325.4 📋 章末速記 Summary

325.4.1 🔑 一句話總結

NSCLC treatment 已進入 precision medicine + immunotherapy 時代；by stage：(1) Stage I-II = lobectomy + adjuvant chemo (II+) + adjuvant osimertinib (ADAURA) if EGFR+ + atezolizumab (IMpower010) if PD-L1+；(2) Stage III unresectable = concurrent chemoradiation + durvalumab consolidation (PACIFIC 2018) or osimertinib consolidation (LAURA 2024) if EGFR+；(3) Stage IV = molecular profiling drives → targeted (EGFR/ALK/ROS1/KRAS G12C/MET/HER2/BRAF/NTRK/RET) or IO (PD-L1 ≥ 50% pembrolizumab mono; otherwise combo chemo + IO)；neoadjuvant immunotherapy (CheckMate 816, AEGEAN, KEYNOTE-671 2022-2024) 改寫 perioperative paradigm；EGFR osimertinib (FLAURA) + ALK alectinib (ALEX) or lorlatinib (CROWN) + KRAS G12C sotorasib/adagrasib (CodeBreaK) + HER2 trastuzumab deruxtecan (DESTINY-Lung) + NTRK larotrectinib + RET selpercatinib (rare but effective)；ADCs for HER2 + emerging TROP2 + HER3；irAEs (pneumonitis 5-10%, myocarditis rare but severe Ch292)；MRD + ctDNA-guided adjuvant 為前沿。

325.4.2 💊 治療精要

• Stage I-II surgery：lobectomy > sublobar (JCOG0802 segmentectomy non-inferior for ≤ 2 cm)；VATS / robotic
• adjuvant chemotherapy：cisplatin-based × 4 cycles for stage IB ≥ 4 cm + II + IIIA → ↑ survival 4-5%
• adjuvant osimertinib (ADAURA 2020)：EGFR+ stage IB-IIIA × 3 years → dramatic DFS improvement
• adjuvant atezolizumab (IMpower010 2021)：PD-L1 ≥ 1% stage II-IIIA × 16 cycles
• Stage III unresectable：concurrent chemoradiation + durvalumab consolidation (PACIFIC 2018) × 12 months OR osimertinib (LAURA 2024) for EGFR+
• neoadjuvant + perioperative：CheckMate 816 (nivolumab + chemo), AEGEAN (durvalumab + chemo), KEYNOTE-671 (pembrolizumab perioperative)
• Stage IV EGFR：osimertinib 80 mg daily (FLAURA); post-resistance amivantamab + chemo (MARIPOSA-2)
• Stage IV ALK：alectinib (ALEX), brigatinib (ALTA-1L), lorlatinib (CROWN — most potent)
• Stage IV ROS1：repotrectinib (2023, addresses resistance) > entrectinib > crizotinib
• Stage IV KRAS G12C：sotorasib (CodeBreaK 100, 200), adagrasib (KRYSTAL-1)
• Stage IV MET exon 14：capmatinib, tepotinib
• Stage IV HER2 mutation：trastuzumab deruxtecan (Enhertu) — DESTINY-Lung
• Stage IV BRAF V600E：dabrafenib + trametinib
• Stage IV NTRK：larotrectinib, entrectinib
• Stage IV RET：selpercatinib (Retsevmo), pralsetinib
• Stage IV PD-L1 ≥ 50%：pembrolizumab monotherapy (KEYNOTE-024)
• Stage IV PD-L1 < 50% / no driver：pembrolizumab + chemo (KEYNOTE-189 non-squamous, KEYNOTE-407 squamous)
• brain mets：CNS-penetrant TKIs (osimertinib, alectinib, brigatinib, lorlatinib, entrectinib) + SRS for limited, WBRT for diffuse

325.4.3 🎯 盧醫師的考前提醒

1. ADAURA (2020) + LAURA (2024) 改寫 EGFR+ NSCLC early/locally advanced：adjuvant osimertinib × 3 years stage IB-IIIA；consolidation osimertinib after chemoradiation stage III unresectable
2. PACIFIC (2018) 確立 stage III unresectable + durvalumab consolidation × 12 months 為 SOC
3. molecular profiling 必做 for advanced NSCLC：EGFR + ALK + ROS1 + KRAS G12C + MET + HER2 + BRAF + NTRK + RET + PD-L1 TPS + TMB
4. EGFR + Asian women non-smokers ~ 50% prevalence：osimertinib (FLAURA) → median OS 38.6 months
5. ALK 三大新藥：alectinib (ALEX, 2017)、brigatinib (ALTA-1L)、lorlatinib (CROWN, most potent + longest PFS)
6. KRAS G12C 新利器：sotorasib (Lumakras, CodeBreaK 100, 200) + adagrasib (Krazati, KRYSTAL-1) — 第一個成功 KRAS-targeted therapy
7. HER2 mutation NSCLC：trastuzumab deruxtecan (Enhertu) DESTINY-Lung01/02 — ADC with ~ 50% response rate
8. neoadjuvant immunotherapy 改寫 2022-2024：CheckMate 816 (nivolumab + chemo) + AEGEAN (durvalumab + chemo) + KEYNOTE-671 (pembrolizumab perioperative — first to show OS benefit)
9. irAEs：pneumonitis (5-10%, 1-3% severe), colitis, hepatitis, endocrine (hypophysitis, T1D), skin, myocarditis (rare but 50% mortality, Ch292) — high-dose steroids + IS
10. CNS-penetrant TKIs：osimertinib, alectinib, brigatinib, lorlatinib, entrectinib — brain mets responsive；reduces need for WBRT；SRS for limited brain mets