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MET inhibitors have shown promising efficacy for MET-dysregulated non-small cell lung cancer (NSCLC). However, quite a few patients cannot benefit from it due to the lack of powerful biomarkers. This study aims to explore the potential role of plasma proteomics-derived biomarkers for patients treated with MET inhibitors using mass spectrometry. We analyzed the plasma proteomics from patients with MET dysregulation (including MET amplification and MET overexpression) treated with MET inhibitors. Thirty-three MET-dysregulated NSCLC patients with longitudinal 89 plasma samples were included. We classified patients into the PD group and non-PD group based on clinical response. The baseline proteomic profiles of patients in the PD group were distinct from those in the non-PD group. Through protein screening, we found that a four-protein signature (MYH9, GNB1, ALOX12B, HSD17B4) could predict the efficacy of patients treated with MET inhibitors, with an area under the curve (AUC) of 0.93, better than conventional fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) tests. In addition, combining the four-protein signature with FISH or IHC test could also reach higher predictive performance. Further, the combined signature could predict progression-free survival for MET-dysregulated NSCLC (p < 0.001). We also validated the performance of the four-protein signature in another cohort of plasma using an enzyme-linked immunosorbent assay. In conclusion, the four plasma protein signature (MYH9, GNB1, ALOX12B, and HSD17B4 proteins) might play a substitutable or complementary role to conventional MET FISH or IHC tests. This exploration will help select patients who may benefit from MET inhibitors.

BackgroundMETamplification plays an important role in the development of non-small-cell lung cancer (NSCLC) either de novo or in resistance to epidermal growth factor receptor tyrosine–kinase inhibitor (EGFR-TKI) settings. Fluorescence in situ hybridization (FISH) is the standard method forMETamplification. With more and more discoveries of oncogenic driver genes, next-generation sequencing (NGS) plays a significant role in precision oncology. Meanwhile, the role of NGS inMETamplification remains uncertain.MethodsForty patients diagnosed with advanced NSCLC were included. FISH and NGS were conducted prior to MET inhibitors treatment.METamplification by FISH was defined as a MET/CEP7 ratio of > 2.0 and/or copy number (CN) > 5.METamplification by NGS was defined as gene copy number (GCN) ≥ 5.ResultsThe concordance rate among FISH and NGS was 62.5% (25/40).METamplification identified by FISH showed the optimal predictive value. The partial response (PR) rate was 68.0% (17/25 withMETamplification) vs. 6.7% (1/15 withoutMETamplification); the median progression-free survival (PFS) was 5.4 months versus 1.0 months (P METamplification identified by NGS failed to distinguish significant clinical outcomes. The PR rate was 60.0% (6/10, withMETGCN ≥ 5) vs. 40.0% (12/30, withMETGCN ConclusionsMETamplification identified by FISH remains the optimal biomarker to identify suitable candidates for MET-TKI therapy. In comparison, amplification identified by NGS seems not as robust to be effective predictive biomarker. Further exploration is needed regarding the focal amplification by NGS in predicting the efficacy.

e20672 Background: Retinoblastoma transcriptional corepressor 1 (RB1) mutation is strikingly more frequent in non-small cell lung cancer (NSCLC) with SCLC transformation (SCLC-T) than that remain NSCLC. However, NSCLC patients harboring RB1 mutations do not necessarily transform to SCLC. Thus, exploring RB1 mutation frequency and co-occurring genomic alterations is potentially important to understand the SCLC-T mechanism. Methods: We investigated 47 NSCLC pts with RB1 aberrations at our institution. Submitted samples (tissue, plasma, cerebrospinal fluid and pleural effusion) were analyzed using next-generation sequencing across at least 139 genes (139-520). Demographics, molecular features and outcomes were analyzed. Results: Among 47 pts (27F/20M), median age was 58. Twenty (47%) had brain metastases and 7 (15%) underwent SCLC-T. A total of 39 types of RB1 mutations were identified, in which copy number deletion is the most common (40%). RB1 mutations were present from early NSCLC and were detected in 88%(29/33), 82%(9/11), 70%(9/13) and 42% (20/48) of tissue, pleural effusion, CSF and plasma samples, respectively. The most frequent co-occurring alterations were TP53 (100%, 95%) and EGFR (100%, 93%) in both SCLC-T group and non-transformed group. Besides, mutations involving in the PI3K pathway were often detected: PIK3CA (57%, 20%), AKT (43%, 10%), PTEN (14%, 15%), MET (14%, 15%), NTRK1 (14%, 13%). Notably, RB1 also co-occurred with ALK fusion (1/47). Moreover, SCLC-T group harbored significant higher frequency of RB1 mutation compared with non-transformed group. Conclusions: RB1 mutations in NSCLC are associated with a trend toward SCLC-T, and the mechanisms may be increased frequency of RB1 mutations and co-occurring similar molecular alterations to those in SCLC.