REVEL

一行要約

プラチナ既治療の進行 NSCLC における Ramucirumab + Docetaxel vs Placebo + Docetaxel の phase III。OS HR 0.86 (10.5 vs 9.1 mo) で有意な生存改善を示し、組織型を問わず 2L 抗血管新生＋化療の standard を確立した。

試験デザイン

• 対象: Stage IV NSCLC、1L プラチナベース化療後の進行、組織型不問 (扁平上皮含む)、N=1253 (1:1)
• 介入群 (n=628) : Ramucirumab 10mg/kg + Docetaxel 75mg/m² IV q3w
• 対照群 (n=625) : Placebo + Docetaxel 75mg/m² IV q3w
• 層別化: 性別、地域、ECOG PS、前治療 (Bevacizumab 使用歴)
• 特徴: 扁平上皮癌を含む全組織型で登録可能 (Bevacizumab と異なる点)

主要結果

• OS (primary) : HR 0.86 (95% CI 0.75–0.98, p=0.023)、median 10.5 vs 9.1 mo
• PFS: HR 0.76 (95% CI 0.68–0.86, p<0.0001)、median 4.5 vs 3.0 mo
• ORR: 23% vs 14%
• 組織型別 OS: Non-squamous HR 0.83、Squamous HR 0.88 (いずれも改善傾向)
• 安全性: Grade ≥3 AE 79% vs 71%。好中球減少 (49% vs 40%)、高血圧 (6% vs 2%)、出血 (2% vs 1%) が増加。出血リスクは扁平上皮でも許容範囲

臨床的意義

• 扁平上皮 NSCLC で使用可能な抗血管新生: Bevacizumab が禁忌の扁平上皮でも使用可能な唯一の抗血管新生レジメンとして位置づけ
• 2L 化療のベンチマーク: Docetaxel 単独を超える 2L レジメンの OS 改善証拠 (REVEL と OAK が 2L の dual pillars)
• IO 時代以降の位置づけ: 1L IO/IO+化療後の 2L における Ramucirumab + Docetaxel の再評価が進行中
• EGFR+ NSCLC への展開: RELAY 試験 (Ramucirumab + Erlotinib, EGFR+ 1L) で PFS 改善を示し、抗 VEGFR2 の TKI 併用コンセプトへ発展

Open Questions

• 1L IO 後 2L での Ramucirumab + Docetaxel の有効性: IO exposed 集団での prospective data は限定的
• Biomarker-driven patient selection: VEGF/VEGFR pathway biomarker による enrichment は未確立
• RAM + DTX vs IO re-challenge: 2L における抗血管新生 vs IO 再投与の head-to-head データ不在

重要論文 Top 10

1. Garon et al. — REVEL primary publication、OS HR 0.86
2. Reck et al. LancetOncol 2014 — LUME-Lung-1 (Nintedanib + Docetaxel) —2L 抗血管新生の競合試験
3. ★★★★ Nakagawa et al. LancetOncol 2019 — RELAY (Ramucirumab + Erlotinib, EGFR+ 1L) —VEGFR2 × TKI コンセプト
4. ★★★★ Herbst et al. Lancet 2016 — KEYNOTE-010—2L Pembrolizumab vs Docetaxel、IO との比較
5. Paz-Ares et al. AnnOncol 2017 — REVEL long-term update、2 年 OS 率と biomarker 解析

関連エンティティ・概念

• anti-VEGFR2-antibody — Ramucirumab
• Taxane — Docetaxel
• anti-VEGF-antibody — Bevacizumab (扁平上皮禁忌との対比)
• OAK — 2L NSCLC の IO アプローチ
• EGFR — RELAY 試験で EGFR+ への展開

関連論文

Basic-Others

• Casak et al. ClinCancerRes 2015 — FDA approval summary ramucirumab for gastric cancer

Basic-Tumor microenvironment

• Manegold et al. JThoracOncol 2017 — The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC
• Ferrara et al. NatRevDrugDiscov 2016 — Ten years of anti-vascular endothelial growth factor therapy
• Jain et al. Science 2005 — Normalization of tumor vasculature an emerging concept in antiangiogenic therapy

Clinical-NSCLC-Driver negative

• Ramalingam et al. ClinLungCancer 2018 — Efficacy and safety of ramucirumab with docetaxel versus placebo with docetaxel as second-line treatment of advanced
• Garon et al. ESMOOpen 2020 — Exploratory analysis of front-line therapies in REVEL a randomised phase 3 study of ramucirumab plus docetaxel versus
• Su et al. EurJCancer 2017 — Treatment of elderly patients or patients who are performance status 2 (PS2) with advanced non-small cell lung cancer
• Tabchi et al. FrontOncol 2017 — Antiangiogenesis for advanced non-small-cell lung cancer in the era of immunotherapy and personalized medicine
• Sugawara et al. IntJClinOncol 2019 — Japanese subgroup analysis of a phase III study of S-1 versus docetaxel in non-small cell lung cancer patients after
• Garon et al. Lancet 2014 — Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung
• Mok et al. Lancet 2014 — A REVELation in non-small-cell lung cancer treatment
• Yoh et al. LungCancer 2016 — A randomized, double-blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in japanese patients
• Paz-Ares et al. LungCancer 2017 — Treatment outcomes by histology in REVEL A randomized phase III trial of ramucirumab plus docetaxel for advanced
• Reck et al. LungCancer 2017 — Outcomes in patients with aggressive or refractory disease from REVEL A randomized phase III study of docetaxel with
• Aprile et al. OncoTargetsTher 2014 — Ramucirumab Preclinical research and clinical development
• Shiono et al. ThoracCancer 2019 — Improved efficacy of ramucirumab plus docetaxel after nivolumab failure in previously treated non-small cell lung

Clinical-NSCLC-Driver-Other

• Skoulidis et al. NEnglJMed 2021 — Sotorasib for lung cancers with KRAS p.g12c mutation

Clinical-NSCLC-EGFR

• Bonomi et al. AnnOncol 2018 — Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer

Clinical-NSCLC-HER2

• Goto et al. JClinOncol 2023 — Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer primary results from the
• Yu et al. JClinOncol 2023 — HERTHENA-lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor-mutated

Clinical-Supportive care

• Hata et al. Oncotarget 2018 — Docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte-colony stimulating factor for pretreated

Clinical-Thymic

• Proto et al. AnnOncol 2024 — Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma RELEVENT