Irinotecan-Topotecan

トポイソメラーゼ I 阻害薬 (Irinotecan / Topotecan)

一行要約

Camptothecin 誘導体の topoisomerase I 阻害薬。SCLC 2L 治療の backbone で、Topotecan が western standard、Irinotecan は日本で JCOG9511 に基づき 1L EP 代替 (IP 療法) としても使用される。Sensitive relapse (初回治療後 60-90 日超で再発) vs resistant relapse で効果が大きく異なり、resistant relapse での ORR は 10-20% にとどまる。近年は DLL3-targeted-therapy (Tarlatamab) 等の新規 modality が 2L に登場。

メンバー比較表

薬剤	製品名	投与経路	主要適応 (肺癌)	代謝	備考
Irinotecan (CPT-11)	Camptosar	IV	SCLC 1L (IP, 日本) / 2L	CES → SN-38 (active) → UGT1A1	UGT1A1 多型で毒性変動
Topotecan	Hycamtin	IV / PO	SCLC 2L (western standard)	腎排泄主体	経口剤あり
Nogitecan	—	IV	SCLC 2L (日本)	—	Topotecan の日本語一般名

主要エビデンス

SCLC 1L (Topo-I + Platinum doublet)

• JCOG9511 (Noda et al. NEnglJMed 2002) : Irinotecan + Cisplatin (IP) vs Etoposide + Cisplatin (EP) ES-SCLC 1L、OS 12.8 vs 9.4 mo (HR 0.60、p=0.002) → 日本で IP 標準化
• Hanna et al. JClinOncol 2006 confirmation (Hanna et al. JClinOncol 2006) : 北米での IP vs EP 確認試験で OS 9.3 vs 10.2 mo、HR 1.09 → JCOG9511 再現せず、地域差・薬理遺伝学・schedule 差の議論を喚起
• JCOG0509 (Satouchi JCO 2014) : CDDP+AMR vs CDDP+CPT-11 ED-SCLC 1L で IP に対する amrubicin doublet の non-inferiority 検証 (HR 1.43、IP 優位を支持)
• Topotecan + Cisplatin vs EP (Fink JTO 2012) : SCLC 1L で代替 doublet 試験

SCLC 2L Topo-I 単剤

• vonPawel et al. JClinOncol 1999: Topotecan vs CAV SCLC 2L、ORR 24% vs 18%、OS 同等、症状緩和で Topotecan 優位 → Topotecan 2L 標準化の起点
• Oral Topotecan vs BSC (OBrien et al. JClinOncol 2006) : SCLC 2L、OS 25.9 vs 13.9 weeks (HR 0.64) → BSC 比較での生存延長を示し経口剤承認の根拠
• Oral vs IV Topotecan (Eckardt et al. JClinOncol 2007) : bioequivalence + ORR 同等 (18.3% vs 21.9%) → 経口剤の利便性を確立
• Topotecan maintenance (Schiller et al. JClinOncol 2001) : ECOG E7593、ES-SCLC 1L EP 後の topotecan maintenance vs 観察、OS 改善せず → maintenance 戦略の negative result
• Carboplatin+Etoposide vs Topotecan (Baize et al. LancetOncol 2020) : 仏 phase 3、sensitive relapse SCLC で carbo+etop 再投与が topotecan より OS 優位 (7.5 vs 5.7 mo、HR 0.70) → sensitive relapse での re-challenge 支持
• JCOG0605 (Goto LancetOncol 2016) : CDDP+ETP+CPT-11 (PEI) vs Topotecan 単剤、sensitive relapse SCLC で OS 18.2 vs 12.5 mo (HR 0.67) → aggressive triplet が日本での選択肢

SCLC 2L 新規 modality との比較

• Lurbinectedin (Trigo et al. LancetOncol 2020) : SCLC 2L ORR 35.2% (sensitive 45%、resistant 22%) → FDA 加速承認、Topotecan の代替候補
• Tarlatamab (Mountzios et al. NEnglJMed 2025 / DeLLphi-304) : phase 3 で Tarlatamab vs chemotherapy (topotecan / lurbinectedin / amrubicin) 2L SCLC、Topo-I 単剤 standard を覆す可能性

高悪性度神経内分泌癌 (NEC)

• JCOG1205-1206 (Eba JpnJClinOncol 2014 / Kenmotsu JCO 2020) : 完全切除 high-grade pulmonary NEC 術後補助 IP vs EP、OS / RFS で有意差なし → SCLC とは異なる NEC では EP / IP 同等
• LCNEC IP (Niho JTO 2013) : 進行 LCNEC 1L IP 多施設 phase 2、ORR 47% / mOS 12.6 mo → SCLC レジメンの LCNEC 適用根拠

結腸直腸癌 (cross-tumor reference)

• FOLFIRI / FOLFIRINOX: Irinotecan が CRC・膵癌の backbone。pancreatic FOLFIRINOX は ECOG-PS 0-1 患者の標準
• Sacituzumab govitecan (Trop-2 ADC) : SN-38 を payload とする ADC、HR+/HER2- BC (Rugo JCO 2022) で承認、SCLC での開発も進行

メカニズム

Topoisomerase I inhibition:

• Topoisomerase I は DNA 超らせん構造を一本鎖切断 → 回転 → 再結合で解消する酵素
• Camptothecin 誘導体は topoisomerase I-DNA cleavable complex を安定化 → 一本鎖切断が持続
• Replication fork が cleavable complex に衝突 → 二重鎖切断 (DSB) → apoptosis

Irinotecan の代謝:

• Irinotecan (prodrug) → carboxylesterase (CES) → SN-38 (active metabolite)
• SN-38 → UGT1A1 → SN-38G (inactive glucuronide)
• UGT1A1*28 多型: TA repeat 7/7 (homozygous) で SN-38 蓄積 → 重症下痢・骨髄抑制リスク (Gilbert 症候群)
• Late-onset diarrhea (SN-38 腸管内蓄積) が dose-limiting toxicity

Topotecan の特徴:

• Active form で投与 (prodrug ではない)
• Neutropenia が dose-limiting (Irinotecan の下痢 vs Topotecan の骨髄抑制)
• 経口バイオアベイラビリティ約 40% → 経口剤使用可能

臨床位置づけ

• SCLC 2L (Western) : Topotecan が historical standard → Tarlatamab (DLL3-targeted-therapy)、Lurbinectedin が新規選択肢
• SCLC 1L (日本) : IP 療法 (Irinotecan + Cisplatin) が EP と並列 → IO 時代は Atezo/Durva + EP が global 標準
• Sensitive relapse: 初回化療再投与 or Topotecan / Irinotecan で ORR 20-40%
• Resistant relapse: 有効治療に乏しく、Tarlatamab / Lurbinectedin / 臨床試験が推奨
• CRC: Irinotecan は FOLFIRI の backbone (CRC 1L/2L)

Open Questions

• Tarlatamab vs Topotecan 2L: DeLLphi-304 (Mountzios et al. NEnglJMed 2025) の結果で 2L standard 交代なるか、特に CNS mets / poor PS subset での positioning
• IP vs EP 地域差の分子基盤: UGT1A1*28 / *6 / CES 多型の人種差が efficacy に影響？日本 IP 優位・北米 negative の薬理遺伝学的説明仮説
• Irinotecan liposomal (nal-IRI) : SCLC での liposomal formulation の有効性検証 (NAPOLI paradigm の SCLC 展開)
• Trilaciclib による myelosuppression 軽減: ES-SCLC 1L での topo-I 含む regimen での好中球減少抑制効果 (CDK4/6 transient arrest)
• ADC payload としての DXd / SN-38: HER2-directed-therapy / HER3-directed-therapy の DXd (topoisomerase I 阻害)、Sacituzumab govitecan の SN-38 → camptothecin 耐性との cross-resistance、Topo-I 既治療例での ADC 効果差
• Sensitive vs resistant relapse の定義再考: IO 時代に platinum-free interval の SCLC re-challenge benefit が変化するか

重要論文 Top 10

1. ★★★★★ Noda et al. NEnglJMed 2002 — JCOG9511 — IP vs EP ES-SCLC (日本 landmark)
2. vonPawel et al. JClinOncol 1999 — Topotecan SCLC 2L 標準化
3. ★★★★ OBrien et al. JClinOncol 2006 — Oral Topotecan vs BSC — 経口剤
4. ★★★★ Hanna et al. JClinOncol 2006 — IP vs EP western confirmation (negative)
5. ★★★★ Trigo et al. LancetOncol 2020 — SCLC 2L Lurbinectedin — Topo-I 代替

関連エンティティ・概念

• 関連 class: Etoposide (SCLC 1L backbone 競合 / EP vs IP), Platinum-chemotherapy (doublet partner), DLL3-targeted-therapy (SCLC 2L 競合)
• 関連概念: SCLC-molecular-subtypes
• 試験: JCOG9511 / DeLLphi-304
• ドメイン: lung-cancer-treatment

関連論文

直近 30 件のみ表示中 (関連 190 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Lu et al. JClinOncol 2026 — Multicenter cohort study of original or substitute systemic therapy with or without brain radiotherapy for

Basic-Extracellular vesicles

• Tsering et al. CellDeathDis 2024 — Extracellular vesicle-associated DNA ten years since its discovery in human blood

Basic-Immunotherapy

• Kureshi et al. CancerCell 2026 — Dendritic cell redundancy enables priming of anti-tumor cd4+ t cells in pancreatic cancer
• Zhang et al. Cell 2026 — A convergent uPAR-positive tumor ecosystem creates broad vulnerability to CAR t cell therapy
• Rojas et al. Nature 2023 — Personalized RNA neoantigen vaccines stimulate t cells in pancreatic cancer

Basic-Oncogene and genetics

• Yap et al. Cell 2026 — Targeting genomic instability in cancer

Basic-Others

• Falzone et al. Cell 2023 — Cancer chemotherapy
• Tanaka et al. FEBSOpenBio 2023 — A mouse model of lung cancer induced via intranasal injection for anticancer drug screening and evaluation of pathology
• Oberstein et al. JClinOncol 2026 — Amivantamab monotherapy in chemorefractory RASBRAF wild-type metastatic colorectal cancer results from OrigAMI-1, an
• OReilly et al. NEnglJMed 2026 — Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer

Clinical-NEC

• Fujiwara et al. AnnSurgOncol 2024 — Clinical and pathologic differences between small-cell carcinoma and large-cell neuroendocrine carcinoma of the lung
• Sen et al. LancetOncol 2025 — Pulmonary neuroendocrine neoplasms the molecular landscape, therapeutic challenges, and diagnosis and management
• Shirai et al. LungCancer 2025 — Epidemiology and clinical course of large cell neuroendocrine carcinoma of the lung the japanese lung cancer registry

Clinical-NSCLC-Driver-Other

• 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-HER2

• Ruan et al. AnnOncol 2026 — Preclinical characterization and phase 1 results of TQB2102, a first-in-class HER2 biparatopic antibody-drug conjugate,

Clinical-Novel modalities

• Garrido-Castro et al. AnnOncol 2026 — SACI-IO HR+ A randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with
• Hofman et al. LungCancer 2026 — New biomarkers for antibody-drug conjugates in lung cancer the pathologist’s perspective
• High et al. TrendsCancer 2026 — Lgr5 from stem cell marker to therapeutic target

Clinical-Others

• Fan et al. LancetOncol 2026 — Novel strategies to overcome the blood-brain barrier in triple-negative breast cancer brain metastases

Clinical-SCLC

• Doshita et al. AdvRadiatOncol 2023 — Incidence and treatment outcome of radiation pneumonitis in patients with limited-stage small cell lung cancer treated
• Asao et al. BMCCancer 2022 — A phase II study of carboplatin and etoposide plus durvalumab for previously untreated extensive-stage small-cell lung
• Sethakorn et al. Cancer 2026 — The future promise of antibody-drug conjugates in extensive-stage small cell lung cancer
• Lee et al. CancerResTreat 2023 — A randomized phase II study of irinotecan plus cisplatin with or without simvastatin in ever-smokers with extended
• Wang et al. CellRepMed 2026 — Spatial multi-omics unveils the monoclonal origin, neuroendocrine plasticity, and microenvironment niches in combined
• Guan et al. CritRevOncolHematol 2026 — Overcoming immunotherapy resistance in extensive-stage small cell lung cancer insights into mechanisms and therapeutic
• Falchero et al. EurJCancer 2024 — Real-life nationwide characteristics and outcomes of small cell lung cancer over the last 20 years impact of
• Liu et al. FrontPharmacol 2026 — Cost-effectiveness of tarlatamab versus chemotherapy for patients with small-cell lung cancer after platinum-based
• Khurshid et al. JClinOncol 2023 — Systemic therapy for small-cell lung cancer ASCO-ontario health (cancer care ontario) guideline
• Mountzios et al. NEnglJMed 2025 — Tarlatamab in small-cell lung cancer after platinum-based chemotherapy
• Byers et al. NatMed 2026 — SEZ6-targeting antibody-drug conjugate ABBV-706 in advanced small cell lung cancer and solid tumors a phase 1 trial

合成 (Outputs)

• adc-payload-diversity-ild-management