PROFILE 1014

一行要約

未治療 ALK+ advanced NSCLC への Crizotinib vs Pemetrexed-Platinum 化療の phase III。ALK-TKI 1L を化療を超えて初確立した landmark trial。PFS HR 0.45 (mPFS 10.9 vs 7.0 mo)。後続 ALEX / ALTA-1L / CROWN で 2nd/3rd-gen に置換されたが、ALK targeted therapy paradigm の起点。

試験デザイン

• 対象: Stage IIIB/IV、未治療 ALK+ NSCLC (FISH/IHC central confirmation)、N=343 (1:1)
• 介入群 (n=172) : Crizotinib 250mg BID
• 対照群 (n=171) : Pemetrexed + Cisplatin or Carboplatin × 6 cycles
• Cross-over: 対照群進行時 Crizotinib cross-over 許容 (実 約70%)

主要結果

• PFS (primary) : HR 0.45 (95% CI 0.35–0.60, p<0.001), median 10.9 vs 7.0 mo
• OS: HR 0.85 (cross-over heavy で benefit 中立化)
• ORR: 74% vs 45%
• CNS efficacy: Crizotinib では限定的 (後続 2nd-gen で改善)
• AE: Crizotinib で視覚障害・嘔気・浮腫、化療で骨髄抑制

臨床的意義

• ALK-TKI 1L paradigm を化療超越で確立 (第一の “targeted > chemo” 1L NSCLC trial の 1 つ)
• ALK targeted therapy の global standardization
• Crizotinib CNS 限定が次世代 ALK-TKI (Alectinib / Brigatinib / Lorlatinib) 開発を駆動
• 後続: ALEX / J-ALEX / ALTA-1L / CROWN / ALINA で paradigm 進化

Open Questions

• Historical perspective: PROFILE 1014 がなければ ALK-TKI paradigm はあったか
• Crizotinib の現代位置づけ: もはや 1L 標準ではないが ROS1 / MET ex14 で還元
• 化療 vs targeted の長期成績: long-term follow-up での化療群との convergence

重要論文 Top 10

1. ★★★★★ Solomon et al. NEnglJMed 2014 — PROFILE 1014 primary
2. ★★★★ Solomon et al. JClinOncol 2018 — Final OS analysis
3. ★★★★★ Peters et al. NEnglJMed 2017 — ALEX — successor
4. ★★★★★ Shaw et al. NEnglJMed 2020 — CROWN — 3rd-gen successor
5. ★★★★ Hida et al. Lancet 2017 — J-ALEX — parallel

関連エンティティ

• 薬剤クラス: ALK-TKI (Crizotinib), Pemetrexed / Platinum-chemotherapy
• 遺伝子: ALK
• 関連試験: ALEX / ALTA-1L / CROWN / IPASS (EGFR の paradigm parallel)
• ドメイン: lung-cancer-treatment

関連論文

直近 30 件のみ表示中 (関連 34 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Clinical-NSCLC-ALK

• Lovly et al. AmSocClinOncolEducBook 2017 — Managing resistance to EFGR-and ALK-targeted therapies
• Gadgeel et al. AnnOncol 2018 — Alectinib versus crizotinib in treatment-naive anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer
• Soria et al. AnnOncol 2018 — Correlation of extent of ALK FISH positivity and crizotinib efficacy in three prospective studies of ALK-positive pat…
• Mok et al. AnnOncol 2020 — Updated overall survival and final progression-free survival data for patients with treatment-naive advanced
• Zou et al. CancerCell 2015 — PF-06463922, an ALKROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical
• Lin et al. CancerDiscov 2017 — Targeting ALK Precision medicine takes on drug resistance
• Yoda et al. CancerDiscov 2018 — Sequential ALK inhibitors can select for lorlatinib-resistant compound ALK mutations in ALK-positive lung cancer
• Toyokawa et al. CancerMetastasisRev 2015 — Insights into brain metastasis in patients with ALK+ lung cancer is the brain truly a sanctuary
• Katayama et al. CancerSci 2018 — Drug resistance in anaplastic lymphoma kinase-rearranged lung cancer
• Matikas et al. ClinLungCancer 2016 — Management of resistance to crizotinib in anaplastic lymphoma kinase-positive non-small-cell lung cancer
• Watanabe et al. ClinLungCancer 2016 — Progression-free and overall survival of patients with ALK rearrangement-positive non-small cell lung cancer treated
• Cadranel et al. ERJOpenRes 2018 — Real-life experience of ceritinib in crizotinib-pretreated ALK+ advanced non-small cell lung cancer patients
• Mascarenhas et al. JCOGlobOncol 2026 — Current access to anaplastic lymphoma kinase testing and targeted therapies for non-small cell lung cancer in brazil
• Ou et al. JClinOncol 2016 — Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer A phase II global study
• Tamura et al. JClinOncol 2017 — Three-year follow-up of an alectinib phase III study in ALK-positive non-small-cell lung cancer AF-001jp
• Solomon et al. JClinOncol 2018 — Final overall survival analysis from a study comparing first-line crizotinib versus chemotherapy in
• Camidge et al. JClinOncol 2020 — Brigatinib versus crizotinib in advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer second interim
• Gemma et al. JThoracOncol 2019 — Interstitial lung disease onset and its risk factors in japanese patients with ALK-positive NSCLC after treatment with
• Soria et al. Lancet 2017 — First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer
• Kim et al. LancetOncol 2016 — Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1) updated results
• Zhou et al. LancetRespirMed 2019 — Alectinib versus crizotinib in untreated asian patients with anaplastic lymphoma kinase-positive non-small-cell lung
• Chiari et al. LungCancer 2015 — Clinical impact of sequential treatment with ALK-TKIs in patients with advanced ALK-positive non-small cell lung cancer
• Shaw et al. NEnglJMed 2013 — Crizotinib versus chemotherapy in advanced ALK-positive lung cancer
• Solomon et al. NEnglJMed 2014 — First-line crizotinib versus chemotherapy in ALK-positive lung cancer
• Peters et al. NEnglJMed 2017 — Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer
• Jahanzeb et al. Oncologist 2020 — Real-world treatment patterns and progression-free survival associated with anaplastic lymphoma kinase (ALK) tyrosine

Clinical-NSCLC-Driver-Other

• Johnson et al. JClinOncol 2014 — Recent clinical advances in lung cancer management

Clinical-NSCLC-EGFR

• Asao et al. RespirInvestig 2019 — Resistance to molecularly targeted therapy in non-small-cell lung cancer

Clinical-NSCLC-ROS1

• Shaw et al. AnnOncol 2019 — Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC) updated results, including overall survival,
• Yu et al. ClinLungCancer 2019 — Multiple biomarker testing tissue consumption and completion rates with single-gene tests and investigational use of