EGFR inhibitor for treating cancers comprising atypical EGFR mutations

Abstract

The present application provides methods of treating cancer in an individual in need thereof, wherein in the cancer in the individual has been determined to comprise one or more atypical epidermal growth factor receptor (EGFR) mutations, comprising administering to the individual (R)-N-(2-(4-(4-cyclopropylpiperazin-l-yl)piperidin-l-yl)-5-((6-(3-(3,5- difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, or a pharmaceutically acceptable salt thereof.

Description

EGFR INHIBITOR FOR TREATING CANCERS COMPRISING ATYPICAL EGFR MUTATIONS Abstract The present application provides methods of treating cancer in an individual in need thereof, wherein in the cancer in the individual has been determined to comprise one or more atypical epidermal growth factor receptor (EGFR) mutations, comprising administering to the individual EGFR for the treatment of cancers containing atypical EGFR mutations Inhibitor Summary This application provides a method for treating cancer in an individual in need, wherein the cancer in the individual has been determined to contain one or more atypical epidermal growth factor receptor (EGFR) mutations, comprising administering (R)-N-(2-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide or a pharmaceutically acceptable salt thereof to the individual.

Claims

CLAIMSWhat is claimed is:

1. A method of treating cancer in an individual in need thereof, wherein in the cancer in the individual has been determined to comprise one or more atypical epidermal growth factor receptor (EGFR) mutations, comprising administering to the individual (R)-N-(2-(4-(4- cyclopropylpiperazin-l-yl)piperidin-l-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2- yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the one or more atypical epidermal growth factor receptor (EGFR) mutations in the cancer of the individual comprises one or more (a) P-loop and alpha C-helix compressing (PACC) EGFR mutations, (b) Exon 18 mutations, (c) Exon 19 mutations, (d) Exon20 point mutations, (e) Exon21 mutations, (f) mutations in the extracellular domain of EGFR, (g) mutations in the transmembrane domain of EGFR, and (h) Exon20 insertion mutations, provided that the Exon20 insertion mutations do not include EGFR_Exon20insNPH, EGFR_Exon20insSVD, EGFR_Exon20insFQEA, EGFR_Exon20insH, and EGFR_Exon20insASV, EGFR_Exon20insYVMA.

3. The method of claim 1, wherein the more atypical epidermal growth factor receptor (EGFR) mutations in the cancer of the individual is selected from the group consisting of EGFR A702T, EGFR E709A, EGFR E709A G719A, EGFR E709A G719S, EGFR E709K, EGFR E709K G719S, EGFR_E709_T710delinsD, EGFR_E709_T710del insD S22R, EGFR L718Q, EGFR L718Q L858R, EGFR L718V, EGFR L718V L858R, EGFR G719A, EGFR G719A D761Y, EGFR G719A L861Q, EGFR G719A R776C, EGFR G719A S768I, EGFR G719C, EGFR G719C S768I, EGFR G719S, EGFR G719S L861Q, EGFR T725M, EGFR G719S S768I, EGFR_S720P,EGFR_E736K, EGFR G724S, EGFR G724S Exl9del, EGFR G724S L858R, EGFR_I740dupIPVAK, EGFR_E746_A750del A647T, EGFR_E746_A750del G724S, EGFR_ E746_A750del S768I, EGFR_E746_A750del R675W, EGFR_E746_T751del insV, EGFR_E746_T751del insV S768C, EGFR T751 I759 delinsN, EGFR L747P, EGFR L747S, EGFR L747S V774M, EGFR L747S L858R, EGFR_L747_S752del A755D, EGFR_ A750_I759del insPN, EGFR S752 I759del V769M, EGFR K757M L858R, EGFR K757R, EGFR D761N, EGFR_A767dupASV, EGFR S768C, EGFR S768I, EGFR S768I V769L, EGFR S768I V774M, EGFR S768I L858R, EGFR S768I L861Q, EGFR_S768dupSVD, EGFR V769L,EGFR V769M, EGFR N771G, EGFR_H773dup, EGFR V774M, EGFR R776C, EGFR R776H, EGFR G779F, EGFR L792H, EGFR_Exl9del L792H, EGFR G796S, EGFR V774M, EGFR S784F, EGFR_Exl9del G796S, EGFR L833V, EGFR V834L, EGFR T854I, EGFR_Exl9del T854I, EGFR L858R L792H, EGFR L858R C797S, EGFR L858R T854S, EGFR L861Q, EGFR L861R, EGFR S811F, EGFR_A763insFQEA, EGFR_A763insLQEA, EGFR_E746_A750delL41W, EGFR_E746_A750delR451H, EGFR K754E, EGFR_L747_E749del, EGFR A750P, EGFR_L747_T751del, and EGFR L833F.

4. The method of claim 1, wherein the (R)-N-(2-(4-(4-cyclopropylpiperazin-l- yl)piperidin-l-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4- methoxyphenyl)acrylamide is administered to the individual in the form of a fumarate, hemifumarate, glycolate or malonate salt.

5. The method of claim 4, wherein the (R)-N-(2-(4-(4-cyclopropylpiperazin-l- yl)piperidin-l-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4- methoxyphenyl)acrylamide is administered to the individual in the form of a malonate salt.

6. The method of claim 5, wherein the malonate salt is in a crystalline form.

7. The method of claim 6, wherein the crystalline form of the malonate salt maintains at least 95% of the crystalline form following storage in an open container for at least 7 days at 40 °C and 75% relative humidity, and wherein the amount of the crystalline form of the salt is measured by XRPD.

8. The method of claim 7, wherein the crystalline form of the malonate salt exhibits an XRPD pattern comprising a peak at 5.9 ± 0.2 degrees 2-theta.

9. The method of claim 5, wherein the malonate salt of (R)-N-(2-(4-(4- cyclopropylpiperazin-l-yl)piperidin-l-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2- yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide is in crystalline form, and wherein the crystalline form exhibits (a) an XRPD pattern comprising a peak at 5.9 ± 0.2 degrees 2- theta, and (b) a differential scanning calorimetry trace comprising a peak of from about 147 °C to about 151 °C.

10. The method of claim 1, wherein the cancer in the individual is selected from the group consisting of metastatic brain cancer, breast cancer, and non-small cell lung cancer.

11. The method of claim 10, wherein the cancer in the individual is metastatic brain cancer.

12. The method of claim 10, wherein the cancer in the individual is non-small cell lung cancer.

13. The method of claim 1, wherein the cancer comprises one or more central nervous system (CNS) metastases.

14. The method of claim 1, wherein the cancer is non-small cell lung cancer and the individual is EGFR inhibitor naive prior to administration to the individual of (R)-N-(2-(4-(4- cyclopropylpiperazin-l-yl)piperidin-l-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2- yl)pyrimidin-4-yl)amino)-4-methoxyphenyl)acrylamide, or a pharmaceutically acceptable salt thereof.

15. The method of claim 1, wherein the cancer is non-small cell lung cancer and the individual has received one or more prior EGFR inhibitor therapies for treatment of the cancer before administration to the individual of (R)-N-(2-(4-(4-cyclopropylpiperazin-l- yl)piperidin-l-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidin-2-yl)pyrimidin-4-yl)amino)-4- methoxyphenyl)acrylamide, or a pharmaceutically acceptable salt thereof.

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