KEYNOTE-091

一行要約

完全切除後 stage IB-IIIA NSCLC における adjuvant Pembrolizumab vs Placebo の phase III。全集団 DFS HR 0.76 で有意であったが、PD-L1 TPS≥50% サブグループでは有意差なし (HR 0.82) という paradoxical な結果 が議論を呼んだ。ADAURA (adjuvant Osimertinib) / IMpower010 (adjuvant Atezolizumab) と並ぶ adjuvant IO/TKI の主要試験。

試験デザイン

• 対象: 完全切除 (R0) Stage IB (≥4cm) –IIIA NSCLC、adjuvant 化療は許容 (最大 4 cycles)、N=1177 (1:1)
• 介入群 (n=590) : Pembrolizumab 200mg IV q3w × 18 cycles (約 1 年間)
• 対照群 (n=587) : Placebo IV q3w × 18 cycles
• 層別化: Stage (IB vs II vs IIIA)、PD-L1 TPS (<1% vs 1-49% vs ≥50%)、地域、adjuvant 化療有無
• Dual primary: (1) 全集団 DFS、(2) PD-L1 TPS≥50% の DFS — hierarchical testing

主要結果

• DFS (全集団, co-primary) : HR 0.76 (95% CI 0.63–0.91, p=0.0014)、median 53.6 vs 42.0 mo
• DFS (PD-L1 TPS≥50%, co-primary) : HR 0.82 (95% CI 0.57–1.18, p=0.14) — 有意差なし
• DFS (PD-L1 TPS 1-49%) : HR 0.67 — 最も benefit が大きいサブグループ
• DFS (PD-L1 TPS <1%) : HR 0.78
• OS: 未成熟 (immature data)
• 安全性: Grade ≥3 immune-related AE 5.7% vs 0.3%。治療中止率 14.5% vs 2.4%

臨床的意義

• Adjuvant IO の 2 番目の positive trial: IMpower010 (Atezolizumab, PD-L1 TC≥1%) に続く positive trial だが、PD-L1 高発現での paradoxical な非有意が特異的
• PD-L1 TPS≥50% paradox の解釈: (1) adjuvant setting では PD-L1 がpredictive でない可能性、(2) sample size の問題、(3) PD-L1 high 群は化療自体の benefit が大きい可能性、など multiple explanations
• EGFR 変異と adjuvant IO: EGFR 変異陽性例は除外されておらず、ADAURA (adjuvant Osimertinib) との対象重複あり
• 規制上の影響: FDA は DFS 全集団で承認。EMA は PD-L1≥50% 非有意のため承認に慎重

Open Questions

• PD-L1 TPS≥50% での non-significant DFS の biological explanation: Tumor-intrinsic vs immune microenvironment factors
• OS maturation: DFS benefit が OS に translate するか (adjuvant IO 試験全般の未解決課題)
• Adjuvant IO vs neoadjuvant IO: CheckMate-816 (neoadjuvant) / KEYNOTE-671 (perioperative) との比較で最適 timing は?
• ctDNA-MRD guided adjuvant: TRACERx 知見を踏まえ、MRD 陽性例に限定した adjuvant IO の戦略

重要論文 Top 10

1. O’Brien et al. — KEYNOTE-091 primary publication
2. ★★★★★ Felip et al. Lancet 2021 — IMpower010 (Adjuvant Atezolizumab) —KEYNOTE-091 との比較対象
3. ADAURA—Adjuvant Osimertinib、DFS HR 0.20 — NEJM 2020
4. Herbst et al. — KEYNOTE-091 updated DFS and subgroup analysis
5. ★★★★★ Forde et al. NEnglJMed 2022 — CheckMate-816—Neoadjuvant Nivolumab+化療 (perioperative IO 文脈)

関連エンティティ・概念

• PD-1-inhibitor — Pembrolizumab
• PD-L1 — Biomarker (paradoxical non-significance)
• ADAURA — Adjuvant Osimertinib (同時期 adjuvant trial)
• CheckMate-816 — Neoadjuvant IO
• KEYNOTE-671 — Perioperative Pembrolizumab
• irAE-pathophysiology — Adjuvant IO の安全性

関連論文

Basic-Extracellular vesicles

• Shurer et al. Cell 2019 — Physical principles of membrane shape regulation by the glycocalyx

Basic-Others

• Osarogiagbon et al. AmSocClinOncolEducBook 2026 — Optimal use of targeted therapy and immunotherapy in early-stage, resectable non-small cell lung cancer

Clinical-Epidemiology

• Potter et al. AnnThoracSurg 2023 — Recurrence after complete resection for non-small cell lung cancer in the national lung screening trial

Clinical-NSCLC-Driver negative

• Rossi et al. ESMOOpen 2025 — Immunotherapy for resectable NSCLC neoadjuvantperioperative followed by surgery over surgery followed by adjuvant
• Chaft et al. JAMA 2026 — Adjuvant nivolumab vs observation in resected Non-Small cell lung cancer
• Pathak et al. JAMAOncol 2020 — Association of survival with adjuvant chemotherapy among patients with early-stage non-small cell lung cancer with vs
• Fick et al. JThoracCardiovascSurg 2025 — High-risk features associated with recurrence in stage I lung adenocarcinoma
• OBrien et al. LancetOncol 2022 — Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer
• Bennouna et al. LungCancer 2011 — Impact of histology on survival of resected non-small cell lung cancer (NSCLC) receiving adjuvant chemotherapy subgroup
• Cooper et al. LungCancer 2015 — PD-L1 expression is a favorable prognostic factor in early stage non-small cell carcinoma
• Eichhorn et al. LungCancer 2021 — Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer first
• Heymach et al. NEnglJMed 2023 — Perioperative durvalumab for resectable non-small-cell lung cancer
• Wakelee et al. NEnglJMed 2023 — Perioperative pembrolizumab for early-stage non-small-cell lung cancer