MET-TKI

MET 阻害薬 (MET-TKI)

一行要約

MET exon 14 skipping mutation (NSCLC 腺癌の約 3-4%、高齢者に多い) および MET amplification を標的とする小分子 kinase inhibitor。Capmatinib (Wolf et al. NEnglJMed 2020 = GEOMETRY mono-1) と Tepotinib (Paik et al. NEnglJMed 2020 = VISION) が METex14 skipping 変異陽性 NSCLC で承認され、Savolitinib はアジア圏で開発先行。MET amplification は EGFR-TKI 耐性機構 (Engelman et al. Science 2007、Turke et al. CancerCell 2010) としても重要で、Sequist et al. LancetOncol 2020 (TATTON) の savolitinib + osimertinib 併用や EGFR-MET-bispecific (Amivantamab) との競合・棲み分けが進む。

メンバー比較表

薬剤	製品名	選択性	主要試験	承認状況	備考
Capmatinib	Tabrecta	Type Ib MET 選択的	GEOMETRY mono-1	FDA 承認 (METex14)	1L ORR 68%, 2L+ 41%
Tepotinib	Tepmetko	Type Ib MET 選択的	VISION	FDA/日本承認 (METex14)	Liquid biopsy concordance 高
Savolitinib	—	Type Ib MET 選択的	TATTON, Phase II/III	中国承認 (METex14)	Osimertinib 併用も検討
Crizotinib	Xalkori	Multi-target (ALK/ROS1/MET)	PROFILE 1001 MET cohort	Off-label MET	MET 選択性低い

主要エビデンス

METex14 skipping de novo

GEOMETRY mono-1 (Wolf et al. NEnglJMed 2020) は Capmatinib METex14 skipping NSCLC で 1L ORR 68% (CR 4%)、2L+ ORR 41%、mDOR 12.6 mo を示し、FDA accelerated approval を獲得。VISION (Paik et al. NEnglJMed 2020) は Tepotinib で ORR 46% (tissue) / 48% (liquid biopsy)、mPFS 8.5 mo を示し、liquid biopsy concordance の高さが特徴。長期 follow-up は Le et al. ClinCancerRes 2022 が更新し、durability を確認した。METex14 skipping の clinico-genomic 特徴は Awad et al. JClinOncol 2016 が advanced age・stage-dependent co-amplification・c-MET overexpression を示し、Crizotinib による初期 activity は Drilon et al. NatMed 2020 が報告。総説的整理は Bylicki et al. OncoTargetsTher 2020 を参照。

MET amplification as EGFR-TKI resistance

Engelman et al. Science 2007 が ERBB3 を介した bypass mechanism を初記述し、Turke et al. CancerCell 2010 が pre-existing subclone の clonal selection を示した。Osimertinib 後の主要耐性機構として MET amplification (15-20%) への対応として TATTON (Sequist et al. LancetOncol 2020) が Savolitinib + Osimertinib の ORR 30-33% を示し、MET-TKI + EGFR-TKI 併用が標準戦略化。MET amplification 後の転移挙動は Baldacci et al. LungCancer 2018 が EGFR 変異 NSCLC で metastatic spread の増大を報告。

MET-TKI 耐性機構

Recondo et al. ClinCancerRes 2020 は METex14 mutant NSCLC で MET-TKI 後の secondary kinase domain mutation (D1228、Y1230) と bypass pathway (KRAS amplification、EGFR activation) を体系的に分類。

脳転移

Tepotinib の CNS 透過性は Friese-Hamim et al. LungCancer 2022 が PDX 脳転移モデルで in vivo activity を示し、intracranial response 報告の前臨床基盤を成す。

メカニズム

MET (hepatocyte growth factor receptor) は receptor tyrosine kinase で、HGF-MET signaling axis は細胞増殖・遊走・浸潤・血管新生を制御する。

MET 活性化の 2 大機構:

1. Exon 14 skipping mutation: Splice site mutation → exon 14 欠失 → Cbl 結合部位 (Y1003) 消失 → MET 分解抑制 → 恒常的活性化
2. MET gene amplification: Copy number gain → MET 過剰発現 → ligand 非依存的シグナル活性化 (de novo または EGFR-TKI 耐性として出現)

Type Ib inhibitor の特徴: ATP-competitive で active conformation の DFG-in state に結合。Capmatinib / Tepotinib / Savolitinib はいずれも Type Ib で高い MET 選択性を持つ。Crizotinib は Type Ia multi-kinase inhibitor で MET 選択性が低い。

耐性機構 (Recondo et al. ClinCancerRes 2020) :

• MET kinase domain secondary mutations (D1228N/V、Y1230C/H)
• HGF autocrine loop
• Bypass pathway activation (KRAS amplification、EGFR activation)
• EGFR-mutant NSCLC で MET amplification 獲得後の osimertinib + MET-TKI 併用下では再耐性が KRAS amp / EMT で観察される (Martinez-Marti et al. AnnOncol 2017)

臨床位置づけ

• METex14 skipping 1L/2L+: Capmatinib / Tepotinib が標準。高齢者に多い変異 (中央値 72-74 歳) で tolerability 重要
• EGFR-TKI 耐性 MET amplification: Savolitinib + Osimertinib、または EGFR-MET-bispecific (Amivantamab) + Lazertinib が競合
• コンパニオン診断: METex14 は NGS (RNA-based preferred)、MET amplification は FISH / NGS (copy number)
• MET amplification de novo: 頻度低い (NSCLC 1-5%) が、単剤 MET-TKI の有効性データ限定的
• 脳転移: Tepotinib / Capmatinib の CNS 透過性は限定的データ、intracranial response 報告あり

Open Questions

• 1L MET-TKI vs IO+chemo: METex14 は PD-L1 高発現例あるが TMB 低く IO 単剤効果不良 → MET-TKI 1L 確立が課題
• MET amplification 耐性での最適併用: MET-TKI + EGFR-TKI vs EGFR-MET-bispecific + Lazertinib の head-to-head なし
• MET-TKI 耐性後戦略: D1228N/Y1230C secondary mutation に対する次世代 MET-TKI 開発
• Combination with IO: MET-TKI + anti-PD-1 の phase III 試験データ不足
• MET overexpression (IHC 3+) : Amplification / mutation なしの MET overexpression への MET-TKI 効果は限定的

重要論文 Top 10

1. ★★★★★ Wolf et al. NEnglJMed 2020 — GEOMETRY mono-1 — Capmatinib pivotal、METex14 初承認
2. ★★★★★ Paik et al. NEnglJMed 2020 — VISION — Tepotinib pivotal、liquid biopsy concordance
3. ★★★★ Sequist et al. LancetOncol 2020 — TATTON — Savolitinib + Osimertinib MET amp 耐性
4. ★★★★★ Engelman et al. Science 2007 — EGFR-TKI 耐性 MET amp + ERBB3 bypass を初記述
5. ★★★★ Recondo et al. ClinCancerRes 2020 — MET-TKI 耐性機構 (D1228/Y1230、bypass) の体系化

関連エンティティ・概念

• 関連遺伝子: MET
• 関連 class: EGFR-TKI (耐性パートナー), EGFR-MET-bispecific (競合/併用), ALK-TKI (Crizotinib 共通)
• 関連概念: T790M-and-sequential-EGFR-TKI (MET bypass resistance context)
• 試験: GEOMETRY mono-1 / VISION / TATTON
• ドメイン: lung-cancer-treatment

関連論文

直近 30 件のみ表示中 (関連 299 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Mavrikios et al. AnnOncol 2026 — Lung cancer brain metastases management at the dawn of personalized medicine are we ready to break the barriers
• Friese-Hamim et al. LungCancer 2022 — Brain penetration and efficacy of tepotinib in orthotopic patient-derived xenograft models of MET-driven non-small cell

Basic-Oncogene and genetics

• Scaparone et al. CancerDiscov 2026 — EML4-ALK mediates resistance to KRAS G12C inhibition and induces an
• Li et al. JThoracOncol 2021 — Potential unreliability of uncommon ALK, ROS1, and RET genomic breakpoints in predicting the efficacy of targeted
• Li et al. NatCommun 2026 — Molecular glue that stabilizes the LRPPRC-MET-G4 interaction complex to drive MET downregulation

Basic-Others

• Osarogiagbon et al. AmSocClinOncolEducBook 2026 — Optimal use of targeted therapy and immunotherapy in early-stage, resectable non-small cell lung cancer
• Peng et al. NatMed 2026 — Savolitinib in MET-amplified gastric or gastroesophageal junction adenocarcinoma a phase 2 trial
• Yue et al. Nature 2026 — Spatial distribution of the proteome in the human body and in cancers
• Dymun et al. SciTranslMed 2026 — Clinicogenomic analysis of

Basic-Tumor microenvironment

• Remsing et al. SciSignal 2022 — IGF-binding proteins secreted by cancer-associated fibroblasts induce context-dependent drug sensitization of lung

Clinical-NEC

• Lindsay et al. BrJCancer 2021 — Large cell neuroendocrine lung carcinoma consensus statement from the british thoracic oncology group and the
• Heijboer et al. JCOPrecisOncol 2025 — Actionable genomic alterations in large cell neuroendocrine carcinoma A european case series of patients treated with a

Clinical-NSCLC-ALK

• Felip et al. AnnOncol 2021 — Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer
• Tanimoto et al. ClinCancerRes 2021 — Proteasome inhibition overcomes ALK-TKI resistance in ALK-RearrangedTP53-mutant NSCLC via noxa expression
• Ito et al. EurJCancer 2021 — Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma
• Kim et al. FutureOncol 2021 — ALTA-2 phase II study of brigatinib in patients with ALK-positive, advanced non-small-cell lung cancer who progressed
• Solomon et al. JClinOncol 2024 — Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer 5-year outcomes from the
• Camidge et al. JThoracOncol 2021 — Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC final results of phase 3 ALTA-1l trial
• Nishio et al. JThoracOncol 2021 — Brigatinib in japanese patients with ALK-positive NSCLC previously treated with alectinib and other tyrosine kinase

Clinical-NSCLC-Driver-Other

• Le et al. ClinCancerRes 2022 — Tepotinib efficacy and safety in patients with MET exon 14 skipping NSCLC outcomes in patient subgroups from the VISION
• Sharma et al. JClinOncol 2026 — Phase I study of telisotuzumab adizutecan (temab-A, ABBV-400), a novel c-met antibody-drug conjugate, in patients with

Clinical-NSCLC-EGFR

• Piotrowska et al. CancerDiscov 2026 — ELIOS A multicenter, molecular profiling study of patients with EGFR-mutant advanced non-small cell lung cancer treated
• Wang et al. LungCancer 2026 — Vebreltinib plus EGFR-TKI for EGFR-mutated NSCLC with MET-driven resistance A real-world study of chinese patients
• Zhao et al. NatRevClinOncol 2026 — Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC-mechanisms and evolving treatment approaches

Clinical-NSCLC-ROS1

• Lin et al. ClinCancerRes 2021 — Spectrum of mechanisms of resistance to crizotinib and lorlatinib in ROS1 fusion-positive lung cancer
• Almquist et al. JCOOncolPract 2021 — The road less traveled A guide to metastatic ROS1-rearranged non-small-cell lung cancer
• Dziadziuszko et al. JClinOncol 2021 — Updated integrated analysis of the efficacy and safety of entrectinib in locally advanced or metastatic ROS1
• Ou et al. JTOClinResRep 2021 — Efficacy of taletrectinib (AB-106ds-6051b) in ROS1+ NSCLC an updated pooled analysis of U.S. and japan phase 1 studies
• Itchins et al. LungCancer 2026 — Real-world treatment sequencing and survival in ROS1-rearranged NSCLC across evolving treatment eras findings from the

Clinical-Others

• Cowzer et al. ClinCancerRes 2026 — Molecular and clinical determinants of targeted therapy treatment in biliary tract cancer