CROWN

一行要約

未治療 ALK+ NSCLC (n=296) への 3rd-gen Lorlatinib vs 1st-gen Crizotinib の phase III。5-yr PFS 60% vs 8% という ALK-TKI 史上最強の長期効果を示し、CNS protection (intracranial PFS 96% at 12mo) でも圧倒的優位。Alectinib (ALEX) と並ぶ 1L 選択肢。

試験デザイン

• 対象: Stage IIIB/IV、未治療 ALK+ (IHC / FISH)、N=296 (asymptomatic CNS metastasis 許容)
• 介入群 (n=149) : Lorlatinib 100mg/day
• 対照群 (n=147) : Crizotinib 250mg BID
• 層別化: 人種、CNS metastasis status

主要結果

• PFS (primary, BICR) : HR 0.28 (95% CI 0.19–0.41)、initial 5-yr update HR 0.19、5-yr PFS 60% vs 8%
• Intracranial PFS: 12-month CNS PFS 96% vs 18%
• ORR: 76% vs 58%
• AE: Grade 3-4 76% vs 57%。Lorlatinib 特有: 高脂血症 (70%), edema, 神経精神症状 (mood, weight, hyperlipidemia, peripheral neuropathy), hyperlipidemia 管理が必須

臨床的意義

• ALK+ 1L で 5-yr PFS 60% は過去全世代の TKI を超える歴史的成績
• CNS 効果は Alectinib を超え、baseline CNS met / 高 CNS 再発リスク症例で第一選択
• 但し神経精神症状 / 代謝障害が long-term QoL を制約
• 1L Lorlatinib 後の 2L 戦略は化療 ± IO (次世代 ALK-TKI 開発前)

Open Questions

• CROWN vs ALEX direct comparison: 1L Alectinib vs Lorlatinib の patient selection (CNS / co-morbid / age)
• Lorlatinib 神経精神症状 management: dose reduction の efficacy 影響
• 5-yr 60% PFS の OS への波及: long-term OS update (10-yr 目標)
• Lorlatinib 耐性 compound mutation 後: 4th-gen ALK-TKI (NUV-655 等) 開発
• Lineage plasticity in 1L Lorlatinib: SCLC transformation 頻度

重要論文 Top 10

1. ★★★★★ Shaw et al. NEnglJMed 2020 — CROWN primary publication
2. ★★★★★ Solomon et al. JClinOncol 2024 — 5-yr update — 60% PFS plateau
3. ★★★★ Peters et al. NEnglJMed 2017 — ALEX — 比較対象
4. ★★★★ Recondo et al. ClinCancerRes 2020 — Lorlatinib 耐性 compound mutation
5. NEJM-2017-Shaw-Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement — Lorlatinib first-in-human ALK/ROS1

関連エンティティ

• 薬剤クラス: ALK-TKI (Lorlatinib / Crizotinib)
• 遺伝子: ALK
• 関連試験: ALEX / J-ALEX / ALTA-1L / ALINA
• ドメイン: lung-cancer-treatment / lung-cancer-biology

関連論文

Basic-Brain metastasis

• Mavrikios et al. AnnOncol 2026 — Lung cancer brain metastases management at the dawn of personalized medicine are we ready to break the barriers

Basic-Neutrophil and myeloid cell

• Kloosterman et al. Cell 2023 — Macrophages at the interface of the co-evolving cancer ecosystem

Clinical-Epidemiology

• Thai et al. Lancet 2021 — Lung Cancer

Clinical-NSCLC-ALK

• Felip et al. AnnOncol 2021 — Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer
• Zou et al. CancerCell 2015 — PF-06463922, an ALKROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical
• Yoda et al. CancerDiscov 2018 — Sequential ALK inhibitors can select for lorlatinib-resistant compound ALK mutations in ALK-positive lung cancer
• Shaw et al. ClinCancerRes 2011 — Targeting anaplastic lymphoma kinase in lung cancer
• Costa et al. JClinOncol 2011 — CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib
• Johung et al. JClinOncol 2016 — Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain
• Lin et al. JClinOncol 2018 — Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer
• Solomon et al. JClinOncol 2024 — Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer 5-year outcomes from the
• Naito et al. JpnJClinOncol 2021 — Brigatinib and lorlatinib their effect on ALK inhibitors in NSCLC focusing on resistant mutations and central nervous
• Shaw et al. LancetOncol 2017 — Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement an international, multicentre, open-label,
• Peters et al. NEnglJMed 2017 — Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer
• Shaw et al. NEnglJMed 2020 — First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer

Clinical-NSCLC-Driver negative

• Wang et al. NatMed 2021 — Toward personalized treatment approaches for non-small-cell lung cancer

Clinical-NSCLC-ROS1

• Solomon et al. LancetOncol 2018 — Lorlatinib in patients with ALK-positive non-small-cell lung cancer results from a global phase 2 study

Clinical-irAE

• Johnson et al. JAMAOncol 2016 — Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders

合成 (Outputs)

• alk-g1202r-compound-mutation-sequencing
• bbb-permeability-cns-drug-selection
• novel-modality-sequencing-driver-resistance