What is the treatment for non-small cell lung cancer (NSCLC) with a positive Epidermal Growth Factor Receptor (EGFR) mutation?

Treatment for EGFR-Positive Non-Small Cell Lung Cancer

Osimertinib is the preferred first-line treatment for patients with advanced or metastatic NSCLC with EGFR-activating mutations (exon 19 deletion or exon 21 L858R) due to superior efficacy and safety compared to other EGFR TKIs. 1

First-Line Treatment Options

Preferred Treatment

• Osimertinib (single-agent) is the preferred first-line therapy for patients with EGFR exon 19 deletion or exon 21 L858R mutations due to superior progression-free survival (18.9 vs 10.2 months) and overall survival (38.6 vs 31.8 months) compared to first-generation EGFR TKIs 1
• Osimertinib demonstrates better blood-brain barrier penetration with CNS response rates >60%, making it particularly beneficial for patients with brain metastases 1
• Osimertinib has lower rates of serious adverse events compared to first- and second-generation EGFR TKIs 1

Alternative First-Line Options

• Other FDA-approved first-line options include erlotinib, gefitinib, afatinib, and dacomitinib (all category 1 recommendations) 1
• Combination regimens can also be considered:
  • Osimertinib plus pemetrexed and platinum-based chemotherapy (category 1 for nonsquamous histology) 1, 2
  • Erlotinib plus bevacizumab (for nonsquamous histology without recent hemoptysis) 1
  • Erlotinib plus ramucirumab 1

Treatment Selection Considerations

• Performance status: All EGFR TKIs are appropriate for patients with performance status 0-4 1
• Brain metastases: Osimertinib is preferred due to superior CNS penetration 1
• Toxicity profile: Second-generation TKIs (afatinib, dacomitinib) are associated with more toxicities (acneiform rash, stomatitis, diarrhea) leading to dose reductions 1
• Mutation subtype: Consider specific TKIs based on mutation type (exon 19 deletion vs L858R) 1

Disease Progression Management

After First-Line Osimertinib

• For patients with symptomatic systemic progression after osimertinib:
  • Amivantamab-vmjw plus carboplatin and pemetrexed is the preferred option (category 1) for patients with multiple lesions (nonsquamous histology) 1
  • Rebiopsy is recommended to rule out transformation to small cell histology (occurs in ~5% of EGFR TKI-resistant tumors) 1
  • Standard chemotherapy options can be considered 1

After First/Second-Generation EGFR TKIs

• Test for EGFR T790M mutation, which occurs in approximately 50% of cases 1, 3
• If T790M positive, osimertinib is the standard therapy 1, 4
• If T790M negative, platinum-based chemotherapy is recommended 1, 3

Special Considerations

• Oligometastatic disease (1-3 metastases): Consider definitive local therapy (stereotactic ablative radiotherapy or surgery) as consolidation after systemic therapy 1
• For brain metastases: Stereotactic radiosurgery is preferred for 1-3 lesions; whole brain radiation therapy for >3 lesions 1, 5
• Avoid PD-1/PD-L1 inhibitor monotherapy in EGFR-positive NSCLC as it shows inferior efficacy regardless of PD-L1 expression 1
• Be cautious when using EGFR TKIs in combination with or following immune checkpoint inhibitors due to potential for increased adverse events, particularly pneumonitis 1

Treatment Algorithm

1. Confirm EGFR mutation status (exon 19 deletion or exon 21 L858R) 1, 2
2. Assess for brain metastases and overall performance status 1
3. Initiate first-line therapy:
   • Preferred: Osimertinib monotherapy 1
   • Alternative: Other EGFR TKIs or combination regimens based on individual factors 1
4. Monitor for disease progression with regular imaging 1
5. Upon progression:
   • If on first/second-generation TKI: Test for T790M mutation 1, 3
   • If T790M positive: Switch to osimertinib 1
   • If on osimertinib or T790M negative: Consider amivantamab-vmjw plus chemotherapy or standard chemotherapy options 1
6. Consider local therapy for oligometastatic progression 1

Common Pitfalls to Avoid

• Failing to test for EGFR mutations before initiating therapy in advanced nonsquamous NSCLC 1, 5
• Using immune checkpoint inhibitors as monotherapy in EGFR-positive disease 1
• Not considering the potential for small cell transformation at progression 1
• Overlooking the importance of brain imaging in initial staging and follow-up 1
• Starting a new EGFR TKI too soon after immune checkpoint inhibitor therapy (increased risk of pneumonitis) 1