Progression-free Survival In Non-small Cell Lung Cancer Research Articles

Real-world safety and efficacy of concurrent immunotherapy and thoracic chemoradiotherapy: A multi-institutional analysis.

e23262 Background: Despite the success of Immune checkpoint inhibitors (ICIs) as consolidation following concurrent chemoradiotherapy (CCRT), 22% to 30% of patients still cannot be treated with durvalumab due to progression or adverse events (AEs) during or after CCRT. Concurrent ICIs with CCRT would offer the opportunity to receive ICIs and may provide treatment benefit to a greater proportion of patients. In this study, we performed a multicenter investigation to evaluate the safety and efficacy of ICIs and chemotherapy with concurrent thoracic radiotherapy. Methods: All patients from three institutions who underwent ICIs and concurrent thoracic radiotherapy were included. The rate of 12-month progression-free survival (PFS) was estimated using the Kaplan-Meier method and evaluated with 95% CIs calculated using the Greenwood formula. Therapy-related pneumonitis (TRP) and esophagitis (TRE) were defined per CTCAE v5.0. Statistics utilized logistic regression modeling and receiver operating characteristic (ROC) analysis. Results: 69 patients (median [range] age, 62 [52-76]; 61 [88.4%] male; median follow-up 30.4 months) were collected, including 18 (26.1 %) cases of non-small cell lung cancer (NSCLC), 26 (37.7 %) cases of small cell lung cancer (SCLC), and 25 (36.2 %) cases of esophageal cancer (EC). The 12-month PFS rates in NSCLC, SCLC and EC were 72.2%, 69.2% and 72.0%, respectively. The median PFS in NSCLC and SCLC was 24.3 and 13.1 months, and not reached (mean 29 months) for EC. The incidences of all-grade TRP and TRE were 60.7% and 57.7%, respectively. Grades 1-5 TRP occurred in 15.9%, 30.4%, 8.6%, 1.4%, and 0, respectively. Grades 1-5 TRE occurred in 20.2%, 28.9%, 8.6%, 0, and 0, respectively. On multivariable analysis, age and MLD significantly predicted for any-grade and grade ≥2 TRP. Only age significantly predicted for grade ≥3 TRP. ROC analysis was able to pictorially model RP risk probabilities for a variety of MLD and age thresholds. Conclusions: This real-world study can be helpful for understanding the true efficacy and toxicity of ICIs and chemotherapy with concurrent thoracic radiotherapy given the lack of robust clinical data. Close monitoring should be recommended in this patient population during RT and follow-up.

Gut Microbiome Is Associated With the Response to Chemoradiotherapy in Patients With Non-small Cell Lung Cancer

To explore the dynamic change of gut microbiota and its predictive role in progression-free survival (PFS) in non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT). Forty-one patients with NSCLC in 2 phase 2 trials (NCT02573506 and NCT03006575) were analyzed. A total of 102 fecal samples were collected at 3 time points (T0, before CCRT; T1, 2 weeks after the initiation of CCRT; and T2, the end of CCRT). Gut microbiota composition and functionality were analyzed by 16S rRNA gene sequencing and shotgun metagenomics, respectively. Alpha diversity, taxonomic composition, and KEGG functional pathways were compared between patients in the long-PFS group (PFS ≥11.0 months) and short-PFS group (PFS <11.0 months). A random forest classifier was constructed to identify microbial signature related to PFS. Clinical and microbial factors potentially predictive of PFS were assessed in the univariate and multivariate Cox regression analysis. The abundance of Bacteroidota and Proteobacteria increased, while the abundance of Firmicutes decreased after CCRT. Shannon index (P=.006) and PD index (P=.022) were significantly higher in the long-PFS group than for those in the short-PFS group at T1. The PFS-prediction microbial signature at T1 included unclassified members of the Lanchospiraceae spp., such as NK4A136 and UCG-003 groups, Dorea sp., various strains from within the Eubacterium hallii and E. siraeum groups, and an unclassified member of the Muribaculaceae, which yielded an area under the ROC curve of 0.87. These discriminatory genera mostly belong to phylum Firmicutes/family Clostridia. Multivariate analysis indicated PD index (HR=8.036, P=.016) and the abundance of Dorea sp. at T1 (HR=4.186, P=.043) were independent predictors of PFS. The KEGG pathways at T1 overrepresented in the long-PFS group included fatty acid metabolism, fatty acid biosynthesis, and arginine biosynthesis. Those overrepresented in the short-PFS group included lipopolysaccharide biosynthesis, ascorbate and aldarate metabolism, and biosynthesis of vancomycin group antibiotics. Gut microbiota composition and functionality at 2 weeks after the initiation of CCRT were associated with PFS in NSCLC. Further research is needed to confirm these results.

ARL14 as a Prognostic Biomarker in Non-Small Cell Lung Cancer.

PurposeNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. The mechanisms underlying NSCLC initiation and progression require further investigation. The purpose of this study was to investigate the role of ADP ribosylation factor-like GTPase 14 (ARL14) related to the progression of NSCLC.Patients and MethodsWe analyzed the correlation between clinical characteristics and ARL14 expression using data from The Cancer Genome Atlas (TCGA). Kaplan–Meier analysis was conducted to evaluate the prognostic value of ARL14 in NSCLC. Functions of ARL14 were identified by enrichment analysis. The relationship between ARL14 expression and immune cell infiltration was also studied. Furthermore, ARL14 expression was examined using immunohistochemistry, and its clinical significance was analyzed in 120 patients with NSCLC.ResultsOur study revealed that the expression level of ARL14 in patients with NSCLC was higher than that in normal tissues. Using TCGA data, higher ARL14 expression in lung adenocarcinoma was associated with residual tumor (P = 0.017), while it was associated with age (P = 0.003) and N stage (P = 0.009) in lung squamous cell carcinoma. Similar results were obtained from 120 patients with NSCLC. High ARL14 expression was associated with poor overall survival and progression-free survival in NSCLC. Multivariate analysis revealed that ARL14 was an independent risk factor for patients with NSCLC. Functional enrichment analysis indicated that ARL14 was related to the occurrence and development of tumors.ConclusionIncreased ARL14 expression was considerably correlated with poor survival in NSCLC, and it might be a promising prognostic biomarker for NSCLC.

Prognostic and predictive impact of creatine kinase level in non-small cell lung cancer treated with tyrosine kinase inhibitors.

BackgroundThe use of tyrosine kinase inhibitors (TKIs) is associated with incident creatine kinase (CK) elevation in the treatment of advanced non-small cell lung cancer (NSCLC) patients. However, whether higher CK levels are associated with better antitumor responses or survival remains to be explored. We intend to investigate the clinical correlation between CK levels and TKI efficacy in advanced NSCLC.MethodsIn this retrospective study, we enrolled 135 patients with stage IV NSCLC receiving TKI-based therapy in our center between June 2012 to July 2020. CK levels were monitored from the initiation of TKI medication and during the administration period. An X-tile analysis provided the optimal cutoff point for higher baseline CK. Patients were identified and grouped according to their baseline CK level and fold changes during TKI therapy. The primary endpoints included progression-free survival (PFS) and overall survival (OS), and the objective response rate (ORR) was calculated as the secondary endpoint.ResultsAmong the 135 patients included in our study, those with higher baseline CK levels (≥70 U/L) had favorable PFS (15.2 vs. 8.8 months; P=0.028), while patients with significantly elevated CK (the highest CK value/baseline CK value ≥2 times) appeared to gain better PFS (14.6 vs. 10.0 months; P=0.139). The overall ORR was 67.4%. Patients with higher baseline CK levels had numerically higher ORR (74.6% vs. 60.3%; P=0.076). Similarly, patients with significant CK elevation had a superior 4-month PFS rate (77.6% vs. 59.7%; P=0.029). Results from the subgroup analyses were identical to the overall ones. For patients with higher baseline CK levels, those experiencing significant CK elevation had prolonged PFS (17.2 vs. 14.2 months; P=0.038); a same trend was obtained from the lower baseline CK group (<70 U/L) (9.4 vs. 7.9 months; P=0.038). In multivariable analysis, higher baseline CK level and significant CK elevation remained statistically associated with PFS, with hazard ratios of 0.48 and 0.59, respectively.ConclusionsBoth higher baseline CK levels and significant CK elevation after treatment were correlated with prolonged PFS in NSCLC treated with TKIs, suggesting the potential prognostic and predictive impact of CK level on these patients.

Clinical evaluation of plasma coagulation parameters in patients with advanced‐stage non‐small cell lung cancer treated with palliative chemotherapy in China

Blood coagulation parameters are colossally important for clinical evaluation of palliative chemotherapy; however, this niche was not explored earlier for advanced-stage non-small cell lung cancer (NSCLC). Study focuses to explore the clinical relevancy of Coagulation parameters; prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen(FIB), D-dimer and international normalised ratio (INR) and their response to palliative chemotherapy in advanced-stage NSCLC. A retrospective study was conducted between 2013 and 2019 in Jiangsu Cancer hospital, Nanjing, PR. China. Medical records of 5445 patients were succinctly reviewed and classified accordingly to the inclusion and exclusion criteria. A total of 216 advanced NSCLC patients who used a first-line chemotherapy and antiangiogenic therapy regimen were enrolled in this study under ethical approval (JSCH-2020C-009). Blood samples were collected from these patients to measure the response levels of these coagulation parameters at time of admission to hospital and at the beginning of 4 cycles of Palliative therapy. We find the clinical value of all these coagulation parameters by using SPSS 24. Univariate Cox regression and Multivariate Cox regression models were used to identify the factors that were associated with progression-free survival (PFS) and the response to palliative chemotherapy. In the Kaplan-Meier survival analysis for overall median (95% CI) survival of high pre-treatment coagulation parameters showed shorter PFS compared with normal pre-treatment except TT and their overall median (95% CI) follow-up was 3.3 (3.12-3.47). Coagulation parameters have showed clinical relevance as a potential independent prognostic factor of PFS in the Univariate Cox regression. In multivariable model, Age (≥60years vs<60years), cancer differentiation (Unknown vs Poor), PT (High vs Normal) range, FIB (High vs Normal) range and D-dimer (High vs Normal) range, (P=.025, P=.045, P=.029, P=.049 and P=.011, respectively) were associated as a prognostic factor of PFS in NSCLC. Patients on 3-drugs regimen found to have better PFS compared with the ones taking the 2-drugs treatment regimen (P=.043). The high range of PT, FIB and D-dimers was associated with poor prognosis of advanced-stage NSCLC. Our findings also confirmed that patients on 3-drugs regimen showed longer PFS compared with 2-drugs regimen.

LPAR5 stimulates the malignant progression of non-small-cell lung carcinoma by upregulating MLLT11.

This study aims to explore the diagnostic and prognostic values of Lysophosphatidic acid receptor 5 (LPAR5) in non-small-cell lung cancer (NSCLC) and its regulatory effects on biological functions of NSCLC cells. NSCLC and adjacent non-tumoral tissues were collected for analyzing differential levels of LPAR5 by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). Clinical information of recruited NSCLC patients was collected for assessing the diagnostic and prognostic values of LPAR5. In vitro regulation of LPAR5 on proliferative and migratory potentials of H1299 and SPC-A1 cells was examined by Cell Counting Kit-8 (CCK-8) and transwell assay, respectively. In addition, in vivo regulation of LPAR5 on the growth rate of NSCLC in nude mice was detected by tumorigenicity assay. The interaction between LPAR5 and its downstream target MLLT11 was determined by rescue experiments. LPAR5 was upregulated in NSCLC tissues than adjacent non-tumoral ones. High level of LPAR5 predicted higher rates of lymphatic metastasis and distant metastasis, as well as worse overall survival and progression-free survival in NSCLC. Knockdown of LPAR5 not only attenuated in vitro proliferative and migratory abilities in H1299 and SPC-A1 cells, but also slowed down in vivo growth of NSCLC in nude mice. MLLT11 was upregulated in NSCLC tissues, and displayed a positive correlation to LPAR5. Overexpression of MLLT11 was able to reverse the attenuated in vitro proliferative and migratory abilities, and the suppressed in vivo growth of NSCLC because of LPAR5 knockdown. LPAR5 stimulates proliferative and migratory potentials in NSCLC by positively regulating MLLT11, which can be served as an effective diagnostic marker for early stage NSCLC.

Statin treatment improves response to anti-PD1 agents in patients with malignant pleural mesothelioma and non-small cell lung cancer.

3074 Background: After progression to standard chemotherapy, only a small proportion of malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC) patients (pts) benefit from anti-programmed cell death (PD-1) treatment. Combination strategies might improve response. In pre-clinical models, statins showed vaccine adjuvant activities and synergized with anti-PD1 agents. In this multi-center study, we evaluated the impact of baseline statin treatment in MPM and NSCLC pts. Methods: We separately examined MPM and NSCLC pts treated with anti-PD1 monotherapy after progression to standard chemotherapy at two European academic institutions. As control cohort, MPM pts treated with first-line chemotherapy were also examined. Pts receiving statins at start of treatment were compared with those who did not. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were analyzed. Results: A total of 287 patients were examined. Twenty-seven out of 80 (34%) MPM and 36 out of 130 (20%) NSCLC pts received statins at start of anti-PD1 treatment. The most common statins were simvastatin, atorvastatin and rosuvastatin. In MPM pts, statin use was associated with improved ORR (22% versus 5%, P = 0.05), longer PFS (median 6.7 versus 2.4 months, hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.23–0.77, P &lt; 0.01), and longer OS (median not reached versus 6.0 months, HR 0.43, 95% CI 0.21–0.85, P = 0.01). In NSCLC pts, statin use was associated with improved ORR (40% versus 22%, P = 0.04), longer PFS (median 7.8 versus 3.6 months, HR 0.59, 95% CI 0.37–0.97.2, P = 0.03) but similar OS (median 13.1 versus 10.1 months, HR 0.79, 95% CI 0.49–1.28, P = 0.30). At multivariate analyses, after adjusting for ECOG performance status (PS) and histological subtype, the impact of statins remained significant for ORR, PFS and OS in MPM and for PFS in NSCLC. Conversely, no association between statin use and outcomes was found in 77 MPM pts treated with first-line chemotherapy. Conclusions: This study shows that statin use at start of anti-PD1 treatment improves response to anti-PD1 agents in MPM and NSCLC pts who progressed to standard chemotherapy in routine clinical practice. This association could not be found in MPM pts treated with first-line chemotherapy, thus suggesting a synergy between statins and anti-PD1 agents. Prospective studies are needed to confirm whether the combination of statin and anti-PD1 therapy could improve outcome in pts with poorly immunogenic thoracic malignancies.

Impact of antibiotics and proton pump inhibitors on clinical outcomes of immune check point blockers in advanced non-small cell lung cancers and metastatic renal cell cancer.

e20520 Background: Studies have suggested that antibiotics can negatively influence efficacy of immune check-point blockers (ICB) but the results are inconsistent. The impact of concomitant proton pump inhibitors (PPI) is not known. We evaluated whether antibiotic and PPI use in patients with advanced non-small-cell lung cancer (NSCLC) and metastatic renal cell cancer (RCC) affects ICB efficacy. Methods: We identified advanced NSCLC and RCC patients treated with anti-PD1/PD-L1 at our institution between 5/2015 to 1/2019. Data regarding systemic antibiotics and PPI use &lt; 1 month or during ICB treatment were collected. The primary outcome was progression free survival (PFS) per response evaluation criteria in solid tumors (RECIST 1.1). Secondary outcomes were overall survival (OS) and objective response rate (ORR). Logistic regression and cox proportional hazards model were used for statistical analysis. Results: 87/148 (58%) and 40/55 (72%) patients received antibiotics and 57/148 (39%) and 17/55 (31%) received PPI &lt; 1 month or during ICI therapy in NSCLC and RCC respectively. In RCC, antibiotic use was associated with inferior PFS (2.9 v 5.0 months, HR = 2.3 95%CI 1.0-5.0; p = 0.04) but OS and ORR were not affected. In NSCLC, antibiotic exposure was associated with superior PFS (5.0 v 2.5 months, HR = 0.5, 95% CI 0.3-0.7; p &lt; 0.01), OS (13.0 v 8.0 months, HR = 0.5, 95% CI 0.3-0.8; p &lt; 0.01) and ORR (33% v 11%, OR = 4.6, p &lt; 0.01). On univariate analysis, there was trend towards inferior OS in NSCLC (9.0 v 13.0 months, p = 0.05) with PPI use. PPI use was not associated with other primary or secondary outcomes in both the cohorts. The antibiotic effect remained significant for PFS in NSCLC and RCC in multivariate analysis. Conclusions: Antibiotic use significantly affected PFS in both NSCLC and RCC. PPI use did not affect outcomes. In contrast to previous studies, this is the first study to show that antibiotic use was associated with favorable outcomes in NSCLC. More studies are needed to explain this association. Future clinical trials with ICB should consider stratification of patients based on antibiotic exposure.

Abstract 617: Nivolumab efficacy and safety in veterans with and without HIV infection

Abstract The objective of this study was to compare the efficacy and safety of nivolumab in the HIV-infected and HIV-uninfected veteran populations. WHAT IS NEW: Most clinical trials highlighting checkpoint inhibitors excluded people living with HIV (PLWH). This is the first study to report equivalent nivolumab tumor response rates in PLWH, but higher rates of pneumonitis.METHODS: We searched the Corporate Data Warehouse (CDW) to identify all HIV-positive patients who used the Veterans Health Administration (VA) between 2000 and 2016. For this cohort of 46,916 PLWH, we obtained a 4:1 age-matched HIV-negative control cohort. We used pharmacy database to identify all nivolumab recipients through July 26, 2017. We reviewed patients' electronic medical records using Compensation and Pension Records Interchange (CAPRI) to obtain age, sex, geographic location, cancer type, number of nivolumab doses received, previous cancer therapy, adverse events, and response to therapy. We calculated summary descriptive measures for both groups and compared the proportion of patients experiencing adverse event or pneumonitis in groups by HIV status, using chi-square or Fisher's exact test. RESULTS: Sixteen PLWH and 68 HIV-negative controls received nivolumab during the study period. Only 51 controls had accessible data. Median age at nivolumab initiation was 65 years in both groups (range, 47-85 [IQR, 59-68] in PLWH; range, 42-79 [IQR 59-68] in controls); all patients were male. Overall, 63% received nivolumab for non-small cell lung cancer (NSCLC): 8/16 (50%) in PLWH, 34/51 (67%) in controls. Other indications in PLWH included renal cell carcinoma (RCC) (2/16 [13%]), Hodgkin lymphoma (HL) (2/16 [13%]), hepatocellular carcinoma (HCC) (2/16 [13%]). Other indications in controls were RCC (9/51 [18%]), melanoma (5/51, [10%]), and head and neck squamous cell carcinoma (3/51 [6%]).Regardless of HIV status, the median number of prior lines of therapy was 1, median number of nivolumab doses received was 6, and median progression-free survival (PFS) in NSCLC was 2.75 months. Half of each NSCLC group received radiation; fewer PLWH had COPD (50%, vs. 82% of controls). PLWH had a trend towards more adverse events (AEs) (6/15 [40%], vs. 13/51 [26%] of controls, p=0.28). A significantly higher proportion of PLWH experienced pneumonitis (4/15 [27%], vs. 2/51 [4%] of controls, p=0.007).Other AEs among PLWH were rash, hypothyroidism, and autoimmune diabetes mellitus. Other AEs among controls were fatigue, colitis, rash, hypothyroidism, arthritis, and hepatitis (1-3 patients each). CONCLUSION: Among veteran PLWH, rates of nivolumab administration, and PFS in NSCLC, were comparable to those of HIV-uninfected counterparts. Pneumonitis was significantly more frequent in PLWH. Further studies should investigate the mechanism of pneumonitis in this population, confirm the high frequency in larger cohorts of PLWH, and identify clinical risk factors for pneumonitis. Citation Format: Elaine Chang, Aaron P. Thrift, Donna L. White, Jennifer Kramer, Anita L. Sabichi, Christine Hartman, Kathryn E. Royse, Peter A. Richardson, Elizabeth Y. Chiao. Nivolumab efficacy and safety in veterans with and without HIV infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 617.

Efficacy of Tumor Vaccines and Cellular Immunotherapies in Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

Programmed cell death protein-1- checkpoint blockers have recently been approved as second-line treatment for advanced non-small-cell lung cancer (NSCLC). Unfortunately, only a subgroup of patients responds and shows long-term survival to these therapies. Tumor vaccines and cellular immunotherapies could synergize with checkpoint blockade, but which of these treatments is most efficacious is unknown. In this meta-analysis, we assessed the efficacy of tumor vaccination and cellular immunotherapy in NSCLC. We searched for randomized controlled trials (RCTs) investigating cellular immunotherapy or vaccines in NSCLC. We used random effects models to analyze overall survival (OS) and progression-free survival (PFS), expressed as hazard ratios (HRs), and differences in time (months). The effect of immunotherapy type, disease stage, tumor histology, and concurrent chemotherapy was assessed using subgroup analysis and meta-regression. All procedures were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We identified 18 RCTs that matched our selection criteria; these included a total of 6,756 patients. Immunotherapy extended NSCLC survival and PFS, expressed as HR (OS: HR, 0.81, 95% CI, 0.70 to 0.94, P = .01; PFS: HR, 0.83, 95% CI, 0.72 to 0.95, P = .006) and month difference (OS: difference, 5.43 months, 95% CI, 3.20 to 7.65, P < .005; PFS: difference, 3.24 months, 95% CI, 1.61 to 4.88, P < .005). Cellular therapies outperformed tumor vaccines (OS as HR: P = .005, month difference: P < .001; PFS as HR: P = .001, month difference: P = .004). There was a benefit of immunotherapy in low-stage compared with high-stage NSCLC and with concurrent administration of chemotherapy only in one of four outcome measures evaluated (PFS in months: P = .01 and PFS as HR: P = .031, respectively). There was no significant effect of tumor histology on survival or PFS. Tumor vaccines and cellular immunotherapies enhanced OS and PFS in NSCLC. Cellular immunotherapy was found to be more effective than tumor vaccination. These findings have implications for future studies investigating combination immunotherapy in NSCLC.

Predictive and prognostic value of circulating endothelial cells in non-small cell lung cancer patients treated with standard chemotherapy

Monitoring circulating endothelial cells (CECs) count reflects the tumor vasculature in cancer patients and might be a predictor of response to chemotherapy. We therefore investigated the clinical significance of changes in CECs count after three cycles of platinum-based chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Peripheral blood samples were collected from 89 naive NSCLC patients at diagnosis and after chemotherapy. The CECs were quantified by an immuno-magnetic technique and fluorescent microscopy. After chemotherapy, patients were assessed according to the response evaluation criteria in solid tumors as partial response (PR), stable disease (SD) or progression disease (PD). Baseline CECs levels were significantly higher in PR patients (n = 62) than those in patients with SD/PD (n = 27) (p = 0.0007). Although there was no significant correlation between baseline CECs levels and progression-free survival (PFS) (p = 0.287), patients with high percentage change in CECs count after chemotherapy had significantly longer PFS than those with low percentage change (p = 0.048). Regarding treatment efficacy, CECs count significantly decreased after chemotherapy in comparison with CECs count at baseline in patients with PR (p < 0.0001). By contrast, CECs levels after chemotherapy were significantly higher than those at diagnosis in patients with PD (p = 0.002). Moreover, there was no significant change between pre- and post-treatment CECs amount in patients with SD (p = 0.681). Baseline CECs levels might be an early predictive biomarker for treatment efficacy in advanced NSCLC patients. Our results suggest the change in CECs count after chemotherapy as a prognostic factor for tumor response and PFS in NSCLC.

Treatment of central type lung cancer by combined cryotherapy: Experiences of 47 patients

Most patients with central type lung cancer (CTLC) are not candidates for surgery; systemic chemotherapy and external beam radiotherapy are the main treatments but have not greatly affected patient outcome. Combined percutaneous and endobronchial cryotherapy has been used successfully to treat CTLC; this study aimed to determine its feasibility and safety. Forty-seven patients with unresectable CTLC (22 endotracheal, 26 tracheal wall and 21 extratracheal tumors) underwent 69 sessions of combined percutaneous cryosurgery, endobronchial cryosurgery and airway stenting. The long diameter of all tumors was <5cm. Biopsy showed non-small cell lung cancer (NSCLC) in 40 patients (medium or well differentiated in 20 cases, poorly differentiated in 20) and small cell lung cancer (SCLC) in seven. Within 3days after treatment, ventilatory capacity and performance status had obviously increased and cough, signs of dyspnea, hemoptysis and atelectasis improved significantly, but symptoms of pneumothorax and pleural effusion emerged. After 2weeks, all complications had disappeared completely, as had cough. Progression-free survival (PFS) for endotracheal tumors (8±4months) was shorter than that for tracheal wall (13±6months, P<0.05) and extratracheal (14±8months, P<0.01) tumors. The PFS of NSCLC (11±5months) was significantly longer than that of SCLC (4±2months, P<0.0001). The PFS of medium or well differentiated CTLC (15±8months) was significantly longer than that of poorly differentiated CTLC (7±3months, P<0.0001). In conclusion, combined cryotherapy is a safe and effective treatment for CTLC, with PFS largely influenced by tumor location and pathologic type.

Abstract 4660: A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small cell lung cancer.

Abstract Tumor regrowth after chemotherapy may be driven by growth of tumor ‘stem cells’. Telomerase, required for indefinite replication, is upregulated in tumor progenitor cells. Imetelstat is a 13-mer oligonucleotide which is a potent and specific telomerase inhibitor. Progression-free survival (PFS) and the duration of responses after 1st-line chemotherapy for non-small-cell lung cancer (NSCLC) are short, which has led to an interest in developing active maintenance therapies. A randomized phase II study was conducted to assess whether imetelstat, given as maintenance therapy, prolongs PFS in NSCLC. Pts were eligible with advanced NSCLC not progressing after completing 4-6 cycles of platinum-based doublet induction chemotherapy, any NSCLC histology, performance status (PS) ECOG 0 or 1, and not scheduled to receive maintenance with pemetrexed or erlotinib. Pts were randomized 2:1 to imetelstat 9.4 mg/kg (d1 and 8 of a 21d cycle) or observation until progressive disease or unacceptable toxicity (concomitant use of bevacizumab was permitted). The 1o endpoint was PFS; safety/tolerability and objective response rate were 2o endpoints. 116 pts were enrolled between Jul 2010 to Apr 2012, with 114 completing a first visit (i.e. efficacy population). Baseline characteristics of age, gender, PS and number of induction cycles were well balanced. 18.4% had squamous histology; 31.6% received concomitant bevacizumab (bev). The median number of imetelstat maintenance cycles was 3. In the overall analysis of PFS, a non significant improvement in favor of the imetelstat arm was observed (HR = 0.77, P=0.295, 95% CI 0.48 - 1.25). Median PFS was 2.8m for imetelstat and 2.6m for control. In the subgroup of patients who did not receive bevacizumab, the HR was 0.59 (vs. 1.07 for the bevacizumab subgroup; interaction P=0.15). The objective response rate was 4.3% in the imetelstat arm and 2.8% in the control arm. Six month overall survival was 80% for imetelstat and 72% for control (HR = 0.86, P=0.642, 95% CI 0.44 - 1.66). Imetelstat was generally well tolerated although hematologic toxicity, predominantly neutropenia and thrombocytopenia, was increased in the imetelstat arm (grade 3/4 neutropenia 18% for imetelstat vs 0% for control, grade 3/4 thrombocytopenia 37% for imetelstat vs 0% for control). The most frequent non-hematologic toxicities were fatigue (imetelstat 42.1% vs control 18.4%), nausea (43.4% vs 7.9%), vomiting (25.0% vs 5.3%) and anaemia (19.7% vs 5.3%). The overall findings suggest that imetelstat has modest, but not clinically meaningful, activity as a maintenance therapy in pts with NSCLC. A pre-specified exploratory subgroup analysis of PFS by tumor telomere length is reported separately. Citation Format: Alberto Chiappori, Tatjana Kolevska, Bart Burington, David Spigel, Steven Hager, Mark Rarick, Shirish Gadgeel, Normand Blais, Joachim Von Pawel, Lowell Hart, Martin Reck, Joan Schiller. A randomized phase II study of the telomerase inhibitor imetelstat as maintenance therapy for advanced non-small cell lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4660. doi:10.1158/1538-7445.AM2013-4660

Axitinib for the treatment of advanced non-small-cell lung cancer

Introduction: Lung cancer is the most frequently diagnosed cancer in men and comprises 23% of total cancer deaths worldwide. The majority of patients present with advanced disease, for whom the 5-year survival is < 5%. Since angiogenesis plays a central role in tumourigenesis, inhibiting this pathway may improve outcomes in non-small-cell lung cancer (NSCLC). Axitinib is one of the latest and most potent anti-angiogenic tyrosine kinase inhibitors (TKI) currently being evaluated to treat NSCLC.Areas covered: In this review, the rationale for targeting angiogenesis in lung cancer, other angiogenic agents in NSCLC, axitinib's mechanism of action, pharmacology and metabolism, and the preclinical and clinical data to date in NSCLC will be discussed.Expert opinion: Several TKI which target angiogenesis pathways have resulted in improved response rates and progression-free survival in NSCLC, but no improvement in overall survival in clinical trials. Axitinib is a more potent inhibitor of vascular endothelial growth factor receptors than other TKI, but this has yet to translate into a clinical benefit. Phase II trials are ongoing, but the published data to date has yet to support a role for axitinib in the treatment algorithm for NSCLC.

191P - Prognostic and Predictive Impact Of KI-67 Index in Neo-Adjuvant Chemotherapy Before Surgery in Non-Small Cell Lung Cancer

ABSTRACT Background Immunohistochemical assessment of the proportion of Ki-67-expressing cells is a method for evaluating proliferation rates in malignant tumors. Ki-67 index is therefore a proliferation marker and may potentially be used as a prognostic or predictive marker during chemotherapy. In this study we correlated Ki-67 index to prognosis and chemo-sensitivity in non-small cell lung cancer (NSCLC) patients treated with neoadjuvant chemotherapy before surgery. Materials and methods Immunohistochemical assessment of Ki-67 index was performed on diagnostic biopsies from patients with histologically verified NSCLC stages T1-3N2M0 treated with neo-adjuvant chemotherapy (paclitaxel 225 mg/m2 and carboplatin AUC 6) followed by attempt of tumor resection and radiotherapy (2 Gy x 30Fr/ 5F/W). Ki-67 index was defined as the percentage of stained tumor cells in biopsies containing at least 100 tumor cells. Results A total of 64 biopsies (26 biopsies from primary tumors and 38 from lymph node metastases) from 51 consecutive patients were suitable for analysis. No significant differences in Ki-67 index between primary tumor (median ki-67 index 40%) and lymph nodes (median Ki-67 index 50%) were observed (p = 0.871). The 5-year-survival was 30% (Ki-67 index Conclusion When assessed in hotspots, Ki-67 index is a prognostic marker for overall-survival and progression-free survival in NSCLC treated with neoadjuvant paclitaxel and carboplatin before surgery, which may reflect detection of areas with more malignant tumor clones with higher proliferation rate. However, Ki-67 index is not predictive marker for paclitaxel and carboplatin efficacy. Disclosure All authors have declared no conflicts of interest.

Analysis of c-Met gene amplification in Japanese patients with advanced non-small cell lung cancer (NSCLC).

e18021 Background: Several studies have reported that increased gene copy number (GCN) of c-Met is associated with poor prognosis and resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI). A recent phase II study of mostly Caucasian subjects showed that addition of a c-Met receptor TKI to EGFR-TKI prolonged progression-free survival in NSCLC. It is unclear whether c-Met gene status differs between Caucasians and Asians. Thus, c-Met GCN was evaluated in Japanese patients with advanced NSCLC to determine whether c-Met could be a therapeutic target in Asian patients. EGFR mutation and GCNs of EGFR and Her2 were also analyzed. Methods: Tumor samples suitable for gene amplification and mutation analysis were collected from 40 patients with institutional review board approval. Fluorescence in situ hybridization was used to assess c-Met, EGFR, and Her2 GCNs. DNA was extracted from tumor tissue after micro dissection. PCR and direct sequencing of exons 18, 19, and 21 of the EGFR gene were also performed. Results: Of the 40 patients, 10 (25%) were female, 12 (40.0%) were light or never-smokers, and 34 (85%) had adenocarcinoma. The median age was 63 (range 41-81) years, and 36 patients (90.0%) had a good PS (0-1). The median GCNs of c-Met, EGFR, and Her2 were 1.1 (range 0.3-1.7), 1.1 (range 0.9-7.0), and 1.2 (range 0.9-3.5). No patients had more than 4 c-Met copies. Overall survival was not significantly different between patients with more than 1.1 copies of c-Met and those with less than 1.0 copy of c-Met. GCNs of c-Met, EGFR, and Her2 were not associated with any patients’ characteristics. The c-Met GCN was significantly correlated with Her2 GCN (r=0.401), but not EGFR mutation status or EGFR gene amplification. Thirteen patients were treated with EGFR-TKI; the response rate was higher in patients with EGFR mutations (7/11 vs. 0/2). The mean c-Met GCN was not correlated with EGFR-TKI response (1.08 vs. 1.07). The mean EGFR and Her2 GCNs were higher in EGFR-TKI responders than non-responders (2.91 vs. 1.05, p=0.03; 1.46 vs. 1.12, p=0.053). Conclusions: The c-Met GCN of Japanese NSCLC patients was obviously smaller than in the previous study of Caucasians. There might be ethnic difference in c-Met gene amplification such as EGFR mutation.