Clinical significance of EGFR amplification in patients with EGFR-mutated metastatic non-small cell lung cancer receiving first-line osimertinib.

Abstract

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. 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. 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). EGFRAMP correlates with distinct characteristics and worse outcomes to osimertinib monotherapy among patients with EGFR-mutated NSCLC.