors may result both from alterations in the ATP cleft associated with these mutations, which lead to enhanced inhibition of the mutant kinase by these drugs, and from biological dependence of these cancer cells on the increased survival signals transduced by the mutant receptors, a phenomenon described as “oncogene addiction” (6, 7).

Although therapeutic responses to both gefitinib and erlotinib can persist for as long as 2-3 years, the mean duration of response in most cases of NSCLC is only 6-8 months (8-10). The mechanisms underlying acquired drug resistance are not well understood. By analogy with imatinib (GLEEVEC), which inhibits the BCR-ABL kinase involved in chronic myeloid leukemias (CMLs), the C-KIT kinase implicated in gastrointestinal stromal tumors (GISTs), and the FIP1L1-PDGFR-α kinase in idiopathic hypereosinophilic syndrome (HES), secondary kinase domain mutations can potentially suppress drug binding (11-16). However, recurrent NSCLC is not readily biopsied; hence, only limited clinical specimens are available for analysis. Recently, a single secondary mutation, T790M, within the EGFR kinase domain has been reported in three of six cases with recurrent disease after gefitinib or erlotinib therapy (17, 18). Codon 315 of BCR-ABL, which is analogous to EGFR codon 790, is frequently mutated in imatinib-resistant CML (11, 12), and mutation of the corresponding residue in C-KIT (codon 670) and FIP1L1-PDGFR-α (codon 674) is associated with imatinib-resistant GIST and HES, respectively (15, 16). Early in vitro modeling of resistance to EGFR inhibitors indicated that mutation of codon 790 within the wild-type receptor would similarly suppress inhibition by an EGFR tyrosine kinase inhibitor (19). Recently, transfected EGFR proteins containing activating mutations together with the T790M substitution were shown to exhibit reduced inhibition by gefitinib and erlotinib (17, 18). Although the T790M mutation seems to contribute to acquired resistance in some cases of NSCLC, the mechanisms underlying treatment failure in cases lacking secondary EGFR mutations remain unexplained.

In contrast to the cytoplasmic kinase BCR-ABL, signaling by the membrane-bound EGFR involves a complex pathway of ligand binding, receptor hom*odimerization, and heterodimerization with ERBB2 and other family members, followed by internalization and recycling of the ligand-bound receptor or ubiquitin-mediated receptor degradation (20). Significant EGF-dependent signaling is thought to occur during the process of internalization, which is also associated with the dissociation of EGFR complexes at the low pH of intracellular vesicles. As such, multiple factors modulate the strength and quality of the signal transduced by the receptor, and alterations in EGFR trafficking have been closely linked with the regulation of EGF-dependent cellular responses (20).

The present invention is based on the discovery that gefitinib resistant cancers can include those wherein the T790M EGFR mutation is only present in a subset of resistant tumor cells and those wherein the T790M mutation is not observed, but increased EGFR internalization is observed. The invention is further based on the discovery that irreversible EGFR inhibitors, which covalently crosslink the receptor, are effective in inhibiting cancers with the T790M mutation and in cancers with altered EGFR trafficking that can make such cancers resistance to treatment with gefitinib and/or erlotinib. Accordingly, the present invention provides a method of treating gefitinib and/or erlotinib resistant cancers comprising administering irreversible EGFR inhibitors.

Method of Treating a Patient

In one embodiment, the invention provides a method for treating gefitinib/erlotinib resistant cancer. The method comprises administering to a patient in need of such treatment an effective amount of certain irreversible EGFR inhibitors, including EKB-569 (4-anilinoquinoline-3-carbonitrile; Greenberger et al., 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy, Amsterdam, Nov. 7-10, 2000, abstract 388; Wyeth), HKI-357 (a derivative of 4-anilinoquinoline-3-carbonitrile; Tsou et al. J. Med. Chem. 2005, 48: 1107-1131; Wyeth) and/or HKI-272 (a derivative of 4-anilinoquinoline-3-carbonitrile; Rabindran et al., Cancer Res. 2004, 64, 3958-3965; Wyeth). In one preferred embodiment, the invention provides a method comprising administering to a patient in need of such treatment an effective amount of EKB-569. In one preferred embodiment, the invention provides a method comprising administering to a patient in need of such treatment an effective amount of HKI-357.

The treatment may also involve a combination of treatments, including, but not limited to a tyrosine kinase inhibitor in combination with other tyrosine kinase inhibitors, chemotherapy, radiation, etc.

Cancers may initially be diagnosed as gefitinib/erlotinib sensitive or predicted to be gefitinib/erlotinib sensitive by means of the methods described in Lynch et al., 2004; 350:2129-2139. Gefitinib/erlotinib sensitivity may be predicted by the presence in the tumor of EGFR mutations including, for example, deletion of residues 747 (lysine) to 749 (glutamic acid) combined with a mutation in 750 (alanine), deletion of residues 747 (lysine) to 750 (alanine), substitution of arginine for leucine at residue 858, of substitution of glutamine for leucine at residue 861.

Cancers may be diagnosed as gefitinib and/or erlotinib resistant after treatment with gefitinib and/or erlotinib has commenced. Alternatively, cancers may be diagnosed as gefitinib and/or erlotinib resistant prior to initiation of treatment with such compounds. Gefitinib and/or erlotinib resistance in the tumor may occur after, e.g., 6 months or longer of gefitinib and/or erlotinib treatment. Alternatively, gefitinib and/or erlotinib resistance of the tumor may be diagnosed less than 6 months after gefitinib and/or erlotinib treatment has commenced. Diagnosis of gefitinib and/or erlotinib resistance may be accomplished by way of monitoring tumor progression during gefitinib and/or erlotinib treatment. Tumor progression may be determined by comparison of tumor status between time points after treatment has commenced or by comparison of tumor status between a time point after treatment has commenced to a time point prior to initiation of gefitinib and/or erlotinib treatment. Tumor progression may be monitored during gefitinib and/or erlotinib treatment visually, for example, by means of radiography, for example, X-ray, CT scan, or other monitoring methods known to the skilled artisan, including palpitation of the cancer or methods to monitor tumor biomarker levels. Progression of the cancer during treatment with gefitinib and/or erlotinib indicates gefitinib and/or erlotinib resistance. A rise in level of tumor biomarkers indicates tumor progression. Thus, a rise in tumor biomarker levels during treatment with gefitinib and/or erlotinib indicates gefitinib and/or erlotinib resistance. Detection of new tumors or detection of metastasis indicates tumor progression. Cessation of tumor shrinkage indicates tumor progression. Growth of the cancer is indicated by, for example, increase in tumor size, metastasis or detection of new cancer, and/or a rise in tumor biomarker levels.

The development of gefitinib and/or erlotinib resistance may be monitored by means of testing for presence of a gefitinib and/or erlotinib resistance associated mutation in circulating tumor cells obtained from the circulation, or other bodily fluid, of the subject. Presence of gefitinib and/or erlotinib resistance associated mutations in tumor cells from the subject is indicative of a gefitinib and/or erlotinib resistant tumor.

In one embodiment, the subject's tumor harbors mutations indicative of gefitinib and/or erlotinib sensitivity, yet it is resistant to gefitinib and/or erlotinib treatment. In one embodiment, the subject's tumor harbors mutations indicative gefitinib and/or erlotinib sensitivity and harbors mutations indicative of gefitinib and/or erlotinib resistance, e.g., the T790M mutation, that is, where a methione residue is substituted for the native threonine residue, in EGFR, e.g. increased EGFR internalization. In one embodiment, the subject's tumor does not harbor mutations indicative of gefitinib and/or erlotinib sensitivity and does harbor mutations indicative of gefitinib and/or erlotinib resistance, e.g., the T790M mutation in EGFR, e.g., increased EGFR internalization.

In connection with the administration of the drug, an “effective amount” indicates an amount that results in a beneficial effect for at least a statistically significant fraction of patients, such as a improvement of symptoms, a cure, a reduction in disease load, reduction in tumor mass or cell numbers, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition.

The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the severity of the condition being treated. The skilled artisan is aware of the effective dose for each patient, which may vary with disease severity, individual genetic variation, or metabolic rate. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.5 to about 1000 mg/kg of body weight, optionally given in divided doses two to four times a day, or in sustained release form. The total daily dosage is projected to be from about 1 to 1000 mg, preferably from about 2 to 500 mg. Dosage forms suitable for internal use comprise from about 0.5 to 1000 mg of the active compound in intimate admixture with a solid or liquid pharmaceutically acceptable carrier. This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.

The route of administration may be intravenous (I.V.), intramuscular (I.M.), subcutaneous (S.C.), intradermal (I.D.), intraperitoneal (I.P.), intrathecal (I.T.), intrapleural, intrauterine, rectal, vagin*l, topical, intratumor and the like. The compounds of the invention can be administered parenterally by injection or by gradual infusion over time and can be delivered by peristaltic means.

Administration may be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration may be through nasal sprays, for example, or using suppositories. For oral administration, the compounds of the invention are formulated into conventional oral administration forms such as capsules, tablets and tonics.

For topical administration, the pharmaceutical composition (inhibitor of kinase activity) is formulated into ointments, salves, gels, or creams, as is generally known in the art.

The therapeutic compositions of this invention, e.g. irreversible EGFR inhibitors, are conventionally administered intravenously, as by injection of a unit dose, for example. The term “unit dose” when used in reference to a therapeutic composition of the present invention refers to physically discrete units suitable as unitary dosage for the subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required diluents; i.e., carrier, or vehicle.

The compositions are administered in a manner compatible with the dosage formulation, and in a therapeutically effective amount. The quantity to be administered and timing depends on the subject to be treated, capacity of the subject's system to utilize the active ingredient, and degree of therapeutic effect desired. Precise amounts of active ingredient required to be administered depend on the judgment of the practitioner and are peculiar to each individual.

The therapeutic composition useful for practicing the methods of the present invention, e.g. irreversible EGFR inhibitors, are described herein. Any formulation or drug delivery system containing the active ingredients, which is suitable for the intended use, as are generally known to those of skill in the art, can be used. Suitable pharmaceutically acceptable carriers for oral, rectal, topical or parenteral (including inhaled, subcutaneous, intraperitoneal, intramuscular and intravenous) administration are known to those of skill in the art. The carrier must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, the terms “pharmaceutically acceptable”, “physiologically tolerable” and grammatical variations thereof, as they refer to compositions, carriers, diluents and reagents, are used interchangeably and represent that the materials are capable of administration to or upon a mammal without the production of undesirable physiological effects.

Formulations suitable for parenteral administration conveniently include sterile aqueous preparation of the active compound which is preferably isotonic with the blood of the recipient. Thus, such formulations may conveniently contain distilled water, 5% dextrose in distilled water or saline. Useful formulations also include concentrated solutions or solids containing the compound which upon dilution with an appropriate solvent give a solution suitable for parental administration above.

For enteral administration, a compound can be incorporated into an inert carrier in discrete units such as capsules, cachets, tablets or lozenges, each containing a predetermined amount of the active compound; as a powder or granules; or a suspension or solution in an aqueous liquid or non-aqueous liquid, e.g., a syrup, an elixir, an emulsion or a draught. Suitable carriers may be starches or sugars and include lubricants, flavorings, binders, and other materials of the same nature.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form, e.g., a powder or granules, optionally mixed with accessory ingredients, e.g., binders, lubricants, inert diluents, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered active compound with any suitable carrier.

A syrup or suspension may be made by adding the active compound to a concentrated, aqueous solution of a sugar, e.g., sucrose, to which may also be added any accessory ingredients. Such accessory ingredients may include flavoring, an agent to retard crystallization of the sugar or an agent to increase the solubility of any other ingredient, e.g., as a polyhydric alcohol, for example, glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppository with a conventional carrier, e.g., cocoa butter or Witepsol S55 (trademark of Dynamite Nobel Chemical, Germany), for a suppository base.

Formulations for oral administration may be presented with an enhancer. Orally-acceptable absorption enhancers include surfactants such as sodium lauryl sulfate, palmitoyl carnitine, Laureth-9, phosphatidylcholine, cyclodextrin and derivatives thereof; bile salts such as sodium deoxycholate, sodium taurocholate, sodium glycochlate, and sodium fusidate; chelating agents including EDTA, citric acid and salicylates; and fatty acids (e.g., oleic acid, lauric acid, acylcarnitines, mono- and diglycerides). Other oral absorption enhancers include benzalkonium chloride, benzethonium chloride, CHAPS (3-(3-cholamidopropyl)-dimethylammonio-1-propanesulfonate), Big-CHAPS (N, N-bis(3-D-gluconamidopropyl)-cholamide), chlorobutanol, octoxynol-9, benzyl alcohol, phenols, cresols, and alkyl alcohols. An especially preferred oral absorption enhancer for the present invention is sodium lauryl sulfate.

Alternatively, the compound may be administered in liposomes or microspheres (or microparticles). Methods for preparing liposomes and microspheres for administration to a patient are well known to those of skill in the art. U.S. Pat. No. 4,789,734, the contents of which are hereby incorporated by reference, describes methods for encapsulating biological materials in liposomes. Essentially, the material is dissolved in an aqueous solution, the appropriate phospholipids and lipids added, along with surfactants if required, and the material dialyzed or sonicated, as necessary. A review of known methods is provided by G. Gregoriadis, Chapter 14, “Liposomes,” Drug Carriers in Biology and Medicine, pp. 287-341 (Academic Press, 1979).

Microspheres formed of polymers or proteins are well known to those skilled in the art, and can be tailored for passage through the gastrointestinal tract directly into the blood stream. Alternatively, the compound can be incorporated and the microspheres, or composite of microspheres, implanted for slow release over a period of time ranging from days to months. See, for example, U.S. Pat. Nos. 4,906,474, 4,925,673 and 3,625,214, and Jein, TIPS 19:155-157 (1998), the contents of which are hereby incorporated by reference.

In one embodiment, the tyrosine kinase inhibitor of the present invention can be formulated into a liposome or microparticle which is suitably sized to lodge in capillary beds following intravenous administration. When the liposome or microparticle is lodged in the capillary beds surrounding ischemic tissue, the agents can be administered locally to the site at which they can be most effective. Suitable liposomes for targeting ischemic tissue are generally less than about 200 nanometers and are also typically unilamellar vesicles, as disclosed, for example, in U.S. Pat. No. 5,593,688 to Baldeschweiler, entitled “Liposomal targeting of ischemic tissue,” the contents of which are hereby incorporated by reference.

Preferred microparticles are those prepared from biodegradable polymers, such as polyglycolide, polylactide and copolymers thereof. Those of skill in the art can readily determine an appropriate carrier system depending on various factors, including the desired rate of drug release and the desired dosage.

In one embodiment, the formulations are administered via catheter directly to the inside of blood vessels. The administration can occur, for example, through holes in the catheter. In those embodiments wherein the active compounds have a relatively long half life (on the order of 1 day to a week or more), the formulations can be included in biodegradable polymeric hydrogels, such as those disclosed in U.S. Pat. No. 5,410,016 to Hubbell et al. These polymeric hydrogels can be delivered to the inside of a tissue lumen and the active compounds released over time as the polymer degrades. If desirable, the polymeric hydrogels can have microparticles or liposomes which include the active compound dispersed therein, providing another mechanism for the controlled release of the active compounds.

The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier or a finely divided solid carrier and then, if necessary, shaping the product into desired unit dosage form.

The formulations may further include one or more optional accessory ingredient(s) utilized in the art of pharmaceutical formulations, e.g., diluents, buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, suspending agents, preservatives (including antioxidants) and the like.

Compounds of the present methods (i.e. irreversible EGFR inhibitors) may be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 microns, preferably less than 10 microns, more preferably between 2 and 5 microns.

Generally for nasal administration a mildly acid pH will be preferred. Preferably the compositions of the invention have a pH of from about 3 to 5, more preferably from about 3.5 to about 3.9 and most preferably 3.7. Adjustment of the pH is achieved by addition of an appropriate acid, such as hydrochloric acid.

The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art and need not be limited based on formulation. Typically such compositions are prepared as injectables either as liquid solutions or suspensions, however, solid forms suitable for solution, or suspensions, in liquid prior to use can also be prepared. The preparation can also be emulsified.

The active ingredient can be mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient and in amounts suitable for use in the therapeutic methods described herein. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like and combinations thereof. In addition, if desired, the composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like which enhance the effectiveness of the active ingredient.

The irreversible kinase inhibitors of the present invention can include pharmaceutically acceptable salts of the components therein. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide) that are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, tartaric, mandelic and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine and the like.

Physiologically tolerable carriers are well known in the art. Exemplary of liquid carriers are sterile aqueous solutions that contain no materials in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate-buffered saline. Still further, aqueous carriers can contain more than one buffer salt, as well as salts such as sodium and potassium chlorides, dextrose, polyethylene glycol and other solutes.

Liquid compositions can also contain liquid phases in addition to and to the exclusion of water. Exemplary of such additional liquid phases are glycerin, vegetable oils such as cottonseed oil, and water-oil emulsions.

The terms “ErbB1”, “epidermal growth factor receptor” and “EGFR” are used interchangeably herein and refer to native sequence EGFR as disclosed, for example, in Carpenter et al. Ann. Rev. Biochem. 56:881-914 (1987), including variants thereof (e.g. a deletion mutant EGFR as in Humphrey et al. PNAS (USA) 87:4207-4211 (1990)). erbB1 refers to the gene encoding the EGFR protein product. As used herein, the EGFR protein is disclosed as GenBank accession no. NP_005219 (SEQ ID NO: 1) which is encoded by the erbB1 gene, GenBank accession no. NM_005228 (SEQ ID NO: 2). Nucleotide and amino acid sequences of erbB1/EGFR may be found in FIG. 5.

The term “kinase activity increasing nucleic acid variance” as used herein refers to a variance (i.e. mutation) in the nucleotide sequence of a gene that results in an increased kinase activity. The increased kinase activity is a direct result of the variance in the nucleic acid and is associated with the protein for which the gene encodes.

The term “drug” or “compound” as used herein refers to a chemical entity or biological product, or combination of chemical entities or biological products, administered to a person to treat or prevent or control a disease or condition. The chemical entity or biological product is preferably, but not necessarily a low molecular weight compound, but may also be a larger compound, for example, an oligomer of nucleic acids, amino acids, or carbohydrates including without limitation proteins, oligonucleotides, ribozymes, DNAzymes, glycoproteins, siRNAs, lipoproteins, aptamers, and modifications and combinations thereof.

As used herein, the terms “effective” and “effectiveness” includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the treatment to result in a desired biological effect in the patient. Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (often referred to as side-effects) resulting from administration of the treatment. “Less effective” means that the treatment results in a therapeutically significant lower level of pharmacological effectiveness and/or a therapeutically greater level of adverse physiological effects.

Nucleic acid molecules can be isolated from a particular biological sample using any of a number of procedures, which are well-known in the art, the particular isolation procedure chosen being appropriate for the particular biological sample. For example, freeze-thaw and alkaline lysis procedures can be useful for obtaining nucleic acid molecules from solid materials; heat and alkaline lysis procedures can be useful for obtaining nucleic acid molecules from urine; and proteinase K extraction can be used to obtain nucleic acid from blood (Rolff, A et al. PCR: Clinical Diagnostics and Research, Springer (1994).

As used herein, a “cancer” in a subject or patient refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. In some circ*mstances, cancer cells will be in the form of a tumor, or such cells may exist locally within an animal, or circulate in the blood stream as independent cells.

Compounds used herein, including EKB-569, HK1-357, and HK1-272 as described in U.S. Pat. No. 6,002,008; Greenberger et al., Proc. 11th NCI EORTC-AACR Symposium on New Drugs in Cancer Therapy, Clinical Cancer Res. Vol. 6 Supplement, November 2000, ISSN 1078-0432; in Rabindran et al., Cancer Res. 64: 3958-3965 (2004); Holbro and Hynes, Ann. Rev. Pharm. Tox. 44:195-217 (2004); and Tejpar et al., J. Clin. Oncol. ASCO Annual Meeting Proc. Vol. 22, No. 14S: 3579 (2004).

Analysis of Recurrent NSCLC and Generation of Gefitinib-Resistant NCI-H1650 Cells.

Clinical specimens of recurrent NSCLC were obtained at autopsy after appropriate consent. The entire kinase domain of EGFR was sequenced after analysis of uncloned PCR products. Multiple clones of exon 20 were sequenced to examine codon 790. Mutational analysis of EGFR (exons 1-28), ERBB2 (exons 1-24), PTEN (exons 1-9), Kras (codons 12, 13, and 61), and p53 (exons 5-8) in gefitinib-resistant clones as well as the parental NCI-H1650 cell line was performed by automated sequencing of individual exons and flanking intronic sequence (PCR conditions available on request) with bidirectional sequencing by using dye terminator chemistry (BIGDYE version 1.1, Applied Biosystems). Sequencing reactions were run on an ABI3100 sequencer (Applied Biosystems), and electropherograms were analyzed by using SEQUENCE NAVIGATOR and FACTURA software (Applied Biosystems).

To generate resistant subclones of NCI-H1650 cells, these were treated with ethyl methane sulfonate (EMS; 600 μg/ml), allowed to recover for 72 h, and then seeded at a density of 6×104 cells per 10-cm2 dish in 20 μM gefitinib. Relative resistance of these cells to gefitinib, compared with the irreversible inhibitors, was achieved by seeding 5×104 cells in six-well plates in 5% FCS and 100 ng/ml EGF (Sigma), in the presence of varying concentrations of drugs, followed after 72 h by fixing cells with 4% formaldehyde, staining with 0.1% crystal violet, and quantifying cell mass by using the Odyssey Infrared Imaging System (LI-COR Biosciences, Lincoln, Nebr.). For small interfering RNA (siRNA) knockdown experiments, cells were transfected with double-stranded RNA oligonucleotides targeting EGFR, ERBB2 (both SMARTpool from Dharmacon, Lafayette, Colo.), or nonspecific control (LRT1B), using X-treme GENE transfection reagent (Roche Applied Science). After 72 h, cells were stained with crystal violet and analyzed on the Odyssey Infrared scanner.

Immunoblotting and Signaling Studies.

Inhibition of EGFR signaling by increasing concentrations of gefitinib or the irreversible inhibitors was determined by seeding 9×104 cells in 24-well plates, adding the drugs to medium containing 5% FCS for 15 min, followed by a 2-h pulse with 100 ng/ml EGF, and harvesting of lysates. Lysates were prepared in 2× gel loading buffer, sonicated, boiled, and then separated by 10% SDS/PAGE, followed by electrotransfer to polyvinylidene fluoride (PVDF) membranes, and immunoblotting. Antibodies used were phospho-EGFR Y1068 and phospho-mitogen-activated protein kinase (MAPK) (Cell Signaling Technology, Beverly, Mass.), phospho-AKT (BioSource International, Camarillo, Calif.), and total EGFR, MAPK, AKT, and tubulin (Santa Cruz Biotechnology).

Analysis of EGFR Internalization.

To demonstrate internalization of EGFR by fluorescence microscopy, cells were grown on coverslips and incubated with 1 ng/ml recombinant human (rh) EGF (Molecular Probes, Eugene, Oreg.) for various intervals before fixing in 4% paraformaldehyde for 10 min. Coverslips were washed in PBS and mounted with ProLong Gold antifade reagent (Molecular Probes). To quantify EGFR internalization by cell surface biotinylation, cells were grown to confluency, pretreated with cyclohexamide, incubated on ice for 1 h with 1.5 mg/ml sulfosuccinimidyl-2-(biotinamido)ethyl-1,3-dithiopropionate (sulfo-NHS-SS-biotin; Pierce), and washed with blocking buffer (50 nM NH4CL/1 mM MgCl/0.1 mM CaCl2 in PBS) to quench free sulfo-NHS-SS-biotin, followed by several further washes with PBS. The cells were then incubated in culture medium at 37° C. for various intervals to allow internalization of the biotinylated molecules, washed twice for 20 min in a glutathione solution (50 mM glutathione/75 mM NaCl/75 mM NaOH/1% BSA) on ice to strip all of the biotinyl groups from the cell surface, and then scraped and lysed in 500 μM radioimmunoprecipitation assay (RIPA) buffer (25 mM Tris-HCl, pH 7.4, with 150 mM NaCL/0.1% SDS/1% Triton X-100) supplemented with NaF, Na-orthovanadate, and protease inhibitors. Cell extracts were centrifuged, and the supernatants were incubated with streptavidin beads (Sigma) to collect the biotinylated proteins, which were then analyzed by SDS/PAGE and immunoblotting with anti-EGFR antibody (SC-03, Santa Cruz Biotechnology) or antibody against transferrin receptor (Santa Cruz Biotechnology).

Results and Discussion

Analysis of Recurrent Lung Cancers with Acquired Resistance to Gefitinib.

Recurrent gefitinib-resistant NSCLC developed in two patients whose tumors had harbored an activating mutation of the EGFR kinase at the time of diagnosis and who had shown a dramatic initial clinical response to the drug (1). In both cases, progressive metastatic disease in the liver led to the patients' demises, 1-2 years after initiation of treatment. In case 1, analysis of the major liver metastasis obtained at the time of autopsy indicated persistence of the sensitizing EGFR mutation (L858R), as well as the presence of a newly acquired T790M mutation (FIG. 1A). Interestingly, analysis of uncloned PCR products showed the initial L858R mutation to be present at an abundance consistent with a heterozygous mutation that is present in all tumor cells, whereas the secondary T790M mutation was seen at approximately one-fifth the abundance of the corresponding wild-type allele. Thus, this resistance-associated mutation seems to be present in only a fraction of cells within the recurrent tumor.

Case 2 involved eight distinct recurrent metastases in the liver after the failure of gefitinib therapy. In all of these independent lesions, the sensitizing L861Q EGFR mutation was present at the expected ratio for a heterozygous mutation. No secondary EGFR mutation was detectable by analysis of uncloned PCR products from any of these metastases. However, after subcloning of the PCR products, the T790M mutation was found to be present at very low frequency in two of the four metastatic tumors analyzed (T790M, 2 of 50 clones sequenced from lesion 1 and 1 of 56 from lesion 2), but not from two other recurrent metastases (0 of 55 clones from lesion 3 and 0 of 59 from lesion 4), or the primary tumor (0 of 75 clones) (FIG. 1B and Table 1). Taken together, these results are consistent with previous reports that the T790M mutation is present in some, but not all, cases of acquired gefitinib resistance (three of seven tumors; see refs. 17, 18, and 21). Furthermore, as previously noted (18), even in some cases with this resistance-associated mutation, it seems to be present in only a small fraction of tumor cells within a recurrent lesion. These observations suggest that additional mechanisms of resistance are involved in cases without a secondary EGFR mutation and that such mechanisms coexist with the T790M mutation in other cases.

Generation of Gefitinib-Resistant Cell Lines with Susceptibility to Irreversible Inhibitors.

Given the excellent correlation between the clinical responsiveness of EGFR-mutant NSCLC and the enhanced gefitinib-sensitivity of NSCLC cell lines with these mutations (2, 6, 22, 23), and the limited availability of clinical specimens from relapsing patients, we modeled gefitinib resistance in vitro. We cultured the bronchoalveolar cancer cell line NCI-H1650, which has an in-frame deletion of the EGFR kinase (de1E746-A750), in 20 μM gefitinib, either with or without prior exposure to the mutagen ethyl methane sulfonate. This cell line exhibits 100-fold increased sensitivity to gefitinib, compared with some NSCLC lines expressing wild-type EGFR (6). Whereas the vast majority of these cells are efficiently killed by 20 μM gefitinib, drug-resistant colonies were readily observed at a frequency of ≈10−5, irrespective of mutagen treatment. Forty-nine independent drug-resistant clones were isolated, showing an average 50-fold decrease in gefitinib sensitivity (FIG. 2A). All of these showed persistence of the sensitizing mutation without altered expression of EGFR, and none had acquired a secondary EGFR mutation or new mutations in ERBB2, p5.3, Kras, or PTEN. Gefitinib-resistant clones demonstrated comparable resistance to related inhibitors of the anilinoquinazoline class. Remarkably, however, they displayed persistent sensitivity to three inhibitors of the ERBB family (FIG. 2A): HKI-272 (24) and HKI-357 (compound 7f in ref. 25), which are dual inhibitors of EGFR and ERBB2 (IC50 values of 92 and 34 nM, respectively, for EGFR and 59 and 33 nM, respectively, for ERBB2), and EKB-569 (26), a selective inhibitor of EGFR (IC50 values of 39 nM for EGFR and 1.3 μM for ERBB2) (Wyeth) (FIG. 2B). All three drugs are irreversible inhibitors, most likely via a covalent bond with the cys773 residue within the EGFR catalytic domain or the cys805 of ERBB2. Like gefitinib, these compounds demonstrate increased killing of NSCLC cells harboring an EGFR mutation, compared with cells expressing wild-type receptor (FIG. 2A). However, in contrast to gefitinib, against which resistant clones are readily generated, even at high drug concentrations, we were unable to establish clones of cells that were resistant to the irreversible inhibitors at concentrations above 10 μM, even after ethyl methane sulfonate mutagenesis (FIG. 2C).

Dependence of Gefitinib-Resistant Cells on EGFR and ERBB2 Expression.

To gain insight into the mechanisms underlying the acquisition of gefitinib resistance and the persistent sensitivity to the irreversible inhibitors, we first determined whether resistant cell lines remain dependent upon EGFR for their viability. We have previously shown that siRNA-mediated knockdown of EGFR triggers apoptosis in cells harboring mutant EGFRs, but not in those with wild-type alleles (6). Significantly, parental NCI-H1650 cells as well as their gefitinib-resistant derivatives showed comparable reduction in cell viability after transfection with siRNA targeting EGFR (FIG. 3A). Thus, acquisition of gefitinib-resistance does not involve EGFR-independent activation of downstream effectors. Because HKI-272 and HKI-357 target both EGFR and ERBB2, we also tested suppression of this related receptor. Knockdown of ERBB2 in NCI-H1650 and its gefitinib-resistant derivatives also caused loss of viability (FIG. 3A), suggesting a role for EGFR-ERBB2 heterodimers in transducing essential survival signals in tumor cells harboring EGFR mutations. Inhibition of EGFR alone by an irreversible inhibitor seems to be sufficient to induce apoptosis in gefitinib-resistant cells, as demonstrated by the effectiveness of EKB-569, which primarily targets EGFR (26). However, given the potentially complementary effects of targeting both EGFR and ERBB2 by using siRNA and the availability of irreversible inhibitors that target both of these family members, the potential benefit of dual inhibition warrants consideration.

We compared the ability of gefitinib and irreversible ERBB family inhibitors to suppress signaling via downstream effectors of EGFR that mediate its proliferative and survival pathways. HKI-357 was 10-fold more effective than gefitinib in suppressing EGFR autophosphorylation (measured at residue Y1068), and AKT and MAPK phosphorylation in parental NCI-H1650 cells harboring the de1E746-A750 EGFR mutation (FIG. 3B). In a gefitinib-resistant derivative, NCI-H1650(G7), gefitinib exhibited considerably reduced efficacy in suppressing AKT phosphorylation, a key EGFR signaling effector linked to gefitinib responsiveness (6), whereas HKI-357 demonstrated persistent activity (FIG. 3B).

Altered EGFR Internalization in Gefitinib-Resistant Clones.

Given the absence of secondary mutations in EGFR and the persistent susceptibility of gefitinib-resistant cells to siRNA-mediated suppression of EGFR, we tested whether the mechanism underlying the differential inhibition of EGFR signaling in gefitinib-resistant cells by reversible and irreversible inhibitors might be correlated with alterations in receptor trafficking, a well documented modulator of EGFR-dependent signaling (20). Indeed, analysis of EGFR trafficking in NCI-H1650-derived resistant cells demonstrated a consistent increase in EGFR internalization, compared with the parental drug-sensitive cells, as measured both by internalization of fluorescein-labeled EGF (FIG. 3C) and quantitation of cytoplasmic biotinylated EGFR (FIG. 3D). No such effect was observed with the transferrin receptor, suggesting that this did not result from a generalized alteration in all receptor processing. Although further work is required to define the precise mechanism for this alteration in EGFR trafficking, a complex process in which numerous regulatory proteins have been implicated, these results suggest that gefitinib's ability to inhibit EGFR activation is compromised in these cells, whereas the action of the irreversible inhibitors are not detectably affected.

Inhibition of T790M EGFR Signaling and Enhanced Cell Killing by Irreversible Inhibitors.

The enhanced suppression of EGFR signaling by irreversible ERBB inhibitors raised the possibility that these drugs may also exhibit persistent activity in the context of cells harboring the T790M secondary mutation in EGFR. We therefore tested the effect of these inhibitors on the NCI-H1975 bronchoalveolar cancer cell line, which harbors both L858R and T790M mutations in EGFR (18). Significantly, this cell line was derived from a patient that had not been treated with an EGFR inhibitor, indicating that this mutation is not uniquely associated with acquired drug resistance. Both HKI-357 and HKI-272 were considerably more effective than gefitinib in suppressing ligand-induced EGFR autophosphorylation and its downstream signaling, as determined by AKT and MAPK phosphorylation (FIG. 4A). Similarly, all three irreversible inhibitors suppressed proliferation in this cell line under conditions where it is resistant to gefitinib (FIG. 4B). Thus, irreversible ERBB inhibitors seem to be effective in cells harboring the T790M EGFR as well as in cells with altered trafficking of the wild-type receptor.

Our results confirm the report of T790M mutations in EGFR as secondary mutations that arise in previously sensitive NSCLCs harboring an activating mutation, associated with the emergence of acquired resistance (17, 18). However, this mutation is present only in a subset of cases, and even tumors that harbor the T790M mutation may contain only a small fraction of cells with this mutation. These observations imply that multiple resistance mechanisms can coexist in recurrent tumors after an initial response to gefitinib or similar reversible EGFR inhibitors. Moreover, these findings suggest that T790M-independent resistance mechanisms may be equally, if not more, effective than the T790M substitution itself in conferring drug resistance and may explain why recurrent tumors rarely exhibit clonality for T790M (17, 18). In vitro mechanisms of acquired gefitinib resistance do not involve secondary EGFR mutations at a significant frequency, but instead are correlated with altered receptor trafficking. However, it should be noted that we have not examined EGFR trafficking in all of the resistant clones that we established in vitro, and it remains possible that additional mechanisms may contribute to gefitinib resistance in some of the clones. Nonetheless, virtually all gefitinib-resistant clones exhibited comparable sensitivity to the irreversible ERBB inhibitors.

Our results indicate striking differences between competitive EGFR inhibitors such as gefitinib, whose effectiveness is limited by the rapid development of drug resistance in vitro, and irreversible inhibitors, to which acquired resistance appears to be rare (FIG. 2C). We speculate that increased internalization of ligand-bound EGFR in resistant cells may be linked to dissociation of the gefitinib-EGFR complex at the low pH of intracellular vesicles. In contrast, irreversible cross-linking of the receptor would be unaffected by such alterations in receptor trafficking. Acquired resistance to gefitinib is stably maintained after passage of cells for up to 20 generations in the absence of drug, suggesting that genetic or epigenetic alterations in genes that modulate EGFR turnover may underlie this phenomenon. Because receptor trafficking cannot be readily studied by using available clinical specimens, identification of such genomic alterations may be required before clinical correlations are possible. Nonetheless, such a mechanism may contribute to in vivo acquired gefitinib-resistance in patients with recurrent disease who do not have secondary mutations in EGFR.

Irreversible ERBB inhibitors also seem to be effective in overcoming gefitinib resistance mediated by the T790M mutation, an effect that presumably results from the preservation of inhibitor binding despite alteration of this critical residue. While this work was in progress, another irreversible inhibitor of EGFR [CL-387,785, Calbiochem (27)] was shown to inhibit the kinase activity of the T790M EGFR mutant (17). The effectiveness of CL-387,785 in the context of T790M was proposed to result from the absence of a chloride at position 3 of the aniline group, which is present in gefitinib and was postulated to interfere sterically with binding to the mutant methionine at codon 790. However, EKB-569, HKI-272, and HKI-357 all have chloride moieties at that position in the aniline ring, suggesting that their shared ability to bind irreversibly to EGFR is likely to explain their effectiveness, rather than the absence of a specific steric interaction with T790M (24-26). Thus, these irreversible inhibitors may prove to be broadly effective in circumventing a variety of resistance mechanisms, in addition to the T790M mutation.

TABLE 1
Presence of EGFR T790M mutation at very low frequency in recurrent
tumors from case 2
No. of clones
TumorT790M mutantWild type
Primary075
Recurrent 1248
Recurrent 2155
Recurrent 3055
Recurrent 4059

Sequencing of large numbers of cloned PCR products revealed that a minority of alleles within two of four liver lesions contain the T790M mutation.

The references cited throughout the application are incorporated herein by reference in their entirety.

  • 1. Schiller J H, Harrington D, Belani C P, et al. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med 2002; 346:92-98.
  • 2. Druker B J, Talpaz M, Resta D J et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in Chronic Myeloid Leukemia. N Engl J Med 2001; 344:1031-1037.
  • 3. Arteaga C L. ErbB-targeted therapeutic approaches in human cancer. Exp Cell Res. 2003; 284:122-30.
  • 4. Jorissen R N, Walker F, Pouliot N, Garrett T P, Ward C W, Burgess A W. Epidermal growth factor receptor: mechanisms of activation and signaling. Exp Cell Res 2003; 284:31-53
  • 5. Luetteke N C, Phillips H K, Qui T H, Copeland N G, Earp H S, Jenkins N A, Lee D C. The mouse waved-2 phenotype results from a point mutation in the EGF receptor tyrosine kinase. Genes Dev 1994; 8:399-413.
  • 6. Nicholson R I, Gee J M W, Harper M E. EGFR and cancer prognosis. Eur J Cancer. 2001; 37:S9-15
  • 7. Wong A J, Ruppert J M, Bigner S H, et al. Structural alterations of the epidermal growth factor receptor gene in human gliomas. Proc Natl Acad Sci. 1992; 89:2965-2969.
  • 8. Ciesielski M J, Genstermaker R A. Oncogenic epidermal growth factor receptor mutants with tandem duplication: gene structure and effects on receptor function. Oncogene 2000; 19:810-820.
  • 9. Frederick L, Wang W-Y, Eley G, James C D. Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 2000; 60:1383-1387.
  • 10. Huang H-J S, Nagane M. Klingbeil C K, et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phophorylation and unattenuated signaling. J Biol Chem 1997; 272:2927-2935
  • 11. Pegram M D, Konecny G, Slamon D J. The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer. Cancer Treat Res 2000; 103:57-75.
  • 12. Ciardiello F, Tortora G. A novel approach in the treatment of cancer targeting the epidermal growth factor receptor. Clin Cancer Res. 2001; 7:2958-2970
  • 13. Wakeling A E, Guy S P, Woodburn J R et al. ZD1839 (Iressa): An orally active inhibitor of Epidermal Growth Factor signaling with potential for cancer therapy. Cancer Res 2002; 62:5749-5754.
  • 14. Moulder S L, Yakes F M, Muthuswamy S K, Bianco R, Simpson J F, Arteaga C L. Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. Cancer Res 2001; 61:8887-8895.
  • 15. Moasser M M, Basso A, Averbuch S D, Rosen N. The tyrosine kinase inhibitor ZD1839 (“Iressa”) inhibits HER2-driven signaling and suppresses the growth of HER-2 overexpressing tumor cells. Cancer Res 2001; 61:7184-7188.
  • 16. Ranson M, Hammond L A, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol. 2002; 20: 2240-2250.
  • 17. Herbst R S, Maddox A-M, Rothernberg M L, et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well tolerated and has activity in non-small cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol. 2002; 20:3815-3825.
  • 18. Baselga J, Rischin J B, Ranson M, et al. Phase I safety, pharmaco*kinetic and pharmacodynamic trial of ZD1839, a selective oral Epidermal Growth Factor Receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Onc 2002; 20:4292-4302.
  • 19. Albanell J, Rojo F, Averbuch S, et al. Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol. 2001; 20:110-124.
  • 20. Kris M G, Natale R B, Herbst R S, et al. Efficacy of Gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: A randomized trial. JAMA 2003; 290:2149-2158.
  • 21. f*ckuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21:2237-2246.
  • 22. Giaccone G, Herbst R S, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial-INTACT 1. J Clin Oncol 2004; 22:777-784.
  • 23. Herbst R S, Giaccone G, Schiller J H, et al. Gefitinib in combination with pacl*taxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial-INTACT 2. J Clin Oncol 2004; 22:785-794.
  • 24. Rich J N, Reardon D A, Peery T, et al. Phase II Trial of Gefitinib in recurrent glioblastoma. J Clin Oncol 2004; 22:133-142
  • 25. Cohen M H, Williams G A, Sridhara R, et al. United States Food and Drug Administration Drug Approval Summary: Gefitinib (ZD1839; Iressa) Tablets. Clin Cancer Res. 2004; 10:1212-1218.
  • 26. Cappuzzo F, Gregorc V, Rossi E, et al. Gefitinib in pretreated non-small-cell lung cancer (NSCLC): Analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or Metastatic NSCLC. J Clin Oncol. 2003; 21:2658-2663.
  • 27. Fitch K R, McGowan K A, van Raamsdonk C D, et al. Genetics of Dark Skin in mice. Genes & Dev 2003; 17:214-228.
  • 28. Nielsen U B, Cardone M H, Sinskey A J, MacBeath G, Sorger P K. Profiling receptor tyrosine kinase activation by using Ab microarrays. Proc Natl Acad Sci USA 2003; 100:9330-5.
  • 29. Burgess A W, Cho H, Eigenbrot C, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell 2003; 12:541-552.
  • 30. Stamos J, Sliwkowski M X, Eigenbrot C. Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4-anilinoquinazoline inhibitor. J Biol Chem. 2002; 277:46265-46272.
  • 31. Lorenzato A, Olivero M, Patrane S, et al. Novel somatic mutations of the MET oncogene in human carcinoma metastases activating cell motility and invasion. Cancer Res 2002; 62:7025-30.
  • 32. Davies H, Bignell G R, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417:906-7.
  • 33. Bardelli A, Parsons D W, Silliman N, et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science 2003; 300:949.
  • 34. Daley G Q, Van Etten R A, Baltimore D. Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome. Science 1990; 247:824-30.
  • 35. Heinrich, M C, Corless C L, Demetri G D, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 2003; 21:4342-4349.
  • 36. Li B, Chang C, Yuan M, McKenna W G, Shu H G. Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. Cancer Res 2003; 63:7443-7450.
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