JP2021534094A - 未分化リンパ腫キナーゼ阻害剤と組み合わせてegf/egfr経路を抑制するための方法および組成物 - Google Patents
未分化リンパ腫キナーゼ阻害剤と組み合わせてegf/egfr経路を抑制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、2018年8月7日に出願された米国仮特許出願第62/715,351号、2018年9月5日に出願された米国仮特許出願第62/727,056号、2018年10月22日に出願された米国仮特許出願第62/748,772号、2018年11月13日に出願された米国仮特許出願第62/760,529号、および2019年3月22日に出願された米国仮特許出願第62/822,290号の優先権および利益を主張し、全ての目的のためにその内容全体を本明細書に参照として含む。
クリゾチニブを標準化学療法と比較する2つの後続の無作為第3相研究は、クリゾチニブの完全な承認を導き、最近まで、ALK陽性NSLCの第一治療のための「ゴールドスタンダート」と位置付けられてきた。第2相研究データと一致して、クリゾチニブは、化学療法と比較して印象的な結果を示し、orr(65%対20%)およびpfs[ハザード比(hr):0.49;7.7ヶ月対3ヶ月]の改善を示した。その後、クリゾチニブは、ALK陽性未治療患者において、白金−ペメトレキセド化学療法と比較した。再度、クリゾチニブは、化学療法と比較して、orr(74%対45%)、mpfs(時間:0.45、10.9ヶ月対7ヶ月)及び重要な生活の質の改善と関連があった。全生存率には差がなかった。(Rothenstein et al.Current Oncology、2018)
(セリチニブ)
セリチニブは、クリゾチニブ耐性のALK陽性NSLCの治療において利点を示した初めての次世代阻害剤である。セリチニブは、クリゾチニブと比較して、アルクを抑制する効能が20倍高く、クリゾチニブ耐性が発生した患者の生検の細胞株研究では、セリチニブが、一部発見された耐性突然変異の強力な阻害剤であることを示している。
アレクチニブは、クリゾチニブ耐性ALK突然変異に対する活性を有するまた別の高度に選択的なALK阻害剤である。アレクチニブの独特な特徴の1つに、クリゾチニブを服用する患者のCNS耐性機序と関係しているP糖タンパク質のための基質ではないというものがある。アレクチニブは現在、進行したALK陽性NSCLC患者のための新規な標準の第一治療剤として確立されている。第一治療剤としてのアレクチニブに対する殆どの反応は恒久性があるが、本質的に、全ての患者に耐性が生じて臨床的再発につながる。他の2つの第二世代ALK阻害剤であるセリチニブとブリガチニブは、クリゾチニブ未投与および/またはクリゾチニブ耐性の環境でのみ試験される。
ALK遺伝子の変化に対する治療的意味は、主にALK阻害剤に対する腫瘍の反応を予測するALK遺伝子融合と関連がある。クリゾチニブ、セリチニブ、および最近のアレクチニブは、腫瘍がALK融合に対して陽性である転移性NSCLC患者の治療のためにFDAから承認を受けた。初期の第1相研究では、クリゾチニブがALK融合陽性転移性NSCLC患者において一貫した反応をもたらすということを示す。クリゾチニブのFDA承認から続いた2つの第3相研究では、クリゾチニブが未治療の進行したALK再編成NSCLC患者において、標準の1次ペメトレキセド+シスプラチン化学療法よりも優れていることがさらに確認された。
ALK TKIで治療を受けた患者は、EGFR TKIで治療を受けたEGFR突然変異の患者に比べて、より長い無進行生存期間を達成した。クリニックでは、患者の20〜30%が急速に耐性を有することになった。しかし、かかる患者に耐性が生じたり反応がないか否かは分かっていない。また、かかる患者においてEGFが循環する効果が何なのかも明確でない。本発明は、TKI耐性に対するEGFの効果を扱っており、NSCLC患者の主要ALK再編成を含む2つの細胞株を用いる。
大腸がん(CRC)は、最も広く知られている腫瘍性がんであるだけでなく、特に治療が難しいことで知られている。KRAS突然変異のないCRC患者は、クリニックでセツキシマブやエルロチニブなどのEGFを標的とする療法により治療できる。しかし、KRAS突然変異、BRAF突然変異またはPIK3CA突然変異を保有する大規模なCRC患者群がある。現在、かかる患者のための効果的な治療法はない。化学療法や血管新生標的化が一般に用いられているが、大きな欠点がある。
SW900野生型細胞において、pEGFRに対するヒト患者(22180004)抗EGF血清の効果は、EGFの存在下で観察された。2a=ワクチン接種前の患者。3d=ワクチン接種後の患者。図70に示すように、pEGFR活性化の完全な抑制は、抗EGF血清の存在下で観察され、pERK1/2の一部減少も観察された。図71に示すように、SW900野生型細胞において、pEGFRに対する2人のさらなる患者からのヒト患者抗EGF血清の効果は、EGFの存在下で観察された。患者27030004において、pEGFRおよびpERK1/2活性化の顕著な抑制が観察されたのに対し、患者29080005では、両方とも少ない抑制が観察された。3人のさらなる患者からの抗EGF血清の結果は、図72に示している。29040007および33080020の2人の患者において、pEGFRおよびpERK1/2のシグナル伝達の相当な抑制が観察された。患者31070004において、最小限の変化が観察された。図70〜図72の結果は図73および図74に要約している。
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Claims (9)
- ELM4−ALK融合遺伝子を発現する非小細胞肺がん(NSCLC)を患う患者を治療する方法であって、
前記患者は、EGFRの突然変異型を発現する腫瘍を有し、前記方法は、未分化リンパ腫キナーゼ阻害剤(ALK阻害剤)とEGFを標的とする能動免疫とを併用するための柔軟かつ積極的なレジメンをそのような治療を必要とする患者に投与するステップを含み、前記方法において、ALK阻害剤は、治療学的に有効な1日投与量で投与し、能動免疫は、1週間に3回、2回もしくは1回、2週間に1回、3週間に1回または少なくとも1ヶ月に1回繰り返される治療有効量に従って同時に施す方法。 - ALK阻害剤は、クリゾチニブ、セリチニブ、アレクチニブ、ブリガチニブおよびロルラチニブ、またはそれらの薬学的に許容される塩からなる群より選択され、EGFRの突然変異型を発現する腫瘍を有する患者の治療のために、約10〜250mgの範囲の1日平均投与量に基づく連続したレジメンに従って投与し、EGFを標的とする能動免疫は、1週間に3回、2回もしくは1回、2週間に1回、3週間に1回または少なくとも1ヶ月に1回繰り返される治療有効量に従って同時に施す、請求項1に記載の方法。
- 前記がんは、その転移性型を含むELM4−ALK融合遺伝子を発現するNSCLCであり、ALK阻害剤は、クリゾチニブ、セリチニブ、アレクチニブ、ブリガチニブおよびロルラチニブ、またはそれらの薬学的に許容される塩からなる群より選択され、EGFR突然変異およびALK阻害剤治療に対する耐性を獲得した患者に、約10〜250mgの範囲の1日平均投与量に基づく連続したレジメンに従って投与し、EGFを標的とする能動免疫は、1週間に2回もしくは1回、または2週間に1回繰り返される治療有効量に従って同時に施し、
前記方法は、ALK阻害剤治療に対する耐性の克服をもたらす、請求項1に記載の方法。 - 前記がんは、その転移性型を含むELM4−ALK融合遺伝子を発現するNSCLCであり、ALK阻害剤は、クリゾチニブ、セリチニブ、アレクチニブ、ブリガチニブおよびロルラチニブ、またはそれらの薬学的に許容される塩からなる群より選択され、ALK阻害剤治療に対する耐性を獲得した患者に、約10〜250mgの範囲の1日平均投与量に基づく連続したレジメンに従って投与し、EGFを標的とする能動免疫は、1週間に2回もしくは1回、または2週間に1回繰り返される治療有効量に従って同時に施す、請求項1に記載の方法。
- ELM4−ALK融合遺伝子を発現する非小細胞肺がん(NSCLC)を患う患者を治療する方法であって、ALK阻害剤とモノクローナル抗EGF抗体の受動投与とを併用するための柔軟かつ積極的なレジメンをそのような治療を必要とする患者に投与するステップを含み、ここで、ALK阻害剤は、治療学的に有効な1日投与量で連続したレジメンに従って投与し、能動免疫は、1週間に3回、2回もしくは1回、2週間に1回、3週間に1回または少なくとも1ヶ月に1回繰り返される治療有効量に従って同時に施す方法。
- ELM4−ALK融合遺伝子を発現する脱制御されたヒト上皮成長因子受容体(HER/ヒトEGFR)によって誘導された非小細胞肺がん(NSCLC)を患う患者を治療する方法であって、
前記患者は、EGFRの突然変異型を発現する腫瘍を有し、前記方法は、ALK阻害剤とモノクローナル抗EGFR抗体の受動投与とを併用するための柔軟かつ積極的なレジメンをそのような治療を必要とする患者に投与するステップを含み、ここで、ALK阻害剤は、約10〜250mgの範囲の1日平均投与量に基づく連続したレジメンに従って投与し、能動免疫は、1週間に3回、2回もしくは1回、2週間に1回、3週間に1回または少なくとも1ヶ月に1回繰り返される治療有効量に従って同時に施し、ALK阻害剤治療に対する耐性の獲得を防止する、方法。 - 脱制御されたヒト上皮成長因子受容体(HER/ヒトEGFR)によって誘導された非小細胞肺がん(NSCLC)を患う患者を治療する方法であって、
前記患者は、突然変異したELM4−ALK融合遺伝子を発現する腫瘍を有し、前記方法は、ALK阻害剤とモノクローナル抗EGFR抗体の受動投与とを併用するための柔軟かつ積極的なレジメンをそのような治療を必要とする患者に投与するステップを含み、前記方法において、ALK阻害剤は、約10〜250mgの範囲の1日平均投与量に基づく連続したレジメンに従って投与し、能動免疫は、1週間に3回、2回もしくは1回、2週間に1回、3週間に1回または少なくとも1ヶ月に1回繰り返される治療有効量に従って同時に施し、ALK阻害剤およびモノクローナル抗EGFR抗体の投与は、その後に行われる方法。 - ELM4−ALK融合遺伝子を発現する脱制御されたヒト上皮成長因子受容体(HER1/ヒトEGFR)NSCLCによって誘導された非小細胞肺がん(NSCLC)を患う患者を治療する方法であって、
前記患者は、EGFRの突然変異型を発現する腫瘍を有し、前記方法は、ALK阻害剤とEGFを標的とする能動免疫とを併用するための柔軟かつ積極的なレジメンをそのような治療を必要とする患者に投与するステップを含み、能動免疫は、約10〜250mgの範囲の1日平均投与量に基づく連続したレジメンによりALK阻害剤を投与する前に、1週間に3回、2回もしくは1回、2週間に1回、3週間に1回または少なくとも1ヶ月に1回繰り返される治療有効量に従って施し、ALK阻害剤治療に対する耐性の獲得を防止する、方法。 - 免疫原性タンパク質は、STAT3活性化を減少させるために治療量で投与される、請求項1に記載の方法。
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