What are the recommended management options after disease progression on first‑line osimertinib in a patient with EGFR‑mutated non‑small cell lung cancer?

Management After Osimertinib Progression in EGFR-Mutant NSCLC

The first critical step after osimertinib progression is to perform tissue rebiopsy (preferred) or liquid biopsy using next-generation sequencing to identify the specific resistance mechanism, which will determine whether you pursue targeted therapy, chemotherapy, or local ablative approaches. 1

Initial Assessment: Pattern of Progression

Your management strategy depends entirely on the pattern of disease progression:

Oligoprogression (1-3 Sites)

• Continue osimertinib and add local ablative therapy (surgery, stereotactic body radiation therapy, or radiofrequency ablation) to the progressing sites. 1
• For isolated CNS oligoprogression, use stereotactic radiosurgery while maintaining osimertinib. 1
• For leptomeningeal involvement or non-SRS candidates, consider whole-brain radiotherapy if symptomatic, while continuing osimertinib. 1

Slow/Minor Progression

• Continue osimertinib at standard dose (80 mg daily) if the patient remains asymptomatic with indolent radiological progression between stable disease and progressive disease by RECIST criteria. 1
• Consider dose escalation to 160 mg daily as an alternative strategy, though this remains optional rather than standard. 1

Symptomatic Systemic Progression with Multiple Lesions

• Stop osimertinib and proceed immediately to molecular profiling to guide next treatment. 1

Molecular Profiling to Guide Treatment Selection

Obtain comprehensive next-generation sequencing (NGS preferred) on tissue rebiopsy or liquid biopsy to identify one of four resistance patterns: 1

1. MET Amplification (15-30% of cases)

• Amivantamab plus carboplatin and pemetrexed is the preferred regimen (Category 1 recommendation), achieving median PFS of 6.3 months versus 4.2 months with chemotherapy alone and objective response rate of 64% versus 36%. 2
• This represents one of the two most actionable resistance mechanisms on repeat biopsy. 1

2. Histological Transformation (12-15% of cases)

• Small-cell transformation: Treat with carboplatin plus etoposide chemotherapy; whether to continue osimertinib concurrently remains unknown and is under investigation. 1
• Squamous transformation: Use histology-appropriate chemotherapy for squamous cell carcinoma. 1
• Note that small-cell transformation can only be detected with tissue biopsy, not liquid biopsy. 1

3. On-Target EGFR Alterations (10-20% of cases)

• EGFR C797S mutations and other resistant EGFR mutations fall into this category. 1
• Enroll in clinical trials with next-generation EGFR inhibitors when available; no standard targeted therapy currently exists for these mutations. 1, 3

4. No Targetable Mechanism Identified (40-50% of cases)

• Platinum-based chemotherapy with or without bevacizumab is the standard treatment, with expected response rates of approximately 30% and median PFS of 5-6 months. 1
• Atezolizumab plus bevacizumab plus platinum-based chemotherapy may be considered as an alternative option based on IMpower-150 subgroup data showing OS improvement (HR 0.60; 95% CI 0.31-1.14) in EGFR-mutant patients, though this was a small subgroup (n=58). 1
• The ORIENT-31 trial showed sintilimab plus bevacizumab and chemotherapy achieved median PFS of 6.9 versus 4.3 months (HR 0.46; 95% CI 0.33-0.63; P<0.0001), though this was conducted in a Chinese population. 1

Critical Pitfalls to Avoid

• Never use immune checkpoint inhibitor monotherapy in EGFR-mutant NSCLC, as it shows markedly inferior efficacy with response rates of only 3.6% versus 23% in EGFR wild-type patients, regardless of PD-L1 expression. 1, 4, 5
• Do not administer osimertinib within 3 months of immune checkpoint inhibitors due to significantly increased risk of pneumonitis (approximately 38% incidence). 1, 4
• Do not continue osimertinib with chemotherapy at progression based on IMPRESS trial data showing no improvement in PFS or OS with continuation of first-generation EGFR TKIs plus chemotherapy; while osimertinib has a different profile, extrapolation suggests this strategy lacks evidence. 1

Special Consideration: EGFR TKI Rechallenge

• Osimertinib rechallenge may be considered if the patient has been off EGFR TKIs for ≥6 months, has no targetable resistance mechanisms identified, and particularly for isolated CNS progression. 1
• Use standard dose of 80 mg daily for rechallenge. 1
• This strategy is based on limited evidence (Level III, Grade C) and should only be pursued when molecular-driven clinical trials are unavailable. 1

Algorithm Summary

1. Determine progression pattern → Oligoprogression = local therapy + continue osimertinib; Slow progression = continue osimertinib; Systemic progression = stop osimertinib
2. Obtain NGS profiling (tissue preferred, liquid if tissue unavailable) → If liquid biopsy negative, attempt tissue biopsy when feasible 5
3. Match treatment to mechanism:
   • MET amplification → Amivantamab + carboplatin + pemetrexed
   • Small-cell transformation → Carboplatin + etoposide
   • No targetable mechanism → Platinum doublet ± bevacizumab or atezolizumab + bevacizumab + chemotherapy
   • Off TKI ≥6 months with no target → Consider osimertinib rechallenge
4. Prioritize clinical trial enrollment whenever molecular profiling identifies resistance mechanisms without established targeted therapies 1, 3