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 EGFR-mutated non-small cell lung cancer (NSCLC), identifying biomarkers that may assist 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 ≥6. Results: Among 473 patients, 81 (17.1%) had EGFRAMP. Compared to patients with non-amplified EGFR (EGFRNon-AMP) (n=392), they frequently had TP53 co-mutations (80.0% 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 metastasis (65.4% vs 51.3%, p=0.028). When treated with osimertinib, patients with EGFRAMP achieved similar objective response rate (88% vs 83%, p=0.23), but shorter median progression-free survival (PFS) (11.6 vs 19.0 months, HR 1.77, p<0.0001) and overall survival (OS) (34.0 vs 40.1 months, HR 1.40, p=0.040). EGFRAMP was consistently associated with worse PFS regardless of TP53 co-mutations; however, EGFRAMP was associated with worse PFS and OS in patients with EGFR ex19del, but not in those with EGFR L858R. Within EGFRAMP cases, a higher EGFR copy number 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: EGFRAMP correlates with distinct characteristics and worse outcomes to osimertinib monotherapy among patients with EGFR-mutated NSCLC.