What is the management of Epidermal Growth Factor Receptor (EGFR) mutant metastatic Non-Small Cell Lung Cancer (NSCLC)?

Management of EGFR Mutant Metastatic NSCLC

Osimertinib is the preferred first-line treatment for patients with metastatic NSCLC harboring EGFR-activating mutations (exon 19 deletions or exon 21 L858R mutations) due to superior efficacy, safety, and CNS penetration compared to other EGFR TKIs. 1, 2

First-Line Treatment

Common EGFR Mutations (Exon 19 deletions, L858R)

• Osimertinib (80 mg daily) is the preferred first-line therapy due to superior progression-free survival and overall survival compared to first-generation EGFR TKIs 3, 1, 2
• Osimertinib demonstrates better blood-brain barrier penetration with CNS response rates >60%, making it particularly beneficial for patients with brain metastases 3, 1
• Alternative first-line options include erlotinib, gefitinib, afatinib, and dacomitinib, though none are considered preferred over osimertinib 3, 4
• Erlotinib plus bevacizumab represents another front-line treatment option 3
• Addition of carboplatin and pemetrexed to gefitinib is also a first-line option 3

Uncommon EGFR Mutations

• Afatinib shows activity in uncommon mutations including G719X (77.8% response), L861Q (56.3%), and S768I (100%) 3, 5
• For EGFR exon 20 insertions, platinum-based chemotherapy should be offered as first-line therapy, followed by targeted agents like amivantamab or mobocertinib after platinum failure 3

Management of Disease Progression

Oligoprogressive Disease

• For patients with localized distant progression and ongoing systemic control, continuation of EGFR TKI with local treatment of progressing sites may be considered 3
• Local therapy options include stereotactic body radiation therapy (SBRT), image-guided ablation, or surgical resection for isolated lesions 3, 1

Systemic Progression

• For patients with symptomatic systemic progression after osimertinib, amivantamab plus carboplatin and pemetrexed is preferred for patients with multiple lesions 1
• Rebiopsy is recommended to rule out transformation to small cell histology (occurs in ~5% of EGFR TKI-resistant tumors) 1
• Patients who have radiological progression with ongoing clinical benefit may continue with EGFR TKIs 3

CNS Progression

• For isolated CNS progression on osimertinib, consider stereotactic radiosurgery (SRS) while continuing osimertinib 3
• For leptomeningeal disease, osimertinib at 160 mg (if available) may be beneficial 3
• Avoid whole brain radiotherapy when possible due to neurocognitive side effects 3

Special Considerations

Immune Checkpoint Inhibitors (ICIs)

• ICIs as monotherapy are not recommended before other standard therapeutic options are exhausted, regardless of PD-L1 expression, due to limited efficacy in EGFR-mutant NSCLC 3
• Avoid sequencing ICIs followed by osimertinib due to potential for increased toxicity, particularly pneumonitis 3, 1

Toxicity Management

• Common EGFR TKI toxicities include diarrhea, rash, mucositis, and paronychia 6
• Second-generation TKIs (afatinib, dacomitinib) are associated with more toxicities leading to dose reductions compared to first- or third-generation agents 1, 7
• For severe adverse reactions (Grade 3 or higher), withhold treatment until resolution to Grade 1 or baseline, then resume at a reduced dose 4

Treatment Algorithm

1. First-line therapy: Osimertinib 80 mg daily for common EGFR mutations (exon 19 deletions, L858R) 3, 1
2. Monitor for progression: Regular imaging including brain MRI every 6 months 3
3. Upon progression:
   • Oligoprogressive disease: Continue EGFR TKI + local therapy 3
   • Systemic progression: Rebiopsy to identify resistance mechanism 3
   • If T790M-negative: Consider platinum-based chemotherapy 3
   • CNS-only progression: Continue EGFR TKI + SRS 3

Caveats and Pitfalls

• Ensure comprehensive molecular testing before initiating therapy to identify specific EGFR mutation subtypes 1
• Do not use immune checkpoint inhibitors as monotherapy in EGFR-mutant NSCLC regardless of PD-L1 expression 3, 1
• Be vigilant for treatment-related interstitial lung disease, which requires permanent discontinuation of EGFR TKI therapy 4
• For patients with brain metastases, osimertinib should be prioritized over other EGFR TKIs due to superior CNS penetration 3, 1
• Recognize that treatment beyond progression may be appropriate in selected patients with slow growth, minimal symptoms, or oligoprogressive disease 3