A 52-year-old never-smoking woman undergoes routine chest CT for dyspnea and is found to have a peripheral spiculated mass with pleural retraction in the right lower lobe, as marked **B** in the diagram. Tissue diagnosis confirms lung adenocarcinoma. Molecular profiling reveals an EGFR exon 19 deletion. Which of the following is the most appropriate first-line targeted therapy for this patient's advanced disease?

Question

Accepted Answer

B. Osimertinib. ## Why Osimertinib is right

Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) that is the standard first-line targeted therapy for EGFR-mutant lung adenocarcinoma, including exon 19 deletions and L858R mutations. According to the WHO Classification of Lung Tumors 2021 and NCCN NSCLC Guidelines, EGFR mutations (particularly exon 19 deletions) are common driver mutations in adenocarcinomas arising from the peripheral lung epithelium (bronchiolar/alveolar origin), especially in never-smokers, women, and younger patients—exactly matching this patient's profile. Osimertinib has superior efficacy and tolerability compared to first-generation TKIs (gefitinib, erlotinib) and is now the preferred upfront choice.

## Why each distractor is wrong

- **Crizotinib**: This is a first-line targeted therapy for ALK rearrangements (EML4-ALK fusion), not EGFR mutations. The patient's molecular profiling shows EGFR exon 19 deletion, not ALK rearrangement.
- **Sotorasib**: This is a KRAS G12C inhibitor used for KRAS-mutant adenocarcinomas. The patient has an EGFR-driven tumor, not KRAS-driven disease.
- **Pembrolizumab monotherapy**: While pembrolizumab (anti-PD-L1 checkpoint inhibitor) is appropriate for PD-L1+ adenocarcinomas without driver mutations, it is not first-line for EGFR-mutant disease. Targeted TKI therapy (osimertinib) is superior and is the standard of care when a driver mutation is present.

**High-Yield:** EGFR-mutant lung adenocarcinoma (exon 19 del, L858R) → osimertinib first-line; ALK rearrangement → crizotinib/alectinib; KRAS G12C → sotorasib; driver-negative/PD-L1+ → immunotherapy.

[cite: WHO Classification of Lung Tumors 2021; NCCN NSCLC Guidelines]

Answer

A. Pembrolizumab monotherapy

Answer

C. Sotorasib

Answer

D. Crizotinib

Explanation

Why Osimertinib is right

Why each distractor is wrong

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