TATTON

一行要約

EGFR-TKI 耐性 NSCLC における Osimertinib ベースの combination platform trial (phase Ib)。特に Savolitinib との併用で MET amplification 耐性例に ORR 30-49% を示し、EGFR-TKI acquired resistance に対する mechanism-directed combination のコンセプトを実証した。

試験デザイン

• 対象: EGFR-TKI 既治療・進行 NSCLC、耐性機序別にコホートを設定
• プラットフォーム構成:
• Part B (Savolitinib combination) : Osimertinib 80mg + Savolitinib 300-600mg daily。MET amplification/overexpression (IHC/FISH で確認) 例、n=138
• Part C (Selumetinib combination) : Osimertinib + MEK inhibitor。RAS/MAPK pathway 活性化例
• Part D (Durvalumab combination) : Osimertinib + anti-PD-L1。— 間質性肺炎リスクで早期中止
• エンドポイント: Primary = Safety / Tolerability、Secondary = ORR, PFS, DOR

主要結果

• Savolitinib combo (Part B, T790M 陰性/MET+ cohort) : ORR 33%、PFS median 5.4 mo
• Savolitinib combo (Part B, post-osimertinib/MET+ cohort) : ORR 48-49% (MET IHC 3+ and/or FISH≥10 subgroup)
• Selumetinib combo: 限定的な有効性。RAS/MAPK reactivation 例で一部奏効
• Durvalumab combo: 間質性肺炎 (ILD) rate が高く早期中止。EGFR-TKI + IO の safety concern を浮き彫りに
• 安全性 (Savolitinib combo) : Grade ≥3 AE 約35%。悪心・嘔吐・末梢浮腫が主。用量調整で管理可能

臨床的意義

• Mechanism-directed resistance treatment の proof-of-concept: 耐性機序 (MET amp, RAS activation) に基づく rational combination の有効性を示した初の platform trial
• SAVANNAH / MARIPOSA への橋渡し: TATTON Part B の MET データが SAVANNAH (phase II) および osimertinib progression 後 combination 開発の根拠
• EGFR-TKI + IO の安全性警告: Part D の ILD 高発現が EGFR-TKI + IO combination の領域全体に警鐘 (CAURAL 中止にも影響)
• Resistance biopsy の必要性: 耐性機序同定 (MET FISH/IHC) を治療選択に直結させるモデルを提示

Open Questions

• MET 検査の最適 assay: IHC 3+ vs FISH GCN≥10 vs NGS-based copy number のどれが最も predictive か
• Savolitinib vs Capmatinib vs Tepotinib: MET bypass resistance における MET-TKI head-to-head データなし
• Triple combination の feasibility: EGFR-TKI + MET-TKI + 化療/IO の安全性と有効性
• EGFR-C797S-resistance との co-occurrence: C797S + MET amp の double resistance への対策

重要論文 Top 10

1. ★★★★★ Sequist et al. LancetOncol 2020 — TATTON primary publication (Part B: Savolitinib combo)
2. ★★★★★ Oxnard et al. JAMAOncol 2018 — AURA3 後の resistance mechanism landscape — MET amp prevalence
3. Ahn et al. — TATTON Part D (Osimertinib + Durvalumab) — ILD safety signal
4. Wu et al. — SAVANNAH primary — TATTON を phase II に発展
5. Hartmaier et al. — Osimertinib resistance genomic atlas — TATTON / SAVANNAH の molecular 文脈

関連エンティティ・概念

• EGFR-TKI — Osimertinib (backbone)
• MET-TKI — Savolitinib (combination partner)
• MET — Bypass resistance mechanism
• EGFR-C797S-resistance — Osimertinib on-target resistance
• EGFR-T790M-resistance — 1st/2nd gen TKI resistance (TATTON entry criteria)
• SAVANNAH — TATTON を発展させた phase II
• PD-L1-inhibitor — Durvalumab (Part D、ILD で中止)

関連論文

Basic-Oncogene and genetics

• Wang et al. NatCommun 2018 — Whole-genome sequencing reveals genomic signatures associated with the inflammatory microenvironments in chinese NSCLC

Clinical-NSCLC-ALK

• Lovly et al. AmSocClinOncolEducBook 2017 — Managing resistance to EFGR-and ALK-targeted therapies

Clinical-NSCLC-Driver-Other

• Bylicki et al. OncoTargetsTher 2020 — Targeting the MET-signaling pathway in NSCLC

Clinical-NSCLC-EGFR

• Ricordel et al. AnnOncol 2018 — Molecular mechanisms of acquired resistance to third-generation EGFR-TKIs in EGFR T790M-mutant lung cancer
• Niu et al. FrontImmunol 2026 — Efficacy and mechanisms of immune checkpoint inhibitors in late-stage EGFR-mutated non-small cell lung cancer following
• Chen et al. JThoracOncol 2015 — Upregulation of PD-L1 by EGFR activation mediates the immune escape in EGFR-driven NSCLC implication for optional
• Su et al. JThoracOncol 2018 — Strong programmed death ligand 1 expression predicts poor response and de novo resistance to EGFR tyrosine kinase
• Aredo et al. JThoracOncol 2021 — Durvalumab for stage III EGFR-mutated NSCLC after definitive chemoradiotherapy
• Sequist et al. LancetOncol 2020 — Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after
• Soo et al. LungCancer 2018 — Immune checkpoint inhibitors in epidermal growth factor receptor mutant non-small cell lung cancer current
• 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
• Asao et al. RespirInvestig 2019 — Resistance to molecularly targeted therapy in non-small-cell lung cancer
• Sugiyama et al. SciImmunol 2020 — Blockade of EGFR improves responsiveness to PD-1 blockade in EGFR-mutated non-small cell lung cancer