JP6894952B2 - 癌治療のためのpd−1拮抗薬およびvegfr阻害剤の組み合わせ - Google Patents
癌治療のためのpd−1拮抗薬およびvegfr阻害剤の組み合わせ Download PDFInfo
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Description
本出願は、2014年2月4日に出願した米国仮出願第61/935809号の全体を参考として援用しその優先権を主張する。
本出願は、ASCII形式で電子的に提出された配列表を含み、本明細書にその全体を参考として援用する。2015年1月29日に作成されたASCIIコピーは、PCFC-956-WO1_SL.txtと命名し、そのサイズは32535バイトである。
管間質腫瘍および肝細胞癌を含む様々なタイプの癌治療のために承認されており、臨床的な設定で調査すべきものとして継続している。このような阻害剤の有効性は、もし、他の承認済の又は試験的な癌療法、例えば放射線、外科手術、化学療法剤、標的療法、腫瘍中で制御不能になった他のシグナル伝達経路を阻害する医薬及び他の免疫増強剤、と組み合わせて投与するならば、強化できるかもしれないという提案がなされて来た。
性白血病(CML)びまん性大細胞型B細胞リンパ腫(DLBCL)、EBV陽性DLBCL、縦隔原発B細胞性大細胞型リンパ腫、T細胞/組織球リッチ大細胞型B細胞リンパ腫、濾胞性リンパ腫、
ホジキンリンパ腫(HL)、マントル細胞リンパ腫(MCL)、多発性骨髄腫(MM)、骨髄性
細胞白血病-1タンパク質(MCL-1)、骨髄異形成症候群(MDS)、非ホジキンリンパ腫(NHL )、または小リンパ球性リンパ腫(SLL)である。
BID 一日二回1用量
CDR 相補性決定領域
CHO チャイニーズハムスター卵巣
DFS 無病生存
DTR 用量制限毒性
FFPE ホルマリン固定パラフィン包埋
FR フレームワーク領域
IgG 免疫グロブリンG
IHC 免疫組織化学または免疫組織化学的
MTD 最大耐用量
NCBI 米国国立生物工学情報センター
NCI 米国国立癌研究所
OR 総合的な奏功
OS 全生存期間
PD 進行性疾患
PFS 無増悪生存期間
PR 部分的奏功
Q2W 隔週1用量
Q3W 3週1用量
QD 1日1用量
RECIST 固形腫瘍効果判定基準
SD 安定な疾患
VH 免疫グロブリン重鎖可変領域
VK 免疫グロブリンκ軽鎖可変領
本発明がより容易に理解できるように、一定の技術用語および科学用語を、以下に具体的に定義する。本明細書のどこにも具体的に定義されなければ、本明細書で使用される他のすべての技術用語および科学用語は、本発明が属する技術分野の当業者によって理解される一般的な意味を有する。
及び「(the)」など、単数形の単語は、文脈上で明確に指示しない限り、それらに対応
する複数形の関連を含む。
味する。「対象」という用語は、任意の生物、好ましくは動物、より好ましくは哺乳動物(例えば、ラット、マウス、イヌ、ネコ、ウサギ)、および最も好ましくはヒトを含む。
プへの結合を可能にしている。一般に、N末端からC末端に、軽鎖及び重鎖の可変ドメインは両方共に、FR1、CDR1、FR2、CDR2、FR3、CDR3およびFR4を含む。各ドメインに割当てられるアミノ酸は、一般に、以下の文献の定義に一致する。Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md. ; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917又は、Chothia, et al., (1989) Nature 342:878-883.
、ダイアボディ、直鎖状抗体、単鎖抗体分子、例えば、SC-FV、ナノボディおよび抗体フラグメントから形成される多重特異性抗体などが挙げられる。
たPD-Lは、前分泌リーダー配列を欠いており、リーダーペプチドとも称する。本明細書において、用語「PD-L」及び「成熟PD-L」は交換可能に使用され、かつ特に指示しない限り、同一の分子を意味することを理解すべきであり、さもなければ、文脈から、容易に理解出来る。
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEMEDKNIIQFVHGEEDLKVQHSS
YRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET (配列番号25)
ブリン可変領域を意味する。
抗体を含む。「モノクローナル」修飾因子は、実質的に均一な抗体集団から得られたままの抗体の特徴を示し、かつ特定の如何なる方法によっても抗体の産生を必要とすると解釈されるべきではない。例えば、本発明に従って、使用するモノクロナール抗体は、Kohler
et al. (1975) Nature 256: 495、に記載されたハイブリドーマ法により、作製しても良く、また、または組換えDNA法(参照、例えば米国特許第4,816,567号)によって作製しても良い。「モノクローナル抗体」は、又、例えば、Clackson et al. (1991) Nature 352:
624-628、及びMarks et al. (1991) J. Mol. Biol. 222: 581-597、に記載された技術を用いてファージ抗体ライブラリーから単離しても良い。Presta (2005) J. Allergy Clin.
Immunol. 116:731.も又、参照のこと。
たPD-Lタンパク質の、又は細胞又は組織内での指定されたPD-L mRNAの、検出可能なレベルの何れかの発現を意味する。PD-Lタンパク質の発現は、診断用PD-L抗体を用いて、腫瘍組織部位をIHCアッセイにおいて、またはフローサイトメトリーによって、検出し得る。
あるいは、腫瘍細胞によるPD-Lタンパク質の発現は、所望のPD-L標的、例えば、PD-L1ま
たはPD -L2、に特異的に結合する、結合剤(例えば、抗体フラグメント、アフィボディなど)を使用して、PET画像化によって検出しても良い。PD-L mRNAの発現を検出し、及び測定する技術は、RT-PCR、及びリアルタイム定量RT-PCRを含む。
Thompson, R. H., et al., PNAS 101 (49); 17174-17179 (2004);
Thompson, R. H. et al., Cancer Res. 66:3381-3385 (2006);
Gadiot, J., et al., Cancer 117:2192-2201 (2011);
Taube, J. M. et al., Sci Transl Med 4, 127ra37 (2012);及び
Toplian, S. L. et al., New Eng. J Med. 366 (26): 2443-2454 (2012)。
瘍細胞中で、ならびに浸潤性免疫細胞中で定量化する。膜染色を示す腫瘍細胞と浸潤免疫細胞のパーセンテージとを別々に、5%未満、5から9%、次いで、10%の増分で100%まで定量化する。腫瘍細胞について、PD-L1発現はスコアが5%未満であれば負として、また5%以上であれば正としてカウントする。免疫浸潤物内のPD-L1 発現を準定量的測定として、調整炎症得点(AIS)と称し、報告されており、それは染色膜細胞のパーセントと浸
潤強度とを掛合わせることにより、定量化し、無(0)、穏やか(得点1、リンパ球 稀)、中位(得点2、リンパ組織球性凝集体による限局性腫瘍浸潤)又は、厳しい(得点3、びまん性浸潤)と格付けされる。腫瘍組織部位はAISが5以上の場合、免疫浸潤物によるPD-L1発現については、正としてカウントする。
たはmRNAの発現レベルは、同じ型の非悪細胞内の、または対応する正常組織からの部位内の定量レベルであっても良い。いくつかの好ましい実施態様で、腫瘍試料中のPD-L1の発
現は、試料中のPD-L1タンパク質(及び/又はPD-L1 mRNA)が、コントロール中のそれより、少なくとも10%、20%、または30%大きい場合、上昇したと判定される。
ば、癌細胞数の減少、腫瘍の縮小、末梢器官への癌細胞浸潤速度減少、または腫瘍転移速度若しくは腫瘍増殖速度の減少等、少なくとも一つの肯定的な治療効果を達成することを意味する。癌における肯定的な治療効果は、多くの方法で測定することができる。( W. A. Weber, J. Nucl. Med.50:1S-10S (2009))参照のこと)。例えば、腫瘍増殖阻害に関して、NCI標準によれば、T/Cが42%以下は、抗腫瘍活性の最低レベルである。T/C が10%未満は高い抗腫瘍活性レベルと見なされ、ここでT/C(%)=治療を受けた腫瘍の体積の中央値/コントロールの腫瘍体積の中央値x100である。いくつかの実施態様において、本発明の組み合せによって達成した治療は、PR、CR、OR、PFS、DFSおよびOSの何れかである。PFSは又、「腫瘍の進行までの時間」を意味し、治療中及び治療後に癌が増殖しない時間の長さを示し、かつ、患者がCRまたはPRを経験した時間の量、並びに、患者が経験したSDの時間の量を含む。DFSとは、治療中及び治療後に患者に疾患のないままの時間の長さを意味する。OSとは、無処置または未処理の個体または患者と比較した、平均余命の延長を意味する。いくつかの好ましい実施態様では、本発明の組み合わせの効果は、RECIST 1.1効果基準を用いて評価するPR、CR、PFS、DFS、ORまたはOSの何れかである。癌患者の治療に有効な、本発明を組み合わせるための治療計画は、疾患の状態、年齢、患者の体重、及び被験者における抗癌効果を引き出す治療の能力などの要因によって、変更し得る。 本発明のいずれかの観点による実施態様は、すべての被験者に対し、肯定的な治療効果を達成するのに有効であるとは言えないかもしれないが、統計的に有意な被験者数で、当該分野で周知の何れかの統計的検定、Studentのt-検定, カイ二乗検定, Mann及びWhitneyによるU-検定, Kruskal-Wallis検定 (H-検定)、Jonckheere-Terpstra-検定及びWilcoxon-検定などによって決定するべきである。
本発明の一態様において、本発明は、個体における癌を治療するための方法を提供するものであり、PD-1拮抗薬およびVEGR阻害剤を含む併用療法で個体に投与することを含む。
期の腫瘍の治療に使用される。
量が増加するに連れて、約0.005 mg/kg から約 10 mg/kgになろう。他の用量増加の実施
態様では、用量の間隔は漸次、短くなり、例えば、最初と第2回目の間隔は約30日(±2日)、第2回目と第3回目の用量の間隔は約14日(±2日)となる。ある実施態様では、第2回目以降の用量については、用量の間隔は約14日(±2日)となるであろう。
方の用量漸増により見極めることが出来る。一実施形態では、アキシチニブを5mg BIDで投与し、MK-3475は、開始用量2 mg/kg Q2Wで投与し、そしてこの用量組合せが患者に許容される場合、MK-3475の用量は、10 mg/kg Q2W用量まで増量し、一方、開始用量の組合せが患者に許容されない場合、その時はMK-3475の用量を減量する。
Q3Wで投与し、そしてこの用量の組合せが患者に許容されない場合には、アキシチニブの用量を3 mg BID.に減量する。
含む液体、及び、凍結乾燥した医薬の製剤を記載する。いくつかの好ましい実施態様では、MK-3475を含む医薬は、MK-3475 約50mgを含有するガラスバイアル中で提供される。
1.PD-1拮抗薬及びVEGFR阻害剤を含む併用療法を個体に投与することを含む個体中の癌を治療する方法。
2.PD-1拮抗薬が、モノクローナル抗体、又はその抗原結合フラグメントである、実施態様1に記載の方法。
3.VEGFR阻害剤が化合物N- メチル-2- [3 -((E)-2- ピリジン-2- イル-ビニル)-1H-インダゾール-6-イルスルファニル] -ベンズアミドまたはその薬学的に許容される塩である、実施態様1または2に記載の方法。
4.個体中の癌を治療するためにVEGFR阻害剤と組み合わせて使用するPD-1拮抗薬を含む医薬であり、PD-1拮抗薬が、モノクローナル抗体、またはその抗原結合フラグメントである前記医薬。
5.個体中の癌を治療するためにPD-1拮抗薬と組み合わせて使用するVEGFR阻害剤を含む医薬。
6.薬学的に許容される賦形剤をさらに含む、実施態様4または5に記載の医薬。
7.個体中の癌を治療するため、VEGFR阻害剤と組み合わせて投与する時の医薬の製造における、PD-1拮抗薬の使用。
8.個体中の癌を治療するため、PD-1拮抗薬と組み合わせて投与する時の医薬の製造にお
ける、VEGFR阻害剤化合物の使用。
9.個体中の癌を治療するための医薬製造における、PD-1拮抗薬及びVEGFR阻害剤の使用。
10.第一容器、第二容器及びパッケージ挿入物を含むキットであり、第一容器は、少なくとも1用量の抗PD-1拮抗薬を含む医薬を含み、第二容器は、少なくとも1用量のVEGFR阻害剤を含む医薬を含み、及びパッケージ挿入物は、医薬を使用して個体の癌治療をするための使用説明書を含む。
11.使用説明書に、医薬は免疫組織化学(IHC)分析によるPD-L.1発現に関する検査が陽性である癌、を有する個体の治療に使用することを企図している、と明言している、実施態様10に記載のキット。
12.個体がヒトであり、かつPD-1拮抗薬がモノクローナル抗体であるか、又はその抗原結合フラグメントであり、具体的には、ヒトPD-L1に結合し、かつヒトPD-L1がヒトPD-1に結合するのをブロックする、実施態様1から11の何れかに記載の方法、医薬、使用又はキッ
ト。
13.PD-1拮抗薬がMPDL3280A、BMS-936559、MEDI4736、MSB0010718C又は重鎖及び軽鎖可変領域を含むモノクローナル抗体であり、これは、国際特許公開第2013/019906号にそれぞれ記載の配列番号24及び配列番号21である、実施態様11に記載の方法、医薬、使用又はキット。
14.個体はヒトであり、かつ、PD-1拮抗薬はモノクローナル抗体、であるか、又はその抗原結合フラグメントであり、具体的には、ヒトPD-1に結合し、かつヒトPD-L1がヒトPD-1に結合するのをブロックする、実施態様1から11の何れかに記載の方法、医薬、使用又はキット。
15.PD-1拮抗薬もまた、ヒトPD-L2がヒトPD-1に結合するのをブロックする、実施態様14に記載の、方法、医薬、使用又はキット。
16.モノクローナル抗体、又はその抗原結合フラグメントは、
(a)配列番号が1、2及び3である軽鎖CDR、及び配列番号が4、5及び6である、重鎖CDR、
又は
(b)配列番号が7、8及び9である軽鎖CDR、及び配列番号が10、11及び12である重鎖CDR
を含む、実施態様15に記載の方法、医薬、使用又はキット。
17.モノクローナル抗体、又はその抗原結合フラグメントは、配列番号が7、8及び9である軽鎖CDR、及び配列番号が10、11及び12である重鎖CDRを含む、実施態様15に記載の方法、医薬、使用又はキット。
18.PD-1拮抗薬が、重鎖及び軽鎖を含む抗PD-1モノクローナル抗体であり、重鎖が、配列番号21であり、及び軽鎖が配列番号22である実施態様15に記載の方法、医薬、使用又はキット。
19.PD-1拮抗薬が、重鎖及び軽鎖を含む抗PD-1モノクローナル抗体であり、重鎖が、配列番号23であり、及び軽鎖が配列番号24である実施態様15に記載の方法、医薬、使用又はキット。
20.癌が固形腫瘍である実施態様12から19の何れかに記載の方法、医薬、使用又はキット。
21.癌が膀胱癌、乳癌、明細胞腎臓癌、頭部/頸部扁平上皮癌、肺扁平上皮癌、悪性黒色腫、非小細胞肺癌(NSCLC)、卵巣癌、膵臓癌、前立腺癌、腎細胞癌、小細胞肺癌(SCLC)又はトリプルネガティブ乳癌である、実施態様12から19の何れかに記載の方法、医薬、使用又はキット。
22.癌が、進行性腎細胞癌である、実施態様12から19の何れかに記載の方法、医薬、使用又はキット。
23.個体はそれ以前に進行性腎細胞癌の治療を受けたことがない、実施態様12から19の何れかに記載の方法、医薬、使用又はキット。
24.癌が、明細胞腎臓癌である、実施態様12から19の何れかに記載の方法、医薬、使用又はキット。
25.癌が、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、大規模びまん性B細胞リンパ腫(DLBCL)、濾胞性リンパ腫、ホジキンリンパ腫(HL)、マントル細胞リンパ腫(MCL)、多発性骨髄腫(MM)、骨髄性細胞白血病-1タンパク質(MCL-1)、骨髄異形成症候群(MDS)、非ホジキンリンパ腫(NHL)、又は小リンパ球性リンパ腫(SLL)である、実施態様12から19の何れかに記載の方法、医薬、使用又はキット。
26.癌検査がヒトPD-L1に関し陽性である、実施態様12から25の何れかに記載の方法、医薬、使用又はキット。
27.ヒトPD-L1の発現が上昇している、実施態様26に記載の、方法、医薬、使用又はキット。
28.PD-1拮抗薬がMK-3475、又はニボルマブである、実施態様15に記載の、方法、医薬、使用又はキット。
29.MK-3475が、液体医薬として調剤され、pH 5.5のヒスチジン緩衝液10 mM中、MK-3475
25mg/ml、スクロース 7%(w / v)、ポリソルベート80 0.02%(w / v)を含む、実施態様28に記載の方法、医薬、使用又はキット。
30.VEGR阻害剤が、スニチニブ、ソラフェニブ又はチボザニブである、実施態様1から29の何れかに記載の方法、医薬、使用又はキット。
31.VEGR阻害剤が、N-メチル-2-[3-((E)-2-ピリジン-2-イル-ビニル)-1H-インダゾール-6-イルスルファニル]-ベンズアミド、又は薬学的に許容されるその塩である、実施態様1から29の何れかに記載の方法、医薬、使用又はキット。
32.VEFR阻害剤がアキシチニブで、かつ1mgの錠剤又は5mgの錠剤として調剤する、実施態様1から29の何れかに記載の方法、医薬、使用又はキット。
33.癌と診断されたヒト個体を治療する方法であり、(a)アキシチニブを5 mg BID用量で投与し、及びMK-3475を1 mg/kg Q3W, 2 mg/kg Q3W 及び 200 mg Q3Wからなる群から選択される用量で投与するか、又は(b)アキシチニブを、3 mg BID用量で投与し、及びMK-3475を1 mg/kg Q3W, 2 mg/kg Q3W 及び 200 mg Q3Wからなる群から選択される用量で投与する、MK-3475及びアキシチニブを含む併用療法、
を個体に投与することを含む前記ヒト個体を治療する方法。
34.MK-3475を含む医薬であり、ヒト個体における癌を治療するために、
(a)アキシチニブを5mgBID用量で、及びMK-3475を1 mg/kg Q3W, 2 mg/kg Q3W 及び 200 mg Q3Wからなる群から選択される用量で、又は、(b) アキシチニブを3 mg BID用量で、及びMK-3475を1 mg/kg Q3W, 2 mg/kg Q3W 及び 200 mg Q3Wからなる群から選択される用量で、個体に投与することを含む方法により、アキシチニブと組み合わせて使用するための前記医薬。
35.アキシチニブを含む医薬であり、ヒト個体の癌を治療するために、
(a)アキシチニブを5mgBID用量で、及びMK-3475を1 mg/kg Q3W, 2 mg/kg Q3W 及び 200 mg Q3Wからなる群から選択される用量で、又は、(b) アキシチニブを3 mg BID用量で、及びMK-3475を1 mg/kg Q3W, 2 mg/kg Q3W 及び 200 mg Q3Wからなる群から選択される用量で、個体に投与することを含む方法により、MK-3475と組み合わせて使用する前記医薬。
36.アキシチニブを5 mg BID の用量で投与し、かつ、MK-3475 を1 mg/kg Q3Wの用量で投与する、実施態様33から35の何れかに記載の方法又は医薬。
37.アキシチニブを5 mg BID の用量で投与し、かつ、MK-3475 を2 mg/kg Q3Wの用量で投与する、実施態様33から35の何れかに記載の方法又は医薬 。
38.アキシチニブを3 mg BID の用量で投与し、かつ、MK-3475 を1 mg/kg Q3Wの用量で与する、実施態様33から35の何れかに記載の方法又は医薬。
39.アキシチニブを3 mg BID の用量で投与し、かつ、MK-3475 を2 mg/kg Q3Wの用量で投与する、実施態様33から35の何れかに記載の方法又は医薬。
40.アキシチニブを3 mg BID の用量で投与し、かつ、MK-3475 を200 mg/kg Q3Wの用量で 投与する、実施態様33から35の何れかに記載の方法又は医薬。
41.癌が腎細胞癌である、実施態様33から40の何れかに記載の方法又は医薬 。
42.個体がそれ以前に腎細胞癌の治療を受けたことがない、実施態様41に記載の方法又は医薬。
43.癌が明細胞腎臓癌である、実施態様33から40の何れかに記載の方法又は医薬 。
44.併用療法の投与前に、個体から取り出した癌の組織切片の検査が、PD-L1の発現に関して陽性である、実施態様33から43の何れかに記載の方法又は医薬。
45.組織切片における腫瘍細胞の少なくとも50%が免疫組織化学(IHC)分析による検査でPD-L1発現に関して陽性である、実施態様44に記載の方法又は医薬。
46.IHC分析で抗体22C3を使用して、PD-L1の発現を検出する、実施態様45に記載の方法又は医薬。
47.MK-3475をIV注入によって投与する、33から46の何れかに記載の方法又は医薬 。
分子生物学における標準的な方法は、Sambrook, Fritsch and Maniatis (1982 & 1989 2nd Edition, 2001 3rdEdition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NYS、ambrook and Russell (2001) Molecular Cloning, 3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA, Vol. 217, Academic Press, San Diego, CA)に記載されている。又、標準的方法がAusbel, et al. (2001) Current Protocols in Molecular Biology, Vols.1-4, John Wiley and Sons, Inc. New York, NY、にも見られ、細菌細胞およびDNA変異誘発におけるクローニング(第1巻)哺乳動物細胞および酵母におけるクローニング(第2巻)、複合糖質およびタンパク質発現(第3巻)、および生物情報科学(第4巻)について説明している。
この研究では、RCCを有するヒト患者におけるアキシチニブとMK-3475との組み合わせの有効性を評価する。患者をアキシチニブ5 mg BID又は3 mg BIDにより、及びMK-3475を1 mg/kg又は2 mg/kg、3週間毎に静脈内注入により、18ヶ月の期間、治療する。
うち少なくとも1つと比べ、どれよりも効果が高いであろうことが期待される。
評価基準(RECIST )に従って確定した完全寛解(CR)又は部分寛解(PR)の評価に基づ
く、ORを有する参加者の割合。確定した寛解とは骨髄芽球が5%未満を繰り返し示す骨髄
を有し、全ての細胞株が正常に成熟し、しかも、末梢血の絶対値は少なくともは2ヶ月間
持続するものである。PRとは、予備治療を含め芽細胞中の少なくとも50%の減少分を除いた、すべてのCRの基準を有するものである。
日遅れでの最初の投与日と最終投与日の間の時間)の治療に関し、参加者の全身状態を、5点満点で評価し、0=十分活動的/疾患前の全ての活動を制限なしに実行出来る。
研究対象年齢:18歳以上。
研究対象性別:両方。
健康なボランティアの受入れ:否
主に明細胞サブタイプを有する原発腫瘍であると組織学的または細胞学的に確定した進行性RCCを摘除する。
固形腫瘍における奏功評価基準(RECIST)バージョン1.1で定義された少なくとも一つの測定可能病変である。
東部共同腫瘍学グループの全身状態0または1; 及び、
高血圧は制御下にある。
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Claims (6)
- 個体中の癌の併用療法治療のための医薬の製造のための、プログラム死1タンパク質(PD−1)の拮抗薬及び血管内皮増殖因子受容体(VEGFR)阻害剤の使用であって、PD−1拮抗薬が、重鎖及び軽鎖を含む抗PD−1モノクローナル抗体であり、重鎖及び軽鎖は、それぞれ、配列番号21及び、配列番号22を含み、さらに、VEGFR阻害剤がN−メチル−2−[3−((E)−2−ピリジン−2−イル−ビニル)−1H−インダゾール−6−イルスルファニル]−ベンズアミドまたは薬学的に許容されるその塩である、前記使用。
- 個体がヒトである、請求項1に記載の使用。
- 癌が固形腫瘍である、請求項1または2に記載の使用。
- 癌が腎細胞癌である、請求項1または2に記載の使用。
- PD−1拮抗薬が、ペムブロリズマブであり、かつVEGFR阻害剤がアキシチニブである、請求項1〜4の何れか1項に記載の使用。
- 癌が膀胱癌、乳癌、明細胞腎臓癌、頭部/頸部扁平上皮癌、肺扁平上皮癌、悪性黒色腫、非小細胞肺癌(NSCLC)、卵巣癌、膵臓癌、前立腺癌、腎細胞癌、小細胞肺癌(SCLC)又はトリプルネガティブ乳癌、急性リンパ芽球性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ球性白血病(CLL)、慢性骨髄性白血病(CML)、大規模びまん性B細胞リンパ腫(DLBCL)、濾胞性リンパ腫、ホジキンリンパ腫(HL)、マントル細胞リンパ腫(MCL)、多発性骨髄腫(MM)、骨髄性細胞白血病−1タンパク質(MCL−1)、骨髄異形成症候群(MDS)、非ホジキンリンパ腫(NHL)、又は小リンパ球性リンパ腫(SLL)である、請求項1〜3の何れか1項に記載の使用。
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