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PURPOSE ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079 ), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor ( EGFR) mutation-positive resected stage II-IIIA (N1-N2) non–small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results. METHODS From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and EGFR-activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat [ITT] population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data. RESULTS Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio [HR], 0.92; 95% CI, 0.62 to 1.36; P = .674); respective 5-year OS rates were 53.2% and 51.2% ( P = .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP ( P = .316) and 5y DFS rates were 22. 6% and 23.2% ( P = .928), respectively. CONCLUSION Adjuvant therapy with gefitinib in patients with early-stage NSCLC and EGFR mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.

PURPOSE To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced EGFR mutation-positive non–small-cell lung cancer. PATIENTS AND METHODS This was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non–small-cell lung cancer with EGFR mutations in exon 19 or 21 (EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postsurgery. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS Of 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84; P = .092). No pathologic complete response was identified in either arm. Three (9.7%) of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms, respectively, had a major pathologic response. Median PFS was significantly longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard ratio, 0.39; 95% CI, 0.23 to 0.67; P < .001). Observed adverse events reflected those most commonly seen with the two treatments. CONCLUSION The primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.

9136 Background: Lung cancer organoids (LCOs) were expected to be the potential precision medicine approach for clinical response prediction. However, the clinical applications of both tissue and malignant serous effusions (MSE) derived LCOs were rarely reported. Our previous work demonstrated that MSE-derived LCOs maintain the genomic signature of the original tumor. In this study, we aimed to create LCOs using tissue or MSE, then validate the reliability of the model by comparing LCOs and their origin from the pathological and molecular levels. Furthermore, drug sensitivity tests of LCOs were also performed to evaluate the feasibility of LCO drug test as an approach for personalized medicine. Methods: Primary or metastatic tumor tissues were obtained from advanced lung cancer patients through core biopsy or surgically resected biopsy at the Guangdong Provincial People’s Hospital. MSEs were also collected. LCOs were generated from the obtained tissue and MSE, and the pathological features and genomic profiles were verified by analyzing the consistency with their origin. Then, the drug sensitivity scheme was formulated to follow the principles of clinical medication. In addition, proteomics analysis by 4D LC-MS/MS was also performed to analysis the molecular details of combinational therapy. Results: In our study, we generated 213 LCOs from 106 patients, mainly from MSE. The success rate to generate LCOs derived from MSE was 81.4% (131/161). The concordance rate of pathological phenotypes of LCOs samples verified by immunohistochemistry with clinical samples was 75% (63/84). In our cohort, LCO based drug sensitivity tests (LCO-DST) of targeted therapies were performed to predict the tumor response, and the AUC value of ROC analysis of osimertinib in EGFR-mutant adenocarcinoma reached 0.94(LCOs samples = 15, p= 0.0047). There were 2 patients with advanced lung adenocarcinoma, one with de novo EGFR mutation /MET amplification and the other with EGFR mutation combined with acquired RET fusion. The results of LCO based drug tests of 2 patients showed that combined targeted therapy (osimertinib plus savolitinib/cabozantinib) showed high tumor inhibition rate validated in clinical treatment and made differences. Then, 4D label-free high through-put proteomic analysis was performed in the patient with EGFR mutation and acquired RET fusion, demonstrating caspase 3 increased dramatically in combination of osimertinib and BLU-667 and the downstream proteins of EGFR and RET were down-regulated. Conclusions: LCOs derived from MSE faithfully reflected the pathological and genomic features of their original patients. The LCOs based drug test results are remarkably consistent with the tumor response. These results suggested the important prospects of LCO as an in vitro model for lung cancer precision medicine.

9076 Background: SAF-189s is a potent, brain-penetrant, next-generation anaplastic lymphoma kinase (ALK) inhibitor with preclinical activity against most known resistance mutations of ALK. We investigated safety, population pharmacokinetics, efficacy, and antitumor activity of SAF-189s in advanced, ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Methods: In this first-in-human phase 1/2 trial (NCT04237805), patients aged ≥18 years with histologically or cytologically confirmed, advanced, ALK+ NSCLC (with or without brain metastases) and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited from 41 hospitals in China. Oral SAF-189s was given in escalating doses of 20–210 mg once daily in continuous, 21-day cycles until disease progression, unacceptable toxicity, consent withdrawal, or death. Phase 1 data were presented at ASCO 2020. Here, we report updated phase 1 results and preliminary phase 2 data. Results: At a clinical cutoff date of January 18, 2022, 45 patients with prior systemic therapy enrolled in phase 1 and 150 were enrolled in phase 2. SAF-189s was well tolerated, the most common grade 3–4 treatment-related adverse events were hyperglycemia (7%), hypertension (6%) and diarrhea (3%). No treatment-related death was reported. 160 mg was chosen as the recommended phase 2 dose. In phase 1, 11 (24%) patients were ALK inhibitor (ALKi)-naive and 34 (76%) were ALKi-pretreated. Median progression-free survival (PFS) was 33.1 and 22.1 months (95% CI 6.9–not reached: 13.8–26.6) in ALKi-naive and ALKi-pretreated patients, respectively. Disease control rates (DCRs) were 100% in both ALKi-naive and ALKi-pretreated patients. Most patients in phase 2 were ALKi-naive (n=104, 69%), 26 (17%) received prior crizotinib only and 20 (12%) were pretreated with ≥1 non-crizotinib ALKi. The median duration of follow-up was 11.7 months (range 10.3–16.8), ORRs were comparable between the full analysis set and the 71 patients with brain metastases at 78.7% (95% CI 71.2–84.9) and 74.6% (95% CI 62.9–84.2) respectively. ALKi-naive patients had ORR of 92.3% (95% CI 85.4–96.6), compared to 65.4% (95% CI 44.3–82.8) in the crizotinib-pretreated group. DCR was 98.1% in ALKi-naive and 88.5% in crizotinib-pretreated patients. PFS data are not mature. Conclusions: SAF-189s showed clinical antitumor activity and was well tolerated in patients with advanced, ALK+ NSCLC, including those with brain metastases and pretreated with crizotinib. SAF-189s represents a promising, next-generation, targeted therapy for patients with ALK+ NSCLC. Clinical trial information: NCT04237805. [Table: see text]

9120 Background: Tepotinib is a highly selective, potent MET inhibitor approved in several Asian countries for the treatment of advanced METex14 skipping NSCLC. In VISION (n=275; data cut-off: Feb 1, 2021), tepotinib had an objective response rate (ORR) of 49.1% (95% CI: 43.0, 55.2) by independent review (IRC), with a median (m) DOR of 13.8 months (9.9, 19.4) across treatment lines. Here, we report outcomes in Asian pts. Methods: Pts with advanced METex14 skipping NSCLC, detected by liquid (L+) or tissue (T+) biopsy, received tepotinib 500 mg (450 mg active moiety) QD. Primary endpoint was objective response by IRC. Efficacy was assessed in 79 Asian pts with ≥3 months’ follow-up, and safety was assessed in 88 Asian pts who received tepotinib by data cut-off (Feb 1, 2021). Only pts enrolled in Asia were assessed for HRQoL. Results: In 79 Asian pts assessed for efficacy (38% female, 42% smoking history, 34% treatment-naïve [1L] and 82% adenocarcinoma), ORR was 54.4% (42.8, 65.7), mDOR was 18.5 months (8.3, ne), mPFS was 12.1 months (6.9, ne) and mOS was 20.4 months (19.1, ne). ORR was 66.7% (46.0, 83.5) in 1L pts (n=27), and 48.1% (34.0, 62.4) in previously treated pts (n=52). Meaningful activity was observed irrespective of METex14 skipping detection method (Table). In pts analyzed for HRQoL (n=73), mean change from baseline for EORTC QLQ-C30 GHS (3.94), EQ-5D-5L VAS (0.83), and EORTC QLQ-LC13 for cough (-6.59), dyspnea (-1.26), and chest pain (-6.14) symptom scores, demonstrated stability in QoL. In 88 Asian pts analyzed for safety, the most common adverse events (AEs) were peripheral edema, increased blood creatinine, and diarrhea. 29.5% of pts had Grade ≥3 treatment-related (TR) AEs. TRAEs led to dose reductions in 29.5%, temporary interruption in 43.2%, and permanent discontinuation in 14.8% of pts. Conclusions: In VISION, tepotinib showed robust and durable clinical activity in Asian pts with METex14 skipping NSCLC. TRAEs were manageable, with few leading to treatment discontinuation. Currently, VISION has enrolled 106 Asian pts with METex14 skipping NSCLC; analysis in this population is ongoing. Clinical trial information: NCT02864992. [Table: see text]

e21107 Background: As the standard first-line treatment for NSCLC patients with EGFR-sensitive mutation, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) were proved to be highly effective and less toxic compared to traditional chemotherapeutic regimens. But little is known about the correlation between tumor-infiltrating immune cells in the tumor microenvironment and clinical outcomes. This study was designed to investigate the association between tumor-infiltrating immune cells and the clinical outcome after first-line targeted therapy in EGFR exon 21 mutated lung adenocarcinoma (LUAD) patients. Methods: A total of 26 advanced LUAD patients with EGFR exon 21 mutation who received first-generation EGFR-TKIs as initial therapy between January 2017 and October 2019 were included in this study. All the patients were treated at Affiliated Dongguan Hospital, Southern Medical University, China. Patients who progressed within 12 months after first-line EGFR-TKIs therapy were defined as experiencing early progression (EP), and patients who progressed after 12 months or without progression were defined as experiencing late progression (LP). We analyzed immune markers in biopsy from these patients before treatment with EGFR-TKIs and examined the infiltration of immune cells and expression of PD-L1 in immune cells using fluorescent multiplex immunohistochemistry (mIHC) stained with CD8/CD56/CD68/CD163/FOXP3/PD-L1 antibodies. Results: In this cohort, we observed that after first-line EGFR-TKIs therapy in EGFR exon 21 mutated LUAD patients, the density of CD8+ FOXP3+T cells infiltrated in tumor area of LP group was significantly lower than EP group (P = 0.038). However, the difference of the density of the other infiltrated immune cells including CD8+T cells, FOXP3+Treg cells, CD8+PD-L1+T cells, CD68+CD163+M2macrophages, etc., were not significant between LP group and EP group (P > 0.05). The “optimal” cutoff value for CD8+ FOXP3+T cells infiltrated in tumor area was 5.45 (n/mm2) using the survminer package in R software according to PFS. Kaplan-Meier analysis suggested that the density of CD8+ FOXP3+T tell infiltrated in tumor area contributed to risk factor for PFS (HR = 5.56, P = 0.00054). Taking 5.45 (n/mm2) as the cutoff value, the percent of LP patients in low density of CD8+ FOXP3+T cells infiltrated in tumor area group was close to being statistically significant higher than high density of CD8+ FOXP3+T cells group (47% vs. 0%. P = 0.058). Conclusions: This study indicated that the low density of CD8+FOXP3+ T cells infiltrated in tumor area was associated with favorable clinical outcome in EGFR exon 21 mutated LUAD patients treated with first-generation EGFR-TKIs at first-line.

2591 Background: Immune checkpoint inhibitors (ICIs) have suboptimal efficacy in non-small cell lung cancer (NSCLC) patients with ERBB2 mutations, including ERBB2 exon 20 insertions. This study aims to investigate the efficacy of ICIs and immune characteristics in NSCLC patients harboring ERBB2 ex20ins and non-ex20ins mutations. Methods: Advanced NSCLC patients harboring ERBB2 mutations were recruited from January 2016 to December 2020. Pre-ICI tumor tissue samples were collected and performed with targeted next-generation sequencing. Patients received ICIs were followed up every 3 months until November 2021. Genomic features were compared between patients with ERBB2 ex20ins and non-ex20ins mutations. Progression-free survival (PFS), overall survival (OS), and tumor immune microenvironment (TIME) features characterized by multiplex immunohistochemistry (IHC) were further analyzed in patients receiving ICIs. Two-sample T-tests were performed to compare means; Cox models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Two external datasets of ERBB2-mutant NSCLC patients, including TCGA (n = 23) and META (n = 33), were used for validation. Results: A total of 117 eligible patients were enrolled (median age: 59 [range: 24-82], males 57.3%, stage IV 68.4%, adenocarcinoma 93.2%), of whom 37 received subsequent ICI treatment. similar PD-L1 tumor proportion score (mean: 8.1% vs. 13.2%, p = 0.25) and significantly lower mutation number (mean: 3.0 vs. 6.2 muts/person, p < 0.01) were detected in patients with ERBB2 ex20ins, compared to patients with ERBB2 mutations other than ex20ins. Similarly, in the TCGA cohort, tumor mutation burden was significantly lower in ERBB2 ex20ins patients (mean: 2.2 vs. 10.3 muts/Mb, p = 0.02). Of 37 patients receiving ICIs, ERBB2 non-ex20ins patients displayed superior PFS (mPFS: 13.5 vs. 4.4 months, HR: 0.31, 95% CI: 0.14-0.71), relatively long OS (mOS: 27.5 vs. 8.1 months, HR: 0.47, 95% CI: 0.20-1.14), and a relatively high rate of durable clinical benefit (64.3% vs. 34.8%, p = 0.10) than ex20ins patients, consistent with what was observed in the META cohort (PFS, mPFS: 13.2 vs. 2.5 months, HR: 0.20, 95% CI: 0.06-0.68; OS, mOS: 23.3 vs. 8.0 months, HR: 0.32, 95% CI: 0.11-0.90). Moreover, the CD4+ T cell density appeared to be lower in the tumor stroma of ERBB2 ex20ins patients than that of non-ex20ins patients (300.5 vs. 1288.0 /mm2, p = 0.08), even though the general TIME features of ex20ins patients were similar to those of non-ex20ins patients. Conclusions: NSCLC patients carrying ERBB2 ex20ins demonstrated worse clinical outcome under ICI treatment, similar PD-L1 expression and lower mutation number when compared to those with non-ex20ins mutations. Genomic and TIME characteristics should be further investigated to elucidate the efficacy of ICIs in lung cancer patients carrying ERBB2 mutations.

8578 Background: IMpower133 showed benefits in both progression-free survival (PFS) and overall survival (OS) of etoposide/carboplatin plus atezolizumab (ECT) regimen in extensive-stage small-cell lung cancer (ES-SCLC), but the absolute benefit was limited. Previous studies have classified SCLC patients by RNA-seq clustering analysis to explore the dominant population for treatment, but was difficult for clinical application. We aimed to explore whether expressive status of Yes-Associated Protein 1 (YAP-1) can screen dominant population of immunotherapy among ES-SCLC patients. Methods: We selected ES-SCLC patients treated in our hospital from Jan, 2018 to Jul, 2021, and enrolled 21 patients with ES-SCLC received ECT regimen whose formaldehyde-fixed, paraffin-embedded sample was reachable. Assessments of complete remission (CR), partial remission (PR), disease stable (SD) and progressive disease (PD) were according to the efficacy evaluation criteria of solid tumor (RECIST) version 1.1. Immunohistochemistry (IHC) of YAP-1 (ET1608-30, 1/100) was conducted. The H-score was calculated by IHC Profiler. All statistical analyses were evaluated using SPSS 22.0, X-tile 3.6.1, and Excel. P values < 0.05 were considered statistically significant. Results: Baseline information was provided in table. The median H-score of responders (CR/PR patients) and non-responders were 13.97 (95%CI: 8.97-16.30) and 23.72 (95%CI: 8.13-75.40) that were significantly different (P＜0.05). H-score and PFS showed negative correlation by spearman (r = -0.603). Patients were divided into two groups as low expression group (H-score ≤25.00, n = 16) and high expression group (H-score ＞25.00, n = 5) according to the cut-off value of H-score. The median PFS of these two groups were 7.1m (95%CI: 2.6-11.6m) and 3.4m (95%CI: 0.9-5.9m), respectively. K-M curves of PFS were significantly different (P＜0.05). Conclusions: Our preliminary results have indicated a potential efficacy predictive value of YAP-1 protein. And the expression level of YAP-1 protein was negatively correlated with efficacy of ECT in ES-SCLC patients. [Table: see text]

Purpose The Iressa Mutation-Positive Multicentre Treatment Beyond ProgRESsion Study (IMPRESS) compared the continuation of gefitinib plus chemotherapy with placebo plus chemotherapy in patients with epidermal growth factor receptor ( EGFR) mutation–positive advanced non–small-cell lung cancer with progression (Response Evaluation Criteria in Solid Tumors 1.1) after first-line gefitinib. Primary results indicated no difference between treatments in terms of progression-free survival (PFS). The current analysis presents final, mature, overall survival (OS) data, together with exploratory analyses that examined whether specific biomarkers, including T790M mutation status, were able to differentiate a relative treatment effect. Patients and Methods Patients were randomly assigned to gefitinib 250 mg or placebo, in addition to cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 (maximum of six cycles of chemotherapy). EGFR mutation status was determined from plasma-derived circulating free tumor-derived DNA samples (beads, emulsification, amplification, and magnetics digital polymerase chain reaction assay, allelic fraction analysis). Results A total of 265 patients with non–small-cell lung cancer were randomly assigned, and overall data maturity was 66%. Continuation of gefitinib plus cisplatin and pemetrexed was detrimental to OS when compared with placebo plus cisplatin and pemetrexed (hazard ratio [HR], 1.44; 95% CI, 1.07 to 1.94; P = .016; median OS, 13.4 v 19.5 months). The detriment was statistically significant in patients with T790M mutation–positive plasma samples (HR, 1.49; 95% CI, 1.02 to 2.21), whereas statistical significance was not reached in T790M mutation–negative patients (HR, 1.15; 95% CI, 0.68 to 1.94). PFS in T790M mutation–positive patients was similar between treatments, and the difference observed in T790M mutation–negative patients did not reach statistical significance (HR, 0.67; 95% CI, 0.43 to 1.03; P = .0745). Conclusion Final OS data from IMPRESS are supportive of earlier PFS results and are sufficient to warn physicians against the continuation of treatment with first-generation EGFR tyrosine kinase inhibitors beyond radiologic disease progression when chemotherapy is initiated. Plasma biomarker analyses suggest that this effect may be driven by T790M-positive status.

e21081 Background: Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC), whereas they also can cause various adverse events (AEs). We reported the incidences, spectrum and severity of AEs in real-life practice after the approval of ICIs in Chinese NSCLC patients. Methods: In this single center, retrospective study, anonymized electronic medical record data were collected from the dedicated lung cancer immunotherapy outpatient clinic of Guangdong Provincial People’s Hospital through the LinkDoc database. The patients (≥18 years old) with pathologically diagnosed metastatic NSCLC who receiving ICIs between 1 June 2019 and 31 December 2020 were included. The immune-related adverse events (irAEs) were diagnosed and assessed by oncologists. All AEs were classified and graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE V5.0). Results: A total of 203 patients with a median age of 60.5 years were included in this study. Most patients were male (81.8%), smokers (49.8%), non-squamous histological type (51.7%). 61.1% of patients visited the outpatient clinic more than once. Pembrolizumab and Nivolumab were given to the majority of patients (80.8%). 114 patients (56.2%) received single-agent and 89 patients (43.8%) received combination therapy. The median duration of ICIs therapy was 271.2 days. In our study, 68.0% of patients experienced any-grade AEs, and 19.7% experienced grade≥3 AEs. The most commonly AEs were abnormal laboratory findings (57.1%), blood and lymphatic system disorders (25.1%), and respiratory disorders (19.7%). All of 93 patients (45.8%) experienced irAEs and 6 patients (8.4%) developed grade≥3 irAEs. The most frequent irAEs included blood and lymphatic system disorders (25.1%), hepatobiliary disorders (17.7%), and cardiac disorders (9.9%). Cough (3.4%), sputum (2.5%), and pain (2.0%) were the most frequent AEs which received treatment. Conclusions: Our results showed 68.0% and 45.8% patients experienced AEs and irAEs, respectively. The AEs and irAEs were primarily low grade. This study also demonstrated the information of AEs could be well collected and managed through our dedicated lung cancer immunotherapy outpatient clinic. [Table: see text]

8502 Background: Median Overall survival (mOS) of stage IIIA resected NSCLC was 59.4 months (m) in CTONG 1104 adj gefitinib and 26.2m in SAKK neoadjuvant chemo trial. EMERGING-CTONG1103 showed neo-adjuvant/adjuvant erlotinib treatment significantly improved progression-free survival (PFS) vs standard doublet chemotherapy in patients (pts) with epidermal growth factor receptor ( EGFR) mutation-positive resectable stage IIIA (N2) non-small-cell lung cancer (NSCLC). Here, we present the final overall survival (OS) results from the study. Methods: This was a multicenter (17 centers in China) phase II randomized controlled trial of erlotinib（E）versus gemcitabine plus cisplatin (GC) as neoadjuvant/adjuvant therapy in pts with stage IIIA-N2 NSCLC with EGFR mutations in exon 19 or 21. From Dec 2011 to Dec. 2017, 386 pts sites were screened and 72 pts were randomly assigned to neoadjuvant/adjuvant E arm (N = 37) or GC arm(N = 35). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postoperative. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, downstaging rates of pathological lymph nodes, PFS, OS, safety, and tolerability. Data cut-off date was January, 29 2021. Results: With a median follow-up of 62.5 months, the median OS was 42.2months based on 47 (65.3%) events in ITT whole population. The mOS was 42.2m in E and 36.9m in GC (HR 0.83, 95%CI 0.47-1.47, p = 0.513). The 3-,5-year OS rate were 58.6%, 40.8% in E and 55.9%, 27.6% in GC respectively (p3-y = 0.819, p5-y = 0.252). All predefined subgroups including age, gender, EGFR mutation type had no significant difference in statistics between two arms. Subsequent treatments (ST) especially targeted therapy contributed most to OS (HR = 0.35,95% CI 0.18- 0.70). Median OS of pts receiving ST was 45.8m (n = 38), 34.6m in other treatment (n = 12), 24.6m in without ST (n = 15). For E mOS were 46.4 (n = 15; target therapy), 42.2m (n = 8; other) and 24.6m (n = 9; without, p = 0.021), for GC 42.6 (n = 23; target therapy), 30.1m (n = 4;other) and 24.6m(n = 6; without, p = 0.130). The RR was 53.3%, DCR 93.3%, mPFS 10.9m and mPPS 21.9m for patients with rechallenged EGFR TKI in E arm (n = 15). No novel unexpected SAE was observed during follow up. Conclusion: Erlotinib as neoadjuvant/adjuvant therapy for resected N2 NSCLC was feasibility and had a promising OS. The PFS survival advantage of E did not translate to OS difference in EMERGING trial (NCT01407822). Clinical trial information: NCT01407822.

e21670 Background: Chronic hepatitis B virus infection patients are noted about 7% in Chinese population who are excluded from the clinical trials of the nivolumab or pembrolizumab in non-small cell lung cancer (NSCLC). However, in clinical practice these patients received checkpoint inhibitors as well. Limited evidence exist on the safety of the checkpoint inhibitors in hepatitis B surface antigen positive NSCLC patients. Methods: From January 1, 2018 to September 30, 2019, clinical information of advanced non-small cell lung cancer patients who received nivolumab or pembrolizumab ± chemotherapy as routine clinical practice in Guangdong Lung Cancer Institute were collected according to a standardized procedure. Gender, histology, treatment regimens, experimental test, respose rate, and adverse events were recorded. Status of hepatitis B surface antigen (HBsAg) were tested for every patient before the treatment and data of the positive patients were accessed for this research. Adverse events were assessed according to Common Terminology Criteria for Adverse Events v5.0. Results: Among 232 eligible patients, HBsAg were found positive in 17 patients(7.3%). Clinical characteristics were list in the table. The median age was 55.2 years (range 39-72) and transaminase and bilirubin of all the patients were normal before treatment. The median treatment cycle was 7 (95%CI 4.6-10.3) and the median time to discontinuation was 4.4 months (95%CI 2.8-7.1). 8 patients received anti-virus therapy including entecavir and adefovir during the treatment. Grade 1 transaminase or bilirubin elevation were noted in 6 patients during the treatment. Grade 3 transaminase and grade 4 bilirubin elevation were found in 1 patient without evidence of viral reactivation. Conclusions: Nivolumab or pembrolizumab are safety treatment options for HBsAg positive NSCLC patients. [Table: see text]

9005 Background: ADJUVANT-CTONG1104, a randomized phase 3 trial showed adjuvant gefitinib treatment significantly improved disease-free survival (DFS) vs standard doublet chemotherapy in patients (pts) with epidermal growth factor receptor ( EGFR) mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). 5-year survival rate of N1N2 were 38%-50% in IASLC staging system. Here, we present the final overall survival (OS) results from the study. Methods: From Sep 2011 to April 2014, 222 patients, aged 18-75 years, with EGFR activating mutation through completely resection and diagnosed as stage II-IIIA (N1-N2) NSCLC pathologically from 27 sites were enrolled. The enrolled patients were 1:1 randomized to receive adjuvant gefitinib (250 mg once per day) for 24 months (G, n=111) or vinorelbine (25 mg/m2, d1 and d8) plus cisplatin (75 mg/m2, d1) every 3 weeks for 4 cycles (C, n=111). The primary endpoint was DFS in the ITT population. Secondary endpoints included OS, 3 and 5-year DFS rate, 5-year OS rate. The subsequent therapy data were collected, including crossover from C to G, re-challenge TKI and other treatment. Data cut-off date was Jan. 13, 2020. Results: A median follow-up was 76.9 months. The median OS (mOS) was 75.5 months based on 95 (42.8%) events in ITT whole population. The mOS was 75.5m in G arm and 79.2m in C arm (HR 0.96, 95%CI 0.64-1.43, p=0.823). The 3, 5-year OS rate were 68.6%, 53.8% in G and 67.5%, 52.4% in C respectively. DFS in 3, 5-y were 40.3%, 23.4% in G and 33.2%, 23.7% in C, respectively (P3-y=0.395, P5-y=891). All predefined subgroups including age, gender, lymph node, EGFR mutation type had no significant difference in statistics but in favor of G arm in trend. Subsequent treatment especially targeted therapy contributed most to OS (HR = 0.46, 95% CI 0.26 – 0.83). Median OS of patients receiving subsequent target therapy was75.5m (n=35), 36.4m in other treatment (n=33; (P

e21563 Background: Osimertinib is standard of care for patients with advanced non–small-cell lung cancer (NSCLC) carrying acquired epidermal growth factor receptor ( EGFR) T790M mutation. However, few studies have been conducted to investigate the impact of rebiopsy on clinical outcomes after resistance to osimertinib. We evaluated whether next-generation sequencing (NGS) of tissue and liquid rebiopsy could favor post-progression outcomes of T790M-positive advanced NSCLC patients treated with osimertinib. Methods: Immediately just after resistance to second- or further-line osimertinib, advanced NSCLC patients with acquired EGFR T790M mutation were retrospectively divided into the NGS and non-NGS groups according to whether they underwent NGS of tissue or liquid rebiopsy. The co-primary endpoints were post-progression survival (PPS) defined as the time from osimertinib resistance to subsequent-line treatment resistance, and post-progression overall survival (pOS) defined as from osimertinib resistance to death or end of the last follow-up. Multivariable analyses were done using Cox proportional hazards regression model and log-rank test. Results: Between January 2017 and July 2019, 89 patients (62 vs. 27 for the NGS and non-NGS groups respectively) were eligible for final analyses. In the NGS group, 3.2% (2/62) underwent tissue rebiopsy only, 29.0% (18/62)only had liquid rebiopsy, and 66.8% (42/62)with both tissue and liquid rebiopsy.The NGS group received more targeted or combined therapy after resistance to osimertinib (62.9% vs. 40.8%, P= 0.053). The NGS group was significantly superior to the non-NGS group in the co-primary endpoints. The median PPS was 6.1 vs. 2.7 months (hazard ratio [HR], 0.49; 95%CI, 0.30 to 0.80; 2-sided log-rank P= 0.004). Meanwhile, the median pOS was 11.7 vs. 6.8 months (HR, 0.50; 95%CI, 0.29 to 0.85, 2-sided log-rank P= 0.009). Conclusions: Providing more opportunities for individualized treatment, NGS of tissue and liquid rebiopsy favors post-progression outcomes of EGFR T790M-positive advanced NSCLC patients treated with osimertinib.

e14022 Background: Immunotherapy (IO) has become the fourth pillar of clinical cancer care. There is an increasing need to the treatment of more patients for a longer period with acceptable cost and risk. We here described the development and operationalization of the first dedicated lung cancer IO outpatient clinic in China using an iterative process. Methods: The clinic is staffed by one attending physician, one medical oncologist, several nurses, and medical assistants along with a dedicated care coordinator. Patients (pts) were scheduled to visit every Thursday morning for the treatment and then visit every 2-4 weeks as per IO regimen. Written informed consent were obtained after well-informing about the IO and possible side-effects, and administration of self-purchased drugs. The minimum workup including routine general physical examinations or tests along with tests specific for IO, and toxicities was undertaken during the clinic visits. Treatments response, adverse events (AE), quality of life (QOL), and patient reported outcomes were measured/reviewed by the oncologist accordingly (CTCAE 5.0, RECIST 1.1, and iRECIST criteria). Pts can report their symptoms and be noticed/alerted during the clinic visits or between visits via electronic interfaces. All these data were integrated into the EMR database (LinkDoc) and valued as continuous documentation to support clinical decisions making, so as to improve clinical symptom management and overall QOL. Also, the pts were coached about possible symptoms and corresponding self-monitoring and management strategies. A standardized workflow was established, as well as staff education and training programs. Results: During May to December 2019, 99 pts presented at our IO clinic, and 79 received IO therapy (46 pembrolizumab, 32 nivolumab, and 1 camrelizumab). Pts on average received 3 cycles (Total: 280; range 1-11 cycles). AE were noted in 57 (72.2%) pts. All pts were well. Conclusions: This study demonstrates that our dedicated lung cancer IO clinic worked well. Therapeutic alliance of IO clinics has already been established with primarily 15 hospitals participated in. The design process and standardized workflow components will be further expanded to other cancers or conditions.

e21702 Background: Aberrant activation of the MET pathway is associated poor prognosis and poor response to standard therapies in cancer patients. Glumetinib (SCC224) is an oral potent and highly selective MET inhibitor. This is an open label, dose-escalation, phase I clinical study to determine the safety, pharmacokinetics and anti-tumor activity in patients with advanced NSCLC regardless of MET status. Methods: Patients with advanced NSCLC failed standard treatments received glumetinib orally according to one of four dose escalation regimens on a 28-day cycle: 100 mg, 200 mg, 300mg and 400 mg once daily, in a Pharmacologically Guided Dose Escalation (PGDE) design (a variation of the standard 3+3 design). The primary endpoints are the incidence of dose limit toxicity (DLT), maximally tolerated dose (MTD), biologically effective dose (BED). The secondary endpoints are treatment-emergent adverse events (TEAE), safety and tolerability, anti-tumor efficacy, pharmacokinetics, and its metabolites. Results: As of Feb 7, 2020, a total of eighteen eligible (18) patients were enrolled into this study: 3 at 100 mg, 3 at 200 mg, 6 at 300 mg and 6 at 400 mg. Only one patient among 6 evaluable patients at 400mg cohort reported one DLT of grade 3 vomiting. Treatment-related adverse events mostly were grade 1 or 2 nausea, vomiting, elevated alkaline phosphatase, elevated conjugated bilirubin, edema, headache, asthenia and decreased appetite. Non-DLT treatment related G3/4 adverse events were peripheral edema (n = 1, 5.5%), hypothyroidism (n = 1, 5.5%). Absorption was rapid after dosing and the median time to reach maximum plasma drug concentration ( Tmax) was 2.0‐6.0 hours. The mean value of half-life(t1/2) in each dose group ranged from 20.43h to 35.36 h. In response to glumetinib, one patient with MET overexpression at 200mg dose level had a best of response of partial response and completed 44 weeks glumetinib treatment, 4 patients (3 with MET amplification) had a best of response of stable disease. Conclusions: Glumetinib was well tolerated at doses up to 400 mg once daily and demonstrated clinical activity in advanced NSCLC with MET alterations. Glumetinib is used in ongoing clinical trials to further explore safety and efficacy in NSCLC. Clinical trial information: NCT03466268.

e21689 Background: Patients(pts) with ALK-rearranged non-small cell lung cancer (NSCLC) are sensitive but progress in 8–11 months with treatment of ALK inhibitor crizotinib, with leading progression in brain metastasis. SAF-189s is a novel and selective ALK inhibitor, can penetrate through blood brain barrier, and overcome multiple resistance mutation. This study aimed to explore the safety, efficacy, and pharmacokinetic properties of SAF-189s in patients with advanced ALK-rearranged NSCLC. Methods: In this multicenter I/II study, SAF-189s was orally administered under fasting condition at doses ranging from 20–210 mg once daily in a 21-day cycle to 36 pts with advanced ALK-positive NSCLC who had failed to prior systemic therapy. In this analysis report, anti-tumor activity of SAF-189s was evaluated in 34 pts received 40(n = 6), 80(n = 8), 120(n = 8), 160(n = 9) and 210(n = 3) mg doses daily. Safety was evaluated in all 36 pts who received ≥1 treatment. This study is registered with clinicaltrials.gov, NCT04237805. Results: 36 pts were enrolled in total, 22 pts had CNS metastases at baseline and 26 pts had progressed to prior TKIs therapy. There was no treatment-related SAE among the 36 pts. The most common drug-related events were nausea (14 [38.9%] of 36 pts), vomiting (10[27.8%] of 36 pts), QT prolongation (9 [25.0%] of 36 pts), sinus bradycardia (7 [19.4%] of 36 pts), ALT increase (10 [27.8%] of 36 pts), diarrhea (6 [16.7%] of 36 pts). Only one DLT of grade 3 blood glucose increase occurred at 210 mg out of the first 3 pts, so another 3 pts will be enrolled to determine RP2D/MTD. SAF-189s had shown response in the starting dose of 20mg, with 1of 2 pts achieving partial response (PR) over 43 cycles until clinical data cut off. All 34 pts in efficacy analysis set had achieved tumor shrinkage, with 17 confirmed PR (50%) (95% CI, 32.4–67.6%) and 4 unconfirmed PR (11.7%). 11 (45.8%) pts had confirmed PR among 24 pts who had failed to Crizotinib or Ceritinib and 10 (47.6%) pts had confirmed PR among 21pts who had CNS metastases. PFS data is pre-mature, with only median PFS of the 80 mg cohort being inferred as 19.42 months. Conclusions: In the dose-escalation portion of this study, SAF-189s was safe, very tolerable, and demonstrated both systemic and intracranial activity in pts with advanced ALK-positive NSCLC who had failed to at least 1 prior systemic therapy. Therefore, this study warrants further investigation to prove SAF-189s as an effective therapeutic option for pts who have ALK+ NSCLC. Clinical trial information: NCT04237805.

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.

e20678 Background: Next-generation sequencing (NGS) is beneficial to precision medicine. However, it remains elusive whether the epidermal growth factor receptor ( EGFR) mutant allele frequency (MAF) tested by NGS is predictive for tyrosine kinase inhibitors (TKIs) therapy in advanced non-small-cell lung cancer (NSCLC). Methods: We enrolled 194 advanced NSCLC EGFR mutant patients receiving erlotinib or gefitinib orally. A total of 196 baseline tissue samples from a phase III clinical trial (CTONG 0901; clinicaltrials.gov No.NCT01024413) between July 2009 and 2014 were analyzed by a panel of 168 lung cancer-related genes NGS. The median EGFR MAF was 25.8% (range, 1.4%-86.2%). Patients were divided into MAF low group (1.4%-25.8%) and high group (25.8%-86.2%). We defined PFS as the time of randomization to confirmed disease progression or death from any cause. OS was calculated from randomization to the last visit or death from any cause. Tumor response was assessed by investigators according to RECIST version 1.1. Survival was estimated using the Kaplan-Meier method. The relationship between the response of TKIs and EGFR MAF were evaluated by Pearson Chi-square test or Fisher’s exact test. Results: The median age was 58.7 years (range,31.2- 85.1), 92 (47.4%) were male, 41(21.1%) were smokers,189 (97.4%) had adenocarcinoma, 105 (54.1%) patients were identified as carrying EGFR exon 19 deletion, while one patient with the co-existence of T790M mutation. 85 (43.8%) patients harbored EGFR exon 21 L858R mutation. After 5 weeks of treatment, the initial response was assessed. No significant difference was observed in initial response between the high and low groups ( P = 0.502). The difference in best response to EGFR-TKIs between the groups was not significant ( P = 0.557). Objective response rate (ORR) was 56.2% and 57.5% respectively. There was no significant difference in median PFS [11.2 (95% CI,10.0 -12.3) vs 12.4 (95% CI,10.3-14.5) months, P = 0.509] between the groups. The high group was not significantly superior to the low group in median OS[20.5 (95% CI,18.0-23.0) vs 23.1 (95% CI,19.3-27.0) months, P = 0.500]. Conclusions: EGFR mutant allele frequency tested by NGS is not associated with the efficacy of EGFR TKIs in advanced NSCLC.

e20730 Background: MET second-site mutations were previously reported in a few cases of MET-amplified or exon 14-mutant advanced non-small-cell lung cancer (NSCLC) treated with MET inhibitors. However, both the frequency of MET second-site mutations and clinical outcome of patients with such genetic alterations have not been investigated, particularly in EGFR-mutant, MET-amplified advanced NSCLC treated with combinatorial targeted therapy. Methods: Retrospectively, from November 2016 to January 2019, 22 patients with EGFR-mutant, MET-amplified advanced NSCLC had sufficient tumor samples after resistance to a combinatorial therapy with both EGFR and MET inhibitors. All tissue samples were detected using Next-generation sequencing (NGS). The progression-free survival (PFS) was calculated the start of subsequent treatment to progressive disease or death from any cause. The overall survival (OS) was calculated from the start of subsequent treatment to death from any cause. Last follow-up was on January 31, 2019. Results: Five kinds of MET second-site mutations were found in 7 patients: D1246N D1228N, D1228H, D1231Y and Y1230H. The frequency of MET second-site mutations was 31.8% (7/22). The median PFS and OS were 3.7 (95%CI: 1.13-6.3) months and 6.9 (95%CI: 0.2-13.7) months respectively. The ORR of EGFR TKIs plus cabozantinib for suchsecond-site mutaant patients was 50% (2/4). However, the ORR of other treatments was 0% (0/3), Two of them received single agent cabozantinib, and PFS was 0.7 and 1.7 months respectively. One had a PFS of 2.5 months with pemetrexed/carboplatin plus bevacizumab. Conclusions: MET second-site mutation might be one of the commonly-seen molecular mechanisms of acquired resistance to combinatorial targeted therapy in EGFR-mutant, MET-amplified advanced NSCLC. Patients with such mutations could respond to cabozantinib plus EGFR TKI. Further more investigations are warranted to improve the efficacy.

e20626 Background: Resistance mechanisms to osimertinib have raised growing concerns, but those with acquired RET rearrangement is poorly characterized. Methods: We retrospectively identified advanced, EGFR-mutant NSCLC (non-small-cell lung cancer) patients treated with osimertinib between April 9th, 2015 and November 1st, 2018 at our institute. Clinicopathologic features and clinical outcomes were analyzed. Subsequent genetic profiling was performed at the time of progression by next-generation sequencing (NGS). Overall survival (OS) since 1st line treatment was calculated from first-line treatment start to death or last follow up, and OS post-progression was calculated from osimertinib progression. Median follow-up time was 43.4 months. Results: In the 192 patients treated with osimertinib, 57 had follow-up NGS information after progression, and six harboured acquired RET rearrangement (11%, 6/57). For patients with RET rearrangements when progressed on osimertinib, OS since 1st line treatment (22.9m vs 59.5m, P = 0.021) and OS post-progression (2.1m vs 10.0m, P = 0.031) were significantly shorter compared with non- RET-rearranged cases, whereas no significant difference was found in demographics at the initial lung cancer diagnosis or progression-free survival (PFS) of osimertinib (12.1m vs 5.8m, P = 0.34). Among these six patients, one received best supportive care, two continued to use drugs targeting EGFR but deteriorating soon, three patients tried osimertinib combined with cabozantinib with one benefit from this combination approach. Conclusions: RET rearrangements could exist in EGFR-mutant NSCLC with acquired resistance to osimertinib and linked to inferior survival. Study on the molecular evolution and heterogeneity during treatment course are warranted for further therapeutic strategies. [Table: see text]

e20615 Background: Although the third-generation Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib is more potent, histologic transformation from lung adenocarcinoma to other histological types is still a mechanism of resistance in EGFR-mutant adenocarcinoma. Those with histologic transformation usually have poor prognosis. Hence, we focused on the unique molecular mechanism of histologic transformation after osimertinib and explore the strategy of treatment. Methods: Pathology was confirmed in 55 EGFR-mutant patients treated with osimertinib at baseline and disease progression. They were all lung adenocarcinoma at baseline. We established the patient-derived xenograft (PDX) mouse model from an EGFR-mutant adenocarcinoma transforming to neuroendocrine carcinoma. Preclinical efficacy of erlotinib versus osimertinib was evaluated in vivo. All the clinical data of these patients were analyzed. Results: The frequency of histologic transformation after resistance to osimertinib was 14.5% (8/55). Three of them were transformed to small-cell lung cancer totally, two transformed to complex small-cell lung cancer, two transformed to adenosquamous cell carcinoma and one transformed to neuroendocrine carcinoma without T790M mutation in which an PDX mouse model was successfully established. The genetic profiles of those transformed to small-cell lung cancer were characterized by Rb1, TP53 mutations, and PI3K/AKT/MTOR aberrances. Those transformed to adenosquamous carcinoma were characterized by KRAS amplification and EGFR amplification. The median progression-free survival (PFS) was not significantly different between the patients with histologic transformation and those without during the treatment of osimertinib (7.7 VS. 5.7 months, P = 0.763). One went on first-line osimertinib, added etoposide/ cisplatin (EP) chemotherapy meanwhile after progressive disease, and achieved minor response after 2 cycles. The other one received the treatment of EP + osimertinib + erlotinib, and acheived partial response with a PFS of 7 months without obvious toxicities. The PDX model showed more sensitivity to erlotinib than osimertinib. Conclusions: Continued osimertinib plus chemotherapy might be effective in overcoming the resistance. Particularly, the first-generation EGFR-TKI seems to be efficacious in histologically-transformed EGFR-mutant patients without T790M mutation. Further investigations of these patients and PDXs are warranted.

e20675 Background: Acquired ALK mutations pose a challenge in multiple ALK tyrosine kinase inhibitors (TKIs) for lung cancer. In our study, we examined the profiles of ALK resistance mutations and co-occurring genetic alterations after targeted therapy. Methods: Using targeted gene capture and next-generation sequencing technologies, we analyzed the somatic mutations from174 patients (pts) with post-TKI samples. Among them, 123 pts received first-generation TKI crizotinib only, 51 pts (34 with second-generation TKI, 17 with third-generation TKI) treated with multiple ALK-TKIs. Results: After the treatment of ALK-TKIs, 29% (50/174) patients developed ALK resistance point mutations, including G1202R (22 pts), G1269A (13 pts), L1196M (8 pts), D1203N (5 pts), F1174L (4 pts), I1171T (4 pts), E1210K (4 pts), G1128A (3 pts), F1174C (3 pts), C1156Y (1 pts), G1123S (1 pts), I1171S (1 pts), L1152R (1 pts), and 10 of them had multi-clone. Specifically, G1269A was found a higher proportion in crizotinib group contrast to multi-TKIs cohort (10/24 vs 3/26, p = 0.024). The recalcitrant G1202R was another common resistance mutation, but there was no significant difference between the two groups (p = 0.052). Other concurrent genetic alterations related to clinical response were usually observed in TP53 mutations (46%), furthermore it seemed to be more frequently detected in post-crizotinb compared with multi-TKIs (P = 0.023). Activated bypass signaling may promote tumor progression. In non-ALK resistance point mutations samples (n = 124), co-occurring genomic alterations in EGFR (32/124, p = 0.004) were significantly more enriched in crizotinib group (n = 99). The driver gene mutation may limit crizotinib response. However, EP300 (24%), CDKN2A (12%), TRIM58 (12%), STK11 (12%) or KRAS (8%) mutations were common in the multiple ALK-TKIs group (n = 25). Conclusions: In lung cancer patients, ALK resistance point mutations G1269A was significantly enriched in post-crizotinib, while patients with multiple ALK-TKIs may frequently found G1202R or L1196M. The co-occurring genetic alterations in TP53 or EGFR after the TKIs therapeutic may offer directions for further research and therapy in lung cancer.

e20726 Background: Osimertinib is used to treat EGFR-mutant non–small-cell lung cancer (NSCLC) with acquired T790M mutation. Next-generation sequencing (NGS) is helpful to understand mechanisms of resistance to osimertinib. However, whether NGS after resistance to osimertinib has an impact on clinical outcomes of patients treated with subsequent treatments has been elusive. Methods: We retrospectively identified advanced, EGFR-mutant T790M positive NSCLC patients treated with the 2nd or further-line osimertinib from January 27th, 2015 to January 31th, 2019 at our institute. Genetic profiles and clinical outcomes were analyzed. These patients were divided into 2 groups based on NGS data after resistance to osimertinib. Progression-free survival1 (PFS1) was calculated from the start of osimertinib to progression or death. PFS2 was calculated from the start of subsequent-line treatment to progression or death. Objective response rate (ORR) of subsequent-line treatments was evaluated by RECIST1.1. Results: Among 187 patients treated with osimertinib, 66 had NGS data and 27 had no NGS data after progression. Maintained EGFR T790M was detected in 23 patients (34.8%), and loss of T790M was seen in 43 patients (65.2%). Mutations of EGFR C797S were detected in 12 patients (18.1% overall; 52.2% of those with retained T790M), 11 in cis with a maintained T790M, 1 in trans with a maintained T790M. There was no significant difference in median PFS1 between the maintained T790M group and the loss of T790M group (10.8 vs. 7.0 months, P = 0.085).The NGS group was treated with TKIs according to the results of NGS strictly (n = 36), the non-NGS group received chemotherapy or best supportive care (n = 11).There was a significant difference in median PFS2 between the NGS and non-NGS groups (5.4 vs. 2.9 months, P = 0.043). The ORR of the NGS group was significantly superior to that of the non-NGS group (16.2% vs 11.1%, P < 0.001). Conclusions: NGS after resistance to osimertinib might favor clinical outcomes of advanced EGFR-mutant NSCLC patients. Further more investigations are warranted.

First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI.

e21219Background: Not all advanced non-small-cell lung cancer (NSCLC) patients respond equally to tyrosine kinase inhibitor (TKI) treatments, despite the presence of sensitizing epidermal growth fa...

1545Background: Comprehensive NGS panel based genetic testing is becoming more common to help clinicians provide personalized cancer care. Matched tumor-normal sequencing is recommended primarily t...