琥珀酸瑞波西利片

1/2ᰕᵏ˖2023 ᒤ 01 ᴸ 19 ᰕ᭩ᰕᵏ˖

⩕⡷䈤᰾Җ⭘

Ǐ㦟૱਽〠ǐ⡷ѭ䲶®˗Kisqali®㤡᮷਽〠˖Ribociclib Succinate Tablets≹䈝᤬丣˖Huposuan Ruiboxili PianǏᡀԭǐDŽॆᆖ਽〠˖7-⧟ᠺส-N,N-Ҽ⭢ส-2-{[5-˄ૼచ-1-ส˅ੑ஦-2-ส]≘ส}-7H-ੑ૟ᒦ[2,3-d]౗஦-6-⭢䞠㜪⩕⧰䞨ⴀ˄1:1˅ॆᆖ㔃ᶴᔿ˖

ᆀᔿ˖C23H30N8O•C4H6O4ᆀ䟿˖552.64DŽǏᙗ⣦ǐ࡫ࠩRIC࡫ࠩNVRˈⴤᖴ㓖 11.1 ∛㊣DŽ

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ǏǏ䘲ᓄ⯷ǐᵜ૱䘲⭘Ҿ◰㍐ਇփ˄HR˅䱣ᙗǃӪ㺘Ⳟ⭏䮯ഐᆀਇփ 2˄HER2˅䱤ᙗተ䜘ᲊᵏᡆ䖜〫⋼⋫⯇DŽᡆത㔍㓿ᵏྣᙗᛓ㘵ᰦᓄ㚄⭘哴փ⭏ᡀ㍐䟺᭮◰㍐˄ LHRH˅DŽǏ㿴Ṭǐ200mg˄᤹ C23H30N8O 䇑˅Ǐ⭘⌅⭘䟿ǐ༷ᣇⱼ⋫⯇㓿傼Ⲵ५⭏ᔰ࿻ᵜ૱⋫⯇DŽ⭘䟿䟿Ѫ 600 mg ˄3 × 200 mg 㮴㟌व㺓⡷˅ˈ⇿ᰕа⅑㔉㦟ˈ䘎㔝ᴽ㦟 21 ཙˈ㦟 7 ཙˈ28 ཙѪањᆼᮤ⋫⯇ઘᵏDŽਚ㾱ᛓ㘵Ӿ⋫⯇ѝ㧧ᗇѤᒺ㧧⳺ᡆⴤ㠣ਁ⭏нਟ᧕ˈᓄ㔗㔝䘋㹼⋫⯇DŽᵜ૱ᓄо 2.5 mgᓄ൘ᮤњ 28 ཙઘᵏ᚟DŽ઼ത㔍㓿ᵏྣᙗᰦˈ䘈⭘ LHRHDŽᛓ㘵൘⇿ᰕབྷ㠤⴨਼Ⲵᰦ䰤ᴽ⭘㦟нᓄ൘ᖃᰕ仍ཆᴽ㦟DŽᓄ᤹➗ᑨ༴ᯩ㦟⢙DŽ䟿䈳ᮤ䟽ᓖᡆᰐ⌅㙀ਇⲴн㢟৽ᓄ˄ AR⭘ᵜ૱DŽྲ᷌Ҿ㺘 1DŽ㺘 1 䟿䈳ᮤᤷইᵜ૱䟿 200 mgⲴᮠ䟿䟿 600 mg/ ཙ 3ㅜ 1䟿 400 mg/ ཙ 2ㅜ 2䟿 200 mg*/ ཙ 1

䟿䱽㠣 200 mg/⋫⯇DŽ

㺘 2ǃ3ǃ4ǃ5 ઼ 6⭘ᵜ᚟DŽ⋫⯇५⭏สҾњփ㧧⳺ /ᛓ㘵Ⲵ㇑⨶ᯩṸ˄㿱⌘᜿һ亩˅DŽ㹰㓶㜎䇑ᮠ˄CBCࡽ2⇿޵2 ઘⴁ⍻ CBCˈ䲿ਾ 4൘⇿ањઘᵏᔰ࿻ᰦⴁ⍻ CBCṩᦞѤᒺᤷᖱⴁ⍻ CBCDŽ

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㺘㺘 2 䟿䈳ᮤ઼㇑⨶-ቁ⯷1 㓗ᡆ 2 㓗*˄ANC1000/mm3 - ” LLN˅3 㓗*˄ANC 500 - <1000/mm3˅3 㓗*ਁ✝ᙗѝᙗ㋂㓶ቁ⯷**4 㓗*˄ANC < 500/mm3˅ѝᙗ㋂㓶߿ቁ⯷䟿䈳ᮤDŽ ѝᯝ㔉㦟ˈⴤ㠣ᚒ༽㠣” 2 㓗DŽ䟿≤ᒣ䟽ᯠᔰ࿻ᵜ૱㔉㦟DŽྲ᷌ 3 㓗∂ᙗ༽ਁ˖ѝᯝ㔉㦟ⴤ㠣ᚒ༽㠣 ” 2㓗ˈ❦ਾᚒ༽ᵜ૱㔉㦟ᒦ䱽վ 1䟿≤ᒣDŽ

ѝᯝ㔉㦟ˈⴤ㠣ᚒ༽㠣 ” 2 㓗DŽᚒ༽ᵜ૱㔉㦟ᒦ䱽վ 1䟿≤ᒣѝᯝ㔉㦟ˈⴤ㠣ᚒ༽㠣” 2 㓗DŽᚒ༽ᵜ૱㔉㦟ᒦ䱽վ 1䟿≤ᒣDŽ* ṩᦞ CTCAE ⡸ᵜ 4.03˄CTCAE = 㓗DŽ** 3ቁ⯷դа⅑փ⑙!ႏਁ✝˄ᡆփ⑙ᤱ㔝 ႏԕк 1 ሿᰦԕк઼/ᡆᒦਁᝏḃ˅DŽANC =㔍ሩѝᙗ㋂㓶㜎䇑ᮠ˗LLN =↓ᑨл䲀㜭Ự⍻˄LFTࡽ2⇿޵2 ઘⴁ⍻ LFTˈ䲿ਾ 4൘⇿ањઘᵏᔰ࿻ᰦⴁ⍻ LFTṩᦞѤᒺᤷᖱⴁ⍻ LFTDŽྲ᷌ࡠ ı 2ⴁ⍻仁⦷DŽ㺘 3 䟿䈳ᮤ઼㇑⨶-㛍㛶∂ᙗ1 㓗㓗*(>ULN – 3 ×ULN)2 㓗㓗*(>3 㠣 5 × ULN)3 㓗㓗*(>5 㠣 20 × ULN)4 㓗㓗*(>20 × ULN)AST ઼઼/ᡆᡆ ALT ⴨⴨ሩҾส㓯ॷ儈**ˈնᙫ㛶㓒㍐ॷ儈н儈Ҿ 2 ×ULN䟿䈳ᮤDŽส㓯ᰦ<2 㓗˖ѝᯝ㔉㦟ˈⴤ㠣ᚒ༽㠣” ส㓯䟿≤ᒣ䟽ᯠᔰ࿻ᵜ૱⋫⯇DŽྲ᷌ 2 㓗һ䟿≤ᒣ䟽ᯠᔰ࿻ᵜ૱㔉㦟DŽѝᯝᵜ૱㔉㦟ⴤ㠣ᚒ༽㠣” ส㓯*ˈ❦ਾԕл䟿≤ᒣ䟽ᯠᔰ࿻㔉㦟DŽྲ᷌ 3 㓗һԦ༽⭘ᵜ૱DŽ⭘ᵜ૱࡛2˖ᰐ䴰ѝᯝ㔉㦟DŽAST ઼઼/ᡆᡆ ALT 㚄㚄ਸॷ儈դᙫ㛶㓒㍐ॷ儈ˈˈնᰐ㛶≱␔〟ྲ᷌ᛓ㘵ਁ⭏ ALT ઼/ᡆ AST > 3 × ULN դᙫ㛶㓒㍐> 2 × ULNྲօˈ⭘ᵜ૱DŽ*ṩᦞ CTCAE ⡸ᵜ 4.03˄CTCAE = 㓗DŽ**ส㓯 = DŽṩᦞ CTCAE 4.03㓗DŽULN = ↓ᑨк䲀AST = ≘䞨≘ส䖜〫䞦˗ALT = щ≘䞨≘ส䖜〫䞦ᓄ䇴ՠ ECGDŽ⋫⯇ᔰ࿻ਾˈ൘ㅜ 1 њઘᵏⲴབྷ㓖ㅜ 14 ཙǃㅜ 2 њઘᵏ⧠Ҷ QTcF࣐ECG ⴁ⍻仁⦷DŽ

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㺘㺘 4 䟿䈳ᮤ઼㇑⨶-QT 䰤ᵏᔦ䮯ECG QTcF>480 ms Ɣ ѝᯝᵜ૱㔉㦟Ɣ ྲ᷌ QTcF 䰤ᵏᔦ䮯㕃䀓㠣< 481 ms䟿≤ᒣ䟽ᯠᔰ࿻⋫⯇˗Ɣ ⧠ QTcF 䰤ᵏ ı 481 ms ѝᯝᵜ૱㔉㦟ˈⴤ㠣 QTcF 䰤ᵏ㕃䀓㠣<481 ms䟿≤ᒣ䟽ᯠᔰ࿻ᵜ૱㔉㦟DŽECG QTcF>500 ms Ɣ ྲ᷌ QTcF 䰤ᵏ>500 msѝᯝᵜ૱㔉㦟ⴤ㠣 QTcF 䰤ᵏ< 481 msԕл䟿≤ᒣ䟽ᯠᔰ࿻㔉㦟DŽྲ᷌ QTcF 䰤ᵏᔦ䮯>500 ms ᡆ⴨∄ส㓯Ⲵਈॆ>60 ms䗷䗷䙏ᡆѕ䟽ᗳᖻཡᑨⲴփᖱ/⭘ᵜ૱DŽ㺘 5 䟿䈳ᮤ઼㇑⨶-ILD/㛪䜘⚾⯷ILD/㛪䜘⚾⯷ 1 㓗*˄ᰐ⯷⣦˅2 㓗*˄ᴹ⯷⣦˅3 㓗ᡆ 4 㓗*˄䟽ᓖ˅䟿䈳ᮤDŽṩᦞѤᒺᤷᖱˈ䘋㹼䘲ᖃⲴ㦟⢙⋫⯇ᒦ䘋㹼ⴁ⍻DŽѝᯝᵜ૱㔉㦟ˈⴤ㠣ᚒ༽㠣İ1 㓗ˈ❦ਾԕлањ䟿≤ᒣ䟽ᯠᔰ࿻ᵜ૱㔉㦟**DŽ⭘ᵜ૱DŽ*ṩᦞ CTCAE ⡸ᵜ 4.03˄CTCAE = 㓗DŽ**㘳㲁䟽ᯠᔰ࿻ᵜ૱㔉㦟ᰦˈᓄ䘋㹼њփॆⲴ㧧⳺-仾䲙䇴ՠDŽILD=䰤䍘ᙗ㛪⯮⯵㺘 6 䟿䈳ᮤ઼㇑⨶-Ԇ∂ᙗ*Ԇ ∂ᙗ1 㓗㓗ᡆ 2 㓗㓗** 3 㓗㓗** 4 㓗㓗**䟿䈳ᮤDŽṩᦞѤᒺᤷᖱˈ䘋㹼䘲ᖃⲴ㦟⢙⋫⯇ᒦ䘋㹼ⴁ⍻DŽѝᯝ㔉㦟ˈⴤ㠣ᚒ༽㠣İ 1 㓗ˈ䟿≤ᒣ䟽ᯠᔰ࿻ᵜ૱㔉㦟DŽྲ᷌ 3ԕлањ䟿≤ᒣ䟽ᯠᔰ࿻ᵜ૱㔉㦟DŽ⭘ᵜ૱DŽ*ቁ⯷ǃ㛍∂ᙗǃQT 䰤ᵏᔦ䮯઼ ILD/㛪䜘⚾⯷DŽ**ṩᦞ CTCAE 4.03 ⡸˄CTCAE = 㓗DŽ

᚟ˈ䈧৲䰵㚄⭘㦟⢙㣣俉ॆ䞦ᣁᡆ LHRH᚟DŽᵜ૱оᕪ᭸ CYP3A䟿䈳ᮤᵜ૱оᕪ᭸ CYP3A⭘ CYP3A֌⭘䖳ᕡⲴᴯԓ㚄⭘㦟⢙DŽྲ᷌ᛓ㘵䴰㾱ᗵ享㚄⭘ᕪ᭸ CYP3A䟿䱽㠣 400 mg ⇿ᰕа⅑˄㿱㦟⢙⴨ӂ֌⭘˅DŽ䟿䱽㠣 400 mg ᔰ࿻㚄⭘ᕪ᭸ CYP3A4㚄ਸ㔉㦟Ⲵᛓ䟿䘋а↕䱽㠣 200 mgDŽ䟿䱽㠣 200 mgᔰ࿻㚄⭘ᕪ᭸ CYP3A4㚄ਸ㔉㦟Ⲵᛓ㘵ѝˈᓄѝᯝᵜ૱⋫⯇DŽ

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࠷ᓄ൘㠣ቁ 5 њᕪ᭸ CYP3AⲴ⎸䲔ॺ㺠ᵏਾሶ䟿᭩Ѫ㚄⭘ᕪ᭸ CYP3A䟿˄㿱⌘᜿һ亩ǃ㦟⢙⴨ӂ֌⭘઼Ѥᒺ㦟⨶˅DŽ⢩↺Ӫ㗔㛮㛮ᦏᇣᛓ㘵䟿Ѫᵜ૱ 200mgDŽቊᵚ൘䟽ᓖ㛮ᦏᇣң㞪ⱼᛓ㘵ѝ⹄ウᵜ૱˄㿱Ѥᒺ㦟⨶˅DŽ㛍ᦏᇣᛓ㘵䖫ᓖ㛍ᦏᇣ˄Child-Pugh A䟿DŽᵜ૱൘ѝᓖ˄Child-Pugh B ㊫˅઼䟽ᓖ㛍ᦏᇣ˄Child-Pugh C˄վҾ 2䟿Ѫ 400mg ⇿ᰕа⅑˄㿱Ѥᒺ㦟⨶˅DŽㄕӪ㗔ㄕоᒤ喴н┑ 18ᮠᦞਟ⭘DŽ㘱ᒤᛓ㘵65䟿˄㿱Ѥᒺ㦟⨶˅DŽ㔉㦟ᯩ⌅нᗇર೬ǃ঻⺾нᗇᴽ⭘DŽǏн㢟৽ᓄǐᙗ⢩ᖱᙫ㔃ሩ➗ III ᵏѤᒺ⹄ウ˄MONALEESA-2ˈMONALEESA-7-NSAI 㓴ˈMONALEESA-3˅ѝ 1065⋼⋫⯇Ⲵ HR 䱣ᙗǃHER2ࡲࡦN=582ˈ㚄⭘≏㔤ਨ㗔 N=483˅Ⲵ≷ᙫᮠᦞ䳶DŽ≷ᙫⲴ III ᵏ⹄ウᮠᦞ䳶ѝᵜ૱⹄ウ⋫⯇Ⲵѝս᳤䵢ᰦ䰤Ѫ 19.2 њᴸˈ61.7%ᛓ㘵Ⲵ᳤䵢ᰦ䰤ı12 њᴸDŽ൘ IIIᴹ 39.5%઼ 4.3%Ⲵᛓ㘵ഐн㢟һԦ˄AEԆ㦟⢙㓴઼ᆹហᴹ 8.7%઼ 3.1%Ԇ㦟Ⲵᴰᑨ㿱 AE ᱟ ALT ॷ儈˄4.5%˅ǃAST ॷ儈˄2.5%˅઼અੀ˄1.1%˅DŽ൘ 3 亩 IIIԆ㦟⢙⋫⯇㓴 22˄2.1%ࡲԆ㦟⢙⋫⯇㓴 16˄2.0%˅ᛓ㘵൘⋫⯇ᵏ䰤↫ӑDŽ䲔ᴰᑨ㿱Ⲵ↫ഐ⯮⯵䘋ኅѻཆˈԆ㦟⢙⋫⯇㓴䘈ᣕ੺Ҷ 3Ⲵ↫ഐˈवᤜᙕᙗબ੨ト䘛㔬ਸᖱ˄1˗0.1%˅ǃᙕᙗબ੨㺠ㄝ˄2˗0.2%˅઼⥍↫˄1ᛓ㘵ਁ⭏ 3 㓗վ䫮㹰⯷઼ 2 㓗 QT 䰤ᵏᔦ䮯ˈᒦ൘਼аཙ᭩ழ㠣 1ࡽ10 ཙᣕ੺˅˄1˗0.1%˅DŽ≷ᙫ III ᵏ⹄ウѝᴰᑨ㿱Ⲵ㦟⢙н㢟৽ᓄ˄ ADR˗ਁ⭏⦷ı20%㓴ਁ⭏⦷˅

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〈ǃ㝡ਁǃ㜭ỰḕᔲᑨDŽ≷ᙫᮠᦞѝᴰᑨ㿱Ⲵ 3/4 㓗 ADR˄ਁ⭏⦷ı2%㓴ਁ⭏⦷˅ቁ⯷ǃᝏḃǃ㛼Ⰻǃ䍛㹰ǃ⯢ѿǃվ⼧䞨㹰⯷઼અੀDŽṩṩᦞ 3 亩 III㺘ᙫ㔃Ⲵ㦟⢙н㢟৽ᓄDŽ᤹ MedDRA㊫ᙫ㔃 III ᵏѤᒺ⹄ウ˄㺘 7˅ѝⲴ ADR㊫亩л㊫亩лⲴ㦟⢙н㢟৽ᓄ൷᤹ѕ䟽〻ᓖӾ㊫ᯩ⌅˄ CIOMS III ˅ˈሩ⇿⿽㦟⢙н㢟৽ᓄⲴਁ⭏㊫˖䶎ᑨᑨ㿱˄ı1/10˅˗ᑨ㿱˄ı1/100 㠣<1/10˅˗нᑨ㿱˄ı1/1,000 㠣<1/100˅˗㖅㿱˄ı1/10,000 㠣<1/1,000˅˗䶎ᑨ㖅㿱˄<1/10,000˅DŽ㺘 7 ṩᦞ 3 亩 III ᵏѤᒺ⹄ウ≷ᙫᮠᦞ䳶ᙫ㔃Ⲵ㦟⢙н㢟৽ᓄ㦟⢙н㢟৽ᓄKisqaliN=1065n˄%˅ᡰᴹㅹ㓗ᆹហࡲN=818n˄%˅ᡰᴹㅹ㓗KisqaliN=1065n˄%˅3/4 㓗㓗ࡲN=818n˄%˅3/4 㓗㓗㊫

ᡰᴹㅹ㓗ḃ㊫⯮⯵ᝏḃ 1 502 (47.1) 282 (34.5) 49 (4.6) 12 (1.5) 䶎ᑨᑨ㿱㹰⏢৺⏻ᐤ㌫㔏⯮⯵ቁ⯷ 803 (75.4) 54 (6.6) 662 (62.2) 18 (2.2) 䶎ᑨᑨ㿱ቁ⯷ 350 (32.9) 27 (3.3) 184 (17.3) 5 (0.6) 䶎ᑨᑨ㿱䍛㹰 228 (21.4) 69 (8.4) 41 (3.8) 18 (2.2) 䶎ᑨᑨ㿱ቁ⯷ 124 (11.6) 21 (2.6) 67 (6.3) 8 (1.0) 䶎ᑨᑨ㿱ቁ⯷ 105 (9.9) 15 (1.8) 9 (0.8) 2 (0.2) ᑨ㿱ቁ⯷ 18 (1.7) 2 (0.2) 17 (1.6) 2 (0.2) ᑨ㿱⵬ಘᇈ⯮⯵࣐77 (7.2) 11 (1.3) 0 0 ᑨ㿱ᒢ⵬ 64 (6.0) 24 (2.9) 0 0 ᑨ㿱㊫⯮⯵伏Ⅲл䱽 182 (17.1) 110 (13.4) 6 (0.6) 1 (0.1) 䶎ᑨᑨ㿱վ䫉㹰⯷ 50 (4.7) 14 (1.7) 12 (1.1) 0 ᑨ㿱վ䫮㹰⯷ 44 (4.1) 23 (2.8) 16 (1.5) 6 (0.7) ᑨ㿱վ⼧䞨㹰⯷ 35 (3.3) 12 (1.5) 22 (2.1) 7 (0.9) ᑨ㿱਴㊫⾎⾎㓿㌫㔏⯮⯵ཤⰋ 290 (27.2) 191 (23.3) 7 (0.7) 5 (0.6) 䶎ᑨᑨ㿱ཤᲅ 149 (14.0) 93 (11.4) 2 (0.2) 1 (0.1) 䶎ᑨᑨ㿱ⵙᲅ 64 (6.0) 14 (1.7) 2 (0.2) 0 ᑨ㿱ᗳ㜿ಘಘᇈ⯮⯵ᲅ৕ 25 (2.3) 13 (1.6) 18 (1.7) 8 (1.0) ᑨ㿱બ੨㌫㔏ǃ㜨৺㓥㞸⯮⯵ૣభ 258 (24.2) 152 (18.6) 0 0 䶎ᑨᑨ㿱બ੨ഠ䳮 155 (14.6) 95 (11.6) 20 (1.9) 8 (1.0) 䶎ᑨᑨ㿱਴⿽㚼㚼㚹僘僬৺㔃㕄㓴㓷⯮⯵㛼Ⰻ 256 (24.0) 180 (22.0) 23.0 (2.2) 11 (1.3) 䶎ᑨᑨ㿱㛳㛐㌫㔏⯮⯵

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㦟㦟⢙н㢟৽ᓄKisqaliN=1065n˄%˅ᡰᴹㅹ㓗ᆹហࡲN=818n˄%˅ᡰᴹㅹ㓗KisqaliN=1065n˄%˅3/4 㓗ࡲN=818n˄%˅3/4 㓗㓗㊫

ᡰᴹㅹ㓗ᚦᗳ 496 (46.6) 242 (29.-6) 18 (1.7) 5 (0.6) 䶎ᑨᑨ㿱㞩⌫ 354 (33.2) 191 (23.3) 20 (1.9) 6 (0.7) 䶎ᑨᑨ㿱અੀ 307 (28.8) 143 (17.5) 23 (2.2) 3 (0.4) 䶎ᑨᑨ㿱〈 271 (25.4) 140 (17.1) 9 (0.8) 0 䶎ᑨᑨ㿱㞩Ⰻ 2 208 (19.5) 121 (14.8) 16 (1.5) 5 (0.6) 䶎ᑨᑨ㿱ਓ㞄哿㟌⚾ 147 (13.8) 59 (7.2) 4 (0.4) 1 (0.1) 䶎ᑨᑨ㿱⎸ॆн㢟 108 (10.1) 48 (5.9) 1 (0.1) 0 䶎ᑨᑨ㿱䭉 75 (7.0) 39 (4.8) 1 (0.1) 0 ᑨ㿱㛍㛶㌫㔏⯮⯵㛍㜿∂ᙗ 3 20 (1.9) 7 (0.9) 16 (1.5) 4 (0.5) ᑨ㿱Ⳟ㛔৺Ⳟл㓴㓷㊫⯮⯵㝡ਁ 268(25.2) 102 (12.5) 0 0 䶎ᑨᑨ㿱Ⳟ⯩ 4 253 (23.8) 81 (9.9) 10 (0.9) 1 (0.1) 䶎ᑨᑨ㿱ⱉⰂ 197 (18.5) 57 (7.0) 5 (0.5) 0 䶎ᑨᑨ㿱Ⳟ㛔ᒢ⠕ 96 (9.0) 23 (2.8) 0 0 ᑨ㿱㓒ᯁ 55 (5.2) 13 (1.6) 2 (0.2) 1 (0.1) ᑨ㿱ⲭⲌ仾 30 (2.8) 0 1 (0.1) 0 ᑨ㿱䓛ᙗ⯮⯵৺㔉㦟䜘ս਴਴⿽৽ᓄ⯢ѿ 373 (35.0) 263 (32.2) 23 (2.2) 5 (0.6) 䶎ᑨᑨ㿱ཆઘ≤㛯 171 (16.1) 83 (10.1) 2 (0.2) 0 䶎ᑨᑨ㿱ਁ✝ 168 (15.8) 60 (7.3) 5 (0.5) 1 (0.1) 䶎ᑨᑨ㿱࣋161 (15.1) 108 (13.2) 10 (0.9) 3 (0.4) 䶎ᑨᑨ㿱ਓ૭⯬Ⰻ 87 (8.2) 46 (5.6) 0 0 ᑨ㿱ਓᒢ 83 (7.8) 51 (6.2) 1 (0.1) 0 ᑨ㿱਴㊫ỰỰḕ㜭Ựḕᔲᑨ 5 216 (20.3) 89 (10.9) 105 (9.9) 17 (2.1) 䶎ᑨᑨ㿱㹰㚼䞀ॷ儈 84 (7.9) 20 (2.4) 7 (0.7) 0 ᑨ㿱ᗳ⭥മ QT 䰤ᵏᔦ䮯 73 (6.9) 14 (1.7) 14 (1.3) 2 (0.2) ᑨ㿱1 ᝏḃ˖਴⿽ቯ䐟ᝏḃ˗਴㊫બ੨䚃ᝏḃ˗㛳㛐⚾˗㝃∂⯷˄<1%˅DŽ2 㞩Ⰻ˖㞩Ⰻǃк㞩ⰋDŽ3˅DŽ4 Ⳟ⯩˖Ⳟ⯩ǃᯁш⯩ǃⱉⰂᙗⳞ⯩DŽ5㜭Ựḕᔲᑨ˖ALT ॷ儈ǃAST ॷ儈ǃ㹰㛶㓒㍐ॷ儈DŽ

ᇎ傼ᇔỰḕᔲᑨ㺘 8Ҷ 3 亩 IIIⲴᑨ㿴㹰⏢ᆖᡆ⭏ॆᇎ傼ᇔỰḕᔲᑨDŽ㺘 8 สҾ III ᵏѤᒺ⹄ウ≷ᙫᮠᦞ䳶Ⲵᇎ傼ᇔỰḕᔲᑨᇎ傼ᇔỰḕᔲᑨKisqaliN=1065n˄%˅ᡰᴹㅹ㓗ࡲN=818n˄%˅ᡰᴹㅹ㓗KisqaliN=1065n˄%˅3/4 㓗㓗ࡲN=818n˄%˅3/4 㓗㓗㊫˄ᡰᴹㅹ㓗˅㹰⏢ᆖ৲ᮠⲭ㓶㜎䇑ᮠ䱽վ 1009 (94.7) 268 (32.8) 380 (35.7) 10 (1.2) 䶎ᑨᑨ㿱

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ᇎᇎ傼ᇔỰḕᔲᑨKisqaliN=1065n˄%˅ᡰᴹㅹ㓗ࡲN=818n˄%˅ᡰᴹㅹ㓗KisqaliN=1065n˄%˅3/4 㓗ࡲN=818n˄%˅3/4 㓗㓗㊫˄ᡰᴹㅹ㓗˅ѝᙗ㋂㓶㜎䇑ᮠ䱽վ 994 (93.3) 227 (27.8) 660 (62.0) 20 (2.4) 䶎ᑨᑨ㿱㹰㓒㳻ⲭ䱽վ 728 (68.4) 339 (41.4) 54 (5.1) 19 (2.3) 䶎ᑨᑨ㿱⏻ᐤ㓶㜎䇑ᮠ䱽վ 703 (66.0) 228 (27.9) 209 (19.6) 37 (4.5) 䶎ᑨᑨ㿱㹰ሿᶯ䇑ᮠ䱽վ 366 (34.4) 86 (10.5) 16 (1.5) 5 (0.6) 䶎ᑨᑨ㿱⭏ॆ৲ᮠAST ॷ儈 580 (54.5) 343 (41.9) 83 (7.8) 17 (2.1) 䶎ᑨᑨ㿱Ȗ-GT ॷ儈 1 390 (53.4) 229 (46.9) 67 (9.2) 51 (10.5) 䶎ᑨᑨ㿱ALT ॷ儈 548 (51.5) 315 (38.5) 119 (11.2) 14 (1.7) 䶎ᑨᑨ㿱㚼䞀ॷ儈 447 (42.0) 121 (14.8) 14 (1.3) 2 (0.2) 䶎ᑨᑨ㿱㹰␵㪑㨴㌆䱽վ 216 (20.3) 113 (13.8) 3 (0.3) 2 (0.2) 䶎ᑨᑨ㿱ቁ 190 (17.8) 79(9.7) 46 (4.3) 8 (1.0) 䶎ᑨᑨ㿱ⲭ㳻ⲭ䱽վ 122 (11.5) 53 (6.5) 1 (0.1) 1 (0.1) 䶎ᑨᑨ㿱ቁ 118 (11.1) 76 (9.3) 22 (2.1) 10 (1.2) 䶎ᑨᑨ㿱㛶㓒㍐ॷ儈 64 (6.0) 46 (5.6) 12 (1.1) 9 (1.1) ᑨ㿱1 Ӿ⹄ウ MONALEESA-3 ઼⹄ウ MONALEESA-7 䟷䳶ⲴᮠᦞDŽสҾ ribociclib 㓴Ⲵṧᵜ䟿 N = 731㓴 N = 488 ⲴᮠᦞDŽкᐲਾᮠᦞˈӾᵜ૱Ⲵкᐲਾ㓿傼ѝ㧧ᗇԕл ADRDŽ⭡Ҿ䘉Ӌ৽ᓄਁ⭏仁⦷ˈഐ↔ˈᖂ㊫Ѫ仁⦷ᵚ⸕DŽ㺘 9 ᶕ㠚㠚ਁᙗᣕ੺઼᮷⥞Ⲵ㦟⢙н㢟৽ᓄ˄仁⦷ᵚ⸕˅બ੨㌫㔏ǃ㜨৺㓥㞸⯮⯵䰤䍘ᙗ㛪⯮⯵˄ILD˅/㛪䜘⚾⯷Ⳟ㛔৺Ⳟл㓴㓷㊫⯮⯵ѝ∂ᙗ㺘Ⳟൿ↫ᶮ䀓⯷˄TEN˅㦟⢙н㢟৽ᓄ䘹䘠ቁ⯷ቁ⯷ᱟ IIIѕ䟽〻ᓖˈѝᙗ㋂ቁ⯷Ⲵ㇑⨶ᯩ⌅वᤜᇎ傼ᇔⴁ⍻ǃѝᯝ㔉㦟઼ /Ԇ㦟ቁ⯷ሬ㠤Ⲵ⋫⯇㓸→˄0.8%˅(㿱⭘⌅⭘䟿৺⌘᜿һ亩)DŽ㛍㛶∂ᙗ൘ III儈ҾᆹហѪ 27.3%઼ 19.6%Ԇ㦟⢙㓴 3/4 㓗 AE Ⲵਁ⭏Ѫ 13.2%઼ 6.1%˅DŽᵜ૱⋫⯇㓴ᴹ 12.3%Ⲵᛓ㘵ഐ㛍㛶∂ᙗһԦ˄ѫ㾱वᤜ ALT ॷ儈˄7.9%˅઼/ᡆ AST ॷ儈˄7.3%˅˅㘼ѝᯝ㔉㦟઼/ᡆ䈳ᮤᴹ 2.4%઼ 0.3%⭘ᵜ૱˄㿱⌘᜿һ亩ࠋ

9/10

QT ᔦᔦ䮯൘ IIIᴹ 9.3%઼ 3.5%Ⲵᛓ㘵ਁ⭏㠣ቁа䎧 QT 䰤ᵏᔦ䮯һԦ˄वᤜ ECG QT ᔦ䮯ǃᲅ৕˅DŽᵜ૱⋫⯇㓴ᴹ 2.9%Ⲵᛓ㘵ഐᗳ⭥മ QT 䰤ᵏᔦ䮯઼ᲅ䟿DŽሩ ECG ᮠᦞ˄Ựḕ 3࠶ᴹ 55˄5.2%˅઼ 12˄1.5%˅ᛓ㘵㠣ቁᴹа⅑ส㓯 QTcF 䰤ᵏ>480 msDŽ൘ QTcF 䰤ᵏᔦ䮯>480 msਁ֌ѝսᰦ䰤Ѫ 15 ཙˈ䘉Ӌਈॆ䙊䗷ѝᯝ⋫⯇઼/䟿䈳ᮤਾ൷ਟ䘶˄㿱⭘⌅⭘䟿ǃ⌘᜿һ亩৺Ѥᒺ㦟⨶˅DŽǏ⾱ᗼǐᡆԫօ䖵ᯉ䗷᭿Ⲵᛓ㘵⾱⭘ᵜ૱DŽǏ⌘᜿һ亩ǐቁ⯷൘ 3 亩 III ᵏѤᒺ⹄ウѝ˄MONALEESA-2ǃMONALEESA-7 ઼ MONALEESA-3˅ˈѝᙗቁ⯷ᱟᴰᑨᣕ੺Ⲵ㦟⢙н㢟৽ᓄ˄75.4%˅ˈф൘ IIIަԆ㦟⢙㓴ᴹ 62.0%Ⲵᛓ㘵ᣕ੺Ҷ 3 㓗ᡆ 4ቁ˄ṩᦞᇎ傼ᇔỰḕ㔃᷌˅DŽ൘ III⧠ 2ǃ3 ᡆ 4ቁ⯷Ⲵᛓ㘵ѝˈ2ǃ3 ᡆ 4 㓗ѝᙗ㋂㓶㜎ቁ⯷ਁ⭏Ⲵѝսᰦ䰤Ѫ 17Ԇ㦟⢙㓴ѝˈ ı3 㓗һԦ⎸䘰˄㠣ᚒ༽↓ᑨᡆ<3 㓗˅Ⲵѝսᰦ䰤Ѫ 12DŽ൘ III ᵏѤᒺ⹄ウѝ᳤䵢Ҿᵜ૱Ⲵᛓ㘵ѝˈᴹ 1.7%ቁ⯷DŽ५⭏ᓄ੺⸕ᛓ㘵䴰৺ᰦᣕ੺ਁ✝һԦ˄㿱нн㢟৽ᓄ˅DŽ㹰㓶㜎䇑ᮠ˄CBCࡽ2ᓄ⇿ 2 ઘⴁ⍻а⅑ CBCˈ䲿ਾ 4൘⇿њઘᵏᔰ࿻ᰦⴁ⍻ CBCˈ❦ਾṩᦞѤᒺᤷᖱⴁ⍻ CBCDŽ⭘ᵜ૱ˈ䈖㿱㺘 2˄㿱⭘⌅⭘䟿˅DŽ㛍㛶∂ᙗ൘ III䖜≘䞦ॷ儈DŽԆ㦟⢙㓴ᣕ੺Ҷ 3 㓗ᡆ 4 㓗 ALT˄11.2%vs.1.7%˅઼ AST˄7.8% vs. 2.1%Ԇ㦟⢙㓴ᣕ੺Ҷ 4 㓗 ALT˄2.0% vs. 0.2%˅઼ AST˄1.1% vs. 0.1%˅ॷ儈DŽ൘რᵏѤᒺ⹄ウѝˈ70.9%˄90/127˅Ⲵ 3 㓗ᡆ 4 㓗 ALT ᡆ AST ॷ儈һԦਁ⭏Ҿᔰ࿻⋫⯇ਾ 6˄㿱н㢟৽ᓄ˅DŽབྷཊ ALT ઼ AST ॷ儈һԦ൷ᵚդ䲿㛶㓒㍐ॷ儈DŽ൘ 3 㓗ᡆ 4 㓗ALT/ASTԆ㦟⢙⋫⯇㓴Ⲵਁ֌ѝսᰦ䰤Ѫ 92 ཙDŽᵜ૱㚄⭘ԫԆ㦟⢙㓴Ⲵ⎸䘰ѝսᰦ䰤˄㠣ᚒ༽↓ᑨᡆİ2 㓗˅Ѫ 21 ཙDŽ6ᛓ㘵˄⹄ウ A2301 ѝ 4⭘ᵜ૱ਾ 154ᚒ༽↓ᑨ˗⹄ウ F2301 ѝ2⭘ᵜ૱ਾ 121 ઼ 532ᚒ༽↓ᑨDŽ⹄ウ E2301˅ALT ᡆ AST˚3×ULNˈфᙫ㛶㓒㍐˚2×ULNˈն⻡ᙗ⼧䞨䞦≤ᒣ↓ᑨˈфᵚਁ⭏㛶≱␔〟DŽ

10/11

ᓄ䘋㹼 LFTࡽ2ᓄ⇿ 2 ઘⴁ⍻а⅑ LFTˈ䲿ਾ 4޵൘⇿њઘᵏᔰ࿻ᰦⴁ⍻ LFTˈ❦ਾṩᦞѤᒺᤷᖱⴁ⍻ LFTDŽ⭘ᵜ૱ˈ䈖㿱㺘 3˄㿱⭘⌅⭘䟿˅DŽቊᰐሩส㓯ᰦ AST/ALT ॷ儈ı3 㓗ᛓ㘵Ⲵᔪ䇞DŽQT 䰤䰤ᵏᔦ䮯൘ IIIԆ㦟⢙⋫⯇Ⲵᲊᵏᡆ䖜〫ᙗң㞪ⱼᛓ㘵ѝˈᗳ⭥മᮠᦞᱮ⽪ 15ᛓ㘵˄1.4%˅ส㓯ਾ QTcF٬500 ms ˈ61˄5.8%˅ᛓ㘵Ⲵ QTcF䰤ᵏ䖳ส㓯ᔦ䮯>60 msDŽ൘ E2301˄MONALEESA-7ӊ㓴ᒣ൷ QTcF 䰤ᵏ⴨∄ส㓯Ⲵᔦ䮯ᰦ䰤㓖∄ NSAIӊ㓴䮯 10 msᴹᔦ䮯 QTcF 䰤ᵏⲴ֌⭘ˈ䘉ਟ㜭ࡠQTcF 䰤ᵏᔦ䮯Ⲵ৏ഐ˄㿱Ѥᒺ㦟⨶-ᗳ㜿⭥⭏⨶ᆖ˅DŽ൘ᆹ㓴ѝˈ6/90˄6.7%˅᧕ਇԆ㧛᱄㣜Ⲵᛓ㘵⴨∄ส㓯ᔦ䮯>60 ms ˈ᧕ਇ NSAI Ⲵᛓ㘵ѝᰐᛓ㘵Ⲵ QTcF ⴨∄ส㓯ᔦ䮯>60 msDŽ൘᧕ਇᵜ૱㚄⭘Ԇ㧛᱄㣜Ⲵ 14/87˄16.1%˅ᛓ㘵઼᧕ਇᵜ૱㚄⭘ NSAI Ⲵ 18/245˄7.3%ࡠQTcF 䰤ᵏ⴨∄ส㓯ᔦ䮯>60 msDŽ䇴ՠ ECGDŽӵ QTcF٬450 ms Ⲵᛓ㘵᡽ਟ੟⭘ᵜ૱⋫⯇DŽ൘ㅜ 1 њઘᵏㅜ 14ਾԕ৺ㅜ 2ṩᦞѤᒺᤷᖱỰḕᗳ⭥മDŽࡽ6 њઘᵏ⇿њઘᵏᔰ࿻ᰦԕ৺ᴹѤᒺᤷᖱᰦሩ㹰␵⭥䀓䍘˄वᤜ䫮ǃ઼⋫⯇ᵏ䰤㓐↓⧠ⲴԫօᔲᑨDŽ⧠ QTc 䰤ᵏᔦ䮯ᡆ QTcփवᤜⲴᛓ㘵˖

x 䮯 QT 㔬ਸᖱx 㺠ㄝǃнっᇊරᗳ㔎Ⰻ઼㕃ធරᗳᖻཡᑨx ⭥䀓䍘㌺ҡሶᵜ૱оᐢ⸕ਟᔦ䮯 QTc 䰤ᵏ઼/ᡆ CYP3AⲴ㦟૱㚄⭘ˈԕ䱢 QTcF 䰤⧠ᴹѤᒺ᜿ѹⲴᔦ䮯˄㿱⭘⌅⭘䟿ǃ㦟⢙⴨ӂ֌⭘৺Ѥᒺ㦟⨶˅DŽṩᦞ MONALEESA-7˄E2301˅Ⲵ⹄ウ㔃᷌ˈнᔪ䇞ሶᵜ૱оԆ㧛᱄㣜㚄⭘˄㿱Ѥᒺ⹄ウ˅DŽⲴ QT⭘ᵜ૱ˈ䈖㿱㺘 4˄㿱⭘⌅⭘䟿ǃн㢟৽ᓄ৺Ѥᒺ㦟⨶˅DŽ⭏⇆∂ᙗ䙐ᡀᦏᇣDŽᔪ䇞ᴹ⭏㛢㜭Ⲵྣᙗ൘ᵜ૱⋫⯇ᵏ䰤ԕ৺ᵛ⅑㔉㦟ਾ㠣ቁ 21䟷ਆᴹ᭸Ⲵ䚯ᆅ᧚ᯭ˄㿱ᆅྷ৺ପңᵏྷྣ⭘㦟˅DŽ

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䟽䟽ᓖⳞ㛔৽ᓄᵜ૱Ⲵ⋫⯇ᴮᣕ੺䗷ѝ∂ᙗ㺘Ⳟൿ↫ᶮ䀓⯷˄TENྲˈ⭘ᵜ૱DŽ䰤䍘ᙗ㛪⯮⯵˄ILD˅/㛪䜘⚾⯷ᴮᴹ CDK4/6⋫⯇Ⲵ ILD/DŽ൘ 3 亩 III ᵏѤᒺ⹄ウ˄ MONALEESA-2˄A2301˅ǃ MONALEESA-7˄E2301-NSAI ˅઼MONALEESA-3 ˄F2301˅˅ѝˈᵜ૱⋫⯇㓴ᣕ੺Ҷ ILD˄0.3%ѝ 0.1%Ѫ 3࡛0.6%ˈvs 0.4%˅ˈєњ⋫⯇㓴൷ᵚᣕ੺ 3/4Ԇ ILD/㛪䜘˄㿱н㢟৽ᓄ˅DŽṩᦞ ILD/⭘ᵜ૱ˈ䈖㿱㺘 5˄㿱⭘⌅⭘䟿˅DŽᓄⴁ⍻ᛓ㘵ᱟ੖ᆈ൘ᨀ⽪ ILD/㛪䜘⚾⯷Ⲵ⯷⣦ˈਟ㜭वᤜ㕪≗ǃૣభ઼બ੨ഠ䳮DŽਁ⭏ 1㓗 ILD/䟿䈳ᮤDŽṩᦞѤᒺᤷᖱˈ䘋㹼䘲ᖃⲴ㦟⢙⋫⯇ᒦ䘋㹼ⴁ⍻DŽਁ⭏ 2 㓗 ILD/㛪䜘⚾⯷Ⲵᛓ㘵ˈᓄѝᯝᵜ૱㔉㦟ˈⴤ㠣ᚒ༽㠣İ1䟿䟽ᯠ੟⭘ᵜ૱㔉㦟DŽਁ⭏ 3 㓗ᡆ 4 㓗 ILD/⭘ᵜ૱˄㿱⭘⌅⭘䟿˅DŽǏᆅྷ৺ପңᵏྷྣ⭘㦟ǐྺၐ仾䲙ᙫ㔃䙐ᡀᦏᇣDŽᑖᶕ仾䲙DŽ⭏⇆⹄ウ㺘᰾ˈᵜ૱ਟ䈡ሬ⵰ᒺਾђཡ઼㛾Ԅփ䟽䱽վⲴਁվҾᡆ 1.5ҾӪփ᳤䵢䟿˄สҾ AUC䟿 600 mg/㜿઼僘僬ᔲᑨ˅Ⲵਁ⭏仾䲙ⲴӪփᮠᦞDŽᮠᦞ⢙ᮠᦞ㜊㛾-䟿İ 1,000 mg/kg/ཙ઼ 60 mg/kg/ཙⲴᵜ૱㓿ਓ㔉㦟DŽ൘བྷ啐ѝˈ1,000 mg/kg/䟿DŽ䇔Ѫ൘ 300 mg/kg/Ⲵ⇽փѪа䗷ᙗ઼/DŽ൘ 50 ᡆ 300 mg/kg/㜊㛾-ᖡ䟿˄ NOAEL˅Ѫ 300mg/kg/ཙDŽ㜊㛾-㛾Ԅਁ㛢Ⲵᰐਟ㿱֌⭘≤ᒣ˄NOEL˅Ѫ 50 mg/kg/ཙDŽ䟿ı30 mg/kg/㜿઼僘僬ᔲᑨ˅઼㛾Ԅ⭏䮯㺘᰾㦟⢙ሩ㜊㛾 -㛾Ԅਁ㛢ӗ⭏н㢟ᖡ૽DŽ䘉Ӌ㔃᷌वᤜ㛪

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ቁ/ቁ /ሿ˄30઼ 60 mg/kg⧠ㅜ 13 ṩ㚻僘/ᴹㅜ 13߿ቁDŽ⋑ᴹ㜊㛾-㛾Ԅ↫ӑⲴ䘩䊑DŽ⇽փ∂ᙗᰐਟ㿱֌⭘≤ᒣ˄ NOEL˅㠣ቁѪ 30 mg/kg/ ཙˈ㜊㛾-㛾Ԅਁ㛢Ⲵ NOEL Ѫ 10 mg/kg/ཙDŽབྷ啐᧕ਇ 300 mg/kg/᧕ਇ 30 mg/kg/䓛᳤䵢䟿˄AUCѪ13,800 ng×h/mL ઼ 36,700 ng×h/mL䟿 600 mg/ ཙᰦ AUC Ⲵ 1.5DŽପପң仾䲙ᙫ㔃Ⲵᖡ૽ᡆᵜ૱ሩ⋼ң䟿ᖡ૽ѝᕅ䎧ѕ䟽⭘㦟DŽᔪ䇞ྣᙗᛓ㘵൘ᴰਾа⅑ᴽ⭘ᵜ૱ਾ㠣ቁ 21н㾱ପңDŽᮠᦞ⢙ᮠᦞ൘᧕ਇ 50 mg/kg অ⅑㔉㦟Ⲵପңᵏབྷ啐ѝˈң≱ѝᵜ૱Ⲵ᳤䵢䟿ᱟ⇽փ㹰⍶Ⲵ 3.56DŽⲴྣᙗ઼⭧ᙗ䙐ᡀᦏᇣ˄㿱∂⨶⹄ウ˅DŽྺၐ䈅傼⺞䇔ྺၐ⣦ᘱDŽ䚯ᆅ⢙⹄ウᱮ⽪ˈᵜ૱ਟሩਁ㛢ѝⲴ㛾Ԅ䙐ᡀᦏᇣDŽ⭘ᵜ૱⋫⯇ਾ 21֯⭘ᴹ᭸Ⲵ䚯ᆅ᧚ᯭ˄ྺၐ⦷<1%Ⲵᯩ⌅˅DŽн㛢⹄ウѝˈ൘İ300 mg/kg/䟿 600 mg/ᡆᰙᵏ㜊㛾ਁ㛢ӗ⭏ᖡ૽DŽ⹄ウˈնᱟ൘བྷ啐઼⣜䟽༽㔉㦟∂ᙗ⹄ウ˄᳤䵢䟿İӪ᧕䟿 600 mg/ޣDŽㄕ⭘㦟ǐᙗ઼⯇᭸DŽǏ㘱ᒤ⭘㦟ǐ65䟿˄㿱Ѥᒺ㦟⨶˅DŽ

13/14

ǏǏ㦟⢙⴨ӂ֌⭘ǐᵜ૱ѫ㾱⭡ CYP3A ԓ䉒ˈᱟ CYP3ADŽഐ↔ˈਟᖡ૽ CYP3AᆖDŽᵜ૱㹰⍶⎃ᓖⲴ㦟૱о CYP3A4ࡠ࣐3.21㚄⭘ CYP3A᣹䴹㍐ǃ㥊ൠ䛓世ǃԺᴢᓧୁǃ䞞ᓧୁǃᢈ䛓世ǃ⋉ཾ䛓世ǃ⢩᣹३世ǃ⌠䴹㍐ǃ㔤᣹ᑅ㊣઼Կ・ᓧୁ˄㿱⌘᜿һ亩˅DŽᓄ㘳㲁㚄⭘ሩ CYP3AԆ㦟⢙ˈᒦⴁ⍻ᛓ㘵Ⲵ ADR˄㿱⭘⌅⭘䟿ǃ⌘᜿һ亩৺Ѥᒺ㦟⨶˅DŽྲ᷌ᗵ享㚄⭘ᵜ૱о CYP3A䟿㠣 400 mgޣ䟿ᚒ༽˄㠣ቁ CYP3AⲴ 5 њ⎸䲔ॺ㺠ᵏਾ˅㠣੟⭘ CYP3A䟿DŽ⭡Ҿᛓ㘵ⴁ⍻ ADRDŽ䟿˄㿱⭘⌅⭘䟿˅ˈᡆѝᯝ㔉㦟ⴤ㠣∂ᙗ⎸䘰˄㿱⭘⌅⭘䟿৺Ѥᒺ㦟⨶˅DŽ㓶㜎㢢㍐ CYP3A 䞦ˈᒦᵜ૱Ⲵ᳤䵢䟿DŽਟ㜭䱽վᵜ૱㹰⍶⎃ᓖⲴ㦟૱о CYP3A4Ⲵᵜ૱㹰⍶᳤䵢䟿䱽վ 89%DŽнᗇ㚄⭘ CYP3A⾿ᒣǃ঑傜㾯ᒣ઼൓㓖㘠㥹˄䍟ਦ䘎㘈˅DŽᓄ㘳㲁㚄⭘ሩ CYP3AԆ㦟⢙˄㿱⌘᜿һ亩৺Ѥᒺ㦟⨶˅DŽ㹰⍶⎃ᓖⲴ㦟૱о૚䗮ୁԁ˄CYP3A4 ᓅ⢙˅অ⤜㔉㦟⴨∄ˈ૚䗮ୁԁоᵜ૱˄400 mg ˅ཊ⅑㚄ਸ㔉㦟ਟ࣐280%˄3.80˅DŽ⭏⨶ᆖ PK˄PBPK˅⁑ර⁑ᤏ㔃᷌㺘᰾ˈᵜ૱൘ 600 mg૚䗮ୁԁ AUCࡠ࣐5.2DŽഐ↔ˈᔪ䇞ሶᵜ૱о⋫⯇ᤷᮠゴⲴ CYP3A ᓅ⢙㚄⭘ᰦˈ䴰䉘᝾DŽਟ㜭䴰㾱䱽վ⋫⯇ᤷᮠゴⲴ᭿ᝏ CYP3A㔤㧛ਨǃ㣜ཚቬǃ䘉Ӌ㦟⢙Ⲵ᳤䵢䟿˄㿱Ѥᒺ㦟⨶˅DŽо૆஑ഐ˄CYP1A2 ᓅ⢙˅অ⤜㔉㦟⴨∄ˈ૆஑ഐоᵜ૱˄400 mg࣐֯20%˄1.20˅DŽ൘ 600 mg䟿лˈPBPK ⁑ර⁑ᤏ㔃᷌㺘᰾ˈᵜ૱亴䇑ሩ CYP1A2֌⭘˄ AUC࣐2˅˄㿱Ѥᒺ㦟⨶˅DŽ኎Ҿ䖜䘀㳻ⲭᓅ⢙Ⲵ㦟૱㦟⢙䖜䘀㳻ⲭ P-gpǃOAT1/3ǃOATP1B1/B3ǃMATEK2 ઼ OCT1ࡦBCRPǃOCT2ǃMATE1઼Ӫ BSEP˄㿱Ѥᒺ㦟⨶˅DŽ

14/15

㦟㦟⢙-伏⢙⴨ӂ֌⭘ᵜ૱ਟդᡆнդ伏⢙ᴽ⭘˄㿱⭘⌅⭘䟿˅DŽоオ㞩⣦ᘱ⴨∄ˈঅ⅑ਓᴽ 600 mg ᵜ૱㮴㟌व㺓⡷ᰦ਼ᰦ伏⭘儈㜲儈✝䟿㟣伏ሩᵜ૱Ⲵ੨᭦䙏⦷઼੨᭦〻ᓖ⋑ᴹᖡ૽˄Cmax GMR˖1.00˗90% CI˖0.898ˈ1.11˗AUCinf GMR˖1.06˗90% CI˖1.01ˈ1.12˄㿱Ѥᒺ㦟⨶˅DŽ㛳 pHⲴ㦟⢙ᵜ૱൘ pH 4.5 ᡆ 4.5ส˄pH 5.0 ઼ 6.5˅ѝⲴⓦ䀓ᓖ䖳儈DŽᵚ൘Ѥᒺ㛳 pH⭘PBPKᖡ૽˄㿱Ѥᒺ㦟⨶˅DŽ亴ᵏⲴ⴨ӂ֌⭘Ԇਟ㜭ᔦ䮯 QT 䰤ᵏⲴ㦟૱˖ሶᐢ⸕ᴹਟ㜭ᔦ䮯 QT 䰤ᵏⲴ㦟૱˄ྲ㚄⭘ᣇᗳᖻཡᑨ㦟˄वᤜնн䲀Ҿ㜪⻈䞞ǃщੑ㜪ǃᲞ励঑ഐ㜪ǃཾቬб઼㍒Ԇ⍋ቄ˅ǃᐢ⸕ਟᔦ䮯 QTԆ㦟૱˄वᤜնн䲀Ҿ≟௩ǃঔ⌋㗔ǃ᣹䴹㍐ǃ⧟щ⋉ᱏǃᐖ≗≏⋉ᱏǃ䱯ཷ䴹㍐ǃ≏ૼ஦䞷ǃ㖾⋉䞞ǃ㧛㾯⋉ᱏǃ㣴Პൠቄǃ३㧛喀⢩઼ᰲѩਨ⩬˄䶉㜹⌘ሴ˅˅DŽнᔪ䇞ሶᵜ૱оԆ㧛᱄㣜㚄⭘˄㿱⌘᜿һ亩˅DŽǏ㦟⢙䗷䟿ǐл൷ᓄ䝼ᛵ䟷ਆа㡜ሩ⯷઼᭟ᤱᙗ⋫⯇᧚ᯭDŽǏѤᒺ㦟⨶ǐࡦ䎆ᙗ◰䞦˄CDK˅4 ઼ 6DŽ䘉Ӌ◰䞦о D-㓶㜎ઘᵏਧՐሬ䙊䐟ѝਁᥕ⵰䟽㾱֌⭘DŽ㓶㜎ઘᵏ㳻ⲭ D-CDK4/6 ༽ਸ⢙䙊䗷㿶㖁㟌⇽㓶㜎ⱔ㳻ⲭ˄pRb˅Ⲵ⼧䞨ॆ䈳᧗㓶㜎ઘᵏ䘋〻DŽᵜ૱൘փཆਟ䱽վ pRb㓶㜎ઘᵏ G1㕃ң㞪ⱼ㓶㜎㌫ѝⲴ㓶㜎䟿лሩ pRb ⼧䞨ॆਟDŽ⹄ウѝˈᵜ૱઼ᣇ䳼◰㍐⭏䮯ᔦ䘏33 ཙDŽ↔ཆˈ൘ ZR751 ER+⯛㕪䲧ሿ啐ѝ䇴ՠҶᵜ૱о≏㔤ਨ㗔㛯ⱔ⭏䮯DŽᆖ˄PD˅ࡦCDK4/㓶㜎ઘᵏ㳻ⲭ-D1 ઼ CDK6/㓶㜎ઘᵏ㳻ⲭ-D3 䞦༽ਸ⢙ˈ⎃ᓖ˄IC50Ѫ 0.01 ȝmol˄4.3 ng/mL˅઼ 0.039 ȝPRO˄16.9 ng/mL˅DŽࡦCDK4/6䎆ᙗ pRb ⼧䞨ॆˈᒣ൷ IC50 Ѫ 0.06 ȝmol˄26ng/mL˅DŽṩᦞ⍱ᔿ㓶㜎Ԛ⍻䟿㔃᷌ˈᵜ૱ਟ䱫→㓶㜎ઘᵏӾ G1 ᵏ䗷⑑㠣 S ᵏˈᒣ൷ IC50 Ѫ0.11 ȝmol˄47.8 ng/mL ˅DŽṩᦞⓤ㝡≗ቯ㤧˄BrdU㓶㜎໎⇆ˈIC50 Ѫ

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0.8 ȝmol˄34.8 ng/mL ˅DŽ䶦ੁ䈳᧗ǃ㓶㜎ઘᵏ઼㓶㜎໎⇆䈅傼ᡰᗇ IC50⴨լ㺘᰾ˈᵜ૱ሩpRb ⼧䞨ॆⲴ䱫ᯝ֌⭘ਟⴤ᧕䱫→ G1 ᵏ䗷⑑㠣 S⭘ ER ⣦ᘱᐢ⸕Ⲵа㓴ң㞪ⱼ㓶㜎㌫䘋㹼䈅傼ᰦਁ⧠ˈᵜ૱൘ ER+ң㞪ⱼ㓶㜎㌫ѝⲴ᭸᷌ྭҾ ER-㓶㜎㌫DŽᗳᗳ㜿⭥⭏⨶ᆖっᘱᰦ䘎㔝⍻䟿 3 ⅑ ECGˈԕ䇴ՠᵜ૱ሩᲊᵏⱼ⯷ᛓ㘵 QTc 䰤ᵏⲴᖡᆖ-ޕ997䟿㤳തѪ 50-1,200 mg ˅⋫⯇Ⲵᛓ֯QTc䎆ᙗᔦ䮯DŽᵜ૱ 600 mg 㚄⭘ NSAI ᡆ≏㔤ਨ㗔ᰦՠ䇑Ⲵᒣ൷ QTcFѪ 22.00 ms˄90% CI˖20.56ˈ23.44˅઼ 23.7ms˄90% CI ˖22.31ˈ25.08օᒣ൷ Cmax лˈ㚄⭘Ԇ㧛᱄㣜ᰦѪ 34.7 ms˄90%CI˖31.64 37.78˅˄㿱⌘᜿һ亩˅DŽᆖ൘ᲊᵏⱼ⯷ᛓ㘵⇿ᰕਓᴽ 50 mg 㠣 1,200 mgᓧਇ䈅㘵অ⅑ਓᴽ 400 ᡆ 600 mg䟿ˈᡆ⇿ᰕਓᴽа⅑ 400 mgˈ䟽༽㔉㦟 8 ཙDŽ੨᭦ᲊᵏᇎփⱔᡆ⏻ᐤⱔᛓ㘵ਓᴽᵜ૱ਾ 1-4 h ˄䗮ጠᰦ䰤ˈTmax٬˄Cmaxᓧਇ䈅㘵൘অ⅑ਓᴽᵜ૱ 600 mgօᒣ൷∄⦷Ѫ 65.8%DŽ൘䈅傼Ⲵ 50-1,200 mgˈᵜ૱᳤䵢䟿˄Cmax ઼ AUC∄DŽ⇿ᰕа⅑䟽༽㔉㦟ᵏ䰤ˈа㡜൘㔉㦟 8օᒣ൷㫴〟∄Ѫ 2.51˄㤳ത˖0.972-6.40)DŽ伏⢙ᖡ૽˖оオ㞩⣦ᘱ⴨∄ˈঅ⅑ਓᴽ 600 mg ᵜ૱㮴㟌व㺓⡷ᰦ਼ᰦ伏⭘儈㜲儈✝䟿㟣伏ሩᵜ૱Ⲵ੨᭦䙏⦷઼੨᭦〻ᓖ⋑ᴹᖡ૽˄ Cmax G M R˖1.00˗90% CI ˖0.898ˈ1.11˗AUCinf G M R˖1.06˗90% CI˖1.01ˈ1.12)˄㿱㦟⢙⴨ӂ֌⭘˅DŽᐳᵜ૱൘փཆоӪ㹰⍶㳻ⲭⲴ㔃ਸ⦷㓖Ѫ 70%˄10-10,000 ng/mL˅DŽᵜ૱൘㹰⏢о㹰⍶∄Ѫ 1.04᷀㔃᷌ˈᐳᇩ〟˄Vss/F˅Ѫ 1,090 LDŽ⭏⢙䖜ॆ/ԓ䉒⹄ウ㺘᰾ˈᵜ૱൘Ӫփѝѫ㾱䙊䗷 CYP3A4 䘋㹼ᒯ⌋Ⲵ㛍㜿ԓ䉒DŽӪঅ⅑ਓᴽ 600 mg [14C]ᵜ૱ਾˈᵜ૱Ⲵѫ㾱ԓ䉒䙄ᖴ⎹৺≗ॆ˄㝡✧สॆǃC ઼/ᡆ N-≗ॆǃ≗ॆ(-2H)˅ѝ਴⿽ԓ䉒䙄ᖴⲴн਼㓴ਸDŽᵜ૱ I ⴨ԓ䉒⢙Ⲵ II ⴨㔃ਸ⢙वᤜ N-҉䞠ॆǃ⺛䞨ॆǃॺ㜡ᇎփ˄43.5%˅DŽѫ㾱ᗚ⧟ԓ䉒⢙वᤜԓ䉒⢙ M13˄CCI284ˈN-㗏สॆ˅ǃM4˄LEQ803ˈN-৫⭢สॆ˅઼ M1䟿Ⲵ 9.39%ǃ8.60%઼ 7.78%ˈ㓖ঐᵜ૱᳤䵢䟿Ⲵ 21.6%ǃ19.8%઼ 17.9%ᙗ˅ѫ㾱ᶕ㠚Ҿ⇽փ㦟⢙ˈᗚ⧟ԓ䉒⢙ӗ⭏Ⲵ⍫ᙗਟᘭ⮕н䇑DŽ

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ঐ 17.3%઼ 12.1%DŽԓ䉒⢙ LEQ803䟿Ⲵ 13.9%઼ 3.74%઼ቯ䟿Ⲵ 2.78%˅DŽ⎸⎸䲔൘ᲊᵏⱼ⯷ᛓ㘵ѝˈ 600 mgօᒣ൷㹰⍶ᴹ᭸ॺ㺠ᵏ˄สҾ㫴〟∄˅Ѫ 32.0 h ˄63% CVօᒣ൷㺘㿲ਓᴽ␵䲔⦷˄CL/F˅Ѫ 25.5 L/h ˄66% CVڕᓧਇ䈅㘵⹄ウѝˈ600 mgօᒣ൷㹰⍶㓸ᵛॺ㺠ᵏ˄T1/2˅㤳തѪ 29.7-54.7 h ˈօᒣ൷ CL/F 㤳തѪ 39.9-77.5 L/hDŽ⎸䲔ˈ㛮㜿⎸䲔䟿ᖸቁDŽ6ᓧ⭧ᙗਇ䈅㘵অ⅑ਓᴽ[14C]ᵜ૱ਾˈ൘21䟿Ⲵ 91.7%ᱟѫ㾱Ⲵᧂ⋴䙄ᖴ˄69.1%˅ˈ൘ቯ⏢ѝ䟿ঐ 22.6%DŽ㓯ᙗ/䶎㓯ᙗ൘䈅傼Ⲵ 50-1,200 mgঅ⅑઼ཊ⅑㔉㦟ਾˈᵜ૱᳤䵢䟿˄Cmax ઼ AUC˅Ⲵ໎ᮠᦞᶕ㠚Ҿ 600 mg䟿㓴ˈ䟿㓴Ⲵṧᵜ䟿ሿDŽ⢩↺Ӫ㗔㛮ᦏᇣ䘈൘а亩 14㜭↓ᑨ˄㔍ሩ㛮ሿ⨳└䗷⦷˄aGFR˅ı90 mL/min˅ǃ8䖫ᓖ㛮ᦏᇣ˄aGFR 60 㠣<90 mL/min ˅ǃ6ѝᓖ㛮ᦏᇣ˄ aGFR 30 㠣<60 mL/min ˅ǃ7䟽ᓖ㛮ᦏᇣ˄aGFR 15 㠣<30 mL/min ˅઼ 3㓸ᵛᵏ㛮㜿⯮⯵˄ESRD˗aGFR<15 mL/min˅䶎ⱼ⯷ਇ䈅㘵᧕ਇ 400 mg/ᆖⲴᖡ૽DŽ㜭↓ᑨਇ䈅㘵⴨∄ˈ䖫ᓖǃѝᓖ઼䟽ᓖ㛮ᦏᇣਇ䈅㘵Ⲵ AUCinfࡠ࣐1.62ǃ1.94઼ 2.67ˈCmaxࡠ࣐1.80ǃ1.79઼ 2.30DŽESRD ਇ䈅㘵Ⲵᮠ䟿䖳ቁˈഐ↔˄㿱⭘⌅⭘䟿˅DŽᆖⲴᖡ૽DŽṩᦞሩ 438㜭↓ᑨ˄eGFRı90 mL/min/1.73 m 2˅ǃ488䖫ᓖ㛮ᦏᇣ˄eGFR 60㠣<90 mL/min/1.73 m 2˅઼ 113ѝᓖ㛮ᦏᇣ˄eGFR 30 㠣<60 mL/min/1.73 m 2˅ᛓ㘵䘋㹼Ⲵ㗔᷀㔃᷌ˈ䖫ᓖ઼ѝᓖ㛮ᦏᇣሩᵜ૱Ⲵ᳤䵢䟿⋑ᴹᖡ૽DŽਖཆˈ൘ሩཊ亩ⱼ⯷ᛓ㘵᧕ਇᵜ૱ 600 mg অ⅑ਓᴽ㔉㦟ᡆཊ⅑ਓᴽ㔉㦟⹄ウ˄MONALEESA-7ǃCLEE011X2101 ઼CLEE011X2107˅㧧ᗇⲴ PK᷀ѝˈሶ䖫ᓖᡆѝᓖ㛮ᦏᇣᛓ㘵᧕ਇᵜ૱অ⅑㔉㦟ᡆ൘っᘱлⲴ AUC ઼ Cmax㜭↓ᑨᛓ㘵䘋㹼Ҷሩ∄ˈ㺘᰾䖫ᓖᡆѝᓖ㛮ᦏᇣሩᵜ૱Ⲵ᳤䵢䟿нᆈ൘ᴹѤᒺ᜿ѹⲴᖡ૽˄㿱⭘⌅⭘䟿˅DŽ㛍ᦏᇣ䖫ᓖ㛍ᦏᇣ˄ Child-Pugh A䟿˗ѝᓖ˄ Child-Pugh B 㓗˅઼䟽ᓖ˄Child-Pugh C䟿Ѫ 400 mgDŽṩᦞ൘㛍ᦏᇣᛓ㘵ѝօᒣ൷∄˖Cmax˖1.44˗AUCinf˖1.28˅઼䟽ᓖ㛍ᦏᇣ˄ GMR˖Cmax˖1.32˗AUCinf˖1.29˅ᛓ㘵ѝˈᵜ૱

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Ⲵᒣ൷᳤䵢䟿໎ᑵሿҾ 2DŽሩ 160㜭↓ᑨᛓ㘵઼ 47䖫ᓖ㛍ᦏᇣᛓ㘵䘋㹼㗔փ㦟ԓ᷀ˈ㔃᷌㺘᰾ˈ䖫ᓖ㛍ᦏᇣሩᵜ૱Ⲵ᳤䵢䟿⋑ᴹᖡ૽ˈ䘉䘋а↕᭟ᤱҶу亩㛍ᦏᇣ⹄ウⲴ㔃᷌˄㿱⭘⌅⭘䟿˅DŽᒤ઼Ӫ⿽Ⲵᖡ૽ᖡ䟿DŽ㘱ᒤᛓ㘵൘ III ᵏ⹄ウѝ᧕ਇᵜ૱㔉㦟Ⲵ 334ᛓ㘵˄MONALEESA 2 ˈᵜ૱+ᶕᴢୁ㓴˅ѝˈ150ᛓ㘵˄44.9%˅Ⲵᒤ喴ı65 ኱ˈ35ᛓ㘵˄10.5%˅ı75 ኱DŽ൘ III ᵏ⹄ウѝ᧕ਇᵜ૱㔉㦟Ⲵ483ᛓ㘵˄MONALEESA 3 ˈᵜ૱+≏㔤ਨ㗔㓴˅ѝˈ226ᛓ㘵˄46.8%˅Ⲵᒤ喴ı65 ኱ˈ65ᛓ㘵˄13.5%˅ı75ᵜ૱൘䘉Ӌ㘱ᒤᛓ㘵оᒤ䖫ᛓ㘵ѻ䰤ᆈ൘ᙗᡆᴹ᭸ᙗᐞᔲ˄㿱⭘⌅⭘䟿˅DŽ⴨ӂ֌⭘CYP3A˖ᢈ䛓世˄CYP3A˅䘋㹼а亩㦟⢙⴨ӂ⭘ 400 mg ᢈ䛓世˄100 mg b.i.d ˈᤱ㔝㔉㦟 14ᵜ૱ C max ઼ AUCinfࡠ࣐1.7઼ 3.2DŽLEQ803˄ᵜ૱Ⲵѫ㾱ԓ䉒⢙ˈн䏣⇽փ᳤䵢䟿Ⲵ 10%˅Ⲵ Cmax ઼ AUClastл䱽 96%઼ 98%DŽสҾ PBPK ⁑ᤏ㔃᷌㺘᰾ˈ㚄⭘ CYP3A4ᵜ૱ 400 mgঅ⅑㔉㦟ਾⲴ Cmax ઼ AUC࠶࣐1.3઼ 1.9˄㿱⭘⌅⭘䟿ǃ⌘᜿һ亩৺㦟⢙⴨ӂ֌⭘˅DŽCYP3A˖⾿ᒣ˄CYP3A4˅䘋㹼Ҷа亩㦟⢙⴨⭘ 600 mg ⾿ᒣ˄600 mg⇿ᰕ 1 ⅑ˈᤱ㔝㔉㦟 14ᵜ૱ C max ઼ AUCinf䱽վ 81%઼ 89%DŽLEQ803 C maxࡠ࣐1.7ˈAUCinf 䱽վ 27%DŽPBPK ⁑ᤏ㔃᷌㺘᰾ˈCYP3Aᵜ૱অ⅑㔉㦟ਾⲴ Cmax ઼ AUCл䱽 37%઼ 60%˄㿱㦟⢙⴨ӂ֌⭘˅DŽ㓶㜎㢢㍐ P450 䞦˄CYP3A4 ઼ CYP1A2 ᓅ⢙˅˖⭘૚䗮ୁԁ˄᭿ᝏⲴCYP3A4 ᓅ⢙˅઼૆஑ഐ˄᭿ᝏⲴ CYP1A2 ᓅ⢙˅䘋㹼Ҷа亩㦟⢙呑ቮ䞂㦟⢙⴨ӂ֌⭘⹄ウDŽо૚䗮ୁԁ઼૆஑ഐঅ⤜㔉㦟⴨∄ˈᵜ૱ཊ⅑㔉㦟˄400 mg ⇿ᰕа⅑ˈᤱ㔝㔉㦟 8࡛࠶૚䗮ୁԁ Cmax ઼ AUCinfࡠ࣐2.1઼ 3.8DŽPBPK ⁑ᤏ㔃᷌㺘᰾ˈᵜ૱൘ 600 mg䟿л૚䗮ୁԁ Cmax ઼ AUCࡠ࣐2.4઼ 5.2DŽᵜ૱ཊ⅑㔉㦟ሩ૆஑ഐⲴᖡ૽ᖸሿ˖૆஑ഐ Cmax л䱽 10%ˈAUCinf࣐20%DŽPBPK ⁑ᤏ㔃᷌㺘᰾ˈᵜ૱൘ 600 mg䟿лሩ CYP1A2֌⭘˄㿱㦟⢙⴨ӂ֌⭘˅DŽ⎃ᓖлሩ CYP2E1ǃCYP2A6ǃCYP2B6ǃCYP2C8ǃCYP2C9ǃCYP2C19 ઼CYP2D6֌⭘ˈሩ CYP1A2ǃCYP2C9 ઼ CYP2D6֌⭘DŽ⎃ᓖлሩ CYP1A2ǃCYP2B6ǃCYP2C9 ᡆ CYP3A4 ⋑ᴹ䈡ሬ֌⭘˄㿱㦟⢙⴨ӂ֌⭘˅DŽ㛳 pHⲴ㦟⢙˖ᵜ૱൘ pH 4.5 ᡆ 4.5ส˄pH 5.0 ઼ 6.5˅ѝⲴⓦ䀓㛳 pHⲴ㦟૱㚄⭘ᰦⲴ᭸᷌˗նᱟˈ൘㗔փ㦟ԓ⭘ PBPKᖡ૽˄㿱⭘⌅⭘䟿৺㦟

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⢙⴨ӂ֌⭘˅DŽᶕᶕᴢୁ˖ң㞪ⱼᛓ㘵Ѥᒺ䈅傼ᮠᦞ઼㗔փ PK᷀㺘᰾ˈᵜ૱઼ᶕᴢୁ㚄⭘ਾ⋑ᴹӗ⭏㦟⢙⴨ӂ֌⭘DŽ䱯䛓ᴢୁ˖ᙗⲴ㦟⢙⴨ӂ֌⭘DŽ≏㔤ਨ㗔˖ާᙗⲴᖡ૽DŽԆ㧛᱄㣜˖ࡠ࣐2DŽᵜ૱ሩ䖜䘀㳻ⲭⲴᖡ૽˖㦟⢙䖜䘀㳻ⲭ P-gpǃOATP1B1/B3ǃOCT1 ઼ MATE2KࡦBCRPǃOCT2ǃMATE1 ઼Ӫ㊫ BSEP˄㿱㦟⢙⴨ӂ֌⭘˅DŽ䖜䘀㳻ⲭሩᵜ૱Ⲵᖡ૽˖ṩᦞփཆᮠᦞˈP-gp ઼ BCRPࡲ䟿лⲴਓᴽ੨᭦〻ᓖDŽᵜ૱൘փཆнᱟ㛍ᩴਆ䖜䘀㳻ⲭ OATP1B1/1B3 ᡆ OCT-1 Ⲵᓅ⢙˄㿱㦟⢙⴨ӂ֌⭘˅DŽǏѤᒺ䈅傼ǐ⹄ウ CLEE011A2301˄MONALEESA-2˅ሩ➗ǃཊѝᗳ III ᵏѤᒺ⹄ウѝˈ൘ᰒᖰᵚ᧕ਇ䗷ᲊᵏ⯮⯵⋫⯇Ⲵ HR 䱣ᙗǃHER2 䱤ᙗǃᲊᵏң㞪ⱼ㔍㓿ਾྣᙗѝ∄䖳Ҷᵜ૱㚄⭘ᶕᴢୁ⋫⯇оᶕᴢୁঅ⤜㔉㦟ᰦⲴ᭸᷌DŽ䇑 668ᛓ㘵ԕ 1:1䲿ᵪ᧕ਇᵜ૱ 600 mg ઼ᶕᴢୁ˄n=334઼ᶕᴢୁ˄n=334˅⋫⯇ˈṩᦞᱟ੖ᆈ൘㛍㜿઼ /ቲ˄ᱟ [n=292˄44%˅] vs.੖[n=376˄56%˅]˅DŽєњ⹄ウ㓴ⲴӪਓ㔏䇑ᆖ઼ส㓯⯮⯵⢩ᖱ൷㺑ф⴨ᖃDŽᵜ૱઼ᶕᴢୁ㓴㔉㦟ᯩ⌅Ѫ˖ᵜ૱⇿ᰕਓᴽа⅑ˈ⇿⅑ 600 mg ˈᤱ㔝㔉㦟 21㦟 7 ཙ˗ᶕᴢୁ⇿ᰕа⅑ˈ⇿⅑ 2.5 mg ˈᤱ㔝㔉㦟 28㓴ᛓ㘵൘⹄ウᵏ䰤ᡆ⯮⯵䘋ኅਾнᗇӔ৹᧕ਇᵜ૱DŽ㓴ᵜ⹄ウᛓ㘵Ⲵѝսᒤ喴Ѫ 62 ኱˄㤳ത 23-91 ኱˅DŽ44.2%Ⲵᛓ㘵Ⲵᒤ喴ı65ѝ69ᛓ㘵˄10.3%˅Ⲵᒤ喴ı 75㍒Ӫ˄ 82.2%˅ǃӊ⍢Ӫ˄ 7.6%˅઼唁Ӫ˄2.5%˅DŽᡰᴹᛓ㘵Ⲵ ECOG൷Ѫ 0 ᡆ 1䇑 46.6%Ⲵᛓ㘵ᴮॆ⯇ˈ 51.3%ᣇ◰㍐⋫⯇DŽ 34.1%Ⲵᛓ㘵ᴹᯠਁ䖜〫ᙗ⯮⯵DŽ22.0%Ⲵᛓ㘵ӵᴹ僘⯵⚦ˈ58.8%㜿⯮⯵DŽ᷀˄ RECIST v1.1᷀䳶˄ᡰᴹ᧕ਇ䲿ᵪॆⲴࡠ80%Ⲵⴞḷᰐ䘋ኅ⭏ᆈᵏ˄PFSҶ⹄ウⲴѫ㾱㓸⛩DŽ᷀䳶˄FASࡲ+ᶕᴢୁ⋫⯇Ⲵᛓ㘵⴨∄ˈ᧕ਇᵜ૱+ᶕᴢୁ⋫⯇Ⲵᛓ㘵Ⲵ PFS⧠㔏䇑ᆖ᜿ѹⲴ᭩ழ˄HR˖0.556˗95%CI˖0.429ˈ0.720ቲLog-rank Ự傼 p٬0.00000329˅ˈՠ䇑ᵜ૱+ᶕᴢୁ⋫⯇㓴ᛓ㘵䘋ኅ仾䲙䱽վ 44%᷀ᰦˈᵜ૱+ѝս PFS˄95%CI˖19.3ˈNEࡲ+ᶕᴢୁ㓴Ⲵѝս PFS Ѫ

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14.7 њᴸ˄95%CI˖13.0ˈ16.5ࣙ/ ॆ⯇ᡆ㘵◰㍐⋫⯇ǃᱟ੖㍟৺㛍㜿઼/ᡆ㛪䜘ǃᱟ੖ӵᴹ僘䖜〫ӊ㓴ѝⲴ㔃᷌а㠤DŽᰐ䘋ኅ⭏ᆈᵏᙫ㔃㿱㺘 10ˈPFS Ⲵ Kaplan-Meier ᴢ㓯㿱മ 1ᆖ䇴ՠⲴ PFS 㔃᷌оสҾ⹄ウ㘵䇴ՠⲴѫ㾱⯇᭸㔃᷌а㠤˄HR˖0.592˗95%CI˖0.412ˈ0.852˅DŽቲⲴ Log-rank Ự傼 pѪ 0.002DŽᵜ૱+ࡲ+ ߥ/ ⭏⍫䍘䟿˄QoL˅⋑ᴹ᰾ᱮᐞᔲDŽ㺘 11 ઼മ 2ҶᴤѪᡀ⟏Ⲵ⯇᭸ᮠᦞᴤᯠDŽᵜ૱+ᶕᴢୁ㓴ѝսPFSѪ 25.3 њᴸ˄95% CI ˖23.0ˈ30.3˅઼ 16.0 њᴸ˄95%CI˖13.4ˈ18.2˅DŽᵜ૱+ᶕᴢࡲ+㓖ᴹ 54.7%઼ 35.9%Ⲵᛓ㘵Ⲵᰐ⯮⯵䘋ኅ⭏ᆈᵏѪ 24 њᴸDŽ᷀ᡰᗇ仾䲙∄ᱮ⽪ᵜ૱ +ࡲ+ ᶕᴢୁ㓴ˈ㺘᰾ᛓ㘵ࣙ/ ॆ⯇ᡆ◰㍐⋫⯇ǃᱟ੖㍟৺㛍㜿઼/ᡆ㛪䜘ԕ৺ᱟ੖ӵᴹ僘䖜〫DŽ㺘㺘 10 MONALEESA-2 ˄A2301˅สҾ⹄ウ㘵䇴ՠⲴѫ㾱⯇᭸㔃᷌˄PFS˗ᡚ→ᰕᵏ2016 ᒤ 1 ᴸ 29 ᰕ˅ᵜ૱+ᶕᶕᴢୁN=334ࡲ+ᶕᶕᴢୁN=334ᰐ䘋ኅ⭏ᆈᵏѝս PFS[ᴸ]˄95% CI˅ NE (19.3 – NE) 14.7 (13.0 – 16.5)仾䲙∄˄95% CI˅ 0.556 (0.429 - 0.720)p٬a 0.00000329CI=४䰤˗N=ᮠ˗NE=нਟՠ䇑DŽaቲ Log-rankⲴ pDŽ㺘 11 MONALEESA-2 ˄A2301˅สҾ⹄ウ㘵䇴ՠⲴѫ㾱⯇᭸㔃᷌˄PFS˗ᡚ→ᰕᵏ2017 ᒤ 1 ᴸ 2 ᰕ˅ᵜ૱+ᶕᶕᴢୁN=334ࡲ+ᶕᶕᴢୁN=334ᰐ䘋ኅ⭏ᆈᵏѝս PFS[ᴸ]˄95% CI˅ 25.3 (23.0 - 30.3) 16.0 (13.4 - 18.2)仾䲙∄˄95% CI˅ 0.568 (0.457-0.704)p٬a 9.63×10 -8CI=४䰤˗N=ᮠ˗aቲ Log-rankⲴ pDŽ

20/21

മമ 1 สҾ⹄ウ㘵䇴ՠⲴ PFS Ⲵ Kaplan-Meier മ–⹄ウ MONALEESA-2˄A2301˅˄FAS˗ᡚ→ᰕᵏ 2016 ᒤ 1 ᴸ 29 ᰕ˅

മ 2 สҾ⹄ウ㘵䇴ՠⲴ PFS Ⲵ Kaplan-Meier മ̢⹄ウ MONALEESA-2˄A2301˅˄FAS˗ᡚ→ᰕᵏ 2017 ᒤ 1 ᴸ 2 ᰕ˅

Ԇ⅑㾱㓸⛩वᤜᙫ㕃䀓⦷˄ORR˅ǃ㠣 ECOGᙗ઼㙀ਇ⭏⍫䍘䟿Ⲵᛓ㘵ᣕ੺㔃ተ˄PRO˅ⲴਈॆDŽ൘ FAS ѝˈṩᦞᖃൠ᭮ሴ、५⭏䇴ՠⲴ㔃᷌ˈᵜ૱ +ࡲ+ Ѫ 40.7%˄95%CI˖35.4%ˈ1 X P E H UR IS D WLH Q WV V WLOOD WULV N                                    3O DFHER5 L ERFL FO L E7L P H5 L ERFL FO L E 1   3O DFHER 1   & HQVRU L QJ 7L P HV            7L P H 0 RQW KV(Y HQW  I U HH SU REDELOLW\ ཡᰦ䰤Ribociclib˄N=334˅˄N=334˅˅ᮠᰦ䰤˄ᴸ˅ᰐһԦᾲ⦷˄%˅˅ᰦ䰤Ribociclibࡲཡᰦ䰤Ribociclib (N=334)˄N=334˅˅һԦᮠRibociclib˖140˖205

仾䲙∄ = 0.56895% CI [0.457, 0.704]

Kaplan-Meier ѝսᮠRibociclib˖25.3 њᴸ˖16.0 њᴸ

Log-rank Ự傼 p٬9.63* 10^(-8)ᰦ䰤RibociclibࡲᰐһԦᾲ⦷˄%˅˅ᰦ䰤˄ᴸ˅ᮠ

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46.0%˅઼ 27.5%˄95%CI˖22.8%ˈ32.3%˗p=0.000155˅ˈѤᒺ㧧⳺⦷˄CBRѪ 79.6%˄95%CI˖75.3%ˈ84.0%˅઼ 72.8%˄95%CI˖68.0%ˈ77.5%˗p=0.018˅DŽ൘ᴹਟ⍻䟿⯵⚦Ⲵᛓ㘵ѝˈṩᦞᖃൠ᭮ሴ、५⭏䇴ՠⲴ㔃᷌ˈᵜ૱ +ࡲ+ ࠶Ѫ 52.7%˄95%CI˖46.6%ˈ58.9%˅઼ 37.1%˄95%CI˖31.1%ˈ43.2%˗p=0.00028˅DŽᵜ૱+ࡲ+Ѫ 80.1%˄95%CI˖75.2%ˈ85.0%˅઼ 71.8%˄95%CI˖66.2%ˈ77.5%˗p=0.018˗㿱㺘 12˅DŽ㿴ᇊⲴӊ㓴䘋㹼Ҷཊ亩 PFS䜘ॆ⯇ᡆ◰㍐⋫⯇ǃᱟ੖㍟৺㛍㜿઼ /ᡆᵜ૱ +ᶕᴢୁ㓴൘䱽վ⯮⯵䘋ኅᡆ↫ӑ仾䲙ᯩ䶒ՈҾᵜ૱+㓴DŽ൘ᴹ㛍㜿઼/ᡆ㛪䜘⯮⯵˄HR˖0.561 [95% CI˖0.424ˈ0.743]˗Ѫ 24.8 њᴸ઼ 13.4᰾ᱮˈ൘ᰐ㛍㜿઼/ᡆ㛪䜘⯮⯵˄HR˖0.597 [95% CI˖0.426ˈ0.837]㓴 mPFSѪ27.6 њᴸ઼ 18.2 њᴸ˅DŽᙫ㕃䀓⦷઼Ѥᒺ㧧⳺⦷Ⲵᴤᯠ㔃᷌㿱㺘 13DŽ㺘㺘 12 MONALEESA-2 ˄A2301˅ѝสҾ⹄ウ㘵䇴ՠⲴ⯇᭸㔃᷌˄ORRˈCBR˗ᡚ→ᰕᵏ 2016 ᒤ 1 ᴸ 29 ᰕ˅᷀ ᵜ૱+ᶕᶕᴢୁ(%, 95% CI)ࡲ+ᶕᶕᴢୁ(%, 95% CI) p٬c᷀䳶 N=334 N=334ᙫ㕃䀓⦷ a 40.7 (35.4 , 46.0) 27.5 (22.8, 32.3) 0.000155Ѥᒺ㧧⳺⦷ b 79.6 (75.3, 84.0) 72.8 (68.0, 77.5) 0.018ᴹਟ⍻䟿⯵⚦Ⲵᛓ㘵 N=256 N=245ᙫ㕃䀓⦷ a 52.7 (46.6, 58.9) 37.1 (31.1, 43.2) 0.00028Ѥᒺ㧧⳺⦷ b 80.1 (75.2, 85.0) 71.8 (66.2, 77.5) 0.020aORR㕃䀓+ֻbCBR㕃䀓+㕃䀓+㕃䀓/⯮⯵ᰐ䘋ኅᰦ䰤ı24ֻc חCochran-Mantel-Haenszel ঑ᯩỰ傼㧧ᗇⲴ pDŽ

㺘 13 MONALEESA-2 ˄A2301˅ѝสҾ⹄ウ㘵䇴ՠⲴ⯇᭸㔃᷌˄ORRˈCBR˗ᡚ→ᰕᵏ 2017 ᒤ 1 ᴸ 2 ᰕ˅᷀ ᵜ૱+ᶕᶕᴢୁ(%, 95% CI)ࡲ+ᶕᶕᴢୁ(%, 95% CI) p٬c᷀䳶 N=334 N=334ᙫ㕃䀓⦷ a 42.5 (37.2, 47.8) 28.7 (23.9, 33.6) 9.18 × 10 -5Ѥᒺ㧧⳺⦷ b 79.9 (75.6, 84.2) 73.1 (68.3, 77.8) 0.018ᴹਟ⍻䟿⯵⚦Ⲵᛓ㘵 N=257 N=245ᙫ㕃䀓⦷ a 54.5 (48.4, 60.6) 38.8 (32.7, 44.9) 2.54 × 10 -4Ѥᒺ㧧⳺⦷ b 80.2 (75.3, 85.0) 71.8 (66.2, 77.5) 0.018a ORR㕃䀓+ֻb CBR㕃䀓+㕃䀓˄+㕃䀓/⯮⯵ᰐ䘋ኅᰦ䰤ı24ֻc חCochran-Mantel-Haenszel ঑ᯩỰ傼㧧ᗇⲴ p٬

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ᴰᴰ㓸 OS᷀൘ᴰ㓸ᙫ⭏ᆈᵏ˄OS᷀ᰦ˄ᡚ→ᰕᵏ 2021 ᒤ 06 ᴸ 10䭞⅑㾱㓸⛩ˈ㺘᰾ OSᴹѤᒺ᜿ѹⲴ᭩ழˈ਼ᰦ↫ӑ仾䲙⴨ሩ䱽վҶ 23.5%˄HR˖0.765˗95% CI˖0.628ˈ0.932˗p٬0.004˅DŽOSˈKisqali 㓴Ⲵ 6 ᒤ⭏ᆈ⦷Ѫ 44.2%˄38.5ˈ49.8ࡲ㓴Ѫ 32.0%˄26.8ˈ37.3˅DŽKisqali 㓴Ⲵѝս OS Ѫ 63.9 њᴸ˄95% CI ˖52.4ˈ71.0ࡲ㓴Ѫ 51.4 њᴸ˄95% CI ˖47.2ˈ59.7˅ˈKisqali 㓴Ⲵѝս OS ᭩ழѪ 12.5᷀Ⲵ᧒㍒ᙗ OS 㔃᷌㺘᰾ˈOSॆ⯇ᡆ◰㍐⋫⯇ǃ㛍઼/ᡆ㛪ਇ㍟ԕ৺ӵ僘䖜᷀Ⲵ OS 㔃᷌㿱㺘 14ˈKaplan-Meier ᴢ㓯㿱മ3DŽ㺘 14 MONALEESA-2 ˄A2301˅⯇᭸㔃᷌˄OS˅˄ᡚ→ᰕᵏ 2021 ᒤ 06 ᴸ 10 ᰕ˅ᙫ⭏ᆈᵏˈᙫփ⹄ウӪ㗔 Kisqali 600 mg + ᶕᴢୁN = 334ࡲ + ᶕᴢୁN = 334һԦᮠ-n [%] 181 (54.2) 219 (65.6)ѝս OS [ᴸ]˄95% CI˅ 63.9 (52.4, 71.0) 51.4 (47.2, 59.7)仾䲙∄ a˄95% CI˅ 0.765 (0.628, 0.932)p٬b 0.004OS ᰐһԦ⦷˄%˅˄95% CI˅24 њᴸ 86.6 (82.3, 89.9) 85.0 (80.5, 88.4)60 њᴸ 52.3 (46.5, 57.7) 43.9 (38.3, 49.4)72 њᴸ 44.2 (38.5, 49.8) 32.0 (26.8, 37.3)CI = ४䰤˗aቲ Cox PH ⁑රѝ㧧ᗇⲴ仾䲙∄˗bחLog-rank Ự傼ѝ㧧ᗇⲴ pDŽṩᦞ IRTˈ᤹㛪઼/ቲDŽ

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മമ 3 MONALEESA-2 ˄A2301˅ѝ OS˄FAS˅Kaplan-Meier മ˄ᮠᦞᡚ→ᰕᵏ 2021ᒤ 06 ᴸ 10 ᰕ˅

Log-rank Ự傼઼ Cox PH ⁑රṩᦞ IRT ᤹㛍઼/ቲDŽחPቲ Log-rank Ự傼ѝ㧧ᗇDŽ↔ཆˈKisqali㓴⴨∄ˈ㠣俆⅑ਾ㔝ॆ⯇Ⲵѝսᰦ䰤ᔦ䮯Ҷ 11.7 њᴸ˄50.6 њᴸˈ95% CI˖38.9ˈ60.0 њᴸ vs 38.9 њᴸˈ95% CI˖31.4ˈ45.4˅DŽKisqali㓴⴨∄ˈ⭘ᾲ⦷䱽վҶ 25.8%˄HR˖0.742˗95% CI˖0.606ˈ0.909˅DŽ⹄ウ CLEE011E2301˄MONALEESA-7˅ሩ➗ǃཊѝᗳ IIIо˄NSAI˅઼ᠸ㠽⪎᷇⋫⯇ HR 䱣ᙗǃHER2 䱤ᙗ઼ത㔍㓿ᵏྣᙗˈሩᵜ૱䘋㹼䇴ԧDŽ䇑 672ᛓ㘵䲿ᵪ᧕ਇᵜ૱ 600 mg+Ԇ㧛᱄㣜ᡆ NSAI+ᠸ㠽⪎᷇˄n=335ࡲ+Ԇ㧛᱄㣜ᡆ NSAI+ᠸ㠽⪎᷇˄n=337˅⋫⯇ˈᒦṩᦞᱟ੖ᆈ൘㛍㜿઼/ᡆ㛪䜘䖜〫˄ᱟ vs.੖˅ǃᰒᖰᱟ੖᧕ਇ䗷ᲊᵏ⯮⯵ॆ⯇˄ᱟ vs.˄NSAI ઼ᠸ㠽⪎᷇ vs.Ԇ㧛ቲDŽєњ⹄ウ㓴ⲴӪਓ㔏䇑ᆖ઼ส㓯⯮⯵⢩ᖱ൷㺑ф⴨ᖃDŽԆ㧛᱄㣜 20 mg ᡆ NSAI˄ᶕᴢୁ 2.5 mg ᡆ䱯䛓ᴢୁ 1 mg˅⇿ᰕа⅑ᤱ㔝ਓᴽˈᠸ㠽⪎᷇3.6 mg ൘⇿њઘᵏ˄Ѫᵏ 28 ཙ˅ㅜ 1 ཙⳞл⌘ሴˈ㚄⭘ᵜ૱ 600 mgᰕа⅑ᤱ㔝ਓᴽ 21㦟 7㓴ᛓ㘵൘⹄ウᵏ䰤ᡆ⋼⋫⯇ᯩṸDŽ㓴⹄ウᛓ㘵Ⲵѝսᒤ喴Ѫ 44 ኱˄㤳ത˖25-58 ኱˅ˈ27.7%ᛓ㘵Ⲵᒤ喴ሿҾ 40 ኱DŽབྷཊ㍒Ӫ˄57.7%˅ǃӊ⍢Ӫ˄29.5%˅ᡆ唁Ӫ˄2.8%Ѿᡰᴹᛓ㘵˄99.0%˅ⲴECOG൷Ѫ 0 ᡆ 1DŽ൘䘉 672ᴹ 32.6%Ⲵᛓ㘵ᴮ᧕ਇ䗷ॆ⯇ˈ18.0%ॆ⯇ˈ 39.6%⋼⋫⯇ˈ 0.7%⋼⋫⯇˗ 40.2%Ⲵᛓ㘵ᆈ൘ᯠਁ䖜〫ᙗ⯮⯵ˈ 23.7%Ⲵᛓ㘵ӵᴹ僘⯵⚦ˈ56.7%㜿⯮⯵DŽ1 X P E H UR IS D WLH Q WV V WLOOD WULV N                                                                   3ODFHER5 L ERFL FO L E7L P H5 L ERFL FO L E 1   3O DFHER 1   & HQVRU L QJ 7L P HV1 R R IH Y H Q WV5 LE R F LF OLE    3 OD F H E R  + D ] D UG 5 D WLR       & ,>    @.DSO DQ 0 HL HU  P HGL DQ5 L ERFL FO L E     0 RQW KV3O DFHER     0 RQW KV/RJ U DQN S Y DO XH                         7L P H 0 RQW KV(Y HQW  I U HH SU REDELOLW\ ཡᰦ䰤Ribociclib˄N = 334˅˄N = 334˅

ᰐһԦᾲ⦷˄%˅˅ᰦ䰤˄ᴸ˅ᮠᰦ䰤Ribociclibࡲཡᰦ䰤Ribociclib˄N = 334˅˄N = 334˅

һԦᮠRibociclib˖181˖219

仾䲙∄ = 0.76595% CI [0.628ˈ0.932]

Kaplan-Meier ѝսᮠRibociclib˖63.9 њᴸ˖51.4 њᴸLog-rank Ự傼 p٬0.004ᰦ䰤˄ᴸ˅

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ѫ᷀⭘ RECIST v1.1᷀䳶˄ᡰᴹ᧕ਇ䲿ᵪॆⲴᛓ㘵˅Ⲵ䇴ՠˈᒦ൘䲿ᵪ䘹ᤙⲴ㓖 40%Ⲵ᧕ਇ䲿ᵪॆⲴᛓ㘵˄BIRCᆖ䇴ՠⲴ⺞䇔ਾˈ൘㿲ࡠ318 䎧ᰐ䘋ኅ⭏ᆈᵏ˄PFSҶ⹄ウⲴѫ㾱㓸⛩DŽ䘋㹼ѫ㾱 PFS᷀ᰦⲴѝս䲿䇯ᰦ䰤Ѫ 19.2 њᴸDŽ൘ᙫփ⹄ウӪ㗔ѝˈᵜ૱+Ԇ㧛᱄㣜ᡆ NSAIࡲ+Ԇ㧛᱄㣜ᡆ NSAI 㓴ѝս PFS˄95%CIѪ 23.8 њᴸ˄19.2ˈNE˅઼ 13.0 њᴸ˄11.0ˈ16.4˗HR˖0.553 [95% CI˖0.441ˈ0.694]ቲ Log-rank Ự傼Ⲵ p˖9.83×10-8˅DŽ⯇᭸㔃᷌㿱മ 4 Ⲵ PFS Kaplan-Meier ᴢ㓯DŽสҾ BIRCⲴѫ㾱⯇᭸㔃᷌˄HR˖0.427˗95%CI˖0.288ˈ0.633˅DŽᵜ૱㓴⹄ウ㘵ṩᦞ RECISTv1.1 䇴ՠⲴᙫ㕃䀓⦷˄ORR˅˄40.9%˗95%CI˖35.6ˈ46.2˅㓴˄29.7%˗95%CI˖24.8ˈ34.6˗p = 0.00098˅˄㿱㺘 16˅DŽᤷᇊⲴѫ㾱 QoLᚦॆⲴᰦ䰤˄TTD˅DŽ᰾⺞ᚦॆ 10%ⲴᇊѹѪ EORTC QLQ-C30⴨∄ส㓯㠣ቁᚦॆ 10%٬ҏᵚᴮ᭩ழˈᡆഐԫօ৏ഐሬ㠤↫ӑDŽᵜ૱+Ԇ㧛᱄㣜ᡆ NSAI 㓴ਟ㠣 EORTC QLQ-C30 ᙫփࡲ+Ԇ㧛᱄㣜ᡆ NSAI 㓴˄ѝսᮠ˖нਟՠ䇑 vs.21.2 њᴸ˗HR˖0.699˗[95% CI˖0.533ˈ0.916]˗p=0.004˅DŽമ 4 MONALEESA -7˄E2301˅ѝสҾ⹄ウ㘵䇴ՠⲴ PFS Ⲵ Kaplan-Meier മ˄FAS˗ᡚ→ᰕᵏ 2017 ᒤ 8 ᴸ 20 ᰕ˅

ሩ 495㚄ਸ NSAI+᷀ਾਁ⧠ˈᵜ૱+NSAIࡲNSAI ӊ㓴Ⲵѝս PFS˄95%CIѪ 27.5 њᴸ˄19.1ˈNE˅઼13.8 њᴸ˄12.6ˈ17.4˗HR˖0.569 [95% CI: 0.436, 0.743] ˅DŽ⯇᭸㔃᷌ᙫ㔃㿱㺘 15ˈPFS ⲴKaplan-Meier ᴢ㓯㿱മ 5DŽ⭡Ҿᆈ൘ QTc 䰤ᵏᔦ䮯Ⲵ仾䲙ˈнᔪ䇞ሶᵜ૱оԆ㧛᱄㣜㚄⭘˄㿱1 X P E H UR IS D WLH Q WV V WLOOD WULV N                                                    3O DFHER5 L ERFL FO L E7L P H5 L ERFL FO L E 1   3O DFHER 1   & HQVRU L QJ 7L P HV1 R R IH Y H Q WV5 LE R F LF OLE    3 OD F H E R   + D ] D UG 5 D WLR       & ,>    @.DSO DQ 0 HL HU  P HGL DQ5 L ERFL FO L E     0 RQW KV3O DFHER     0 RQW KV/RJ U DQN S Y DO XH   A                 7L P H 0 RQW KV(Y HQW  I U HH SU REDELOLW\ ཡᰦ䰤Ribociclib (N=335)˄N=337˅һԦᮠRibociclib˖131˖187

仾䲙∄ = 0.55395% CI [0.441, 0.694]

Kaplan-Meier ѝսᮠRibociclib˖23.8 њᴸ˖13.0 њᴸ

Log-rank Ự傼 p٬9.83 * 10^(-8)ᰐһԦᾲ⦷˄%˅ᰦ䰤˄ᴸ˅ᮠᰦ䰤Ribociclibࡲ

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⌘᜿һ亩˅DŽ൘ᵜ૱+NSAIࣙ/ ॆ⯇ᡆ◰㍐⋫⯇ǃᱟ੖㍟৺㛍㜿઼/ᡆ㛪䜘ԕ৺ᱟ੖ӵᴹ僘䖜〫ӊ㓴䰤Ⲵ㔃᷌а㠤DŽ൘ NSAIѝս㠣㕃䀓ᰦ䰤˄TTRࡲ㓴 6Ѫ 34.7%˄95%CI˖29.0ˈ41.1˅઼ 23.7%˄95%CI˖18.8ˈ29.6˅ˈ㓴DŽ൘ NSAIѝս㕃䀓ᤱ㔝ᰦ䰤˄DOR˗95%CI˖18.3 њᴸˈNE˅ˈᆹ㓴 DOR Ѫ 17.5 њᴸ˄95%CI˖12.0ˈNE㕃䀓Ⲵᛓ㘵ѝˈ12 њѪ 23.5%˄95%CI˖15.6ˈ34.5˅઼ 36.4%˄95%CI˖25.6ˈ49.8˅DŽ㺘㺘 15 MONALEESA-7 ˄E2301˅᧕ਇ NSAI ⋫⯇ᛓ㘵ѝสҾ⹄ウ㘵䇴ՠⲴѫ㾱⯇᭸㔃᷌˄PFS˗ᡚ→ᰕᵏ 2017 ᒤ 8 ᴸ 20 ᰕ˅ᵜ૱+NSAI+ᠸᠸ㠽⪎᷇N=248ࡲNSAI+ᠸᠸ㠽⪎᷇N=247ᰐ䘋ኅ⭏ᆈᵏ aѝս PFS[ᴸ]˄95% CI˅ 27.5 (19.1, NE) 13.8 (12.6, 17.4)仾䲙∄˄95% CI˅ 0.569 (0.436, 0.743)CI=४䰤˗N=ᮠ˗NE=нਟՠ䇑DŽa –ᆖ䇴ՠⲴ PFSമ 5 สҾ⹄ウ㘵䇴ՠⲴ PFS Ⲵ Kaplan-Meier മ-⹄ウ MONALEESA-7˄E2301˅᧕ਇNSAI ⋫⯇Ⲵᛓ㘵˄ᡚ→ᰕᵏ 2017 ᒤ 8 ᴸ 20 ᰕ˅㺘 16 MONALEESA-7 ˄E2301˅᧕ਇ NSAI ⋫⯇ᛓ㘵ѝสҾ⹄ウ㘵䇴ՠⲴ⯇᭸㔃᷌˄ORRˈCBR˅˄ᡚ→ᰕᵏ 2017 ᒤ 8 ᴸ 20 ᰕ˅᷀ ᵜ૱+NSAI+ᠸᠸ㠽⪎᷇(%, 95% CI)ࡲNSAI+ᠸᠸ㠽⪎᷇(%, 95% CI)ཡᰦ䰤Ribociclib (N=248)˄N=247˅һԦᮠRibociclib˖92˖132

仾䲙∄ = 0.56995% CI [0.436, 0.743]

Kaplan-Meier ѝսᮠRibociclib˖27.5 њᴸ˖13.8 њᴸᰐһԦᾲ⦷˄%˅ᰦ䰤˄ᴸ˅ᮠᰦ䰤Ribociclibࡲ

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ޘ᷀䳶 N=248 N=247ᙫᙫ㕃䀓⦷ a 39.1 (33.0, 45.2) 29.1 (23.5, 34.8)ѤѤᒺ㧧⳺⦷ b 80.2 (75.3, 85.2) 67.2 (61.4, 73.1)ᴹᴹਟ⍻䟿⯵⚦Ⲵᛓ㘵 N=192 N=199ᙫᙫ㕃䀓⦷ a 50.5 (43.4, 57.6) 36.2 (29.5, 42.9)ѤѤᒺ㧧⳺⦷ b 81.8 (76.3, 87.2) 63.8 (57.1, 70.5)aORR㕃䀓+ֻbCBR㕃䀓+㕃䀓+㕃䀓/⯮⯵ᰐ䘋ኅᰦ䰤ı24ֻ

ᴰᴰ㓸 OS᷀൘ㅜҼ⅑ OS᷀ᰦ˄ᡚ→ᰕᵏ 2018 ᒤ 11 ᴸ 30䭞⅑㾱㓸⛩ˈOSᴹ㔏䇑ᆖ᜿ѹⲴ᭩ழDŽ㓿䇱ᇎⲴ OS࠶᷀㔃᷌а㠤DŽ㺘 17 ԕ৺മ 6 ઼ 7ҶᴤѪᡀ⟏Ⲵᙫ⭏ᆈᵏᮠᦞᴤᯠ˄ᡚ→ᰕᵏ 2018 ᒤ 11 ᴸ 30 ᰕ˅DŽ㺘 17 MONALEESA-7 ˄E2301˅Ⲵ⯇᭸㔃᷌˄OS˗ᡚ→ᰕᵏ 2018 ᒤ 11 ᴸ 30 ᰕ˅ᙫ⭏ᆈᵏˈᙫփ⹄ウӪ㗔 Ribociclib 600 mgN=335ࡲN=337һԦᮠ - n [%] 83 (24.8) 109 (32.3)ѝս OS [ᴸ]˄95% CI˅ NE (NE, NE) 40.9 (37.8, NE)HR˄95% CI˅ 0.712 (0.535, 0.948)p٬a 0.00973ᙫ⭏ᆈᵏˈNSAI ӊӊ㓴 Ribociclib 600 mgN=248ࡲN=247һԦᮠ - n [%] 61 (24.6) 80 (32.4)ѝս OS [ᴸ]˄95% CI˅ NE (NE, NE) 40.7 (37.4, NE)HR˄95% CI˅ 0.699 (0.501, 0.976)CI=४䰤ˈNE=нਟՠ䇑ˈN=ᮠˈNSAI =ࡲࡦa ᤹➗㛪઼/ᡆ㛍䖜〫ǃᲊᵏ⯮⯵Ⲵᰒᖰॆ⯇઼สҾ IRTቲⲴ Log-rankחpDŽ

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മമ 6 MONALEESA-7 ˄E2301˅ѝ OS˄FAS˅Ⲵ Kaplan Meier മ˄ᡚ→ᰕᵏ 2018 ᒤ11 ᴸ 30 ᰕ˅

Log-rank Ự傼઼ Cox ⁑ර൷᤹➗㛪䜘઼/ᡆ㛍㜿䖜〫ǃᲊᵏ⯮⯵Ⲵᰒᖰॆ⯇઼สҾ IRTቲമ 7 MONALEESA-7 ˄E2301˅᧕ਇ NSAI ⋫⯇ᛓ㘵Ⲵ OS Ⲵ Kaplan Meier മ˄ᡚ→ᰕᵏ 2018 ᒤ 11 ᴸ 30 ᰕ˅

ቲ Cox仾䲙∄DŽ

ᰦ䰤˄ᴸ˅ᮠᰦ䰤Ribociclibࡲཡᰦ䰤Ribociclib˄N=335˅˄N=337˅ᰐһԦᾲ⦷˄%˅һԦᮠRibociclib˖83˖109

仾䲙∄ = 0.71295% CI [0.535ˈ0.948]

Kaplan-Meier ѝսᮠRibociclib˖NE˖40.9 њᴸ

Log-rank Ự傼 p٬0.00973ᰦ䰤˄ᴸ˅ᮠᰐһԦᾲ⦷˄%˅ཡᰦ䰤Ribociclib˄N=248˅˄N=247˅ᰦ䰤RibociclibࡲһԦᮠRibociclib˖61˖80

仾䲙∄ = 0.69995% CI [0.501ˈ0.976]

Kaplan-Meier ѝսᮠRibociclib˖NE˖40.7 њᴸ

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↔ཆˈᙫփ⹄ウӪ㗔ѝˈ Kisqali 㓴ᛓ㘵൘лањ⋫⯇ѝⲴ㠣⯮⯵䘋ኅᰦ䰤ᡆ㠣↫ӑᰦ䰤˄PFS2㓴Ⲵᛓ㘵˄ HR˖0.692˄95% CI ˖0.548ˈ0.875㓴ⲴѝսPFS2 Ѫ 32.3 њᴸ˄95% CI ˖27.6ˈ38.3˅ˈKisqaliѝս PFS2˄95% CI ˖39.4ˈNE˅DŽNSAI㊫լ㔃᷌˄HR˖0.660˄95% CI˖0.503ˈ0.868˅˗ѝս PFS2˖ᆹហ㓴Ѫ 32.3њᴸ˄95% CI˖26.9ˈ38.3˅ˈribociclib˄95% CI˖39.4ˈNE˅˅DŽ

ǏǏ㦟⨶∂⨶ǐ㦟⨶֌⭘䎆ᙗ◰䞦˄CDK˅4 ઼ 6DŽ䘉Ӌ◰䞦о㓶㜎ઘᵏ㳻ⲭ DਧՐሬ䙊䐟ѝਁᥕ⵰䟽㾱֌⭘DŽ㓶㜎ઘᵏ㳻ⲭ D-CDK4/6 ༽ਸ⢙䙊䗷㿶㖁㟌⇽㓶㜎ⱔ㳻ⲭ˄pRb˅Ⲵ⼧䞨ॆ䈳᧗㓶㜎ઘᵏ䘋〻DŽਟ䱽վ pRb ⼧䞨ॆ≤ᒣˈሬ㠤㓶㜎ઘᵏ G1ң㞪ⱼ㓶㜎㌫ࡦpRbDŽ൘ᛓ㘵ᶕⓀⲴ䳼◰㍐ਇփ䱣ᙗң㞪ⱼᔲ⿽〫Ἵ⁑රѝˈоঅ㦟⴨∄ˈ⪎⌒㾯DŽ↔ཆˈ൘䳼◰㍐ਇփ䱣㛯ⱔ⭏䮯DŽ∂⨶⹄ウ䚇Ր∂ᙗ˖Ⲵ Ames 䈅傼ǃӪ⏻ᐤ㓶㜎ḃ㢢փ⮨ਈ䈅傼ǃབྷ啐ᗞṨ䈅傼㔃᷌൷Ѫ䱤ᙗDŽ⭏⇆∂ᙗ˖ࡽ14 ཙ㠣ྺၐਾㅜ 1 ઘˈ㓿ਓ䟿儈䗮 300mg/kg/ཙ[ԕ㦟⢙᳤䵢䟿˄ AUC䟿600mg/ཙⲴ 0.6ؽ]઼ᰙᵏ㜊㛾ਁ㛢Ⲵᖡ૽DŽ⹄ウDŽ൘བྷ啐 26 ઘ઼⣜ 39 ઘ˄⇿њઘᵏ㔉㦟3㦟 1 ઘ˅䟽༽㓿ਓ㔉㦟∂ᙗ䈅傼ѝˈਟ㿱ⶮѨ㨾㕙ᙗਈॆˈवᤜབྷ啐઼⣜ࡲ䟿•  PJNJ䟿•  PJNJᰦਟ㿱к䘠ਈॆˈԕ AUC䟿600 mg/ཙⲴ 1.4 ઼ 0.03ˈሬ㠤ᴢ㓶㋮㇑㨾㕙ˈ൘ 4 DŽབྷ啐㜊㛾-㛾Ԅਁ㛢∂ᙗ䈅傼ѝˈྺၐབྷ啐Ҿ GD6~GD17࡙50ǃ300 ઼ 1000 mg/kg/䟿Ѫ 300mg/kg/ཙ˄ԕ AUC䟿 600mg/ཙⲴ 0.6ቁ઼㛾Ԅփ䟽л䱽ˈդ䲿ഐ㛾Ԅփ䟽䱽վሬ㠤Ⲵ僘僬ਈॆDŽ50 о 300mg/kg/ཙˈᵚᕅ䎧㜊㛾-㛾ԄⲴਈᔲо⮨ᖒDŽ㜊㛾-Ҿ GD7~GD20࡙10ǃ30 ઼60 mg/kg/䟿ı30 mg/kg/ ཙ˄ԕ AUC䟿 600mg/ཙⲴ 1.5˅㜿઼僘僬ਈᔲ˅઼㛾Ԅ⭏䮯ᔲᑨ˄㛾Ԅփ䟽䱽վ˅ਁ⭏ቁ /ਦ㕪ཡ

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ቁ/ਈሿǃ仍ཆ/䘰ॆⲴㅜ 13 㚻僘ǃ㠼僘⮨ᖒǃ㠼僘㘬ᕟᴢǃ᣷ቁDŽ⋑ᴹ䇱ᦞ㺘᰾㜊㛾 -䟿İ 30 mg/kg/ ཙᰦˈᵚ㿱⇽փ∂ᙗDŽ࡙50mg/kg൘ң≱ѝⲴ᳤䵢䟿∄⇽փ㹰⍶ѝⲴ᳤䵢䟿儈 3.56DŽ㠤㠤ⱼᙗ˖൘а亩Ѫᵏ 2Ⲵ㠤ⱼᙗDŽ࡙2 ᒤˈı300 mg/kg/䟿㓴䳼ᙗབྷ啐ਟ㿱ᆀᇛ/㟌кˈ50 mg/kg/䟿㓴䳴ᙗབྷ啐ਟ㿱⭢⣦㞪└⌑ᙗ㛯㛯ⱔਈॆⲴ䳼ᙗ઼䳴ᙗབྷ啐Ⲵっᘱᒣ൷᳤䵢䟿˄ AUC0-24hᱟ䟿 600 mg/䟿㓴ᛓ㘵᳤䵢䟿Ⲵ 1.2઼ 1.4ˈᱟ 400 mg/䟿㓴ᛓ㘵᳤䵢䟿Ⲵ 2.2઼ 2.5DŽԆ䶎㛯ⱔᙗ໎⭏ᙗਈॆवᤜı5 mg/kg/ཙ઼ 50 mg/kg/䟿㓴䳴ᙗབྷ啐Ⲵ㛍㜿᭩ਈ˄ఌ઼ⶮѨ䰤䍘˄Leydig˅㓶㜎໎⭏DŽሩᆀᇛ/ᆀᇛ亸઼ⶮѨ䰤䍘˄Leydig˅㓶㜎Ⲵᖡ૽ਟ㜭о CDK4㜭ǃ᭩ਈлш㝁-඲փ-DŽ⢙⢩ᔲᙗᗞ㋂փ䞦䈡ሬ઼ /ᡆ㔗ਁң㍐㹰⯷Ⲵлш㝁-඲փ-ⶮѨ-⭢⣦㞪䖤ཡ䈳DŽ䳼◰㍐ /ሶ䙊䗷դ䲿ᣇ䳼◰㍐⋫⯇ሩ䳼◰⭘DŽң㍐ਸᡀ઼֌⭘ᯩ䶒ᆈ൘䟽བྷᐞᔲˈ亴ᵏ䈕֌⭘ᯩᔿнՊሩӪ㊫ӗ⭏ᖡ૽DŽԆ∂ᙗ˖㦟⨶ᆖ䈅傼㔃᷌ᱮ⽪ˈᕅ䎧 QTc䟿઼⎃ᓖоᛓ㘵᧕ਇ 600mg˄བྷ㓖Ѫ亴ᵏѤᒺ Cmax Ⲵ 5˅ᰦˈᴹਟ㜭䈡ਁᇔᙗᰙᨿ˄PVC˅ਁ⭏DŽǏ䍞㯿ǐн䎵䗷 30ᆈDŽㄕн㜭᧕䀖ⲴൠᯩDŽǏव㻵ǐ㚊≟҉✟/㚊й≏≟҉✟പփ㦟⭘༽ਸ⺜⡷઼㦟⭘䬍㇄व㻵21 ⡷/ⴂ˗42 ⡷/ⴂ˗63 ⡷/ⴂDŽǏᴹ᭸ᵏǐ36 њᴸ

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ǏǐJX20230001᮷ਧǐᆇ HJ20230003Ǐкᐲ䇨ਟᤱᴹӪǐ਽〠˖Novartis Pharma Schweiz AGൠ൰˖6343 Risch, SwitzerlandǏ⭏ӗԱъǐԱъ਽〠˖Novartis Singapore Pharmaceutical Manufacturing Pte. Ltd.⭏ӗൠ൰˖10 Tuas Bay Lane, 637461 Singapore, Singaporeव㻵Աъ਽〠˖Novartis Pharma Stein AGव㻵ൠ൰˖Schaffhauserstrasse, 4332 Stein, Switzerland㚄㌫Ӫǐਨൠ൰˖ेӜᐲ᰼ᒣ४≨ᆹ䐟 31 ਧ䛞᭯㕆⸱˖102200⭥䈍ਧ⸱˖400 818 0600800 990 0016ᓗᵪᤘᢃ˅Րⵏਧ⸱˖010-65057099㖁൰˖www.novartis.com.cn