DNMT3A governs tyrosine kinase inhibitors responses through IAPs and in a cell senescence-dependent manner in non-small cell lung cancer.

Patients with non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) inevitably exhibit drug resistance, which diminishes therapeutic effects. Nonetheless, the molecular mechanisms of TKI resistance in NSCLC remain obscure. In this study, data from clinical and TCGA databases revealed an increase in DNMT3A expression, which was correlated with a poor prognosis. Using NSCLC organoid models, we observed that high DNMT3A levels reduced TKI susceptibility of NSCLC cells via upregulating inhibitor of apoptosis proteins (IAPs). Simultaneously, the DNMT3Ahigh subset, which escaped apoptosis, underwent an early senescent-like state in a CDKN1A-dependent manner. Furthermore, the cellular senescence induced by TKIs was observed to be reversible, whereas DNMT3Ahigh cells reacquired their proliferative characteristics in the absence of TKIs, resulting in subsequent tumour recurrence and growth. Notably, the blockade of DNMT3A/IAPs signals enhanced the efficacy of TKIs in DNMT3Ahigh tumour-bearing mice, which represented a promising strategy for the effective treatment of NSCLC.

Real-world evidence of osimertinib in Chinese patients with EGFR T790M-positive non-small cell lung cancer: a subgroup analysis from ASTRIS study.

PURPOSE: ASTRIS study aimed the largest to evaluate the effectiveness and safety of second- or higher-line osimertinib in patients with advanced/metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) in the real-world setting. Here we report the results of Chinese patients in ASTRIS study. METHODS: Adults with EGFR T790M-positive advanced NSCLC pretreated with EGFR-tyrosine kinase inhibitor (EGFR-TKI), having a WHO performance status score of 0-2 and asymptomatic, stable central nervous system (CNS) metastases were included. All patients received once-daily osimertinib 80 mg orally. The outcomes included investigator-assessed clinical response, progression-free survival (PFS), time-to-treatment discontinuation (TTD), and safety. RESULTS: A total of 1350 patients were included. Response rate was 55.7% (95% confidence interval [CI] 0.53-0.58). The median PFS and the median TTD were 11.7 months (95% CI 11.1-12.5) and 13.9 months (95% CI 13.1-15.2), respectively. Overall, 389 patients (28.8%) had at least one protocol-specified adverse event (AE); AEs of interstitial lung diseases/pneumonitis-like events and QT prolongation were reported in 3 (0.2%) and 59 (4.4%) patients, respectively. CONCLUSION: Osimertinib was effective in Chinese patients with T790M-positive NSCLC who had progressed after first- or second-generation EGFR-TKI in real-word setting and the results were consistent with ASTRIS study overall population and AURA studies. No new safety signals or events were identified. CLINICAL TRIAL NUMBER: NCT02474355.

A Novel Combined Conjugate Therapeutic Cancer Vaccine, Recombinant EGF-CRM197, in Patients With Advanced Solid Tumors: A Phase I Clinical Study.

INTRODUCTION: The therapeutic cancer vaccine recombinant Epidermal Growth Factor (EGF)-CRM197 is a novel combined conjugate EGF with CRM197 as a carrier protein. Immunization with the EGF-CRM197 vaccine can induce high levels of neutralizing anti-EGF antibodies that inhibit EGF/EGFR signaling and thereby suppress growth of tumors that rely on this signaling pathway. Herein, we characterize the humoral immune responses elicited by the recombinant EGF-CRM197 vaccine in patients with advanced solid tumors in a phase I clinical trial and assess the safety, tolerability, and immunogenicity of this vaccine (CTR20190473). METHODS: A total of 16 subjects were enrolled in this study. Under 6 + 3 design, patients in each dosing cohort were administrated subcutaneously at a dosage of 0.4 mg, 0.8 mg, and 1.6 mg, respectively. The patients received vaccinations for immune induction (once a week for 4 consecutive weeks) and booster vaccinations (once every 4 weeks). Safety evaluation was performed 1 week after the immune induction. Booster vaccination was given until the occurrence of disease progression, intolerance, withdrawal of informed consent by the patient, or negative result of anti-EGF test after two booster vaccinations. RESULTS: Vaccination with EGF-CRM197 is safe and well-tolerated in patients with advanced solid tumors. Adverse reactions at the injection site were the most common adverse events (AEs) in recipients. No severe adverse reactions post vaccination were observed in the present study. Vaccinated patients developed a robust neutralizing antibody response triggered by EGF-CRM197 that significantly reduced the levels of EGF in serum. For lung cancer patients who were super good antibody responders (sGAR) to EGF-CRM197, the median progress-free survival (PFS) was 4.83 months, significantly longer than that of the good antibody responder (GAR) patients with lung cancer whose median PFS was 2.10 months (P=0.0018). The median overall survival (OS) of GAR lung cancer patients was 10.67 months while the OS) for sGAR lung cancer patients was not reached until analysis was performed. The median follow-up of the sGAR lung cancer patients was 14.6 months. CONCLUSION: Our study demonstrates that the recombinant EGF-CRM197 therapeutic cancer vaccine can induce a good immune response in patients with advanced solid tumors and is safe and well tolerated, which ensures further clinical development of the vaccine for extending the survival time of EGF-CRM197 sensitive patients with advanced solid tumors. CLINICAL TRIAL REGISTRATION: http://www.chinadrugtrials.org.cn, identifier CTR20190473, EGF-CRM197.

Differences in Immunological Landscape between EGFR-Mutated and Wild-Type Lung Adenocarcinoma.

Recent clinical trials of lung adenocarcinoma with immune checkpoint inhibitors revealed that lung adenocarcinoma patients with EGFR mutations have a poor response to immunotherapy. However, the mechanisms have not been addressed. We performed immunohistochemistry analyses of resected lung adenocarcinoma tissues with and without EGFR mutations to investigate and compare the characteristics of the tumor microenvironment (TME). We retrospectively enrolled a total of 323 lung adenocarcinoma patients (164 had EGFR mutations), and their corresponding tissue samples were analyzed by the EGFR mutation test and immunohistochemistry. We selected the markers of the immune checkpoint molecule (PD1, PD-L1, and LAG-3) and immune cell (CD3, CD4, CD8, and Foxp3) as markers of the tumor microenvironment. Our results revealed that patients had a distinct tumor microenvironment between EGFR-mutant and wild-type lung adenocarcinomas; the expression of CD3, CD4, PD-L1, and Foxp3 in EGFR-mutant tumors was significantly higher than that in wild-type tumors, while the expression of LAG3 and PD-1 showed a positive correlation with EGFR-wild-type tumors. In survival analysis, EGFR-wild-type patients had longer disease-free survival (DFS) than EGFR-mutant patients (P = 0.0065). Our research demonstrates significant differences in tumor microenvironment composition between EGFR-mutant and wild-type patients. Our findings provide novel evidence that contributes to understanding the mechanism underlying the poor efficacy of immune checkpoint inhibitors.

Phase III study of selpercatinib versus chemotherapy ± pembrolizumab in untreated RET positive non-small-cell lung cancer.

Selpercatinib, a novel, highly selective and potent, inhibitor of RET, demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pretreated and treatment-naive RET fusion-positive non-small-cell lung cancer patients in a Phase I/II clinical trial. LIBRETTO-431 (NCT04194944) is a randomized, global, multicenter, open-label, Phase III trial, evaluating selpercatinib versus carboplatin or cisplatin and pemetrexed chemotherapy with or without pembrolizumab in treatment-naive patients with locally advanced/metastatic RET fusion-positive nonsquamous non-small-cell lung cancer. The primary end point is progression-free survival by independent review. Key secondary end points include overall survival, response rate, duration of response and progression-free survival. Clinical trial registration: NCT04194944 (ClinicalTrials.gov).

Comparison among different presentations of venous thromboembolism because of lung cancer.

INTRODUCTION: Venous thromboembolism (VTE) because of lung cancer has been sufficiently studied, nevertheless, little is known regarding the discrepancy of clinical characteristics and predictive factors among different presentations of VTE because of lung cancer. OBJECTIVES: This study was designed to investigate the distinction of clinical characteristics and predictive factors among different presentations of VTE because of lung cancer. METHODS: All patients concomitant lung cancer and VTE were stratified into three groups: pulmonary embolism (PE) group in which patients had sole PE, deep vein thrombosis (DVT) group with sole DVT and concomitance group with both PE and DVT. RESULTS: Concomitance of PE and DVT (28.2 days) mostly occurred at the early stage after the diagnosis of lung cancer, by contrast with DVT (63.6 days) which did at the latest stage, whereas PE (36.7 days) generally developed intermediately in between (P = .02). In a Kaplan-Meier analysis, the cumulative survival rate of DVT group was higher than that of concomitance group, whereas the rate of PE group lied in between. (P = .002) The strongest correlated factors with the development of DVT, PE and concomitance were adenocarcinoma (HR 3.27, P = .003), chemotherapy (HR 2.62, P = .005) and D-Dimer (HR 3.88, P < .001), respectively. The strongest correlated factors with the mortality of DVT, PE and concomitance were comorbidity (HR 2.32, P = .003), metastasis (HR 3.12, P < .001), and metastasis (HR 4.29, P < .001), respectively. CONCLUSION: Concomitance of DVT and PE represents the severest state of lung cancer, the earliest occurrence of VTE, and the worst survival rate, whereas DVT stands for the mildest condition of lung cancer and stablest pattern of VTE.

SPOP promotes FADD degradation and inhibits NF-κB activity in non-small cell lung cancer.

FAS-associated protein with death domain (FADD) is the pivotal adaptor protein, which transmits apoptotic signals mediated by the death receptors. Here we report that high FADD protein level predicts poor prognosis of non-small cell lung cancer (NSCLC) patients and its protein level is mainly regulated by the 26S proteasome. We also found that ubiquitin ligase SPOP (speckle-type POZ protein) binds to FADD and mediates its degradation, which can be blocked by MG132 treatment. Notably, SPOP inhibits NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activity and its target genes expression via FADD. These results reveal the function of SPOP-FADDNFκB axis in NSCLC cells, which is associated with prognosis of NSCLC patients.

A consensus on immunotherapy from the 2017 Chinese Lung Cancer Summit expert panel.

The notable clinical success of cancer immunotherapy using checkpoint blockade suggests that it is likely to form the foundation of curative therapy for many malignancies. However, checkpoint blockades do not achieve sustained clinical response in most patients and thus amounts of problems needed to be figured out. Regarding these challenges, the 2017 Chinese Lung Cancer Summit expert panel organized a forum on the 14th Chinese Lung Cancer Summit to formally discuss these controversies. Five consensuses finally were reached to guide the application of checkpoint blockades.

Effect of nicotine dependence on quality of life and sleep quality in patients with lung cancer who continue to smoke after diagnosis.

BACKGROUND: Hundreds of millions of Chinese individuals continue to smoke and rates of lung cancer still continue to rise. However, there were few studies that examined the effects of nicotine dependence on quality of life (QOL) and sleep quality in lung cancer patients. This study aimed to investigate the effect of nicotine dependence on QOL and sleep quality in lung cancer patients who continue to smoke after diagnosis. METHODS: This cross-sectional survey study included 202 patients with lung cancer. Smokers were separated into two groups based on the Fagerstrom Test for Nicotine dependence: the low dependence (LD) (<4 score) group (n=59) and the high dependence (HD) (≥4 score) group (n=143). Both Chinese version of the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) and Chinese version of Pittsburgh Sleep Quality Index (PSQI) were used to evaluate the two groups of lung cancer patients. Then we analyzed the difference of QOL and sleep quality between two distinct nicotine dependence groups. RESULTS: Physical functioning, role functioning, emotional functioning, cognitive functioning, global health status and social functioning items in the LD group were significantly higher than the HD group (P<0.001). Fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, diarrhea and financial problems in the LD group were significantly lower than those in the HD group (P<0.001). Significantly higher scores in the HD group were found concerning the three sleep components including sleep duration, sleep efficiency and daytime function. The mean global PSQI score in the HD group was significantly higher than the LD group (P=0.014). CONCLUSIONS: These findings suggest that lung cancer patients who continue to smoke after diagnosis should receive health education in order to improve their QOL and quality of sleep after the word education. This can be useful for clinicians and nurses who are trying to motivate smokers to quit smoking.

Transition from Ambrisentan to Bosentan in Pulmonary Arterial Hypertension: A Single-Center Prospective Study.

Background and objective: Two endothelin receptor antagonists (ETRAs), bosentan and ambrisentan, are approved for patients with pulmonary arterial hypertension (PAH). However, there is little information about the transition strategy between these two ETRAs. We aimed to evaluate the safety and efficacy from ambrisentan to bosentan. Methods: Twenty PAH patients were enrolled into the single-center, open-labelled prospective study. Echocardiogram, WHO functional class (WHO-FC), 6-minute walking distance (6MWD), right heart catheterization, and hemotology were collected. After receiving oral 5 mg ambrisentan daily initially for one year, the patients were divided into two arms: eight patients switched to bosentan, while the remaining 12 patients continued ambrisentan. Characteristics at baseline, 1-and 2-year follow-up points were compared. RESULTS: There were no significant differences in echocardiogram, WHO-FC, hemodynamics, demographics and liver function at baseline, 1-and 2-year points in both arms. 6MWD in bosentan group was significantly shorter at baseline. But there were no significant differences of 6MWD at 1- and 2-year points. CONCLUSIONS: It is safe for stable PAH patients to transition from ambrisentan to bosentan without hemodynamic or hematologic deterioration.

Management of Progressive Pulmonary Nodules Found during and outside of CT Lung Cancer Screening Studies.

Although the effectiveness of screening for lung cancer remains controversial, it is a fact that most lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, albeit with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them is the open question of how enlarging pulmonary nodules detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches and the potential therapeutic options for enlarging pulmonary nodules, followed by a meeting report including consensus statements of an interdisciplinary expert panel that discussed the potential of the different therapeutic options.

Endobronchial ultrasound-guided transbronchial needle aspiration for diagnosing mediastinal lymphadenectasis: a cohort study from a single center.

OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is commonly used for clinical diagnosis of mediastinal lymphadenectasis. This study aimed to evaluate the diagnostic significance of EBUS-TBNA for mediastinal lymphadenectasis in a large single center. METHODS: A total of 846 patients who were not definitively diagnosed with mediastinal lymphadenectasis underwent EBUS-TBNA were retrospectively analyzed in this study. RESULTS: In total, 842 patients underwent EBUS-TBNA successfully. There were 589 patients with malignancy, including squamous carcinoma (118 cases; 20.6%), adenocarcinoma (187 cases; 32.7%) and small cell carcinoma (88 cases; 15.4%). A total of 253 patients were diagnosed with benign disease, including tuberculosis (111 cases; 43.9%) and sarcoidosis (93 cases; 36.7%). The diagnostic sensitivity of lung cancer, tuberculosis and sarcoidosis were 94.4%, 81.1% and 51.6%, respectively. The overall sensitivity of EBUS-TBNA was 92.0%. N2 stage in lung cancer patients who were diagnosed by EBUS-TBNA was significantly higher than other stages. The positive rate of targeted puncture is high for the lymph nodes whose short-axis diameters were larger than 1 cm. CONCLUSION: The operation risk of EBUS-TBNA is relatively small. In diseases complicated by mediastinal lymphadenectasis, malignant diseases are most, and benign diseases mainly are granulomatous. EBUS-TBNA is a valuable diagnostic technique in patients with mediastinal lymphadenectasis whose diagnosis have not been determined.

Meta-Analysis of First-Line Pemetrexed Plus Platinum Treatment in Compared to Other Platinum-Based Doublet Regimens in Elderly East Asian Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

BACKGROUND: Pemetrexed plus platinum has become a standard of care in first-line treatment for patients with advanced nonsquamous non-small-cell lung cancer. However, elderly lung cancer patients are generally understudied and undertreated in clinical practice in East Asia because of safety concerns. This analysis aimed to provide a picture of the clinical benefit of pemetrexed/platinum in the first-line setting for elderly (age ≥ 65 years) East Asian patients. PATIENTS AND METHODS: Individual patient data from 3 randomized controlled phase 3 trials that enrolled East Asian patients were analyzed in this meta-analysis. RESULTS: In elderly East Asian patients (63 in the pemetrexed/platinum group and 42 in the control group), pemetrexed/platinum treatment achieved more benefits compared to other platinum-based doublets, including better overall response rate (32.8% vs. 7.5%), favorable progression-free survival (not statistically significant in adjusted hazard ratio), and significantly longer (3.15 vs. 1.54 months) survival without drug-related grade 3/4 toxicity. Overall survival was numerically prolonged (16.33 vs. 13.77 months; not statistically significant). These benefit trends were similar to those in all-age East Asian patients. In elderly East Asians, pemetrexed/platinum treatment was also associated with a lower incidence rate of drug-related grade 3/4 adverse events. The adverse event profile was similar to that in all-age East Asians. There were no unexpected adverse events. CONCLUSION: Pemetrexed/platinum had good efficacy and also resulted in better overall response and tolerability than other platinum-based doublets as first-line treatment in nonsquamous non-small cell lung cancer in elderly East Asians, which was consistent with data observed in all-age East Asians.

Integrin ß1-mediated acquired gefitinib resistance in non-small cell lung cancer cells occurs via the phosphoinositide 3-kinase-dependent pathway.

The present study aimed to explore the role of integrin ß1 and the relevant signaling pathways in acquired gefitinib resistance in non-small cell lung cancer (NSCLC). The inhibitory effects of gefitinib, with or without LY294002, on cellular proliferation were evaluated by 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were analyzed by flow cytometry, while western blotting was used to evaluate the expression of EGFR, phosphorylated (phospho)-EGFR, protein kinase B (Akt), phospho-Akt, extracellular signal-regulated kinase (Erk) and phospho-Erk. The gene expression profiles of PC9 and PC9/G cells were determined by DNA microarray. Integrin ß1 was knocked down in PC9/G cells by transiently transfected short interfering RNA (siRNA). A scrambled siRNA sequence was used as a control. Apoptosis of transfected cells was determined by Annexin V-phycoerythrin-Cy5/propidium iodide staining. Sequencing products were amplified by nested PCR. The resistant index of PC9/G cells to gefitinib was ~138- to 256-fold higher than that of PC9 cells, and this resistance was accompanied by significant increase in integrin ß1 expression in PC9/G cells. Knockdown of integrin ß1 with short hairpin RNA in PC9/G cells markedly inhibited proliferation and enhanced apoptosis in response to gefitinib, restoring the sensitivity of PC9/G cells gefitinib. Phosphoinositide 3-kinase (PI3K)/Akt activation was observed in PC9/G cells in the presence of gefitinib and the sensitivity of PC9/G cells to gefitinib was also able to be restored by PI3K/Akt pathway inhibitor LY294002. Finally, knockdown of integrin ß1 significantly reduced the levels of phospho-Akt. These findings suggest that integrin ß1 signaling via the PI3K/Akt pathway may be a significant mechanism underlying gefitinib resistance, and may potentially present an alternative therapeutic target for the treatment of NSCLC unresponsive to EGFR inhibitors.

Targeted therapies for patients with advanced NSCLC harboring wild-type EGFR: what's new and what's enough.

Historically, non-small cell lung cancer (NSCLC) is divided into squamous and nonsquamous subtypes based on histologic features. With a growing number of oncogenic drivers being identified in squamous and nonsquamous NSCLC, this malignancy has been recently divided into several distinct subtypes according to the specific molecular alterations. This new paradigm has substantially highlighted the treatment of advanced NSCLC, shifting it from standard chemotherapy according to specific histologic subtypes to targeted therapy according to specific oncogenic drivers. The application of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in NSCLC patients harboring activating EGFR mutations has been a representative model of precise medicine in the treatment of NSCLC. As the role of EGFR-TKIs in routine management of patients with advanced NSCLC has been well established, this review provides an overview of alternative targeted therapy in the treatment of NSCLC, including EGFR-TKIs for patients with wild-type EGFR NSCLC, as well as other targeted agents either clinical available or in early- to late-stage development.

Mosquito coil exposure associated with small cell lung cancer: A report of three cases.

Mosquito coils, which are commonly used as residential insecticides in Asia, contain different concentrations of octachlorodipropyl ether (S-2) as a synergist or an active ingredient. As bis(chloromethyl) ether (BCME) is an extremely potent lung carcinogen that can be produced by the thermolytic degradation of S-2, contact with mosquito coils is likely to expose individuals to a certain level of BCME, and therefore increase the risk of lung cancer. However, the significance of exposure is uncertain, as clinical and epidemiological studies concerning mosquito coil users and workers are lacking. The present study describes three cases of small cell lung cancer treated at the Shanghai Pulmonary Hospital that were likely to be the result of exposure to mosquito coils. All patients had worked in the mosquito coil manufacturing industry, with an mean occupational duration of 9.1 years, and presented with similar respiratory symptoms, such as cough and dyspnea. Upon diagnosis, no metastasis to other organs was identified in any of the cases. Subsequently, the three patients were treated with chemotherapy as well as radiotherapy in one case, however, all patients succumbed to the disease, with a mean overall survival time of 10.7 months. We conclude that contact with mosquito coils is likely to expose individuals to a level of S-2 that may increase the risk of SCLC.

Efficacy of pemetrexed in a patient with brain metastases during crizotinib treatment.

ALK-positive patients with non-small-cell lung cancer (NSCLC) exhibit more aggressive clinical progression, a poorer response to chemotherapy, and less favorable survival outcomes in comparison with ALK-negative patients. Although crizotinib has proved effective in treating ALK-positive NSCLC, this agent penetrates the blood-brain barrier poorly and CNS progression is common. As pemetrexed, a multitargeted antifolate chemotherapeutic agent, has demonstrated benefit in the control of brain metastases in patients with NSCLC, treatment with pemetrexed was added to crizotinib in a young male patient with ALK-positive NSCLC who had developed brain metastases during crizotinib therapy. After four cycles of pemetrexed chemotherapy, the patient's brain lesions were significantly reduced in size and a chest CT scan showed that the lung lesions had stabilized.

A double-blind, randomized phase II study of dicycloplatin plus paclitaxel versus carboplatin plus paclitaxel as first-line therapy for patients with advanced non-small-cell lung cancers.

INTRODUCTION: The aim of this study was to compare the efficacy and toxicity of dicycloplatin plus paclitaxel with those of carboplatin plus paclitaxel as first-line treatment for patients with advanced non-small-cell lung cancer (NSCLC). MATERIAL AND METHODS: In this study, 240 NSCLC patients with stage IIIB (with pleural effusion) and stage IV disease were randomly assigned (1: 1) to receive dicycloplatin 450 mg/m(2) or carboplatin AUC = 5, in combination with paclitaxel 175 mg/m(2) (D + P or C + P) every 3 weeks for up to 4 to 6 cycles. The primary endpoint was response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: The response rates for the D + P and C + P arm were 36.44% and 30.51%, respectively (p = 0.33). The median PFS was 5.6 months in the D + P arm and 4.7 months in the C + P arm (p = 0.31). The median OS was 14.9 months for D + P and 12.9 months for C + P (p = 0.37). Adverse events in the two arms were well balanced. The most common grade 3/4 adverse event was hematologic toxicity. CONCLUSIONS: Patients treated with D + P had similar response and survival rates to those treated with C + P, and toxicities of both treatments were generally tolerable.

Efficacy of first-line chemotherapy affects the second-line setting response in patients with advanced non-small cell lung cancer.

BACKGROUND: Chemotherapy is the mainstay of treatment for the majority of patients with advanced non- small cell lung cancer (NSCLC) without driver mutations and many receive therapies beyond first-line. Second- line chemotherapy has been disappointing both in terms of response rate and survival and we know relatively little about the prognostic factors. MATERIALS AND METHODS: One thousand and eight patients with advanced NSCLC who received second-line chemotherapy after progression were reviewed in Shanghai Pulmonary Hospital, China, from September 2005 to July 2010. We analyzed the effects of potential prognostic factors on the outcomes of second-line chemotherapy (overall response rate, ORR; progression free survival, PFS; overall survival, OS). RESULTS: The response and progression free survival of first-line chemotherapy affects the ORR, PFS and OS of second-line chemotherapy (ORR: CR/PR 15.4%, SD 10.1%, PD2.3%, p<0.001; PFS: CR/PR 3.80 months, SD 2.77 months, PD 2.03 months, p<0.001; OS: CR/PR 11.60 months, SD 10.33 months, PD 6.57 months, p=0.578, p<0.001, p<0.001, respectively). On multivariate analysis, better response to first-line therapy (CR/PR: HR=0.751, p=0.002; SD: HR=0.781, p=0.021) and progression within 3-6 months (HR=0.626, p<0.001), together with adenocarcinoma (HR=0.815, p=0.017), without liver metastasis (HR=0.541, p=0.001), never-smoker (HR=0.772, p=0.001), and ECOG PS 0-1 (HR=0.745, p=0.021) were predictors for good OS following second- line chemotherapy. CONCLUSIONS: Patients who responded to first-line chemotherapy had a better outcome after second-line therapy for advanced NSCLC, and the efficacy of first-line chemotherapy, period of progression, histology, liver metastasis, smoking status and ECOG PS were independent prognostic factors for OS.