What's the approach to first-line therapy in a metastatic lung cancer patient with an Epidermal Growth Factor Receptor (EGFR) exon 19 deletion?

First-Line Therapy for Metastatic Lung Cancer with EGFR Exon 19 Deletion

Single-agent osimertinib is the preferred first-line treatment for patients with metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletion due to superior efficacy and safety compared to other EGFR tyrosine kinase inhibitors (TKIs). 1, 2

Preferred First-Line Treatment Options

• Osimertinib (80 mg once daily) is the NCCN-preferred first-line therapy for patients with metastatic NSCLC with EGFR exon 19 deletion due to superior progression-free survival (PFS) and overall survival (OS) compared to first-generation EGFR TKIs 1, 2
• The FLAURA trial demonstrated that osimertinib monotherapy resulted in significantly longer median OS (38.6 months) compared to erlotinib or gefitinib (31.8 months) with a hazard ratio of 0.8 (p=0.046) 1, 3
• Osimertinib demonstrates better blood-brain barrier penetration with significantly fewer CNS progression events (6% vs 15%) compared to first-generation TKIs, making it particularly beneficial for patients with brain metastases 1, 2

Alternative First-Line Treatment Options

• Other FDA-approved first-line options include erlotinib, gefitinib, afatinib, and dacomitinib (all category 1 recommendations) 1, 4, 5
• All of these EGFR TKIs are appropriate for patients with performance status 0-4 1, 2
• Second-generation TKIs (afatinib, dacomitinib) are associated with more toxicities leading to dose reductions compared to osimertinib 1, 2

Combination Therapy Options

• Osimertinib in combination with pemetrexed and either cisplatin or carboplatin (category 1 for nonsquamous histology) is an "other recommended" option that demonstrated longer PFS (25.5 vs 16.7 months; HR 0.62; p<0.001) compared to osimertinib monotherapy in the FLAURA2 trial 1, 6
• Erlotinib in combination with bevacizumab (for nonsquamous histology with no recent history of hemoptysis) or erlotinib in combination with ramucirumab are also listed as "other recommended" options 1
• Combination therapy is associated with higher rates of grade 3 or higher adverse events compared to monotherapy, primarily driven by known chemotherapy-related toxicities 1, 6

Treatment Selection Algorithm

1. First choice: Osimertinib monotherapy (80 mg daily) for most patients with EGFR exon 19 deletion 1, 2
2. Consider osimertinib + chemotherapy for patients with high disease burden or those at risk for rapid progression who can tolerate increased toxicity 1, 6
3. Consider alternative EGFR TKIs (erlotinib, gefitinib, afatinib, dacomitinib) if osimertinib is not available or contraindicated 1

Important Considerations and Pitfalls

• Avoid PD-1/PD-L1 inhibitor monotherapy in EGFR-positive NSCLC as multiple studies have shown inferior efficacy regardless of PD-L1 expression 1, 2
• If an EGFR mutation is discovered during first-line immunotherapy, be cautious when initiating EGFR TKIs due to potential for increased adverse events, particularly pneumonitis when osimertinib is started within 3 months of immunotherapy 1, 2
• For patients with oligometastatic disease (3-5 metastases), consider definitive local therapy (SABR or surgery) as consolidation after initiating EGFR TKI therapy 1, 2
• When disease progression occurs on osimertinib, rebiopsy is recommended to rule out transformation to small cell histology, which occurs in approximately 5% of EGFR TKI-resistant tumors 1
• For progression after first-line osimertinib, amivantamab-vmjw plus carboplatin and pemetrexed is the preferred option (category 1) for patients with multiple lesions and nonsquamous histology 1, 2

Monitoring and Adverse Event Management

• Monitor for common EGFR TKI adverse events including rash, diarrhea, and elevated liver enzymes 4, 5
• For osimertinib, monitor for specific toxicities including interstitial lung disease/pneumonitis, QT prolongation, and cardiomyopathy 1
• Dose modifications may be required for significant adverse events; follow specific guidance for each agent 4, 5