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9043 Background: MET amplification is an important mechanism mediating acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Until now, no consensus exists on the standard treatment strategy for this subset of patients due to the lack of clinical data from large cohort or controlled trials. In our clinical practice, three regimens were commonly administered to patients after MET amplification-mediated EGFR-TKI progression: EGFR-TKI and MET-TKI combination therapy, MET-TKI monotherapy, or chemotherapy. Our study aimed to compare the effectiveness of these three regimens. Methods: Seventy patients with EGFR-mutant advanced NSCLC who progressed from prior EGFR-TKI through the acquisition of MET amplification and received treatment between March 2015 and March 2020 were included in this study. Of them, 38 received EGFR-TKI plus crizotinib, 10 received crizotinib monotherapy, and 22 received platinum-based doublet chemotherapy. Somatic mutation profiling was performed on blood and tissue biopsy samples. Resistance mechanisms to the combination targeted therapy were also explored in 12 patients. Results: The objective response rate (ORR) and disease control rate (DCR) were 47.5% and 84.0% for EGFR-TKI+crizotinib group, 40.0% and 70.0% for crizotinib monotherapy group, and 18.2% and 50.0% for chemotherapy group, respectively. The EGFR-TKI+crizotinib group had significantly better ORR (P = 0.026) and DCR (P = 0.016) than the chemotherapy group but was not statistically different from the crizotinib monotherapy group (ORR, P = 0.73; DCR, P = 0.39). Progression-free survival (PFS) was significantly longer for the EGFR-TKI+crizotinib group than those who received crizotinib monotherapy (5.0 vs 2.3 months, P = 0.004) or chemotherapy (5.0 vs 2.9 months, P = 0.036), but overall survival was comparable (10.0 vs 4.1 vs 8.5 months, P = 0.088). TP53 mutation (58.5%) and EGFR amplifications (42.9%) were the two common concurrent mutations in the three cohorts. PFS was significantly longer for patients with either concurrent TP53 mutation (n = 17) (6.0 vs 2.3 vs 2.9 months, P = 0.009) or concurrent EGFR amplification (n = 13) (5.0 vs 1.2 vs 2.4 months, P = 0.016) who received EGFR-TKI+crizotinib. Potential molecular mechanisms of acquired resistance to EGFR-TKI+crizotinib therapy included EGFR T790M (n = 2), EGFR L718Q (n = 1), EGFR S645C (n = 1), MET D1228H (n = 1), BRAF V600E (n = 1), NRAS Q61H (n = 1), and amplifications in KRAS (n = 2), ERBB2 (n = 1), CDK4 (n = 1), and MYC (n = 2). Conclusions: Our study provides real-world clinical evidence, in the largest cohort to date, that simultaneous inhibition of EGFR and MET improves clinical outcomes of patients with EGFR-mutant NSCLC who acquired MET amplification from prior EGFR-TKI therapy, indicating that combinatorial regimen of EGFR-TKI and MET-TKI could be a more effective therapeutic strategy in this subset of patients.

e21617 Background: With the advancements in the development of targeted therapy, the detection of actionable genes has become routine practice in diagnosing lung cancer. Plasma-based mutation profiling is widely used in clinical settings. Profiling using other body fluids is actively explored. In this study, we investigated the potential of induced sputum obtained from non-small cell lung cancer (NSCLC) patients for mutation profiling. Methods: We performed targeted sequencing on matched FFPE, plasma and induced sputum samples of 41 treatment-naïve advanced NSCLC using a panel consisting of 168 lung cancer-related genes. 10ml of whole blood and 8 ml of induced sputum were obtained from each patient. Induced sputum samples were fractionated into supernatant (sup) and precipitates (ppt). The cohort had a median age of 65 with a majority (32/41) diagnosed with lung adenocarcinoma. 7 of them were diagnosed with squamous cell carcinoma and the remaining 2 patients were diagnosed with neuroendocrine tumor. All patients had advanced disease (stage III or IV). Results: First, we investigated the optimal sputum fraction for mutation profiling by comparing the detection rates and maximum allelic fraction (maxAF) between sputum sup and ppt samples using matched tissue and plasma as references. The detection rate was defined as any mutation detected from the panel used; while maxAF was defined as the highest mutation allelic fraction among all mutations detected. Tissue, plasma, sputum sup and ppt achieved a rate of detection of 100%, 76.9%, 72.4% and 65.7% respectively, revealing comparable detection rates between plasma and sputum sup (p = 0.89). Sup had a significantly higher average maxAF than plasma (p = 0.03) and ppt samples (p < 0.01). Using driver mutations detected from tissue samples as references, sup, ppt and plasma samples achieved a sensitivity of 63.2%, 50% and 67.8%, respectively. Next, we investigated whether induced sputum obtained from smokers would be more informative than non-smokers. Our analysis revealed that sup from smokers had a significantly higher average AF than sup from non-smokers (p < 0.001). Furthermore, there was a statistical significant difference in average AF between sup and ppt obtained from smoker (p < 0.001) but such difference was non-existent in non-smokers (p = 0.46). Conclusions: Our study demonstrated that sputum sup demonstrates a comparable performance as plasma samples and is as a better sampling source than its ppt. Induced sputum from advanced stage NSCLC patients is an alternative media for mutation profiling.