What is the recommended treatment and dosing for a patient with non‑small‑cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) T790M resistance mutation?

EGFR T790M Mutation-Positive NSCLC: Treatment Recommendations

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

Mandatory Pre-Treatment Testing

• All patients with clinical resistance to first- or second-generation EGFR TKIs (erlotinib, gefitinib, afatinib) must be tested for T790M mutation status before selecting therapy. 1, 2
• Use liquid biopsy (plasma ctDNA) as the initial test; if negative, perform tissue re-biopsy when feasible. 2
• T790M mutations occur in approximately 50-60% of patients who develop resistance to first-generation TKIs. 1
• Testing must be performed using an FDA-approved assay or validated laboratory test in a CLIA-approved facility. 2

Osimertinib Efficacy and Dosing

Standard Dosing

• Osimertinib 80 mg orally once daily until disease progression or unacceptable toxicity. 2, 3

Clinical Outcomes

• Objective response rate: 71% with osimertinib versus 31% with platinum-pemetrexed chemotherapy (OR 5.39,95% CI 3.46-8.48; P < 0.001). 1, 2
• Median progression-free survival: 10.1-10.2 months with osimertinib versus 4.4 months with chemotherapy (HR 0.30,95% CI 0.23-0.41; P < 0.0001). 1, 2
• Median overall survival: 26.8 months (95% CI 24.0-29.1 months) in pooled phase 2 data. 4
• Disease control rate: approximately 93% (95% CI 90%-96%). 2

Safety Profile

• Grade ≥3 adverse events occur in 23% of patients with osimertinib versus 47% with chemotherapy. 1, 2
• Most common adverse events: diarrhea (39-43%), rash (40-42%), dry skin, and paronychia—all predominantly grade 1-2. 2, 4, 5
• Serious but rare events include interstitial lung disease/pneumonitis (4%), QTc prolongation, and cardiomyopathy. 4, 5

Special Populations

Brain Metastases (Category 1 Recommendation)

• Osimertinib is specifically recommended for T790M-positive patients with symptomatic brain metastases. 1, 2
• Among patients with CNS metastases, median PFS was 8.5 months with osimertinib versus 4.2 months with platinum-pemetrexed (HR 0.32,95% CI 0.21-0.49). 1, 2
• For intracranial progression on standard-dose osimertinib, deliver stereotactic radiosurgery while continuing osimertinib, or consider dose escalation to 160 mg daily if accessible. 2

Leptomeningeal Disease

• Osimertinib 160 mg daily is the preferred dose for leptomeningeal carcinomatosis, based on BLOOM study data demonstrating good anticancer activity. 2

Treatment for T790M-Negative Patients

Standard Approach

• For patients who test negative for T790M mutation after progression on EGFR TKIs, platinum-based doublet chemotherapy is the standard of care. 1, 2
• The IMPRESS trial established that continuing EGFR TKI with chemotherapy provides no benefit (response rates 32% vs 34%, median PFS 5.4 months in both groups). 1, 2

Alternative Options

• Combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel may be considered in non-squamous NSCLC patients with performance status 0-1 after targeted therapies are exhausted (Level IV, C evidence). 1, 2
• 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). 2

Critical Pitfall

• Checkpoint inhibitor monotherapy shows poor efficacy in EGFR-mutant patients, with response rates of only 3.6% versus 23% in EGFR wild-type patients, regardless of PD-L1 status. 2, 6

Management After Osimertinib Failure

Molecular Profiling

• Comprehensive next-generation sequencing is essential to identify resistance mechanisms when osimertinib fails. 1, 2, 7
• On-target EGFR mutations (e.g., C797S) occur in approximately 15% after first-line osimertinib. 2, 7
• Off-target mechanisms include MET amplification (15-30%), HER2 amplification, and histologic transformation (12-15%). 2, 7, 8

Treatment by Resistance Mechanism

• MET amplification: Amivantamab combined with carboplatin and pemetrexed is the preferred regimen (Category 1). 7
• Small-cell transformation: Treat with carboplatin plus etoposide; transformation can only be confirmed on tissue biopsy. 7
• No targetable mechanism: Standard platinum-based doublet chemotherapy ± bevacizumab, yielding approximately 30% objective response rate and median PFS of 5-6 months. 7
• On-target EGFR alterations (e.g., C797S): No approved targeted agents; enroll patients in clinical trials of next-generation EGFR inhibitors. 7

Continuation Beyond Progression

Oligoprogression

• For oligoprogression (1-3 sites), continue osimertinib at standard dose and add local ablative therapy (surgery, stereotactic body radiation, or radiofrequency ablation) to progressing lesions (Category 1). 1, 7
• For isolated CNS oligoprogression, treat brain lesions with stereotactic radiosurgery while maintaining osimertinib. 7

Slow/Indolent Progression

• For asymptomatic, RECIST-defined radiological progression, maintain osimertinib 80 mg daily. 1, 7
• Optional dose escalation to 160 mg daily may be used in selected patients, but it is not standard of care. 7

Critical Immunotherapy Contraindications

• Never use PD-1/PD-L1 inhibitor monotherapy in EGFR-mutant NSCLC, as it shows inferior efficacy regardless of PD-L1 expression. 2, 6
• Avoid osimertinib within 3 months of immune checkpoint inhibitors due to significantly increased risk of pneumonitis (approximately 38%). 1, 6
• Do not continue osimertinib together with chemotherapy at progression; IMPRESS trial data showed no PFS or OS benefit. 1, 7

Alternative Third-Generation TKIs

• In Asian countries where approved, alternative third-generation TKIs include almonertinib, lazertinib, and alflutinib. 2
• Rociletinib development was discontinued after FDA Oncologic Drugs Advisory Committee recommended against accelerated approval due to lower-than-expected response rates (28-34% vs initially reported 59%). 1