TRIDENT-1

一行要約

次世代 macrocyclic ROS1-TKI repotrectinib が TKI-naive ORR 79%・mPFS 35.7 mo を達成し、G2032R solvent-front 耐性変異もカバーする。

試験デザイン

• 対象: ROS1 fusion-positive 進行 NSCLC (TKI-naive コホートおよび prior TKI コホート)
• 介入: Repotrectinib 160mg/day (dose-escalation → expansion)
• コホート構成: TKI-naive / 1 prior ROS1 TKI / 2+ prior TKI
• Phase: Phase I/II registrational (single-arm、ORR が primary)
• 特徴: Macrocyclic 構造により G2032R solvent-front mutation に結合可能

主要結果

• TKI-naive ORR: 79% (CR 6%)、mPFS 35.7 mo
• 1 prior ROS1 TKI ORR: 38%、mPFS 9.0 mo
• G2032R+ 患者 ORR: 59% — crizotinib 耐性後の key population
• CNS ORR: intracranial response あり (BBB 透過性良好)
• 主要 AE: Dizziness (dose-dependent)、dysgeusia、Grade ≥3 少ない

臨床的意義

• ROS1 TKI-naive で crizotinib (ORR 72%, mPFS 19.3 mo) を超える efficacy — 新 1L candidate
• G2032R solvent-front resistance をカバー: lorlatinib (non-selective) に次ぐ選択肢、ROS1 selective で毒性プロファイル優位
• Phase III (TRIDENT-2, vs crizotinib) が進行中 → confirmatory data 待ち
• ROS1+ は NSCLC の 約1-2% — rare driver での sequential TKI 戦略の精緻化

重要論文 Top 10

1. ★★★★★ Drilon et al. NEnglJMed 2024 — TRIDENT-1 primary publication
2. ★★★★★ Shaw et al. NEnglJMed 2014 — Crizotinib ROS1 registrational — historical comparator
3. JCO-2023-Dziadziuszko-Taletrectinib in ROS1-fusion-positive NSCLC — Taletrectinib — competing next-gen ROS1 inhibitor
4. JCO-2017-Lim-Open-label multicenter phase II study of ceritinib in patients with ROS1-rearranged NSCLC — Ceritinib ROS1 — 2nd-gen cross-reactivity
5. ★★★★ Lin et al. ClinCancerRes 2021 — ROS1 resistance landscape — G2032R の位置づけ

関連エンティティ

• Drugs: ROS1-TKI、Crizotinib
• Genes: ROS1
• Concepts: Solvent-front-mutation
• Trials: LIBRETTO-431

関連論文

Clinical-NSCLC-ALK

• Zou et al. CancerCell 2015 — PF-06463922, an ALKROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical

Clinical-NSCLC-Driver-Other

• Hong et al. AnnOncol 2019 — Larotrectinib in adult patients with solid tumours a multi-centre, open-label, phase I dose-escalation study
• Vaishnavi et al. CancerDiscov 2015 — TRKing down an old oncogene in a new era of targeted therapy
• Huang et al. Cell 2019 — A tumor-agnostic NTRK (TRK) inhibitor
• Cocco et al. NatRevClinOncol 2018 — NTRK fusion-positive cancers and TRK inhibitor therapy

Clinical-NSCLC-ROS1

• Kim et al. AnnOncol 2013 — The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma
• Roys et al. CancerChemotherPharmacol 2019 — Resistance mechanisms and potent-targeted therapies of ROS1-positive lung cancer
• DAngelo et al. Cancers 2020 — Focus on ROS1-positive non-small cell lung cancer (NSCLC) crizotinib, resistance mechanisms and the newer generation of
• Yun et al. ClinCancerRes 2020 — Repotrectinib exhibits potent antitumor activity in treatment-naive and solvent-front-mutant ROS1-rearranged non-small
• Lin et al. ClinCancerRes 2021 — Spectrum of mechanisms of resistance to crizotinib and lorlatinib in ROS1 fusion-positive lung cancer
• Almquist et al. JCOOncolPract 2021 — The road less traveled A guide to metastatic ROS1-rearranged non-small-cell lung cancer
• Lin et al. JThoracOncol 2017 — Recent advances in targeting ROS1 in lung cancer
• Ou et al. LungCancer 2019 — CNS metastasis in ROS1+ NSCLC an urgent call to action, to understand, and to overcome
• Drilon et al. NEnglJMed 2024 — Repotrectinib in ROS1 fusion-positive non-small-cell lung cancer