Combination therapy of her expressing tumors

• US 20070020261A1
• Filed: 07/19/2006
• Published: 01/25/2007
• Est. Priority Date: 07/22/2005
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Sliwkowski, Mark, Kelsey, Stephen
• Granted Patent: US 8,163,287 B2
• Time in Patent Office: Days
• US Class Current: 424/141.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 239/86 with hetero atoms directly attached in position 4
• CPC Class Codes: C07D 239/94 Nitrogen atoms
• CPC Class Codes: C07K 16/2863 against receptors for growth factors, growth regulators
• CPC Class Codes: C07K 16/32 against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

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

Claims

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:

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 II 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.