What is the recommended treatment for a patient with the epidermal growth factor receptor (EGFR) T790M mutation?

Treatment of EGFR T790M Mutation-Positive NSCLC

Osimertinib 80 mg orally once daily is the standard of care for patients with metastatic EGFR T790M mutation-positive non-small cell lung cancer who have progressed on first- or second-generation EGFR TKIs (erlotinib, gefitinib, or afatinib). 1, 2

Confirming T790M Status Before Treatment

• All patients with clinical resistance to first- or second-generation EGFR TKIs must be tested for T790M mutation before selecting therapy. 1
• Liquid biopsy (plasma ctDNA) should be used as the initial test for T790M detection; if negative, tissue re-biopsy should be attempted when feasible. 1
• T790M must be detected by an FDA-approved test or validated laboratory test performed in a CLIA-approved laboratory. 1, 2
• T790M mutations occur in approximately 49-60% of patients who develop resistance to first-generation TKIs. 1

Osimertinib Efficacy Data

The AURA 3 phase III trial demonstrated superior outcomes with osimertinib compared to platinum-pemetrexed chemotherapy:

• Objective response rate: 71% vs 31% (OR 5.39,95% CI 3.46-8.48; P < 0.001) 1
• Median progression-free survival: 10.2 months vs 4.4 months (HR 0.30,95% CI 0.23-0.41; P < 0.0001) 1
• Disease control rate: approximately 93% (95% CI 90%-96%) 1
• Grade ≥3 adverse events: 23% with osimertinib vs 47% with chemotherapy 1

Special Populations

Patients with CNS Metastases

Osimertinib is specifically recommended (Category 1) for T790M-positive patients with brain metastases. 1

• Among 144 patients with CNS metastases in AURA 3, median PFS was 8.5 months with osimertinib vs 4.2 months with platinum-pemetrexed (HR 0.32,95% CI 0.21-0.49). 1
• For intracranial progression on standard-dose osimertinib (80 mg), deliver local stereotactic radiation while continuing osimertinib, or consider increasing to 160 mg if accessible. 1

Patients with Leptomeningeal Disease

• Osimertinib 160 mg daily is the preferred dose for leptomeningeal carcinomatosis, based on the BLOOM study demonstrating good anticancer activity. 1
• This higher dose has been accepted as standard of care in many countries for this specific indication. 1

Patients with Poor Performance Status

• Osimertinib demonstrates efficacy and acceptable safety even in patients with ECOG PS 2-3, with an overall response rate of 53% and PS improvement rate of 63%. 3
• Performance status 2-4 is an independent adverse prognostic factor but does not preclude osimertinib use. 4

Treatment for T790M-Negative Patients

For patients who test negative for T790M mutation after progression on EGFR TKIs, platinum-based doublet chemotherapy is the standard of care. 1

• The IMPRESS trial established platinum-based chemotherapy as the recommended approach for T790M-negative resistance. 1
• Combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel may be considered in non-squamous NSCLC patients with PS 0-1 after targeted therapies are exhausted (Level IV, C evidence). 1
• Checkpoint inhibitor monotherapy (pembrolizumab, nivolumab, atezolizumab) shows poor efficacy in EGFR-mutant patients, with response rates of only 3.6% vs 23% in EGFR wild-type patients. 1

Alternative Options When Osimertinib Is Unavailable

• Afatinib plus cetuximab may be considered for patients who have progressed after EGFR TKI therapy and chemotherapy, with response rates of 32% in T790M-positive and 25% in T790M-negative tumors (Category 2A). 1
• In Asian countries where approved, alternative third-generation TKIs include almonertinib (aumolertinib), lazertinib, and alflutinib. 1

Critical Safety Monitoring

Baseline ECG is mandatory before initiating osimertinib; patients with mean resting QTc >470 msec should not receive osimertinib. 5, 6, 2

• QTc prolongation occurs in 10% of patients (grade ≥3 in 2.2%). 5
• Discontinue or substitute all concomitant QT-prolonging medications before starting osimertinib. 5, 6
• Interstitial lung disease/pneumonitis occurs in 3.9-56% of patients, with fatal events reported (2 respiratory failure deaths, 1 pneumonitis death in clinical trials). 5
• Real-world data suggest pneumonitis incidence may be higher (10.7%) than in clinical trials. 7

Treatment Duration and Line of Therapy

• Continue osimertinib until disease progression or unacceptable toxicity. 2
• Osimertinib demonstrates similar efficacy when used as second-line vs third-/later-line therapy (median PFS 14.5 vs 11.0 months, P = 0.327). 7
• The PFS achieved with prior first-generation EGFR TKI independently predicts osimertinib outcomes (HR 0.98,95% CI 0.97-1.00, P = 0.009). 4

Management After Osimertinib Failure

When osimertinib fails, comprehensive molecular profiling with next-generation sequencing is essential to identify resistance mechanisms. 1

• On-target EGFR mutations (C797S, L718Q, L792F, G796S) occur in ~15% after first-line osimertinib. 1
• Off-target mechanisms include MET amplification (10-15%), HER2 amplification, and histologic transformation (12-15%). 1
• Standard platinum-based chemotherapy remains the default option, but enrollment in clinical trials targeting specific resistance mechanisms should be prioritized. 1