325.1 🎓 醫孞生版

325.1.0.1 📌 䞀頁重點

325.1.0.1.1 Treatment by Stage Overview

325.1.1 Stage I (T1-T2a, N0)

  • Surgical resection (lobectomy preferred over wedge or sublobar)
  • VATS / robotic approach
  • Adjuvant chemotherapy NOT routine for stage IA (debated for IB > 4 cm)
  • Adjuvant osimertinib (ADAURA) for EGFR+ stage IB-IIIA (resected)

325.1.2 Stage II (T2b-T3, N0; T1-T2, N1)

  • Surgical resection
  • Adjuvant chemotherapy (cisplatin-based) ↑ survival
  • Adjuvant atezolizumab if PD-L1 ≥ 1% (IMpower010)
  • Adjuvant osimertinib if EGFR+ (ADAURA)

325.1.3 Stage IIIA (T3-T4, N1; T1-T2, N2)

  • Multimodality treatment:
    • Surgery + adjuvant
    • Neoadjuvant therapy
    • Concurrent chemoradiation + durvalumab (PACIFIC) for unresectable
  • Highly individualized

325.1.4 Stage IIIB-IIIC (unresectable locally advanced)

  • Concurrent chemoradiation (cisplatin + etoposide or carboplatin + paclitaxel)
  • Durvalumab consolidation × 12 months (PACIFIC 2018)
  • Osimertinib consolidation for EGFR+ (LAURA 2024)

325.1.5 Stage IV (Metastatic)

  • Molecular profiling-driven first
  • Targeted therapy if actionable mutation
  • Immunotherapy + chemotherapy otherwise
325.1.5.0.1 Surgical Resection

325.1.6 Approach

  • Lobectomy = standard (versus wedge or segmentectomy)
  • JCOG0802 (2022): segmentectomy non-inferior for stage IA ≀ 2 cm — practice-changing for small peripheral
  • Sublobar resection: limited lung function or small tumor
  • Pneumonectomy: only when necessary; higher morbidity
  • VATS or robotic (less invasive)
  • Open for complex

325.1.7 Lymph Node Dissection

  • Systematic lymph node sampling or dissection
  • Mediastinal staging
  • Predicts prognosis

325.1.8 Adjuvant Therapy

Chemotherapy: - Cisplatin-based (cisplatin + vinorelbine, gemcitabine, docetaxel, or pemetrexed for non-squamous) - For Stage IB ≥ 4 cm, II, IIIA - 4 cycles - ↑ Survival 4-5% absolute

Atezolizumab (IMpower010, 2021): - Stage II-IIIA + PD-L1 ≥ 1% - 16 cycles q3 weeks - ↑ DFS

Osimertinib (ADAURA, 2020): - EGFR+ (exon 19 del or L858R) - Stage IB-IIIA - Adjuvant 3 years - Significantly improves DFS (≥ 80%)

325.1.8.0.1 Neoadjuvant Therapy (Pre-Surgery)

325.1.9 Chemotherapy Alone

  • Cisplatin-based × 3-4 cycles
  • ↑ Survival modestly

325.1.10 Neoadjuvant Immunotherapy (NEW 2022-2024)

CheckMate 816 (2022): - Resectable NSCLC stage IB-IIIA - Neoadjuvant nivolumab + chemo × 3 cycles vs chemo - ↑ Pathologic complete response (pCR) 24% vs 2.2% - ↑ EFS

AEGEAN (2023): - Neoadjuvant + adjuvant durvalumab + chemo - ↑ pCR, EFS

KEYNOTE-671 (2023): - Pembrolizumab perioperative (neoadjuvant + adjuvant) - ↑ OS (first to show)

Practice-Changing: - Resectable NSCLC stage IB-IIIA → neoadjuvant chemo + IO + surgery + adjuvant IO

325.1.10.0.1 Targeted Therapy (Stage IV)

325.1.11 EGFR Mutation

First-Line: - Osimertinib (Tagrisso) 80 mg daily — preferred (FLAURA 2018) - ↑ Median OS to 38.6 months (vs 31.8 with gefitinib) - CNS penetration excellent - Side effects: rash, diarrhea, ILD (uncommon, watch), QTc

Resistance Mechanisms: - C797S mutation (acquired) - MET amplification (~ 20%) - Histologic transformation (SCLC, squamous) - Bypass pathways

Post-Osimertinib: - Amivantamab (MET + EGFR bispecific) + chemo (MARIPOSA-2) - Re-biopsy critical

Other EGFR Mutations: - Exon 20 insertion: less responsive to osimertinib; amivantamab, mobocertinib - T790M acquired: osimertinib responsive

325.1.12 ALK Rearrangement

First-Line: - Alectinib (Alecensa) (ALEX 2017) — median PFS 34.8 months - Brigatinib (ALTA-1L) - Lorlatinib (CROWN — most potent, longest PFS but more CNS side effects) - All have CNS penetration

Resistance: - Next-gen ALK TKI (lorlatinib for many) - Combination strategies emerging

325.1.13 ROS1 Rearrangement

  • Crizotinib (older)
  • Entrectinib (CNS penetration)
  • Repotrectinib (2023) — addresses resistance, broader

325.1.14 KRAS G12C

  • Sotorasib (Lumakras) — CodeBreaK 100 (2020)
  • Adagrasib (Krazati) — KRYSTAL-1 (2022)
  • ~ 35% response rate; ~ 30% median survival
  • Better than chemo but lower than EGFR/ALK targets
  • Resistance mechanisms studied

325.1.15 MET Exon 14 Skipping

  • Capmatinib (Tabrecta)
  • Tepotinib (Tepmetko)
  • GEOMETRY-mono, VISION trials

325.1.16 HER2 Mutation

  • Trastuzumab deruxtecan (Enhertu) — DESTINY-Lung01/02
  • ADC (antibody-drug conjugate)
  • Response 50% in HER2-mutant NSCLC

325.1.17 BRAF V600E

  • Dabrafenib + trametinib
  • BRF113928 trial

325.1.18 NTRK Fusion (Rare; 1%)

  • Larotrectinib (Vitrakvi)
  • Entrectinib (Rozlytrek)

325.1.19 RET Fusion (Rare; 1-2%)

  • Selpercatinib (Retsevmo) — LIBRETTO
  • Pralsetinib (Gavreto) — ARROW
325.1.19.0.1 Immunotherapy (Stage IV)

325.1.20 PD-L1 ≥ 50% (TPS Score)

  • Pembrolizumab monotherapy (KEYNOTE-024)
  • 1st-line
  • Median OS 30 months
  • 6% complete response

325.1.21 PD-L1 1-49% or < 1%

  • Combination: pembrolizumab + chemo (KEYNOTE-189 non-squamous; KEYNOTE-407 squamous)
  • Standard of care 1st-line

325.1.22 Nivolumab + Ipilimumab + Limited Chemo

  • CheckMate 9LA, CheckMate 227
  • Alternative regimens
  • Some patients

325.1.23 Atezolizumab Combinations

  • IMpower150, IMpower130

325.1.24 Durvalumab + Tremelimumab + Chemo

  • POSEIDON

325.1.25 Cemiplimab Monotherapy

  • High PD-L1 (≥ 50%)
  • EMPOWER-Lung 1

325.1.27 Concurrent Chemoradiation

  • Cisplatin + etoposide + radiation (60-70 Gy)
  • OR carboplatin + paclitaxel + radiation
  • For unresectable

325.1.28 Durvalumab Consolidation (PACIFIC 2018)

  • 1 year × 12 months
  • ↑ Median OS 47.5 vs 29.1 months
  • Class I

325.1.29 Osimertinib Consolidation (LAURA 2024)

  • For EGFR+ stage III unresectable
  • Median PFS 39.1 months
  • Practice-changing

325.1.30 Neoadjuvant Strategy

  • Some stage IIIA resectable
  • Chemoradiation → surgery → adjuvant IO
325.1.30.0.1 Brain Metastases

325.1.31 Prevalence

  • 25-30% of NSCLC develop
  • ~ 50% have at diagnosis or develop

325.1.32 Treatment

  • CNS-penetrant TKIs: osimertinib, alectinib, brigatinib, lorlatinib, entrectinib
  • Stereotactic radiosurgery (SRS): for limited brain mets
  • Whole-brain radiotherapy (WBRT): for multiple or symptomatic
  • Surgery: for single large symptomatic
  • Pembrolizumab: CNS-penetrating to extent

325.1.33 Leptomeningeal Disease

  • More refractory
  • Intrathecal chemotherapy
  • Osimertinib for EGFR+
  • Poor prognosis
325.1.33.0.1 Special Situations

325.1.34 Older Adults

  • Performance status + frailty important
  • Single-agent therapy often
  • TKIs well-tolerated
  • IO tolerable in many

325.1.35 Renal/Hepatic Dysfunction

  • Adjust doses
  • Specific drugs vary

325.1.36 Pregnancy

  • Rare consideration
  • Many drugs teratogenic
  • Multidisciplinary

325.1.36.1 🩺 床邊速查

  • Stage I-II: lobectomy + adjuvant chemo (II+); adjuvant osimertinib for EGFR+ (ADAURA)
  • Stage III unresectable: chemoradiation + durvalumab (PACIFIC) or osimertinib (LAURA EGFR+)
  • Stage IV with driver: targeted therapy first (EGFR, ALK, ROS1, KRAS G12C, MET, HER2, BRAF, NTRK, RET)
  • Stage IV PD-L1 ≥ 50%: pembrolizumab monotherapy
  • Stage IV PD-L1 < 50% or driver-negative: pembrolizumab + chemo
  • Neoadjuvant IO: CheckMate 816, KEYNOTE-671 for resectable stage IB-IIIA
  • Brain mets: CNS-penetrant TKIs (osimertinib, alectinib, lorlatinib) + SRS