Cetuximab Responsiveness in Patients with Non-Small Cell Lung Cancer and EGFR Exon 20 Insertion Alterations

Epidermal Growth Factor Receptor (EGFR) exon 20 insertion alterations represent 4%-10% of all EGFR mutations in Non-Small Cell Lung Cancer (NSCLC) and result in resistance to standard EGFR-directed therapies. EGFR exon 20 insertions restrict the size of the kinase pocket, prohibiting the entry of approved EGFR kinase inhibitor drugs. Structural In Silico modeling also predicts that EGFR exon 20 insertion anomalies increase attractive electrostatic dimerization, hence stabilizing the activating dimer configuration. EGFR antibodies such as cetuximab that interfere with dimerization may lead to responses. We identified three non-smoking patients with NSCLC and EGFR exon 20 insertions treated with cetuximab-based therapy. All three patients demonstrated clinical benefit. A 58-year-old woman achieved prolonged stable disease lasting 9 months, while a 76-year-old woman and 38-year-old man maintained a partial response with progression-free survivals of 13 months and 32 months, respectively. In conclusion, cetuximab merits further investigation as it appears to be an additional promising therapy for overcoming EGFR exon 20 insertion-related resistance.