When should combination osimertinib (osimertinib) with chemotherapy be given to a patient with stage 4 non-small cell lung cancer (NSCLC) and an epidermal growth factor receptor (EGFR) exon 19 deletion who has progressed on osimertinib (osimertinib) monotherapy?

When to Give Combination Osimertinib with Chemotherapy

Combination osimertinib with chemotherapy should be given as first-line treatment for patients with EGFR-mutated (exon 19 deletion or L858R) advanced NSCLC, particularly those with CNS metastases or L858R mutations, based on the FLAURA2 trial showing superior overall survival (47.5 vs 37.6 months) and progression-free survival (25.5 vs 16.7 months) compared to osimertinib monotherapy. 1, 2

First-Line Treatment Setting

The NCCN 2024 guidelines now include osimertinib plus pemetrexed and platinum (cisplatin or carboplatin) as a Category 1 "other recommended" first-line option for nonsquamous EGFR-mutated NSCLC. 2

Specific Patient Populations That Benefit Most:

• Patients with CNS metastases at baseline: Median PFS was 24.9 months with combination versus 13.8 months with osimertinib alone 2
• Patients with L858R exon 21 mutations: Median PFS was 24.7 months with combination versus 13.9 months with osimertinib alone 2
• Patients with high disease burden or multiple metastatic sites 2, 1

Trade-offs to Discuss:

The combination increases grade ≥3 adverse events (64-70% vs 27-34% with monotherapy), primarily driven by chemotherapy-related toxicities including neutropenia, thrombocytopenia, and anemia. 2, 1 However, these are reversible and manageable. 1

Most patients should still receive osimertinib monotherapy as the preferred first-line option, with combination therapy reserved for selected high-risk patients after discussing benefits and toxicities. 2, 3

After Progression on First-Line Osimertinib

If a patient progresses on first-line osimertinib monotherapy, continuing osimertinib with chemotherapy in the second-line setting is associated with superior outcomes compared to chemotherapy alone. 4

Evidence for Osimertinib Continuation:

• Median PFS: 10.1 months with osimertinib plus chemotherapy versus 5.9 months with chemotherapy alone (HR 0.48, P <.001) 4
• Median OS: 17.0 months versus 12.8 months (HR 0.64, P = 0.018) 4
• This benefit is most pronounced in patients with EGFR exon 19 deletions 4

Alternative Second-Line Options:

For patients with symptomatic systemic progression and multiple lesions after osimertinib, amivantamab plus carboplatin and pemetrexed is the NCCN Category 1 preferred option (nonsquamous histology). 2, 3

• Median PFS: 6.3 months with amivantamab plus chemotherapy versus 4.2 months with chemotherapy alone (HR 0.48, P <.001) 2
• Objective response rate: 64% versus 36% 2
• No OS benefit demonstrated yet in interim analysis 2

Clinical Decision Algorithm

First-Line Treatment:

1. Standard approach: Osimertinib monotherapy 80 mg daily 3
2. Consider combination (osimertinib + pemetrexed + platinum):
   • CNS metastases present at baseline 2
   • L858R mutation (versus exon 19 deletion) 2
   • High disease burden with multiple metastatic sites 2
   • Patient willing to accept higher toxicity for improved survival 1

After Progression on First-Line Osimertinib:

1. Rebiopsy to rule out small cell transformation (~5% of cases) 2, 3
2. For symptomatic systemic progression with multiple lesions:
   • Preferred: Amivantamab plus carboplatin/pemetrexed (nonsquamous) 2, 3
   • Alternative: Continue osimertinib plus platinum doublet chemotherapy 4
3. For oligometastatic disease (1-3 sites): Consider definitive local therapy (SABR or surgery) with continued systemic therapy 3

Critical Pitfalls to Avoid

• Do not use PD-1/PD-L1 inhibitors in EGFR-mutated NSCLC: They show inferior efficacy regardless of PD-L1 expression 2, 3
• Avoid osimertinib within 3 months of immune checkpoint inhibitors: Risk of pneumonitis is significantly increased 2
• Screen for QTc prolongation: Patients with baseline QTc >470 msec should not receive osimertinib 5
• Monitor for interstitial lung disease/pneumonitis: Occurs in 3.9-56% of patients, with rare fatal events 5
• Discontinue or substitute QT-prolonging medications before starting osimertinib 5

Third-Line and Beyond

For heavily pretreated patients who have progressed on osimertinib and chemotherapy, osimertinib plus chemotherapy combination can be considered with median duration of treatment of 6.1 months with platinum doublet and 2.6 months with single-agent chemotherapy. 6 This approach showed favorable CNS disease control with only 24% experiencing CNS progression. 6