203P - Genomic characterization of sporadic MET amplified non-small cell lung cancer (NSCLC) and association with real-world outcomes

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Tempus Labs, Inc.

Funding

Tempus Labs, Inc.

Disclosure

R.D. Gentzler: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda, Gilead, Janssen, Mirati, Daiichi Sankyo, Sanofi, Oncocyte, Jazz Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Clinical Care Options, OncLive, Targeted Oncology, Society for Immunotherapy of Cancer (SITC); Financial Interests, Institutional, Local PI: Janssen, Mirati, Daiichi Sankyo, Bristol Myers Squibb, AstraZeneca, Jounce Therapeutics, Takeda, Bristol Myers Squibb, Merck, Chugai, Amgen; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Coordinating PI: Mirati; Non-Financial Interests, Leadership Role: Hoosier Cancer Research Network; Non-Financial Interests, Principal Investigator: NCI ETCTN; Non-Financial Interests, Other, Member of Lung Cancer Scientific Review Committee: American Society of Clinical Oncology, Scientific Review Committee; Non-Financial Interests, Other, Committee Member: NCI Investigational Drug Steering Committee; Non-Financial Interests, Officer, Associate Editor: Journal of Thoracic Oncology, ASCO Meeting Abstracts; Non-Financial Interests, Personal, Other, Travel support for attending meetings for invited speaker: International Association for the Study of Lung Cancer (IASLC). N. Sharma: Financial Interests, Personal, Full or part-time Employment: Tempus labs; Financial Interests, Personal, Stocks/Shares: Tempus labs. A. Mitra: Financial Interests, Personal, Stocks or ownership: Tempus Labs, Inc., Guardant Health. R. Ben-Shachar: Financial Interests, Personal, Stocks or ownership: Tempus Labs, Inc.; Financial Interests, Personal, Full or part-time Employment: TTempus Labs, Inc. M. Stein: Financial Interests, Personal, Full or part-time Employment: Tempus Labs. J. Guinney: Financial Interests, Institutional, Full or part-time Employment: Tempus Labs; Financial Interests, Institutional, Stocks/Shares: Tempus Labs. H. Nimeiri: Financial Interests, Full or part-time Employment: Tempus Labs, Inc.; Financial Interests, Stocks/Shares: Tempus Labs, Inc., AbbVie. W. Iams: Financial Interests, Personal, Advisory Board: Tempus, EMD Serono, Amgen, Sanofi, NovoCure, Genentech, AstraZeneca, Catalyst, Jazz Pharma, Elevation Oncology, Bristol Myers Squibb, Janssen, Takeda, Mirati, G1 Therapeutics. C. Aggarwal: Financial Interests, Personal, Advisory Board: AstraZeneca, Celgene, Genentech, Lilly, Merck, Bluprint, Daiichi/Sankyo, Sanofi, Eisai, BeiGene, Shionogi, Turning Point, Pfizer, Janssen, Boehringer Ingelheim. J. Patel: Financial Interests, Personal, Advisory Board: AstraZeneca, Takeda.