Clinical Significance of EGFR Amplification in Patients with EGFR-Mutated Metastatic Non-Small Cell Lung Cancer Receiving First-line Osimertinib.
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Di Federico Alessandro, Pecci Federica, Jeng Mark, Peroni Marianna, Marinelli Daniele, Leonetti Alessandro, Stumpo Sara, Mantuano Francesco, Zannini Irene, Gariazzo Eleonora, Makarem Maisam, Pupo Amanda, Lo Bianco Francesca, De Giglio Andrea, de Biase Dario, Altimari Annalisa, Gruppioni Elisa, Minari Roberta, Verzè Michela, Repetto Matteo, Sperandi Francesca, Melotti Barbara, Gelsomino Francesco, Landi Lorenza, Giammaruco Maristella, Scalera Stefano, Cipriani Laura, Maugeri-Saccà Marcello, Calonaci Nicola, Caravagna Giulio, Ricciuti Biagio, Sholl Lynette M, Yang Soo Ryum, LoPiccolo Jaclyn, Rotow Julia K, Awad Mark M, Cappuzzo Federico, Tiseo Marcello, Yu Helena A, Jänne Pasi A, Ardizzoni Andrea
Аннотация
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.