What is the first-line treatment for non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) overexpression?

First-Line Treatment for NSCLC with EGFR Mutations

First-line treatment with a tyrosine kinase inhibitor (TKI) such as osimertinib is the preferred treatment for patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations. 1

Treatment Selection Based on EGFR Mutation Type

Common EGFR Mutations (Exon 19 deletion or Exon 21 L858R)

For patients with the most common EGFR mutations (exon 19 deletion or exon 21 L858R):

• Preferred first-line option:

  • Osimertinib (category 1) 1

• Other recommended options:

  • Erlotinib (category 1) 1, 2
  • Gefitinib (category 1) 1
  • Afatinib (category 1) 1, 3
  • Dacomitinib (category 1) 1

Osimertinib has demonstrated superior efficacy compared to first-generation EGFR TKIs with:

• Longer median progression-free survival (18.9 vs 10.2 months) 1
• Improved median overall survival (38.6 vs 31.8 months) 1
• Better CNS penetration for patients with brain metastases 1
• Lower rates of serious adverse events 1

Uncommon EGFR Mutations (S768I, L861Q, and/or G719X)

For patients with less common EGFR mutations:

• Preferred first-line options:
  • Afatinib 1
  • Osimertinib 1

Response rates vary by specific mutation:

• For EGFR L861Q: Osimertinib shows 78% response rate vs 56.3% with afatinib 1
• For EGFR G719X: Afatinib shows 77.8% response rate vs 53% with osimertinib 1
• For EGFR S768I: Afatinib shows 100% response rate vs 38% with osimertinib 1

EGFR Exon 20 Insertions

These mutations are generally resistant to standard EGFR TKIs and require different treatment approaches:

• Platinum-based chemotherapy is typically used first-line 1
• Amivantamab-vmjw is FDA-approved for subsequent therapy after platinum-based chemotherapy 1

Special Patient Populations

Poor Performance Status (PS 3-4)

• EGFR TKIs are recommended even for patients with poor performance status (PS 3-4) who have EGFR mutations 1
• For patients without EGFR mutations and poor PS, best supportive care is recommended 1

Elderly Patients

• Single-agent chemotherapy is standard for unselected elderly patients 1
• For elderly patients with EGFR mutations, EGFR TKIs are preferred 1

Management of Treatment Resistance

When progression occurs on first-line osimertinib:

1. Rebiopsy to rule out transformation to small cell histology (occurs in ~5% of cases) 1
2. For multiple lesions: Amivantamab-vmjw plus carboplatin and pemetrexed (category 1, preferred for non-squamous) 1
3. For symptomatic systemic progression: Consider chemotherapy 1

Common Side Effects and Management

EGFR TKIs have distinct toxicity profiles compared to chemotherapy:

• Common side effects include rash, diarrhea, mucositis, and paronychia 4
• First-generation TKIs (erlotinib, gefitinib) generally have fewer severe toxicities than second-generation TKIs (afatinib, dacomitinib) 1
• Osimertinib has a more favorable toxicity profile than earlier-generation TKIs 1

Key Clinical Considerations

• Molecular testing for EGFR mutations should be performed for all patients with non-squamous NSCLC 5
• PD-1/PD-L1 inhibitor monotherapy is less effective in EGFR-mutated NSCLC, regardless of PD-L1 expression 1
• Caution should be exercised when transitioning from immunotherapy to EGFR TKIs due to potential for increased toxicity, particularly pneumonitis 1

Treatment Algorithm

1. Confirm EGFR mutation status and specific mutation type
2. For common mutations (exon 19 deletion or L858R):
   • First choice: Osimertinib
   • Alternative options: Erlotinib, gefitinib, afatinib, or dacomitinib
3. For uncommon mutations (S768I, L861Q, G719X):
   • Choose between afatinib or osimertinib based on specific mutation
4. For exon 20 insertions:
   • First-line: Platinum-based chemotherapy
   • Subsequent therapy: Amivantamab-vmjw

By following this evidence-based approach, patients with EGFR-mutated NSCLC can achieve significant improvements in progression-free survival, overall survival, and quality of life compared to traditional chemotherapy.