Combination therapy of her expressing tumors

Abstract

The invention relates to tumors expressing HER2 and EGFR, using HER2-dimerization inhibitors (HDIs) and EGFR inhibitors.

1 . A method for the treatment of tumor comprising administering to a human subject with a tumor expressing EGFR and HER2, an effective amount of a HER2-dimerization inhibitor and an EGFR inhibitor, wherein the subject's tumor does not show a complete response to treatment with said HER2 dimerization inhibitor or said EGFR inhibitor when administered as a single agent. 
     
     
         2 . The method of  claim 1  wherein said tumor shows a partial response to treatment with said EGFR inhibitor administered as a single agent. 
     
     
         3 . The method of  claim 1  wherein said tumor shows a partial response to treatment with said HER2-dimerization inhibitor administered as a single agent. 
     
     
         4 . The method of  claim 1  wherein said tumor additionally expresses HER3. 
     
     
         5 . The method of  claim 1  wherein said tumor is refractory to chemotherapy and/or radiation therapy. 
     
     
         6 . The method of  claim 1  wherein said tumor displays HER2 receptor overexpression or amplification. 
     
     
         7 . The method of  claim 1  wherein said tumor does not display HER2 receptor overexpression or amplification. 
     
     
         8 . The method of  claim 1  wherein said treatment increases the time to tumor progression and/or the time to death relative to treatment with said HER2 dimerization inhibitor or said EGFR inhibitor when administered as a single agent. 
     
     
         9 . The method of  claim 1  wherein said tumor is selected from the group consisting of lung cancer, prostate cancer and colon cancer. 
     
     
         10 . The method of  claim 9  wherein said tumor is lung cancer. 
     
     
         11 . The method of  claim 10  wherein said lung cancer is selected from the group consisting of small-cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung, and squamous carcinoma of the lung. 
     
     
         12 . The method of  claim 11  wherein said lung cancer is non-small cell lung cancer (NSCLC). 
     
     
         13 . The method of  claim 12  wherein said NSCLC said treatment is provided as a second or third line therapy. 
     
     
         14 . The method of  claim 9  wherein said cancer is pancreatic cancer. 
     
     
         15 . The method of  claim 14  further comprising the administration of gemcitabine. 
     
     
         16 . The method of  claim 9  wherein said cancer is colon cancer. 
     
     
         17 . The method of  claim 16  wherein said treatment is provided as a third line therapy. 
     
     
         18 . The method of  claim 16  wherein said human subject in unsuitable for chemotherapy. 
     
     
         19 . The method of  claim 1  wherein said HER2 dimerization inhibitor is a HER2 antibody. 
     
     
         20 . The method of  claim 19  wherein said HER2 antibody binds to domain II of HER2 extracellular domain. 
     
     
         21 . The method of  claim 19  wherein said HER2 antibody binds to a junction between domains I, II and III of HER2 extracellular domain. 
     
     
         22 . The method of  claim 19  wherein said HER2 antibody is a humanized 2C4 antibody. 
     
     
         23 . The method of  claim 22  wherein said HER2 antibody comprises the variable light and variable heavy amino acid sequences in SEQ ID Nos. 11 and 12, respectively. 
     
     
         24 . The method of  claim 23  wherein said HER2 antibody is rhuMAb 2C4 (pertuzumab). 
     
     
         25 . The method of  claim 1  wherein said EGFR inhibitor is a non-peptide small molecule. 
     
     
         26 . The method of  claim 1  wherein said EGFR inhibitor is an EGFR antibody. 
     
     
         27 . The method of  claim 1  wherein said EGFR inhibitor blocks the formation of EGFR-EGFR homodimers but not the formation of EGFR-HER2 heterodimers. 
     
     
         28 . The method of  claim 27  wherein said EGFR inhibitor has formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         X is halo or hydroxy; 
         m is 1, 2, or 3; 
         each R 1  is independently selected from the group consisting of hydrogen, halo, hydroxy, hydroxyamino, carboxy, nitro, guanidino, ureido, cyano, trifluoromethyl, and —(C 1 -C 4  alkylene)-W-(phenyl) wherein W is a single bond, O, S or NH; 
         or each R 1  is independently selected from R 9  and C 1 -C 4  alkyl substituted by cyano, wherein R 9  is selected from the group consisting of R 5 , —OR 6 , —NR 6 R 6 , —C(O)R 7 , —NHOR 5 , —OC(O)R 6 , cyano, A and —YR 5 ; R 5  is C 1 -C 4  alkyl; R 6  is independently hydrogen or R 5 ; R 7  is R 5 , —OR 6  or —NR 6 R 6 ; A is selected from piperidino, morpholino, pyrrolidino, 4-R 6 -piperazin-1-yl, imidazol-1-yl, 4-pyridon-1-yl, —(C 1 -C 4  alkylene)(CO2H), phenoxy, phenyl, phenylsulfanyl, C 2 -C 4  alkenyl, and —(C 1 -C 4  alkylene)C(O)NR 6 R 6 ; and Y is S, SO, or SO 2 ; 
         wherein the alkyl moieties in R 5 , —OR 6  and —NR 6 R 6  are optionally substituted by one to three halo substituents and the alkyl moieties in R 5 , —OR 6  and —NR 6 R 6  are optionally substituted by 1 or 2 R 9  groups, and wherein the alkyl moieties of said optional substituents are optionally substituted by halo or R 9 , with the proviso that two heteroatoms are not attached to the same carbon atom; 
         or each R 1  is independently selected from —NHSO 2 R 5 , phthalimido-(C 1 -C 4 )-alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R 10 —(C 2 -C 4 )-alkanoylamino wherein R 10  is selected from halo, —OR 6 , C 2 -C 4  alkanoyloxy, —C(O)R 7 , and —NR 6 R 6 ; and wherein said —NHSO 2 R 5 , phthalimido-(C 1 -C 4 -alkylsulfonylamino, benzamido, benzenesulfonylamino, 3-phenylureido, 2-oxopyrrolidin-1-yl, 2,5-dioxopyrrolidin-1-yl, and R 10 —(C 2 -C 4 )-alkanoylamino R 1  groups are optionally substituted by 1 or 2 substituents independently selected from halo, C 1 -C 4  alkyl, cyano, methanesulfonyl and C 1 -C 4  alkoxy; 
         or two R 1  groups are taken together with the carbons to which they are attached to form a 5-8 membered ring that includes 1 or 2 heteroatoms selected from O, S and N; 
         R 2  is hydrogen or C 1 -C 6  alkyl optionally substituted by 1 to 3 substituents independently selected from halo, C 1 -C 4  alkoxy, —NR 6 R 6 , and —SO 2 R 5 ; 
         n is 1 or 2 and each R 3  is independently selected from hydrogen, halo, hydroxy, C 1 -C 6  alkyl, —NR 6 R 6 , and C 1 -C 4  alkoxy, wherein the alkyl moieties of said R 3  groups are optionally substituted by 1 to 3 substituents independently selected from halo, C 1 -C 4  alkoxy, —NR 6 R 6 , and —SO 2 R; and, 
         R 4  is azido or -(ethynyl)-R 11  wherein R 11  is hydrogen or C 1 -C 6  alkyl optionally substituted by hydroxy, —OR 6 , or —NR 6 R 6 . 
       
     
     
         29 . The method of  claim 28  wherein the EGFR inhibitor is a compound of formula I selected from the group consisting of:
 (6,7-dimethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; (6,7-dimethoxyquinazolin-4-yl)-[3-(3′-hydroxypropyn-1-yl)phenyl]-amine; [3-(2′-(aminomethyl)-ethynyl)phenyl]-(6,7-dimethoxyquinazolin-4-yl)-amine; (3-ethynylphenyl)-(6-nitroquinazolin-4-yl)-amine; (6,7-dimethoxyquinazolin-4-yl)-(4-ethynylphenyl)-amine; (6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-2-methylphenyl)-amine; (6-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(6-methanesulfonylaminoquinazolin-4-yl)-amine; (3-ethynylphenyl)-(6,7-methylenedioxyquinazolin-4-yl)-amine; (6,7-dimethoxyquinazolin-4-yl)-(3-ethynyl-6-methylphenyl)-amine; (3-ethynylphenyl)-(7-nitroquinazolin-4-yl)-amine; (3-ethynylphenyl)-[6-(4′-toluenesulfonylamino)quinazolin-4-yl]-amine; (3-ethynylphenyl)-{6-[2′-phthalimido-eth-1′-yl-sulfonylamino]quinazolin-4-yl}-amine; (3-ethynylphenyl)-(6-guanidinoquinazolin-4-yl)-amine; (7-aminoquinazolin-4-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(7-methoxyquinazolin-4-yl)-amine; (6-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; (7-carbomethoxyquinazolin-4-yl)-(3-ethynylphenyl)-amine; [6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-(3-ethynylphenyl)-amine; (3-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine; (3-azido-5-chlorophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine; (4-azidophenyl)-(6,7-dimethoxyquinazolin-4-yl)-amine; (3-ethynylphenyl)-(6-methansulfonyl-quinazolin-4-yl)-amine; (6-ethansulfanyl-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6,7-dimethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine; (6,7-dimethoxy-quinazolin-4-yl)-[3-(propyn-1′-yl)-phenyl]-amine; [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(5-ethynyl-2-methyl-phenyl)-amine; [6,7-bis-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-4-fluoro-phenyl)-amine; [6,7-bis-(2-chloro-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine; [6-(2-chloro-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine; [6,7-bis-(2-acetoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine; 2-[4-(3-ethynyl-phenylamino)-7-(2-hydroxy-ethoxy)-quinazolin-6-yloxy]-ethanol; [6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine; [7-(2-chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine; [7-(2-acetoxy-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine; 2-[4-(3-ethynyl-phenylamino)-6-(2-hydroxy-ethoxy)-quinazolin-7-yloxy]-ethanol; 2-[4-(3-ethynyl-phenylamino)-7-(2-methoxy-ethoxy)-quinazolin-6-yloxy]-ethanol; 2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol; [6-(2-acetoxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine; (3-ethynyl-phenyl)-{6-(2-methoxy-ethoxy)-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinazolin-4-yl}-amine; (3-ethynyl-phenyl)-[7-(2-methoxy-ethoxy)-6-(2-morpholin-4-yl)-ethoxy)-quinazolin-4-yl]-amine; (6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine; (6,7-dibutoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine; (6,7-diisopropoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine; (6,7-diethoxyquinazolin-1-yl)-(3-ethynyl-2-methyl-phenyl)-amine; [6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynyl-2-methyl-phenyl)-amine; (3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine; [6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine; 2-[4-(3-ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethanol; (6,7-dipropoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine; (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-5-fluoro-phenyl)-amine; (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-fluoro-phenyl)-amine; (6,7-diethoxy-quinazolin-4-yl)-(5-ethynyl-2-methyl-phenyl)-amine; (6,7-diethoxy-quinazolin-4-yl)-(3-ethynyl-4-methyl-phenyl)-amine; (6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine; (6-aminomethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6-aminocarbonylethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6-aminocarbonylmethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6-aminocarbonylethyl-7-ethoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6-aminocarbonylmethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6-aminocarbonylmethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6-aminocarbonylmethyl-7-methoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6-aminocarbonylethyl-7-isopropoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; and (6-aminocarbonylethyl-7-propoxy-quinazolin-4-yl)-(3-ethynylphenyl)-amine; (6,7-diethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-[6-(2-hydroxy-ethoxy)-7-(2-methoxy-ethoxy)-quinazolin-1-yl]-amine; [6,7-bis-(2-hydroxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine; [6,7-bis-(2-methoxy-ethoxy)-quinazolin-1-yl]-(3-ethynylphenyl)-amine; (6,7-dimethoxyquinazolin-1-yl)-(3-ethynylphenyl)-amine; (3-ethynylphenyl)-(6-methanesulfonylamino-quinazolin-1-yl)-amine; and (6-amino-quinazolin-1-yl)-(3-ethynylphenyl)-amine. 
 
     
     
         30 . The method of  claim 28  wherein the EGFR inhibitor of formula I is N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine. 
     
     
         31 . The method of  claim 30  wherein the EGFR inhibitor N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine is an HCl salt form. 
     
     
         32 . The method of  claim 31  wherein the EGFR inhibitor N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine is erlotinib, which is present in a substantially homogeneous crystalline polymorph form that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.26, 12.48, 13.39, 16.96, 20.20, 21.10, 22.98, 24.46, 25.14 and 26.91. 
     
     
         33 . The method of  claim 1  wherein the EGFR inhibitor blocks the formation of EGFR-EGFR homodimers and EGFR-HER2 heterodimers. 
     
     
         34 . The method of  claim 33  wherein said EGFR inhibitor is an EGFR antibody. 
     
     
         35 . The method of  claim 34  wherein said EGFR antibody is cetuximab. 
     
     
         36 . The method of  claim 1  comprising administering to said human subject an effective amount of pertuzumab and erlotinib. 
     
     
         37 . The method of  claim 36  wherein said pertuzumab and erlotinib exhibit a synergistic anti-tumor activity. 
     
     
         38 . The method of  claim 36  wherein said cancer is non-small cell lung carcinoma (NSCLC). 
     
     
         39 . The method of  claim 38  wherein said cancer is metastatic NSCLC. 
     
     
         40 . The method of  claim 39  wherein said cancer is poor-risk stage 11 or stage III NSCLC. 
     
     
         41 . The method of  claim 36  wherein said cancer is pancreatic cancer. 
     
     
         42 . The method of  claim 36  wherein said cancer is ovarian cancer. 
     
     
         43 . The method of  claim 36  wherein said cancer is breast cancer. 
     
     
         44 . The method of  claim 1  comprising administering to said patient an effective amount of pertuzumab and cetuximab. 
     
     
         45 . The method of  claim 44  wherein said pertuzumab and cetuximab exhibit a synergistic anti-tumor activity. 
     
     
         46 . The method of  claim 44  wherein said cancer is colorectal cancer. 
     
     
         47 . The method of  claim 46  wherein said colorectal cancer is colon cancer. 
     
     
         48 . The method of  claim 47  wherein said colon cancer is metastatic colon cancer. 
     
     
         49 . The method of  claim 48  wherein said colon cancer is stage II-stage IV colon cancer. 
     
     
         50 . The method of  claim 47  wherein said colon cancer is unsuitable for chemotherapy. 
     
     
         51 . The method of  claim 44  wherein said cancer is breast cancer. 
     
     
         52 . The method of  claim 1  wherein said HER2 dimerization inhibitor and said EGFR inhibitor are administered simultaneously. 
     
     
         53 . The method of  claim 1  wherein said HER2 dimerization inhibitor and said EGFR inhibitor are administered consecutively. 
     
     
         54 . The method of  claim 1  further comprising treating said patient with at least one chemotherapeutic agents. 
     
     
         55 . The method of  claim 1  further comprising subjecting said patient to radiation therapy. 
     
     
         56 . The method of  claim 1  further comprising subjecting said patient to standard of care treatment. 
     
     
         57 . A method for the treatment of cancer comprising administering to a human subject, an effective amount of a HER2-dimerization inhibitor and an EGFR inhibitor, wherein the subject's cancer is not driven solely by EGFR, and the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), pancreatic cancer, and colon cancer. 
     
     
         58 . A method for the treatment of cancer comprising administering to a human subject an effective amount of pertuzumab and erlotinib, wherein the subject's cancer is not driven solely by EGFR, and the cancer is selected from the group consisting of non-small cell lung cancer (NSCLC), pancreatic cancer, and colon cancer. 
     
     
         59 . A method for the treatment of EGFR and HER2 expressing cancer comprising administering to a human subject, an effective amount of a HER2-dimerization inhibitor and an EGFR inhibitor, wherein the subject's cancer is refractory or responds poorly to an EGFR inhibitor. 
     
     
         60 . A method for the treatment of EGFR and HER2 expressing cancer comprising administering to a human subject, an effective amount of a HER2-dimerization inhibitor and an EGFR inhibitor, wherein the subject's tumor s refractory or responds poorly to a HER2-dimerization inhibitor.