Yes, repeat T790M testing is strongly recommended when EGFR exon 20 deletion NSCLC progresses on gefitinib.
All tumors with clinical evidence of EGFR TKI resistance should be tested for the presence of the EGFR exon 20 T790M mutation 1, 2. This is a Grade A, Level I recommendation across multiple international guidelines.
Why T790M Testing is Critical
The T790M mutation is the most common resistance mechanism to first- and second-generation EGFR TKIs like gefitinib, accounting for 50-60% of acquired resistance cases 2. Detecting this mutation is clinically essential because:
- Osimertinib is highly effective for T790M-positive disease, with median PFS of 10.1 months versus 4.4 months for chemotherapy (HR 0.30) 2
- Treatment decisions fundamentally change based on T790M status—positive patients receive osimertinib, while negative patients should receive platinum-based chemotherapy 1, 3
- Patients with T790M-negative tumors obtain significantly less benefit from osimertinib 2
Testing Strategy: Liquid Biopsy First, Then Tissue if Needed
Start with liquid biopsy (plasma ctDNA testing) as the initial approach 1, 4:
- Convenient, rapid turnaround (ideally ≤2 weeks) 4
- Non-invasive and easily repeatable
- If T790M is detected in plasma, proceed directly to osimertinib—no tissue confirmation needed 2
If liquid biopsy is negative for T790M, perform tissue rebiopsy 1, 4, 2:
- Liquid biopsy has lower sensitivity than tissue biopsy due to tumor heterogeneity and variable ctDNA shedding 4
- Tissue rebiopsy also allows assessment for histologic transformation (e.g., small cell transformation) 4
- Use assays capable of detecting T790M in as little as 5% of EGFR alleles 5
Important Caveats About Your Patient
Critical clarification needed: You mention "exon 20 deletion" but this is likely a misstatement. EGFR mutations are typically:
- Exon 19 deletions (common, TKI-sensitive)
- Exon 20 insertions (uncommon, TKI-resistant)
- Exon 21 L858R (common, TKI-sensitive)
If your patient truly has an exon 20 insertion mutation (not deletion), this changes everything:
- Exon 20 insertions are inherently resistant to gefitinib and other first/second-generation TKIs 6, 7, 8
- Gefitinib should not have been used as first-line therapy for exon 20 insertions 9
- T790M testing would be less relevant, as the primary mutation itself confers resistance
- Treatment should involve exon 20-specific agents like amivantamab 3, 10
If Repeat Testing is Negative
Consider repeat liquid biopsy over time if the first test is negative 11:
- T790M can emerge dynamically during disease progression
- Repeated testing increases detection rates—one study found 11 of 21 initially T790M-negative patients became positive on second rebiopsy 12
Screen for alternative resistance mechanisms if T790M remains negative 13:
- MET amplification (5%)
- HER2 amplification (12-13%)
- PIK3CA mutations (5%)
- Small cell transformation (14%)
- BRAF mutations (1%)
Proceed to platinum-based chemotherapy if no actionable resistance mechanism is identified 1, 3, 2.