Ryan D Gentzler, MD, Sharma, Nitya, PhD, Mitra, Akash, PhD, Ben-Shachar, Rotem, PhD, Stein, Michelle M., PhD, Guinney, Justin PhD, Nimeiri, Halla, MD, Iams, Wade, MD, Aggarwal, Charu, MD, Jyoti Patel, MD
MET copy-number amplifications (CNAs) are implicated as a resistance mechanism in patients treated with EGFR-targeted tyrosine kinase inhibitors and are associated with poor outcomes. However, data are limited on associations of immune biomarker and clinical outcomes among patients with sporadic MET CNAs — defined as preceding first-line (1L) therapy. This is the first real-world dataset to assess the prevalence of sporadic MET amplifications and their association with real-world clinical outcomes.
We analyzed a de-identified, multimodal dataset of 3,998 NSCLC patients biopsied prior to or within 30 days after the start of 1L therapy. Samples underwent NGS testing with Tempus xT (DNA-seq of 595-648 genes, 500x coverage). MET CNAs were identified using a CN threshold of ≥ 4 copies and compared to patients that were copy-number neutral (CN-N); patients with MET exon14 skipping mutations were excluded.
The prevalence of sporadic MET CNAs in NSCLC patients was 5.7% (n=227). Patients with MET CNAs were more likely to harbor EGFR mutations compared to CN-N patients (17.6% vs 12.3%; p=0.02). In the subset of EGFR mutation-negative patients with PD-L1 data (n=2,230), a higher proportion of patients with MET CNAs were PD-L1-H (tumor proportion score ≥ 50%) compared to MET CN-N patients (45% vs 25.9%; p<0.001). Amongst EGFR mutation-negative patients (n=3,494), MET CNA-H patients were significantly enriched for High Tumor Mutational Burden (TMB-H, ≥ 10 Mut/Mb) compared to CN-N patients (21.4% vs 13.5%, p=0.004). In the subset of EGFR mutation-negative patients treated with 1L immune checkpoint inhibitors (ICIs, n=1,464); there was no significant difference in rwOS for patients with MET CNAs (median OS 21.5 months) vs CN-N patients (median OS 16.5 months), (HR=0.81, CI=[0.57, 1.14], p=0.22).
The majority of treatment-naive patients with sporadic MET CNAs are EGFR mutation-negative and enriched with biomarkers that are predictive of immune therapy benefit (PD-L1-H and TMB-H). Future clinical trials evaluating MET targeted therapy should account for this genomic heterogeneity and immunogenic therapeutic potential.