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PURPOSE The CHOICE-01 study investigated the efficacy and safety of toripalimab in combination with chemotherapy as a first-line treatment for advanced non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients (N = 465) with treatment-naive, advanced NSCLC without EGFR/ALK mutations were randomly assigned 2:1 to receive toripalimab 240 mg (n = 309) or placebo (n = 156) once every 3 weeks in combination with chemotherapy for 4-6 cycles, followed by the maintenance of toripalimab or placebo once every 3 weeks plus standard care. Stratification factors included programmed death ligand-1 expression status, histology, and smoking status. The primary end point was progression-free survival (PFS) by investigator per RECIST v1.1. Secondary end points included overall survival and safety. RESULTS At the final PFS analysis, PFS was significantly longer in the toripalimab arm than in the placebo arm (median PFS, 8.4 v 5.6 months, hazard ratio = 0.49; 95% CI, 0.39 to 0.61; two-sided P < .0001). At the interim OS analysis, the toripalimab arm had a significantly longer OS than the placebo arm (median OS not reached v 17.1 months, hazard ratio = 0.69; 95% CI, 0.53 to 0.92; two-sided P = .0099). The incidence of grade ≥ 3 adverse events was similar between the two arms. Treatment effects were similar regardless of programmed death ligand-1 status. Genomic analysis using whole-exome sequencing from 394 available tumor samples revealed that patients with high tumor mutational burden were associated with significantly better PFS in the toripalimab arm (median PFS 13.1 v 5.5 months, interaction P = .026). Notably, patients with mutations in the focal adhesion-PI3K-Akt signaling pathway achieved significantly better PFS and OS in the toripalimab arm (interaction P values ≤ .001). CONCLUSION Toripalimab plus chemotherapy significantly improves PFS and OS in patients with treatment-naive advanced NSCLC while having a manageable safety profile. Subgroup analysis showed the OS benefit was mainly driven by the nonsquamous subpopulation.

e21157 Background: In ORIENT-11, first-line (1L) SPP improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and duration of response (DoR) compared with placebo plus pemetrexed-platinum (PPP) in pts with AMnsqNSCLC. We report outcomes from ORIENT-11 (NCT03607539) for pts treated with SPP with stage III (b & c) compared with stage IV disease. Methods: Pts with treatment-naïve locally AMnsqNSCLC without sensitizing EGFR/ALK alterations were randomly assigned to SPP (n = 266) or PPP (n = 131), stratified by PD-L1 expression, platinum-chemotherapy and sex. Primary endpoint was PFS (RECIST v1.1). Secondary endpoints included OS, ORR, DoR and safety. Kaplan-Meier method was used to analyze median PFS, OS and DoR. Stratified Cox model was used to analyze the hazard ratio (HR) of SPP vs. PPP. Clopper-Pearson method was used to calculate the 95% confidence intervals (CI) of ORR for each group. Miettinen-Nurminen method was used to analyze 95% CI of ORR difference between SPP and PPP. Data cutoff for OS data was September 15, 2021, providing a median follow-up of 30.8 months. Cutoff for other data was November 15, 2019, providing a median follow-up of 8.9 months. Results: 21 pts (7.9%) receiving SPP had stage III disease and 245 pts (92.1%) had stage IV disease. Baseline sex, age and PD-L1 expression ≥1% were similar between subgroups (Table). There were differences between subgroups in number of pts receiving carboplatin and ECOG performance status at baseline. PFS, OS, ORR and DoR outcomes were comparable between pts with stage III and stage IV disease based on the ad-hoc analyses. Any-grade adverse events (AEs) (100.0% vs. 99.6%) and AEs of Grade ≥3 (57.1% vs. 62.0%) were similar in pts with stage III and stage IV disease. Conclusions: In ORIENT-11, outcomes for pts receiving SPP as 1L therapy in AMnsqNSCLC with stage III and stage IV disease were comparable. Clinical trial information: NCT03607539. [Table: see text]

e21140 Background: Limited data is known regarding osimertinib plus anlotinib as first line treatment in EGFRm advanced NSCLC patients. Earlier we have reported that osimertinib in combination with anlotinib was well tolerated. Here we further present the efficacy and safety profile of the combined therapy. Methods: In this phase Ib/IIa, open-label study, treatment-naïve patients with an activating EGFR mutation, advanced or metastatic lung adenocarcinoma were eligible. Patients with stable CNS metastases were allowed to enroll. Patients were treated with anlotinib at dose of 8mg, 10mg and 12mg, all patients received osimertinib 80mg. Primary endpoint was objective response rate (ORR) by investigator using RECIST v1.1. Secondary endpoints include disease control rate (DCR), depth of response, median progression free survival, overall survival rate at 12 months and safety profile. Data cut-off: Nov. 23rd, 2021. Results: From November 2020 through June 2021, 25 patients were enrolled in the study and started treatment. Median age was 59 years (38-77years), 11 (44%) were female, 24 (96%) were ECOG PS 1. 24 (96%) patients were stage IV and 6 (24%) had CNS metastases. At DCO, 18 (72%) patients remained on treatment. Among 23 response evaluable patients, the overall ORR was 65.2% (95%CI 42.7,83.6), DCR was 95.7% (95%CI 78.0,99.9) and median depth of response was -40.7% (range, -70.6 to 49.7). Adverse events (AEs) were observed in 21 (84%) patients. The most common AEs were platelet count decreased (56.5%), thyroid-stimulating hormones increased (39.1%) and diarrhea (30.4%), no unexpected AEs occurred. Grade≥3 AEs and SAEs were experienced by 5 (20%) and two (8.0%) patients, respectively. Dose reduction occurred in 8 (32%) patients and all were related to anlotinib. There was no fatal AE event reported in this study. Conclusions: Osimertinib in combination with anlotinib as first-line treatment for naïve EGFRm advanced NSCLC patients showed encouraging antitumor activity with manageable safety profile. The study is ongoing and more results will be updated in the future. Clinical trial information: NCT04770688.

9090 Background: With PD-1/PD-L1 inhibitors moving to first line in NSCLC, 2nd/3rd line NSCLC is a severe unmet medical need, dominated by docetaxel-based therapies with > 40% severe neutropenia and limited survival. Plin, a novel immune-enhancing small molecule, enhances dendritic cell maturation and T-Cell proliferation. In the ITT population, the Plin/Doc combination had superior Efficacy (mOS; HR = 0.82, p = 0.0399), Safety (lower Gr3/4 AE rate/pt/year (yr); p = 0.038) and better Quality of Life (QTWiST; p = 0.026) versus (vs) standard of care (SoC) Doc alone in advanced and metastatic NSCLC pts in DUBLIN-3 (Han, ESMO 2021) who failed platinum therapy. Here we report on the N-Sq pts subgroup. Methods: DUBLIN-3(NCT02504489) was a randomized, single-blind (pts only), active controlled Ph3 study in 2nd/3rd line stage IIIB/IV, EGFR wt NSCLC pts with a measurable lesion (RECIST 1.1) in the lung, and ECOG ≤ 2, conducted in US, Australia and China. Pts (n = 559) were randomized 1:1 to Plin/Doc or Doc/Placebo (21-day (D) cycle (C)). Doc (75 mg/m2 on D1 and Plin 30 mg/m2 on D1 and D8 were given by IV infusion. A post-hoc analysis of median Overall Survival (mOS) and restricted mean survival time (RMST) from K-M curves, OS rate at 24,36 and 48 month (Mo), and grade 4 neutropenia (Gr4N) rates was performed for the N-Sq patients (n = 153 for Plin/doc and n = 178 for Doc). Results: Baseline characteristics were balanced between both groups. Primary and key secondary objectives in the ITT population were met (Han, ESMO 2021). Plin/Doc was well tolerated. Estimated Adverse Event Rate per Year [95% CI] was 1.43 [1.13,1.81] for Plin/Doc versus 2.77 [2.33,3.28] for Doc alone (p < 0.001). The median OS benefit is 2.6 months (p = 0.023). The table below summarizes the results for the N-Sq subgroup. Conclusions: The addition of Plin to Doc was superior to SoC Doc alone for efficacy and safety in the clinically relevant subgroup of non-squamous EGFR-wild type, 2nd/3rd line NSCLC pts. Clinical trial information: NCT02504489. [Table: see text]

Purpose Patients with squamous non–small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.

2611 Background: DNA damage response and repair (DDR) pathway-related gene mutations have been reported to predict the efficacy of immune checkpoint inhibitor (ICI). However, therapeutic effect of DDR pathway with different functional annotations is not fully studied. Here we explore the relationship of DDR pathway with different functional annotations and clinical outcomes in public cohorts of immunotherapy and chemotherapy. Methods: Genetic testing and clinical outcomes data were obtained from the public clinical cohorts across 10 tumor types. 232 DDR pathway-related gene were assigned to eight pathway according to the literature. Nine predictive models for the mutation pathogenicity were included in the analysis, of which at least five returned positive results were defined as deleterious mutations. All annotations were according to the American College of Medical Genetics (ACMG) standards and guidelines. To explore the association between DDR pathways and ICI, DDR pathway mutation is grouped. Patients, who harbored mutations in two or more DDR pathways and meanwhile had deleterious mutation in at least one DDR pathway, were enrolled in group A. Patients, who harbored deleterious mutations in only one DDR pathway or had only uncertain significance mutations, were enrolled in group B. Patients with no DDR gene mutations were enrolled in Group C. We analyzed relation of the group and survival outcomes in four public cohorts. Results: Of 4 clinical cohort analyzed, the group A treated with ICI has the best PFS or OS outcomes. However, the comparison of group B and group C is not coincide across different cohorts. Treatment is the key factor that influents the relation of DDR pathway mutations and clinical outcomes. As shown in POPLAR/OAK cohort, patients in group C has the best PFS (p=0.0381) or OS (p=0.0350) outcome when treated with chemotherapy, but patients in group A has the best PFS (p=0.0083) or OS (p=0.0222) outcome when treated with ICI. Conclusions: When treated with ICI, patients with at least one deleterious mutation and another deleterious or uncertain significance mutation has the best PFS or OS outcomes, but not for chemotherapy. Our study suggested that DDR pathway with deleterious mutations might be a potential predictive factor for immunotherapy.[Table: see text]

e20568 Background: Non-small cell lung cancer (NSCLC) patients harboring mutations in the epidermal growth factor receptor (EGFR) gene dramatically respond to EGFR tyrosine kinase inhibitors (TKIs). However, these patients inevitably developed acquired resistance to TKIs. Among them, small cell lung cancer (SCLC) transformation is a relatively rare mechanism of resistance. However, the mechanism of SCLC transformation is largely unclear. Methods: We performed a 639 cancer-relevant gene panel to detect genetic differences of tissues before and after TKIs resistance caused by SCLC transformation. In vitro experiments were conducted to study the role of ETS variant transcription factor 1 (ETV1) on SCLC transformation and TKIs resistance. Results: We present two EGFR-mutant pulmonary adenocarcinoma (ADC) patients. One with EGFR exon 19 deletion (Ex19del) accepted first-line gefitinib treatment and then received osimertinib(AZD9291) treatment due to acquisition of EGFR-T790M mutation. A novel ETV1 mutation (p.P159S) was detected in SCLC samples after SCLC transformation when not coexisting with T790M. Another patient harbored an EGFR exon 21 mutation (p.L858R) with a long-lasting response to first-line gefitinib and then transformed to SCLC. A previously unreported ETV1 mutation (p.E462Q) was detected in SCLC tissue. In vitro, ETV1 p.E462Q and p.P159S mutations participated in neuroendocrine differentiation by inducing the expression of the neuroendocrine transcription factor, achaete-scute homolog 1 (ASCL1) and promoted H69 cells proliferation. Besides, ETV1 p.E462Q and p.P159S mutations were resistant to first-generation (gefitinib) and third-generation (osimertinib) TKIs after introducing into NCI-H358 cells. Conclusions: Novel ETV1 p.E462Q and p.P159S mutations were found in SCLC tissues of TKIs resistant patients, providing novel understanding of ETV1 involved in acquired resistance to EGFR-TKIs via SCLC transformation.

e21072 Background: Penpulimab is a human IgG1 monoclonal antibody (mAb) directed against human programmed cell death-1 (PD-1). Penpulimab, with its unique binding epitope, was engineered to eliminate Fc-mediated effector function that compromises anti-tumor immune cell function, and to optimize receptor occupancy by improving duration of drug binding. As a promising multi-target tyrosine kinase inhibitor (TKI), anlotinib significantly improved overall survival in advanced NSCLC patients (pts) in the phase 3 trial ALTER0303. Antiangiogenesis therapy combined with PD-1/PD-L1 inhibitors has shown excellent efficacy in advanced NSCLC pts. This is the trial evaluating chemo-free combination of penpulimab plus anlotinib in treatment-naive advanced NSCLC pts regardless of PD-L1 expression (NCT03866980). Methods: Pts with previously untreated, stage IIIB/IIIC/IV non-squamous NSCLC without sensitizing mutation of the epidermal growth factor receptor (EGFR) gene or translocation of the anaplastic lymphoma kinase (ALK) gene were enrolled. Eligible pts received penpulimab 200mg Q3W in combination with anlotinib 12mg QD (2 weeks on 1 week off) until loss of clinical benefit or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included ORR, disease control rate (DCR), duration of response (DoR) and overall survival. Results: As of January 13, 2021, 26 pts had received the combination therapy of penpulimab plus anlotinib (median age 59.5yrs [range 30-71], 76.9% male, 76.9% ECOG PS 1), with a median treatment duration of 3.5 months. Of 21 pts who have had at least one tumor assessment, the ORR was 57.1% (12 PRs) and DCR was 90.5% (12 PRs, 7 SDs). Median PFS has not been reached, and eleven responders remain in response. Treatment-related adverse events (TRAEs) occurred in 53.8% of pts (≥G3 TRAEs occurred in 15.4% [4/26]). Treatment-related SAEs occurred in 15.4% [4/26], and 7.7% of pts [2/26] had drug interruption or discontinuation due to TRAEs. Most common TRAEs (≥15%) were ALT increased, AST increased, hyperthyroidism and hypertension (15.4% each). Conclusions: The combination of penpulimab plus anlotinib as first-line treatment for locally advanced/metastatic NSCLC showed the promising efficacy with a manageable safety profile, thereby suggesting that this combination therapy may be a viable chemo-free treatment strategy for locally advanced/metastatic NSCLC pts. Clinical trial information: NCT03866980.

e21073 Background: Anlotinib, a multi-target tyrosine kinase inhibitor antiangiogenic drug, had been recommended by guideline for the 3 lines or more treatment of non-small cell lung cancer (NSCLC) in China. However, data of anlotinib based combination in the first-line treatment remains unknown. Therefore, this study aims to evaluate efficacy and safety of the combination of erlotinib, chemotherapy or sintilimab with anlotinib respectively, in Chinese patients with locally advanced or metastatic NSCLC. Methods: In this open-label, three arms, prospective study, locally advanced or metastatic NSCLC patients with EGFR mutation (exon 19 deletion or L858R) (Cohort A) receive anlotinib (10 mg QD from day 1 to 14 of a 21-day cycle) and erlotinib (150 mg once daily) until disease progression or treatment intolerance. For patients with EGFR mutation negative, the treatment regimen was anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) in combination with chemotherapy (Cohort B) or sintilimab (Cohort C) according to investigator. The primary outcome was objective response (ORR), the secondary outcomes were progression free survival (PFS), disease control rate (DCR), overall survival (OS) and safety. Results: A total of 80 patients were enrolled with 30 patients in Cohort A, 28 patients in Cohort B, and 22 patients in Cohort C. Among these patients, 16 (57.1%), 7 (23.3%) and 1(4.5%) were female in Cohort A, B, and C, respectively. And 9 (32.1%) and 4 (18.2%) of them had brain metastasis in Cohort A and C, respectively. Till December 2020, all the patients received tumor assessment at least once. In Cohort A, 26 patients achieved confirmed PR, the ORR was 92.9%, and DCR was 96.4%. Median PFS was 20.53 months, and the 12-month PFS rate was 81.5%. In Cohort B, 17 patients achieved PR, the ORR was 60.0%, while DCR was 96.7%. Median PFS was 13.3 months, and the 12-month PFS rate was 55.5%. In Cohort C, medium PFS was 15.6 months. The 18- and 24-month PFS rate was 45.9% and 26.2%, respectively. The most common grade 3 adverse events (AEs) were rash (17.2%), oral mucositis (10.3%), diarrhea (6.9%) and proteinuria (6.9%) in Cohort A, and a grade 4 hypertension was observed. In Cohort B, the most common grade 3 AEs were platelet count decreased (20.0%), leucopenia (16.7%), hand-foot-skin reaction (10.0%), hypertriglyceridemia (10.0%), oral mucositis (6.7%) and thrombus (6.7%). Grade 4 platelet count decreased occurred in three patients (10.0%). Safety data of Cohort C had been published elsewhere. Conclusions: This study suggest that anlotinib-based combination treatment for patients with advanced non-small cell lung cancer might be new first-line therapy strategy. For EGFR-mutated positive patients, anlotinib plus erlotinib shows good efficacy and well tolerability. For EGFR-mutated negative patients, anlotinib combines with chemotherapy or sintilimab also may be a promising first-line treatment. Clinical trial information: NCT03628521.

e21163 Background: Deleterious somatic DNA damage repair (DDR) gene mutations are frequent in non-small cell lung cancer (NSCLC) and are associated with improved clinical outcomes of immunotherapy. DDR gene mutations are associated with higher tumor mutational burden (TMB) in cancer. However, the effect of germline DDR-related genes mutation with different functional annotations on TMB in NSCLC patients is still unclear. Methods: 1671 Chinese patients with NSCLC were enrolled in this study. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples or peripheral blood by next generation sequencing (NGS) with 733 cancer-related genes panel. The germline mutation data were obtained. All annotations in clinical significance were according to the 2015 American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Results: 1076 patients (64.39%) had germline DDR-related gene mutations and 595 (35.61%) had no germline DDR-related gene mutations. Among patients with DDR-related gene mutations, 78 (7.25%) patients had the pathogenic (P) mutations or likely pathogenic (LP) mutations and 1056 (98.14%) had variants of unknown significance (VOUS) mutations. In total, the median TMB was 3.91 mutations/MB (range, 0-68.16) and 4.47 mutations/MB (range, 0-51.40) in patients with P, LP or VOUS mutations and no germline DDR-related gene mutations, respectively. To the further analysis, we divided patients with germline DDR-related gene mutations into three groups: only P or LP mutations (Group 1), only VOUS mutations (Group 2) and concurrence with P/LP/VOUS mutations (Group 3). Compare to the DDR-negative group, TMB was significantly lower in Group 2 (P < 0.001). No significant differences in Group 1 and Group 3 were observed. In addition, we found that mutations in different DDR pathway could not affect TMB value significantly. Conclusions: Germline DNA damage repair-related genes mutation may be not associated with TMB.

e20507 Background: In ALTER 0303, the common adverse reaction (AE) included hypertension (HTN) and hand foot syndrome (HFS). In this subgroup analysis, we aim to assess the relationship between common AEs and clinical benefit in anlotinib cohort. Methods: Eligible patients showed disease progression after second-line or further treatment were randomly assigned in a 2:1 ratio to receive 12 mg/day of anlotinib or placebo. The primary endpoint was overall survival (OS). This subgroup analysis was based on anlotinib cohort. Results: Patients with HTN had significantly improved median OS, median progress-free survival (PFS), objective response (ORR) and disease control rate (DCR) compared with patients without HFS in anlotinib cohort. Similarly, patients with HFS had better clinical outcomes in anlotinib cohort. Not surprisingly, patients occurred both HFS and HTN had more superior medium OS compared with only HFS, only HTN and neither HFS nor HTN. Conclusions: HTN or HFS is associated with better clinical outcomes in advanced NSCLC patients received anlotinib. Clinical trial information: NCT02388919. [Table: see text]

e20503 Background: As a promising multi-target tyrosine kinase inhibitor (TKI), anlotinib hydrochloride significantly improved overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients in the phase 3 trial (ALTER0303). Here, we demonstrated the efficacy of anlotinib in SCC patients with or without hypertension. Methods: Patients (n = 439) were randomized in a 2:1 ratio to receive anlotinib (12mg daily for 14 days in a 21 day cycle) or placebo. The primary endpoint was OS and second endpoints were PFS, ORR, DCR and QoL. The correlation between hypertension and efficacy (PFS and OS) was analyzed in SCC patients treated with anlotinib. Results: For different ECOG score (0 and 1) SCC patients (n = 46) in the anlotinib arm, the PFS was significantly improved in patients with hypertension in ECOG 1 group (7.00 vs 4.83 months, p = 0.043). There is no statistical difference in other subgroups. Moreover, for the SCC patients in anlotinib arm, PFS was significantly prolonged in patients with hypertension compared to the patients without hypertension (7.23 vs 3.23 months; HR = 0.36; 95% CI, 0.16–0.84; P = 0.001). However, the median OS of the patients with hypertension was numerically but not statistically longer than the patients without hypertension (13.93 vs 6.30 months; HR = 0.56; 95%CI, 0.26-1.22; P = 0.100). Conclusions: In the ALTER0303 trial, anlotinib significantly improved PFS with a potential benefit of OS for SCC patients with hypertension. And ECOG score does not affect the efficacy of anlotinib in SCC patients with or without hypertension. Clinical trial information: NCT02388919. [Table: see text]

9091 Background: Abivertinib (AC0010) is a potent, selective third-generation EGFR tyrosine kinase inhibitor (TKI) that demonstrated clinical efficacy and manageable adverse events (AEs) in the phase 1 portion of the study in Chinese patients with EGFR T790M+ NSCLC. Here we report the results from patients enrolled to the phase 2 portion of the study (NCT02330367). Methods: The study enrolled locally advanced or metastatic NSCLC patients who were ≥ 18 years, progressed with the prior EGFR-TKI therapy, and must have T790M+ in tumor based on the central laboratory test. All patients received the recommended phase 2 doses of 300 mg twice daily [BID]. Results: As of March 5, 2018, 227 patients received treatment, majority of patients had adenocarcinoma (n = 220, 97%) with the median age of 59 years, 65% (n = 148) patients were female, most patients were non-smoker (n = 171, 75%), ECOG performance status of 1 (n = 162, 71%). The median treatment duration was 21 week. The treatment-related adverse events (AEs) were reported for 96.9% (n = 220) patients, mostly of grade 1 or 2 severity. The most common drug-related grade 3/4 AE (≥2%) was ALT increase (7.0%), AST increase (4.8%), diarrhea (4.4%), interstitial lung disease (4.0%), neutrophil count decrease (3.5%), and there was no drug-related grade 5 AEs. Among 209 response evaluable patients, per investigator’s assessment, 90.0% (n = 188) patients had tumor size reduction, the objective response rate (Complete Response + Partial Response [PR]) was 50.2% (n = 105; 95% CI 43.3%, 57.2%); 37.8% (n = 79) had stable disease, and the disease control rate was 88% (95% CI 82.9%, 92.1%). The median duration of response and progression-free survival estimated by Kaplan-Meier was 7.5 months (95% CI 6.0, 9.2) and was 7.5 months (95% CI 6.0, 8.8), respectively. Conclusions: Abivertinib demonstrated the clinical efficacy with manageable side-effects in patients with EGFR T790M+ NSCLC. Therefore, abivertinib could be a suitable treatment for patients with EGFR T790+ disease who have progressed on an EGFR-TKI. Clinical trial information: NCTNCT02330367.

e21182Background: ALTER 0303 trial (NCT02388919) has demonstrated that anlotinib could significantly prolonged OS (primary point) and PFS in refractory advanced NSCLC pts as 3rd line treatment. Met...

9080Background: In the ALTER0303 trial (NCT02388919), anlotinib hydrochloride was used as subsequence therapy for adult IIIB/IV NSCLC pts who progressed after at least 2 lines of prior systemic the...

e21013Background: Anlotinib, a novel multi-targeted TKI targeting VEGFR, FGFR, PDGFR and c-Kit, significantly prolonged OS and PFS in ALTER0303 trial (NCT02388919) Here we report the efficacy of an...

e20571 Background: Lung adenosquamous cell carcinoma (ASC) is a rare subtype of lung cancer. Little is known about the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) for lung ASC with EGFR mutation. Methods: We retrospectively analyzed 44 patients with advanced or recurrent lung ASC harboring EGFR mutation who were treated with EGFR-TKI from two cancer centers to investigate the efficacy. Then a pooled analysis on the efficacy of EGFR-TKI was performed in 74 patients including 30 patients selected from 11 published reports. Results: In our bicenter research, for the ASC patients treated with EGFR-TKI, the objective response rate (ORR), the disease control rate (DCR), the median progression free survival (mPFS) and the median overall survival (mOS) were 54.5%, 79.5%, 8.8 months and 19.43 months, respectively. In pooled analysis, the ORR, DCR, mPFS and mOS of ASC patients were 63.4%, 85.9%, 10.00 months and 21.37 months, respectively. Similar PFS (11.0 vs. 10.0 months; P= 0.771) and OS (23.67 vs. 20.33 months; P= 0.973) were found in patients with deletion in exon 19 and exon 21 L858R mutation. The patients treated with erlotinib or gefitinib had a trend of better OS than those treated with icotinib. Conclusions: EGFR-TKI is an effective treatment for ASC harboring EGFR mutation, comparing with historical data, similar to EGFR-mutated adenocarcinoma (ADC). Further study is needed to identify the different role of the two components of ASC in EGFR treatment.

e14578 Background: The main reason for tumor MDR (multidrug resistance ,MDR) is the presence of CSC(cancer stem cells,CSC). In the CSC of lung cancer, OCT4 and Sox2 are closely related to the tumor MDR. Therefore, in the current study, we introduced a method for the generation of OCT4+/Sox2+ CSC specific CTL(cytotoxic T lymphocytes,CTL) through co-culture with CD154+ feeder layer cells. Methods: Lenti/CD154 was constructed. The NIH3T3 cells were incubated with Lenti/CD154 (103 vp per cell) for 24 h at 37 °C and 5% CO2. Then the NIH3T3 cells were subsequently maintained in fresh complete DMEM medium. Lenti/GFP was used as a control. On the 6th day post infection, the infection rate was determined by flow cytometry after incubation with CD154-PE antibody. The feeder layer cells were co-cultured with CD40B cells and the biomarkers of CD40B cells were determined by flow cytometry. The CTL were treated with OCT4 plus Sox2 antigen and then the biomarkers of CTL were examined by flow cytometry and IL-2 and IFNγ were determined by ELISA. Results: The rate of CD154+ NIH3T3 cells was 99.7%, which was higher than that of uninfected-cells (14.8%). After co-culture with CD154+ NIH3T3 cells, the rates of CD40B expressing CD80, CD86 and HLA-A were significantly increased. OCT4 plus Sox2 treatment further increased the CD3, CD4 and CD8 expression and elevated the secretion of IL-2 and IFNγ. After co-culture of CTL with MDR PC9-drived cancer stem cells (CSC) and parental PC9 cells at different ratio, CTL significantly killed the tumor cells compared with control. Conclusions: The generation and expansion of OCT/Sox2 specific CTL is a feasible method for the treatment of lung cancer.

e13007 Background: Genetic mutations in Mitofusin-2(MFN2) interrupt mitochondrial fusion and cause the untreatable neurodegenerative condition Charcot-Marie-Tooth disease type 2A( Nature, December 2016). MFN2 was initially identified as a hypertension-associated gene and implicated in the pathogenesis of multiple cancer types. However, underlying mechanisms of MFN2 in lung adenocarcinoma was unclear. Methods: MFN2 expression at protein level was examined in 30 pair lung adenocarcinoma/adjacent normal lung samples with immunohistochemistry staining. Then MFN2 knocked down in human lung adenocarcinoma cells A549 with lentiviral-mediated shRNA strategy. The effects of MFN2 knockdown on cell proliferation, cell cycle process, cell migration and invasion was investigated in A549 cells. MFN2-knockdown induced gene expression changes was analyzed by microarray assay and then functional pathway enrichment analysis was performed to identify critical pathways involved in MFN2-mediated lung adenocarcinoma development. The expression changes of downstream factors were determined by western blot. Furthermore, tumor models in nude mice were generated. Tumor formation and progression in these mice were analyzed. Results: As compared to adjacent normal lung tissues, MFN2 expression was significantly higher in lung adenocarcinoma tissues with positive MFN2 signals in 90% (27/30) lung adenocarcinoma tissues and only in 26.7% (8/30) adjacent normal tissues. Furthermore, MFN2 knockdown inhibited cell proliferation, induced cell cycle arrest and blocked invasion behavior in A549 cells. MFN2-knockdown induced gene expression changes in A549 cells was analyzed by microarray assay. Functional pathway enrichment analysis revealed that 6 pathways were enriched in deregulated genes including Cell cycle, DNA replication, ECM-receptor interaction, Focal adhesion, MAPK signaling pathway and Chemokine signaling pathway. Downregulation of RAP1A and upregulation of RALB and ITGA2 identified in MFN2-knockdown cells by microarray analysis were confirmed by western blot. In vivo, tumor formation and progression in nude mice showed that MFN2 knockdown reduced tumorigenesis of A549 cells. Conclusions: MFN2 overexpression run a risk of lung adenocarcinoma.

8566Background: Small-cell lung cancer (SCLC) accounts for 10-15% of all lung malignancies and is characterized by its neuroendocrine differentiation, prominent association with tobacco, elevated s...

9041Background: Icotinib is an oral, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), which is non-inferior to gefitinib in treating unselected or EGFR-mutated advan...

e20051Background: Small pulmonary nodules less than 10 mm are difficult to diagnose lung cancer, but it is also the best opportunity to cure lung cancer. The national lung cancer screening test (NL...

e20519Background: Increasing elderly patients suffer from non-small cell lung cancer (NSCLC) due to aged population, which is associated with more comorbidities and reduced organ function. Here we ...

e13591 Background: Hyperplasia suppressor gene (HSG) encodes a mitochondrial protein associated with mitochondrial fusion process. HSG was initially identified as a hypertension-associated gene and...

8039 Background: Platinum-based doublet chemotherapy is the standard chemotherapy regimen for treatment-naive advanced Non-Small-Cell Lung Cancer (NSCLC). S-1, an oral fluoropyrimidine, combined wi...

e19066 Background: Cyclooxygenase-2 (COX-2) protein expression in patients with non-small-cell lung cancer (NSCLC) has been proved a prognostic marker for COX-2 inhibition. But we need a feasible p...

e22177 Background: Our previous study suggested that hyperplasia suppressor gene (HSG) induced apoptosis of mitochondrial pathway via MAPK signal transduction pathway. In order to study on the apoptosis mechanisms via mitochondrial pathway induced by the HSG gene on human lung adenocarcinoma cells, we constructed and identified the efficacy of a lentiviral vector harboring RNA Interference sequence targeting the HSG gene. Methods: Three siRNA sequences targeting the HSG mRNA were designed. The levtivirus vectors of GCSIL-GFP-HSG were constructed and confirmed by DNA sequencing. The 293T cells were co-transfected with pGCSIL-GFP-HSG, pHelperl.0 and pHelper2.0 in order to produce the virus stocks. The titer of the virus was also tested. The lentivirus was transfected to human A549 lung adenocarcinoma cells. The expression of the HSGgene was analyzed by Real-time PCR. Results: DNA sequencing suggested that the DNA sequences were consisted with it designed, which meant that the RNAi sequence targeting the hum...

7507 Background: Etoposide combined with cisplatin (EP) has been the first-line chemotherapy regimen for small cell lung cancer (SCLC) for >20 years; however, a more effective regimen has been recommended by many clinical oncologists. Thus, we here present our preliminary results of a phase III clinical trial of the novel drug amrubicin in combination with cisplatin (AP) in comparison to EP in patients with previously untreated extensive SCLC (ED-SCLC). Methods: A total of 299 previously untreated ED-SCLC patients were randomized (ratio, 1:1) into two treatment groups: (1) the AP group (n = 149): 4–6 cycles of amrubicin (40 mg/m2/day on days 1–3) and cisplatin (60 mg/m2/day on day 1) and (2) the EP group (n = 150): 4–6 cycles of etoposide (100 mg/m2/day on days 1–3) and cisplatin (80 mg/m2/day on day 1 every 21 days). Patients were evaluated for therapy response and electrocardiography results every 2 cycles. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), overall response rate (ORR), and general safety. Results: Baseline characteristics were similar among the two groups. For AP and EP groups, the median OS was 11.79 and 10.28 months, the median PFS was 7.13 and 6.37 months, and ORR was 69.8% and 57.3%, respectively. The most frequent adverse events (≥grade 3) in AP and EP groups were bone marrow failure (23.5% and 21.3%, respectively), neutropenia (54.4% and 44.0%, respectively), and leukopenia (34.9% and 19.3%, respectively). Conclusions: Our phase III trial demonstrated that for previously untreated ED-SCLC patients, AP therapy was not inferior to EP therapy in terms of OS and offered predictable and manageable toxicities. Clinical trial information: NCT00660504.

e19018 Background: Advanced non-small cell lung cancer (NSCLC) remains an incurable disease by following conventional chemotherapy and is the major cause of cancer–related mortality worldwide. Dendritic cells (DC) play a central role in the induction of an effective antitumor immune response. Cytokine-induced killer (CIK) cells, the subset of T lymphocytes, have a profound capacity to cytolytically eliminate cancer cells. This study was designed to evaluate how the times of receiving DC/CIKs vaccination following regular chemotherapy impact the overall survival time in patients of advanced lung cancer. Methods: 43 patients suffering from IIIB-IV NSCLC were enrolled in the study between August 2004 and December 2008, and all received four courses of vinolbine-platinum (NP) chemotherapy followed by vaccinated with carcinoembryonic antigen (CEA) peptide-pulsed autologus dendritic cells and CIK cells. Vaccination was repeated at 30-day intervals until the patient refused to accept. The adverse effect and overall survival (OS) were evaluated. Results: Median survival time (MST) of all patients was 19.50 months. The 1-, 2- and 3-year overall survival rate was 66.50%, 41.04%, 28.14% respectively. The 1-, 2- and 3-year overall survival rate of patients who received no less than two times of vaccination therapy was 83.92%, 74.59%, 49.73% and who received only one time was 59.44%, 23.71%, 17.78% respectively. A statistically significant difference between the two groups was identified (p=0.0052). The adverse effect as a result of chemoimmunotherapy was tolerable. Conclusions: Advanced NSCLC patients can benefit from the combination of DC-CIK vaccination followed conventional chemotherapy,and the more vaccination therapy received the longer overall survival time observed.

e17551 Background: Patients with stage IIIA N2 NSCLC have poor outcomes with 5-year survival rate. Tyrosine kinase inhibitor monotherapy have been demonstrated a significant improvement in OR rate and PFS as first-line treatment for metastatic NSCLC patients with EGFR mutation. The objective of trial is to explore the efficacy and safety profile of erlotinib as neoadjuvant treatment in patients of stage IIIA-N2 NSCLC with EGFR mutation. The purpose of this neoadjuvant regime is to down-stage and increase complete resection rate in this patients setting. Methods: This is a single arm, one center, phase II study of erlotinib as neoadjuvant treatment in patients with Endobronchial Ultrasound (EBUS) confirmed stage IIIA-N2 NSCLC with activating EGFR mutation in exon 19 or 21. The primary endpoint is to evaluate radical resection rate. The secondary endpoint is pathological complete resection rate (pCR), objective response rate (ORR), disease free survival (DFS), overall survival (OS), quality of life (QoL) and safety profile. A total of 44 patients will be enrolled. Patients with IIIA-N2 NSCLC with pathologically confirmed ipsilateral mediastinal metastasis by EBUS. The biopsy specimen shows EGFR mutation in exon 19 or 21. All patients will be treated by erlotinib 150mg orally per day for 56 days. Patients will be assessed by Chest CT for the efficacy evaluation in day 29 and right after day 56. Patients get benefit from neoadjuvant treatment and evaluated as technically resectable will receive surgery. All the post-operative patients will receive standard adjuvant treatment. The adjuvant regime is decided by the investigator for the patients’ benefits. After adjuvant treatment patients will enter nomal follow-up including regular chest CT and ultrasound examination Results: Current enrollment: The study has enrolled 5 patients. One male patient, aged 47, with stable disease after neoadjuvant treatment, got right upper lobe resection on 17 Jan 2012. Conclusions: Erlotinib as neoadjuvant treatment in patients of stage IIIA-N2 NSCLC with activating EGFR mutation is feasible.

e18038 Background: Background: As the non-smoking Asian patients with adenocarcinoma of the EGFR gene tend to have higher mutation rate, and serum CEA levels in patients with lung cancer, especially adenocarcinoma, high expression in many recent years, studies have also found that serum CEA levels in EGFR-changes before and after TKI therapy efficacy and treatment are closely related. However, whether serum CEA level and EGFR gene mutations is a correlation between two biomarkers. This study attempts to explore its relevance between EGFR gene mutations and analysis of serum CEA levels in non-smoking patients with lung cancer and it’s various clinical and pathological features. Methods: 84 cases of histologically confirmed non-smoking history in newly diagnosed lung cancer patients, respectively, serum CEA levels and histological detection of EGFR gene. According to the expression level of serum CEA patients were divided into high expression and did not express two groups were compared in patients with EGFR gene mutations. Results: 58/84 cases were found with activity EGFR gene mutations, the overall mutation rate was 69.0%, serum CEA levels high expression of EGFR gene mutation was significantly higher than non-expression group (serum CEA levels were

e12013 Background: Vitamin D and its receptor (VDR) have been implicated in lung cancer incidence and mortality. Here we assess the relationships between VDR single nucleotide polymorphisms (SNPs) (FokI, BsmI, ApaI, Taq, Cdx2) and lung cancer incidence in Chinese patients. Methods: Genomic DNA was extracted from peripheral blood samples. Five VDR SNPs (FokI, BsmI, ApaI, Taq, Cdx2) were detected by polymerase chain reaction. Genotype analysis was conducted using mass spectrograph. Results: A total of 67 lung cancer patients and 72 healthy controls participated in the study. There were more males and current smokers among the lung cancer patients than among healthy controls. Lung cancer patients were much older than controls. Age and smoking status were included in the equation for predicting disease status. The CC-AA (Apa1-Cdx2) and the CC-AA-CC (ApaI-Cdx2- FokI) haplotypes were associated with higher lung cancer incidence. The rs1544410 (BsmI) and rs731236 (TaqI) were not associated with higher lung cancer incidence, but they were associated with rs797523 (ApaI). Conclusions: There is a significant correlation between certain VDR SNPs (FokI, ApaI, Cdx2) and lung cancer incidence in Chinese people.

e13528 Background: The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. SIM-89, developed by Simcere Bio-Pharmaceutical Co, Ltd, is a small-molecule kinase inhibitor that targets members of the HGF receptor tyrosine kinase families. Methods: Kinase inhibition was investigated using Z-lyte detection technique(Invitrogen), LanthaScreen Tb-activity technique and LanthaScreen Binding technique. Inhibition of p-Met and Met is validated through Westernblot. IC50 of the compound is determined by CCK-8. HGF level in culture medium is determined by ELISA.Migration and invasion assayare done with Transwell system. A549 and H460(2×106)are implanted subcutaneous in right upper extremity of nude mice.Once daily oral administration of SIM-89/ placebo are given to nude mice for 35d.Tumor growth curve is calculated. B16F10 tumor cells (2 × 105) were implanted via i.v. tail vein injection into mice on day 0. SIM-89/ placebo administration was initiated 3 days after implantation for 10 days followed by assessment of lung tumor burden. Lung nodule diameters were morphometrically measured on digitally captured images. The results for each treatment group (n = 10 animals) were averaged, and statistical t test analysis was done comparing each treatment group to the placebo treated control. Results: SIM-89 is a small-molecule kinase inhibitor that targets members of the HGF receptor tyrosine kinase families,with additional inhibitory activity toward AMPK (A1/B1/G1) and TRKA. SIM-89 significantly decreases HGF level in culture medium of nsclc cell lines at the IC50 of 625nmol/l. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis. Once daily oral gavage administration of SIM-89 resulted in a dose-dependent reduction in tumor burden, as determined by a reduction in lung wet weights. Conclusions: These data indicate that SIM-89 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion mediated by HGF receptors.

e18013 Background: Adjuvant chemotherapy demonstrated a 5-15% benefit in 5-year survival in early-stage NSCLC. Endostar,a recombinant human Endostatin, could inhibit tumor angiogenesis. In a phase III trial, the addition of Endostar to NP regimen resulted in higher response rate, clinical benefit rate and longer median time to progression compared with NP alone in advanced NSCLC patients. Methods: Completely resected patients (stage IB-IIIA) were randomized to receive adjuvant NP plus Endostar (arm A, Vinorelbine 25mg/m2 on d1 and d8 plus Cisplatin 80 mg/m2 intravenously plus Endostar 7.5mg/m2 per day, iv, for 14 consecutive days. 21 days as one cycle(arm A) or NP regimen alone (arm B) for four cycles. The randomization was stratified by gender, stage and histology. The primary endpoint was OS and the secondary endpoints were RFS and safety. Results: 1037 patients (arm A: 520; arm B: 517) from 43 centers in China were enrolled between 9/2007 and 12/2010. Two arms were well-balanced with regard to age, gender, histology, stage, and resection type. 184 patients in arm A and 202 patients in arm B had relapsed disease or died. The median RFS was 34.1 months in arm A and 30.3 months in arm B (p=0.1573). 79.0% of patients in arm A and 76.0% of patients in arm B received 4 cycles of chemotherapy. Median survival time was not available at this time. Grade 3/4 toxicities in arm A included leukopenia (57.4%), neutropenia (75.0%), anemia (12.9%), nausea (11.3%). Grade 3/4 toxicities in arm B included leukopenia (35.0%) neutropenia (60.5%), anemia (8.5%) and nausea (8.5%). It is worth noting that the incidence of cardiac toxicities in arm A (26.3%) was slightly higher than that in arm B (21.4%). Conclusions: The preliminary result showed that patients in arm A experienced a longer median relapse-free survival time than in arm B (34.1 months vs. 30.3 months), although the difference was not statistically significant by far. The toxicity profiles for both arms were tolerable in this study. The patient follow-up is still ongoing.

e21001 Background: Tumors are dynamic organs, in which active processes of cell differentiation affect disease course by regulating the composition of cells at the tumor site. we hypothesize that regDC form the premalignant niche in the lung to support lung cancer development and sustain lung cancer growth and progression. Furthermore, we evaluated if paclitaxel affected regDC and paclitaxel in noncytotoxic concentrations prevents polarization of cDC into regDC.Methods: Bone marrow-derived cDC were treated with tumor conditioned media from 3LL lung cancer cell lines for 48 h, washed, depleted of GR1+ cells and added to ConA-stimulated syngeneic T cells. 3LL-induced regDC were isolated by cell sorting from the in vitro generated cultures or from lungs harvested from 3LL-bearing mice. Analysis of immunosuppressive DC revealed them as CD11clowCD11bhigh CD80lowCD86lowMHC-IIlowPDCA1negGR1neg cells. For the in vivo evaluation of the potential protumorigenic properties of regDC, sorted CD11clowCD11bhigh (regDC) and CD11chighCD11blow/neg (cDC) subsets were injected (5x105cells i.p.) into mice together with 1/15 of the minimum tumorigenic dose of 3LL tumor cells (2x104cells, i.v.). As expected, no tumor nodules were detected in lungs in mice treated with saline or cDC (0/6 mice).However, >30% of mice injected with regDC developed lung tumors, suggesting that regDC exhibit a potent protumorigenic activity in vivo. Next, we asked if paclitaxel could alter regDC formation in vivo. Paclitaxel was administered in 3LL lung metastasis bearing mice. Lymphoid and non-lymphoid tissues were harvested 3 weeks later and analyzed for regDC subsets by flow cytometry.Results: The addition of tumor conditioned converts immunostimulatory cDC into regDC that can suppress proliferation of T cells. Paclitaxel in ultra low noncytotoxic concentrations in vitro could prevent tumor-induced polarization of conventional cDC into regDC. Furthermore, administration of paclitaxel prevented formation of regDC in the lung and significantly inhibited formation of metastases .Conclusions: These data suggest that paclitaxel in ultra low nontoxic doses is able to module the tumor immunoenvironment and support the anti-cancer efficacy of cancer vaccine.

e18088 Background: Combinations of anti-angiogenic drugs with chemotherapeutics are widely used for cancers control. Whether can better efficacy of such a combinated modality be achieved and predicted earlier is a great challenge. Circulating endothelial cells (CECs) and cytokeratins (CKs) might have a role in tumour angiogenesis and in tumour cell death. Measurement of CECs and CKs in the blood of patients with tumors could be a simple, non-invasive approach to monitor or predict responses and survival to treatment. Methods: One hundred and seven patients with primary advanced non-small cell lung cancer (NSCLC) were enrolled, randomly assigned to either the endostatin treatment group (paclitaxel+ carboplatin+ endostatin) or the control group (paclitaxel+carboplatin). CEC count and serum CK8, caspase-cleaved CK18 (ccCK18) and uncleaved CK18 (CK18) were measured in the 107 subjects at before treatment (baseline), week 3, and week 6 of treatment, respectively. Results: Higher baseline CEC count was observed in patients with good tumor response (p=0.002 for all the 107 patents; p=0.000 in the treatment group). When compared with the baseline level, after 6 weeks therapy in the endostatin group, CECs decreased significantly (p=0.000), but the CKs levels increased. The increased levels of ccCK18 and CK18 at week 6 reached significance in the treatment group (p=0.001 and p=0.048, respectively). Tumor response showed strong correlation with the reduction extent of CECs (p=0.000) and the increase value of ccCK18 (p=0.040) after endostatin therapy. The best cut-off values of the changes of CECs and ccCK18 for prediction of survival were designed being 0.58/ul and 19.6ng/ml, respectively. Furthermore, obvious reduction of CECs and more rise of ccCK18 significantly correlated with the longer median survival (p= 0.013 and p = 0.016 for PFS, p = 0.009 and p=0.012 for OS, respectively). Conclusions: CECs and CKs would be the impressive biomarkers to explore for selecting NSCLC patients who might benefit from endostain in combination with paclitaxel plus carboplatin treatment.

1551 Background: No clear consensus has been reached on the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene C609T polymorphism and lung cancer risk. We performed a meta-analysis to summarize the possible association. Methods: We conducted a computer retrieval of PUBMED and EMBASE databases prior to January 2012. References of retrieved articles were also screened. According to the inclusion criteria, 24 articles (31 studies) were finally included. The fixed-effects model and the random-effects model were applied for dichotomous outcomes to combine the results of the individual studies. Results: There was no statistical association between C609T polymorphism and lung cancer risk in overall, East Asians, African-Americans or Hispanics. In Caucasians, significant association was found in allele comparison model (T vs. C) (P=0.04, OR=1.09, 95%CI [1.00–1.19], Pheterogeneity=0.24, fixed-effects model). In Hawaiians, significant association could be found in dominant genetic model ((TT+CT) vs. CC) (P=0.04, OR=0.52, 95%CI [0.28–0.96], fixed-effects model). In the subgroup of squamous cell carcinoma, a borderline significance could be found in the dominant genetic model ((TT+CT) vs. CC) (P=0.05, OR=1.20, 95%CI [1.00–1.43], Pheterogeneity=0.65, fixed-effects model). Significant association could also be found in allele comparison (T vs. C) (P=0.03, OR=1.21, 95%CI [1.01–1.44], Pheterogeneity=0.68, fixed-effects model). In the subgroup of small cell lung cancer risk, significant association were found in allele comparison (T vs. C) (P=0.03, OR=1.68, 95%CI [1.05–2.68], Pheterogeneity=0.10, random-effects model) and in the homozygote comparison (TT vs. CC) (P=0.02, OR=2.79, 95%CI[1.14–6.85], Pheterogeneity=0.72, fixed-effects model). No association was observed in adenocarcinoma subgroup. Conclusions: NQO1 C609T polymorphism might associate with lung cancer risk in Caucasians and Hawaiians. NQO1 C609T polymorphism might also associate with squamous cell carcinoma and small cell lung cancer risk.

7527 Background: Endostatin is one of the most effective inhibitors of tumor angiogenesis. Clinical studies have shown that chemotherapy combined with endostatin could improve response rate and the...

e18145 Background: Sunitinib, a small molecule, is a multitargeted receptor kinase inhibitor which targets the vascular endothelial growth factor receptor and platelet-derived growth factor receptor as well as several others. Several clinical trial results have already demonstrated the therapeutic potential of this agent in renal cell carcinoma and gastrointestinal stromal tumor, however, only few studies were conducted to investigate the effectiveness of the use of sunitinib in refractory NSCLC. We reported a case series of patients with previously treated, refractory non-small cell lung cancer and evaluated the clinical activity and tolerability of sunitinib. Methods: Patients with stage IIIb or IV NSCLC for whom platinum-based chemotherapy had failed received sunitinib at a dose of 37.5 mg orally once daily combination with or without standard agents or regimens currently used in the NSCLC. Results: We illustrated 24 refractory NSCLC patients who received sunitinib treatment. Two patients were treated ...

e19095 Backgrounds: Recent studies reported that zoledronic acid, a biphosphonate with proposed apoptotic activity, could cause a direct antitumor effect. Our prior study [J Clin Oncol 26: 2008 (May 20 suppl; abstr 19116)] reported that Zoledronic acid combined with Cisplatin shows significantly synergistic antitumor effects on lung cancer cell line A549 and subcutaneous implanted tumor on nude mice. Investigate whether zoledronic acid, augmented the cytotoxicity of cisplatin and/or paclitaxel in A549 lung cancer cell line. Methods: This cell line was subjected to different concentrations of the above chemotherapeutic agents and zoledronic acid. Cytotoxicity was assessed by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrasodium bromide) assay. Flow cytometry was used to examine cell cycle,cell apoptosis rate. Results: Zoledronic acid in in 50 micromolar (mM) concentration augmented the cytotoxicity by cisplatin in 10μmol/L and paclitaxel in 5μmol/L. Zoledronic acid could inhibit the proliferation of lung cancer cells in vitro,which was associated with arresting of G1 phase and inducing apoptosis by a time-dependent and dose-dependentmanner. The apoptosis rate of cell increased after zoledronic acid combined with cisplatin and/or paclitaxel. Conclusions: Zoledronic acid can induce apoptosis and block cell cycle of lung cancer cells. Zoledronic acid has also shown synergistic antitumor effects when combined with cisplatin and/or paclitaxel. The clinical potential of this finding should be further studied. No significant financial relationships to disclose.

8041^ Background: The IRESSA Pan Asia Study (IPASS) demonstrated superiority of G vs C/P for progression-free survival (PFS) in 1,217 chemonaïve, never/light ex-smokers with WHO PS 0–2, adenocarcinoma histology and stage IIIB/IV NSCLC. PFS favored C/P initially then G, likely driven by different outcomes according to EGFR mutation (M) status. Planned analyses of pts recruited in China are reported. Methods: 372 pts in China (31% of overall population) were randomized to G 250 mg/day (n=184) or C (AUC 5 or 6)/P (200 mg/m2) (n=188). Primary objective was to assess PFS in ITT population; a treatment by country interaction test (China vs other) was performed. Secondary endpoints were overall survival (OS), objective response rate (ORR, RECIST), QoL (FACT-L, TOI), symptom improvement (LCS) and tolerability. Results: PFS results for pts in China did not significantly differ from other pts (interaction test p=0.4265). G demonstrated numerically longer PFS vs C/P; effect was not constant over time, favoring C/P initially then G. Preliminary OS (28% maturity; follow-up ongoing) was similar for G and C/P. ORR was significantly higher with G (45%) than C/P (30%). QoL improvement rates were higher with G than C/P (FACT-L 44 vs 34%; TOI 45 vs 25%); symptom improvement rates were similar (LCS 48 vs 42%). G had a more favorable tolerability profile than C/P. Conclusions: For pts in China, efficacy and tolerability data were generally consistent with the overall population. G demonstrated improved efficacy (PFS and ORR), similar OS, higher QoL and similar symptom improvement rates and more favorable tolerability profile compared with C/P in chemonaïve, never/light ex-smokers with advanced NSCLC and adenocarcinoma histology. In IPASS, EGFR mutation status appeared to be a strong predictive biomarker for G efficacy compared with C/P. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

e19094 Purpose: We investigated whether Treatment Guided by ERCC1,RRM1 and BRCA1 protein expression levels could improve clinical outcomes in Patients With Advanced-Stage NSCLC. Experimental Design: Eligibility: Main inclusion criteria: Stage IV or stage IIIB NSCLC; Eastern Cooperative Oncology Group(ECOG) performance status (PS) 0–1; Measurable disease; Adequate bone marrow, kidney, liver function. Main exclusion criteria: previous NSCLC therapy; Central nervous system metastasis; Requiring immediate intervention or Untreated with radiation within 28 days of study regimen initiation. Previously untreated patients with Stage IV or stage IIIB NSCLC(N=180): Standard chemotherapy group(N=60): Cisplatin 75mg/m2 Day1+Vinorelbine 25mg/m2 Days 1,8 every 28 days; Individualized chemotherapy group (N=120) (ERCC1,RRM1 and BRCA1 protein expression assayed with IHC); Low ERCC1 protein expression subgroup: Cisplatin 75mg/m2 Day1+Vinorelbine 25mg/m2 Days 1,8 every 28 days; High ERCC1 protein subgroup: Vinorelbine 25mg/m2 Days 1,8+Gemcitabine 1250mg/m2 Days 1,8 every 28 days. Description of Current Analysis: ERCC1,RRM1 and BRCA1 protein expression assayed with IHC; Assigned treatment based on ERCC1 protein expression; Primary endpoint: overall response rate; Secondary endpoints: Overall survival (OS), Progression-free survival (PFS). Enrollment progress (As of time Dec-31–2008): See Table . [Table: see text] No significant financial relationships to disclose.

19126 Background: Patients with non-small cell lung cancer are currently treated with concomitant or sequential chemotherapy and radiotherapy. However, the effect of existing treatment modalities i...

4560 Background: We investigated the impact of expression of hypoxia inducible factor (HIF)-1α and phosphorylated Akt (p-Akt) on prognosis of gastric adenocarcinoma patients. Methods: Expressions of HIF-1α protein and p-Akt were studied by immunohistochemistry in 188 gastric adenocarcinoma patients. We investigated the impact of HIF-1α and p-Akt on survival. Furthermore we analyzed the correlation of expression of HIF-1α and p-Akt to clinicopathologic features. Results: Among 188 gastric adenocarcinoma patients, 158 (84%) and 148 (78.7%) were positive for HIF-1α and p-Akt. HIF-1α protein expression showed an impact on survival of gastric adenocarcinoma patients by both univariate and multivariate factors analysis. The median survival was significantly different between HIF-1α negative and positive patients (not reached vs 30.9 months, p=0.039, log rank test). High expressions of HIF-1α and p-Akt were significantly correlated with pTNM stage (p=0.004 for HIF-1α and p=0.031 for p-Akt), depth of invasion (p

20743 Background: To determine the efficacy and safety of epoetin beta in the prevention and treatment of anaemia in non-small cell lung cancer (NSCLC) patients treated with chemotherapy. Methods: ...

15062 Background: The survival of advanced gastric cancer remains poor, while no chemotherapy regimen was recognized standard. Oxaliplatin and Capecitabine (Xeloda) have demonstrated promising antitumor efficacy in advanced colorectal cancer. The present study was conducted to further evaluate the efficacy and safety of XELOX (Oxaliplatin and Xeloda) regimen in gastric cancer. Methods: Patients with unresectable or metastatic gastric cancer were enrolled into this study. They all receive the XELOX regimens (Oxaliplatin 130mg/ m2 intravenously in 2 hours on day 1 followed by oral capecitabine 1000mg/ m2 twice daily for 14 days every 3 weeks).We evaluated the response every 2 cycles. Results: The median age of the total enrolled 45 patients was 55 years (range, 22–82 years), including 32 male and 13 female. They received a median of 5 cycles (range, 2–8 cycles) of XELOX. 21 of 45 patients (46.7%) achieved an objective response, 1 patient (2.2%) had completed response. 17 patients (37.8%) experienced stable disease. Median time to tumor progression (TTP) and median overall survival were not available yet due to the further follow-up needed. Most toxicity events were mild to moderate in XELOX regimen, with grade 3/4 neutropenia of 8.9 %, thrombocytopenia of 6.7%, anemia of 11.1%, hand-foot syndrome of 6.7 % and diarrhea of 6.7 %. Grade 3 neuropathy was 4.4%. The patients with advanced gastric cancer had a good tolerance to this chemotherapy. Conclusions: XELOX is a highly effective first-line treatment for unrsectable and metastatic gastric cancer. The response rates in this trial seems to be similar to those observed with FU/leucovorin/oxaliplatin combinations. XELOX is tolerable well in the treatment of advanced gastric cancer. No significant financial relationships to disclose.