TW201304777A - Method for treating non-small cell lung cancer in a subpopulation - Google Patents

Abstract

The present invention provides a method of improving the survival rate associated with cancer in a general population subpopulation. The present invention provides a method of improving the survival rate associated with cancer in a patient with an Asian ethnic background. In addition, the present application relates to the use of kinase inhibitors for the treatment of angiogenesis-related diseases in Asian patients. In addition, the present application relates to the treatment of non-small cell lung cancer in Asian patients using motesanib.

Description

Method for treating non-small cell lung cancer in a subpopulation

The present invention provides a method of improving the survival rate associated with cancer in a general population subpopulation. The present invention provides a method of improving the survival rate associated with cancer in a patient with an Asian ethnic background. In addition, the present application relates to the use of kinase inhibitors for the treatment of angiogenesis-related diseases in Asian patients. In addition, the present application relates to the treatment of non-small cell lung cancer in Asian patients using motetanil.

Certain diseases are known to be associated with dysregulated angiogenesis, such as ocular neovascularization, such as retinopathy (including diabetic neuropathy), age-related macular degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis, Inflammatory diseases such as rheumatoid or rheumatic inflammatory diseases, especially arthritis (including rheumatoid arthritis); or other chronic inflammatory conditions such as chronic asthma, atherosclerosis or post-transplant atherosclerosis, uterus Endometriosis; and malignant tumor diseases, such as so-called solid tumors.

For example, angiogenesis plays a key role in tumor progression. Primary and small tumors can be obtained by simply diffusing enough oxygen and nutrients to maintain their growth. However, after a diameter of more than 1 mm to 2 mm, the diffusion does not provide the elements required for further growth. For growth beyond this size, all tumors require the vasculature regardless of the cause, origin, type, age or location of the tumor. Therefore, tumors that grow more than 1 mm to 2 mm in diameter require angiogenesis. Thus, angiogenesis has been seen as a promising target for effective general treatment of tumors.

There are three major mechanisms that play an important part in the anti-tumor activity of angiogenesis inhibitors: (i) inhibiting the growth of blood vessels, especially capillaries, to become avascular-free tumors, as a result of cell death and proliferation. The balance achieved without net tumor growth; (ii) preventing tumor cell migration due to no blood flowing to and from the tumor; and (iii) inhibiting endothelial cell proliferation, thereby avoiding endothelial cell pairs normally lining the blood vessel The paracrine growth stimulating effect exerted by the surrounding tissue. See Exp. Opin. Ther. Patents, 11: 77-114 (2001).

Efforts have been made to develop therapeutically effective angiogenesis inhibitors for all three of these primary mechanisms. Due to these efforts, various promising anti-angiogenic agents have been identified.

During embryonic development and normal growth, and in many pathological abnormalities and diseases, the network center that regulates the growth and differentiation of the vasculature and its components is called Vascular Endothelial Growth Factor (VEGF). Angiogenic factors known as Vascular Permeability Factor (VPF) and their cellular receptors (see Trends, in Cell Biology, 6:454-456 (1996)).

VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein associated with Platelet-Derived Growth Factor (PDGF); it is produced by normal cell lines and tumor cell lines; a cell-specific mitogen; it exhibits angiogenic activity in an in vivo test system (eg, rabbit cornea); chemotaxis to endothelial cells and monocytes; and induces a plasminogen activator in endothelial cells, It involves proteolytic degradation of the extracellular matrix during capillary formation. Has Knowing many isoforms of VEGF, these exhibit comparable biological activities, but differ in the cell type secreted by them and their heparin binding ability. In addition, other members of the VEGF family exist, such as "Placental Growth Factor" (PlGF) and VEGF-C.

The VEGF receptor (VEGFR) is a transmembrane receptor tyrosine kinase. These receptors are characterized by an extracellular domain with seven immunoglobulin-like domains and an intracellular tyrosine kinase domain. Various types of VEGF receptors are known, such as VEGFR-1 (also known as flt-1), VEGFR-2 (also known as KDR), and VEGFR-3.

Lung cancer is the most common cancer in the world, causing about 18% of cancer deaths. Most patients present with advanced disease and >80% have non-small cell lung cancer (NSCLC). The median survival time was approximately 8 months in patients receiving standard two-drug chemotherapy regimens as first-line therapy.

The pro-angiogenic cytokine vascular endothelial growth factor (VEGF) and its important target for systemic NSCLC therapy. In the E4599 study of patients with stage IIIB or stage IV non-squamous NSCLC, anti-VEGF-A monoclonal antibody was used in comparison with carboplatin/paclitaxel plus placebo. Treatment with bevacizumab plus carboplatin/paclitaxel improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Bevacizumab plus carboplatin/pacific paclitaxel is currently the only anti-angiogenic therapy approved in the United States for the treatment of NSCLC. Adding bevacizumab to cisplatin/gemcitabine has been shown to improve PFS in NSCLC, but for whole Body viability did not have a statistically significant effect. Other anti-angiogenic agents fail to show improved clinical outcome when used in combination with chemotherapy as first-line therapy for advanced disease.

Mordisani is a VEGF receptor (VEGFR) 1, 2 and 3; oral administration of a small molecule antagonist of platelet-derived growth factor receptor and Kit, which has been demonstrated in solid tumors as a monotherapy and in combination with chemotherapy Promising anti-tumor activity. Phase I dose-finding study evaluated the safety, pharmacokinetics, and pharmacokinetics of AMG 706 in patients with advanced refractory solid tumors. Journal of Clinical Oncology (2007), 25 (17), 2369-2376. In the Phase 1b study in NSCLC, treatment with motetanil plus carboplatin/paclitaxel was dosed up to 125 mg once daily (QD), with pharmacokinetics supporting the dose regimen as a combination therapy. Clinical Cancer Research (2010), 16(1), 279-290. OBJECTIVE: This phase II study investigated the efficacy and tolerability of motetanil in advanced medullary thyroid cancer (MTC), a vascular endothelial growth factor receptor 1, 2 and 3; platelet-derived growth factor receptor; and high-selective inhibitors in Kit's test. Patients and Methods: Patients with locally advanced or metastatic, progressive or symptomatic MTC received oral administration of 125 mg/d motfinis for up to 48 weeks or until unacceptable toxicity or disease progression. New England Journal Medicine 2008 359:31-42. The results of an open phase 2 study of motetanil in combination with paclitaxel and carboplatin for advanced non-squamous non-small cell lung cancer are reported at ASCO. Journal of Clinical Oncology, 28, 15s, 2010 (Abstract 7528). Phase 1 study in Japanese patients with advanced solid tumors The safety and pharmacokinetics of motiflini (AMG 706) were studied. Cancer Chemotherapy and Pharmacology (2010), 66(5), 935-943. Phase II clinical studies evaluated the efficacy and safety of a single agent, motytinib, in patients with advanced gastrointestinal stromal tumors and previously exposed to imatinib mesylate. Cancer Chemotherapy and Pharmacology (2010), 65(5), 961-967.

However, as the incidence of lung cancer is increasing in Asian countries, there is a need in the industry for a new and more effective approach to treating cancer in Asian patients.

In the present invention, the results of the MONET1 Phase 3 clinical trial involving the overall survival rate of patients who were administered motithani were re-examined and re-evaluated for the subset population. Responses to patients treated with motetanil in Japan, Korea, Hong Kong, Singapore, Taiwan, and the Philippines provide unexpected survival benefits compared with non-Asian patients .

This application is directed to methods and kits for treating cancer in Asian patients.

This application relates to the use of kinase inhibitors to treat cancer in Asian patients.

The invention also relates to the treatment of malignant tumor formation including cancer and metastasis, including but not limited to lung cancer. The invention also relates to the treatment of non-small cell lung cancer. The invention also relates to the treatment of non-squamous non-small cell lung cancer. The invention also relates to the treatment of adenocarcinoma.

This application relates to first-line treatment of non-squamous non-small cell lungs in Asian patients. A method of cancer comprising administering modisani.

The present application is directed to a method of improving survival associated with non-squamous non-small cell lung cancer in an Asian patient comprising treating the Asian patient with a combination of motetanil, taxane, and a platinum-containing anticancer drug.

The present application is directed to a method of increasing the overall survival of an Asian patient diagnosed with non-squamous non-small cell lung cancer comprising treating the Asian patient with a combination comprising motetanil and taxane.

This application relates to a method wherein the combination comprises a platinum-containing anticancer drug.

The present application is directed to a method of increasing the overall survival of an Asian patient diagnosed with non-squamous non-small cell lung cancer comprising treating the Asian patient with a combination comprising motetanil and a platinum-containing anticancer drug.

This application is directed to a method wherein the combination comprises a taxane.

The present application is directed to a method wherein the motehsani is administered in combination with one or more chemotherapeutic agents.

This application relates to a method wherein the chemotherapeutic agent is paclitaxel or carboplatin.

The present application relates to a method wherein the taxane is paclitaxel and the platinum-containing anticancer drug is carboplatin.

This application relates to a method wherein the paclitaxel is administered at 200 mg/m ² .

This application relates to a method wherein the carboplatin is administered at an AUC 6 mg/mL ̇min.

The present application relates to a method in which the non-small cell lung cancer gland cancer.

The present application is directed to a method wherein the non-small cell lung cancer is non-squamous.

This application relates to a method wherein the treatment is first-line treatment.

The present application is directed to a method wherein the motetanil is administered at a daily dose of 100 mg or 125 mg.

The present application is directed to a method wherein the motetanil is administered at a daily dose of 125 mg.

This application relates to a method in which the Asian patient is a Japanese, Republic of Korea, Taiwan, China (Hong Kong), Philippine or Singaporean ethnic group.

This application relates to a method in which the Asian patient is Japanese.

The present application relates to a method for increasing progression-free survival associated with non-squamous non-small cell lung cancer in Asian patients, comprising treating the Asian patient with a combination of motetanil, taxane, and a platinum-containing anticancer drug .

The present application relates to a method for increasing progression-free survival associated with non-squamous non-small cell lung cancer in Asian patients and greater than the progression-free survival observed using only taxane and platinum-containing anticancer drugs. The treatment of the Asian patient is carried out using a combination of motetanil, taxane and a platinum-containing anticancer drug.

The present application relates to a method for increasing the overall survival rate associated with non-squamous non-small cell lung cancer in Asian patients and greater than the overall survival observed using only taxane and platinum-containing anticancer drugs, including utilization The combination of motiflini, taxane and platinum-containing anticancer drugs treats this Asian patient.

Another aspect of the invention pertains to any of the above embodiments in accordance with the invention One of the compounds is used as a medicine.

Another aspect of the invention relates to the use of a compound according to any of the above embodiments of the invention in the manufacture of a medicament for the treatment of cancer.

Currently, standard treatments for primary tumors consist of surgical resection and subsequent radiation or IV administration of chemotherapy. A typical chemotherapy regimen consists of a DNA alkylating agent, a DNA chelating agent, a CDK inhibitor, or a microtubule poison. The chemotherapeutic dose used is slightly lower than the maximum tolerated dose and thus dose limiting toxicity typically includes nausea, vomiting, diarrhea, hair loss, neutropenia, and the like.

There are a number of anti-neoplastic agents that can be used for commercial use, clinical evaluation, and pre-clinical development, which can be selected for treatment of malignant tumor formation in combination with medicinal chemotherapy. These anti-malignant tumor agents belong to several main types, namely, antibiotic-type agents, alkylating agents, antimetabolites, hormone agents, immunopharmaceuticals, interferon-type agents, and a series of various agents.

The first family of anti-malignant agents that can be used in combination with the compounds of the invention consists of an anti-metabolic/thymidyl synthase inhibitor anti-neoplastic agent. Suitable anti-metabolite anti-neoplastic agents may be selected from, but not limited to, a group consisting of 5-FU, fibrinogen, acanthifolic acid, aminyl thiadiazole, and buquina sodium ( Brequinar sodium), carmofur (carmofur), Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine Ligation, Lilly DATHF, Merrel Dow DDFC, dezaguanine, didoxycytidine, dedeoxyguanosine, Didox, Yoshitomi DMDC, doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine, floxuridine ), fludarabine phosphate, 5-fluorouracil, N-(2'-furanyl)-5-fluorouracil, Daiichi Seiyaku, FO-152, isopropyl Pyrrazine, Lily LY-188011, Lilai LY-264618, methotrexate, methotrexate, weikon MZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin Asahi Chemical, PL-AC, Takeda TAC-788, thioguanine, tiazofurin, Erbamont TIF, trimetrexate, cheese Amino acid kinase inhibitors, Taiho UFT and uricytin.

The second family of anti-neoplastic agents that can be used in combination with the compounds of the invention consists of an alkylated anti-neoplastic agent. Suitable alkylation-type anti-neoplastic agents can be selected from, but not limited to, a group consisting of: Shionogi 254-S, aldoxamine mimetic, altretamine, ana Anaxirone, Boehringer Mannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102, carboplatin, carmustine ), Chinoin-139, Chenoyi-153, Benzin Chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, cyplatate, Degussa D-19-384, Sumimoto DACHP (Myr) 2, diphenylspiromustine, diplatinum cytostatic, Erba distamycin Derivatives, Chugai DWA-2114R, ITI E09, elmustine, Ebmante FCE-24517, estramustine phosphate sodium, fotemustine , Unimed G-6-M, Chenoyi GYKI-17230, and hepsul-fam, ifosfamide, iproplatin, lomustine, horse phosphorus Mafosfamide, mitolactol, Nippon Kayaku NK-121, NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, raising Yakult Honsha SN-22, spiromustine, Tanabe Seiyaku TA-077, tauromustine, temozolomide, teroxirone, Tetraplatin and trimelamol.

The third family of anti-malignant agents that can be used in combination with the compounds of the invention consists of an antibiotic-type anti-neoplastic agent. Suitable antibiotic-type anti-malignant tumor agents may be selected from, but not limited to, a group consisting of: Dapeng 4181-A, aclarubicin, actinomycin D, actinoplanone, Ebmann ADR-456, aeroplysinin derivative, ajinomoto ( Ajinomoto) AN-201-II, Ajinomoto AN-3, Nippon Soda anisomycins, anthracycline, azino-mycin-A, Biscabeerin, Bristol-Myers BL-6859, BJ-25067, BMY-25551, BMY-26605, BMY-27557, must-have Treatment of BMY-28438, bleomycin sulfate, bryostatin-1, Dapeng C-1027, calichemycin, chromoximycin, more mold Dactinomycin, daunorubicin, Kyowa Hakko DC-102, Concord Fermentation DC-79, Concord Fermentation DC-88A, Concord Fermentation DC89-A1, Concord Fermentation DC92-B, Dipropylene Ditrisarubicin B, Saskatchewan DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A, soft Epirubicin, Estrostatin, esorubicin, esperamicin-A1, espermatin-Alb, Ebmante FCE-21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, glidobactin, gregatin-A, grincamycin, herbimycin , idarubicin, illudins, kazusamycin, ketoherin (kesarirhodins), Concord Fermentation KM-5539, Kirin Brewery KRN-8602, Concord Fermentation KT-5432, Concord Fermentation KT-5594, Concord Fermentation KT-6149, American Cyanamide LL-D49194, Meiji Fruit (Meiji) Seika) ME 2303, menogaril, mitomycin, mitoxantrone, sm-M-TAG, neoenactin, imi- sang NK-313 , Miyali Sang Pharmaceutical NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin, peplomycin, pilatin ), pirarubicin, porothramycin, pyrindanycin A, Tobishi RA-I, rapamycin, rhizoxin , rodorubicin, sibanomicin, siwenmycin, Sumitomo SM-5887, Snow Brand SN-706, snow-printed SN-07 , Sorangicin-A, Sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutical SS -9816B, steffimycin B, Dapeng 4181-2, talisomycin, Takeda TAN-868A, terpentecin, thrazine, and iris A ( Tricrozarin A), Puqiang U-73975, Concord Fermentation UCN-10028A, Fujisawa WF-3405, Jifu Y-25024 and zorubicin.

A fourth family of anti-neoplastic agents that can be used in combination with a compound of the invention consists of a variety of anti-neoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibition And a hormonal agent selected from the group consisting of, but not limited to, alpha-carotene, alpha-difluoromethyl-arginine, acitretin, biotechnology ( Biotec) AD-5, Kyorin AHC-52, alstonine, amonafide, amphethinile, amsacrine, Angiostat , annomycin (antinoomycin), antitumor ketone (antineoplaston A10, antitumor ketone A2, antitumor ketone A3, antitumor ketone A5, antitumor ketone AS2-1, Henkel APD, afendimycin Aphidicolin glycinate, aspartate, avarol, baccharin, batracylin, benfluron, chlorpyridinium (benzotript), Ipsen-Beaufour BIM-23015, bisantrene, BMI-40481, Vestar boron-10, bromo-isoprene Bromofosfamide), Wellcome BW-502, Wellcome BW-773, carracemide, carmethizole hydrochloride, ajinophanes CDAF, chlorsulfaquinoxalone, chemical exchange (Ch Emes) CHX-2053, chemical exchange CHX-100, Warner-Lambert CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, Cran Clanfenur, claviridenone, ICN compound 1259, ICN compound 4471, Contracan, Yakult Co., CPT-11, cristatol, curaderm ), cytochalasin B, cytarabine, cytocytin, Merz D-609, DABIS maleate, dacarbazine, dairilam (datelliptinium), film sea Didemnin-B, dihaematoporphyrinether, dihydrolenperone, dinaline, mitomycin, Toyo Pharmar DM-341, Japanese pharmaceutical DM-75, first pharmaceutical DN-9693, docetaxel, elliprabin, elliptinium acetate, Tsumura EMTTC, epothilone ), ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704, gallium nitrate, genkwadaphnin, Chinese and foreign Pharmaceutical GLA-43), Glaxo GR-63178, grifolan NMF-5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine ( Homoharringtonine), hydroxyl, BTG ICRF-187, immolfosine, isoglutamine, isotretinoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamide L-623, Leukocyte Regulator (leucore) Gulin), lonidamine, Lundbeck LU-23-112, Lili LY-186641, NCI (US) MAP, marycin, 麦莱陶MDL-27048, Medco MEDR-340, merbarone, melocyanine derivative, methylanilinoacridine, Molecular Genetics MGI-136, minactivin, mitre Mitonafide, mitoquidone, mopidamol, motretinide, whole medicine industry (Zenyaku Kogyo) MST-16, (N-(iso-dimensional A-mercapto) amino acid, Nisshin Flour Milling N-021, N-deuterated-dehydroalanine), and method of self-cultivation (nafazatrom) ), Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782, NCI NSC-95580, octreotide ), Ono ONO-112, oquizanocine, Akzo Org-10172, paclitaxel, pancratistatin, pazelliptine, Warner-Lambert PD-111707, Warner - Lambert PD-115934), Warner-Lambert PD-131141), Pierre Fabre PE-1001, ICRT peptide D, piroxantrone, polyhaematoporphyrin , polyprenoic acid, evening primrose oil (Efamol), porphyrin, probimane, procarbazine, proglumide, Invitron Protease I (proteasenexin I), Toshiba RA-700, razoxane, Sapporo Breweries RBS, restrictin-P, retelliptine, visual Retinoic acid, Rhone-Poulenc RP-49532, Rhone-Planck RP-56976, Shike SK&F-104864, Sumitomo SM-108, Kuraray SMANCS , SeaPharm SP-10094, spatol, spiropropane derivatives, spirogermanium, Unimed, SS pharmaceutical SS-554, strypoldinone, palm algae (Stypoldione), Suntory SUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama (Toyama) T-506, Toyama T-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman Kodak Eastman Kodak TJB-29), tocotrienol, topotecan, topostin, ren TT-82, co-fermentation UCN-01, co-fermentation UCN-1028, yuco Ukrain, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, Vintriprol, vinzolidine, (withanolides) and Yamauchi (Yamanouchi) YM-534.

Alternatively, the compounds of the invention may also be used in combination therapy with other anti-neoplastic agents such as acemannan, arubicin, aldesleukin, alemtuzumab, ali Alitretinoin, hexamethylene melamine, amifostine, aminolevulinic acid, amrubicin, amsacrine, anagrelide, anastrozole ), ANCER, ancestim, ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide, broxuridine, capecitabine (capecitabine), celmoleukin, cetrorelix, cladribine, clottrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), daclizumab, denileukin diftitox, deslorelin, dexrazoxane, dilazip (dilazep), docetaxel, behenyl alcohol, doxercalciferol, deoxyfluorouridine, doxorubicin, bromocriptine, carmustine, cytarabine, fluorouracil , HIT diclofenac (diclofenac), interferon alpha (interferon alfa), daunorubicin, doxorubicin, retinoic acid (tretinoin), edelfosine (edelfosine), edrecolomab (edrecolomab), fluoro Eflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate, exemestane, exisulind , fadrozole, filgrastim, finasteride, fludarabine, formestane, formoterol, gallium nitrate, gemcitabine, jitozhu Monoclonal oxazuzumab zogamicin, gimester/oteracil/halafluidine combination, glycopine, goserelin, g Heptaplatin, human chorionic gonadotropin, human fetal alp (human fetal alp) Ha fetoprotein), ibandronic acid, idarubicin, imiquimod, interferon alpha, interferon alpha, native interferon alpha-2, interferon alpha-2a, interferon alpha- 2b, interferon α-N1, interferon α-n3, interferon α con-1, interferon α, natural interferon β, interferon β-1a, interferon β-1b, interferon γ, natural interferon γ- 1a, interferon gamma-1b, interleukin-1 beta, iobenguane, irinotecan, isolaladine, lanreotide, LC 9018 (Yakult), leflunomide, lenograstim, sulfation Lentinan sulfate, letrozole, leukocyte alpha interferon, leuprorelin, levamisole + fluorouracil, liarozole, lobaplatin Lobaplatin), lonidamine, lovastatin, masoprocol, melarsoprol, metoclopramide, mifepristone, milford Miltefosine, mirimostim, mismatched double-stranded RNA, mitoguazone, dibromodusol, mitoxantrone, molrasostim, nafarelin (nafarelin), naloxone + pentazocine, nartograstim, nedaplatin, nilutamide, noscapine, novelty Red blood cell stimulating protein, NSC 631570 octreotide, oprelvekin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, poly Ethylene glycol interferon (peginterferon) α-2b, sodium pentosan sulfate (p Entosan polysulfate sodium), pentastatin, picibanil, pirarubicin, rabbit antithymocyte polyclonal antibody, peginterferon alfa-2a, porphyrin Porfimer sodium, raloxifene, raltitrexed, rasburicase, 铼Re 186 etidronate (rhenium Re 186 etidronate), RII retinoic acid (RII retinamide), rituximab, romurtide, lexidronam 153 (153 Sm), sargramostim, sizofiran, Sobuzoxane, sonermin, barium chloride-89, suramin, tasonermin, tazarotene, fluridine, temo Tetoporfin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, torr Toremifene, tositumomab-iodine 131, trastuzumab, treasulfan, retinoic acid, trilostane, top three Qusha, triptorelin, tumor necrosis factor alpha, natural umenimex, bladder cancer vaccine, Maruyama vaccine, melanoma lysate vaccine, valrubicin , verteporfin (Verteporfin), vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid; abarelix; AE 941 (Aeterna), Ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreon), Cetuximab, decitabine, dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche), eniluracil ), etanidazole, retinoic acid, filgrastim SD01 (Amgen), fulvestrant, galocitabine, gastrin 17 immunogen (gastrin 17 immunogen), HLA-B7 gene therapy (Vical), granulocyte macrophage colony stimulating factor, histamine dihydrochloride, tiimumab (ibritumomab) Tiuxetan), ilomastat, IM 862 (Cytran), interleukin-2, iproxifene, LDI 200 (milkhaus), leridistim, lintobe Anti-(lintuzumab), CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2 and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), unique type CEA MAb (Trilex), (LYM-1-iodine 131 MAb (Techniclone), polymorphic epithelial mucin-钇90 MAb (Antisoma), marimastat (marimastat), menogaril, metoprolol Antimit (mitumomab), motexafin gadolinium, MX 6 (Galderma), nairabine, nolatrexed, P 30 protein, pegvisomant, pemei Pemetrexed, porfiromycin, prinomastat, RL 0903 (Shire), rubiconcan, satraplatin, sodium phenylacetate, sparic acid ( Sparfosic acid), SRL 172 (SR Pharma), SU 5416 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, T. chinensis (thalib) Lastine), thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine (Biomira), melanoma vaccine (New York University), Melanoma vaccine (Sloan Kettering Institute), melanoma tumor lysing agent vaccine (New York Medical College), viral melanoma lysate vaccine (Royal Newcastle) Royal Newcastle Hospital, or valspodar.

The taxane system includes a drug group of Pacific Paclitaxel (Troptenol®), and it is a drug group of Taxotere®.

Platinum-containing anticancer drugs include cisplatin (Platinol®, Bristol-Myers Squibb), carboplatin (Paraplatin®, Bristol-Myers Squibb), and oxaliplatin (Eloxatin®, Sanofi-Synthelabo).

Another option is the combination of motetanil with pemetrexed and a platinum-containing anticancer drug.

definition

"Asian patients" have Far East or Southeast Asia (including, for example, Cambodia, China, Japan, Korea, Malaysia, Philippines, Thailand, and Vietnam ( Vietnam)) Any person of origin of the aboriginal.

"Caucasian patients" are people of any Aboriginal origin in Europe, Middle East or North Africa.

"Non-Asian Patient" is a person who has any Aboriginal origin in North America, Central America, or South America and maintains a tribal subordination or community; a person with any African ethnic origin; or a person of Indian origin.

The tyrosine kinase inhibitor is a small molecule inhibitor of tyrosine kinase, including a VEGFR inhibitor.

VEGFR inhibitors are small molecule inhibitors of VEGFR, including modisani, and pharmaceutically acceptable salts thereof. Mordisani is also known as N-(3,3-dimethyl- 2,3-Dihydro-1H-indol-6-yl)-2-((4-pyridylmethyl)amino)-3-pyridinecarboxamide.

The term "OS" is intended to include overall survival.

The term "PFS" is intended to include progression free survival.

The term "PR" is defined as a partial reaction.

The term "CR" is defined as a complete reaction.

As used in connection with the present invention, the terms "treatment" and the like should be understood broadly. It should not be construed as implying that the animal is fully recovered after treatment. Thus, such terms include the purpose of improving the symptoms or severity of a particular condition or preventing the further development of a particular condition or otherwise reducing the risk of further development of a particular condition.

The term "first-line therapy" or "first-line therapy" means that the patient has not previously received treatment for lung cancer (including chemotherapy).

The term "comprising" is intended to have an open end, including the indicated components, but does not exclude other elements.

The phrase "therapeutically effective" is intended to define the amount of each agent that will achieve an improvement in the severity and frequency of the disease over the target of each agent alone, while avoiding the adverse side effects typically associated with the replacement therapy. For example, an effective malignant tumor therapeutic agent prolongs the patient's viability, inhibits rapid proliferation of cell growth associated with the tumor, or achieves regression of the tumor.

It will be appreciated that the method of the invention is applicable to humans.

As used herein, the compounds of the invention include pharmaceutically acceptable derivatives thereof.

In the case of using compounds, salts, and the like, this Also intended to mean a single compound, a salt, and the like.

As used herein, the terms "cancer" and "cancerous" refer to or describe a physiological condition in which a mammal is typically characterized by dysregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, sarcoma, blastoma, and leukemia. More specific examples of such cancers include squamous cell carcinoma, lung cancer, pancreatic cancer, cervical cancer, bladder cancer, hepatoma, breast cancer, colon cancer, thyroid cancer, and head and neck cancer.

Lung cancer means non-small cell lung cancer, including non-squamous non-small cell lung cancer and adenocarcinoma.

The term "pharmaceutically acceptable salts" encompasses salts which are conventionally employed in the formation of alkali metal salts and in the formation of free acid or free base addition salts. The nature of the salt is not critical as long as it is pharmaceutically acceptable. Suitable pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or from organic acids. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid and phosphoric acid. Suitable organic acids may be selected from the group consisting of aliphatic acids, alicyclic acids, aromatic acids, aryl aliphatic acids, heterocyclic acids, carboxylic acids and sulfonic acid organic acids, examples of which are formic acid, acetic acid, adipic acid, butyric acid. , propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid , benzoic acid, o-aminobenzoic acid, methanesulfonic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, pamoic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, Ethylenedisulfonic acid, benzenesulfonic acid, pantothenic acid, 2-hydroxyethanesulfonic acid, toluenesulfonic acid, p-aminobenzenesulfonic acid, cyclohexylaminesulfonic acid, camphoric acid, camphorsulfonic acid, digluconic acid, cyclopentane Alkanoic acid, dodecyl sulfonic acid, glucoheptonic acid, glycerylphosphonic acid, heptanoic acid, caproic acid, 2-hydroxy-ethanesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, palmitic acid, pectin Ester acid, persulfate, 2-phenylpropionic acid, picric acid, pivalic acid, propionic acid, succinic acid, tartaric acid, thiocyanic acid, methanesulfonic acid, undecanoic acid, stearic acid, alginic acid, β- Butyric acid, salicylic acid, mucic acid and galacturonic acid. Suitable pharmaceutically acceptable base addition salts include metal salts such as those prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts prepared from organic bases, including primary amines. , secondary amines and tertiary amines, substituted amines (including cyclic amines), such as caffeine, arginine, diethylamine, N-ethylhexahydropyridine, histidine, glucosamine, isopropylamine, Amino acid, morpholine, N-ethylmorpholine, hexahydropyridyl , hexahydropyridine, triethylamine, trimethylamine. All such salts can be prepared from the corresponding compounds of the invention in a conventional manner by reacting, for example, a suitable acid or base with a compound of the invention. When a basic group and an acidic group are present in the same molecule, the compound of the present invention may also form an internal salt.

Formulation

Also included in the present invention is a pharmaceutical composition comprising an active VEGFR inhibitor and one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants (collectively referred to herein as "carriers" "Materials" and if a combination of other active ingredients is desired. The active compounds of the present invention can be administered by any suitable route, preferably in the form of a pharmaceutical composition suitable for such a route, and administered in a dosage effective for the desired treatment. The compounds and compositions of the present invention can be, for example, orally, transmucosally, topically, rectally, transpulmonarily (e.g., by inhalation spray) or parenteral (including intravascular, intravenous, intraperitoneal, subcutaneous, intramuscular) Internal, synovial cavity and infusion techniques) with commonly used pharmaceutically acceptable The dosage unit formulation of the carrier, adjuvant and vehicle is administered.

The pharmaceutically active compounds of this invention may be processed according to conventional pharmaceutical methods to produce agents for administration to a patient, including humans and other mammals.

For oral administration, the pharmaceutical compositions may be in the form of, for example, a troche, capsule, suspension or liquid. The pharmaceutical compositions are preferably in the form of dosage units containing a particular amount of active ingredient. Examples of such dosage units are tablets or capsules. For example, such may contain from about 1 mg to 2000 mg, preferably from about 1 mg to 500 mg, of the active ingredient. The appropriate daily dose for humans or other mammals may vary depending on the patient's condition and other factors, but may again be determined using routine methods. For example, a dose of from about 10 mg to about 150 mg or from about 25 mg to about 125 mg can be used. The therapeutically effective amount of the VEGFR inhibitor in the composition can be selected to be about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg. The therapeutically effective amount of the VEGFR inhibitor in the composition can be selected to be about 50 mg (administered twice a day), or about 75 mg (administered twice a day), or about 100 mg (administered twice a day), or About 100 mg (administered once a day), or about 125 mg (administered once a day).

The dosage of the compound administered and the dosage regimen for the treatment of the disease condition using the compounds and/or compositions of the invention will depend on a variety of factors including the age, weight, sex and medical condition of the individual, the type of disease, the severity of the disease, and the administration. Routes and frequencies and specific compounds used. Thus, the dosage regimen can vary over a wide range, but can be routinely determined using standard methods. A daily dose of from about 0.01 mg/kg to 500 mg/kg, preferably between about 0.01 mg/kg and about 50 mg/kg, and more preferably about 0.01 mg/kg and about 30 mg/kg body weight, may be suitable. The daily dose can be administered by administering 1 to 4 times a day.

For therapeutic purposes, the active compounds of the invention will generally be combined with one or more adjuvants suitable for the indicated routes of administration. If administered orally, the compound can be combined with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, phosphoric acid and sulfuric acid. Sodium and calcium salts, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol are mixed and subsequently tableted or encapsulated for ease of administration. The capsules or lozenges may contain a controlled release formulation which may be provided as a dispersion of the active compound in hydroxypropylmethylcellulose.

Formulations for parenteral administration may be in the form of aqueous or nonaqueous isotonic sterile injection solutions or suspensions. Such solutions and suspensions may be used as a sterile powder or granules for one or more of the carriers or diluents mentioned for oral administration or by using other suitable dispersing or wetting agents and Suspension preparation. The compounds are soluble in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, tragacanth gum, tragacanth and/or various buffers. Other adjuvants and methods of administration have been fully and widely known for pharmaceutical technology. The active ingredient can also be added by injection as a suitable carrier (including physiological saline, dextrose or water) or with cyclodextrin (ie, Captisol), cosolvent solubilization (ie, polyethylene glycol) or micelles. The composition of the solution (i.e., Tween 80) is administered.

The invention will now be further elucidated with reference to the following non-limiting examples.

Example 1 - NSCLC

Qualified patient ( 18 years old with histologically or cytologically confirmed advanced non-squamous NSCLC (unremovable stage IIIB or stage IV with malignant hydrops), Eastern Cooperative Oncology Group (ECOG) Physical state 1, according to the Response Evaluation Criteria in Solid Tumors (RECIST) measurable disease, and life expectancy 3 months. Patients were excluded if they had the following: central nervous system metastasis; history of pulmonary hemorrhage or severe hemoptysis; bleeding tendency or non-pulmonary hemorrhage within 6 months of randomization; uncontrollable hypertension (>150/ 90 mmHg); peripheral neuropathy grade >1; insufficient heart, liver, blood or kidney function; prior chemotherapy or adjuvant chemotherapy for advanced NSCLC within 52 weeks of randomization; prior targeted therapy; in randomization 7 Anticoagulant therapy for the day; previous chemoradiation for locally advanced stage III disease; central radiotherapy within 28 days of randomization; or other radiation therapy within 14 days of randomization. The research program is approved by the institutional ethics committee at each location. All patients provided written informed consent. This is a phase 3 international multi-center open-label randomized study conducted at >200 centers.

This study evaluated whether motetanib plus carboplatin/paclitaxel improved overall survival in patients with advanced non-squamous NSCLC and in patients with adenocarcinoma compared with placebo and carboplatin/paclitaxel (OS). The patient has stage IIIB/stage IV or relapsed non-squamous NSCLC and has not previously been systemically treated for advanced NSCLC. The study initially recruited all histological subtypes of NSCLC, but due to the high incidence of hemoptysis in squamous NSCLC, the study was modified to exclude such patients. Patients were randomized 1:1 to receive up to 6 carboplatin (AUC 6 mg/mL ‧ min) and paclitaxel (200 mg/m ² ) with motetanib 125 mg QD (arm A) or placebo QD ( The arm B) was cycled for 3 weeks and administered continuously through the mouth. The primary endpoint was OS; secondary endpoints included association between progression-free survival (PFS), severe events (AE), and placental growth factor (PLGF) changes with OS. The OS system was evaluated using a stratified Cox model and a 2-sided log-rank test (for non-squamous patients a = 0.03 and for adenocarcinoma subsets a = 0.02). Demographic and baseline characteristics were balanced in both cohorts (Table 1). 1090 patients with advanced non-squamous NSCLC were randomized (arm A n=541; arm B n=549); 890 patients had adenocarcinoma (n=448/442). 61% were male; the median age was 60 years (range 21-87); 83% had stage IV disease.

At the time of analysis, 753 patients had died (608 patients had adenocarcinoma). The median follow-up was 10.6 months. There was no significant improvement in OS and PFS in the motanib arm A compared to placebo arm B (Table 2). Arm A/B The incidence of grade 3 AE was 73/59%. More frequent in arm A than in arm B Grade 3 AEs included neutropenia (22% vs. 15%), diarrhea (9% vs. 1%), hypertension (7% vs. 1%), and cholecystitis (3% vs. 0%). The incidence of grade 5 AE in arm A/B was 14%/9%.

The response in the motsani arm A was not significantly improved compared to placebo arm B (Table 3).

The Kaplan Meier Plot, plotted against the fraction of the surviving patients treated with motetanil and the number of days of survival, indicates an increase in overall survival. [Fig. 1] Cox proportional hazard - P = 0.137; hazard ratio = 0.897; (95% CI: 0.776, 1.035).

The Kaplan Meyer curve, plotted on the rate of survival of patients treated with motetanil and progression free survival days, indicates an increase in progression free survival. [Fig. 2] Cox proportional risk - P = 0.0006; hazard ratio = 0.785; (95% CI: 0.684, 0.901).

In patients with advanced non-squamous NSCLC, treatment with motetanil and carboplatin/paclitaxel did not significantly improve OS compared to carboplatin/paclitaxel alone.

^A patient with a PR or CR response assessment that was not subsequently confirmed at least 4 weeks later was considered stable.

^b Subjects that had a CR, PR, or SD response assessment prior to the first response evaluation (35 days) scheduled and who did not undergo an additional response evaluation were not assessed.

95% confidence interval of the difference in objective response ^c (CI) of the normal approximation lines using the binomial distribution (normal approximation to the binomial distribution) is calculated.

^{The d} P-value is based on a Cochran-Mantel-Haenszel test stratified by a randomized stratification factor (as recorded in the IVR system at randomization): stage (stage IIIB versus stage IV or relapse), weight loss ( <5% vs. 5%, 6 months prior to randomization), gender (male to female) and prior adjuvant chemotherapy (yes). The non-squamous full analysis set included all randomized subjects with non-squamous histology, as recorded on the CRF at baseline. Subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

Example 2 - Performance Results and Baseline Distribution for Asian Subgroups

The Asian subgroup (N=219) includes patients from Japan, South Korea, Singapore, the Philippines, Taiwan, and China (Hong Kong). Japan contributed 107 patients and South Korea had 63 patients. Demographic and baseline characteristics were balanced in both cohorts (Table 4).

At the time of analysis, 132 Asian patients died. The OS, PFS, and response in the motissani arm A were significantly improved compared to placebo arm B (Table 5-7).

The Kaplan Meyer curve, plotted against the fraction of surviving patients treated with motetanil and the number of days of survival, indicates an increase in overall survival. [Fig. 3] The median value was 20.9 months versus placebo for 15.5 months. Cox proportional hazard - P = 0.017; hazard ratio = 0.657; (95% CI: 0.465, 0.929).

The Kaplan Meyer curve, plotted on the rate of survival of patients treated with motetanil and progression free survival days, indicates an increase in progression free survival. [Figure 4] The median value is 7 months versus 4.5 months. Cox proportional hazard - P = 0.0003; hazard ratio = 0.58; (95% CI: 0.430, 0.782).

In a subset of Asian patients with advanced non-squamous NSCLC, treatment with motetanil and carboplatin/paclitaxel significantly improved OS, PFS, and response compared to carboplatin/paclitaxel alone.

^a subject who has not reported death is considered to be “limited”.

^{b The} overall survival time is calculated as the number of days from randomization to death or set date.

^{The c-} risk ratio is estimated using an unadjusted Cox proportional hazard model.

^{The d} P-value is based on a 2-sided unadjusted log rank test without a stratification factor.

The non-squamous full analysis set included all randomized subjects with non-squamous histology, as recorded on the CRF at baseline. Subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

K-M = Kaplan-Meyer estimate; CI = confidence interval; + indicates that the value is set to limit time; NE = not estimated

^A subject who did not die and did not undergo an assessment of disease progression was "limited."

^b Progression-free survival is calculated as the number of days from the randomization to the radiological evidence of disease progression/date of death or date of limitation. Subjects who were alive but did not undergo a response to disease progression were limited to the date of the last disease assessment. In the event that two or more tumor evaluations are missed after disease progression or die at the next evaluation, the limits will be imposed at the last complete tumor date prior to the missed evaluation.

^{The c-} risk ratio is estimated using an unadjusted Cox proportional hazard model.

^{The d} P-value is based on a 2-sided unadjusted log rank test without stratification.

The non-squamous full analysis set included all randomized subjects with non-squamous histology, as recorded on the CRF at baseline. Subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

K-M = Kaplan-Meyer estimate; CI = confidence interval; + indicates that the value is set to a limited time.

^a patient with a PR or CR response assessment that was not subsequently confirmed at least 4 weeks later was considered stable

^b Subjects that had a CR, PR, or SD response assessment prior to the first response evaluation (35 days) scheduled and who did not undergo an additional response evaluation were not assessed.

95% confidence interval of the difference in objective response ^c (CI) is calculated using an approximate normal lines binomial distribution.

^{The d} P-value is based on a Cochran-Mantel-Haenszel test stratified by a randomized stratification factor (as recorded in the IVR system at randomization): stage (stage IIIB versus stage IV or relapse), weight loss ( <5% vs. 5%, 6 months prior to randomization), gender (male to female) and prior adjuvant chemotherapy (yes).

The number of subjects with a measurable disease at baseline is the denominator of all response categories. The non-squamous full analysis set included all randomized subjects with non-squamous histology, as recorded on the CRF at baseline. Subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

Example 3 - Performance Results and Baseline Distribution for Non-Asian Subgroups

Non-Asian subgroups (N=871) include patients who do not have ethnic groups from Japan, Korea, Singapore, the Philippines, Taiwan, and China (Hong Kong). At the time of analysis, 621 non-Asian patients died. The OS, PFS and response in the motissani arm A were improved compared to placebo arm B (Tables 8-10).

The Kaplan Meyer curve, plotted against the fraction of surviving patients treated with motetanil and the number of days of survival, indicates an increase in overall survival. [Fig. 5] The median value was 10.9 months versus 10.7 months for placebo. Cox proportional hazard - P = 0.774; hazard ratio = 0.977; (95% CI: 0.835, 1.144).

The Kaplan Meyer curve, plotted on the rate of survival of patients treated with motetanil and progression free survival days, indicates an increase in progression free survival. [Figure 6] The median value is 5.5 months versus 5.4 months. Cox proportional hazard - P = 0.03; hazard ratio = 0.847; (95% CI: 0.727, 0.987).

In non-Asian patients with advanced non-squamous NSCLC, treatment with motetanil and carboplatin/paclitaxel did not significantly improve OS, PFS, or response compared to carboplatin/paclitaxel alone.

^a Subjects who have not yet been reported as dead are considered to be “restricted”.

^{b The} overall survival time is calculated as the number of days from randomization to death or set date.

^{The c-} risk ratio is estimated using an unadjusted Cox proportional hazard model.

^{The d} P-value is based on a 2-sided unadjusted log rank test without a stratification factor.

The non-squamous full analysis set included all randomized subjects with non-squamous histology, as recorded on the CRF at baseline. Subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

K-M = Kaplan-Meyer estimate; CI = confidence interval; + indicates that the value is set to a limited time.

^A subject who did not die and did not undergo an assessment of disease progression was "limited."

^b Progression-free survival is calculated as the number of days from the randomization to the radiological evidence of disease progression/date of death or date of limitation. Subjects who were alive but did not undergo a response to disease progression were limited to the date of the last disease assessment. In the event that two or more tumor evaluations are missed after disease progression or die at the next evaluation, the limits will be imposed at the last complete tumor date prior to the missed evaluation.

^{The c-} risk ratio is estimated using an unadjusted Cox proportional hazard model.

^{The d} P-value is based on a 2-sided unadjusted log rank test without stratification.

The non-squamous full analysis set included all randomized subjects with non-squamous histology, as recorded on the CRF at baseline. Subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

K-M = Kaplan-Meyer estimate; CI = confidence interval; + indicates that the value is set to a limited time.

^A patient with a PR or CR response assessment that was not subsequently confirmed at least 4 weeks later was considered stable.

^b Subjects that had a CR, PR, or SD response assessment prior to the first response evaluation (35 days) scheduled and who did not undergo an additional response evaluation were not assessed.

95% confidence interval of the difference in objective response ^c (CI) is calculated using an approximate normal lines binomial distribution.

^{The d} P-value is based on a Cochran-Mantel-Haenszel test stratified by a randomized stratification factor (as recorded in the IVR system at randomization): stage (stage IIIB versus stage IV or relapse), weight loss ( <5% vs. 5%, 6 months prior to randomization), gender (male to female) and prior adjuvant chemotherapy (yes).

The number of subjects with a measurable disease at baseline is the denominator of all response categories. The non-squamous full analysis set included all randomized subjects with non-squamous histology, as recorded on the CRF at baseline. Subjects were included in the treatment group assigned at randomization, regardless of the treatment received.

Example 4 - corrected clinical data

During the follow-up review of the initial clinical data, 8 patients were found to be incorrectly classified. All analyses were regenerated to provide their corrected results as provided below and in Figures 7-10.

An unexpected finding is that Asian patients (as defined herein) respond more favorably to treatment with modisani than non-Asian patients. This study confirms the ethnic differences in the effects of motetanib on overall survival in cancer patients. No evidence of significant ethnic differences was observed with carboplatin/paclitaxel.

The above is only illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and modifications are routinely made by those skilled in the art, and such changes and modifications are intended to be within the scope and nature of the invention and are defined in the scope of the appended claims.

From the above, it will be readily apparent to those skilled in the art that the present invention can be found in various embodiments and various modifications and changes can be made to the various uses and conditions without departing from the spirit and scope of the invention. .

The entire contents of all of the references, patents, applications, and publications are hereby incorporated herein by reference.

Figure 1 shows the overall survival of patients treated with motetanil in the NSCLC Phase 3 study.

Figure 2 shows the median progression-free survival of the full analysis set.

Figure 3 shows the overall survival of patients treated with motetanil from Japan, the Republic of Korea, Taiwan, China (Hong Kong), the Philippines, and Singapore in the NSCLC Phase 3 study.

Figure 4 shows the median progression-free survival rate for the Asian patient analysis subset.

Figure 5 shows the overall survival of a subset of non-Asian patient analyses of modissani treatment in a NSCLC Phase 3 study.

Figure 6 shows the median progression-free survival rate for a subset of non-Asian patient analyses.

Figure 7 shows the overall survival of a subset of Japanese patient treatments treated with motetanil in the NSCLC Phase 3 study.

Figure 8 shows the median progression-free survival rate for a subset of Japanese patient analyses.

Figure 9 shows the updated median progression-free survival rate for the Asian patient analysis subset.

Figure 10 shows the updated overall survival of patients treated with motetanil from Japan, Republic of Korea, Taiwan, China (Hong Kong), the Philippines, and Singapore in the NSCLC Phase 3 study.

Claims (23)

A use of motesanib for the manufacture of a medicament for first-line treatment of non-squamous non-small cell lung cancer in Asian patients. A use of motetanil for the manufacture of a medicament for improving the survival rate associated with non-squamous non-small cell lung cancer in Asian patients, comprising the use of motetanil, taxane and A combination of platinum anticancer drugs treats this Asian patient. Use of motetanil for the manufacture of a medicament for increasing the overall survival rate of an Asian patient diagnosed with non-squamous non-small cell lung cancer, comprising the use of a combination comprising motetanil and acetonide Treat the Asian patient. The use of claim 3, wherein the combination comprises a platinum-containing anticancer drug. A use of motetanil for the manufacture of a medicament for increasing the overall survival rate of an Asian patient diagnosed with non-squamous non-small cell lung cancer, comprising the use of motetaxan and a platinum-containing anticancer drug The combination treats the Asian patient. The use of claim 3, wherein the combination comprises taxane. The use of claim 1, wherein the motehsani is administered in combination with one or more chemotherapeutic agents. The use of claim 4, wherein the chemotherapeutic agent is paclitaxel or carboplatin. The use of claim 2, 3, 4, 5 or 6, wherein the taxane is paclitaxel and the platinum-containing anticancer drug is carboplatin. The use of claim 9, wherein the paclitaxel is administered at 200 mg/m ² . The use of claim 9, wherein the carboplatin is administered at AUC 6 mg/mL ‧ min. The use of claim 1, 2, 3 or 5, wherein the non-squamous non-small cell lung cancer is an adenocarcinoma. The use of claim 2, 3 or 5, wherein the treatment is first-line treatment. The use of claim 1, 2, 3 or 5, wherein the motfinil is administered at a daily dose of 100 mg or 125 mg. The use of claim 1, 2, 3 or 5, wherein the motfinil is administered at a daily dose of 125 mg. The use of claim 1, 2, 3 or 5, wherein the Asian patient is a Japanese, Republic of Korea, Taiwan, China (Hong Kong), Philippines or Singaporean ethnic group. The use of claim 1, 2, 3 or 5, wherein the Asian patient is Japanese. Use of motetanil for the manufacture of a medicament for increasing progression-free survival associated with non-squamous non-small cell lung cancer in Asian patients, comprising the use of motetanil, paclitaxel and platinum A combination of anticancer drugs treats this Asian patient. A use of motetanil for the manufacture of an increase in progression-free survival associated with non-squamous non-small cell lung cancer in Asian patients and greater than that observed with only taxane and platinum-containing anticancer drugs The drug with no progression survival rate, comprising treating the Asian patient with a combination of motetanil, taxane and a platinum-containing anticancer drug. A use of motetanil for the manufacture of Asian patients The overall survival rate associated with non-squamous non-small cell lung cancer is greater than that of the overall survival rate observed with only the taxane and platinum-containing anticancer drugs, including the use of motetanil, taxane and A combination of platinum anticancer drugs treats this Asian patient. The use of claim 20, wherein the medicament increases overall survival when compared to treatment with paclitaxel and carboplatin. The use of claim 18 or 19, wherein the drug increases progression free survival when compared to treatment with paclitaxel and carboplatin. The use of claim 20, wherein the non-squamous non-small cell lung cancer is stage IIIB, stage IV or relapse.