阅读说明：本技术 包含alk抑制剂和shp2抑制剂的药物组合 (Pharmaceutical combination comprising an ALK inhibitor and an SHP2 inhibitor ) 是由 L·达尔代伊阿尔哈兰蒂斯 J·A·恩格尔曼 郝淮湘 李昉 M·J·拉马尔切 王慧琴 于 2018-01-08 设计创作，主要内容包括：本发明涉及用于同时或相继施用的药物组合,所述药物组合包含呈游离形式的ALK抑制剂或其药学上可接受的盐,呈游离形式的SHP2抑制剂或其药学上可接受的盐,以及任选地药学上可接受的载体；涉及这种组合在治疗增殖性疾病中的用途；并且涉及治疗患有增殖性疾病的受试者的方法,所述方法包括施用治疗有效量的这种组合。(The present invention relates to a pharmaceutical combination comprising an ALK inhibitor in free form or a pharmaceutically acceptable salt thereof, an SHP2 inhibitor in free form or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier for simultaneous or sequential administration; to the use of such a combination in the treatment of a proliferative disease; and to a method of treating a subject suffering from a proliferative disease, comprising administering a therapeutically effective amount of such a combination.)

1. A pharmaceutical combination comprising:

(i) an ALK inhibitor or a pharmaceutically acceptable salt thereof, and

(ii) an inhibitor of SHP2, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical combination of claim 1, further comprising at least one pharmaceutically acceptable carrier.

3. A pharmaceutical composition comprising the pharmaceutical combination of claim 1 or claim 2, and at least one pharmaceutically acceptable carrier.

4. The pharmaceutical combination of claim 1 or 2, or the pharmaceutical composition of claim 3, wherein the ALK inhibitor or a pharmaceutically acceptable salt thereof and the SHP2 inhibitor or a pharmaceutically acceptable salt thereof are provided in jointly therapeutically effective amounts for use in the treatment of cancer.

5. The pharmaceutical combination of claim 4, or the pharmaceutical composition of claim 4, wherein the ALK inhibitor or a pharmaceutically acceptable salt thereof and the SHP2 inhibitor or a pharmaceutically acceptable salt thereof are provided in synergistically effective amounts for use in the treatment of cancer.

6. A commercial package comprising a pharmaceutical combination or pharmaceutical composition according to any one of claims 1 to 5 together with instructions for simultaneous or sequential administration of the pharmaceutical combination or pharmaceutical composition for use in the treatment of cancer.

7. The pharmaceutical combination or composition of claim 4 or 5, or the commercial package of claim 6, wherein the cancer is an ALK-positive cancer.

8. The pharmaceutical combination or pharmaceutical composition of claim 4 or 5, or the commercial package of claim 6, wherein said cancer is an ALK-positive cancer selected from anaplastic large cell lymphoma, gastric cancer, breast cancer, esophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastoma, renal cancer, pancreatic cancer, and lung cancer.

9. The pharmaceutical combination or composition of claim 4 or 5, or the commercial package of claim 6, wherein said cancer is ALK-positive non-small cell lung cancer.

10. The pharmaceutical combination or pharmaceutical composition of claim 4 or 5, or the commercial package of claim 6, wherein the cancer is ALK-positive neuroblastoma.

11. The pharmaceutical combination or composition of claim 4 or 5, or the commercial package of claim 6, wherein said cancer is an ALK-positive cancer that is resistant to an ALK inhibitor.

12. The pharmaceutical combination or composition of claim 4 or 5, or the commercial package of claim 6, wherein said cancer is an ALK-positive cancer that is resistant to the ALK inhibitor of the pharmaceutical combination.

13. The pharmaceutical combination or composition of claim 4 or 5, or the commercial package of claim 6, wherein said cancer is an ALK-positive cancer characterized by ALK-independent resistance to an ALK inhibitor.

14. A pharmaceutical combination according to claim 1 or 2, a pharmaceutical composition according to claim 3 or a commercial package according to claim 6, for use as a medicament.

15. A pharmaceutical combination according to claim 1 or 2, a pharmaceutical composition according to claim 3 or a commercial package according to claim 6, for use in the treatment of cancer.

16. Use of the pharmaceutical combination of claim 1 or 2, the pharmaceutical composition of claim 3, or the commercial package of claim 6 in the manufacture of a medicament for the treatment of cancer.

17. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of:

(i) an ALK inhibitor or a pharmaceutically acceptable salt thereof, and

(ii) an inhibitor of SHP2, or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical combination for use according to claim 15, the pharmaceutical composition for use according to claim 15, the commercial package for use according to claim 15, the use of the pharmaceutical combination according to claim 16, the use of the pharmaceutical composition according to claim 16, the use of the commercial package according to claim 16, or the method of treating cancer according to claim 17, wherein the cancer is an ALK-positive cancer.

19. The pharmaceutical combination for use according to claim 15, the pharmaceutical composition for use according to claim 15, the commercial package for use according to claim 15, the use of the pharmaceutical combination according to claim 16, the use of the pharmaceutical composition according to claim 16, the use of the commercial package according to claim 16, or the method of treating cancer according to claim 17, wherein the cancer is an ALK-positive cancer selected from anaplastic large-cell lymphoma, gastric cancer, breast cancer, esophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastoma, renal cancer, pancreatic cancer and lung cancer.

20. The pharmaceutical combination for use according to claim 15, the pharmaceutical composition for use according to claim 15, the commercial package for use according to claim 15, the use of the pharmaceutical combination according to claim 16, the use of the pharmaceutical composition according to claim 16, the use of the commercial package according to claim 16, or the method of treating cancer according to claim 17, wherein the cancer is ALK-positive non-small cell lung cancer.

21. The pharmaceutical combination for use according to claim 15, the pharmaceutical composition for use according to claim 15, the commercial package for use according to claim 15, the use of the pharmaceutical combination according to claim 16, the use of the pharmaceutical composition according to claim 16, the use of the commercial package according to claim 16, or the method of treating cancer according to claim 17, wherein the cancer is ALK-positive neuroblastoma.

22. The pharmaceutical combination for use according to claim 15, the pharmaceutical composition for use according to claim 15, the commercial package for use according to claim 15, the use of the pharmaceutical combination according to claim 16, the use of the pharmaceutical composition according to claim 16, the use of the commercial package according to claim 16, or the method of treating cancer according to claim 17, wherein the cancer is an ALK-positive cancer resistant to an ALK inhibitor.

23. The pharmaceutical combination for use of claim 15, the pharmaceutical composition for use of claim 15, the commercial package for use of claim 15, the use of the pharmaceutical combination of claim 16, the use of the pharmaceutical composition of claim 16, the use of the commercial package of claim 16, or the method of treating cancer of claim 17, wherein the cancer is an ALK-positive cancer that is resistant to the ALK inhibitor of the pharmaceutical combination.

24. The pharmaceutical combination for use according to claim 15, the pharmaceutical composition for use according to claim 15, the commercial package for use according to claim 15, the use of the pharmaceutical combination according to claim 16, the use of the pharmaceutical composition according to claim 16, the use of the commercial package according to claim 16, or the method of treating cancer according to claim 17, wherein the cancer is an ALK-positive cancer characterized by ALK-independent resistance to an ALK inhibitor.

25. The pharmaceutical combination according to claim 1 or claim 2, the pharmaceutical composition according to claim 3, the commercial package according to claim 6, the pharmaceutical combination for use according to any one of claims 4, 5, 7 to 15 or 18 to 24, the pharmaceutical composition for use according to any one of claims 4, 5, 7 to 15 or 18 to 24, the commercial package for use according to any one of claims 4, 5, 7 to 15 or 18 to 24, the use of the pharmaceutical combination according to any one of claims 16 or 18 to 24, the use of the pharmaceutical composition according to any one of claims 16 or 18 to 24, the use of the commercial package according to any one of claims 16 or 18 to 24, or the method of treating cancer according to any one of claims 17 to 24, wherein the ALK inhibitor is selected from the group consisting of 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4, 3-H ] [2, 5, 11] -benzoxadiazacyclotetradecyne-3-carbonitrile (loratinib;

26. the pharmaceutical combination according to claim 1 or claim 2, the pharmaceutical composition according to claim 3, the commercial package according to claim 6, the pharmaceutical combination for use according to any one of claims 4, 5, 7 to 15 or 18 to 24, the pharmaceutical composition for use according to any one of claims 4, 5, 7 to 15 or 18 to 24, the commercial package for use according to any one of claims 4, 5, 7 to 15 or 18 to 24, the use of the pharmaceutical combination according to any one of claims 16 or 18 to 24, the use of the pharmaceutical composition according to any one of claims 16 or 18 to 24, the commercial package for use according to any one of claims 16 or 18 to 24, or the method for treating cancer according to any one of claims 17 to 24, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib).

27. The pharmaceutical combination of any one of claims 1, 2, 25 or 26, the pharmaceutical composition of any one of claims 3, 25 or 26, the commercial package of any one of claims 6, 25 or 26, the pharmaceutical combination for use of any one of claims 4, 5, 7 to 15 or 18 to 26, the pharmaceutical composition for use of any one of claims 6, the commercial package for use of any one of claims 14, 15 or 18 to 26, use of a pharmaceutical combination according to any one of claims 16 or 18 to 26, use of a pharmaceutical composition according to any one of claims 16 or 18 to 26, use of a commercial package according to any one of claims 16 or 18 to 26, the method of treating cancer of any one of claims 17 to 26, wherein the SHP2 inhibitor is selected from the group consisting of:

6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine;

6- (4- (aminomethyl) -4-phenylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine;

6- (4- (aminomethyl) -4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine;

6- (4- (aminomethyl) -4-methylpiperidin-1-yl) -3- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrazin-2-amine;

(R) -8- (6-amino-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine;

(R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine;

(3S, 4S) -8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine;

3- (2, 3-dichlorophenyl) -6- (1, 8-diazaspiro [4.5] decan-8-yl) pyrazin-2-amine;

(R) -8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine;

(S) -8- (6-amino-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrazin-2-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine;

(S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine;

(1R, 3R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-8-azaspiro [4.5] decan-1-amine;

(2S, 4R) -4-amino-8- (6-amino-5- ((2, 3-dichloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-2-ol;

(2R, 4R) -4-amino-8- (6-amino-5- ((2, 3-dichloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-2-ol;

(1R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methyl-8-azaspiro [4.5] decan-1-amine;

(3S, 4S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine;

(3S, 4S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-ethyl-2-oxa-8-azaspiro [4.5] decan-4-amine;

(2R, 4R) -4-amino-8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-2-ol;

(1R, 3R) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-8-azaspiro [4.5] decan-1-amine;

(1R) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methyl-8-azaspiro [4.5] decan-1-amine;

(3S, 4S) -8- (5- ((6-amino-2, 3-dichloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine;

(3S, 4S) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine;

(R) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine:

(S) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine;

6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrimidin-4 (3H) -one;

6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- ((3-chloro-2-methylpyridin-4-yl) thio) -3-methylpyrimidin-4 (3H) -one;

6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- ((2, 3-dichlorophenyl) thio) -3-methylpyrimidin-4 (3H) -one;

6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((3- (trifluoromethyl) pyridin-4-yl) thio) pyrimidin-4 (3H) -one;

6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -5- (2, 3-dichlorophenyl) -3-methylpyrimidin-4 (3H) -one;

6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- ((2-chloro-3-methoxyphenyl) thio) -3-methylpyrimidin-4 (3H) -one;

6-amino-2- ((3S, 4S) -4-amino-3-ethyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrimidin-4 (3H) -one;

6-amino-5- ((3-amino-2- (trifluoromethyl) phenyl) thio) -2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methylpyrimidin-4 (3H) -one;

(R) -6-amino-2- (1-amino-3, 3-difluoro-8-azaspiro [4.5] decan-8-yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyrimidin-4 (3H) -one;

6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((3- (trifluoromethyl) pyridin-4-yl) thio) pyrimidin-4 (3H) -one;

6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -5- (4-chlorophenyl) -3-methylpyrimidin-4 (3H) -one;

6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -3-methyl-5-phenylpyrimidin-4 (3H) -one;

(R) -6- (1-amino-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one;

2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -3, 7-dihydro-4H-pyrrolo [2, 3-d ] pyrimidin-4-one;

(3S, 4S) -8- (3- (2, 3-dichloropyridin-4-yl) -1H-pyrazolo [3, 4-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine;

3- (6-amino-2-methylpyridin-3-yl) -6- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one;

(R) -3- (6-amino-2-methylpyridin-3-yl) -6- (1-amino-3, 3-difluoro-8-azaspiro [4.5] decan-8-yl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one;

6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (3-chloro-2- (cyclopropylamino) pyridin-4-yl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one;

2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- (3-chloro-2-methoxypyridin-4-yl) -3-methyl-3, 7-dihydro-4H-pyrrolo [2, 3-d ] pyrimidin-4-one;

n- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide;

n- (3- ((3-amino-5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide;

n- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-2-oxo-1-phenyl-2, 5-dihydro-1H-pyrrole-3-carboxamide;

(R) -N- (3- ((3-amino-5- (1-amino-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide:

n- (3- ((3-amino-5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide;

(R) -N- (3- ((3-amino-5- (1-amino-3, 3-difluoro-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide;

n- (3- ((3-amino-5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide;

n- (3- ((3-amino-5- (4-amino-4- (fluoromethyl) piperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide;

n- (3- ((3-amino-5- (4-amino-4- (fluoromethyl) piperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide;

(S) -N- (3- ((3-amino-5- (4-amino-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide, and

n- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5-benzyl-4-hydroxy-1-methyl-2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxamide.

Technical Field

The present invention relates to a pharmaceutical combination comprising as one of the combination partners an Anaplastic Lymphoma Kinase (ALK) inhibitor; the use of such a combination in the treatment of a proliferative disease, such as cancer, in particular non-small cell lung cancer (NSCLC); and methods of treating a subject suffering from a proliferative disease, such as cancer, particularly non-small cell lung cancer, comprising administering a therapeutically effective amount of such a combination.

Background

Highly potent and highly selective inhibitors targeting Anaplastic Lymphoma Kinase (ALK) rearranged lung cancer have been used to treat patients with non-small cell lung cancer (NSCLC). However, despite these treatment options, resistant cases still exist. Resistance to these selective inhibitors can develop by a variety of mechanisms, such as by secondary mutations in ALK, or activation of compensatory signalling pathways. Thus, there remains a need for effective and safe therapeutic agents to treat such resistant cases.

Disclosure of Invention

The present invention provides pharmaceutical combinations and therapeutic methods that can be used to treat cancer, particularly ALK rearrangement (i.e., ALK-positive) cancers, such as non-small cell lung cancer (NSCLC). The cancer may also be resistant to ALK inhibitors; for example, due to an activated alternative signaling pathway (off-target resistance). We found that co-targeting ALK and SHP2 amplified the antiproliferative effect of ALK inhibitors, even in ALK-resistant cancers. We have also found that methods involving co-targeting ALK and SHP2 using a combination of an ALK inhibitor and an SHP2 inhibitor reduce RAS-GTP loading potential of cells and inhibit phosphorylated ERK rebound, which can even overcome off-target resistance of ALK-rearrangement cancers (such as NSCLC).

The invention provides the following aspects, advantageous features and specific embodiments, individually or in combination, as set out in the following items:

item 1: a pharmaceutical combination comprising:

(i) an ALK inhibitor or a pharmaceutically acceptable salt thereof, and

(ii) an inhibitor of SHP2, or a pharmaceutically acceptable salt thereof.

Item 2: the pharmaceutical combination according to item 1, further comprising at least one pharmaceutically acceptable carrier.

Item 3: a pharmaceutical composition comprising a pharmaceutical combination according to item 1 or 2, and at least one pharmaceutically acceptable carrier.

Item 4: the pharmaceutical combination of clauses 1 or 2, or the pharmaceutical composition of clause 3, wherein the ALK inhibitor or pharmaceutically acceptable salt thereof and the SHP2 inhibitor or pharmaceutically acceptable salt thereof are provided in jointly therapeutically effective amounts for use in the treatment of cancer.

Item 5: the pharmaceutical combination of item 4, or the pharmaceutical composition of item 4, wherein the ALK inhibitor or pharmaceutically acceptable salt thereof and the SHP2 inhibitor or pharmaceutically acceptable salt thereof are provided in synergistically effective amounts for use in the treatment of cancer.

Item 6: a commercial package comprising a pharmaceutical combination or pharmaceutical composition according to any one of items 1 to 5 together with instructions for simultaneous or sequential administration thereof for use in the treatment of cancer.

Item 7: the pharmaceutical combination of item 4 or 5, the pharmaceutical composition of item 4 or 5, or the commercial package of item 6, wherein the cancer is an ALK-positive cancer.

Item 8: the pharmaceutical combination or pharmaceutical composition of item 4 or item 5, or the commercial package of item 6, wherein the cancer is an ALK-positive cancer selected from anaplastic large cell lymphoma, gastric cancer, breast cancer, esophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastoma, renal cancer, pancreatic cancer, and lung cancer.

Item 9: the pharmaceutical combination or pharmaceutical composition of item 4 or item 5, or the commercial package of item 6, wherein the cancer is ALK-positive non-small cell lung cancer.

Item 10: the pharmaceutical combination or pharmaceutical composition of item 4 or item 5, or the commercial package of item 6, wherein the cancer is ALK-positive neuroblastoma.

Item 11: the pharmaceutical combination or pharmaceutical composition of item 4 or item 5, or the commercial package of item 6.

Item 12: the pharmaceutical combination or pharmaceutical composition of item 4 or item 5, or the commercial package of item 6, wherein the cancer is an ALK-positive cancer that is resistant to the ALK inhibitor of the pharmaceutical combination.

Item 13: the pharmaceutical combination or pharmaceutical composition of item 4 or item 5, or the commercial package of item 6, wherein the cancer is an ALK-positive cancer characterized by ALK-independent resistance to an ALK inhibitor.

Item 14: the pharmaceutical combination according to item 1 or 2, the pharmaceutical composition according to item 3, or the commercial package according to item 6, for use as a medicament.

Item 15: the pharmaceutical combination of item 1 or 2, the pharmaceutical composition of item 3, or the commercial package of item 6, for use in the treatment of cancer.

Item 16: use of the pharmaceutical combination of item 1 or 2, the pharmaceutical composition of item 3, or the commercial package of item 6 in the manufacture of a medicament for the treatment of cancer.

Item 17: a method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of:

(i) an ALK inhibitor or a pharmaceutically acceptable salt thereof, and

(ii) an inhibitor of SHP2, or a pharmaceutically acceptable salt thereof.

Item 18: the pharmaceutical combination for use according to item 15, the pharmaceutical composition for use according to item 15, the commercial package for use according to item 15, the use of the pharmaceutical combination according to item 16, the use of the pharmaceutical composition according to item 16, the use of the commercial package according to item 16, or the method of treating cancer according to item 17, wherein the cancer is an ALK-positive cancer.

Item 19: the pharmaceutical combination for use of item 15, the pharmaceutical composition for use of item 15, the commercial package for use of item 15, the use of the pharmaceutical combination of item 16, the use of the pharmaceutical composition of item 16, the use of the commercial package of item 16, or the method of treating a cancer of item 17, wherein the cancer is an ALK-positive cancer selected from anaplastic large cell lymphoma, gastric cancer, breast cancer, esophageal cancer, colorectal cancer, neuroblastoma, inflammatory myofibroblastoma, renal cancer, pancreatic cancer, and lung cancer.

Item 20: the pharmaceutical combination for use according to item 15, the pharmaceutical composition for use according to item 15, the commercial package for use according to item 15, the use of the pharmaceutical combination according to item 16, the use of the pharmaceutical composition according to item 16, the use of the commercial package according to item 16, or the method of treating cancer according to item 17, wherein the cancer is ALK-positive non-small cell lung cancer.

Item 21: the pharmaceutical combination for use according to item 15, the pharmaceutical composition for use according to item 15, the commercial package for use according to item 15, the use of the pharmaceutical combination according to item 16, the use of the pharmaceutical composition according to item 16, the use of the commercial package according to item 16, or the method of treating cancer according to item 17, wherein the cancer is ALK-positive neuroblastoma.

Item 22: the pharmaceutical combination for use according to item 15, the pharmaceutical composition for use according to item 15, the commercial package for use according to item 15, the use of the pharmaceutical combination according to item 16, the use of the pharmaceutical composition according to item 16, the use of the commercial package according to item 16, or the method of treating a cancer according to item 17, wherein the cancer is an ALK-positive cancer that is resistant to an ALK inhibitor.

Item 23: the pharmaceutical combination for use according to item 15, the pharmaceutical composition for use according to item 15, the commercial package for use according to item 15, the use of the pharmaceutical combination according to item 16, the use of the pharmaceutical composition according to item 16, the use of the commercial package according to item 16, or the method of treating a cancer according to item 17, wherein the cancer is an ALK-positive cancer that is resistant to an ALK inhibitor of the pharmaceutical combination.

Item 24: the pharmaceutical combination for use according to item 15, the pharmaceutical composition for use according to item 15, the commercial package for use according to item 15, the use of the pharmaceutical combination according to item 16, the use of the pharmaceutical composition according to item 16, the use of the commercial package according to item 16, or the method of treating cancer according to item 17, wherein the cancer is an ALK-positive cancer characterized by ALK-independent resistance to an ALK inhibitor.

Item 25: the pharmaceutical combination of item 1 or item 2, the pharmaceutical composition of item 3, the commercial package of item 6, the pharmaceutical combination for use of any one of items 4, 5, 7 to 15, or 18 to 24, the pharmaceutical composition for use of any one of items 4, 5, 7 to 15, or 18 to 24, the commercial package for use of any one of items 4, 5, 7 to 15, or 18 to 24, the use of the pharmaceutical combination of item 16 or 18 to 24, the use of the pharmaceutical composition of item 16 or 18 to 24, the use of the commercial package of item 16 or 18 to 24, or the method of treating cancer of any one of items 17 to 24, wherein the ALK inhibitor is selected from the group consisting of 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] - N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib)), (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4, 3-H ] [2, 5, 11] -benzoxadiazacyclotetradecyne-3-carbonitrile (loratinib); PF-06463922),

Item 26: the pharmaceutical combination of item 1 or item 2, the pharmaceutical composition of item 3, the commercial package of item 6, the pharmaceutical combination for use of any one of items 4, 5, 7 to 15, or 18 to 24, the pharmaceutical composition for use of any one of items 4, 5, 7 to 15, or 18 to 24, the commercial package for use of any one of items 4, 5, 7 to 15, or 18 to 24, the use of the pharmaceutical combination of item 16 or 18 to 24, the use of the pharmaceutical composition of item 16 or 18 to 24, the use of the commercial package of item 16 or 18 to 24, or the method of treating cancer of any one of items 17 to 24, wherein the ALK inhibitor is selected from the group consisting of 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] - N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib).

Item 27: the pharmaceutical combination of any one of items 1, 2, 25 or 26, the pharmaceutical composition of any one of items 3, 25 or 26, the commercial package of any one of items 6, 25 or 26, the pharmaceutical combination for use of any one of items 4, 5, 7 to 15 or 18 to 26, the pharmaceutical composition for use of any one of item 6, the commercial package of any one of items 14, 15 or 18 to 26, the use of the pharmaceutical combination of any one of items 16 or 18 to 26, the use of the pharmaceutical composition of any one of items 16 or 18 to 26, the use of the commercial package of any one of items 16 or 18 to 26, or the method of treating cancer of any one of items 17 to 26, wherein the inhibitor of SHP2 is selected from the group consisting of the SHP2 inhibitors of table 1.

Item 28: the pharmaceutical combination of item 1 or item 2, the pharmaceutical composition of item 3, the commercial package of item 6, the pharmaceutical combination for use of any one of items 4, 5, 7 to 15, or 18 to 24, the pharmaceutical composition for use of any one of items 4, 5, 7 to 15, or 18 to 24, the commercial package for use of any one of items 4, 5, 7 to 15, or 18 to 24, the use of the pharmaceutical combination of item 16 or 18 to 24, the use of the pharmaceutical composition of item 16 or 18 to 24, the use of the commercial package of item 16 or 18 to 24, or the method of treating cancer of any one of items 17 to 24, wherein:

a) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine; or

b) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6- (4- (aminomethyl) -4-phenylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine; or

c) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6- (4- (aminomethyl) -4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine; or

d) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6- (4- (aminomethyl) -4-methylpiperidin-1-yl) -3- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrazin-2-amine; or

e) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -8- (6-amino-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine; or

f) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine; or

g) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (3S, 4S) -8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine; or

h) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 3- (2, 3-dichlorophenyl) -6- (1, 8-diazaspiro [4.5] decan-8-yl) pyrazin-2-amine; or

i) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine; or

j) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (S) -8- (6-amino-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrazin-2-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine; or

k) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine; or

l) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (1R, 3R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-8-azaspiro [4.5] decan-1-amine; or

m) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (2S, 4R) -4-amino-8- (6-amino-5- ((2, 3-dichloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-2-ol; or

N) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (2R, 4R) -4-amino-8- (6-amino-5- ((2, 3-dichloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-2-ol; or

o) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (1R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methyl-8-azaspiro [4.5] decan-1-amine; or

p) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (3S, 4S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine; or

q) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (3S, 4S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-ethyl-2-oxa-8-azaspiro [4.5] decan-4-amine; or

R) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (2R, 4R) -4-amino-8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-2-ol; or

s) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (1R, 3R) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-8-azaspiro [4.5] decan-1-amine; or

t) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (1R) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methyl-8-azaspiro [4.5] decan-1-amine; or

u) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (3S, 4S) -8- (5- ((6-amino-2, 3-dichloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine; or

v) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (3S, 4S) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine; or

w) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine; or

x) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (S) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine; or

y) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrimidin-4 (3H) -one; or

z) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- ((3-chloro-2-methylpyridin-4-yl) thio) -3-methylpyrimidin-4 (3H) -one; or

aa) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- ((2, 3-dichlorophenyl) thio) -3-methylpyrimidin-4 (3H) -one; or

bb) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((3- (trifluoromethyl) pyridin-4-yl) thio) pyrimidin-4- (3H) -one; or

cc) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -5- (2, 3-dichlorophenyl) -3-methylpyrimidin-4 (3H) -one; or

dd) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- ((2-chloro-3-methoxyphenyl) thio) -3-methylpyrimidin-4 (3H) -one; or

ee) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-ethyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrimidin-4 (3H) -one; or

ff) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-5- ((3-amino-2- (trifluoromethyl) phenyl) thio) -2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methylpyrimidin-4 (3H) -one; or

gg) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -6-amino-2- (1-amino-3, 3-difluoro-8-azaspiro [4.5] decan-8-yl) -5- ((2-amino-3-chloropyridin-4-yl) thio) -3-methylpyrimidin-4 (3H) -one; or

hh) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((3- (trifluoromethyl) pyridin-4-yl) thio) pyrimidin-4 (3H) -one; or

ii) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -5- (4-chlorophenyl) -3-methylpyrimidin-4 (3H) -one; or

jj) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -3-methyl-5-phenylpyrimidin-4 (3H) -one; or

kk) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (R) -6- (1-amino-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one; or

11) The ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -3, 7-dihydro-4H-pyrrolo [2, 3-d ] pyrimidin-4-one; or

mm) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (3S, 4S) -8- (3- (2, 3-dichloropyridin-4-yl) -1H-pyrazolo [3, 4-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine; or

nn) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 3- (6-amino-2-methylpyridin-3-yl) -6- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one; or

oo) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -3- (6-amino-2-methylpyridin-3-yl) -6- (1-amino-3, 3-difluoro-8-azaspiro [4.5] decan-8-yl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one; or

pp) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (3-chloro-2- (cyclopropylamino) pyridin-4-yl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one; or

qq) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- (3-chloro-2-methoxypyridin-4-yl) -3-methyl-3, 7-dihydro-4H-pyrrolo [2, 3-d ] pyrimidin-4-one; or

rr) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide; or

ss) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is N- (3- ((3-amino-5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide; or

tt) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-2-oxo-1-phenyl-2, 5-dihydro-1H-pyrrole-3-carboxamide; or

uu) the ALK inhibitor was 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -N- (3- ((3-amino-5- (1-amino-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide; or

vv) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is N- (3- ((3-amino-5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide; or

ww) the ALK inhibitor was 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -N- (3- ((3-amino-5- (1-amino-3, 3-difluoro-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide; or

xx) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is N- (3- ((3-amino-5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide; or

yy) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4- (fluoromethyl) piperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide; or

zz) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4- (fluoromethyl) piperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide; or

aaa) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (S) -N- (3- ((3-amino-5- (4-amino-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide; or

bbb) the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5-benzyl-4-hydroxy-1-methyl-2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxamide.

Item 29: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine.

Item 30: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6- (4- (aminomethyl) -4-phenylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine.

Item 31: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6- (4- (aminomethyl) -4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) pyrazin-2-amine.

Item 32: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is 6- (4- (aminomethyl) -4-methylpiperidin-1-yl) -3- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrazin-2-amine.

Item 33: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -8- (6-amino-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine.

Item 34: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine.

Item 35: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (3S, 4S) -8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decan-4-amine.

Item 36: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 3- (2, 3-dichlorophenyl) -6- (1, 8-diazaspiro [4.5] decan-8-yl) pyrazin-2-amine.

Item 37: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -8- (6-amino-5- (2, 3-dichlorophenyl) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine.

Item 38: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (S) -8- (6-amino-5- ((2- (trifluoromethyl) pyridin-3-yl) thio) pyrazin-2-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine.

Item 39: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-oxa-8-azaspiro [4.5] decane-4- An amine.

Item 40: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (1R, 3R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-8-azaspiro [4.5] decane- 1-amine.

Item 41: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (2S, 4R) -4-amino-8- (6-amino-5- ((2, 3-dichloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-2-ol.

Item 42: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (2R, 4R) -4-amino-8- (6-amino-5- ((2, 3-dichloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-2-ol.

Item 43: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (1R) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methyl-8-azaspiro [4.5] decane-1- An amine.

Item 44: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package, or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (3S, 4S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azalide Spiro [4.5] decan-4-amine.

Item 45: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package, or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (3S, 4S) -8- (6-amino-5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-ethyl-2-oxa-8-azalide Spiro [4.5] decan-4-amine.

Item 46: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (2R, 4R) -4-amino-8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-2-ol.

Item 47: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (1R, 3R) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-8-azaspiro [4.5] decan-1-amine.

Item 48: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (1R) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-methyl-8-azaspiro [4.5] decan-1-amine.

Item 49: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (3S, 4S) -8- (5- ((6-amino-2, 3-dichloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decane [ sic ] -4-amine.

Item 50: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (3S, 4S) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -3-methyl-2-oxa-8-azaspiro [4.5] decane- 4-amine.

Item 51: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (R) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -8-azaspiro [4.5] decan-1-amine.

Item 52: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical combination, use of a pharmaceutical composition, use of a commercial package or a method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), and the SHP2 inhibitor is (S) -8- (5- ((2-amino-3-chloropyridin-4-yl) thio) pyrazin-2-yl) -2-oxa-8-azaspiro [4.5] decan-4-amine.

Item 53: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((2- (tris-piperidinyl) Fluoromethyl) pyridin-3-yl) thio) pyrimidin-4 (3H) -one.

Item 54: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- ((3-chloro-2-methylpyridine Pyridin-4-yl) thio) -3-methylpyrimidin-4 (3H) -one.

Item 55: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- ((2, 3-dichlorophenyl) thio) -3-methylpyrimidin-4 (3H) -one.

Item 56: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((3- (trifluoromethyl) pyridine- 4-yl) thio) pyrimidin-4 (3H) -one.

Item 57: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -5- (2, 3-dichlorophenyl) -3-methylpyrimidin-4 (3H) -one.

Item 58: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- ((2-chloro-3-methoxy-3) Phenyl) thio) -3-methylpyrimidin-4 (3H) -one.

Item 59: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-ethyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((2- (tris-piperidinyl) Fluoromethyl) pyridin-3-yl) thio) pyrimidin-4 (3H) -one.

Item 60: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-5- ((3-amino-2- (trifluoromethyl) phenyl) thio) -2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan 2 Alk-8-yl) -3-methylpyrimidin-4 (3H) -one.

Item 61: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (R) -6-amino-2- (1-amino-3, 3-difluoro-8-azaspiro [4.5] decan-8-yl) -5- ((2-amino-3-chloropyridin-4-yl) thiofide -3-methylpyrimidin-4 (3H) -one.

Item 62: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3-methyl-5- ((3- (tris-piperidinyl) Fluoromethyl) pyridin-4-yl) thio) pyrimidin-4 (3H) -one.

Item 63: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -5- (4-chlorophenyl) -3-methylpyrimidine-4 (3-amino-2- ((1R, 3R) -3-methyl-8-azaspiro [4.5] decan-8-yl) -4 (4-chlorophenyl) -3-methylpyrimidine-4 (3) H) -a ketone.

Item 64: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6-amino-2- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -3-methyl-5-phenylpyrimidin-4 (3H) -one.

Item 65: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (R) -6- (1-amino-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one.

Item 66: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 2- (4- (aminomethyl) -4-methylpiperidin-1-yl) -5- (2, 3-dichlorophenyl) -3, 7-dihydro-4H-pyrrolo [2, 3-d ] pyrimidin-4-one.

Item 67: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (3S, 4S) -8- (3- (2, 3-dichloropyridin-4-yl) -1H-pyrazolo [3, 4-b ] pyrazin-6-yl) -3-methyl-2-oxa-8-azone Heterospiro [4.5] decan-4-amine.

Item 668: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer, according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 3- (6-amino-2-methylpyridin-3-yl) -6- ((1R, 3R) -1-amino-3-methyl-8-azaspiro [4.5] decan-8-yl) -5- Methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one.

Item 69: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (R) -3- (6-amino-2-methylpyridin-3-yl) -6- (1-amino-3, 3-difluoro-8-azaspiro [4.5] decan-8-yl) -5-methylpyridin-3-yl -2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one.

Item 70: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 6- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (3-chloro-2- (cyclopropylamino) pyridine-4-yl) -yl) -5-methyl-2, 5-dihydro-4H-pyrazolo [3, 4-d ] pyrimidin-4-one.

Item 71: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is 2- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -5- (3-chloro-2-methoxypyridin-4-yl) ) -3-methyl-3, 7-dihydro-4H-pyrrolo [2, 3-d ] pyrimidin-4-one.

Item 72: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo- 4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide.

Item 73: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is N- (3- ((3-amino-5- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) pyri zine ) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide.

Item 74: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -4-hydroxy-2-oxo- 1-phenyl-2, 5-dihydro-1H-pyrrole-3-carboxamide.

Item 75: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (R) -N- (3- ((3-amino-5- (1-amino-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy 2 -4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide.

Item 76: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is N- (3- ((3-amino-5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4- Oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide.

Item 77: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (R) -N- (3- ((3-amino-5- (1-amino-3, 3-difluoro-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl 2) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide.

Item 78: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is N- (3- ((3-amino-5- (4- (aminomethyl) -4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4- oxo-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide.

Item 79: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4- (fluoromethyl) piperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo 6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide.

Item 80: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4- (fluoromethyl) piperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo 3-oxo-4H-pyrido [1, 2-a ] pyrimidine-carboxamide.

Item 81: the pharmaceutical combination, pharmaceutical composition, commercial package, pharmaceutical combination for use, pharmaceutical composition for use, commercial package for use, use of a pharmaceutical composition, use of a commercial package or method of treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is (S) -N- (3- ((3-amino-5- (4-amino-2-oxa-8-azaspiro [4.5] decan-8-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -2-hydroxy-4-oxo-6, 7, 8, 9-tetrahydro-4H-pyrido [1, 2-a ] pyrimidine-3-carboxamide.

Item 82: the pharmaceutical combination, the pharmaceutical composition, the commercial package, the pharmaceutical combination for use, the pharmaceutical composition for use, the commercial package for use, the use of the pharmaceutical composition, the use of the commercial package or the method for treating cancer according to clause 28, wherein the ALK inhibitor is 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) and the SHP2 inhibitor is N- (3- ((3-amino-5- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) thio) -2-chlorophenyl) -5-benzyl-4-hydroxy- 1-methyl-2-oxo-2, 5-dihydro-1H-pyrrole-3-carboxamide.

Drawings

Figure 1 images obtained from a cell colony formation assay showing that compound SHP2 inhibitor No. 1 enhances anti-proliferative activity of ceritinib in ALK-positive NSCLC cells. Cells were exposed to ceritinib (0.5 μ M), compound No. 1 (5 μ M), or the combination for 14 days. For each cell line, all dishes were fixed, stained and photographed simultaneously.

Figure 2 is a graph of the growth inhibitory effect of ceritinib, compound No. 1, or a combination of ceritinib and compound No. 1 on an MGH049 tumor model. The MGH049 cell line was implanted in the flank of nude mice. When the mean tumor volume is 200 to 300mm³The animals were randomly divided into 4 groups and the animals received vehicle, ceritinNib (20mg/kg), Compound No. 1 (75mg/kg), or a combination of the two inhibitors. Tumor size and body weight were measured at random groupings, followed by twice weekly measurements for the duration of the study. Mean tumor volume and SEM are shown as a function of time. The data show that the combination of ceritinib and compound No. 1 is more effective at inhibiting tumor growth in vivo than either compound alone.

FIG. 3 is a graph of growth inhibitory effect of ceritinib, compound No. 1, or a combination of ceritinib and compound No. 1 on MGH045-2A tumor model. The MGH045-2A cell line was implanted in the flanks of nude mice. When the mean tumor volume is 200 to 300mm³Animals were randomized into 4 groups and received vehicle, ceritinib (20mg/kg), compound No. 1 (75mg/kg), or a combination of the two inhibitors. Tumor size and body weight were measured at random groupings, followed by twice weekly measurements for the duration of the study. Mean tumor volume and SEM are shown as a function of time. The data show that the combination of ceritinib and compound No. 1 is more effective at inhibiting tumor growth in vivo than either compound alone.

FIG. 4 is a graph of growth inhibitory effect of ceritinib, compound No. 1, or a combination of ceritinib and compound No. 1 on MGH073-2B tumor model. MGH073-2B cell line was implanted in the flanks of nude mice. When the mean tumor volume is 200 to 300mm³Animals were randomized into 4 groups and received vehicle, ceritinib (20mg/kg), compound No. 1 (75mg/kg), or a combination of the two inhibitors. Tumor size and body weight were measured at random groupings, followed by twice weekly measurements for the duration of the study. Mean tumor volume and SEM are shown as a function of time. The data show that the combination of ceritinib and compound No. 1 is more effective at inhibiting tumor growth in vivo than either compound alone.

Detailed Description

Definition of

Unless otherwise specifically indicated, general terms used herein are defined to have the following meanings.

The terms "comprising" and "including" are used herein in their open and non-limiting sense unless otherwise indicated.

The terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. When the plural form is used for compounds, salts, etc., this also means the singular compound, salt, etc.

The term "combination" or "pharmaceutical combination" as used herein refers to a fixed combination, an unfixed combination, or a set of components for combined administration of a unit dosage form (e.g., a capsule, tablet, or sachet), wherein the ALK inhibitor, or a pharmaceutically acceptable salt thereof, and the SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, may be administered simultaneously, independently at the same time, or separately within a time interval that allows the combination partners to show cooperation (e.g., a synergistic, or additive effect).

The term "ALK inhibitor" as used herein refers to a compound that targets, reduces, or inhibits the synthesis or biological activity of Anaplastic Lymphoma Kinase (ALK). In particular, an "ALK inhibitor" may be an IC of less than 1 μ M₅₀ALK inhibiting compounds, wherein IC₅₀Measured by the Caliper (Caliper) mobility shift assay. The karibel mobility shift technique is based on the separation of particles of different charges and sizes in an electric field, similar to capillary electrophoresis. The kalipk assay utilizes a fluorescently labeled peptide as a kinase substrate. Phosphorylation of the peptide during the reaction introduces an additional negative charge via the phosphate, thus allowing it to be separated from the phosphorylated peptide. Both the separation and detection of the labeled peptides were carried out in the microfluidic system of the Caribot Lab Chip. These LabChips have 12 "sipper" tubes capable of analyzing 12 samples simultaneously in parallel. The fact that measurements are performed on both unphosphorylated peptide (substrate) and phosphorylated peptide (product), and that the separation makes the readout relatively insensitive to interference by fluorescent compounds, makes the assay of excellent data quality. A typical assay procedure may be carried out at 30 ℃ in a total volume of 9. mu.L (each including 0.050. mu.L of compound diluent)Or pure DMSO) for 60 min. The reaction can be stopped by adding 16. mu.L of stop solution (100mM Hepes, 5% (v/v) DMSO, 0.1% (v/v) coating reagent, 10mM EDTA, 0.015% (v/v) Brij 35). After the reaction was complete, the plate was transferred to a carlib LabChip 3000 workstation for analysis. The effect of a compound on enzyme activity was obtained from a linear progression curve in the absence and presence of the compound and was routinely determined from one reading (end-point measurement). According to the present invention, the ALK inhibitor may be, for example, a compound selected from the group consisting of: 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl]-N4- [2- (isopropylsulfonyl) phenyl]-2, 4-pyrimidinediamine (ceritinib), (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4, 3-H][2，5，11]-benzoxadiazacyclotetradecyne-3-carbonitrile (Laratinib; PF-06463922),

Preferably, the ALK inhibitor is ceritinib, i.e. 5-chloro-N2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) -N4- [2- (propane-2-sulfonyl) -phenyl]-pyrimidine-2, 4-diamine, or a pharmaceutically acceptable salt thereof. Ceritinib is a compound of formula (I) and is described in example 7 (compound 66) of WO 2008/073687:

the term "SHP 2 inhibitor" as used herein, refers to a compound that targets, reduces or inhibits the biological activity of the non-receptor protein tyrosine phosphatase SHP 2. In particular, an "SHP 2 inhibitor" may be at an IC of less than 0.5. mu.M₅₀Compounds which inhibit SHP2, wherein IC₅₀By the methods as described herein and Nature [ Nature]The SHP2 inhibition assay described in 2016, volume 535, page 148. SHP2 inhibitorThe formulation may be, for example, any compound from table 1.

"ALK-rearranged cancer" or "ALK-positive cancer" refers to a cancer in which the ALK gene is rearranged, mutated, or amplified. This may lead to aberrant expression of full-length ALK or to ALK fusion proteins driving proliferation. There are several different ALK fusion partners.

By "ALK-positive cancer that is resistant to an ALK inhibitor" is meant a cancer or tumor that does not respond favorably to treatment with a prior ALK inhibitor, or alternatively, that relapses or reburns after responding favorably to an ALK inhibitor. The cancer or tumor may be resistant or refractory at the beginning of the treatment, or may become resistant or refractory during the treatment. One mechanism for developing tumor resistance when treated with ALK inhibitors is the occurrence of mutations in the ALK gene. This mechanism has been demonstrated in clinical trials with ALK-positive (mainly non-small cell lung malignancies) patients treated with Crizotinib (Crizotinib). Some of these resistance mutations are similar to those found in neuroblastoma. While not wishing to be bound by any theory, it is hypothesized that these resistance mutations result in ALK activation, thereby further driving tumor proliferation. Alternatively, alternative biochemical pathways are activated via various mechanisms that counter ALK inhibition, which in turn promotes proliferation. These are termed "ALK-independent resistance".

The term "combination of the invention" as used herein refers to a pharmaceutical combination comprising: (i) an ALK inhibitor, or a pharmaceutically acceptable salt thereof, and (ii) an SHP2 inhibitor, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier. The term "combination of the invention" also means a pharmaceutical combination comprising the following components:

A) (i) an ALK inhibitor or a pharmaceutically acceptable salt thereof selected from 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), 9-ethyl-6, 6-dimethyl-8- [4- (4-morpholinyl) -1-piperidinyl ] -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (alenib)) and (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4, 3-H ] [2, 5, 11] -benzoxadiazacyclotetradecyne-3-carbonitrile (Lauratinib), and

(ii) an inhibitor of SHP2, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier;

B) (i) an ALK inhibitor or a pharmaceutically acceptable salt thereof selected from 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib), 9-ethyl-6, 6-dimethyl-8- [4- (4-morpholinyl) -1-piperidinyl ] -11-oxo-6, 11-dihydro-5H-benzo [ b ] carbazole-3-carbonitrile (erlotinib) and (10R) -7-amino-12-fluoro-2, 10, 16-trimethyl-15-oxo-10, 15, 16, 17-tetrahydro-2H-8, 4- (methine bridge) pyrazolo [4, 3-H ] [2, 5, 11] -benzoxadiazacyclotetradecyne-3-carbonitrile (Lauratinib), and

(ii) an inhibitor of SHP2 of table 1, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier;

C) (i) 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) or a pharmaceutically acceptable salt thereof, and

(ii) an inhibitor of SHP2, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier,

and

D) (i) 5-chloro-N2- [ 2-isopropoxy-5-methyl-4- (4-piperidinyl) phenyl ] -N4- [2- (isopropylsulfonyl) phenyl ] -2, 4-pyrimidinediamine (ceritinib) or a pharmaceutically acceptable salt thereof, and

(ii) an inhibitor of SHP2 of table 1, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable carrier.

The term "fixed combination" means that the active ingredient (i.e. ALK inhibitor) as defined herein and one or more combination partners (i.e. SHP2 inhibitor) as defined herein are administered to a patient simultaneously in the form of a single entity or unit dosage form. The term "non-fixed combination" means that the active ingredient (i.e. ALK inhibitor) as defined herein and one or more combination partners (i.e. SHP2 inhibitor) as defined herein are administered to a patient as separate entities either simultaneously or sequentially with no specific time limit, wherein such administration provides therapeutically effective levels of both compounds in the body of the patient. This applies to combinations of two active ingredients, but also to cocktail therapies, for example the administration of three or more active ingredients.

The term "pharmaceutical formulation" is defined herein to refer specifically to a "kit of components" meaning that the combination partners (i.e., the ALK inhibitor and the SHP2 inhibitor as defined herein) can be administered independently, or by using different fixed combinations with significant amounts of the combination partners (e.g., the ALK inhibitor and the SHP2 inhibitor) simultaneously or at different time points. The components of the set of components may then be administered, for example, simultaneously or chronologically staggered, so-called chronologically staggered, i.e. at different time points and using the same or different time intervals for any component of the set. The ratio of the total amount of one combination partner to be administered to the total amount of the other combination partner in the pharmaceutical preparation can be varied, for example, in order to meet the needs of a patient sub-population to be treated or the needs of the individual patient.

The term "pharmaceutical composition" is defined herein to mean a mixture or solution containing at least one active ingredient or therapeutic agent to be administered to a subject (e.g., a mammal or human) in order to prevent or treat a particular disease or condition (particularly a proliferative disease, such as cancer, especially lung cancer) affecting that mammal or human.

The terms "drug", "active substance", "active ingredient", "active agent", "medicament" are to be understood as meaning a compound, in particular a compound specified herein, in free form or in pharmaceutically acceptable salt form. The term ALK inhibitor is also referred to herein as a "combination partner (i)". Similarly, the term SHP2 inhibitor is also referred to as "combination partner (ii)".

The term "co-administration" or "combined administration" as used herein is defined to encompass administration of selected active ingredients to a single subject (e.g., a patient) in need thereof, and is intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or simultaneously.

The term "treating" or "therapy" as used herein includes treatment to relieve, alleviate or alleviate at least one symptom of a subject or to achieve a delay in progression of a disease. For example, treatment may be attenuation of one or more symptoms of the disorder or complete eradication of the disorder (e.g., cancer). Within the meaning of the present invention, the term "treatment" also means preventing, delaying onset (i.e. the period of time before clinical manifestation of the disease) and/or reducing the risk of disease development or disease progression. The term "protect" is used herein to mean to prevent, delay or treat, or both prevent, delay and treat, as the case may be, the development, duration or worsening of a disease in a subject (e.g., a mammal or a human).

The term "preventing", as used herein, includes preventing at least one symptom associated with, or caused by, the condition, disease, or disorder being prevented.

The term "jointly therapeutically effective amount" as used herein means an amount of a therapeutic agent that: in the case of separate administration (in a chronologically staggered manner, in particular in a sequence-specific manner) to warm-blooded animals, in particular to humans to be treated, an (additive, but preferably synergistic) interaction (combination therapeutic effect) is shown. Whether this is the case can be determined in particular by: the blood levels are followed, confirming that both compounds are present in the blood of the person to be treated, at least during certain time intervals.

The term "pharmaceutically effective amount" of a combination of therapeutic agents is an amount sufficient to provide an observable improvement over the baseline observable indications and symptoms of the disorder being treated with the combination.

The term "synergistic effect" as used herein, refers to this effect of at least two therapeutic agents, namely an ALK inhibitor as defined herein and at least one SHP2 inhibitor as defined herein: this effect is greater than simply adding the individual effects of each drug administered. The effect may be, for example, slowing the progression of symptoms of a proliferative disease (such as cancer, particularly lung cancer) or a symptom thereof. The synergistic effect can be calculated as shown in the example. Similarly, "synergistically effective amounts" refer to the amounts needed to achieve a synergistic effect.

The term "subject" or "patient" as used herein includes an animal susceptible to or afflicted with a proliferative disease, such as cancer, or any disorder involving, directly or indirectly, cancer (particularly lung cancer). Examples of subjects include mammals, such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In a preferred embodiment, the subject is a human, e.g., a human having, at risk of, or potentially predisposed to a proliferative disease (e.g., cancer, particularly an ALK-positive cancer, such as NSCLC).

The term "about" or "approximately" shall have a meaning within 10%, more preferably within 5%, of a given value or range.