ALTA-1L

一行要約

未治療 ALK+ NSCLC への 2nd-gen Brigatinib vs 1st-gen Crizotinib の phase III。PFS HR 0.49 (mPFS 24.0 vs 11.0 mo)、CNS 制御で Crizotinib に対し著明改善。Brigatinib の 1L 適応を確立、ALEX / J-ALEX に並ぶ ALK-TKI 1L 選択肢。

試験デザイン

• 対象: Stage IIIB/IV、未治療 ALK+ NSCLC、N=275 (1:1)
• 介入群 (n=137) : Brigatinib 90mg/day × 7 日 → 180mg/day (ramp-up dosing)
• 対照群 (n=138) : Crizotinib 250mg BID

主要結果

• PFS (primary, BICR) : HR 0.49 (95% CI 0.35–0.68), median 24.0 vs 11.0 mo
• CNS PFS: HR 0.31, intracranial ORR 78% vs 26%
• OS (final) : HR 0.81 (cross-over 多くて中立)
• AE: Brigatinib 特有の early-onset pulmonary event (EOPE) (initial 7 日 90mg dose で軽減), 高血圧, 高 CK / リパーゼ

臨床的意義

• Brigatinib 1L 標準化 — Alectinib (ALEX) / Lorlatinib (CROWN) と並ぶ 2nd-gen ALK-TKI
• CNS 効果優位、特に G1269A / I1171 等の Crizotinib 耐性 mutations cover
• “Ramp-up dosing” で EOPE 軽減 — 7 日 90mg → 180mg full dose
• Sequential 戦略: 1L Brigatinib → 2L Lorlatinib (compound mutation cover)

Open Questions

• Brigatinib vs Alectinib vs Lorlatinib: 直接比較なし、CNS / G1202R での選好
• EOPE 機序解明: ramp-up dosing で軽減も完全解明されず
• Adjuvant Brigatinib: ALINA 後の試験設計
• ALTA-1L 後 progression での 2L 戦略: G1202R / compound mutation の cover

重要論文 Top 10

1. ★★★★★ Camidge et al. NEnglJMed 2018 — ALTA-1L primary
2. ★★★★★ Camidge et al. JClinOncol 2020 — Interim update
3. ★★★★★ Camidge et al. JThoracOncol 2021 — Final results
4. ★★★★ Peters et al. NEnglJMed 2017 — ALEX — parallel ALK 1L
5. ★★★★ Shaw et al. NEnglJMed 2020 — CROWN — Lorlatinib 1L parallel

関連エンティティ

• 薬剤クラス: ALK-TKI (Brigatinib / Crizotinib)
• 遺伝子: ALK
• 関連試験: ALEX / J-ALEX / CROWN / ALINA
• 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

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
• Shaw et al. ClinCancerRes 2011 — Targeting anaplastic lymphoma kinase in lung cancer
• Zhang et al. ClinCancerRes 2016 — The potent ALK inhibitor brigatinib (AP26113) overcomes mechanisms of resistance to first-and second-generation ALK
• 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
• Johung et al. JClinOncol 2016 — Extended survival and prognostic factors for patients with ALK-rearranged non-small-cell lung cancer and brain
• Kim et al. JClinOncol 2017 — Brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small-cell lung cancer A
• Solomon et al. JClinOncol 2018 — Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in
• Shaw et al. JClinOncol 2019 — ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung
• Camidge et al. JClinOncol 2020 — Brigatinib versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer second interim
• Solomon et al. JClinOncol 2024 — Lorlatinib versus crizotinib in patients with advanced ALK-positive non-small cell lung cancer 5-year outcomes from the
• Camidge et al. JThoracOncol 2019 — Management strategies for early-onset pulmonary events associated with brigatinib
• Huber et al. JThoracOncol 2020 — Brigatinib in crizotinib-refractory ALK+ NSCLC 2-year follow-up on systemic and intracranial outcomes in the phase 2
• Ng et al. JThoracOncol 2020 — Early-onset pulmonary events associated with brigatinib use in advanced NSCLC
• Camidge et al. JThoracOncol 2021 — Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC final results of phase 3 ALTA-1l trial
• 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
• Califano et al. LungCancer 2017 — Management of ceritinib therapy and adverse events in patients with ALK-rearranged non-small cell lung cancer
• Descourt et al. LungCancer 2019 — Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors
• Camidge et al. NEnglJMed 2018 — Brigatinib versus crizotinib in ALK-positive non-small-cell lung cancer
• Shaw et al. NEnglJMed 2020 — First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer
• Jahanzeb et al. Oncologist 2020 — Real-world treatment patterns and progression-free survival associated with anaplastic lymphoma kinase (ALK) tyrosine
• Duruisseaux et al. Oncotarget 2017 — Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer