What is the treatment regimen for non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertion mutations using Amivantamab (amivantamab) and Lazertinib (lazertinib)?

Treatment Regimen for NSCLC Patients with EGFR Exon 20 Insertion Mutations Using Amivantamab and Lazertinib

For patients with NSCLC harboring EGFR exon 20 insertion mutations, amivantamab plus carboplatin and pemetrexed is the preferred first-line treatment, while amivantamab monotherapy is recommended after progression on platinum-based chemotherapy. 1

First-line Treatment

Recommended Regimen

• Amivantamab plus carboplatin and pemetrexed (Category 1, preferred) 1
  • Dosing: Amivantamab 1050 mg IV (1400 mg if ≥80 kg) with standard doses of carboplatin and pemetrexed
  • Schedule: Every 3 weeks

Evidence Supporting First-line Use

The PAPILLON phase III randomized trial demonstrated superior efficacy of amivantamab plus chemotherapy compared to chemotherapy alone:

• Median PFS: 11.4 months vs 6.7 months (HR 0.40, p<0.001) 1, 2
• Overall response rate: 73% vs 47% 2
• 18-month PFS rate: 31% vs 3% 2
• Interim OS analysis showed a trend toward improved survival (HR 0.67, p=0.11) 1

Second-line Treatment

For Patients Who Progress After Platinum-based Chemotherapy

• Single-agent amivantamab 1
  • For patients who have not previously received amivantamab
  • Based on the CHRYSALIS phase I study showing:
    • Overall response rate of 40%
    • Median PFS of 8.3 months 1

For Patients Who Progress After First-line Amivantamab Plus Chemotherapy

• Standard subsequent therapy options as per NCCN guidelines NSCL-K 4 of 5 1

Amivantamab Plus Lazertinib Combination

This combination is primarily studied in patients with common EGFR mutations (exon 19 deletion or L858R) who have progressed on osimertinib and platinum-based chemotherapy:

• CHRYSALIS-2 cohort A results for amivantamab plus lazertinib in this population:

  • Investigator-assessed ORR: 28% 3
  • Independent review-assessed ORR: 35% 3
  • Median duration of response: 8.3 months 3
  • Median PFS: 4.5 months 3
  • Median OS: 14.8 months 3

• PALOMA-3 study compared subcutaneous vs intravenous amivantamab (both with lazertinib):

  • Similar efficacy between formulations
  • Subcutaneous administration showed significantly fewer infusion-related reactions (13% vs 66%) 4
  • Subcutaneous administration demonstrated improved OS (HR 0.62, p=0.02) 4

Adverse Events Management

Common Adverse Events

• EGFR-related toxicities: Rash (81%), paronychia (52%) 3
• Infusion-related reactions: 68% with IV administration, 13% with subcutaneous 4
• Hematologic effects with combination chemotherapy 1
• Other: Hypoalbuminemia, hypokalemia 1, 3

Management Strategies

• Premedication before infusions to reduce infusion reactions
• Dose modifications for severe skin reactions
• Consider subcutaneous administration when available to reduce infusion reactions 4
• Monitor for electrolyte abnormalities, particularly hypokalemia

Important Considerations

1. Avoid immunotherapy: Data indicate that immune checkpoint inhibitor monotherapy has low activity in NSCLC with EGFR alterations 1

2. Resistance mechanisms: Upon progression, consider re-biopsy or liquid biopsy to determine resistance mechanisms 5

3. Response evaluation: CT scans after 2 cycles of treatment and then every 2-4 cycles 5

4. Formulation considerations: Subcutaneous amivantamab (when available) offers significant advantages over IV administration with:

   • Shorter administration time (4.8 minutes vs 5 hours)
   • Fewer infusion-related reactions
   • Higher patient convenience ratings 4

The treatment landscape for EGFR exon 20 insertion mutations has evolved significantly, with amivantamab-based regimens demonstrating substantial clinical benefit in this historically difficult-to-treat population.