TW202313041A

TW202313041A - A triple pharmaceutical combination comprising dabrafenib, trametinib and a shp2 inhibitor.

Info

Publication number: TW202313041A
Application number: TW111120996A
Authority: TW
Inventors: 吉歐丹諾卡伯尼吉洛; 凡瑟莉娜庫克; 大衛柯達; 廷芳盧; 莫維里德莫桑尼
Original assignee: 瑞士商諾華公司
Priority date: 2021-06-09
Filing date: 2022-06-07
Publication date: 2023-04-01
Also published as: WO2022259157A1

Abstract

The present invention relates to a pharmaceutical combination comprising dabrafenib, trametinib and a SHP2 inhibitor; pharmaceutical compositions comprising the same; and methods of using such combinations and compositions in the treatment or prevention of conditions in which MAPK pathway inhibition is beneficial, for example, in the treatment of cancers.

Description

包含達拉菲尼、曲美替尼和SHP2抑制劑之三重藥物組合Triple Drug Combination Containing Dabrafenib, Trametinib, and SHP2 Inhibitor

本發明關於包含達拉菲尼（dabrafenib）或其藥學上可接受的鹽、曲美替尼（trametinib）或其藥學上可接受的鹽、和SHP2抑制劑（SHP2i）（例如(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（「化合物A」））或其藥學上可接受的鹽之藥物組合；包含該藥物組合之藥物組成物；包含該藥物組合之商業包裝；以及在治療或預防其中MAPK通路抑制係有益的病症中、例如在治療癌症中使用此類組合和組成物之方法。本發明還提供了此類組合，用於在此類病症或癌症（包括結腸直腸癌（CRC），例如BRAF功能獲得型結腸直腸癌）之治療中使用。The present invention relates to comprising dabrafenib (dabrafenib) or its pharmaceutically acceptable salt, trametinib (trametinib) or its pharmaceutically acceptable salt, and SHP2 inhibitor (SHP2i) (for example (3S,4S) -8-(6-Amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridine-2-yl)-3-methyl-2-oxa-8 - a pharmaceutical combination of azaspiro[4.5]dec-4-amine ("Compound A")) or a pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising the pharmaceutical combination; a commercial package comprising the pharmaceutical combination; and in Methods of using such combinations and compositions in the treatment or prevention of disorders in which inhibition of the MAPK pathway is beneficial, for example in the treatment of cancer. The invention also provides such combinations for use in the treatment of such disorders or cancers, including colorectal cancer (CRC), such as BRAF gain-of-function colorectal cancer.

MAPK通路係驅動細胞增殖、分化和存活之關鍵傳訊級聯反應。此通路之失調係許多腫瘤形成實例之基礎。MAPK通路之異常傳訊或不當活化已顯示於多種腫瘤類型中，並且可以藉由幾種不同的機制發生，包括RAS和BRAF中之活化型突變。MAPK通路頻繁在人類癌症中發生突變，其中 KRAS突變和 BRAF突變係最常見的（大約30%）。已在所有癌症之9%-30%中檢測到 RAS突變，特別是功能獲得型突變，其中 KRAS突變之患病率最高（86%）。 The MAPK pathway is a key signaling cascade that drives cell proliferation, differentiation and survival. Dysregulation of this pathway underlies many instances of tumorigenesis. Aberrant signaling or inappropriate activation of the MAPK pathway has been shown in a variety of tumor types and can occur through several different mechanisms, including activating mutations in RAS and BRAF. The MAPK pathway is frequently mutated in human cancers, with KRAS mutations and BRAF mutations being the most common (approximately 30%). RAS mutations, especially gain-of-function mutations, have been detected in 9%-30% of all cancers, with KRAS mutations having the highest prevalence (86%).

細胞外訊息調節激酶（ERK）係一類涉及傳送細胞外訊息到細胞和亞細胞器中的傳訊激酶。ERK1和ERK2參與調節大範圍的活動，並且已知ERK1/2級聯之失調會導致多種疾病，包括神經退化疾病、發育病、糖尿病和癌症。ERK1/2在癌症中之作用係被特別關注的，因為在ERK1/2傳訊級聯反應中其上游的活化型突變被認為是所有癌症中半數以上癌症發生的原因。此外，過度的ERK1/2活性也在癌症中被發現，其中上游組件沒有突變，這表明ERK1/2傳訊即使是在沒有突變活化的癌症中也在致癌作用中起作用。ERK通路也顯示出控制腫瘤細胞之遷移和侵襲，並且因此可能與轉移有關。Extracellular signal-regulated kinases (ERKs) are a class of signaling kinases involved in the transmission of extracellular messages into cells and subcellular organelles. ERK1 and ERK2 are involved in regulating a wide range of activities, and dysregulation of the ERK1/2 cascade is known to contribute to a variety of diseases, including neurodegenerative, developmental, diabetes and cancer. The role of ERK1/2 in cancer is of particular interest because activating mutations upstream of it in the ERK1/2 signaling cascade are thought to be responsible for more than half of all cancers. Furthermore, excessive ERK1/2 activity was also found in cancers in which upstream components were not mutated, suggesting that ERK1/2 signaling plays a role in oncogenicity even in cancers without mutational activation. The ERK pathway has also been shown to control the migration and invasion of tumor cells, and thus may be involved in metastasis.

患有某些癌症的患者之預後仍然差。對治療之抗性經常發生，並且不是所有患者都對可用治療有響應。例如，患有BRAF突變的晚期結腸直腸癌患者之中位數存活少於12個月。因此，重要的是為患有癌症的患者開發新的療法以達到更好的臨床結果。還需要具有更好的耐受性和/或提供持久的抗腫瘤響應之治療選擇。The prognosis of patients with certain cancers remains poor. Resistance to treatment occurs frequently, and not all patients respond to available treatments. For example, the median survival of patients with advanced colorectal cancer with BRAF mutations is less than 12 months. Therefore, it is important to develop new therapies for patients with cancer to achieve better clinical outcomes. There is also a need for treatment options that are better tolerated and/or provide durable anti-tumor responses.

本發明之三重組合提供了RAF抑制劑、MEK抑制劑和SHP2抑制劑。在一方面，該三重組合：達拉菲尼；曲美替尼；和SHP2抑制劑，例如(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）；可以用作用於治療由MAPK通路之異常活性引起的疾病或障礙之療法，該等疾病或障礙包括但不限於乳癌、膽管癌、唾液腺癌、結腸直腸癌、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。達拉菲尼、曲美替尼和化合物A之三重組合特別是用於治療BRAF功能獲得型或BRAFV600E突變型結腸直腸癌（CRC），包括晚期或轉移性結腸直腸癌。The triple combination of the present invention provides a RAF inhibitor, a MEK inhibitor and a SHP2 inhibitor. In one aspect, the triple combination: dabrafenib; trametinib; and a SHP2 inhibitor, such as (3S,4S)-8-(6-amino-5-((2-amino-3-chloro Pyridin-4-yl)thio)pyridine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (compound A); can be used as Therapies for the treatment of diseases or disorders resulting from aberrant activity of the MAPK pathway including, but not limited to, breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer. The triple combination of dabrafenib, trametinib and compound A is particularly useful for the treatment of BRAF gain-of-function or BRAFV600E mutant colorectal cancer (CRC), including advanced or metastatic colorectal cancer.

本發明提供包含以下之藥物組合： (a) N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）或其藥學上可接受的鹽，具有以下結構：

； (b) N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺（曲美替尼）或其藥學上可接受的鹽或溶劑合物，具有以下結構：

；和 (c) SHP2抑制劑，例如(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）或其藥學上可接受的鹽，具有以下結構：

。 The present invention provides a pharmaceutical combination comprising: (a) N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiary butyl)thiazol-4-yl)-2-fluoro Phenyl)-2,6-difluorobenzenesulfonamide (dabrafenib) or a pharmaceutically acceptable salt thereof, having the following structure:

(b) N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-three sides Oxy-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (trametinib) or its pharmaceutically acceptable Salt or solvate, having the following structure:

and (c) SHP2 inhibitors, such as (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridine-2 -yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (compound A) or a pharmaceutically acceptable salt thereof, having the following structure:

.

達拉菲尼或其藥學上可接受的鹽、曲美替尼或其藥學上可接受的鹽、和SHP2抑制劑（例如化合物A）或其藥學上可接受的鹽之藥物組合在本文中也稱為「本發明之組合」。Pharmaceutical combinations of dabrafenib or a pharmaceutically acceptable salt thereof, trametinib or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor (such as Compound A) or a pharmaceutically acceptable salt thereof are also herein It is called "combination of the present invention".

提供了本發明之組合，用於在癌症之治療中使用，例如，用於在選自以下的癌症中使用：乳癌、膽管癌、唾液腺癌、結腸直腸癌、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。 Combinations of the invention are provided for use in the treatment of cancer, for example, for use in a cancer selected from the group consisting of breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.

提供了達拉菲尼或其藥學上可接受的鹽、曲美替尼或其藥學上可接受的鹽、和SHP2抑制劑（例如化合物A）或其藥學上可接受的鹽之藥物組合，例如，用於在選自以下的癌症中使用：乳癌、膽管癌、唾液腺癌、結腸直腸癌、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。A pharmaceutical combination of dabrafenib or a pharmaceutically acceptable salt thereof, trametinib or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor (such as Compound A) or a pharmaceutically acceptable salt thereof is provided, such as , for use in a cancer selected from the group consisting of breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.

還提供了達拉菲尼或其藥學上可接受的鹽、曲美替尼或其藥學上可接受的鹽、和SHP2抑制劑（例如化合物A）或其藥學上可接受的鹽的組合，用於在BRAF功能獲得型或BRAFV600E、V600D或V600K突變型結腸直腸癌（其包括晚期或轉移性結腸直腸癌）之治療中使用。 Also provided is a combination of dabrafenib or a pharmaceutically acceptable salt thereof, trametinib or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor (such as Compound A) or a pharmaceutically acceptable salt thereof, for use in For use in the treatment of BRAF gain-of-function or BRAF V600E, V600D, or V600K mutant colorectal cancer, including advanced or metastatic colorectal cancer.

本文還提供了本發明之組合，用於在BRAF功能獲得型或BRAFV600E突變型結腸直腸癌（其包括晚期或轉移性結腸直腸癌）之治療中使用。 Also provided herein are combinations of the invention for use in the treatment of BRAF gain-of-function or BRAFV600E mutant colorectal cancer, including advanced or metastatic colorectal cancer.

在本發明之組合之另一個實施方式中，達拉菲尼或其藥學上可接受的鹽、曲美替尼或其藥學上可接受的鹽、和SHP2抑制劑（例如化合物A）或其藥學上可接受的鹽係在同一配製物中。In another embodiment of the combination of the present invention, dabrafenib or a pharmaceutically acceptable salt thereof, trametinib or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor (such as compound A) or a pharmaceutically acceptable salt thereof The above acceptable salts are in the same formulation.

在本發明之組合之另一個實施方式中，達拉菲尼或其藥學上可接受的鹽、曲美替尼或其藥學上可接受的鹽、和SHP2抑制劑（例如化合物A）或其藥學上可接受的鹽係在分開的配製物中。 In another embodiment of the combination of the present invention, dabrafenib or a pharmaceutically acceptable salt thereof, trametinib or a pharmaceutically acceptable salt thereof, and a SHP2 inhibitor (such as compound A) or a pharmaceutically acceptable salt thereof The above acceptable salts are in separate formulations.

在另一個實施方式中，本發明之組合用於同時或依序（以任何順序）投與。In another embodiment, the combinations of the invention are for simultaneous or sequential (in any order) administration.

在另一個實施方式中，本發明提供了用於治療有需要的受試者中的癌症之方法，該方法包括向該受試者投與治療有效量的本發明之組合。In another embodiment, the present invention provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a combination of the present invention.

在該方法之另一個實施方式中，該癌症選自乳癌、膽管癌、唾液腺癌、結腸直腸癌、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。 In another embodiment of the method, the cancer is selected from breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer.

在另一個實施方式中，本發明提供了本發明之組合，用於在製造治療選自以下的癌症之藥物中使用：乳癌、膽管癌、唾液腺癌、結腸直腸癌、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。 In another embodiment, the present invention provides a combination of the present invention for use in the manufacture of a medicament for the treatment of a cancer selected from the group consisting of breast cancer, cholangiocarcinoma, salivary gland cancer, colorectal cancer, melanoma, non-small cell lung cancer , ovarian and thyroid cancers.

在另一個實施方式中，提供了包含本發明之組合的藥物組成物或商業包裝（例如，成套套組（kit-of-parts））。 In another embodiment, there is provided a pharmaceutical composition or commercial pack (eg, a kit-of-parts) comprising the combination of the invention.

在另一個實施方式中，藥物組成物進一步包含一或多種藥學上可接受的賦形劑。In another embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

除非另外指示，否則上文和下文中使用的通用術語較佳的是在本揭露之上下文中具有以下含義，其中無論在什麼情況下使用的更通用的術語可以彼此獨立地由更具體的定義代替或保留，從而定義本發明之更詳細實施方式：Unless otherwise indicated, general terms used above and below preferably have the following meanings in the context of the present disclosure, wherein wherever a more general term is used may be replaced independently of one another by a more specific definition or reserved, thereby defining a more detailed embodiment of the present invention:

「達拉菲尼」係N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺，能夠抑制BRAF（V600E）、BRAF（V600K）和BRAF（V600G）突變的V600突變型BRAF之選擇性抑制劑（也稱為N-{3-[5-(2-胺基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6-二氟苯磺醯胺；Tafinlar ^®；和N-{3[5-(2-胺基-4-嘧啶基)-2-(1,1-二甲基乙基)-1,3-噻唑-4-基]-2-氟苯基}-2,6二氟苯磺醯胺，甲磺酸鹽）。 "Dabrafenib" is N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiary butyl)thiazol-4-yl)-2-fluorophenyl)-2 ,6-Difluorobenzenesulfonamide, a selective inhibitor of V600 mutant BRAF capable of inhibiting BRAF(V600E), BRAF(V600K) and BRAF(V600G) mutations (also known as N-{3-[5-( 2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene Sulfonamide; Tafinlar ^® ; and N-{3[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl ]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide, methanesulfonate).

「西妥昔單抗」係上皮生長因子受體（EGFR）抑制劑，用於治療轉移性結腸直腸癌、轉移性非小細胞肺癌和頭頸癌。西妥昔單抗係靶向上皮生長因子受體之IgG1單株抗體，已批准與伊立替康組合使用或作為治療轉移性CRC之單一療法。西妥昔單抗係藉由靜脈內輸注投與的嵌合（小鼠/人）單株抗體。"Cetuximab" is an epithelial growth factor receptor (EGFR) inhibitor for the treatment of metastatic colorectal cancer, metastatic non-small cell lung cancer, and head and neck cancer. Cetuximab is an IgG1 monoclonal antibody targeting the epithelial growth factor receptor and has been approved for use in combination with irinotecan or as a monotherapy for the treatment of metastatic CRC. Cetuximab is a chimeric (mouse/human) monoclonal antibody administered by intravenous infusion.

「曲美替尼」係N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺，MEK抑制劑（也被稱為：N-{3-[3-環丙基-5-(2-氟-4-碘-苯基胺基)6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫-2H-吡啶并[4,3-d]嘧啶-1-基]苯基}乙醯胺二甲基亞碸溶劑合物；Mekinist ^®）。 "Trametinib" is N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7 -trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide, MEK inhibitor (also known as: N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodo-phenylamino)6,8-dimethyl-2,4,7-trioxy-3,4 , 6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate; Mekinist ^® ).

「化合物A」係SHP2之抑制劑。化合物A係(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺。化合物A之特別較佳的鹽係琥珀酸鹽。"Compound A" is an inhibitor of SHP2. Compound A is (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrro-2-yl)-3-methanol Base-2-oxa-8-azaspiro[4.5]dec-4-amine. A particularly preferred salt of Compound A is the succinate.

SHP2抑制劑包括化合物A（上文）和以下中描述的化合物：WO 2015/107493、WO 2015/107494、WO 2015/107495、WO 2016/203406、WO 2016/203404、WO 2016/203405、WO 2017/216706、WO 2017/156397、WO 2020/063760、WO 2018/172984、WO 2017/211303、WO 21/061706、WO 2019/183367、WO 2019/183364、WO 2019/165073、WO 2019/067843、WO 2018/218133、WO 2018/081091、WO 2018/057884、WO 2020/247643、WO 2020/076723、WO 2019/199792、WO 2019/118909、WO 2019/075265、WO 2019/051084、WO 2018/136265、WO 2018/136264、WO 2018/013597、WO 2020/033828、WO 2019/213318、WO 2019/158019、WO 2021/088945、WO 2020/081848、WO 21/018287、WO 2020/094018、WO 2021/033153、WO 2020/022323、WO 2020/177653、WO 2021/073439、WO 2020/156243、WO 2020/156242、WO 2020/249079、WO 2020/033286、WO 2021/061515、WO 2019/182960、WO 2020/094104、WO 2020/210384、WO 2020/181283、WO 2021/043077、WO 2021/028362、WO 2020/259679、WO 2020/108590以及WO 2019/051469。SHP2 inhibitors include Compound A (above) and compounds described in WO 2015/107493, WO 2015/107494, WO 2015/107495, WO 2016/203406, WO 2016/203404, WO 2016/203405, WO 2017/ 216706, WO 2017/156397, WO 2020/063760, WO 2018/172984, WO 2017/211303, WO 21/061706, WO 2019/183367, WO 2019/183364, WO 2019/165073, WO 20 19/067843, WO 2018/ 218133, WO 2018/081091, WO 2018/057884, WO 2020/247643, WO 2020/076723, WO 2019/199792, WO 2019/118909, WO 2019/075265, WO 2019/051084, WO 2018/136265, WO 2018/ 136264, WO 2018/013597, WO 2020/033828, WO 2019/213318, WO 2019/158019, WO 2021/088945, WO 2020/081848, WO 21/018287, WO 2020/094018, WO 20 21/033153, WO 2020/ 022323, WO 2020/177653, WO 2021/073439, WO 2020/156243, WO 2020/156242, WO 2020/249079, WO 2020/033286, WO 2021/061515, WO 2019/182960, WO 2020/094104, WO 2020/ 210384, WO 2020/181283, WO 2021/043077, WO 2021/028362, WO 2020/259679, WO 2020/108590 and WO 2019/051469.

如本文所用，術語「受試者」或「患者」旨在包括易於患有癌症或任何障礙（直接或間接涉及癌症）或受其折磨的動物。受試者之實例包括哺乳動物，例如人、猿類、猴、狗、乳牛、馬、豬、綿羊、山羊、貓、小鼠、兔、大鼠和轉基因非人動物。在一個實施方式中，受試者係人，例如患有癌症、具有患癌症的風險或可能易於患有癌症的人。As used herein, the term "subject" or "patient" is intended to include an animal susceptible to or afflicted with cancer or any disorder involving cancer, directly or indirectly. Examples of subjects include mammals such as humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In one embodiment, the subject is a human, eg, a human who has, is at risk of, or may be predisposed to cancer.

如本文所用，術語「治療（treating或treatment）」包括解除、減輕或緩解受試者之至少一種症狀或者實現疾病進展延遲之治療。例如，治療可為減弱障礙之一種或幾種症狀或者完全根除障礙（如癌症）。在本揭露之含義範圍內，術語「治療」還表示阻止、延遲發作（即在疾病之臨床表現之前的時間段）和/或降低疾病發展或疾病惡化之風險。As used herein, the term "treating" or "treatment" includes treatment that relieves, alleviates or alleviates at least one symptom in a subject or achieves a delay in disease progression. For example, treatment may reduce one or several symptoms of the disorder or completely eradicate the disorder (eg, cancer). Within the meaning of this disclosure, the term "treat" also means arresting, delaying the onset (ie, the period of time preceding the clinical manifestation of a disease) and/or reducing the risk of disease development or disease progression.

除非另外指明，否則術語「包含」和「包括」在本文中以其開放式和非限制性的含義使用。Unless otherwise indicated, the terms "comprising" and "including" are used herein in their open-ended and non-limiting sense.

除非本文另外指示或與上下文明顯矛盾，否則在描述本發明之上下文中（尤其是下文申請專利範圍之上下文中），術語「一個/種（a和an）」和「該/該等（the）」以及相似的指示語應解釋為包括單數和複數兩者。當將複數形式用於化合物、鹽等時，這也意指單一化合物、鹽等。Unless otherwise indicated herein or clearly contradicted by the context, the terms "a and an" and "the ” and similar designations shall be construed to include both the singular and the plural. When the plural form is used for a compound, salt, etc., this also means a single compound, salt, etc.

「組合」或「與……組合」或「與……共同投與」等並不旨在暗示必須物理混合或同時投與療法或治療劑和/或配製該等治療劑用於一起遞送，儘管該等遞送方法在本文所述之範圍內。該等組合中之治療劑可以與一或多種其他另外的療法或治療劑同時、在其之前或之後投與。該等治療劑或治療方案能以任何順序投與。通常，每種藥劑將以針對該藥劑確定的劑量和/或日程表投與。還應理解，該組合中使用的另外的治療劑可以按單一組成物一起投與或按不同組成物單獨投與。通常，預期組合中使用的另外的治療劑之以不超過它們單獨使用時的水平使用。在一些實施方式中，組合中使用的水平將低於單一藥劑療法中使用的水平。"Combined" or "combined with" or "co-administered with" and the like are not intended to imply that the therapies or therapeutic agents must be physically mixed or administered simultaneously and/or formulated for delivery together, although Such delivery methods are within the scope of those described herein. The therapeutic agents in such combinations can be administered simultaneously with, before, or after, one or more other additional therapies or therapeutic agents. The therapeutic agents or treatment regimens can be administered in any order. Typically, each agent will be administered at a dose and/or schedule established for that agent. It is also understood that the additional therapeutic agents used in the combination may be administered together in a single composition or separately in different compositions. In general, it is contemplated that the additional therapeutic agents used in combination will be used at levels no greater than they would be used alone. In some embodiments, the levels used in the combination will be lower than the levels used in single agent therapy.

當將本文中之劑量（dosage或dose）描述為「約」指定量時，實際劑量（dosage或dose）可以從所述量變化高達10%，例如5%：這種「約」之使用承認，給定劑量或劑型中之精確量可能由於多種原因而與預期量略有不同，但不會實質上影響所投與化合物之體內作用。技術者將理解，當本文引用治療化合物之劑量（dosage或dose）時，該量係指游離形式或非溶劑化形式的治療化合物之量。When a dosage (dosage or dose) is described herein as "about" the indicated amount, the actual dosage (dosage or dose) may vary by up to 10%, for example 5%, from the stated amount: this use of "about" recognizes that The precise amount in a given dose or dosage form may vary slightly from the expected amount for a number of reasons without materially affecting the in vivo effect of the administered compound. The skilled artisan will understand that when a dosage or dose of a therapeutic compound is referred to herein, that amount refers to the amount of the therapeutic compound in free or unsolvated form.

如本文所用，短語「治療有效量」意指包含本發明化合物的化合物、材料或組成物之量，該量對於在動物（包括人）中之至少一個細胞亞群中以適用於任何醫學治療的合理的受益/風險比產生一些所期望的治療效果係有效的。As used herein, the phrase "therapeutically effective amount" means an amount of a compound, material or composition comprising a compound of the present invention that is effective in at least one subpopulation of cells in an animal (including a human) suitable for any medical treatment. A reasonable benefit/risk ratio produces some desired therapeutic effect.

本文使用的短語「藥學上可接受的」係指在合理的醫學判斷之範圍內，適合用於與人和動物之組織接觸而不產生過度毒性、刺激、過敏反應、或其他問題或併發症，同時具有相稱的合理受益/風險比的那些化合物、材料、組成物、和/或劑型。As used herein, the phrase "pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, or other problems or complications. , those compounds, materials, compositions, and/or dosage forms that have a commensurate and reasonable benefit/risk ratio.

本發明之組合（達拉菲尼、曲美替尼和化合物A）還旨在表示化合物之未經標記的形式以及化合物之同位素標記形式。同位素標記的化合物之一或多個原子被具有選定原子質量或質量數之原子代替。可以摻入達拉菲尼、曲美替尼和化合物A的同位素之實例包括氫、碳、氮、氧、磷、氟和氯的同位素，例如，分別係 ²H、 ³H、 ¹¹C、 ¹³C、 ¹⁴C、 ¹⁵N、 ¹⁸F、 ³¹P、 ³²P、 ³⁵S、 ³⁶Cl、 ¹²³I、 ¹²⁴I、 ¹²⁵I。本發明包括同位素標記的達拉菲尼、曲美替尼和化合物A，例如其中存在放射性同位素（如 ³H和 ¹⁴C）或非放射性同位素（如 ²H和 ¹³C）。同位素標記的達拉菲尼、曲美替尼和化合物A可用於代謝研究（用 ¹⁴C）、反應動力學研究（用例如 ²H或 ³H）、檢測或成像技術，例如正電子發射斷層攝影術（PET）或單光子發射電腦斷層掃描攝影術（SPECT），包括藥物或底物組織分佈測定，或用於患者之放射性治療。特別地，用 ¹⁸F標記的達拉菲尼、曲美替尼或化合物A對於PET或SPECT研究可能是特別理想的。本發明之同位素標記的化合物通常可藉由熟悉該項技術者已知的常規技術或與在使用適當的同位素標記的試劑之所附實例中所述之那些類似的方法來製備。 The combination of the invention (dabrafenib, trametinib and compound A) is also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms of the compounds. One or more atoms of isotopically labeled compounds are replaced by atoms of a selected atomic mass or mass number. Examples of isotopes that can be incorporated into dabrafenib, trametinib, and Compound A include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I. The present invention includes isotopically labeled dabrafenib, trametinib and Compound A, eg, in which radioactive isotopes (such as ³ H and ¹⁴ C) or non-radioactive isotopes (such as ² H and ¹³ C) are present. Isotopically labeled dabrafenib, trametinib and compound A can be used in metabolic studies (with ¹⁴ C), reaction kinetics studies (with e.g. ² H or ³ H), detection or imaging techniques such as positron emission tomography PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determination, or for radiation therapy of patients. In particular, dabrafenib, trametinib or compound A labeled ^with18F may be particularly ideal for PET or SPECT studies. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagents.

此外，用較重的同位素，特別是氘（即， ²H或D）取代可以提供來源於更大的代謝穩定性（例如，體內半衰期延長或劑量需求減少或治療指數改進）的某些治療優點。應當理解，在此上下文中，氘被認為是達拉菲尼、曲美替尼或化合物A之取代基。這種較重的同位素（特別是氘）之濃度可以由同位素增濃因數來定義。如本文所用，術語「同位素增濃因數」意指同位素豐度與指定同位素之天然豐度之間的比率。如果達拉菲尼、曲美替尼或化合物A中之取代基指示氘，這種化合物具有針對每個指定的氘原子之同位素增濃因數為至少3500（在每個指定的氘原子上52.5%氘摻入）、至少4000（60%氘摻入）、至少4500（67.5%氘摻入）、至少5000（75%氘摻入）、至少5500（82.5%氘摻入）、至少6000（90%氘摻入）、至少6333.3（95%氘摻入）、至少6466.7（97%氘摻入）、至少6600（99%氘摻入）、或至少6633.3（99.5%氘摻入）。較佳的實施方式之描述 In addition, substitution with heavier isotopes, especially deuterium (ie, ² H or D), may confer certain therapeutic advantages derived from greater metabolic stability (eg, increased in vivo half-life or reduced dosage requirements or improved therapeutic index) . It should be understood that deuterium is considered a substituent for dabrafenib, trametinib or compound A in this context. The concentration of such heavier isotopes (especially deuterium) can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the abundance of an isotope and the natural abundance of a given isotope. If a substituent in dabrafenib, trametinib, or Compound A indicates deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% on each designated deuterium atom deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation) deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Description of the preferred embodiment

達拉菲尼係具有RAF抑制活性之口服生物可利用的小分子。曲美替尼係具有MEK抑制活性之口服生物可利用的小分子。化合物A係具有SHP2抑制活性之口服生物可利用的小分子。Dabrafenib is an orally bioavailable small molecule with RAF inhibitory activity. Trametinib is an orally bioavailable small molecule with MEK inhibitory activity. Compound A is an orally bioavailable small molecule with SHP2 inhibitory activity.

在一個實施方式中，關於本發明之藥物組合係包含以下之藥物組合：N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）、或其藥學上可接受的鹽；N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺（曲美替尼）、或其藥學上可接受的鹽；和(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）、或其藥學上可接受的鹽。In one embodiment, the pharmaceutical combination of the present invention comprises the following pharmaceutical combination: N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiary butyl)thiazole-4 -yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib), or a pharmaceutically acceptable salt thereof; N-(3-(3-cyclopropyl-5 -((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (trametinib), or a pharmaceutically acceptable salt thereof; and (3S,4S)-8-(6-amino -5-((2-amino-3-chloropyridin-4-yl)thio)pyridine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane -4-amine (Compound A), or a pharmaceutically acceptable salt thereof.

在另一個實施方式中，將N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）或其藥學上可接受的鹽、N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺（曲美替尼）或其藥學上可接受的鹽、和(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）或其藥學上可接受的鹽分開地、同時地或以任何順序依序地投與。In another embodiment, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiary butyl)thiazol-4-yl)-2-fluorophenyl)- 2,6-Difluorobenzenesulfonamide (Dabrafenib) or its pharmaceutically acceptable salt, N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl )Amino)-6,8-Dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1(2H)- base) phenyl) acetamide (trametinib) or a pharmaceutically acceptable salt thereof, and (3S,4S)-8-(6-amino-5-((2-amino-3-chloro Pyridin-4-yl)thio)pyridin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (Compound A) or its pharmaceutically acceptable Accepted salts are administered separately, simultaneously, or sequentially in any order.

在另一個實施方式中，藥物組合用於口服投與。In another embodiment, the drug combination is for oral administration.

在藥物組合之另一個實施方式中，N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）呈口服劑型。In another embodiment of the pharmaceutical combination, N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiary butyl)thiazol-4-yl)-2-fluorophenyl )-2,6-Difluorobenzenesulfonamide (dabrafenib) is available in oral dosage form.

在藥物組合之另一個實施方式中，N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺（曲美替尼）呈口服劑型。In another embodiment of the pharmaceutical combination, N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2, 4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (trametinib) in the form of Oral dosage form.

在藥物組合之另一個實施方式中，(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）呈口服劑型。In another embodiment of the drug combination, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrrolidin-2 -yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (compound A) in oral dosage form.

在另一個實施方式中係藥物組成物或商業包裝，該藥物組成物或商業包裝包含（上述實施方式中任一項所述之）藥物組合，和至少一種藥學上可接受的載劑。In another embodiment, it is a pharmaceutical composition or a commercial package, the pharmaceutical composition or commercial package comprising (as described in any one of the above embodiments) a pharmaceutical combination, and at least one pharmaceutically acceptable carrier.

在另一個實施方式中係藥物組合（如在上述實施方式中任一項所述）或藥物組成物或商業包裝（如在上述實施方式中所述），用於在癌症之治療中使用。In another embodiment is a pharmaceutical combination (as described in any of the above embodiments) or a pharmaceutical composition or commercial package (as described in any of the above embodiments) for use in the treatment of cancer.

在另一個實施方式中，該癌症選自乳癌、膽管癌、結腸直腸癌（CRC）、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。In another embodiment, the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer (CRC), melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer.

在另一個實施方式中，該癌症係晚期或轉移性結腸直腸癌。In another embodiment, the cancer is advanced or metastatic colorectal cancer.

在另一個實施方式中，該癌症係BRAF功能獲得型CRC或BRAF V600E、V600D或V600K CRC。In another embodiment, the cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.

在另一個實施方式中係根據上述實施方式中任一項所述之藥物組合或根據上述實施方式所述之藥物組成物或商業包裝，用於製造治療癌症之藥物之用途。In another embodiment, the pharmaceutical combination according to any one of the above embodiments or the pharmaceutical composition or commercial packaging according to the above embodiments is used for the manufacture of a drug for treating cancer.

在另一個實施方式中，該癌症選自乳癌、膽管癌、結腸直腸癌、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌，視需要地其中該癌症係晚期或轉移性結腸直腸癌，視需要地其中該癌症係BRAF功能獲得型CRC或BRAF V600E、V600D或V600K CRC。In another embodiment, the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer, optionally wherein the cancer is advanced or metastatic colorectal cancer, depending on Desirably wherein the cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.

在另一個實施方式中係治療選自乳癌、膽管癌、結腸直腸癌、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌的癌症之方法，該方法包括向有需要的患者投與上述實施方式中任一項所述之藥物組合或商業包裝或根據上述實施方式所述之藥物組成物。In another embodiment is a method of treating a cancer selected from the group consisting of breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer, the method comprising administering the above-described embodiment to a patient in need thereof Any one of the pharmaceutical combination or commercial package or the pharmaceutical composition according to the above-mentioned embodiments.

在另一個實施方式中，該結腸直腸癌係晚期或轉移性結腸直腸癌。In another embodiment, the colorectal cancer is advanced or metastatic colorectal cancer.

在另一個實施方式中，該結腸直腸癌係BRAF功能獲得型CRC或BRAF V600E、V600D或V600K CRC。In another embodiment, the colorectal cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.

在另一個實施方式中，以約從約1至約150 mg/天（例如，1、2、5、10、50、100或150 mg/天）的劑量口服投與N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）。In another embodiment, N-(3-(5 -(2-aminopyrimidin-4-yl)-2-(tertiary butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib ).

在另一個實施方式中，以約0.5635、1.127或2.254 mg/天的劑量每天口服投與N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺（曲美替尼）二甲基亞碸。因此，曲美替尼可以從約0.5至約2 mg/天的劑量，或者以選自每天約0.5、1和2 mg的劑量在本發明之任何方法或用途中投與。In another embodiment, N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amine) is orally administered daily at a dose of about 0.5635, 1.127, or 2.254 mg/day base)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl) Phenyl) Acetamide (Trametinib) Dimethyl Oxide. Accordingly, trametinib may be administered in any method or use of the invention at a dose of from about 0.5 to about 2 mg/day, or at a dose selected from about 0.5, 1 and 2 mg per day.

在另一個實施方式中，將(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）以從約1.5 mg/天、或3 mg/天、或6 mg/天、或10 mg/天、或20 mg/天、或30 mg/天、或40 mg/天、或50 mg/天、或60 mg/天或70 mg/天、或80 mg/天、或90 mg/天至約100 mg/天的劑量口服投與。In another embodiment, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridine-2-yl )-3-Methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (compound A) from about 1.5 mg/day, or 3 mg/day, or 6 mg/day, or 10 mg/day, or 20 mg/day, or 30 mg/day, or 40 mg/day, or 50 mg/day, or 60 mg/day, or 70 mg/day, or 80 mg/day, or 90 mg/day Doses of up to about 100 mg/day are administered orally.

在另一個實施方式中，將(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）口服投與，其中每日劑量（BID或QD）按用藥2週、隨後停藥1週的21天週期進行。In another embodiment, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridine-2-yl )-3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (compound A) administered orally with daily dose (BID or QD) for 2 weeks followed by drug withdrawal 1-week cycle of 21 days.

在另一個實施方式中，將(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）口服投與，其中每日劑量（BID或QD）按用藥2週、隨後停藥1週的14天週期進行。藥理學及效用 In another embodiment, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridine-2-yl )-3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (compound A) administered orally with daily dose (BID or QD) for 2 weeks followed by drug withdrawal 1 week of 14-day cycle. Pharmacology and efficacy

RAS/RAF/MEK/ERK或促***原活化蛋白激酶（MAPK）通路係關鍵的傳訊級聯反應，其整合上游細胞訊息（例如來自生長因子受體酪胺酸激酶之訊息）以協調細胞增殖、分化和存活。MAPK傳訊通路在人類癌症中常常失調，最常見的是藉由RAS基因家族成員之突變。該等突變促進GTP結合狀態，導致RAS活性，進而導致RAF、MEK和ERK蛋白活化。在多種癌症類型（包括結腸直腸癌、肺癌和胰臟癌）中發現了RAS突變。The RAS/RAF/MEK/ERK or mitogen-activated protein kinase (MAPK) pathway is a key signaling cascade that integrates upstream cellular messages, such as those from growth factor receptor tyrosine kinases, to coordinate cell proliferation, differentiation and survival. The MAPK signaling pathway is frequently dysregulated in human cancers, most commonly through mutations in RAS gene family members. These mutations promote the GTP-bound state, leading to RAS activity, which in turn leads to the activation of RAF, MEK, and ERK proteins. RAS mutations are found in several cancer types, including colorectal, lung and pancreatic cancers.

RAF（快速加速纖維肉瘤）係作為反轉錄病毒致癌基因發現的絲胺酸-蘇胺酸蛋白激酶。RAF蛋白家族（ARAF、BRAF、CRAF）在活化的RAS下游發出訊息。活化的與GTP結合的RAS將細胞質失活的RAF單體募集到質膜，在那裡RAF與GTP-RAS結合，從而促進RAF之同源二聚化和異源二聚化。RAF之二聚化有助於構象變化，從而導致催化活化的RAF。活化的RAF二聚物磷酸化並活化MEK1/2（也稱為促***原活化蛋白激酶）蛋白質，其隨後磷酸化並活化細胞外訊息調節激酶（ERK1/2）。ERK使多種底物（包括多個轉錄因子）磷酸化，從而調節數種關鍵的細胞活性（包括增殖、代謝、遷移、和存活）。ERK1/2在癌症中之作用係被特別關注的，因為在ERK1/2傳訊級聯反應中其上游的活化型突變被認為是所有癌症中半數以上癌症發生的原因。RAF (rapidly accelerated fibrosarcoma) is a serine-threonine protein kinase discovered as a retroviral oncogene. The RAF family of proteins (ARAF, BRAF, CRAF) signal downstream of activated RAS. Activated GTP-bound RAS recruits cytoplasmically inactive RAF monomers to the plasma membrane, where RAF associates with GTP-RAS, thereby promoting RAF homodimerization and heterodimerization. Dimerization of RAF contributes to a conformational change resulting in catalytically active RAF. Activated RAF dimers phosphorylate and activate MEK1/2 (also known as mitogen-activated protein kinase) proteins, which in turn phosphorylate and activate extracellular signal-regulated kinase (ERK1/2). ERK phosphorylates a variety of substrates, including multiple transcription factors, thereby regulating several key cellular activities including proliferation, metabolism, migration, and survival. The role of ERK1/2 in cancer is of particular interest because activating mutations upstream of it in the ERK1/2 signaling cascade are thought to be responsible for more than half of all cancers.

MAPK通路中任何步驟的活化失調都會促使腫瘤形成。在大約7%的癌症中可以發現活化型BRAF突變，其中V600E占BRAF中觀察到的突變之90%以上。V600E突變編碼纈胺酸到麩胺酸之取代，從而暴露出BRAF之活性位點，從而使其能夠獨立於RAS地作為單體或二聚物進行組成型活化。活性的RAF抑制劑（例如維莫非尼、達拉菲尼和康奈非尼）已在BRAF V600E轉移性黑色素瘤中顯示出顯著活性，總體響應率（ORR）為50%-70%。在V600E黑色素瘤中，該等抑制劑之成功源自結合並抑制RAF之突變單體形式之能力，RAF係癌細胞之致癌驅動因子。然而，在表現野生型BRAF之癌細胞中，或在V600E驅動的癌症患者之正常細胞中，抑制劑（例如維莫非尼）反常活化RAF傳訊。在BRAF V600E依賴性黑色素瘤細胞死亡而含有野生型BRAF之正常表皮細胞過度增殖的患者中，單體RAF抑制劑存在時MAPK通路傳訊之複雜性凸顯出來。RAF在野生型細胞中之這種反常活化係由於抑制劑與RAF二聚物之一個單元體結合而引起的。這導致構象變化，其阻止抑制劑結合至第二單元體，並且隨後發生二聚物之第二RAF單元體之反式活化。用RAF和MEK指導的組合療法抑制MAPK通路之順序節點可減弱正常細胞中之RAF二聚物傳訊，從而改善轉移性BRAF V600黑色素瘤之安全性和臨床活性。Dysregulated activation of any step in the MAPK pathway contributes to tumor formation. Activating BRAF mutations can be found in approximately 7% of cancers, with V600E accounting for more than 90% of mutations observed in BRAF. The V600E mutation encodes a valine to glutamic acid substitution that exposes the active site of BRAF, allowing its constitutive activation as a monomer or dimer independent of RAS. Active RAF inhibitors such as vemurafenib, dabrafenib, and cannefenib have shown significant activity in BRAF V600E metastatic melanoma, with overall response rates (ORR) of 50%-70%. In V600E melanoma, the success of these inhibitors stems from the ability to bind and inhibit the mutant monomeric form of RAF, an oncogenic driver of cancer cells. However, in cancer cells expressing wild-type BRAF, or in normal cells of V600E-driven cancer patients, inhibitors such as vemurafenib paradoxically activate RAF signaling. The complexity of MAPK pathway signaling in the presence of monomeric RAF inhibitors was highlighted in patients with BRAF V600E-dependent melanoma cell death and hyperproliferation of normal epidermal cells harboring wild-type BRAF. This paradoxical activation of RAF in wild-type cells is due to the binding of the inhibitor to one unit of the RAF dimer. This results in a conformational change that prevents binding of the inhibitor to the second monomer, and subsequent transactivation of the dimer's second RAF monomer. Inhibition of sequential nodes of the MAPK pathway with RAF- and MEK-directed combination therapy attenuates RAF dimer signaling in normal cells, thereby improving safety and clinical activity in metastatic BRAF V600 melanoma.

在BRAF V600E結腸直腸癌（CRC）中，單一藥劑RAF抑制劑或組合RAF/MEK抑制顯示出最小的活性；與黑色素瘤中觀察到的活性相比，臨床受益有限。對RAF抑制劑和MEK抑制劑之內源性和後天性抗性在MAPK通路之多個水平上發展。繞過BRAF抑制的傳訊反饋和替代通路之複雜性係在CRC中靶向活化BRAF的挑戰之核心。在生理條件下，藉由突變型BRAF活化的MAPK傳訊導致藉由活化的RAS產生的訊息之ERK依賴性負反饋。之所以表現出對RAF抑制之內源性抗性，係因為藥物例如維莫非尼或達拉菲尼有效抑制了藉由MEK向ERK的BRAF V600E傳訊；然而，這導致了將ERK依賴性負反饋釋放到RAS傳訊中。因此，上游訊息能夠活化RAS，從而導致BRAF V600E和野生型同源二聚物和異源二聚物之誘導。因為藥劑例如達拉菲尼和維莫非尼會抑制BRAF依賴性CRC細胞中V600E活化的單體，而不影響RAS刺激的RAF二聚物傳訊，導致ERK之再活化程度高於BRAF V600E黑色素瘤中見到的，從而限制了在CRC中療法之有效性。In BRAF V600E colorectal cancer (CRC), single-agent RAF inhibitors or combined RAF/MEK inhibition showed minimal activity; clinical benefit was limited compared to activity observed in melanoma. Intrinsic and acquired resistance to RAF inhibitors and MEK inhibitors develops at multiple levels of the MAPK pathway. The complexity of signaling feedback and alternative pathways that bypass BRAF inhibition is at the heart of the challenge of targeting BRAF activation in CRC. Under physiological conditions, MAPK signaling activated by mutant BRAF results in an ERK-dependent negative feedback of messages generated by activated RAS. Intrinsic resistance to RAF inhibition is exhibited because drugs such as vemurafenib or dabrafenib effectively inhibit BRAF V600E signaling to ERK via MEK; however, this results in negative feedback of ERK dependence released into the RAS arraignment. Thus, upstream signals can activate RAS, leading to the induction of BRAF V600E and wild-type homodimers and heterodimers. Because agents such as dabrafenib and vemurafenib inhibit monomeric V600E activation in BRAF-dependent CRC cells without affecting RAS-stimulated RAF dimer signaling, resulting in greater reactivation of ERK than in BRAF V600E melanoma seen, thereby limiting the effectiveness of therapy in CRC.

在BRAF V600E CRC中受到RAF和MEK抑制的壓力下，後天性抗性迅速發展。例如，在對來自八位在MAPK抑制後經歷疾病進展的患者之九份腫瘤樣本進行的分析中，未發現導致MAPK再活化之基因改變。該等包括在 KRAS或 NRAS中之活化型突變、野生型（WT） NRAS或 KRAS或突變型BRAF V600E之擴增、和在 BRAFV600E中之基因內缺失。還報導了後天性遺傳改變，導致面對MAPK抑制劑之ERK傳訊再活化。後天性抗性也可能藉由腫瘤微環境中之互補傳訊產生。 Acquired resistance develops rapidly under the pressure of RAF and MEK inhibition in BRAF V600E CRC. For example, in an analysis of nine tumor samples from eight patients who experienced disease progression after MAPK inhibition, no genetic alterations leading to MAPK reactivation were found. These include activating mutations in KRAS or NRAS , amplification of wild-type (WT) NRAS or KRAS or mutant BRAF V600E, and intragenic deletions in BRAF V600E. Acquired genetic changes have also been reported leading to reactivation of ERK signaling in the face of MAPK inhibitors. Acquired resistance may also arise through complementary signaling in the tumor microenvironment.

儘管先前針對 BRAF突變型CRC之治療方法集中於化學療法和/或靶向療法，但是免疫療法也起作用。在腫瘤形成期間，癌細胞利用免疫檢查點通路來避免被適應性免疫系統檢測到。計畫性細胞死亡蛋白1（PD-1）和計畫性死亡配體1（PD-L1）免疫檢查點之單株抗體（mAb）抑制劑已在患有各種實性瘤之患者中顯示出顯著的抗腫瘤活性。PD-1係特別重要的免疫學靶標，其抑制劑如派姆單抗和納武單抗在黑色素瘤、非小細胞肺癌（NSCLC）和其他實性瘤中表現出單一藥劑活性。 Although previous treatment approaches for BRAF -mutant CRC have focused on chemotherapy and/or targeted therapy, immunotherapy also plays a role. During tumor formation, cancer cells exploit immune checkpoint pathways to avoid detection by the adaptive immune system. Monoclonal antibody (mAb) inhibitors of the programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) immune checkpoints have been shown in patients with various solid tumors Significant antitumor activity. PD-1 is a particularly important immunological target, and its inhibitors, such as pembrolizumab and nivolumab, have shown single-agent activity in melanoma, non-small cell lung cancer (NSCLC) and other solid tumors.

然而，除了具有微衛星不穩定性之腫瘤外，CRC通常對PD-1阻斷無響應。然而，有理由使用小分子抑制劑來調節免疫響應。抑制癌細胞中MAPK通路之遺傳依賴性的相同療法會抑制免疫細胞中之傳訊級聯反應。例如，臨床前研究表明，MAPK通路抑制劑（例如BRAF和MEK抑制劑）可以藉由增加腫瘤中之腫瘤浸潤淋巴細胞來改善淋巴細胞歸巢和功能。However, CRC is generally unresponsive to PD-1 blockade, except for tumors with microsatellite instability. However, there are reasons to use small molecule inhibitors to modulate the immune response. The same therapy that inhibits the genetic dependence of the MAPK pathway in cancer cells inhibits signaling cascades in immune cells. For example, preclinical studies have shown that MAPK pathway inhibitors, such as BRAF and MEK inhibitors, can improve lymphocyte homing and function by increasing tumor-infiltrating lymphocytes in tumors.

因此，RAF和MEK抑制劑可以調節對腫瘤之免疫響應，並且將該等藥劑與檢查點阻斷組合使用可以提高「免疫冷（immune cold）」腫瘤（如CRC）對PD-1抑制之敏感性。此外，大約20%的 BRAF突變型CRC具有遺傳微衛星不穩定性（MSI-H：微衛星不穩定性高）之特徵。在MSI-H CRC中，無論BRAF之遺傳狀況如何，單一藥劑抗PD-1療法與30%-50%的響應率相關。 Therefore, RAF and MEK inhibitors can modulate the immune response to tumors, and combining these agents with checkpoint blockade can increase the sensitivity of "immune cold" tumors (such as CRC) to PD-1 inhibition . In addition, approximately 20% of BRAF- mutant CRCs are characterized by inherited microsatellite instability (MSI-H: microsatellite instability-high). In MSI-H CRC, single-agent anti-PD-1 therapy is associated with a 30%-50% response rate regardless of BRAF genetic status.

結腸直腸癌（CRC）係常見疾病，2018年全球估計有180萬新病例，死亡人數＞ 800,000（世界衛生組織, Globocan 2018）。若干在CRC起始和進展中起重要作用之關鍵基因和通路已被報導，包括WNT、RAS-MAPK、PI3K、TGF-b、TP53和DNA誤配修補通路。TCGA分析提供了受體酪胺酸激酶（RTK）傳訊通路之另外的遺傳細節，鑒定多達20%的CRC腫瘤含有上調的IGF2、ERBB2或ERBB3。此外，下游PI3K和MAPK傳訊通路也經常失調，其中＞ 40%的CRC腫瘤含有活化型PIK3CA、KRAS或BRAF基因突變（TCGA Network [TCGA網路], 2012）。大約10%-15%的CRC患者中存在編碼 BRAFV600E的基因中之活化型突變，並且突變型 BRAF導致不良預後。V600E突變發生在大約90%的 BRAF突變型CRC中，儘管也可以找到V600D或V600K突變。 Colorectal cancer (CRC) is a common disease with an estimated 1.8 million new cases and >800,000 deaths worldwide in 2018 (World Health Organization, Globocan 2018). Several key genes and pathways that play important roles in CRC initiation and progression have been reported, including WNT, RAS-MAPK, PI3K, TGF-b, TP53, and DNA mismatch repair pathway. TCGA analysis provided additional genetic details of the receptor tyrosine kinase (RTK) signaling pathway, identifying up to 20% of CRC tumors containing upregulated IGF2, ERBB2, or ERBB3. In addition, downstream PI3K and MAPK signaling pathways are also frequently dysregulated, with >40% of CRC tumors harboring activating PIK3CA, KRAS, or BRAF gene mutations (TCGA Network [TCGA Network], 2012). Activating mutations in the gene encoding BRAF V600E are present in approximately 10%-15% of CRC patients, and mutant BRAF leads to poor prognosis. V600E mutations occur in approximately 90% of BRAF- mutant CRCs, although V600D or V600K mutations can also be found.

對於 BRAF突變型CRC之有效治療選擇係有限的。與黑色素瘤（其中單一藥劑BRAF抑制劑在轉移環境中之響應率約為70%）不同，用維莫非尼之單一藥劑抑制轉移性 BRAF突變型CRC與大約5%的ORR相關（Kopetz等人, 2015）。儘管結果仍然差，但是與靶向MAPK通路的藥劑之組合療法已改善了BRAF抑制之有效性。與MEK抑制劑曲美替尼組合之達拉菲尼與12%的ORR以及3.5個月的無進展生存期（PFS）相關（Corcoran等人2015）。在抑制BRAF之有效性後，EGFR抑制劑會適度改善；與EGFR抑制劑組合之BRAF抑制劑與4%-22%的ORR以及3.2-4.2個月的PFS相關（Pan等人. 2018）。 Effective treatment options for BRAF- mutant CRC are limited. Unlike melanoma, where response rates to single-agent BRAF inhibitors in the metastatic setting are approximately 70%, single-agent inhibition of metastatic BRAF- mutant CRC with vemurafenib is associated with an ORR of approximately 5% (Kopetz et al. 2015). Although results are still poor, combination therapy with agents targeting the MAPK pathway has improved the effectiveness of BRAF inhibition. Dabrafenib in combination with the MEK inhibitor trametinib was associated with an ORR of 12% and a progression-free survival (PFS) of 3.5 months (Corcoran et al 2015). EGFR inhibitors improved modestly after inhibiting BRAF effectiveness; BRAF inhibitors in combination with EGFR inhibitors were associated with ORR of 4%-22% and PFS of 3.2-4.2 months (Pan et al. 2018).

含有Src同源-2結構域之蛋白酪胺酸磷酸酶-2（SHP2，由 PTPN11基因編碼）介導多個RTK及其下游通路之間的細胞訊息傳遞，並且為中斷致癌傳訊和抑制腫瘤生長提供重要的干預節點。TNO155係野生型SHP2之同類首個變構抑制劑。TNO155結合SHP2之非活性或「封閉」構象，從而阻止其開口進入活性構象。這就阻止了從活化的RTK到下游RAS/MAPK通路的傳訊之傳遞。 Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2, encoded by the PTPN11 gene) mediates cellular messaging between multiple RTKs and their downstream pathways, and serves as a pathway for interrupting oncogenic signaling and inhibiting tumor growth Provide important intervention nodes. TNO155 is the first-of-its-kind allosteric inhibitor of wild-type SHP2. TNO155 binds the inactive or "closed" conformation of SHP2, preventing it from opening into the active conformation. This prevents the transmission of signaling from activated RTKs to the downstream RAS/MAPK pathway.

在BRAF V600E CRC中進行的臨床研究表明，單獨的RAF抑制劑或與MEK ± EGFR抑制劑組合的活性會受到MAPK通路抑制不足的限制，並且在患者中，即使在最初臨床受益的情況下，抗性機制也會迅速出現。導致患者腫瘤中MAPK通路再活化的後天性抗性機制主要涉及活化RAS、BRAF或MEK中的基因改變。Clinical studies in BRAF V600E CRC have shown that the activity of RAF inhibitors alone or in combination with MEK ± EGFR inhibitors is limited by insufficient inhibition of the MAPK pathway, and that in patients, even in the setting of initial clinical benefit, anti- Sexual mechanics also emerge quickly. The acquired resistance mechanisms leading to reactivation of the MAPK pathway in patient tumors mainly involve genetic alterations in activated RAS, BRAF, or MEK.

工程化為BRAF V600E細胞系的RAS、RAF或MEK抗性突變之臨床前模型支持這一概念。儘管親代BRAF V600E細胞系對BRAF、MEK、EGFR和/或ERK抑制劑之組合敏感，但引入KRAS、NRAS、MEK1或MEK2抗性突變導致工程化BRAF V600E細胞對所有抑制劑組合之敏感性降低，但含有ERK抑制劑之那些除外。此外，與BRAF和MEK抑制劑相比，藉由使用含有BRAF和ERK抑制劑之藥物組合治療，可以更有效地抑制小鼠異種移植物中先前存在的低頻合併抗性殖株之生長。Preclinical models of RAS, RAF or MEK resistance mutations engineered into BRAF V600E cell lines support this notion. Although the parental BRAF V600E cell line is sensitive to combinations of BRAF, MEK, EGFR, and/or ERK inhibitors, introduction of KRAS, NRAS, MEK1, or MEK2 resistance mutations results in reduced sensitivity of engineered BRAF V600E cells to all combinations of inhibitors , except those containing ERK inhibitors. Furthermore, the growth of pre-existing low-frequency pooled resistant colonies in mouse xenografts was more effectively inhibited by treatment with a drug combination containing BRAF and ERK inhibitors than BRAF and MEK inhibitors.

藉由組合抑制RAF、MEK和EGFR傳訊顯示出改善的結果，支持以下觀點：BRAF V600 CRC之治療需要抑制MAPK通路內之多個節點。Improved outcomes were shown by combined inhibition of RAF, MEK and EGFR signaling, supporting the notion that the treatment of BRAF V600 CRC requires inhibition of multiple nodes within the MAPK pathway.

然而，對療法之內源性和後天性抗性仍然是重要的挑戰，並且臨床結果仍然差。組合療法之作用係提供對MAPK傳訊之更強大抑制，並解決MAPK通路內外的抗性機制之複雜性。鑒於表徵 BRAF突變型CRC的訊息傳遞之適應性複雜性，需要抑制除RAF和ERK的蛋白質。舉例來說，一項針對218種 BRAF-V600E突變型CRC腫瘤之研究鑒定了以高KRAS/mTOR/AKT/4EBP1/EMT活化為特徵的腫瘤之不同子集，而細胞週期失調則以其他子集為特徵。 However, intrinsic and acquired resistance to therapy remains an important challenge, and clinical outcomes remain poor. The role of combination therapy is to provide more robust inhibition of MAPK signaling and to address the complexity of resistance mechanisms within and outside of the MAPK pathway. Given the adaptive complexity of signaling that characterizes BRAF- mutant CRC, inhibition of proteins other than RAF and ERK is required. For example, a study of 218 BRAF -V600E-mutant CRC tumors identified a distinct subset of tumors characterized by high KRAS/mTOR/AKT/4EBP1/EMT activation, while cell cycle dysregulation was associated with other subsets as a feature.

儘管有靶向療法組合已取得了進展，例如BEACON試驗中之研究（Kopetz等人2019），但在癌細胞中關閉BRAF V600致癌驅動之能力受限於1.) 無法完全抑制RAF活性（由於RAF激酶具有藉由無效抑制的二聚物發出訊息的適應能力）和2.) 不僅藉由MAPK通路內的適應機制，而且還藉由平行傳訊通路刺激正在進行的ERK活化。達拉菲尼、維莫非尼和康奈非尼有效地抑制RAF在 BRAF突變型癌細胞中之活性，其中單體V600E係致癌驅動因子。然而，該等藥物也可以藉由幾種機制導致ERK之反常活化。 Despite advances in targeted therapy combinations, such as those studied in the BEACON trial (Kopetz et al. 2019), the ability to switch off the BRAF V600 oncogenic driver in cancer cells is limited by 1.) inability to completely inhibit RAF activity (due to RAF Kinases have an adaptive ability to signal via inactively inhibited dimers) and 2.) stimulate ongoing ERK activation not only by adaptive mechanisms within the MAPK pathway, but also by parallel signaling pathways. Dabrafenib, vemurafenib and cannefenib effectively inhibit the activity of RAF in BRAF mutant cancer cells, among which monomeric V600E is an oncogenic driver. However, these drugs can also lead to paradoxical activation of ERK through several mechanisms.

RAF和MEK之組合抑制可藉由抑制通路來改善；然而，ERK傳訊之持久性係這種治療方法之限制基礎。阻斷ERK係MAPK通路之最終訊息，可以繞開自適應上游訊息，並提供改善的功效和對後天性抗性之恢復力。Combined inhibition of RAF and MEK can be improved by inhibiting the pathway; however, the persistence of ERK signaling is a limiting basis for this therapeutic approach. Blocking the final message of the ERK-MAPK pathway bypasses adaptive upstream messages and provides improved efficacy and resilience to acquired resistance.

SHP2係磷酸酶，與活化的RTK結合並在RAS/MAPK和PI3K/AKT通路之下游傳遞其傳訊。因此，SHP2之抑制會抑制RTK介導的傳訊。還已知SHP2調節PI3K、Fak、RhoA、Ca2+振盪、Ca2+/鈣調神經磷酸酶和NFAT傳訊，且SHP2在Jak/Stat傳訊之調節中也在細胞介素傳訊下游起作用。此外，SHP2在免疫檢查點分子PD-1、B和T淋巴細胞減毒劑（BTLA）和吲哚胺2,3-二氧酶（IDO）之下游發出訊息。因此，SHP2藉由調節腫瘤之遷移、侵襲、轉移或抗腫瘤免疫響應，在腫瘤形成中具有獨立於RAS/MAPK的功能。SHP2 is a phosphatase that binds to activated RTKs and transmits its signaling downstream of the RAS/MAPK and PI3K/AKT pathways. Thus, inhibition of SHP2 inhibits RTK-mediated signaling. SHP2 is also known to regulate PI3K, Fak, RhoA, Ca2+ oscillations, Ca2+/calcineurin and NFAT signaling, and SHP2 also functions downstream of interleukin signaling in the regulation of Jak/Stat signaling. In addition, SHP2 signals downstream of the immune checkpoint molecules PD-1, B and T lymphocyte attenuator (BTLA), and indoleamine 2,3-dioxygenase (IDO). Therefore, SHP2 has a function independent of RAS/MAPK in tumor formation by regulating tumor migration, invasion, metastasis or anti-tumor immune response.

添加抗RAF和MEK抑制的抗EGFR抗體之臨床研究表明，BRAF V600 CRC可適度改善結果。然而，臨床前研究表明，其他RTK通路可能會在BRAF V600 CRC的情況下促進訊息活化。SHP2在介導從EGFR以及其他RTK發出的訊息中起著核心作用，因此，當與MAPK通路之抑制劑組合使用時，SHP2具有擴大西妥昔單抗和帕尼單抗等藥物活性之潛力。因此，SHP2抑制可以提供更有效的初始MAPK通路抑制作用，並且可以更好地解決MAPK通路再活化的機制。達拉菲尼 + 曲美替尼 + 化合物A（SHP2i）之三重組合可藉由利用獨特地靶向BRAF V600驅動的癌細胞內源性和後天性抗性機制的潛力來抑制BRAF V600結腸直腸癌中之MAPK通路。Clinical studies with the addition of anti-RAF and MEK-inhibiting anti-EGFR antibodies showed modest improvement in outcome in BRAF V600 CRC. However, preclinical studies suggest that other RTK pathways may contribute to signaling activation in the setting of BRAF V600 CRC. SHP2 plays a central role in mediating messages from EGFR as well as other RTKs, so when combined with inhibitors of the MAPK pathway, SHP2 has the potential to amplify the activity of drugs such as cetuximab and panitumumab. Thus, SHP2 inhibition may provide more potent initial MAPK pathway inhibition and may better address the mechanism of MAPK pathway reactivation. The triple combination of dabrafenib + trametinib + compound A (SHP2i) inhibits BRAF V600 in colorectal cancer by exploiting the potential to uniquely target BRAF V600-driven endogenous and acquired resistance mechanisms in cancer cells The MAPK pathway in it.

南德克薩斯州加速研究治療學（Southern Texas Accelerated Research Therapeutics）（START；聖安東尼奧市（San Antonio），德克薩斯州）已經在免疫受損的小鼠中建立了一組人類CRC之人源腫瘤異種移植（PDX）模型，該等模型從形態學和基因組學兩方面概括了患者腫瘤生物學。下文的實例顯示了使用該等PDX模型，在BRAF突變型CRC中使用達拉菲尼和曲美替尼以及TNO155進行組合治療的體內功效評估。 藥物組成物 Southern Texas Accelerated Research Therapeutics (START; San Antonio, TX) has established a human CRC panel in immunocompromised mice Primary tumor xenograft (PDX) models that recapitulate patient tumor biology both morphologically and genomically. The examples below show the in vivo efficacy assessment of combination therapy with dabrafenib and trametinib and TNO155 in BRAF mutant CRC using these PDX models. drug composition

在另一個方面，本發明提供了藥學上可接受的組成物，其包含治療有效量的達拉菲尼、曲美替尼和化合物A，其與一或多種藥學上可接受的載劑（添加劑）和/或稀釋劑配製在一起。如下面詳細描述的，本發明之藥物組成物可特別配製用於固體或液體形式投與（包括適合口服投與的那些，例如浸液（水性或非水性溶液或懸浮液）、片劑（例如，針對口腔、舌下和全身吸收的那些）、大丸劑、粉劑、顆粒劑、糊劑（應用於舌））。In another aspect, the present invention provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of Dabrafenib, Trametinib and Compound A in combination with one or more pharmaceutically acceptable carriers (additives ) and/or diluents are prepared together. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form (including those suitable for oral administration, such as infusions (aqueous or non-aqueous solutions or suspensions), tablets (such as , those intended for buccal, sublingual and systemic absorption), boluses, powders, granules, pastes (applied to the tongue)).

如本文所用，短語「藥學上可接受的載劑」意指藥學上可接受的材料、組成物或媒介物，如液體或固體填充劑、稀釋劑、賦形劑、製造助劑（例如潤滑劑、滑石鎂、硬脂酸鈣或硬脂酸鋅或硬脂酸）或溶劑封裝材料，參與將主題化合物從一個器官或身體之一部分運送或運輸到另一個器官或身體之另一部分。在與配製物之其他成分相容並且對患者無害的意義上，每種載劑必須是「可接受的」。可用作藥學上可接受的載劑的材料之一些實例包括：(1) 糖類，如乳糖、葡萄糖和蔗糖；(2) 澱粉，如玉米澱粉和馬鈴薯澱粉；(3) 纖維素及其衍生物，如羧甲基纖維素鈉、乙基纖維素和乙酸纖維素；(4) 粉狀黃蓍膠；(5) 麥芽；(6) 明膠；(7) 滑石；(8) 賦形劑，如可可脂和栓劑蠟；(9) 油類，如花生油、棉籽油、紅花子油、芝麻油、橄欖油、玉米油、大豆油等；(10) 二醇類，如丙二醇；(11) 多元醇類，如甘油、山梨醇、甘露醇和聚乙二醇；(12) 酯類，如油酸乙酯和月桂酸乙酯；(13) 瓊脂；(14) 緩衝劑，如氫氧化鎂和氫氧化鋁；(15) 海藻酸；(16) 無熱原水；(17) 等滲鹽水；(18) 林格氏溶液；(19) 乙醇；(20) pH緩衝溶液；(21) 聚酯，聚碳酸酯和/或聚酸酐；以及 (22) 藥物配製物中使用的其他無毒相容物質。As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (such as a lubricating talc, magnesium talc, calcium or zinc stearate, or stearic acid) or solvent-encapsulating materials that participate in the delivery or transport of a subject compound from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives , such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, Such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, etc.; (10) glycols, such as propylene glycol; (11) polyols (12) Esters, such as ethyl oleate and ethyl laurate; (13) Agar; (14) Buffers, such as magnesium hydroxide and hydroxide Aluminum; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) pH buffer solution; (21) polyester, polycarbonate esters and/or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations.

如上文所述，本發明化合物之某些實施方式可含有鹼性官能基，例如胺基或烷基胺基，並且由此能夠與藥學上可接受的酸形成藥學上可接受的鹽。在這方面，術語「藥學上可接受的鹽」係指本發明之化合物之相對無毒的無機和有機酸加成鹽。該等鹽可以在投與媒介物或劑型製造過程中原位製備，或者藉由使純化的游離鹼形式的本發明化合物與合適的有機或無機酸分別反應，並在隨後的純化期間分離由此形成的鹽來製備。代表性鹽包括氫溴酸鹽、鹽酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、硝酸鹽、乙酸鹽、戊酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、苯甲酸鹽、乳酸鹽、磷酸鹽、甲苯磺酸鹽、檸檬酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、琥珀酸鹽、酒石酸鹽、萘酸鹽（napthylate）、甲磺酸鹽、葡庚糖酸鹽、乳糖酸鹽和月桂基磺酸鹽等。As noted above, certain embodiments of the compounds of the present invention may contain basic functional groups, such as amine or alkylamine groups, and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids. In this regard, the term "pharmaceutically acceptable salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds of the present invention. Such salts can be prepared in situ during the administration vehicle or dosage form manufacture, or by separately reacting a purified free base form of a compound of the invention with a suitable organic or inorganic acid and isolating it during subsequent purification. of salt to prepare. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, Benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, methanesulfonate salt, glucoheptonate, lactobionate and lauryl sulfonate, etc.

主題化合物之藥學上可接受的鹽包括化合物之常規的無毒鹽或季銨鹽，例如來自無毒的有機酸或無機酸。例如，此類常規無毒鹽包括衍生自無機酸的那些，該無機酸如鹽酸、氫溴酸、硫酸、胺磺酸、磷酸、硝酸等；以及從有機酸製備的鹽，該有機酸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、棕櫚酸、順丁烯二酸、羥基順丁烯二酸、苯乙酸、麩胺酸、苯甲酸、水楊酸、磺胺酸、2-乙醯氧基苯甲酸、反丁烯二酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、異硫磺酸等。Pharmaceutically acceptable salts of the subject compounds include conventional non-toxic or quaternary ammonium salts of the compounds, eg, derived from non-toxic organic or inorganic acids. Such conventional nontoxic salts include, for example, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and salts prepared from organic acids such as acetic, Propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid , salicylic acid, sulfanilic acid, 2-acetyloxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isosulfuric acid, etc.

在其他情況下，本發明之化合物可以含有一或多個酸性官能基，並且因此能夠與藥學上可接受的鹼形成藥學上可接受的鹽。在該等例子中，術語「藥學上可接受的鹽」係指本發明化合物之相對無毒的無機和有機鹼加成鹽。該等鹽也可以在投與媒介物或劑型製造過程中原位製備，或者藉由使純化的游離酸形式的化合物與合適的鹼（例如，藥學上可接受的金屬陽離子之氫氧化物、碳酸鹽或碳酸氫鹽）與氨、或與藥學上可接受的有機一級、二級或三級胺分別反應來製備。代表性的鹼或鹼土金屬鹽包括鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽和鋁鹽等。可用於形成鹼加成鹽之代表性有機胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌口井等。In other instances, the compounds of the present invention may contain one or more acidic functional groups and are therefore capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. In these instances, the term "pharmaceutically acceptable salt" refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. Such salts can also be prepared in situ during the administration vehicle or dosage form manufacture, or by reacting the purified free acid form of the compound with a suitable base (e.g., hydroxide, carbonate of a pharmaceutically acceptable metal cation). or bicarbonate) with ammonia, or with pharmaceutically acceptable organic primary, secondary or tertiary amines, respectively. Representative alkali or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperamine, and the like.

達拉菲尼之特別較佳的鹽係其甲磺酸鹽。曲美替尼之特別較佳的溶劑合物係其二甲基亞碸溶劑合物。化合物A之特別較佳的溶劑合物係其琥珀酸鹽。A particularly preferred salt of dabrafenib is its mesylate. A particularly preferred solvate of trametinib is its dimethylsulfone solvate. A particularly preferred solvate of Compound A is its succinate salt.

在組成物中還可以存在潤濕劑、乳化劑和潤滑劑，如十二烷基硫酸鈉和硬脂酸鎂，以及著色劑、釋放劑、包衣劑、甜味劑、調味劑和芳香劑、防腐劑和抗氧化劑。Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents may also be present in the composition , preservatives and antioxidants.

藥學上可接受的抗氧化劑之實例包括：(1) 水溶性抗氧化劑，如抗壞血酸、鹽酸半胱胺酸、硫酸氫鈉、偏亞硫酸氫鈉、亞硫酸鈉等；(2) 油溶性抗氧化劑，如抗壞血酸棕櫚酸酯、丁基羥基甲氧苯（BHA）、二丁基羥基甲苯（BHT）、卵磷脂、沒食子酸丙酯、α-生育酚等；和 (3) 金屬螯合劑，如檸檬酸、乙二胺四乙酸（EDTA）、山梨醇、酒石酸、磷酸等。Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as Ascorbyl palmitate, butylated hydroxymethoxybenzene (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.; and (3) metal chelating agents such as lemon acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

本發明之配製物包括適合於口服、鼻、局部（包括口腔和舌下）、直腸、***和/或腸胃外投與的那些。配製物可以方便地以單位劑型存在並且可以藉由藥學領域熟知的任何方法製備。可以與載劑材料組合以產生單一劑型的活性成分之量將根據所治療的宿主和特定的投與方式而變化。可以與載劑材料組合以產生單一劑型的活性成分之量通常為產生治療效果的化合物之量。通常，在百分之百的範圍內，量之範圍為從約0.1%至約99%的活性成分，較佳的是從約5%至約70%，最較佳的是從約10%至約30%。Formulations of the invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, in the hundred percent range, the amount will range from about 0.1% to about 99% active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30% .

在某些實施方式中，本發明之配製物包含選自由以下組成之群組的賦形劑：環糊精、纖維素、脂質體、膠束形成劑（例如膽汁酸）和聚合物載劑（例如聚酯和聚酸酐）；和本發明之化合物。在某些實施方式中，前述配製物使得本發明化合物在口服方面係生物可利用的。In certain embodiments, formulations of the invention comprise excipients selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents (e.g., bile acids), and polymeric carriers ( such as polyesters and polyanhydrides); and compounds of the present invention. In certain embodiments, the aforementioned formulations render the compounds of the invention orally bioavailable.

製備該等配製物或組成物之方法包括將本發明之化合物與載劑和視需要地一或多種輔助成分結合的步驟。通常，藉由將本發明之化合物與液體載劑或細碎固體載劑或兩者均勻且緊密地結合，並且然後如果需要，使產物成形來製備配製物。Methods of preparing such formulations or compositions include the step of bringing into association a compound of the invention with the carrier and, if desired, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

適用於口服投與的本發明之配製物可以呈膠囊、扁囊劑、丸劑、片劑、錠劑（使用調味基質，通常為蔗糖和***膠或黃蓍膠）、粉劑、顆粒劑的形式，或作為在水性或非水性液體中的溶液、懸浮液或固體分散體，或作為水包油或油包水液體乳劑，或作為酏劑或糖漿，或作為軟錠劑（使用惰性基質，例如明膠和甘油，或蔗糖和***膠），和/或作為漱口水等等，每一形式含有預定量的本發明之化合物作為活性成分。本發明之化合物還能以大丸劑、舐劑或糊劑形式投與。Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (with a flavored base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution, suspension or solid dispersion in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and/or as a mouthwash, etc., each form containing a predetermined amount of the compound of the present invention as an active ingredient. The compounds of this invention can also be administered as a bolus, sachet or paste.

在本發明用於口服投與的固體劑型（膠囊、片劑、丸劑、糖衣丸、粉劑、顆粒劑、含片（trouches）等）中，將活性成分與以下混合：一或多種藥學上可接受的載劑，如檸檬酸鈉或磷酸二鈣，和/或以下任何一種：(1) 填充劑或增量劑，如澱粉、乳糖、蔗糖、葡萄糖、甘露醇和/或矽酸；(2) 黏合劑，例如像羧甲基纖維素、藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖和/或***膠；(3) 保濕劑，如甘油；(4) 崩散劑，如瓊脂-瓊脂、碳酸鈣、馬鈴薯或樹薯澱粉、海藻酸、某些矽酸鹽和碳酸鈉；(5) 溶液阻滯劑，如石蠟；(6) 吸收促進劑，如季銨化合物和界面活性劑，如泊洛沙姆和十二烷基硫酸鈉；(7) 潤濕劑，例如像鯨蠟醇、單硬脂酸甘油酯和非離子界面活性劑；(8) 吸收劑，如高嶺土和膨潤土；(9) 潤滑劑，如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、十二烷基硫酸鈉、硬脂酸鋅、硬脂酸鈉、硬脂酸及其混合物；(10) 著色劑；和 (11) 控釋劑，如交聯普維酮或乙基纖維素。在膠囊、片劑和丸劑的情況下，藥物組成物還可以包含緩衝劑。還可以使用此類賦形劑，如乳糖（lactose或milk sugar）以及高分子量聚乙二醇等，將相似類型的固體組成物用作軟殼和硬殼明膠膠囊中的填充劑。In solid dosage forms (capsules, tablets, pills, dragees, powders, granules, trouches, etc.) for oral administration of the present invention, the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders (3) Moisturizing agents, such as glycerin; (4) Disintegrating agents, such as agar-agar, carbonic acid Calcium, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution blockers, such as paraffin; (6) absorption enhancers, such as quaternary ammonium compounds, and surfactants, such as porol Sham and sodium lauryl sulfate; (7) wetting agents such as cetyl alcohol, glyceryl monostearate and nonionic surfactants; (8) absorbents such as kaolin and bentonite; (9) Lubricants such as talc, calcium stearate, magnesium stearate, polyethylene glycol solid, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid and mixtures thereof; (10) Coloring and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical composition may also comprise buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard shell gelatin capsules, using such excipients as lactose (or milk sugar) and high molecular weight polyethylene glycols, among others.

片劑可以藉由壓縮或模製（視需要地與一或多種輔助成分一起）來製備。可以使用黏合劑（例如，明膠或羥丙基甲基纖維素）、潤滑劑、惰性稀釋劑、防腐劑、崩散劑（例如，羥基乙酸澱粉鈉或交聯羧甲基纖維素鈉）、界面活性劑或分散劑來製備壓縮片劑。模製片劑可以藉由在合適的機器中模製用惰性液體稀釋劑潤濕的粉狀化合物之混合物來製備。A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Binders (for example, gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrating agents (for example, sodium starch glycolate or croscarmellose sodium), surface-active agents may be used. agent or dispersant for the preparation of compressed tablets. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

片劑和本發明之藥物組成物之其他固體劑型（如糖衣丸、膠囊、丸劑和顆粒劑）可視需要地進行刻痕或製備有包衣和外殼，例如腸溶包衣和藥物配製領域熟知的其他包衣。也可以使用例如不同比例的羥丙基甲基纖維素將它們配製成使其中之活性成分緩慢或受控釋放以提供所期望的釋放曲線、其他聚合物基質、脂質體和/或微球。可以將它們配製用於快速釋放，例如冷凍乾燥。它們可以例如通過細菌截留過濾器濾過，或藉由摻入呈無菌固體組成物形式的滅菌劑來滅菌，該等無菌固體組成物可以在使用前立即溶解於無菌水或一些其他無菌可注射介質中。該等組成物也可以視需要地包含失透劑並且可為如下組成物，該組成物在胃腸道之某一部分中，視需要地以延遲的方式僅或者優先釋放一或多種活性成分。可利用的嵌入式組成物之實例包括聚合物質以及蠟。活性成分還可為微囊化形式，如果適當的話，可包含一或多種上述賦形劑。Tablets and other solid dosage forms of the pharmaceutical compositions of the invention such as dragees, capsules, pills and granules may optionally be scored or prepared with coatings and shells such as are well known in the art of enteric coatings and pharmaceutical formulations. Other coatings. They may also be formulated so that the active ingredient therein is released slowly or controlled so as to provide the desired release profile using, for example, hydroxypropylmethylcellulose in varying proportions, other polymer matrices, liposomes and/or microspheres. They can be formulated for immediate release, eg, freeze-dried. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use . The compositions may also optionally contain devitrification agents and may be of a composition which releases only or preferentially one or more active ingredients, optionally in a delayed manner, in a certain part of the gastrointestinal tract. Examples of embedding compositions that may be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

用於口服投與本發明之化合物之液體劑型包括藥學上可接受的乳劑、微乳劑、溶液、懸浮液、糖漿和酏劑。除了活性成分之外，液體劑型可以含有本領域常用的惰性稀釋劑（例如像水或其他溶劑）、助溶劑和乳化劑，例如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油類（特別是棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油和芝麻油）、甘油、四氫呋喃甲醇、聚乙二醇和山梨糖醇酐脂肪酸酯，及其混合物。Liquid dosage forms for oral administration of the compounds of this invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art (such as water or other solvents), co-solvents and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuran methanol, polyethylene glycol, and sorbic acid Alcohol fatty acid esters, and mixtures thereof.

除了惰性稀釋劑之外，口服組成物還可包括輔助劑，例如潤濕劑、乳化劑和懸浮劑、甜味劑、調味劑、著色劑、芳香劑以及防腐劑。Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

除了含有活性化合物外，懸浮液還可以含有懸浮劑如，例如乙氧化異硬脂醇、聚氧乙烯山梨醇和山梨糖醇酐酯、微晶纖維素、偏氫氧化鋁（aluminum metahydroxide）、膨潤土、瓊脂-瓊脂和黃蓍膠，及其混合物。Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, Agar - Agar and tragacanth, and mixtures thereof.

可以在本發明之藥物組成物中使用的合適的水性和非水性載劑之實例包括水、乙醇、多元醇（如，甘油、丙二醇、聚乙二醇等）及其合適的混合物、植物油（如橄欖油）和可注射的有機酯（如油酸乙酯）。適當流動性可以例如藉由以下方式來維持：藉由使用包衣材料（如卵磷脂），在分散體的情況下藉由維持所需粒度，以及藉由使用界面活性劑。Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils (e.g., olive oil) and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

該等組成物也可以含有輔助劑如防腐劑、潤濕劑、乳化劑和分散劑。可以藉由包括各種抗菌劑和抗真菌劑（例如，對羥苯甲酸酯、氯丁醇、山梨酸苯酚等）確保阻止微生物對主題化合物起作用。還令人希望的是在組成物中包括等滲劑，如糖、氯化鈉等。These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms on subject compounds can be ensured by the inclusion of various antibacterial and antifungal agents (eg, parabens, chlorobutanol, sorbic acid phenol, and the like). It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions.

當將本發明之化合物作為藥物向人和動物投與時，它們可以本身或作為藥物組成物投與，該藥物組成物含有例如與藥學上可接受的載劑組合的0.1%至99%（更較佳的是10%至30%）的活性成分。When the compounds of the present invention are administered as medicines to humans and animals, they may be administered by themselves or as a pharmaceutical composition containing, for example, 0.1% to 99% (more Preferably 10% to 30%) of active ingredient.

藉由熟悉該項技術者已知的常規方法將本發明之化合物和/或本發明之藥物組成物配製成藥學上可接受的劑型。The compounds of the present invention and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

可以改變本發明藥物組成物中活性成分之實際劑量水平，以便獲得一定量的活性成分，該活性成分之量有效地實現對於特定的患者、組成物和投與方式之所期望的治療響應，而對患者沒有毒性。Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention can be varied in order to obtain an amount of active ingredient effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, while No toxicity to patients.

選擇的劑量水平將取決於各種因素，包括所使用的本發明之特定化合物或其酯、鹽或醯胺之活性，投與途徑，投與時間，所採用的特定化合物之***率或代謝率，吸收之速度和程度，治療之持續時間，與所採用的特定化合物組合使用的其他藥物、化合物和/或材料，正被治療的患者之年齡、性別、體重、病症、一般健康狀況和先前病史，以及在醫學領域中熟知的類似因素。The selected dosage level will depend on various factors, including the activity of the particular compound of the invention employed, or its ester, salt or amide, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors well known in the medical field.

具有本領域普通技術之醫師或獸醫可以容易地確定並開出所需的藥物組成物之有效量。例如，醫生或獸醫能以低於實現所期望的治療效果所需的水平開始給藥於藥物組成物中使用的本發明之化合物，並逐漸增加劑量直至達到所期望的效果。A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start administering the compounds of the invention employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

通常，本發明之組合的合適日劑量將係每種化合物有效產生治療效果的最低劑量之量。這樣的有效劑量通常將取決於上述因素。In general, a suitable daily dose of the combinations of the invention will be that amount of each compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors mentioned above.

在另一個方面，本發明提供了藥學上可接受的組成物，其包含治療有效量的一或多種如上所述主題化合物，主題化合物與一或多種藥學上可接受的載劑（添加劑）和/或稀釋劑配製在一起。實例實例 1達拉菲尼、曲美替尼和化合物A In another aspect, the present invention provides a pharmaceutically acceptable composition comprising a therapeutically effective amount of one or more subject compounds as described above, the subject compound and one or more pharmaceutically acceptable carriers (additives) and/or or diluents are prepared together. Example Example 1 Dabrafenib, Trametinib and Compound A

根據WO 2009/137391之實例58a合成達拉菲尼。根據WO 2005/121142之實例4-1合成曲美替尼。根據WO 2015/107495之實例69合成化合物A。WO 2009/137391、WO 2015/066188和WO 2015/107495藉由引用以其全文併入本文。本文所述之達拉菲尼、曲美替尼和化合物A的組合之效用可以藉由以下實例中之測試來證明。實例 2在結腸直腸PDX小鼠試驗中，達拉菲尼和曲美替尼以及化合物A組合治療之體內功效 Dabrafenib was synthesized according to Example 58a of WO 2009/137391. Trametinib was synthesized according to Example 4-1 of WO 2005/121142. Compound A was synthesized according to Example 69 of WO 2015/107495. WO 2009/137391 , WO 2015/066188 and WO 2015/107495 are hereby incorporated by reference in their entirety. The utility of the combination of dabrafenib, trametinib and compound A described herein can be demonstrated by the tests in the following examples. Example 2 In Vivo Efficacy of Dabrafenib and Trametinib and Compound A Combination Treatment in Colorectal PDX Mice

將達拉菲尼（LIQ288）配製為在水中的0.2%吐溫80 + 0.5%HPMC中之懸浮液，均質化，並且最終pH為8。這係在1.5 mg/ml濃度下製備的，並且在4°C下的黑暗中儲存時具有23天的穩定性。藉由口服強飼法給藥，按10 ml/kg體積，每日兩次。Dabrafenib (LIQ288) was formulated as a suspension in 0.2% Tween 80 + 0.5% HPMC in water, homogenized and the final pH was 8. This was prepared at a concentration of 1.5 mg/ml and was stable for 23 days when stored in the dark at 4°C. Administration was by oral gavage at a volume of 10 ml/kg twice daily.

將曲美替尼（CFF272；DMSO溶劑合物）配製為在水中的0.2%吐溫80 + 0.5% HPMC中之懸浮液，過夜攪拌，並且最終pH為8。這係在0.03 mg/ml和0.0075 mg/ml濃度下製備的，並且在4°C下的黑暗中儲存時具有2週的穩定性。藉由口服強飼法給藥，按10 ml/kg體積，每日一次。Trametinib (CFF272; DMSO solvate) was formulated as a suspension in 0.2% Tween 80 + 0.5% HPMC in water, stirred overnight, and the final pH was 8. This was prepared at concentrations of 0.03 mg/ml and 0.0075 mg/ml and was stable for 2 weeks when stored in the dark at 4°C. Administration was by oral gavage at a volume of 10 ml/kg once daily.

將化合物A（TNO155）配製為在水中的0.1%吐溫80 + 0.5% MC中之懸浮液。這係在1 mg/ml濃度下製備的，並且在4°C下的黑暗中儲存時具有7天的穩定性。藉由口服強飼法給藥，按10 ml/kg體積，每日兩次。Compound A (TNO155) was formulated as a suspension in 0.1% Tween 80 + 0.5% MC in water. This was prepared at a concentration of 1 mg/ml and was stable for 7 days when stored in the dark at 4°C. Administration was by oral gavage at a volume of 10 ml/kg twice daily.

將西妥昔單抗以2 mg/ml儲備液/臨床製劑供應。將其儲存於4°C，並以10 ml/kg體積每週兩次藉由腹膜內注射給藥。Cetuximab was supplied as a 2 mg/ml stock solution/clinical formulation. It was stored at 4°C and administered twice weekly by intraperitoneal injection in a volume of 10 ml/kg.

將雌性無胸腺裸鼠（CRL:Nu（NCr）-foxn1nu；查理斯河實驗室（Charles River Labs），麻塞諸塞州）飼養在溫度和濕度受控的飼養箱中，採取12小時明/暗週期，並且向其隨意提供食物和水。Female athymic nude mice (CRL: Nu(NCr)-foxn1nu; Charles River Labs, Massachusetts) were housed in a temperature- and humidity-controlled vivarium for 12 hours under light/ dark period, and food and water were provided ad libitum.

藉由將患者CRC腫瘤組織直接皮下植入裸鼠，建立了人類CRC之人源腫瘤異種移植（PDX）模型（表1）。藉由體內連續傳代維持PDX模型。 [表1] 模型ID START ID BRAF變體預處理的 30017-HX ST111 V600E XELODA, FOLFOX-6/BEV 30018-HX ST1975 V600E FOLFIRI, FOLFOX, INV/AFLIBERCEPT 30019-HX ST2148 V600E XRT, TAMOXIFEN 30020-HX ST428 V600E UNK, INV 30021-HX ST800 V600E 無 30058-HX ST540 V600E 5-FU, XRT, 西妥昔單抗 30059-HX ST686 V600E 無 30060-HX ST1007 V600E 無 30061-HX ST1053 未決無 30062-HX ST1163 V600E FOLFOX 30063-HX ST1207 V600E 無 30064-HX ST1312 V600E BEV/XELODA 30065-HX ST1419 未決 CARBO/DOCE, 檸檬酸他莫西芬 30066-HX ST1659 未決無 30068-HX ST2087 V600E 無 30069-HX ST2162 F585V 無 30070-HX ST2959 V600E 無 30071-HX ST3096 V600E FOLFOX-BEV A human-derived tumor xenograft (PDX) model of human CRC was established by directly subcutaneously implanting patient CRC tumor tissue into nude mice (Table 1). The PDX model was maintained by serial passage in vivo. [Table 1] model ID START ID BRAF variant Preprocessed 30017-HX ST111 V600E XELODA, FOLFOX-6/BEV 30018-HX ST1975 V600E FOLFIRI, FOLFOX, INV/AFLIBERCEPT 30019-HX ST2148 V600E XRT, TAMOXIFEN 30020-HX ST428 V600E UNK, INV 30021-HX ST800 V600E none 30058-HX ST540 V600E 5-FU, XRT, cetuximab 30059-HX ST686 V600E none 30060-HX ST1007 V600E none 30061-HX ST1053 pending none 30062-HX ST1163 V600E FOLFOX 30063-HX ST1207 V600E none 30064-HX ST1312 V600E BEV/XELODA 30065-HX ST1419 pending CARBO/DOCE, Tamoxifen Citrate 30066-HX ST1659 pending none 30068-HX ST2087 V600E none 30069-HX ST2162 F585V none 30070-HX ST2959 V600E none 30071-HX ST3096 V600E FOLFOX-BEV

使用凱傑公司（Qiagen）AllPrep DNA/RNA迷你套組（凱傑公司#80204），從供體小鼠之PDX腫瘤樣本中提取RNA和DNA。RNA表現和突變呼應源自Illumina RNAseq數據，並且拷貝數和CIN分析源自低通WGS數據上之DNA圖譜。使用在富魯達公司（Fluidigm）平臺上運行的一組48個基因間SNP（SNP48），針對患者腫瘤DNA，驗證了模型特徵。RNA and DNA were extracted from PDX tumor samples of donor mice using the Qiagen AllPrep DNA/RNA Mini Kit (Qiagen #80204). RNA representation and mutation calls were derived from Illumina RNAseq data, and copy number and CIN analysis were derived from DNA profiles on low-pass WGS data. The model features were validated against patient tumor DNA using a panel of 48 intergenic SNPs (SNP48) run on the Fluidigm platform.

上述18個CRC PDX模型和9個治療組（包括未經治療的對照）被納入小鼠臨床試驗中。治療組和給藥方案如表2所示。 [表2] 組 藥物和方案 1 LIQ288（15 mg/kg PO，bid）+ CFF272（0.3 mg/kg PO，qd） 2 LIQ288（15 mg/kg PO，bid）+ CFF272（0.3 mg/kg PO，qd）+ 西妥昔單抗（20 mg/kg IP，2qw） 3 LIQ288（15 mg/kg PO，bid）+ CFF272（0.075 mg/kg PO，qd）+ TNO155（化合物A）（10 mg/kg PO，bid） The above 18 CRC PDX models and 9 treatment groups (including untreated controls) were included in the mouse clinical trial. The treatment groups and dosing regimens are shown in Table 2. [Table 2] Group Drugs and regimens 1 LIQ288 (15 mg/kg PO, bid) + CFF272 (0.3 mg/kg PO, qd) 2 LIQ288 (15 mg/kg PO, bid) + CFF272 (0.3 mg/kg PO, qd) + cetuximab (20 mg/kg IP, 2qw) 3 LIQ288 (15 mg/kg PO, bid) + CFF272 (0.075 mg/kg PO, qd) + TNO155 (compound A) (10 mg/kg PO, bid)

向小鼠群組皮下植入來自每個PDX模型（典型地p4-p9）之腫瘤片段。一旦每隻個體小鼠之腫瘤體積達到200-250 mm ³，將其分配到治療組中進行給藥，或分配到未經治療的對照組。將每個PDX模型之一隻動物分配到每個治療組。一旦入組治療組，每週兩次用卡尺測量腫瘤體積，每週兩次記錄體重。每個模型之研究結束被定義為最少28天的治療，或未經治療的腫瘤達到1500 mm ³的持續時間，或未經治療的腫瘤翻兩番的持續時間，以較慢者為准。 Tumor fragments from each PDX model (typically p4-p9) were implanted subcutaneously into cohorts of mice. Once the tumor volume of each individual mouse reached 200-250 ^mm3 , they were assigned to treatment groups for dosing, or to untreated control groups. One animal per PDX model was assigned to each treatment group. Once enrolled in the treatment group, tumor volume was measured with calipers twice a week and body weight was recorded twice a week. End of study for each model was defined as a minimum of 28 days of treatment, or the duration for untreated tumors to reach 1500 mm, or the duration for untreated tumors to ^quadruple , whichever was slower.

在研究結束時，從每隻經治療的動物和對照動物身上收集腫瘤片段。將冷凍腫瘤樣本儲存於-80°C直至分析。At the end of the study, tumor fragments were collected from each treated and control animal. Store frozen tumor samples at -80°C until analysis.

體重（BW）變化計算為(BW _t- BW _初始)/BW _初始× 100%。數據表示為相比治療開始日之體重變化百分比。 Body weight (BW) change was calculated as (BW _t - BW _initial )/BW _initial × 100%. Data are expressed as percent change in body weight from the day of treatment initiation.

使用下式計算腫瘤體積（TV）：長度 x 寬度 ₂/2。藉由將時間t處的腫瘤體積變化與其基線進行比較，確定響應。ΔTV _t= (TV _t- TV _初始)/TV _初始x 100%。 Tumor volume (TV) was calculated using the following formula: length x width _2/2 . Response was determined by comparing the change in tumor volume at time t to its baseline. ΔTV _t = (TV _t - TV _initial )/TV _initial x 100%.

響應於治療的腫瘤生長動力學表現為最佳最小響應（BestMinResponse）和最佳平均響應（BestAvgResponse）。將這兩個參數用於確定每個模型之響應類別。Tumor growth kinetics in response to treatment are shown for best minimum response (BestMinResponse) and best average response (BestAvgResponse). These two parameters are used to determine the response category for each model.

將最佳最小響應定義為t ≥ 10 d的ΔTV _t之最小值。對於每個時間t，還計算了從t = 0到t的ΔTV _t之平均值。我們將最佳平均響應定義為t ≥ 10 d的該平均值之最小值。該指標將響應之速度、強度和持久性組合為單個值。 The best minimum response is defined as the minimum value of ΔTV _t for t ≥ 10 d. For each time t, the mean value of ΔTV _t from t = 0 to t was also calculated. We define the best mean response as the minimum of this mean for t ≥ 10 d. This metric combines the speed, strength, and durability of responses into a single value.

響應類別改編自RECIST標準（Therasse等人, 2000），並且定義如下（按該順序應用）：完全響應（CR）= 最佳平均響應＜ -40%並且最佳最小響應＜ -95%；部分響應（PR）= 最佳平均響應＜ -20%並且最佳最小響應＜ -50%；穩定疾病（SD）= 最佳平均響應＜ 30%並且最佳最小響應＜ 35%；進展性疾病（PD）= 不符合上述任何標準；如果觀察到響應但是出現抗性，則應用CRàPD、PRàPD、SDàPD。Response categories were adapted from RECIST criteria (Therasse et al., 2000) and are defined as follows (applied in that order): Complete Response (CR) = Best Mean Response < -40% and Best Min Response < -95%; Partial Response (PR) = Best Mean Response < -20% and Best Min Response < -50%; Stable Disease (SD) = Best Mean Response < 30% and Best Min Response < 35%; Progressive Disease (PD) = Does not meet any of the above criteria; if a response is observed but resistance occurs, apply CRàPD, PRàPD, SDàPD.

因不良事件而被處死的小鼠被標記為「有毒」，並且從數據集中排除。Mice sacrificed due to adverse events were marked as "toxic" and excluded from the dataset.

所有數據都被編譯到單個Spotfire（TIBCO軟體公司（TIBCO Software Inc））文庫中。All data were compiled into a single Spotfire (TIBCO Software Inc) library.

使用迴歸建模工具，在Spotfire內進行數據集之間的相關性分析。表示的所有 R ² 值和 P值都係在迴歸分析和F統計工具後在Spotfire內生成的。 Perform correlation analysis between datasets within Spotfire using regression modeling tools. All ^R2 values and P values represented were generated within Spotfire after regression analysis and F statistics tools.

在18個帶有BRAF V600E突變的獨特CRC PDX模型中，評估了達拉菲尼和曲美替尼（LIQ288 + CFF272）組合治療之體內功效。但發現一個模型（30069-HX）反而帶有BRAF F585V突變，將其從分析中排除。The in vivo efficacy of combination therapy with dabrafenib and trametinib (LIQ288 + CFF272) was assessed in 18 unique CRC PDX models with BRAF V600E mutations. However, one model (30069-HX) was found to carry the BRAF F585V mutation instead and was excluded from the analysis.

用達拉菲尼和曲美替尼（LIQ288 + CFF272）之雙重組合進行治療（這係臨床相關劑量下BRAF突變型CRC之標準護理治療）在該小鼠試驗小組之17個BRAF V600E CRC PDX模型中產生2個PR和3個SD（圖1）。Treatment with a dual combination of dabrafenib and trametinib (LIQ288 + CFF272), the standard of care treatment for BRAF-mutant CRC at clinically relevant doses, in this mouse panel of 17 PDX models of BRAF V600E CRC 2 PRs and 3 SDs were produced in (Fig. 1).

在15個模型的子集中，用達拉菲尼、曲美替尼和TNO155（LIQ288 + CFF272 + TNO155）之三重組合進行治療實現了2個PR和6個SD。兩種模型在治療過程中表現出體重減輕＞ 30%，將其從分析中排除。該響應率與達拉菲尼、曲美替尼和EGFR抑制劑西妥昔單抗（LIQ288 + CFF272 + 西妥昔單抗）之其他臨床相關三重組合相當，在17個模型集中產生1個PR和7個SD。In a subset of 15 models, treatment with the triple combination of dabrafenib, trametinib, and TNO155 (LIQ288 + CFF272 + TNO155) achieved 2 PRs and 6 SDs. Both models exhibited >30% weight loss during treatment, which were excluded from the analysis. This response rate was comparable to other clinically relevant triple combinations of dabrafenib, trametinib and the EGFR inhibitor cetuximab (LIQ288 + CFF272 + cetuximab), which produced 1 PR in 17 model sets and 7 SD.

腫瘤加倍時間之卡普蘭-麥爾分析係該小鼠試驗的功效之另一量度（圖2）。雖然與未經治療的PDX相比，達拉菲尼 + 曲美替尼 + TNO155之三重組合治療延長了腫瘤加倍時間（p ＜ 0.05），但是與達拉菲尼 + 曲美替尼雙重組合或達拉菲尼 + 曲美替尼 + 西妥昔單抗三重組合相比，並未實現統計學上的顯著改善（p = 0.33）。Kaplan-Meier analysis of tumor doubling time is another measure of the power of this mouse assay (Figure 2). Although the triple combination of dabrafenib + trametinib + TNO155 prolongs tumor doubling time compared with untreated PDX (p < 0.05), the combination of dabrafenib + trametinib or The triple combination of dabrafenib + trametinib + cetuximab did not achieve a statistically significant improvement (p = 0.33).

在該等治療方案中，模型子集之體重略有減輕（圖3）。將BW減輕＞ 30%的動物從研究中移除並且從分析中排除。In these treatment regimens, a subset of models experienced slight weight loss (Figure 3). Animals with >30% reduction in BW were removed from the study and excluded from the analysis.

達拉菲尼 + 曲美替尼 + TNO155之三重組合治療在BRAF V600E突變型結腸直腸PDX模型之代表性小組中表現出腫瘤生長抑制功效，顯示出優於或相當於當前臨床方案達拉菲尼 + 曲美替尼雙重組合或達拉菲尼 + 曲美替尼 + 西妥昔單抗三重組合之響應率。該結果支持在患有BRAF突變型結腸直腸癌之患者中使用達拉菲尼 + 曲美替尼 + TNO155組合治療方案。The triple combination therapy of dabrafenib + trametinib + TNO155 demonstrated tumor growth inhibitory efficacy in a representative panel of BRAF V600E mutant colorectal PDX models, shown to be superior to or equivalent to current clinical regimen dabrafenib Response rates for the dual combination of + trametinib or the triple combination of dabrafenib + trametinib + cetuximab. The results support the use of dabrafenib + trametinib + TNO155 combination therapy in patients with BRAF-mutant colorectal cancer.

應理解，本文所述之實例和實施方式僅用於舉例說明目的，其各種修飾或改變對於熟悉該項技術者將是明瞭的，並包括在本申請之精神和範圍內和所附申請專利範圍之範圍內。It should be understood that the examples and implementations described herein are for illustrative purposes only, and that various modifications or changes thereof will be apparent to those skilled in the art, and are included within the spirit and scope of the present application and the patent scope of the appended application within the range.

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[圖1]示出了MCT2019中17個CRC PDX模型對達拉菲尼 + 曲美替尼 + TNO155（化合物A）治療之最佳平均響應。[Fig. 1] shows the best average response of 17 CRC PDX models in MCT2019 to dabrafenib + trametinib + TNO155 (Compound A) treatment.

[圖2]示出了與達拉菲尼 + 曲美替尼和達拉菲尼 + 曲美替尼 + 西妥昔單抗治療相比，在達拉菲尼 + 曲美替尼 + TNO155（化合物A）組合之治療期間，MCT2019中CRC PDX模型的腫瘤加倍之卡普蘭-麥爾圖。[Figure 2] shows that compared with dabrafenib + trametinib and dabrafenib + trametinib + cetuximab treatment, in dabrafenib + trametinib + TNO155 ( Compound A) Kaplan-Myer diagram of tumor doubling in CRC PDX models in MCT2019 during treatment with combination.

[圖3]示出了與使用達拉菲尼 + 曲美替尼或達拉菲尼 + 曲美替尼 + 西妥昔單抗治療相比，在使用達拉菲尼 + 曲美替尼 + TNO155（化合物A）組合進行治療期間，PDX荷瘤小鼠之體重變化。[Fig. 3] shows that compared with the treatment with dabrafenib + trametinib or dabrafenib + trametinib + cetuximab, the treatment with dabrafenib + trametinib + Body weight changes of PDX tumor-bearing mice during combined treatment with TNO155 (Compound A).

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Claims

一種藥物組合，其包含：N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）、或其藥學上可接受的鹽；N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺（曲美替尼）、或其藥學上可接受的鹽；和(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）、或其藥學上可接受的鹽。A pharmaceutical combination comprising: N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiary butyl)thiazol-4-yl)-2-fluorophenyl)-2 ,6-difluorobenzenesulfonamide (dabrafenib), or its pharmaceutically acceptable salt; N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl )Amino)-6,8-Dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1(2H)- base) phenyl) acetamide (trametinib), or a pharmaceutically acceptable salt thereof; and (3S,4S)-8-(6-amino-5-((2-amino-3- Chloropyridin-4-yl)thio)pyrbor-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (compound A), or its pharmaceutical acceptable salt.

如請求項1所述之組合，其中將N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）或其藥學上可接受的鹽、N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺（曲美替尼）或其藥學上可接受的鹽、和(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）或其藥學上可接受的鹽分開地、同時地或以任何順序依序地投與。The combination as described in Claim 1, wherein N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiary butyl)thiazol-4-yl)-2-fluorobenzene base)-2,6-difluorobenzenesulfonamide (dabrafenib) or its pharmaceutically acceptable salt, N-(3-(3-cyclopropyl-5-((2-fluoro-4- Iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidine-1( 2H)-yl)phenyl)acetamide (trametinib) or a pharmaceutically acceptable salt thereof, and (3S,4S)-8-(6-amino-5-((2-amino- 3-chloropyridin-4-yl)thio)pyridine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decyl-4-amine (compound A) or The pharmaceutically acceptable salts are administered separately, simultaneously or sequentially in any order.

如請求項1或2所述之藥物組合，其用於口服投與。The drug combination according to claim 1 or 2, which is used for oral administration.

如請求項1至3中任一項所述之藥物組合，其中N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）呈口服劑型。The drug combination as described in any one of claims 1 to 3, wherein N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tertiary butyl)thiazol-4-yl )-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (dabrafenib) is available in oral dosage form.

如請求項1至4中任一項所述之藥物組合，其中N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺（曲美替尼）呈口服劑型。The drug combination as described in any one of claims 1 to 4, wherein N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8 -Dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (trametinib) is available in oral form.

如請求項1至4中任一項所述之藥物組合，其中(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）呈口服劑型。The drug combination as described in any one of claims 1 to 4, wherein (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)sulfur Substitute) pyridoxine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (Compound A) is in oral dosage form.

一種藥物組成物或商業包裝，該藥物組成物或商業包裝包含如前述請求項中任一項所述之藥物組合，和至少一種藥學上可接受的載劑。A pharmaceutical composition or commercial package, the pharmaceutical composition or commercial package comprising the pharmaceutical combination as described in any one of the preceding claims, and at least one pharmaceutically acceptable carrier.

如請求項1至6中任一項所述之藥物組合或如請求項7所述之藥物組成物或商業包裝，用於在癌症之治療中使用。The pharmaceutical combination according to any one of claims 1 to 6 or the pharmaceutical composition or commercial package according to claim 7, for use in the treatment of cancer.

用於如請求項8所述使用的藥物組合或藥物組成物或商業包裝，其中該癌症選自乳癌、膽管癌、結腸直腸癌（CRC）、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌。A pharmaceutical combination or pharmaceutical composition or a commercial package for use as described in claim 8, wherein the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer (CRC), melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer .

用於如請求項8所述使用的藥物組合或藥物組成物或商業包裝，其中該癌症係晚期或轉移性結腸直腸癌。The pharmaceutical combination or pharmaceutical composition or commercial package for use as described in claim 8, wherein the cancer is advanced or metastatic colorectal cancer.

如請求項10所述之藥物組合，其中該癌症係BRAF功能獲得型CRC或BRAF V600E、V600D或V600K CRC。The drug combination according to claim 10, wherein the cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.

如請求項1至6中任一項所述之藥物組合或如請求項7所述之藥物組成物或商業包裝用於製造治療癌症之藥物之用途。Use of the pharmaceutical combination as described in any one of Claims 1 to 6 or the pharmaceutical composition or commercial packaging as described in Claim 7 for the manufacture of medicines for treating cancer.

如請求項12所述之藥物組合或藥物組成物之用途，其中該癌症選自乳癌、膽管癌、結腸直腸癌、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌，視需要地其中該癌症係晚期或轉移性結腸直腸癌，視需要地其中該癌症係BRAF功能獲得型CRC或BRAF V600E、V600D或V600K CRC。The use of the pharmaceutical combination or pharmaceutical composition as described in claim 12, wherein the cancer is selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer and thyroid cancer, where the cancer is optionally is advanced or metastatic colorectal cancer, optionally wherein the cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.

一種治療癌症之方法，該癌症選自乳癌、膽管癌、結腸直腸癌、黑色素瘤、非小細胞肺癌、卵巢癌和甲狀腺癌，該方法包括向有需要的患者投與如請求項1至6中任一項所述之藥物組合或商業包裝或如請求項7所述之藥物組成物。A method of treating cancer selected from breast cancer, cholangiocarcinoma, colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, and thyroid cancer, the method comprising administering to a patient in need as claimed in claims 1 to 6 The pharmaceutical combination or commercial package described in any one, or the pharmaceutical composition as described in Claim 7.

如請求項14所述之方法，其中該結腸直腸癌係晚期或轉移性結腸直腸癌。The method according to claim 14, wherein the colorectal cancer is advanced or metastatic colorectal cancer.

如請求項15所述之方法，其中該結腸直腸癌係BRAF功能獲得型CRC或BRAF V600E、V600D或V600K CRC。The method according to claim 15, wherein the colorectal cancer is BRAF gain-of-function CRC or BRAF V600E, V600D or V600K CRC.

如請求項14所述之方法，其中以約從約1至約150 mg/天的劑量口服投與N-(3-(5-(2-胺基嘧啶-4-基)-2-(三級丁基)噻唑-4-基)-2-氟苯基)-2,6-二氟苯磺醯胺（達拉菲尼）。The method of claim 14, wherein N-(3-(5-(2-aminopyrimidin-4-yl)-2-(tri Butyl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (Dabrafenib).

如請求項14所述之方法，其中以從約0.5至約2 mg/天（例如，約0.5、1或2 mg/天，以及例如，以曲美替尼二甲基亞碸形式約0.5635、1.127或2.254 mg/天）的劑量口服投與N-(3-(3-環丙基-5-((2-氟-4-碘苯基)胺基)-6,8-二甲基-2,4,7-三側氧基-3,4,6,7-四氫吡啶并[4,3-d]嘧啶-1(2H)-基)苯基)乙醯胺（曲美替尼）。The method of claim 14, wherein from about 0.5 to about 2 mg/day (for example, about 0.5, 1 or 2 mg/day, and for example, about 0.5635, Oral administration of N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl- 2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (trametinib ).

如請求項14所述之方法，其中將(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫代)吡口井-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺（化合物A）以從約1.5 mg/天、或3 mg/天、或6 mg/天、或10 mg/天、或20 mg/天、或30 mg/天、或40 mg/天、或50 mg/天、或60 mg/天或70 mg/天、或80 mg/天、或90 mg/天至約100 mg/天的劑量口服投與。The method as described in claim 14, wherein (3S, 4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyridine well- 2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine (Compound A) at a dose of about 1.5 mg/day, or 3 mg/day, or 6 mg/day day, or 10 mg/day, or 20 mg/day, or 30 mg/day, or 40 mg/day, or 50 mg/day, or 60 mg/day, or 70 mg/day, or 80 mg/day, or Doses of 90 mg/day to about 100 mg/day are administered orally.

如請求項19所述之方法，其中化合物A之每日劑量按用藥2週、隨後停藥1週的21天週期進行。The method according to claim 19, wherein the daily dose of compound A is carried out in a 21-day cycle of 2 weeks of administration followed by 1 week of rest.