EGFR inhibitors for treating cancers including atypical EGFR mutations
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- ORIC PHARMACEUTICALS INC
- Filing Date
- 2024-05-03
- Publication Date
- 2026-06-09
Smart Images
Figure 2026518582000001_ABST
Abstract
Claims
1. A method for carrying out treatment of cancer in an individual in need of treatment, wherein the cancer in the individual is determined to contain one or more atypical epidermal growth factor receptor (EGFR) mutations, and the method comprises administering to the individual (R)-N-(2-(4-(4-cyclopropylpiperazine-1-yl)piperidine-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxyphenyl)acrylamide or a pharmaceutically acceptable salt thereof.
2. The method according to claim 1, wherein the one or more atypical epidermal growth factor receptor (EGFR) mutations in the cancer of the individual include one or more (a) P-loop and alpha C-helix compression (PACC) EGFR mutations, (b) exon 18 mutations, (c) exon 19 mutations, (d) exon 20 point mutations, (e) exon 21 mutations, (f) mutations in the extracellular domain of EGFR, (g) mutations in the transmembrane domain of EGFR, and (h) exon 20 insertion mutations, provided that the exon 20 insertion mutations do not include EGFR_exon20insNPH, EGFR_exon20insSVD, EGFR_exon20insFQEA, EGFR_exon20insH, and EGFR_exon20insASV and EGFR_exon20insYVMA.
3. The more atypical epidermal growth factor receptor (EGFR) mutations in the cancer of the aforementioned individual are EGFR_A702T, EGFR_E709A, EGFR_E709A G719A, EGFR_E709A G719S, EGFR_E709K, EGFR_E709K G719S, EGFR_E709_T710delinsD, EGFR_E709_T710delinsD 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_S768IL861Q, 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 The method according to claim 1, selected from the group consisting of 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 according to claim 1, wherein the (R)-N-(2-(4-(4-cyclopropylpiperazine-1-yl)piperidine-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxyphenyl)acrylamide is administered to the individual in the form of a fumarate salt, hemi-fumarate salt, glycolate salt, or malonate salt.
5. The method according to claim 4, wherein the (R)-N-(2-(4-(4-cyclopropylpiperazine-1-yl)piperidine-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxyphenyl)acrylamide is administered to the individual in the form of a malonate salt.
6. The method according to claim 5, wherein the malonate salt is in crystalline form.
7. The method according to claim 6, wherein the crystalline form of the malonate salt retains at least 95% of the crystalline form after being stored in an open container at 40°C and 75% relative humidity for at least 7 days, and the amount of the crystalline form of the salt is measured by XRPD.
8. The method according to claim 7, wherein the crystalline form of the malonate salt exhibits an XRPD pattern including a peak at 5.9 ± 0.2 degrees 2 theta.
9. The method according to claim 5, wherein the malonate salt of (R)-N-(2-(4-(4-cyclopropylpiperazine-1-yl)piperidine-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxyphenyl)acrylamide is in crystalline form, and the crystalline form shows (a) an XRPD pattern including a peak at 5.9 ± 0.2 degrees 2 theta, and (b) a differential scanning calorimetry trace including a peak from about 147°C to about 151°C.
10. The method according to 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 according to claim 10, wherein the cancer in the individual is metastatic brain cancer.
12. The method according to claim 10, wherein the cancer in the individual is non-small cell lung cancer.
13. The method according to claim 1, wherein the cancer includes one or more central nervous system (CNS) metastases.
14. The method according to claim 1, wherein the cancer is non-small cell lung cancer, and the individual is untreated with an EGFR inhibitor prior to administration of (R)-N-(2-(4-(4-cyclopropylpiperazine-1-yl)piperidine-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxyphenyl)acrylamide or a pharmaceutically acceptable salt thereof to the individual.
15. The method according to claim 1, wherein the cancer is non-small cell lung cancer, and the individual has received one or more prior EGFR inhibitor therapies for the treatment of the cancer before administering to the individual (R)-N-(2-(4-(4-cyclopropylpiperazine-1-yl)piperidine-1-yl)-5-((6-(3-(3,5-difluorophenyl)isoxazolidine-2-yl)pyrimidine-4-yl)amino)-4-methoxyphenyl)acrylamide or a pharmaceutically acceptable salt thereof.