JP2022034068A - 非erk mapk経路阻害剤耐性のがんを処置するための方法および組成物 - Google Patents
非erk mapk経路阻害剤耐性のがんを処置するための方法および組成物 Download PDFInfo
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Abstract
Description
本出願は、2013年12月20日に出願された米国特許出願第61/919,551号の利益を主張する、2014年12月19日に出願されたPCT国際出願第PCT/US2014/071749号の部分継続出願である、2016年5月20日に出願された米国特許出願第15/161,137号の利益を主張し、これらの全ては、それらの全体が、本明細書において完全に記載されているかのように参考として援用される。
配列表の参照による組込み
(a)BRAF阻害剤療法、MEK阻害剤療法またはBRAFおよびMEK阻害剤療法に対して抗療性または耐性になったがんを有する対象を同定することと;
(b)前記抗療性または耐性のがんを有する対象にBVD-523または薬学的に許容されるその塩であるERK阻害剤を有効量で投与することと
を含む。
(a)対象から生体試料を得ることと、
(b)対象が、以下のマーカー:
(i)RAFアイソフォームの間のスイッチ、
(ii)受容体チロシンキナーゼ(RTK)またはNRASシグナル伝達の上方制御、
(iii)分裂促進因子活性化プロテインキナーゼ(MAPK)シグナル伝達の再活性化、
(iv)MEK活性化突然変異の存在、
(v)突然変異BRAFの増幅、
(vi)STAT3上方制御、
(vii)MEKへの阻害剤の結合を直接的に遮断するかまたは構成的MEK活性につながるMEKのアロステリックポケットにおける突然変異、
の1つまたは複数を有するかどうか判定するために試料をスクリーニングすることと
を含み、ここで、マーカーの1つまたは複数の存在は、対象のがんがBRAFおよび/またはMEK阻害剤療法に対して抗療性または耐性であること、ならびに、BVD-523または薬学的に許容されるその塩であるERK阻害剤による療法から対象が恩恵を受けるだろうことを確認する。
本発明は、例えば以下を提供する。
(項目1)
切除不能または転移性のBRAF600突然変異陽性メラノーマを有する対象を処置する方法であって、BVD-523または薬学的に許容されるその塩を600mg BIDで前記対象に投与することを含む、方法。
(項目2)
前記突然変異がBRAFV600E突然変異である、項目1に記載の方法。
(項目3)
哺乳動物が、ヒト、霊長類、畜産動物および家畜からなる群から選択される、項目1に記載の方法。
(項目4)
哺乳動物がヒトである、項目1に記載の方法。
(項目5)
前記メラノーマがMAPK活性を有する、項目1に記載の方法。
(項目6)
切除不能または転移性のBRAF600突然変異陽性メラノーマを有する対象を処置するための組成物であって、BVD-523または薬学的に許容されるその塩の600mg、および任意選択で薬学的に許容される担体、アジュバントまたはビヒクルを含む、組成物。
(項目7)
前記対象が哺乳動物である、項目6に記載の組成物。
(項目8)
哺乳動物が、ヒト、霊長類、畜産動物および家畜からなる群から選択される、項目6に記載の組成物。
(項目9)
哺乳動物がヒトである、項目6に記載の組成物。
(項目10)
前記メラノーマがMAPK活性を有する、項目6に記載の組成物。
(項目11)
前記突然変異がBRAFV600E突然変異である、項目6に記載の組成物。
年)に開示されるKobe0065およびKobe2602、HBS3(Patgiriら、2
011年)ならびにAIK-4(Allinky)が含まれる。
2007年)、CTT239065(Institute of Cancer Research)、ダブラフェニブ(GSK2118436)、DP-4978(Deciphera Pharmaceuticals)、HM-95573(Hanmi)、GDC-0879(Genentech)、GW-5074(Sigma Aldrich)、ISIS 5132(Novartis)、L779450(Merck)、LBT613(Novartis)、LErafAON(NeoPharm,Inc.)、LGX-818(Novartis)、パゾパニブ(GlaxoSmithKline)、PLX3202(Plexxikon)、PLX4720(Plexxikon)、PLX5568(Plexxikon)、RAF-265(Novartis)、RAF-365(Novartis)、レゴラフェニブ(Bayer Healthcare Pharmaceuticals,Inc.)、RO 5126766(Hoffmann-La
Roche)、SB-590885(GlaxoSmithKline)、SB699393(GlaxoSmithKline)、ソラフェニブ(Onyx Pharmaceuticals)、TAK 632(Takeda)、TL-241(Teligene)、ベムラフェニブ(RG7204またはPLX4032)(Daiichi Sankyo)、XL-281(Exelixis)、ZM-336372(AstraZeneca)、薬学的に許容されるその塩およびその組合せ。
Sciences)、CAL-253(Gilead Sciences)、CAL-263(Gilead Sciences)、CAS#612847-09-3、CAS#681281-88-9、CAS#75747-14-7、CAS#925681-41-0、CAS#98510-80-6、CCT128930(CAS#885499-61-6)、CH5132799(CAS#1007207-67-1)、CHR-4432(Chroma Therapeutics,Ltd.、Abingdon、UK)、FPA 124(CAS#902779-59-3)、GS-1101(CAL-101)(Gilead Sciences)、GSK 690693(CAS#937174-76-0)、H-89(CAS#127243-85-0)、ホオノキオール、IC87114(Gilead Science)、IPI-145(Intellikine Inc.)、KAR-4139(Karus Therapeutics、Chilworth、UK)、KAR-4141(Karus Therapeutics)、KIN-1(Karus Therapeutics)、KT 5720(CAS#108068-98-0)、ミルテフォシン、MK-2206二塩化水素化物(CAS#1032350-13-2)、ML-9(CAS#105637-50-1)、塩酸ナルトリンドール、OXY-111A(NormOxys Inc.、Brighton、MA)、ペリホシン、PHT-427(CAS#1191951-57-1)、PI3キナーゼデルタ阻害剤、Merck KGaA(Merck & Co.、Whitehouse Station、NJ)、PI3キナーゼデルタ阻害剤、Genentech(Roche Holdings Inc.)、PI3キナーゼデルタ阻害剤、Incozen(Incozen Therapeutics,Pvt.Ltd.、Hydrabad、India)、PI3キナーゼデルタ阻害剤-2、Incozen(Incozen Therapeutics)、PI3キナーゼ阻害剤、Roche-4(Roche Holdings Inc.)、PI3キナーゼ阻害剤、Roche(Roche Holdings Inc.)、PI3キナーゼ阻害剤、Roche-5(Roche Holdings Inc.)、PI3-アルファ/デルタ阻害剤、Pathway Therapeutics(Pathway Therapeutics Ltd.、South San Francisco、CA)、PI3-デルタ阻害剤、Cellzome(Cellzome AG、Heidelberg、Germany)、PI3-デルタ阻害剤、Intellikine(Intellikine Inc.、La Jolla、CA)、PI3-デルタ阻害剤、Pathway Therapeutics-1(Pathway Therapeutics Ltd.)、PI3-デルタ阻害剤、Pathway
Therapeutics-2(Pathway Therapeutics Ltd.)、PI3-デルタ/ガンマ阻害剤、Cellzome(Cellzome AG)、PI3-デルタ/ガンマ阻害剤、Cellzome(Cellzome AG)、PI3-デルタ/ガンマ阻害剤、Intellikine(Intellikine Inc.)、PI3-デルタ/ガンマ阻害剤、Intellikine(Intellikine
Inc.)、PI3-デルタ/ガンマ阻害剤、Pathway Therapeutics(Pathway Therapeutics Ltd.)、PI3-デルタ/ガンマ阻害剤、Pathway Therapeutics(Pathway Therapeutics Ltd.)、PI3-ガンマ阻害剤Evotec(Evotec)、PI3-ガンマ阻害剤、Cellzome(Cellzome AG)、PI3-ガンマ阻害剤、Pathway Therapeutics(Pathway Therapeutics Ltd.)、PI3Kデルタ/ガンマ阻害剤、Intellikine-1(Intellikine Inc.)、PI3Kデルタ/ガンマ阻害剤、Intellikine-1(Intellikine Inc.)、ピクチリシブ(Roche Holdings Inc.)、PIK-90(CAS#677338-12-4)、SC-103980(Pfizer、New York、NY)、SF-1126(Semafore Pharmaceuticals、Indianapolis、IN)、SH-5、SH-6、テトラヒドロクルクミン、TG100-115(Targegen Inc.、San Diego、CA)、トリシリビン、X-339(Xcovery、West Palm Beach、FL)、XL-499(Evotech、Hamburg、Germany)、薬学的に許容される塩およびその組合せが含まれる。
ステロン、アンドロステンジオン、ジヒドロテストステロン、アルドステロン、エストラジオール、エストロン、エストリオール、コルチゾール、プロゲステロン、カルシトリオールおよびカルシジオールが含まれる。
(a)BRAF阻害剤療法、MEK阻害剤療法またはBRAFおよびMEK阻害剤療法に対して抗療性または耐性になったがんを有する対象を同定することと;
(b)前記抗療性または耐性のがんを有する対象にBVD-523または薬学的に許容されるその塩であるERK阻害剤を有効量で投与することと
を含む。
(a)対象から生体試料を得ることと、
(b)BRAF阻害剤療法、MEK阻害剤療法およびその組合せからなる群から選択される阻害剤療法に対象が耐性になったかどうか判定するために試料をスクリーニングすることと
を含む。
、2010年)。
年)ならびにWangおよび同僚(Wangら、2011年)によって以前に同定された。他の突然変異は、P124LおよびQ56Pなどの、N末端の負の調節ヘリックスの中に位置するかまたはそれに接するMEK1コドンに影響することができる(同上)。
に開示されるような様々な合成による配列決定(SBS)方法、ハイブリダイゼーションによる、ライゲーションによる(例えば、WO2005021786)、分解による(例えば、米国特許第5,622,824号および第6,140,053号)配列決定、およびナノポア配列決定(Oxford Nanopore Technologies、UKから市販されている)が含まれる。ディープシークエンシング技術では、配列決定過程の間に配列中の所与のヌクレオチドは2回以上読み取られる。ディープシークエンシング技術は、例えば、米国特許出願公開第20120264632号および国際特許出願公開番号WO2012125848に開示される。
PCRを使用して検出することもできる。例えば、国際出願公開番号WO2012046981を参照。
008年、に開示される。この方法はMIP分子を使用し、それは、遺伝子タイピングのための特別な「南京錠(padlock)」プローブ(Nilssonら、1994年)である
。MIP分子は、特異的領域、汎用性配列、制限部位およびTag(指標)配列(16~22bp)を含有する線状オリゴヌクレオチドである。MIPは、目的の遺伝子マーカー/SNPの周囲に直接的にハイブリダイズする。MIP方法は、並行してゲノムDNAにハイブリダイズするいくつかの「南京錠」プローブセットを使用することもできる(Hardenbolら、2003年)。完全な一致の場合、配置の反転(その技術の名称から示唆され
るように)を経て、環状分子を形成することによって、ゲノム相同性領域はライゲーションされる。第1の制限処理の後、全ての分子は汎用性プライマーで増幅される。ハイブリダイゼーションのための短い断片をマイクロアレイの上に確保するために、アンプリコンは再び制限処理される。生成された短い断片は標識され、Tag配列を通して、アレイの上のcTag(指標のための相補鎖)にハイブリダイズされる。Tag-cTag二重鎖の形成の後、シグナルが検出される。
(a)対象から生体試料を得ることと、
(b)対象が、以下のマーカー:
(i)RAFアイソフォームの間のスイッチ、
(ii)RTKまたはNRASシグナル伝達の上方制御、
(iii)分裂促進因子活性化プロテインキナーゼ(MAPK)シグナル伝達の再活性化、
(iv)MEK活性化突然変異の存在、
(v)突然変異BRAFの増幅、
(vi)STAT3上方制御、
(vii)MEKへの阻害剤の結合を直接的に遮断するかまたは構成的MEK活性につながるMEKのアロステリックポケットにおける突然変異、
の1つまたは複数を有するかどうか判定するために試料をスクリーニングすることと
を含み、ここで、マーカーの1つまたは複数の存在は、対象のがんがBRAFおよび/またはMEK阻害剤療法に対して抗療性または耐性であること、ならびに、BVD-523または薬学的に許容されるその塩であるERK阻害剤による療法から対象が恩恵を受けるだろうことを確認する。
21版、Lippincott Williams and Wilkins、Philadelphia、PA.)を参照。
The Science and Practice of Pharmacy(第21版、Lippincott Williams and
Wilkins、Philadelphia、PA.)、およびThe National Formulary(American Pharmaceutical Association、Washington、D.C.)を参照)、例えば、糖(例えば、ラクトー
ス、スクロース、マンニトールおよびソルビトール)、デンプン、セルロース調製物、リン酸カルシウム(例えば、リン酸二カルシウム、リン酸三カルシウムおよびリン酸水素カルシウム)、クエン酸ナトリウム、水、水溶液(例えば、食塩水、塩化ナトリウム注射、リンゲル注射、デキストロース注射、デキストロースおよび塩化ナトリウム注射、乳酸加リンゲル液)、アルコール(例えば、エチルアルコール、プロピルアルコールおよびベンジルアルコール)、ポリオール(例えば、グリセロール、プロピレングリコールおよびポリエチレングリコール)、有機エステル(例えば、オレイン酸エチルおよびトリグリセリド)、生分解性ポリマー(例えば、ポリラクチド-ポリグリコリド、ポリ(オルソエステル)およびポリ(無水物))、エラストマーマトリックス、リポソーム、マイクロスフェア、油(例えば、コーン、胚芽、オリーブ、ヒマ、ゴマ、綿実および落花生)、カカオバター、ワックス(例えば、坐薬ワックス)、パラフィン、シリコーン、タルク、サリチル酸塩(silicylate)等が含まれる。本発明の医薬組成物において使用される薬学的に許容される希釈剤または担体の各々は、製剤の他の成分に適合し、対象に有害でないという意味において「許容」されるものでなければならない。選択される剤形および予定の投与経路のために適する希釈剤または担体は、当技術分野で周知であり、選択される投与の剤形および方法のための許容される希釈剤または担体は、当技術分野の通常の技術を使用して決定することができる。
材料および方法
がん細胞株を、標準の培地および血清条件下、細胞培養物中で維持した。用量漸増試験のために、A375細胞を分割し、約40~60%集密まで増殖させ、次いで、初回用量の指定の薬物で処置した。表4は、漸増させた薬物による処置の要約を示す。
Blueの読み取り後、培地/Alamar Blue混合物を払い落とし、CellTiter-Glo/PBS(1:1)100μlを添加し、プレートを製造者の指示(Promega)通り処理した。培地のみのバックグラウンド値を差し引いた後、データを分析した。次いで、Bliss相加性モデルを適用した。
Gold(商標)シンチレーション剤(50μL)を添加した後、試料をPackard TopCountで計数した。活性対濃度滴定曲線から、Prismソフトウェア、バージョン3.0を使用してデータを競合的な密接結合阻害動態に関する方程式にあてはめることによってKi値を決定した。
Eraser Tip(The Nest Group、カタログ番号SEM0007)に入れた。ゲル断片を還元し、アルキル化した後、トリプシン消化した。トリプシン断片を50%(v/v)アセトニトリル、0.2%(v/v)トリフルオロ酢酸75μL中に単離し、得られた試料をSpeedVac中に0~10μLまで濃縮した。
0頁)のノックインについてヘテロ接合性の同質遺伝子型SW48細胞株をHorizon Discoveryから得た(カタログ番号;HD 103-002、HD 103-006 HD 103-007、HD 103-009、HD 103-010、HD
103-011、HD 103-013)。増殖アッセイのために、細胞を、96ウェルプレート、10%FBSを補充したマッコイ5A培地中に播種し、終夜接着させた後、化合物またはビヒクル対照を添加した。試験化合物を、細胞と一緒に、37℃、5%CO2雰囲気中で96時間インキュベートした。次いで、Alamar blueを使用して生存能力を評価した。
(実施例2)
用量漸増および増殖アッセイ - 1カ月目
用量漸増の進行 - 1カ月目
増殖アッセイ結果 - 1カ月目
表10は、試験の1カ月目についてのIC50データを示す。
(実施例3)
用量漸増および増殖アッセイ - 2カ月目
用量漸増の進行 - 2カ月目
増殖アッセイ結果 - 2カ月目
用量漸増および増殖アッセイ - 3カ月目
用量漸増の進行 - 3カ月目
増殖アッセイ結果 - 3カ月目
(実施例5)
組合せ試験結果
(実施例6)
BVD-523によりMAPKキナーゼ活性およびエフェクター機能のマーカーが変化した
(実施例7)
生存能力およびMAPKシグナル伝達に対するBVD-523およびベンチマークERK BRAFおよびMEK阻害剤の効果
単剤増殖アッセイ
組合せ増殖アッセイ
(実施例8)
ERK阻害剤間の組合せ相互作用
(実施例9)
がんにおけるMAPKシグナル伝達経路の標的化:新規の選択的ERK1/2阻害剤BVD-523(ウリキセルチニブ)の有望な活性
活性化する変化も標的化療法に対する耐性の状況においてよく見られる(Groenendijkら
、2014年)。したがって、MAPK経路末端マスターキナーゼ(ERK1/2)の標的化は、そのような経路活性化変化(例えば、BRAF、NRAS、およびKRAS)を有する腫瘍に対する有望な戦略である。
然変異、およびRTK活性化(Nazarianら、2010年およびShiら、2014年)を含
む。BRAF阻害剤/MEK阻害剤組合せ療法の状況における耐性機構が出現し始めており、また、これは、BRAF単剤耐性の機構を映すものである(Wagleら、2014年お
よびLongら、2014年)。これらの遺伝子事象は全て、共通して、ERKシグナル伝達を再活性化する能力を共有する。実際に、ERK転写標的によって測定される再活性化されたMAPK経路シグナル伝達は、BRAF阻害剤耐性患者由来の腫瘍生検材料においてよく見られる(Rizosら、2014年)。さらに、ERK1/2再活性化は、耐性の遺伝
子機構の非存在下で観察されている(Carlinoら、2015年)。したがって、永続的な
臨床的利益を達成するための探求するなかで、研究者は下流のMAPK構成成分であるERK1/2を標的とする追加の薬剤を評価することに焦点を当てるようになってきた。ERKの阻害により、獲得BRAF/MEK阻害に対する耐性を有する患者に対して重要な臨床的利益がもたらされ得る。ERKファミリーキナーゼには、BRAF阻害剤またはMEK阻害剤に対して耐性のがんを含めた前臨床的がんモデルにおける治療標的としての見込みが示されている(Morrisら、2013年およびHatzivassiliouら、2012年)。しかし、そのようなERK1/2阻害剤の潜在的使用は、メラノーマにおける獲得耐性を超えて拡大する。
(実施例10)
新規のERK1/2阻害剤、BVD-523(ウリキセルチニブ)の発見および最初の特徴付け
、リン酸化活性ERK2(pERK2)および不活性ERK2のどちらに対しても強力な結合親和性を示した(図29F)。pERK2に対して不活性ERK2と比較してより強力な親和性が観察された。BVD-523は、陰性対照タンパク質p38α MAPキナーゼと相互作用しなかった(図29F)。
BVD-523は、in vitroで、MAPK経路活性化突然変異を有するがん細胞株において、細胞増殖を優先的に阻害し、カスパーゼ-3/7活性を増強する
(実施例12)
BVD-523は、BRAFV600E突然変異体がん細胞株異種移植片モデルにおいてin vivo抗腫瘍活性を示す
(実施例13)
BVD-523により、ERK1/2リン酸化の上昇にもかかわらずERK1/2基質阻害がもたらされる
の細胞株においておよそ40種のタンパク質の大規模逆相タンパク質アレイ(RPPA)を使用した。BRAFおよびRASに共通の変化を有する細胞株をアッセイした:BRAFV600E突然変異体株A375、Colo205、およびHT29;KRASG12C突然変異体細胞株MIAPACa-2;KRASG13D突然変異体細胞株 HCT116;および非定型HRASF82L突然変異を有するAN3Ca。タンパク質レベルの変化は、ジメチルスルホキシド(DMSO)により処置した親対象からの百分率の変化として示される(図32Aおよび表23)。全てのERK阻害剤により、ERK1/2のリン酸化(pERK1/2[ERK1/2-T202、-Y204])以外は定性的に類似したタンパク質への影響が引き出された;SCH7722984ではすべての細胞株においてpERK1/2が阻害されたが、BVD-523、GDC-0994、およびVx-11eでは、pERK1/2が著しく増加した。それぞれpERK1/2の近位標的および遠位標的であるホスホ-p90 RSK(pRSK1)およびサイクリンD1は、ERK1/2リン酸化の程度にかかわらず、試験した全ての阻害剤によって同様に阻害された(図32B)。BVD-523についてのこれらの独立した所見は、pERK1/2および不活性ERK1/2へのBVD-523による結合および安定化を実証するタンパク質結合試験(図29Eおよび図29F)に加えて、A375細胞におけるウェスタンブロットにより、ERK1/2基質RSK1/2のリン酸化が、pERK1/2が劇的に上昇したにもかかわらず阻害されたままであることを示す試験(図32D)と一致する。したがって、pERK1/2レベルの上昇の測定はBVD-523についての臨床的な薬力学的バイオマーカーとみなすことができ、同時に、pRSK1およびDUSP6などのERK1/2標的の阻害を数量化することも同じく同様の目的に役立ち得る。
核画分および細胞質画分のどちらにおいても明らかであり、これは、この細胞株にBRAFV600Eが存在することに起因するMAPK経路活性を反映する可能性がある。BVD-523を用いた処置の結果、DMSOで処置した細胞と比較して核および細胞質におけるpERK1/2の上昇ならびに核内総ERK1/2の穏当な増加がもたらされ、これにより、化合物により誘導されるpERK1/2の安定化によりいくらかの核移行が刺激されることが示唆される。どちらの区画においてもpERK1/2が増加したにもかかわらず、細胞質区画および核区画におけるpRSKレベルはDMSO対照と比較して低い。比較器であるMAPKシグナル伝達阻害剤(すなわち、トラメチニブ、SCH7722984、ダブラフェニブ)では、核区画および細胞質区画におけるレベルがより低いことによって反映される通り、ERK1/2のリン酸化およびRSKが阻害された。これらのデータから、重ねて、細胞質および核の両方においてBVD-523に関連するpERK1/2の増加が明らかであることが示唆される;しかし、これは、標的基質の活性化には転換されない。これは、図30Dおよび図32Aにおいて提示されているデータと一致する。
(実施例14)
BVD-523は、BRAF阻害剤およびMEK阻害剤耐性のin vitroモデルにおいて活性を示した
3年およびEmeryら、2009年)。MEK1Q56Pを含めたMEK1/2突然変異は
、患者における単剤BRAFおよびBRAF/MEK療法の組合せに対する獲得耐性の両方に関係づけられている(Wagleら、2011年、Wagleら、2014年、Emeryら、20
09年およびJohnsonら、2015年)。単剤アッセイにより、親BRAFV600E:
:MEK1wt細胞と比べて、二重突然変異体BRAFV600E::MEK1Q56P細胞はBRAF阻害剤であるベムラフェニブおよびダブラフェニブならびにMEK阻害剤であるトラメチニブに対して著しく低下した感受性を示すことが実証された(図34B)。対照的に、BVD-523に対する応答は、親細胞およびMEKQ56P突然変異体細胞のどちらにおいても基本的に同一であり、これにより、BVD-523が獲得耐性の機構を受けにくいことが示される。これらの結果は、2つの独立に得た二重突然変異体BRAFV600E::MEK1Q56P細胞株クローンにおいて確認され、したがって、結果が、無関係のクローンアーチファクトではなく、MEK1Q56P突然変異の存在に特異的に関連することが検証される(データは示していない)。第2の機構的に別個のERK1/2阻害剤(SCH772984)を用いた場合にも同様の結果が観察され、これにより、これらの観察の予期がERK1/2の機構的阻害に特異的に関連し、オフターゲットの化合物効果に起因するものではないことが裏付けられる。
(実施例15)
BVD-523は、BRAF阻害剤耐性患者由来のメラノーマ異種移植モデルにおいてin vivo活性を示す
(実施例16)
BVD-523とBRAF阻害剤の組合せ療法により有望な抗腫瘍活性がもたらされる
の組合せ手法の考察が正当化される。BVD-523とBRAF阻害剤であるベムラフェニブを組み合わせることの抗増殖効果をBRAFV600E突然変異体メラノーマ細胞株G-361において評価した。期待された通り、単剤BVD-523およびベムラフェニブはどちらも活性であり、組み合わせた場合には穏当な相乗性が観察された(図37B)。これにより、BRAFV600E突然変異を有するメラノーマ細胞株において、BVD-523とBRAF阻害剤の組合せは少なくとも相加性であり、潜在的に相乗性であることが示される。さらに、BRAFV600E突然変異体細胞株(A375)をBRAF阻害剤+BVD-523の下で継続的に培養した後にin vitroにおいて獲得耐性の発生は困難であった。対照的に、ダブラフェニブ単独に対する耐性は比較的急速に生じた(図37C)。ダブラフェニブとトラメチニブの組合せに対して同等の耐性がダブラフェニブ+トラメチニブ前に出現した。
vitro組合せ試験では完全には実現されない可能性がある。組合せの利益を理解するために、BRAFV600E突然変異体ヒトメラノーマ細胞株A375の異種移植片を利用してin vivoにおいて有効性を評価した。組合せ処置に対して注目すべき応答があったので、組合せ群における投薬を20日目に停止して腫瘍の再増殖をモニターし、42日目に再開した(図36A)。45日目に試験を終了するまで腫瘍を週2回測定した。対照についてのエンドポイントまでの時間(TTE)の中央値は9.2日であり、可能な限り最大の腫瘍増殖遅延(TGD)である35.8日を100%と定義した。テモゾロミドによる処置の結果、TGDは1.3日(4%)であり、退縮はもたらされなかった。50mg/kgおよび100mg/kgのダブラフェニブ単剤療法では、それぞれ6.9日(19%)および19.3日(54%)のTGD、有意な生存利益(P<0.001)、および100mg/kg群における1件のPRがもたらされた。100mg/kgのBVD 523単剤療法では、9.3日(26%)のTGD、有意な生存利益(P<0.001)、および2件の永続的な完全奏効がもたらされた。ダブラフェニブとBVD-523の組合せでは、それぞれ可能な限り最大の100%のTGDが注目すべき退縮応答とともにもたらされ、それらの対応する単剤療法と比較して統計学的に優れた全生存がもたらされた(P<0.001)。最低用量での組合せにより、注目すべき7/15の無腫瘍生存者(TFS)がもたらされ、3つの高投与量組合せで、治癒的なまたはほぼ治癒的な活性と一致して合計43/44のTFSがもたらされた(図36B)。要約すると、ダブラフェニブとBVD-523の組合せにより、いずれの単剤よりも多数のTFSおよび優れた有効性がもたらされた。
考察
10年およびWangら、2011年)、標的遺伝子の増幅(Corcoranら、2010年)、および経路構成成分(例えば、RAS、MEK)の活性化突然変異(Wagleら、2011年
、Emeryら、2009年およびWangら、2011年)に起因している。ERK1/2経路
の再活性化は、獲得耐性機構の一般的な結果の1つである。MEKQ56PがBRAFV600E突然変異体メラノーマ細胞株A375に導入されると、MEK阻害およびBRAF阻害に対する耐性が付与される(Wagleら、2011年)。対照的に、BVD-523
は、工学的に操作されたMEKQ56P細胞株においてその強力な阻害活性を保持し、これにより、ERK1/2阻害が、BRAF/MEKによる処置に応答して生じる可能性がある上流活性化変化の状況において有効であることが示される。獲得耐性の状況におけるBVD-523の役割のさらなる証拠として、BVD-523の有効性は、ベムラフェニブで疾患が進行した患者由来の腫瘍試料に由来する異種移植モデルで明らかであった;BRAF阻害剤であるダブラフェニブはこのモデルにおいて有効でなかった。これらのデータから、BRAF/MEK耐性の状況においてERK1/2を標的化することの役割が裏付けられ、以前公開された所見が補完される(Morrisら、2013年およびHatzivassiliouら、2012年)。MAPK経路の阻害剤に対する耐性をさらに特徴付けるために、BVD-523自体に対する耐性の出現を調査した。がん細胞のBVD-523での単剤処置が永続的であり、上流のMAPKシグナル伝達構成成分(すなわち、ダブラフェニブ、トラメチニブ)を標的とする他の薬剤と比較して耐性の発生が困難であることが見出された。これは、ERK1/2-標的化剤に対する耐性の獲得が、BVD-523がATP結合性部位のより保存された活性なコンフォメーション(confirmation)を優先的に標的とするという事実に潜在的に起因して、BRAF療法またはMEK療法に対する耐性の獲得よりも達成しがたいことを示唆するものである可能性がある。しかし、他のERK1/2阻害剤を用いたin vitro試験により、耐性を駆動するERK1/2の特定の突然変異体が同定された(Jhaら、2016年およびGoetzら、2014年);これらの特定の突然変異はERK1/2阻害剤で再発患者に由来する臨床試料ではまだ同定されていない。
MAPKシグナル伝達の最大かつ永続的な減弱のためには組合せ手法が必要になり得る。例えば、KRAS突然変異体結腸直腸がん細胞におけるMEK阻害により、ErbBファミリー活性化の適応応答がもたらされ、これは、MEK阻害に対する応答を低下させるものである(Sunら、2014年)。同様の状況特異的な適応応答がBVD-523を用い
たERK1/2阻害後に生じる可能性がある。種々の遺伝子プロファイルおよびがん組織学的検査に対する最適な処置組合せは、進行中の研究の対象である。BRAFV600突然変異およびRAS突然変異に加えて、MAPKを駆動する他の変化が出現している。例えば、RAF二量体化を促進する新規のRAF融合物および非定型非V600 BRAF突然変異によりMAPK経路が活性化される(Yaoら、2015年)。BRAFV600
突然変異体単量体タンパク質を阻害するベムラフェニブおよびダブラフェニブなどのBRAF阻害剤は、MAPKシグナル伝達を二量体化依存的に駆動する非定型RAF変化では不活性であることが示されている(Yaoら、2015年)。しかし、これらの腫瘍におい
て下流のERK1/2を標的とするためのBVD-523を用いた処置が、このまだ対処されていない医学的必要性に取り組むための新規の手法になり得る。
(実施例17)
進行固形腫瘍を有する患者における画期的医薬品である新規の経口ERK1/2キナーゼ阻害剤BVD-523(ウリキセルチニブ)の第I相用量漸増試験
/2活性化およびキナーゼ活性は、細胞の増殖、分化、および生存に、リボソームS6キナーゼ(RSK)ファミリーメンバーの活性化(Romeoら、2012年)を含めた種々の
機構を通じて影響を及ぼす(Rasolaら、2010年)。
007年およびGollobら、2006年)。KRAS、NRAS、およびHRASなどのRASファミリー遺伝子の突然変異が最も一般的であり、活性化RAS突然変異はヒトがんの約30%において生じる(Schubbertら、2007年)。KRAS突然変異は、膵臓が
ん(>90%)(Kandaら、2012年)、胆道がん(3%~50%)(Hezelら、2014年)、結腸直腸がん(30%~50%)(Arringtonら、2012年)、肺がん(27
%)(Pennycuickら、2012年)、卵巣がん(15%~39%)(Dobrzyckaら、20
09年)、および類内膜子宮内膜がん(18%)(O'HaraおよびBell、2012年)で広く見られ、NRAS突然変異は、メラノーマ(20%)(Khattakら、2013年)およ
び骨髄性白血病(8%~13%)(Yohe、2015年)で広く見られ、HRAS突然変異は、膀胱がん(12%)で広く見られる(Fernandez-MedardeおよびSantos、2011年
)。RAFファミリー遺伝子、とりわけBRAFの突然変異が特にメラノーマにおいて発生頻度が高い。BRAF突然変異は、悪性メラノーマの66%および広範囲の他のがんの約7%で同定されており(Daviesら、2002年)、一方、MEK突然変異はより稀であり、メラノーマにおける全体的な発生頻度は8%である(Nikolaevら、2012年)。対照的に、腫瘍形成をもたらすERK突然変異は現在までめったに報告されていない(Deschenes-Simardら、2014年)。
2014年)。MEK1/2阻害剤であるトラメチニブも、この状況における単剤療法として承認されているが(Mekinist[添付文書])、より一般には、BRAF阻害剤であるダブラフェニブと組み合わせて使用される。トラメチニブとダブラフェニブの組合せ投与という第一選択使用により、ベムラフェニブ単剤療法と比較して、全体的な毒性の増加を伴わずに全生存のはるかに大きな改善がもたらされ(Robertら、2015年)、これにより、このMAPKシグナル伝達経路の多数のタンパク質を同時に標的とすることの潜在的な有用性が強調される。この治療的組合せでは、MEK阻害剤に関連する皮疹およびBRAF阻害剤により誘導される過剰増殖皮膚病変の発生率も各単剤単独と比較して低かった(Flahertyら、2012年)。最近、第III相試験により、BRAFV600E/K突然変異陽性メラノーマを有する患者において、ダブラフェニブ+トラメチニブを用いた場合に、ダブラフェニブ単独に対して、全生存(25.1カ月対18.7カ月、ハザード比[HR]0.71、P=0.0107)、無増悪生存期間(PFS)(11.0カ月対8.8カ月、HR 0.67、P=0.0004)、および全体的な応答(69%対53%;P=0.0014)の有意な改善も実証された(Longら、2015年)。同様に、コビメチニブ+ベムラフェニブの組合せを用いた場合に、ベムラフェニブ単独と比較してPFS(9.9カ月対6.2カ月、HR 0.51、P<0.001)および完全奏効(CR)率または部分奏効(PR)率(68%対45%;P<0.001)の有意な改善も実証された(Larkinら、2014年)。この目的のために、BRAFV600E/K突然変異メラノーマに対するベムラフェニブとコビメチニブ(cobemetinib)の組合せに
対してFDAによる認可が最近与えられた。これらおよび関連する所見に基づいて、BRAF阻害剤+MEK阻害剤の組合せが、BRAFV600E/K突然変異を含有する転移性メラノーマを有する患者に対する標準の標的化処置選択肢になっている。
RKはこのMAPKシグナル伝達経路の最も遠位のマスターキナーゼであるので、ERK阻害により、上流の機構から耐性を回避または克服する機会がもたらされ得る。これは、小分子阻害剤によるERKの阻害が、耐性の出現が阻害されるように、ならびに、BRAF阻害剤およびMEK阻害剤に対する獲得耐性が克服されるように作用するという前臨床的証拠によって裏付けられる(Morrisら、2013年およびHatzivassiliouら、2012年)。
(実施例18)
患者の特性
ex vivoにおけるBVD-523のRSK1/2リン酸化に対する効果
(実施例20)
用量漸増、用量制限毒性(DLT)、最大耐量(MTD)、および推奨される第II相用量(RP2D)
有害事象(AE)
(実施例22)
薬物動態学
(実施例23)
BVD-523による標的阻害の薬力学的確認
(実施例24)
抗腫瘍効果
考察
後の調査は、この用量漸増試験において実証された有効性および安全性プロファイルの両方に拡張され、ERK阻害剤BVD-523のユニークなプロファイルをどのように単剤としてまたは他の薬剤と組み合わせて使用することができるかの手引きになるであろう。
11年、Wagleら、2014年、Ahronianら、2015年およびParaisoら、2010年)。したがって、BVD-523を単独で用いたまたは他のMAPKシグナル伝達経路阻害剤と組み合わせたERK阻害には、既存の療法に対する耐性の発生を遅らせる、およびより広範な患者集団に有益になる潜在性があり得る。BRAF耐性細胞株およびMEK耐性細胞株において効力を保持するBVD-523を含めたERK阻害剤により、標準治療(BRAF/MEK組合せ療法)に対する獲得耐性を有する患者におけるERK阻害剤の使用に関する前臨床的証拠がもたらされる。例えば、実施例9~16を参照されたい。重要なことに、本研究では、最初にBRAF阻害剤(ベムラフェニブ)を用いて処置し、その後、BRAF阻害剤とMEK阻害剤(ダブラフェニブ/トラメチニブ)を組み合わせて処置した場合に疾患の安定後にがんが進行した患者は、単剤BVD-523を受けると部分奏効を有した。この患者は、本明細書において報告されている試験のカットオフ日の時点で合計708日にわたって試験を受け続けた。この患者において観察された抗腫瘍効果に一部基づいて、FDAは、BRAFおよび/またはMEK阻害剤(複数可)を用いた処置に対して抗療性である、または処置後に進行した、切除不能または転移性BRAFV600突然変異陽性メラノーマを有する患者を処置するためのBVD-523に関する調査をFast Track開発プログラムに指定した。BVD-523により厳密にどのように患者の介護を最良に支持できるか(例えば、単剤としてまたは種々の組合せで)を的確に定義するためには追加の臨床試験が必要である。
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WO2015095842A3 (en) | 2015-08-20 |
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US20210038587A1 (en) | 2021-02-11 |
US20180104228A1 (en) | 2018-04-19 |
BR112018073786A2 (pt) | 2019-02-26 |
CN109475541A (zh) | 2019-03-15 |
IL294056A (en) | 2022-08-01 |
MX2018014231A (es) | 2019-05-15 |
ZA202007734B (en) | 2022-04-28 |
EP3458056A1 (en) | 2019-03-27 |
ZA201808480B (en) | 2022-04-28 |
US10881646B2 (en) | 2021-01-05 |
AU2017267804B2 (en) | 2023-04-27 |
US20190201387A1 (en) | 2019-07-04 |
EP3458056A4 (en) | 2020-01-08 |
AU2017267804A1 (en) | 2019-01-17 |
US20220117950A1 (en) | 2022-04-21 |
KR20230025941A (ko) | 2023-02-23 |
CA3024703A1 (en) | 2017-11-23 |
AU2023204587A1 (en) | 2023-08-17 |
JP2019519519A (ja) | 2019-07-11 |
MX2022005473A (es) | 2022-06-02 |
RU2018145048A (ru) | 2020-06-22 |
SG11201810287RA (en) | 2018-12-28 |
IL263108A (en) | 2018-12-31 |
CL2018003282A1 (es) | 2019-10-18 |
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