KEYNOTE-604

一行要約

ES-SCLC 1L における Pembrolizumab + EP vs Placebo + EP の phase III。PFS HR 0.75 は有意であったが、co-primary の OS HR 0.80 (p=0.0164) は事前設定の有意水準 (α=0.0128) を満たさず。IMpower133・CASPIAN と並ぶ SCLC IO 1L 試験だが、承認には至らなかった informative な negative trial。

試験デザイン

• 対象: 未治療 ES-SCLC、ECOG PS 0-1、脳転移は治療済みで安定なら許容、N=453 (1:1)
• 介入群 (n=228) : Pembrolizumab 200mg + Etoposide + Cisplatin/Carboplatin (4 cycles) → Pembrolizumab maintenance (最大 35 cycles)
• 対照群 (n=225) : Placebo + EP → Placebo maintenance
• 層別化: Platinum (Cisplatin vs Carboplatin)、ECOG PS (0 vs 1)、LDH (正常 vs 高値)、地域
• 統計設計: PFS と OS の dual primary endpoint、α を hierarchical に分配

主要結果

• PFS (co-primary) : HR 0.75 (95% CI 0.61–0.91, p=0.0023)、median 4.5 vs 4.3 mo
• OS (co-primary) : HR 0.80 (95% CI 0.64–0.98, p=0.0164) — 事前設定 α=0.0128 を超過し統計的有意差未達、median 10.8 vs 9.7 mo
• ORR: 70.6% vs 61.8%
• 12 か月 OS 率: 45.1% vs 39.6% (late separation 傾向あり)
• 安全性: Grade 3-5 AE 76.7% vs 74.9%。免疫関連 AE (甲状腺障害・肺臓炎) は Pembrolizumab 群で増加

臨床的意義

• SCLC IO landscape の informative negative: IMpower133 (Atezolizumab + EP, OS HR 0.70) と CASPIAN (Durvalumab + EP, OS HR 0.73) は OS 有意であったが、KEYNOTE-604 は α splitting により有意差逸失
• 薬剤間差 vs 統計設計の影響: PD-1 inhibitor (Pembrolizumab) と PD-L1 inhibitor (Atezolizumab/Durvalumab) の SCLC における efficacy 差、または統計的偶然かは未決着
• Maintenance IO の概念: SCLC における IO maintenance の持続効果が限定的である可能性を示唆
• 後続試験への影響: DeLLphi-301 (Tarlatamab) など新規 2L 以降の開発に SCLC IO 1L の landscape 情報を提供

Open Questions

• PD-1 vs PD-L1 の SCLC における差異: KEYNOTE-604 の OS 非有意は drug class effect か試験デザイン差か
• SCLC IO biomarker の不在: PD-L1 / TMB いずれも SCLC IO 効果の reliable predictor となっていない
• SCLC-molecular-subtypes と IO 感受性: ASCL1/NEUROD1/POU2F3/YAP1 subtype 別の IO benefit 差は未解明
• 2L 以降の sequencing: 1L IO 後の Tarlatamab / Lurbinectedin の最適配置

重要論文 Top 10

1. ★★★★★ Rudin et al. JClinOncol 2020 — KEYNOTE-604 primary publication
2. ★★★★★ Horn et al. NEnglJMed 2018 — IMpower133—ES-SCLC 1L IO の first positive trial
3. Paz-Ares et al. Lancet 2019 — CASPIAN—Durvalumab + EP で OS 有意
4. ★★★★ Chung et al. JThoracOncol 2020 — Pembrolizumab の SCLC PD-L1/TMB biomarker 解析
5. ★★★★ Owonikoko et al. JClinOncol 2021 — ES-SCLC における Nivolumab + EP の phase III (EA5161)

関連エンティティ・概念

• PD-1-inhibitor — Pembrolizumab
• Platinum-chemotherapy — Cisplatin/Carboplatin + Etoposide
• IMpower133 — Atezolizumab + EP (ES-SCLC 1L positive)
• CASPIAN — Durvalumab + EP (ES-SCLC 1L positive)
• SCLC-molecular-subtypes — IO 感受性との関連
• DeLLphi-301 — 2L SCLC の新規アプローチ

関連論文

Clinical-SCLC

• Dingemans et al. AnnOncol 2021 — Small-cell lung cancer ESMO clinical practice guidelines for diagnosis, treatment and follow-up
• Agarwal et al. Cancer 2023 — Chemoimmunotherapy in patients with extensive-stage small cell lung cancer and a poor performance status
• Friedlaender et al. ClinLungCancer 2020 — The role of performance status in small-cell lung cancer in the era of immune checkpoint inhibitors
• Dai et al. CurrTreatOptionsOncol 2026 — Addressing unmet needs in the management of small cell lung cancer treatment of brain metastases, quality of life, and
• Ott et al. JClinOncol 2017 — Pembrolizumab in patients with extensive-stage small-cell lung cancer results from the phase ib KEYNOTE-028 study
• Rudin et al. JClinOncol 2020 — Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer
• Liu et al. JClinOncol 2021 — Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated
• Khurshid et al. JClinOncol 2023 — Systemic therapy for small-cell lung cancer ASCO-ontario health (cancer care ontario) guideline
• Elegbede et al. JTOClinResRep 2021 — A real-world evaluation of atezolizumab plus platinum-etoposide chemotherapy in patients with extensive-stage SCLC in
• Asao et al. LancetRespirMed 2025 — Durvalumab, carboplatin, and etoposide in patients who are treatment-naive with extensive-stage small-cell lung cancer
• Rudin et al. NatRevDisPrimers 2021 — Small-cell lung cancer