Can Amivantamab (amivantamab) be used to treat a patient with non-small cell lung cancer (NSCLC) and an exon 20 mutation in the epidermal growth factor receptor (EGFR) gene?

Amivantamab for EGFR Exon 20 Insertion Mutations in NSCLC

Yes, amivantamab is FDA-approved and strongly recommended for patients with NSCLC harboring EGFR exon 20 insertion mutations, with specific indications depending on treatment line and prior therapies. 1

First-Line Treatment (Treatment-Naïve Patients)

Amivantamab combined with carboplatin and pemetrexed is the preferred Category 1 first-line treatment option for advanced or metastatic nonsquamous NSCLC with EGFR exon 20 insertions. 2

Supporting Evidence:

• The PAPILLON phase III trial demonstrated superior efficacy with amivantamab plus chemotherapy versus chemotherapy alone in 308 treatment-naïve patients 2, 3
• Median progression-free survival: 11.4 months (combination) vs 6.7 months (chemotherapy alone); HR 0.40, P < 0.001 2, 4, 3
• Objective response rate: 73% vs 47% (rate ratio 1.50, P < 0.001) 3
• At 18 months, 31% of patients on combination therapy remained progression-free compared to only 3% on chemotherapy alone 3

Second-Line Treatment (Post-Platinum Chemotherapy)

Amivantamab monotherapy is FDA-approved and recommended for patients whose disease has progressed on or after platinum-based chemotherapy. 2, 1

Supporting Evidence:

• The CHRYSALIS phase I study evaluated 81 patients with EGFR exon 20 insertion-positive metastatic NSCLC who received one or more prior lines of therapy 2, 4, 5
• Overall response rate: 40% (including 3 complete responses) 2, 4, 5
• Median progression-free survival: 8.3 months 2, 4
• Median duration of response: 11.1 months (95% CI 6.9 to not reached) 5

Dosing Considerations

The recommended dosage is weight-based and administered intravenously 1:

For combination with carboplatin-pemetrexed:

• Patients <80 kg: 1,400 mg weekly for weeks 1-4, then 1,750 mg every 3 weeks starting week 7 1
• Patients ≥80 kg: 1,750 mg weekly for weeks 1-4, then 2,100 mg every 3 weeks starting week 7 1

For monotherapy:

• Patients <80 kg: 1,050 mg weekly for weeks 1-5, then every 2 weeks starting week 7 1
• Patients ≥80 kg: 1,400 mg weekly for weeks 1-5, then 1,400 mg every 2 weeks starting week 7 1

Critical Safety Considerations

Infusion-Related Reactions

• Occur in 66% of patients receiving IV amivantamab 2, 4
• Administer via peripheral line on weeks 1 and 2 to reduce risk 1
• The initial dose should be split between Day 1 and Day 2 of week 1 1
• Premedications are required 1

Common Adverse Events

• Cutaneous reactions (86% of patients): rash, paronychia, acneiform dermatitis 2, 4, 5
• Hematologic effects when combined with chemotherapy 2
• Grade 3-4 events: hypokalemia (5%), pulmonary embolism (4%), neutropenia (4%), diarrhea (4%), rash (4%) 2, 5

Important Warnings

• Interstitial lung disease/pneumonitis: immediately withhold if suspected and permanently discontinue if confirmed 1
• Can cause severe rash including toxic epidermal necrolysis 1
• Embryo-fetal toxicity: verify pregnancy status before initiating; females of reproductive potential must use effective contraception during treatment and for 3 months after last dose 1

Key Clinical Pitfalls to Avoid

Do not use early-generation EGFR TKIs (erlotinib, gefitinib, afatinib) for EGFR exon 20 insertions - these mutations exhibit inherent resistance to approved tyrosine kinase inhibitors 2, 5

Do not rely on immunotherapy alone - response rates to immunotherapy regimens vary (0%-25%) depending on the specific EGFR exon 20 insertion mutation, and these tumors generally have low tumor mutational burden 2

Ensure proper molecular testing - NGS assay should be prioritized for exon 20 insertion analysis to allow broader detection and characterization, as some commercial allele-specific PCR testing solutions have limited or no coverage 2

Brain Metastases Considerations

• Amivantamab has limited CNS penetration due to its large molecular size as a bispecific antibody 6
• In the CHRYSALIS study, intracranial-only progression occurred in 11% of patients 7
• Stereotactic radiosurgery while continuing amivantamab appears feasible and tolerable (median 4.0 additional months of treatment post-SRS) 7
• The most common first sites of progression were lungs/pleura (29%), bone (21%), brain (15%), and lymph nodes (12%) 7

Treatment After Progression

For patients who progress on first-line amivantamab plus chemotherapy, subsequent therapy options include standard chemotherapy regimens per NCCN guidelines. 2

For patients who received platinum chemotherapy first and then progress on amivantamab monotherapy, 35% continued amivantamab after progression for a median of 4.2 additional months (range 1.0-12.5), suggesting potential benefit in selected patients with oligoprogression. 7