ALEX

一行要約

未治療 ALK 陽性 NSCLC への 2nd-gen Alectinib vs 1st-gen Crizotinib の phase III。IRC PFS HR 0.47 (mPFS 34.8 vs 10.9 mo)、5-yr OS 62.5%、CNS 進行 HR 0.16 で Alectinib 1L 標準を世界中に確立。J-ALEX 日本人試験と並立。

試験デザイン

• 対象: Stage IIIB/IV、未治療、ALK rearrangement (IHC / FISH)、N=303
• 介入群 (n=152) : Alectinib 600mg BID
• 対照群 (n=151) : Crizotinib 250mg BID
• 層別化: ECOG PS、ベースライン CNS metastasis (asymptomatic 許容)、人種

主要結果

• PFS (primary, IRC) : HR 0.47 (95% CI 0.34–0.65)、median 34.8 vs 10.9 mo
• 5-yr OS (Mok et al. AnnOncol 2020 update) : 62.5% vs 45.5%、median NR vs 57.4 mo
• CNS progression: HR 0.16 (CNS 進行リスク 84% 低下)
• Baseline CNS metastasis subgroup: PFS HR 0.40
• AE: Grade 3-5 41% vs 50%、肝毒性は Crizotinib に多く Alectinib で軽減

臨床的意義

• ALK+ NSCLC 1L 標準を Crizotinib → Alectinib に転換
• CNS 透過性の優位性で baseline brain met 患者の標準化
• 後続試験: J-ALEX (並立)、ALTA-1L (Brigatinib)、CROWN (Lorlatinib)、ALINA (adjuvant Alectinib)

Open Questions

• 1L Alectinib vs Lorlatinib (CROWN 5-yr 後) の selection: Long-term PFS vs 神経精神症状 trade-off
• ALEX 後 progression での 2L Lorlatinib efficacy: G1202R 含む耐性 spectrum
• Alectinib continuation past progression: CNS-only progression での local 治療 + Alec 継続戦略
• Adjuvant Alectinib (ALINA) の OS 確認: stage IB-IIIA 切除後 2 年投与
• EML4-ALK variant 1 vs 3 の Alec 反応性差

重要論文 Top 10

1. ★★★★★ Peters et al. NEnglJMed 2017 — ALEX primary publication
2. ★★★★★ Mok et al. AnnOncol 2020 — 5-yr OS update
3. ★★★★★ Hida et al. Lancet 2017 — J-ALEX 並立試験
4. ★★★★ Shaw et al. NEnglJMed 2020 — CROWN — 後継 1L 競合
5. ★★★★ Solomon et al. JClinOncol 2024 — CROWN 5-yr update — Lorlatinib との比較材料

関連エンティティ

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

関連論文

直近 30 件のみ表示中 (関連 101 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

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-Extracellular vesicles

• Clancy et al. CellRep 2022 — Recruitment of DNA to tumor-derived microvesicles
• Clancy et al. NatCellBiol 2021 — Profiling and promise of supermeres
• Gong et al. NatMater 2024 — Tumour-derived small extracellular vesicles act as a barrier to therapeutic nanoparticle delivery
• Verweij et al. NatMethods 2021 — The power of imaging to understand extracellular vesicle biology in vivo
• Ma et al. SciTranslMed 2025 — Tumor extracellular vesicle-derived PD-L1 promotes T cell senescence through lipid metabolism reprogramming

Basic-Immunotherapy

• Gonzalez et al. JImmunotherCancer 2026 — Morning versus afternoon administration of immune checkpoint inhibitors in metastatic non-small-cell lung cancer
• Liu et al. NatMed 2021 — Evolution of delayed resistance to immunotherapy in a melanoma responder
• Ritter et al. Science 2022 — ESCRT-mediated membrane repair protects tumor-derived cells against T cell attack

Basic-Neutrophil and myeloid cell

• Shi et al. CancerCell 2026 — Tumor-immune-neural circuit disrupts energy homeostasis in cancer cachexia
• Marki et al. ImmunolRev 2022 — The expanding family of neutrophil-derived extracellular vesicles
• Sanchez-Garcia et al. NatImmunol 2025 — Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of
• Tang et al. SciAdv 2022 — Single-cell RNA sequencing uncovers a neuron-like macrophage subset associated with cancer pain

Basic-Oncogene and genetics

• Nesta et al. TrendsGenet 2021 — Hotspots of human mutation

Basic-Others

• Tzouanas et al. Cell 2026 — Hepatic adaptation to chronic metabolic stress primes tumorigenesis
• Strohbehn et al. JCOOncolPract 2026 — Maintenance PemetrexedPembrolizumab versus pembrolizumab in non-small cell lung cancer A propensity score-weighted
• De et al. NatMed 2026 — Neoadjuvant stereotactic body radiation therapy with durvalumab and oleclumab in ER

Clinical-Epidemiology

• Thai et al. Lancet 2021 — Lung Cancer

Clinical-NSCLC-ALK

• Mok et al. AnnOncol 2020 — Updated overall survival and final progression-free survival data for patients with treatment-naive advanced
• Ando et al. Cancers 2020 — Brigatinib and alectinib for ALK rearrangement positive NSCLC with or without CNS metastasis
• Tanimoto et al. ClinCancerRes 2021 — Proteasome inhibition overcomes ALK-TKI resistance in ALK-RearrangedTP53-mutant NSCLC via noxa expression
• Ito et al. EurJCancer 2021 — Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma
• Kim et al. FutureOncol 2021 — ALTA-2 phase II study of brigatinib in patients with ALK-positive, advanced non-small-cell lung cancer who progressed
• Nishio et al. JThoracOncol 2021 — Brigatinib in japanese patients with ALK-positive NSCLC previously treated with alectinib and other tyrosine kinase
• Naito et al. JpnJClinOncol 2021 — Brigatinib and lorlatinib their effect on ALK inhibitors in NSCLC focusing on resistant mutations and central nervous

Clinical-NSCLC-Driver negative

• OBrien et al. LancetOncol 2022 — Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer
• Wang et al. NatMed 2021 — Toward personalized treatment approaches for non-small-cell lung cancer

Clinical-NSCLC-Driver-Other

• Wong et al. LungCancer 2021 — MET exon 14 skipping mutation positive non-small cell lung cancer response to systemic therapy

Clinical-NSCLC-HER2

• Friedlaender et al. NatRevClinOncol 2022 — EGFR and HER2 exon 20 insertions in solid tumours from biology to treatment

Clinical-SCLC

• Agarwal et al. Cancer 2023 — Chemoimmunotherapy in patients with extensive-stage small cell lung cancer and a poor performance status

合成 (Outputs)

• alk-g1202r-compound-mutation-sequencing
• bbb-permeability-cns-drug-selection