What is the next line of systemic treatment for a patient with metastatic (mets) lung adenocarcinoma, brain metastases, EGFR (epidermal growth factor receptor) Exon 19 deletion, and MET amplification who has progressed on osimertinib (osimertinib)?

Next-Line Systemic Treatment for Metastatic Lung Adenocarcinoma with Brain Metastases, EGFR Exon 19 Deletion, and MET Amplification After Osimertinib Progression

For a patient with metastatic lung adenocarcinoma harboring EGFR exon 19 deletion and acquired MET amplification who has progressed on osimertinib, the preferred next-line treatment is combination therapy with an EGFR TKI plus a MET inhibitor, specifically amivantamab plus carboplatin and pemetrexed (Category 1 recommendation for symptomatic systemic progression with multiple lesions). 1, 2

Primary Treatment Recommendation

Amivantamab plus carboplatin and pemetrexed is the Category 1 preferred option for patients with symptomatic systemic progression and multiple lesions after osimertinib failure in nonsquamous EGFR-mutant NSCLC. 2 This combination achieves:

• Median PFS of 6.3 months versus 4.2 months with chemotherapy alone (HR 0.48, P <0.001) 2
• Objective response rate of 64% versus 36% with chemotherapy alone 2

The ASCO 2024 guidelines specifically recommend this regimen (recommendation 2.2.1) for patients who have progressed on osimertinib without emergent T790M or other targetable alterations. 1

Critical Importance of MET Amplification

The presence of MET amplification fundamentally changes the treatment approach. The 2022 ESMO consensus guidelines explicitly state that acquired MET amplification is one of the two most actionable findings on repeat biopsy (occurring in 30-60% of osimertinib-resistant cases), and may be treated with a combination of an EGFR and a MET TKI. 1

Evidence for Dual EGFR/MET Inhibition:

• Preclinical data demonstrates that dual MET and ERBB inhibition (capmatinib plus afatinib) completely suppressed tumor growth in osimertinib-resistant tumors with MET amplification. 3
• A recent 2025 case report showed successful treatment with aumolertinib (third-generation EGFR-TKI) plus gumarontinib (MET-TKI) in a patient with brain metastases who had MET amplification, achieving significant radiographic improvement of brain metastases. 4

Treatment Algorithm

Step 1: Confirm Resistance Mechanism

• Perform tissue rebiopsy (preferred) or liquid biopsy to confirm MET amplification and rule out other resistance mechanisms. 1
• Tissue biopsy is essential to exclude small cell transformation (occurs in 12-15% of cases), which cannot be detected on liquid biopsy. 1

Step 2: Assess Disease Burden and Symptoms

For symptomatic systemic progression with multiple lesions:

• Initiate amivantamab plus carboplatin and pemetrexed (Category 1). 1, 2

For oligoprogression (limited sites):

• Consider local therapy (stereotactic radiosurgery for brain metastases, SBRT for extracranial sites) plus continuation of osimertinib. 1
• The 1-year cumulative incidence of local recurrence in brain is <4% for patients achieving complete or partial response to osimertinib. 5

Step 3: Brain Metastases Management

For brain metastases specifically:

• If SRS candidate: proceed with stereotactic radiosurgery. 1
• If not SRS candidate or leptomeningeal involvement: consider whole brain radiotherapy if symptomatic. 1
• The combination of aumolertinib plus gumarontinib showed particular efficacy for brain metastases in MET-amplified disease. 4

Alternative Considerations

If Amivantamab is Not Available:

Platinum-based chemotherapy (carboplatin/pemetrexed) is recommended as the standard second-line option following osimertinib progression. 1

Experimental Approach - Dual TKI Combination:

While not yet standard of care, emerging evidence supports third-generation EGFR-TKI plus MET-TKI combination for MET-amplified resistance:

• This approach directly targets both resistance mechanisms simultaneously. 3, 4
• Case reports demonstrate efficacy, particularly for CNS disease. 4

Critical Pitfalls to Avoid

Do NOT use PD-1/PD-L1 inhibitors in EGFR-mutant NSCLC, as they show inferior efficacy regardless of PD-L1 expression. 2

Do NOT use osimertinib within 3 months of immune checkpoint inhibitors due to significantly increased risk of pneumonitis. 2, 6

Do NOT assume osimertinib rechallenge will work in the presence of confirmed MET amplification without addressing the MET pathway, as this represents a bypass resistance mechanism. 1

Do NOT delay rebiopsy - the resistance mechanism must be identified to guide optimal therapy, as 30-60% of osimertinib resistance involves off-target alterations like MET amplification. 1

Monitoring During Treatment

• CT imaging every 6-12 weeks to assess response. 6
• Brain MRI at each follow-up given baseline CNS involvement. 1
• Monitor for grade ≥3 adverse events, which occur in 64-70% with amivantamab plus chemotherapy (primarily neutropenia, thrombocytopenia, anemia). 2
• Assess for pneumonitis (occurs in 3-10% of patients on osimertinib-based regimens). 6