KEYNOTE-042

一行要約

PD-L1 TPS ≥1% (EGFR/ALK wild-type) の未治療 NSCLC 1L における Pembrolizumab monotherapy vs プラチナ併用化学療法の phase III。TPS ≥50% で OS HR 0.69、TPS ≥20% で HR 0.77、TPS ≥1% 全体で OS HR 0.81 を示し、IO monotherapy の適応を TPS 1-49% まで拡大した。ただし benefit の大部分は TPS ≥50% に集中しており、TPS 1-49% での monotherapy の是非は議論が続く。

試験デザイン

• 対象: Stage IIIB/IV NSCLC、EGFR/ALK wild-type、PD-L1 TPS ≥1% (22C3 pharmDx)、未治療、ECOG PS 0-1、N=1274 (1:1)
• 介入群 (n=637) : Pembrolizumab 200 mg Q3W (最長 35 cycles)
• 対照群 (n=637) : Carboplatin + Paclitaxel or Pemetrexed (非扁平上皮は Pemetrexed 維持可)
• 層別化: PD-L1 TPS (≥50% vs 1-49%)、地域 (East Asia vs non-East Asia)、組織型 (扁平上皮 vs 非扁平上皮)
• Crossover: 対照群の 20% が後治療で IO を受けた

主要結果

• OS TPS ≥50% (co-primary) : HR 0.69 (95% CI 0.56–0.85, p=0.0003)、median 20.0 vs 12.2 mo
• OS TPS ≥20% (co-primary) : HR 0.77 (95% CI 0.64–0.92, p=0.0020)
• OS TPS ≥1% (co-primary) : HR 0.81 (95% CI 0.71–0.93, p=0.0018)、median 16.7 vs 12.1 mo
• TPS 1-49% exploratory: OS HR 0.92 (0.77–1.11) — 有意差なし (統計的 power は計画されていない)
• ORR: TPS ≥50% で 39% vs 32%、TPS 1-49% で 17% vs 29% (化療優位)
• Grade ≥3 AE: Pembrolizumab 18% vs 化療 41%

臨床的意義

• IO monotherapy の TPS ≥1% 拡大: KEYNOTE-024 (TPS ≥50%) の知見を TPS 1-49% に拡大。特にアジア (日本含む) では IO monotherapy option として臨床で活用
• TPS 1-49% の controversy: Exploratory 解析で TPS 1-49% の OS benefit は marginal。IO+化療 (KEYNOTE-189 / KEYNOTE-407) が TPS によらず OS benefit を示すため、TPS 1-49% では IO+化療が推奨される傾向
• East Asian subset: 日本人を含む East Asian で効果が顕著 (地域別 interaction なし)
• Sequential 戦略への影響: 化療 skip での IO monotherapy → PD 後に化療、という sequential strategy の是非 (特に高齢者・PS 不良例)

Open Questions

• TPS 1-49% で IO monotherapy vs IO+化療: 直接比較データの欠如。患者背景 (高齢、PS、合併症) による使い分けの evidence 構築が必要
• PD-L1 以外のバイオマーカー: TMB high / STK11 loss / KEAP1 mutation の IO monotherapy 予測能
• 後治療シーケンス: IO monotherapy 後の PD に対する最適 2L (化療 vs IO+化療 vs 他 IO)

重要論文 Top 10

1. ★★★★★ Mok et al. Lancet 2019 — Primary publication — TPS ≥1% 全体で OS HR 0.81
2. ★★★★★ Reck et al. NEnglJMed 2016 (KEYNOTE-024) — TPS ≥50% 1L IO monotherapy の先行根拠
3. ★★★★★ Gandhi et al. NEnglJMed 2018 (KEYNOTE-189) — IO+化療 — TPS 非依存 benefit との対比
4. ★★★★★ Herbst et al. Lancet 2016 (KEYNOTE-010) — 2L — PD-L1 cutoff の概念を確立
5. Mok et al. (5-year update) — 5-year follow-up — long-term benefit 確認

関連エンティティ・概念

• 薬剤: Pembrolizumab / Platinum-chemotherapy
• 関連試験: KEYNOTE-024 (TPS ≥50% IO mono) / KEYNOTE-189 (非扁平上皮 IO+化療) / KEYNOTE-407 (扁平上皮 IO+化療) / KEYNOTE-010 (2L)
• 関連遺伝子: PD-L1 / STK11 / KEAP1
• ドメイン: lung-cancer-treatment

関連論文

Basic-Brain metastasis

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

Basic-Liquid-biopsy

• Aggarwal et al. NatRevClinOncol 2021 — Strategies for the successful implementation of plasma-based NSCLC genotyping in clinical practice

Clinical-Epidemiology

• Zhang et al. NatRevClinOncol 2026 — Innovative approaches for lung cancer screening and interception

Clinical-NSCLC-Driver negative

• Satouchi et al. CancerSci 2021 — First-line pembrolizumab vs chemotherapy in metastatic non-small-cell lung cancer KEYNOTE-024 japan subset
• Doroshow et al. ClinCancerRes 2019 — Immunotherapy in non-small cell lung cancer facts and hopes
• Gridelli et al. ESMOOpen 2022 — First-line immunotherapy in advanced NSCLC patients with ECOG PS 2 results of an international expert Panel meeting b…
• Rizvi et al. JAMAOncol 2020 — Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell
• Boyer et al. JClinOncol 2021 — Pembrolizumab plus ipilimumab or placebo for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score
• Lantuejoul et al. JThoracOncol 2020 — Interobserver reliability of programmed cell death ligand-1 scoring using the VENTANA PD-L1 (SP263) assay in NSCLC
• Paz-Ares et al. JThoracOncol 2020 — A randomized, placebo-controlled trial of pembrolizumab plus chemotherapy in patients with metastatic squamous NSCLC
• Doroshow et al. JThoracOncol 2021 — Programmed death-ligand 1 tumor proportion score and overall survival from first-line pembrolizumab in patients with
• Mok et al. Lancet 2019 — Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic
• Nosaki et al. LungCancer 2019 — Safety and efficacy of pembrolizumab monotherapy in elderly patients with PD-L1-positive advanced non-small-cell lung
• Reck et al. NEnglJMed 2016 — Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer
• Herbst et al. NEnglJMed 2020 — Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC

Clinical-NSCLC-Driver-Other

• Arbour et al. ClinCancerRes 2021 — Treatment outcomes and clinical characteristics of patients with KRAS-G12C-mutant non-small cell lung cancer
• Finn et al. JThoracOncol 2021 — Prognostic impact of KRAS G12C mutation in patients with NSCLC results from the european thoracic oncology platform

Clinical-irAE

• Govindan et al. JImmunotherCancer 2022 — Society for immunotherapy of cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lung