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Mechanistic Deep Dive
Osimertinib Mechanism
- Irreversible 3rd-gen EGFR TKI
- Targets activating mutations + T790M
- Excellent CNS penetration
- Spares wild-type EGFR (less skin/GI toxicity)
Lorlatinib (3rd-gen ALK)
- Macrocyclic compound
- Broad coverage of resistance mutations
- CNS penetration excellent
- Side effects: hyperlipidemia, weight gain, mood changes, CNS
KRAS G12C Inhibitor Mechanism
- Covalent inhibitor of GDP-bound G12C
- Locks KRAS in inactive state
- Cysteine-specific binding
- Allele-specific (G12C only)
Recent Trials & Updates
ADAURA Long-Term Follow-Up (2023)
- 5-year DFS data
- Sustained benefit
- Practice-changing
LAURA (2024)
- Osimertinib post-chemoradiation in EGFR+ stage III
- Median PFS 39.1 vs 5.6 months
- Game-changing
MARIPOSA + MARIPOSA-2 (2023-2024) â Amivantamab
- EGFR + MET bispecific
- 1st-line and post-osimertinib
CodeBreaK 200 (2023) â Sotorasib vs Docetaxel
- Sotorasib superior to docetaxel
- For pretreated KRAS G12C
TROP2 ADCs
- Datopotamab deruxtecan (Dato-DXd) â TROPION-Lung01
- TROP2 (trophoblast surface antigen 2) overexpressed
- Activity in NSCLC
HER3 ADCs
- Patritumab deruxtecan (HER3-DXd) â HERTHENA-Lung01
- Post-EGFR TKI resistance
- Promising
CheckMate 816 + KEYNOTE-671 + AEGEAN
- Neoadjuvant immunotherapy paradigm shift
- Practice-changing 2022-2024
Long-Term Immunotherapy
- Treatment duration debates
- 2-year vs continuous
- Survival benefits
High-Yield Specialist Points
Stage IB-IIIA EGFR+ Resected
- Adjuvant osimertinib (ADAURA) Ã 3 years
- Significant DFS benefit
- Consider 5-year extension trials
Stage III Unresectable EGFR+
- Concurrent chemoradiation + osimertinib consolidation (LAURA)
- Median PFS 39.1 months
- Game-changing
Sequencing of Therapies
- Targeted therapy first if actionable mutation
- IO + chemo for driver-negative + lower PD-L1
- Multi-line strategies
- Re-biopsy at progression
Resistance to Osimertinib
- C797S (~ 5-15%)
- MET amplification (~ 15-20%)
- Histologic transformation (SCLC, squamous) â re-biopsy
- HER2 amplification
- BRAF mutation
- Bypass pathway activation
Lung Cancer Survivorship
- Smoking cessation
- LDCT surveillance for second primary
- Cardiovascular health
- Pulmonary rehab
- Psychosocial support
Antibody-Drug Conjugates (ADCs)
- HER2: trastuzumab deruxtecan (Enhertu)
- TROP2: datopotamab deruxtecan
- HER3: patritumab deruxtecan
- Mechanism: antibody + cytotoxic linker
Pembrolizumab Pearls
- TPS ⥠50%: monotherapy first-line
- TPS 1-49%: combo with chemo
- Continue 24-25 months
- Watch for delayed irAEs
Pneumonitis (irAE)
- 5-10% incidence
- 1-3% severe
- Steroid responsive
- Hold ICI; reintroduce after grade 1 (in some)
Myocarditis (irAE, Ch292)
- Rare but severe (50% mortality)
- High-dose steroid + IS (infliximab, MMF, ATG, JAK inhibitor)
Bispecific Antibodies + ADCs
- Emerging modalities
- Multi-target inhibition
- Improved efficacy + toxicity profiles
Future Directions
- ctDNA-guided adjuvant
- MRD detection
- New driver mutation targets
- Personalized vaccines
- Adoptive cell therapy
Pearls
- Stage I-II: lobectomy + adjuvant chemo (II+); + osimertinib if EGFR+ (ADAURA)
- Stage III unresectable: chemoradiation + durvalumab (PACIFIC) or osimertinib (LAURA EGFR+)
- Neoadjuvant IO + chemo for resectable IB-IIIA (CheckMate 816, KEYNOTE-671, AEGEAN)
- Stage IV EGFR: osimertinib (FLAURA)
- Stage IV ALK: alectinib (ALEX), brigatinib, lorlatinib (CROWN)
- Stage IV KRAS G12C: sotorasib (CodeBreaK), adagrasib
- Stage IV PD-L1 ⥠50%: pembrolizumab monotherapy
- Stage IV PD-L1 < 50%: pembrolizumab + chemo
- Pneumonitis (irAE): 5-10%; steroids; hold ICI
- ADCs: trastuzumab deruxtecan (HER2), TROP2, HER3 emerging