KEYNOTE-010

一行要約

PD-L1 TPS ≥1% のプラチナ既治療 NSCLC 2L における Pembrolizumab (2 mg/kg または 10 mg/kg) vs Docetaxel の phase II/III。全体で OS HR 0.71、TPS ≥50% では OS HR 0.54 (median 17.3 vs 8.2 mo) と顕著な benefit を示し、PD-L1 cutoff に基づく IO 患者選択の概念を確立した試験。

試験デザイン

• 対象: Stage IIIB/IV NSCLC、PD-L1 TPS ≥1% (22C3 antibody)、プラチナ既治療、EGFR/ALK 陽性例は TKI 既治療、ECOG PS 0-1、N=1034 (1:1:1)
• 介入群 A (n=345) : Pembrolizumab 2 mg/kg Q3W
• 介入群 B (n=346) : Pembrolizumab 10 mg/kg Q3W
• 対照群 (n=343) : Docetaxel 75 mg/m2 Q3W
• 層別化: PD-L1 TPS (≥50% vs 1-49%)、ECOG PS (0 vs 1)、地域
• 主要評価項目: OS および PFS (PD-L1 TPS ≥50% および全登録集団)

主要結果

• OS (TPS ≥50%) : Pembro 2mg HR 0.54 (95% CI 0.38–0.77)、Pembro 10mg HR 0.50 (0.36–0.70)、median 14.9/17.3 vs 8.2 mo
• OS (全体 TPS ≥1%) : Pembro 2mg HR 0.71 (0.58–0.88, p=0.0008)、Pembro 10mg HR 0.61 (0.49–0.75, p<0.0001)
• PFS (TPS ≥50%) : Pembro 2mg HR 0.59、Pembro 10mg HR 0.59
• ORR: TPS ≥50% で 30% (2mg) / 29% (10mg) vs 8%
• TPS 1-49%: OS benefit は認められたが PFS benefit は marginal — 1L への展開 (KEYNOTE-042) で検証
• Grade 3-5 AE: Pembrolizumab 13-16% vs Docetaxel 35%

臨床的意義

• PD-L1 TPS cutoff の確立: TPS ≥50% (strong benefit) と TPS 1-49% (moderate benefit) の区別を初めて前向きに検証。この 2 層構造は KEYNOTE-024 (1L TPS ≥50%)、KEYNOTE-042 (1L TPS ≥1%) の設計根拠
• Companion diagnostic の確立: 22C3 pharmDx assay を companion diagnostic として FDA 承認。PD-L1 testing の標準化を推進
• 用量選択: 2 mg/kg と 10 mg/kg で efficacy は同等 → 固定用量 200 mg Q3W (後続試験で採用) への橋渡し
• 2L IO 標準化の完成: CheckMate-017、CheckMate-057 と合わせて NSCLC 2L における IO の位置づけを確立

Open Questions

• TPS 1-49% の 1L IO monotherapy vs IO+化療: KEYNOTE-042 vs KEYNOTE-189/KEYNOTE-407 の最適選択
• PD-L1 以外の biomarker 統合: TMB、STK11/KEAP1 co-mutation との組み合わせ予測モデル
• 22C3 vs SP263 vs SP142 の harmonization: PD-L1 assay 間差異と臨床判断への影響

重要論文 Top 10

1. ★★★★★ Herbst et al. Lancet 2016 — Primary publication — PD-L1 cutoff 選択の根拠
2. Herbst et al. (5-year update) — 5-year OS data — durable response 確認
3. ★★★★★ Reck et al. NEnglJMed 2016 (KEYNOTE-024) — TPS ≥50% 1L — 本試験 2L 知見の 1L 展開
4. ★★★★★ Mok et al. Lancet 2019 (KEYNOTE-042) — TPS ≥1% 1L — cutoff 拡大の前向き検証
5. ★★★★★ Garon et al. NEnglJMed 2015 (KEYNOTE-001) — Phase I — PD-L1 TPS と response の初期相関

関連エンティティ・概念

• 薬剤: Pembrolizumab / Docetaxel
• 関連試験: KEYNOTE-024 (1L TPS ≥50%) / KEYNOTE-042 (1L TPS ≥1%) / CheckMate-017 / CheckMate-057
• 関連遺伝子: PD-L1 / EGFR / ALK
• ドメイン: lung-cancer-treatment

関連論文

直近 30 件のみ表示中 (関連 36 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Page et al. EurJCancer 2020 — Systemic treatment of brain metastases in non-small cell lung cancer

Basic-Immunotherapy

• Hakozaki et al. CancerImmunolRes 2020 — The gut microbiome associates with immune checkpoint inhibition outcomes in patients with advanced non-small cell lung

Basic-Neutrophil and myeloid cell

• Sekine et al. LungCancer 2018 — Change in the lymphocyte-to-monocyte ratio is an early surrogate marker of the efficacy of nivolumab monotherapy in

Basic-Tumor microenvironment

• Manegold et al. JThoracOncol 2017 — The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced NSCLC

Clinical-NSCLC-Driver negative

• Chatterjee et al. AnnOncol 2016 — Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer
• Planchard et al. AnnOncol 2018 — Metastatic non-small cell lung cancer ESMO clinical practice guidelines for diagnosis, treatment and follow-up
• Doroshow et al. ClinCancerRes 2019 — Immunotherapy in non-small cell lung cancer facts and hopes
• Su et al. EurJCancer 2017 — Treatment of elderly patients or patients who are performance status 2 (PS2) with advanced non-small cell lung cancer
• Horn et al. EurJCancer 2018 — Safety and clinical activity of atezolizumab monotherapy in metastatic non-small-cell lung cancer final results from a
• Lala et al. EurJCancer 2020 — A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and
• Gettinger et al. JAMAOncol 2021 — Nivolumab plus ipilimumab vs nivolumab for previously treated patients with stage IV squamous cell lung cancer the
• Hanna et al. JClinOncol 2017 — Systemic therapy for stage IV non-small-cell lung cancer american society of clinical oncology clinical practice
• Garon et al. JClinOncol 2019 — Five-year overall survival for patients with advanced Non-Small-cell lung cancer treated with pembrolizumab results
• Waterhouse et al. JClinOncol 2020 — Continuous versus 1-year fixed-duration nivolumab in previously treated advanced non-small-cell lung cancer CheckMate
• Kato et al. JImmunotherCancer 2020 — Propensity score-weighted analysis of chemotherapy after PD-1 inhibitors versus chemotherapy alone in patients with
• Shukuya et al. JThoracOncol 2016 — Predictive markers for the efficacy of anti-PD-1pd-L1 antibodies in lung cancer
• Mok et al. Lancet 2019 — Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic
• Galli et al. LungCancer 2019 — Efficacy and safety of immunotherapy in elderly patients with non-small cell lung cancer
• Gubens et al. LungCancer 2019 — Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non-small-cell lung cancer
• Nosaki et al. LungCancer 2019 — Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung
• Eichhorn et al. LungCancer 2021 — Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer first
• Socinski et al. NEnglJMed 2018 — Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC

Clinical-NSCLC-EGFR

• Niu et al. FrontImmunol 2026 — Efficacy and mechanisms of immune checkpoint inhibitors in late-stage EGFR-mutated non-small cell lung cancer following
• Oshima et al. JAMAOncol 2018 — EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer
• Lee et al. JThoracOncol 2017 — Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung Cancer-A meta-analysis
• Garassino et al. JThoracOncol 2018 — Italian nivolumab expanded access program in nonsquamous non-small cell lung cancer patients results in never-smokers
• Soo et al. LungCancer 2018 — Immune checkpoint inhibitors in epidermal growth factor receptor mutant non-small cell lung cancer current
• Dong et al. OncoImmunology 2017 — EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade

Clinical-SCLC

• Tian et al. JHematolOncol 2019 — Potential immune escape mechanisms underlying the distinct clinical outcome of immune checkpoint blockades in small

Clinical-Supportive care

• Turner et al. ClinCancerRes 2018 — Pembrolizumab exposure-response assessments challenged by association of cancer cachexia and catabolic clearance