Clinical Significance of EGFR Amplification in Patients with EGFR -Mutated Metastatic Non–Small Cell Lung Cancer Receiving First-line Osimertinib

PURPOSE: With rapidly expanding treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), identifying biomarkers that may assist in treatment selection is critical. The impact of EGFR amplification (EGFRAMP) on outcomes to osimertinib is currently unknown. EXPERIMENTAL DESIGN: Patients with metastatic EGFR-mutated NSCLC who received first-line osimertinib and had undergone baseline next-generation sequencing (NGS) that included assessment of EGFRAMP were included. EGFRAMP was defined as an EGFR copy number (CN) ≥6. RESULTS: Among 473 patients, 81 (17.1%) had EGFRAMP. Compared with patients with non-amplified EGFR (EGFRNon-AMP; n = 392), they frequently had TP53 comutations (80% vs. 55.4%, P < 0.001) and brain (50.6% vs. 34.3%, P = 0.008), liver (25.9% vs. 13.5%, P = 0.009), and bone (65.4% vs. 51.3%, P = 0.028) metastases. When treated with osimertinib, patients with EGFRAMP achieved a similar objective response rate (88% vs. 83%, P = 0.23) but shorter median progression-free survival [PFS; 11.6 vs. 19 months, hazard ratio (HR), 1.77; P < 0.0001] and overall survival (OS; 34 vs. 40.1 months; HR, 1.40; P = 0.040). EGFRAMP was consistently associated with worse PFS regardless of TP53 comutations; however, EGFRAMP was associated with worse PFS and OS in patients with EGFR exon 19 deletion, but not in those with EGFR L858R. Within EGFRAMP cases, a higher EGFR CN and the amplification of the mutant allele, as opposed to wild-type amplification, correlated with inferior outcomes. Among patients reassessed with NGS after osimertinib resistance (n = 113), those with baseline EGFRAMP more frequently showed acquired MET alterations (29% vs. 12%, P = 0.04). CONCLUSIONS: EGFR AMP correlates with distinct characteristics and worse outcomes to osimertinib monotherapy among patients with EGFR-mutated NSCLC.