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O. Arrieta
Moderator of
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MA15 - Immunotherapy Prediction (ID 400)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 12
- Moderators:O. Arrieta
- Coordinates: 12/07/2016, 14:20 - 15:50, Schubert 1
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MA15.01 - Immunogram for Cancer-Immunity Cycle towards Personalized Immunotherapy of Lung Cancer (ID 4519)
14:20 - 14:26 | Author(s): T. Karasaki, K. Nagayama, H. Kuwano, J. Nitadori, M. Sato, M. Anraku, A. Hosoi, H. Matsushita, Y. Morishita, K. Kashiwabara, M. Takazawa, O. Ohara, K. Kakimi, J. Nakajima
- Abstract
Background:
The interaction of immune cells and cancer cells shapes the immunosuppressive tumor microenvironment. For successful cancer immunotherapy, comprehensive knowledge of anti-tumor immunity as a dynamic spacio-temporal process is required for each individual patient. To this end, we developed an "immunogram for the cancer-immunity cycle" using next-generation sequencing.
Methods:
Whole-exome sequencing and RNA-Seq were performed in 20 non-small cell lung cancer patients (12 adenocarcinoma, 7 squamous cell carcinoma, and 1 large cell neuroendocrine carcinoma). Mutated neoantigens and cancer-germline antigens expressed in the tumor were assessed for predicted binding to patients’ HLA molecules. The expression of genes related to cancer-immunity was assessed and normalized; immunogram was drawn in a radar chart composed of 8 axes reflecting 7 steps of cancer-immunity cycle.
Results:
Distinctive patterns of immunogram were observed in lung cancer patients: T-cell-rich and T-cell-poor. Patients with T-cell-rich pattern had gene signatures of abundant T cells, Tregs and MDSCs, checkpoint molecules and immune-inhibitory molecules in the tumor, suggesting the presence of counter regulatory immunosuppressive microenvironment. Unleashing of counter regulations, i.e. checkpoint inhibitors, may be indicated for these patients (Figure A). Immunogram of T-cell-poor phenotype reflected lack of anti-tumor immunity, inadequate DC activation, and insufficient antigen presentation in the tumor (Figure B). When the immunograms were overlaid within each tumor histology, no typical pattern was elucidated. Both T-cell-rich and T-cell-poor phenotypes were present in each histology, suggesting that histology cannot necessarily reflect the cancer-immunity status of the tumor (Figure C,D). These results were consistent with previous studies showing that clinical responses of checkpoint blockade were not easily predicted by the histology. Figure 1
Conclusion:
Utilizing the immunogram, the landscape of the tumor microenvironment in each patient can be appreciated. Immunogram for the cancer-immunity cycle can be used as an integrated biomarker and thus may become a helpful resource toward optimal personalized immunotherapy.
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MA15.02 - Non-Synonymous Mutation Burden in Lung Carcinoma is Associated with Durable Clinical Response to Immune Checkpoint Blockade (ID 5780)
14:26 - 14:32 | Author(s): N.R. Mahadevan, A. Adeni, P. Hammerman, M.M. Awad, L. Gandhi, L. Sholl
- Abstract
Background:
Recent evidence indicates that efficacy and durability of responses to immune checkpoint inhibitors in lung carcinomas correlate with increased nonsynonymous mutation (NSM) burden, putative neoantigen number, and in some tumor types, PD-L1 protein expression. In this study, we retrospectively analyzed the relationship of lung carcinoma mutation burden, PD-L1 expression and immune infiltrates with clinical response in patients receiving immune checkpoint blockade.
Methods:
Tumor nonsynonymous mutation data derived from clinical targeted next generation sequencing (309 genes) of lung carcinomas from 94 patients treated with immune checkpoint inhibitors was correlated with clinical outcomes, including durable clinical benefit (DCB; >6 months partial or stable response) and progression-free survival (PFS). PD-L1 immunohistochemistry (clone E1L3N, Cell Signaling Technology, Envision+ detection, Dako) was considered positive if ≥1% of tumor cells and/or tumor-infiltrating immune cells (IC) stained. PU.1, CD3, and FOXP3 immunohistochemistry was used to highlight tumor-associated macrophages and non-regulatory and regulatory T cell populations, which were manually quantified per mm[2].
Results:
The mean patient age was 62 years (range: 32-91 years). Lung tumor types included 69 adenocarcinomas, 11 squamous cell carcinomas, 5 small cell carcinomas, and 9 of other/combined histology. Therapies included PD1 inhibitors (82), a PD-L1 inhibitor (5) and multiple agents (7). Across all tumor types, patients with DCB had a significantly higher number of NSM (range: 1-42) than patients who showed no durable benefit (NDB) [DCB: 12; NDB: 8, p = 0.0027]. Patients with greater than the median number of NSM (9) had significantly longer PFS than those with ≤9 (p = 0.015). Increasing smoking history correlated with higher mutation load (p = 0.047) and patients with a longer smoking history tended to have longer PFS although this trend did not reach statistical significance (p = 0.07). Expression of PD-L1 in either tumor cells or ICs was not associated with NSM burden (p = 0.47) or PFS (p = 0.92). PD-L1 expression in the tumor microenvironment was associated with increased numbers of tumor-associated macrophages (p = 0.0002), and non-regulatory and regulatory T cells (p = 0.0038 and 0.01 respectively).
Conclusion:
The non-synonymous mutation burden in lung carcinoma as assessed by targeted next generation sequencing is associated with increased PFS and durable clinical benefit to immune checkpoint inhibitors. In this limited cohort, PD-L1 expression using clone E1L3N does not predict response to these therapies. We add to growing evidence that increased somatic mutations in carcinomas influence response to immune checkpoint blockade.
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- Abstract
Background:
Immune checkpoint, PD-1, inhibitors, have been approved to treat advanced NSCLC patients without oncogenic driver in the second-line setting based on durable clinical benefit. It has been demonstrated that the overall mutational burden in tumor tissue was significantly associated with progression free survival (PFS) of advanced NSCLC patients treated with PD-1 inhibitor. However, tumor tissue may not be available from all patients at any time during PD-1 blockade therapy. Therefore, the purpose of this study was to explore the predictive value of mutation/neoantigen burden from ctDNA on efficacy of PD-1 inhibitors.
Methods:
We treated advanced NSCLC patients without oncogenic drivers with PD-1 inhibitor in the second or more line setting. The whole-exome of tumor tissues and ctDNA at baseline and ctDNA at every time of efficacy evaluation from these patients were sequenced by NGS. The hybrid-capture-enriched libraries were sequenced on the Illumina HiSeq 4000 platform with 75-base paired-end reads, sequencing depth was 300 for ctDNA whole-exome sequencing. We compared the results of whole-exome sequencing between patients who achieved objective response to PD-1 inhibitor and patients who experienced disease progression. Besides, we also compared the results of whole-exome sequencing between baseline ctDNA and ctDNA extracted at efficacy evaluation.
Results:
Up to now, a total of 23 patients treated with PD-1 inhibitor received efficacy evaluation at least once in this study. Of them, 4 patients achieved partial response (PR), 3 patients achieved stable disease (SD). Of 4 patients with PR, 3 patients were found to harbor high mutation burden (more than 400 nonsynonymous mutations) from ctDNA and only 1 patient harbored mutation burden of less than 100 from ctDNA at baseline. We found the mutation or neoantigen burden from ctDNA changed during PD-1 blockade therapy. The efficacy of PD-1 inhibitor appeared to be more significantly associated with neoantigen burden rather than mutation burden. Only one ctDNA sample was found positive for MSH6 mutation (C1337X) and all baseline ctDNA samples were negative for microsatellite instability (MSI) status.
Conclusion:
Evaluating nonsynonymous mutation burden/neoantigen burden from ctDNA was feasible in advanced NSCLC patients treated with PD-1 inhibitors. The predictive value of neoantigen burden from ctDNA on the efficacy of PD-1 inhibitor may be better than that of mutation burden in advanced NSCLC. It may not be feasible to determine the status of mismatch-repair deficiency and MSI using ctDNA samples in advanced NSCLC. An expanded study is ongoing. More details will be presented in the conference.
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MA15.04 - Discussant for MA15.01, MA15.02, MA15.03 (ID 7095)
14:38 - 14:50 | Author(s): J. Fischer
- Abstract
Abstract not provided
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MA15.05 - PD-L1 Immunohistochemistry as Biomarker in Non-Small Cell Lung Cancer (NSCLC) (ID 4982)
14:50 - 14:56 | Author(s): D. Krenbek, B. Weidinger, C. Jarius, S. Holzer, H. Fabican, A. Mohn-Staudner, M.J. Hochmair, A. Chott, U. Setinek
- Abstract
Background:
Anti-PD1 (programmed cell death 1) therapeutic antibodies have recently become available as a promising option in the treatment of patients with NSCLC in Austria. Several clinical studies suggested PD-L1 (programmed cell death ligand 1) protein expression in tumor cells to be a useful prognostic biomarker using several antibodies and different cutoffs. We studied PD-L1 expression in our NSCLC patient cohort and compared the performance of different antibodies. Furthermore we aimed to investigate the value of PD-L1 expression as a biomarker in a subset of patients treated with Anti-PD1 immunotherapy.
Methods:
PD-L1-Imunohistochemistry (IHC) was performed in 437 lung cancer specimens (316 adenocarcinomas, 77 squamous cell carcinomas and 44 NSCLC NOS) using the clones SP263 (Ventana), 28.8 (Abcam) and EL1L3N (Cell Signaling) on the VENTANA IHC platform. The percentages of tumor cells (TC) with membranous staining were determined - irrelevant of staining intensity; TC-counts of less than 1 % were interpreted as negative. Staining with at least two of the antibodies was available in 378 specimens (SP263/28.8 in 320 and 28.8/E1L3N in 117). 60 specimens were stained with three antibodies. From 58 patients receiving Nivolumab clinical information about response to therapy was available.
Results:
PD-L1 was expressed in 244 specimens (54.84%). 112 (25.63%) showed TC counts ≥50%, and 132 (30.21%) were <50%. 193 (44.16%) were negative. SP263 showed stronger staining intensity than 28.8 and E1L3N. Differences in TC-percentage were seen in 67 of 378 specimens, with major changes in 16 specimens (negative to positive in 4 and <50% to ≥50% in 12 cases). Higher TC percentages were seen with SP263. In the 58 treated patients complete remission was seen in 6 (4 ≥50%, 2 negative), partial remission in 14 (10 ≥50%, 3 <50%, 1 negative), stable disease in 4 (2 <50%, 2 negative), paradox reaction in 7 (1 ≥50%, 3 <50%, 3 negative) and progressive disease in 27 (4 ≥50%, 14 <50%, 9 negative).
Conclusion:
PD-L1 is expressed in the majority of NSCLC patients. Despite minor differences in expression levels all three tests provided reliable results. Furthermore PD-L1-IHC showed to be a useful biomarker in NSCLC especially concerning the good response to Anti-PD1 therapy in tumors with PD-L1 expression ≥50%. However as some PD-L1 negative tumors also responded, negative test results cannot definitely exclude patients from immunotherapy.
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MA15.06 - Predictive Value of Measuring Somatic Mutations and Tumor Infiltrating Lymphocytes for PD-1 Axis Therapy in Non-Small Cell Lung Cancer (NSCLC) (ID 6255)
14:56 - 15:02 | Author(s): S.N. Gettinger, J. Choi, N. Mani, I. Datar, E. Kaftan, S.B. Goldberg, D. Zelterman, K. Politi, R. Lifton, D. Rimm, R. Herbst, K.A. Schalper
- Abstract
Background:
Diverse factors have been associated with clinical benefit to PD-1 axis blockers in NSCLC including PD-L1 protein expression by immunohistochemistry and increased mutation load/predicted class-I neoantigens. However, the association and predictive value of the tumor genomic landscape, composition of the tumor immune microenvironment and T-cell function remain unclear.
Methods:
We performed whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) for T-cells in pre-treatment FFPE samples from 45 NSCLC patients treated with PD-1 axis blockers (alone or in combination) in our institution. Genomic analysis was used to evaluate the mutational load and predicted class-I neoantigens. Multiplexed QIF-based immunoprofiling was used to measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3+ cells) and T-cell activation (Granzyme-B in CD3+ cells). We studied the association between the tumor somatic mutations, predicted neoantigens, T-cell infiltration/function and clinical benefit /survival.
Results:
Increased mutational load was positively associated with predicted class-I neoantigens, variants in DNA-repair genes, smoking and absence of activating mutations in EGFR; but not associated with the level of CD3+ T-cells, T-cell proliferation (Ki-67 in CD3+ cells) and function (Granzyme-B in CD3+ cells). Increased mutations and candidate class-I neoantigens were significantly associated with response to therapy (P=0.02 and 0.03, respectively), but not with overall survival at 3-years (median cut-point, log rank P=0.92 and 0.80, respectively). Higher CD3 positivity was not associated with response to therapy (P=0.17), but was significantly associated with overall survival (median cut-point, log rank P=0.03). Regardless of the mutational load and candidate neoantigen content, elevated CD3 with low Ki-67/Granzyme-B in CD3 predicted longer survival after PD-1 axis blockade than high CD3/high Ki-67/Granzyme-B in CD3, or low T-lymphocyte infiltration.
Conclusion:
Increased somatic mutations are associated with smoking and response to PD-1 agents, but not with tumor T-cell infiltration/activation and overall survival. Regardless of the mutational load, increased T-cell infiltration using QIF is significantly associated with longer survival after PD-1 axis blockade in NSCLC. The subgroup of NSCLC with the highest potential of benefit to immune reinvigoration using PD-1 axis blockade comprise tumors with elevated lymphocyte infiltration but low in situ activation/proliferation.
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MA15.07 - Molecular Determinants of Lack of Tumor Immune Infiltration in NSCLC (ID 5191)
15:02 - 15:08 | Author(s): S. Olugbile, R. Bao, T. Hensing, Y. Nakamura, E.E. Vokes
- Abstract
Background:
Non-small cell lung cancer (NSCLC) make up the majority of all lung cancer cases and is associated with very poor prognosis. Immune checkpoint blockers have now been shown to induce unprecedented durable response in a fraction of NSCLC patients with pre-existing T cell infiltration within their tumor. However in order to improve their efficacies beyond this subset of patients, a detailed molecular characterization to identify factors associated with lack of T cell infiltration is needed. A recent analysis in metastatic melanoma identified Wnt/B-catenin pathway activation as a mechanism for lack of T cell infiltration. We pursued similar analyses of immunologic gene signatures and molecular associations in squamous cell lung cancer (SCC) and lung adenocarcinoma (LA).
Methods:
We analyzed RNAseq data from two lung cancer datasets of The Cancer Genome Atlas (TCGA) (N = 499 for SCC and N = 514 for LA). Samples were categorized into non-T cell inflamed and T cell-inflamed groups using unsupervised consensus clustering based on the expression of 160 immune-related genes. Ingenuity pathway analysis was utilized to identify molecular pathways activated in non-T cell-inflamed tumors.
Results:
A similar proportion of non-T cell-inflamed tumors were identified in the two cohorts (SCC: 34%; LA: 31%). 47% of the SCC tumors were identified as T cell-inflamed, as compared to 37% in LA. A positive correlation was observed between CD8A and PD-L1, IDO1, LAG3 and TIM3 (p<0.00001). Total of 1,216 genes are significantly up-regulated in non-T cell-inflamed SCC tumors and 596 in LA with at least 1.5-fold change and FDR-adjusted p<0.05. Among these, a total of 194 genes are up-regulated in both SCC and LA, with the rest being specific for each subtype (SCC: 84%; LA: 67%). Pathway analysis suggested 35 upstream regulators were activated in SCC and 32 in LA (activation z-score≥2.0). Among these, 10 upstream regulators are activated in both datasets (ATF4, CTNNB1, KAT6A, KLF4, MYC, NFE2L2, PI3K, SCAP, SP1, SREBF2). Finally, we performed the same gene expression analysis on RNAseq data from matched normal tissues (N = 51 for SCC and N = 59 for LA) and confirmed that the T-cell inflamed gene signature is a property of the tumor rather than normal lung tissue.
Conclusion:
Our analyses successfully identified genes and associated pathways that are enriched in NSCLC subtypes with no immune infiltration. Rational strategies to improve the efficacy of immune checkpoint blockers beyond the current subset of responders should be based on targeting these pathways.
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MA15.08 - Discussant for MA15.05, MA15.06, MA15.07 (ID 7096)
15:08 - 15:20 | Author(s): I. Kern
- Abstract
Abstract not provided
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MA15.09 - Response to the Treatment Immediately before Nivolumab Monotherapy May Predict Clinical Response to Nivolumab (ID 4400)
15:20 - 15:26 | Author(s): H. Kobayashi, S. Omori, K. Nakashima, K. Wakuda, A. Ono, H. Kenmotsu, T. Naito, H. Murakami, M. Endo, T. Takahashi
- Abstract
Background:
Nivolumab was approved in Japan on December 17, 2015 for previously treated non-small cell lung cancer (NSCLC). The expression of programmed death-ligand 1 (PD-L1) in tumor tissue is considered a predictive factor for clinical response to nivolumab. However, in Japan, there are no commercially available diagnostic kits for evaluating PD-L1 expression. In addition, little is known regarding other predictive factors of response to nivolumab monotherapy in patients with NSCLC. Therefore, we examined the relationships between the response to nivolumab monotherapy and clinical parameters in patients with NSCLC.
Methods:
Between December 2015 and April 2016, we performed a retrospective analysis of 50 patients with NSCLC treated with nivolumab monotherapy (3 mg/kg, every 2 weeks) at our Institution in the clinical setting.
Results:
Baseline characteristics of patients who received nivolumab monotherapy were: median age, 65 years [range:39–76]; 60% male; 26% ECOG-PS 0, 64% ECOG-PS 1; 38% smoker; 58% stage Ⅳ disease, 22% postoperative recurrence; 80% non-squamous (SQ) NSCLC; 36% non-SQ NSCLC patients had active EGFR mutations; 20% second-line, 18% third-line. The objective response rate (ORR) for all patients treated with nivolumab monotherapy was 18% (95%CI 10–31). Univariate analysis revealed that predictive factors of response to nivolumab monotherapy were associated with “SQ”, “response to the treatment immediately before nivolumab monotherapy”, “therapeutic line of nivolumab (second-line and third-line treatment)” and “smoker” categories (Table 1). In the multivariate logistic regression analysis, the independent predictive factors were “SQ” (P = 0.0069) and “response to the treatment immediately before nivolumab monotherapy” (P < 0.0001) (Table 1). Figure 1
Conclusion:
“Response to the treatment immediately before nivolumab monotherapy”, other than “SQ” histology may be predictors of clinical response to nivolumab in patients with NSCLC.
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- Abstract
Background:
Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade remains elusive. This study was sought to identify the potential biomarkers that predicted response to PD-1 blockade immunotherapy in lung adenocarcinoma.
Methods:
We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from cohorts of both lung adenocarcinoma public database including The Cancer Genome Atlas (TCGA), GEO repository (GSE72094) and Broad dataset, and clinical immunotherapeutic patients in our center. Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.
Results:
We observed distinct function of TP53 and KRAS mutation in regulating immune tumor microenvironment (TME). It is TP53 mutation but not KRAS mutation in lung adenocarcinoma that significantly increased expression of immune checkpoints, facilitated CD8+T cell infiltration and activated T-effector and interferon-γ (IFN-γ) signature. Interestingly, TP53 and KRAS co-mutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+. More importantly, TP53 or KRAS mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell cycle regulating, DNA replication and damage repair. Finally, clinical immunotherapeutic data were further confirmed that TP53 or KRAS mutation lung adenocarcinoma patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 blockade immunotherapy. Figure 1
Conclusion:
This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding PD-1 blockade immunotherapy.
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MA15.11 - Acquired Resistance Mechanisms to EGFR Kinase Inhibitors Alter PD-L1 Expression Status in Lung Cancer (ID 4652)
15:32 - 15:38 | Author(s): K. Suda, L. Rozeboom, C.J. Rivard, H. Yu, M.A. Melnick, T. Hinz, K. Ellison, D.C. Chan, K. Politi, L. Heasley, T. Mitsudomi, F.R. Hirsch
- Abstract
Background:
Immunotherapies that target PD-1/PD-L1 exploit the primary roles of cytotoxic agents in lung cancers. However, tyrosine kinase inhibitors (TKIs) are still considered to be the first choice in lung cancer patients with EGFR mutations. Although immunotherapies may be applied as second line or later therapeutic approaches in these patients, after acquisition of resistance to EGFR-TKIs, it is unclear if acquired resistance mechanisms alter PD-L1 expression status that is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents.
Methods:
Lung cancer cell lines with EGFR mutations (HCC827, HCC4006, PC9, and H1975) and their isogenic descendants with acquired resistance to various EGFR-TKIs were examined in this study. The resistance mechanisms of descendants include T790M secondary mutation, MET gene amplification, epithelial to mesenchymal transition (EMT), and loss of amplified EGFR mutant allele. PD-L1 expression status was analyzed by immunohistochemistry (IHC) and immunoblotting. Effects of acquired resistance mechanisms on PD-L1 expression were also evaluated by shRNA mediated knockdown of candidate molecules, and co-localization analysis using fluorescent imaging. IFN-gamma was used to mimic immune cell attack. Published microarray data of cells with acquired resistance to EGFR-TKIs were also employed to evaluate our findings.
Results:
PD-L1 expression was upregulated in several resistant cells and correlated with EGFR activation. In addition, we found that the phosphorylation of EGFR tyrosine (Y) 992 site, but not Y845, Y1068, or Y1173, was correlated with increased expression of PD-L1. We also observed that TKI-resistant cells with marked E-cadherin downregulation (HCC4006 erlotinib resistant cells and H1975 osimertinib resistant cells), one of hallmarks of EMT, showed decreased expression of PD-L1. However, one cell line (853#10), displaying EMT-like phenotype but only slight E-cadherin downregulation, showed PD-L1 upregulation. Published microarray data from three TKI-resistant lines with EMT-like features also support the correlation of low E-cadherin and reduced PD-L1 expression. ShRNA mediated knockdown of E-cadherin decreased the expression of PD-L1 in parental cell lines. IFN-gamma treatment upregulated PD-L1 expression in both parental and in resistant cells with E-cadherin downregulation, however PD-L1 expression in resistant cells was still lower and localized mainly in the cytoplasm rather than the cell membrane.
Conclusion:
We observed a dramatic change of PD-L1 expression status in lung cancers with EGFR mutation after acquisition of resistance to EGFR-TKIs, depending on the resistance mechanisms. These results support the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the resistance mechanisms but also for the evaluation of PD-L1 expression status.
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MA15.12 - Discussant for MA15.09, MA15.10, MA15.11 (ID 7097)
15:38 - 15:50 | Author(s): M. Früh
- Abstract
Abstract not provided
Author of
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MA14 - Immunotherapy in Advanced NSCLC: Biomarkers and Costs (ID 394)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:M. Reck, D.R. Spigel
- Coordinates: 12/06/2016, 16:00 - 17:30, Strauss 2
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MA14.02 - Evaluation of PD1/PDL1 Expression on Peripheral Blood Cells Subpopulations in Patients with Non-Small Cell Lung Cancer (ID 5192)
16:06 - 16:12 | Author(s): O. Arrieta
- Abstract
- Presentation
Background:
Currently the immune system is considered an important target of study within the therapeutic alternatives for many tumors that have developed resistance in lung cancer. Many molecules called checkpoints regulate antitumor immunity as PD-L1 it is expressed in tumour cells and is a biomarker for anti PD-L1/PD-1 therapy. PD-1 / PD-L1 is expressed on exhausted activated T cells. This signaling pathway is involved in tumor evasion of the immune system. It has recently been demonstrated that the blockade of PD-1 or its ligand PD-L1 and PD-L2, restore the antitumor immune response leading to a durable tumor regression. However, the expression of PD-1/PD-L1 in T cells from peripheral blood of patients with non-small cell lung cancer has not been widely studied.
Methods:
We investigated the expression of PD-1 and its ligands PD-L1 and PD-L2 on peripheral blood T cells subpopulations (CD3+ CD4+ / CD8+) of patients with non-small cell lung cancer. We included 50 NSCLC patients (stage IIIB and IV) naive to treatment and 10 healthy subjects. Immunophenotyping was performed using multiparametric flow cytometry. Analyzing its prognostic significance regarding outcome analysis as well as its potential biomarker.
Results:
Our results showed that the percentage of PD-1, PD-L1 and PD-L2 expression in peripheral blood cells in NSCLC patients was lower compared to healthy subjects [P<0.005] and the Mean Fluorescence Intensity (MFI) was higher in patients compared to the control group [P<0.001]; The expression of PD-1 in T-helper or CD4+ of NSCLC patients was significantly higher than in cells from control subjects [P<0.001]. Similarly, the expression of PD-1 in T cytotoxic cells or CD8+ patients was significantly higher than in controls [P<0.001]. In the clinical analysis, we found that a higher percentage of PD-1+ CD3+ cells was statistically associated with tobacco exposure [P=0.0160], and de MFI was associated with the non-adenocarcinoma histology [P=0.0001] additionally, the presence of 3 or more metastases was associated to a higher MFI of PD-1 on CD3+ CD8+ [P=0.0490]. In the overall survival (OS) analysis the percentage of CD3+/CD4+/PD-1+ ≤20.91 was associated with a higher median OS [P= 0.045].
Conclusion:
Several studies demonstrate the importance of infiltrating PD-1+ T cells within tumors; however these results showed that the PD-1/PD-L1/PDL-2 expression in peripheral blood cells could be used also as a potential biomarkers in NSCLC patients.
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P1.01 - Poster Session with Presenters Present (ID 453)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Epidemiology/Tobacco Control and Cessation/Prevention
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.01-016 - An International Epidemiological Analysis of Young Patients Diagnosed with NSCLC (AduJov - CLICaP) (ID 6296)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Eventhough lung cancer remains a disease of a median age at diagnosis of 70y, a proportion of patients are diagnosed at 40y or younger. Patients diagnosed before the age of 40 tend to be never-smokers, are stage IV adenocarcinoma, and tend to have an EGFR activating mutation or a EML4-alk translocation. It is crucial to determine the epidemiological characteristics of patients younger than 40y. Our study groups the largest population of patients less than 40y diagnosed with NSCLC.
Methods:
In this epidemiological retrospective study, 249 patients (Argentina=6, Canada=19, Colombia=29, Costa Rica=9, Mexico=89, Nicaragua=2, Panama=19, and Peru=76) with a histologically confirmed NSCLC aged 40 years or less at diagnosis were included. Data included age, gender, histology, stage, EGFR and alk mutation analysis, and date of death or last follow-up. Progression free survival (PFS) and overall survival (OS) were also recorded.
Results:
NSCLC patients aged 40 years or less accounted around a 4% of the total NSCLC population. Median age was 34.5 years (range 14-40), 137 (55%) were women, and 192 patients (77.1%) were non-smokers. Adenocarcinoma was the most frequent histological subtype with 203 patients (81.6%) and 24 patients (9.6%) were squamous. 214 patients (85.9%) were stage IV and 23 patients (9.2%) were stage III at diagnosis. The site(s) of metastasis was obtained in 203/214 stage IV patients where 39.9% (n=81) had lung, 35.6% (n=72) had SNC, and 31.7% (n=64) had bone metastasis. EGFR mutation (EGFRm) analysis was determined in 103 patients with 40 patients (38.8%) having an EGFRm. EML4-alk analysis was determined in 165 patients with 11 patients having a positive translocation (6.7%). The OS for all patients was 14.4 months (95%CI=11.2-17.6), PFS was 5.7 months (95%CI=4.9-6.5), and there was no significant difference according to histological subtype. OS for EGFRm(+) was 42 months (95%CI=30.8-54.0) and for EGFRm(-) was 19.4 months (95%CI=14.8-24.0) (p=0.002); PFS for EGFRm(+) was 11.9 months (95%CI=6.3-17.5) and for EGFRm (-) was 7.1 months (95%CI=5.3-8.9) (p=0.005). OS for alk(+) was 28.0 months (95%CI=15.4-40.6) and for alk(-) was 10.6 months (95%CI=6.9-14.3) (p=0.065).
Conclusion:
NSCLC patients aged 40 years or less constitute a small but important proportion of patients with this diagnosis. Other risk factors may be involved in the pathogenesis of the disease in this population due to a low smoking history found. SNC metastasis at diagnosis seems to be more frequent in this population. EGFR mutation and EML4-alk translocation frequency is higher than the frequency reported in the general population.
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P1.01-052 - Lung Cancer Mortality in Mexico, 1990-2014 (ID 5810)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Mortality from lung cancer ranks first in men and third in women in Mexico. We aim to assess the mortality rate from lung cancer in the Mexican population during the period from 1990 through 2014.
Methods:
In this longitudinal study we analyzed the mortality rate of lung cancer, adjusted for age, sex and degree of marginalization. The mortality rate was adjusted applying the direct method. In adittion, we used the 2010 Mexican Population,which was taken from the Population and Housing Census. Deaths were taken from the mortality database of the Ministry of Health of Mexico. The degree of marginalization of the population was made based on the marginality index established by the National Population Council, it includes five categories of marginalization: Very low, low, medium, high and very high. The 33 states of the Mexican Republic are divided into these categories, approximately being six to seven in each. Finally, the annual percentage change was calculated.
Results:
During the study period a decrease we observed a decrease in the lung cancer mortality rate adjusted for age and gender. Thus, the rate in 1990 was higher (110 deaths per 100,000 population), which decreased to 90 per 100,000 in 2014, representing a decrease of more than 15%. In relation to gender we observed a decrease in the mortality rate for both genders. In addition, the mortality rate in women was three times lower from that among men througout the whole period of study. Nonetheless, we observed a slight increasing trend for women in the last years. Regarding the marginalization index we observed that the highest mortality rates occur in the states that comprise the categories with low and very low marginalization. Moreover, decline in mortality was also observed in those categories, unlike the categories of high and very high marginalization, where a slightly increase was observed during the period of study.
Conclusion:
Mortality from lung cancer has declined during the studied period, a situation that may be due to various situations such as diagnosis at earlier clinical stages or treatments more effectively, or under registry of mortality in the states that make up the categories with high or very high marginalization. Such situations must be studied in greater depth to identify the causes for the decline in mortality from lung cancer.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-050 - Acquired Resistance to EGFR Tyrosine Kinase Inhibitors (TKIs) in EGFR-Mutant Lung Adenocarcinoma among Hispanics (Rbiop-CLICaP) (ID 5955)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Patients with epidermal growth factor receptor (EGFR)-mutant lung carcinoma eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In 50% of these cases, a secondary EGFR mutation, T790M, underlies the acquired resistance. Other alterations include amplification of MET, PI3K mutations, changes in MAPK1, Her2, AXL and even transformation to small cell lung carcinoma (SCLC). We assessed histological, clinical characteristics and survival outcomes in Hispanic patients with EGFR mutation after disease progression.
Methods:
34 EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective registry (active between January 2011 and January 2015) in which post-progression tumor specimens were collected for molecular analysis using SNaPshot tumor genotyping assay to detect mutations in EGFR, KRAS, BRAF, PI3KCA, TP53, MET and Her2, and FISH for MET, ALK and EGFR. Samples also underwent immunohistochemistry analysis for E-cadherin, synaptophysin, CD56 and PDL1. Post-progression interventions, response and survival were assessed and compared to those with and without T790M.
Results:
Mean age was 59.4±13.9 years; 62% were female, 65% were never-smokers and 53% had a performance status ≥80%; main metastatic sites were lung (16/47%), bone (20/58%), brain (18/52%) and liver (13/38%). All patients received erlotinib as first- line treatment and documented mutations were: 60% DelE19 (Del746–750) and 40% L858R. Overall response rate (ORR) with first line TKI was 61.8% and progression free survival (PFS) was 16.8 months (range, 13.7–19.9 m). After progressing to TKI, all patients were re-biopsied, of whom 16 had the T790M mutation (47.1%); 5 had PI3K mutations (14.7), 5 had EGFR amplification (14.7%), 2 had a KRAS mutation (5.9%), 3 had MET amplification (8.8%), 2 had Her2 alterations (5.8%, deletions/insertions in e20), and one had SCLC transformation (2.9%). 79.4% received treatment after progression. ORR for post-TKI treatments was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (CI95% 2.2–36.6). There were no differences in PFS according to gender (p=0.10) or type of acquired alteration (p=0.63). Median survival was 32.9 months (CI95% 30.4–35.3), and only the use of post-progression therapy affected OS in multivariate analysis (p=0.05).
Conclusion:
Hispanic patients with acquired resistance to EGFR TKIs continued to be sensitive to other treatments after progression. Proportion of T790M+ patients appears to be similar to previously reported results in Caucasians.
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P1.02-058 - EGFR Amplification and Sensitizing Mutations Correlates with Survival from Erlotinib in Lung Adenocarcinoma Patients (MutP-CLICAP) (ID 6335)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Tumor heterogeneity, which causes different EGFR mutation abundance, is believed to be responsible for varied progression-free survival (PFS) in lung adenocarcinoma (ADC) patients receiving EGFR-TKI treatment. Frequent EGFR amplification and its common affection inEGFR mutant allele promote the hypothesis that EGFR mutant abundance might be determined by EGFR copy number variation and therefore examination of EGFR amplification status in EGFR mutant patients could predict the efficacy of EGFR-TKI treatment.
Methods:
72 lung ADC patients who harbored EGFR activating mutations and received erlotinib as first line treatment, were examined for EGFR amplification by FISH. EGFR mutational and copy number status were compared with response, overall-survival (OS), and progression-free-survival (PFS).
Results:
Median age was 62-yo (r, 20-87 years), 53 patients were females (73%), and 89% have common mutations. Twenty-two (30.6%) samples with EGFR activating mutations were identified with EGFR amplification. EGFR amplification was more frequent in patients with exon 19 deletion (p=0.05) and in those with better performance status (p=0.01). Patients with EGFR gene amplification had a significantly longer PFS than those without [(25.2 months, 95%CI 22.0-38.5) vs. (12.4 months, 95%CI 5.3-19.5); p=0.002] as well as better OS [(EGFR amplified 37.8 months, 95%CI 30.9-44.7) vs. (EGFR non-amplified 27.1 months, 95%CI 12.8-41.3); p=0.009]. EGFR amplification significantly influenced the response to erlotinib (p=0.0001).
Conclusion:
EGFR amplification occurs in one third of patients with lung ADC harboring EGFR activating mutations, and could serve as an indicator for better response and survival from EGFR-TKI treatment.
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P1.06 - Poster Session with Presenters Present (ID 458)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.06-007 - Radical Treatment of Synchronous Oligometastatic Non-Small Cell Lung Cancer (NSCLC) (ID 6283)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Cancer represents a large biological spectrum of disease ranging from localized to multisystem involvement with multiple intermediate stages. Oligometastatic NSCLC is thought to carry a better overall survival (OS) but there are few prospective studies that evaluate it.
Methods:
Prospective cohort study with NSCLC patients treated at the Instituto Nacional de Cancerologia of Mexico, with stage IV and oligometastatic disease (≤ 5 metastatic lesions). Patients were enrolled to receive, after 4 cycles of systemic treatment with platinum-doublet chemotherapy or 4 months of tyrosine kinase inhibitors in patients with driver mutations, local consolidative treatment for the primary lesion and their metastases with chemoradiotherapy, surgery, radiotherapy, stereotactic radiosurgery or radiofrequency ablation based on the decision of the Multidisciplinary Thoracic Committee of the institution. The primary outcome was overall survival. The study was approved by de Institutional Ethics Committee and registered in clinical trials NCT02805530.
Results:
Up to this moment, we have evaluated 29 patients with NSCLC and oligometastatic disease. Of these, 62% males with a median age of 58 years (IQR 52.5-64.5), median CEA 10.2 (IQR 3.25-55), 59% former or currently smokers (median 37.5 package/year), wood-smoke exposure 28%. Overall 90% of the patients presented adenocarcinomas, 28% EGFR mutation (50% deletion of exon 19, 38% mutation on exon 21). At diagnosis 93% of the patients had symptoms mainly cough (48%), dyspnea (30%), neurologic symptoms (26%), weight loss (18%) and dysphonia (15%). We evaluated the oligometastatic disease status with PET-CT and MRI in 66% of the patients and the remaining with CT scan plus MRI. At diagnosis 66% had one or two metastases, 14% three to four metastases and 20% five metastases. For metastatic sites CNS was the main site of metastases in 52% of patients, 28% contralateral lung, 17% bone metastases and 7% at suprarenal. For radical treatment to the primary tumor, 59% chemoradiotherapy, 21% radiotherapy, 28% surgery and 3% radiofrequency. For definite treatment for the metastases, 45% received radiotherapy, 14% chemoradiotherapy and 17% surgery. The mean dose of radiotherapy received for the control of the primary tumor was 56.3 Gy (SD 11.28 Gy) and 29.5 Gy (SD 3.84Gy) for metastases. After multimodal treatment 24% had radiologic complete response. The median OS were 18.26 months (95%CI:10.89-25.64), the median OS for those with and without radiologic complete response were 28.58 months (95%CI:12.98-44.18) and 14.45 months (95%CI:10.40-18.51) respectively.
Conclusion:
Patients with oligometastatic NSCLC with agressive treatment have a large OS regardless their mutational status.
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P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.02-006 - Targeted Next Generation Sequencing Reveals Prognostic Recurrent Somatic Mutations in the GNAQ Oncogene in NSCLC (ID 6209)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
GNAQ is a stimulatory αq subunit of heterotrimeric G-proteins that is highly mutated in human melanoma and currently has no targeted treatment. GNAQ protein is similar to the RAS protein, in which activating mutations occurring within the catalytic (GTPase) domain confer constitutive signaling activity of the RAS pathway. However, GNAQ mutations have not been documented in Non-Small Cell Lung Cancer (NSCLC). Therefore, the aim of this study was to examine genomic alterations in GNAQ and correlate its mutation status with clinical characteristics of NSCLC patients.
Methods:
A cohort of 53 patients treated at the Thoracic Oncology Unit of the Instituto Nacional de Cancerologia (INCan) of Mexico were screened in a mutation analysis of the GNAQ oncogene by targeted next generation sequencing (NGS). All information from the patients was recorded in a database containing clinicopathological characteristics.
Results:
Patients characteristics included a median age of 66 years (36-82 years), with 77% of females, 39% of smokers, 51% with wood smoke exposure and the predominant histology was adenocarcinoma (86%) with intermediate grade (acinar-papillary) in 65% of cases. In this study, recurrent somatic mutations in GNAQ were found in 37/53 patients (70%) with a mutant allele (QNAQmut) frequency over 1%. GNAQ mutations were more frequently found in adenocarcinoma and stage IV (p=0.054 and p=0.098 respectively). The GNAQmut allele was associated with metastasis to the Central Nervous System (CNS) and bones (p < 0.001). This mutation was associated with a decrease in overall survival (69 vs. 12 months, p = 0.047). Additionally, two of these GNAQ-mutated patients having co-ocurring oncogenic mutations in GNAS and GNA11 exhibited faster disease progression and a poorer overall survival of only two months. There was no association between GNAQ and frequently mutated genes like EGFR, KRAS or MET.
Conclusion:
This is the first report of the presence of recurrent somatic mutations in GNAQ, GNA11 and GNAS oncogenes in NSCLC based on targeted NGS. We found a correlation between these genomic alterations and the patients response measured as disease progression and overall survival.
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P2.02-062 - Alterations in Pulmonary Function Tests Predict the Development of Radiation-Induced Pneumonitis in Advanced NSCLC (ID 4948)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Chemo and radiation therapy are the standard of treatment in patients with locally advanced NSCLC. Radiation pneumonitis is a frequent complication and its presence is associated with severe symptoms that decrease the quality of life and might result in pulmonary fibrosis or death.
Methods:
Prospective study from June 2013 to July 2015, in patients treated with concurrent chemoradiation for NSCLC at the Instituto Nacional de Cancerología of Mexico. All patients had pulmonary assessment at baseline (prior to chemoradiation) and at 6 weeks, 3, 6 and 12 months (end of chemoradiation). The pulmonary function tests (PFT) included: spirometry, pletismography, oscilometry, diffusing capacity for CO2, molar mass of CO2, arterial gasometry, 6 minutes walk and fraction of exhaled NO (FENO). Radiation pneumonitis was evaluated by RTOG criteria and the CTCAE V.4.0. The study was approved by the ethics committee and was registered in clinicaltrials.gov (NCT01580579).
Results:
Overall 52 patients were included and 37 patients completed one-year follow-up. Severe pneumonitis developed in 11/37 (29%) and 15/37 (40%), according to the RTOG criteria and the CTCAE V.4.0, respectively. Factors associated with pneumonitis development included age and dose per fraction (>250cGy). We observed as well that patients who developed pneumonitis had more often central and lower tumors, and percentage of irradiated lung with 20Gy greater than 35% (PA V20>35%) and 5Gy over 65% (PA V5>65%). PFTs alterations prior to treatment that identified the development of severe pneumonitis included: a lower forced expiratory volume in one second after bronchodilator (FEV1, p= <0.02), ratio for the residual volume between total lung capacity (RV/FTA, p= < 0.02) and FENO (p= <0.04). All PFTs showed changes at the end of chemoradiation, particularly between the third and sixth month of treatment, with a slight recovery at 12 months, without returning to basal values. Although patients who developed pneumonitis had a greater deterioration in the spirometry and plethysmography, changes in PFTs during the first 12 weeks not predicted the development of pneumonitis.
Conclusion:
Alterations in FEV1, RV/TLC and FENO, prior to concomitant chemoradiation predict the development of severe pneumonitis in NSCLC. This study suggests that all patients who receive chemoradiation to the lung must be assessed by PFTs in order to identify patients at high risk for radiation pneumonitis, and have a close follow-up with an early start (beginning of symptoms) of steroids to reduce long-term complications.
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-007 - Pem/CBP/Bev Followed by Pem/Bev in Hispanic Patients with NSCLC: Outcomes According to Combined Score of TS, ERCC1 and VEGF Expression (ID 6293)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS), ERCC1 and VEGF mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS).
Methods:
Patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance pemetrexed and bevacizumab was administered until disease progression or unacceptable toxicity.
Results:
One hundred forty-four Hispanic patients with a median follow-up of 13.8 months and a median number of maintenance cycles of 6 (range, 1- 32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median progression-free and overall survival (OS) rates were 7.9 months (95% CI, 5.9-10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. Median TS, ERCC1 and VEGF mRNA levels were 1.45 (range, 0.17–2.52), 0.58 (range, 0.44-1.20), and 2.72 (range, 1.84-3.21), respectively. OS was significantly higher in patients with the lowest TS mRNA levels [29.6 months (95%CI 26.2-32.9) compared with those with higher levels 9.3 months (95%CI 6.6-12.0); p=0.0001]. ERCC1 mRNA levels also influenced the OS [median for ERCC1 mRNA˂0.58 28.7 months (95%CI 26.3-31.2) vs. ERCC1 mRNA˃0.58 11.1 months (95%CI 9.6-12.7); p=0.0001] as well as VEGF mRNA levels [median OS for VEGF mRNA˂2.72 26.4 months (95%CI 22.8-30.0) vs. VEGF mRNA˃2.72 18.2 months (95%CI 8.4-27.9); p=0.009]. TS mRNA did not influence treatment response, however the ORR was significantly higher in patients with low levels of ERCC1 (p = 0.003) and elevated VEGF (p = 0.005). Multivariate analysis found that TS mRNA levels (p=0.0001), VEGF mRNA levels (p=0.007) and PS (p=0.014) were independent prognostic factors.
Conclusion:
Overall, PCB followed by maintenance pemetrexed and bevacizumab was in Hispanic patients with non-squamous NSCLC. This regimen was associated with prolonged OS, particularly in patients with low TS, ERCC1 and VEGF mRNA expression. These biomarkers alone or in combination may be useful to assess the prognosis of patients with NSCLC treated with CBP/Pem/Bev.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 5
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-003 - Mutation Profile & Histology According to ERS/ATC/IASCL Associated with IPFS to WBI in BM Patients with Recent Adenocarcinoma Lung Cancer (ID 5817)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Brain-metastases (BM) are a common metastatic site in non-small-cell lung cancer (NSCLC). We studied the impact of genetic alterations (EGFR, ALK and KRAS) in relation to objective response rate (ORR), intracranial-progression-free survival (IPFS) and overall-survival (OS) after whole-brain irradiation (WBI) in patients at recently diagnosis with NSCLC and BM.
Methods:
From 2009-2015, 231 NSCLC patients with BM were reviewed for eligibility. Among them, 121 patients with recently diagnosis of NSCLC, were treated with WBI and have available genotyping status.
Results:
EGFR, KRAS, ALK and WT patients were found in 38.0%, 6.6%, 5.8% and 49.6%, respectively. Overall, ORR and disease control rate (DCR) were 62.0% and 76.8%, respectively. ORR for EGFR, KRAS, ALK and WT patients were 82.6%, 25.0%, 71.4% and 50.0%, respectively (p=0.001). Female gender (OR 2.22 [95% CI: 1.01 – 4.89] P=0.047) and EGFR were associated to better response to WBI (OR 5.67 [95% CI 2.0-15.8], P = 0.001). A high architectural histological grade was independently associated with resistance to WBI. Median IPFS was 9.06 months [95% CI 6.5 -11.4]. IPFS for EGFR, K-RAS,ALK and WT patients were 11.9, 4.6,12.5 and 6.6 months, respectively (P <0.0001). EGFR mutation status (HR 0.54 [95%CI 0.3-0.9], P = 0.030) was the only factor associated with higher IPFS in the multivariate Cox-regression analysis. Median OS was 16.6 months [95% CI 11.6-22.6]. OS for EGFR, ALK, KRAS and WT patients were 26.8, 13.5, 4.9 and 13.6 months, respectively (P < 0.001). Intracranial OR was associated with a higher OS (HR 0.28 [95%CI 0.2-0.5], P < 0.001), while KRAS mutation positive status (HR 3.45 [95%CI 1.4-8.4], P = 0.006) was independently associated with worse OS. Figure 1
Conclusion:
EGFR mutation is an independent predictive factor for OR to WBI for BM in patients with NSCLC. KRAS mutation is an independent predictive factor for worse OS after BM.
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P2.03b-025 - Mutation Profile and Histology Subtype According to IASLC/ERS/ATC as Risk Factors for Brain Metastases in Lung Adenocarcinoma (ID 5850)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Brain metastases (BM) are common among patients with adenocarcinoma, affecting treatment response, quality of life and overall survival(OS). We examine the impact of the main histological pattern and the genetic alterations in EGFR and ALK on the incidence of BM in patients with advanced non-small cell lung cancer (NSCLC).
Methods:
From January 2004 through December 2014 the medical records of 991 patients with NSCLC were reviewed for eligibility, among them 711 had adenocarcinoma histology. We describe the factors associated with the overall incidence of BM as well as the incidence of BM stratified on the histological grade pattern according to the ERS/ATC/IASLC classification (lepidic vs acinar+papilar vs micropapilar+solid).
Results:
Among 711 patients, 53.6% were female, 47.1% were less than 60 years-old at the time of diagnosis, exposure to tobacco, wood-smoke and asbestos were found in 52.0%, 40.5% and 13.8%, respectively. Seventy-six percent had a good performance status, and nearly sixty percent (59.8%) had oligometastatic disease. Most of the patients had a stage IV disease at the time of diagnosis (79.3%). Regarding histological grade classification, male patients were more likely to have a poorly differentiated adenocarcinoma in comparison with women (61.2% vs. 51.2%, p=0.027), as well as ever-smokers compared with non-smokers (61.4% vs. 49.9%). Likewise, patients harboring an ALK rearrangement were more likely to have a highly- or moderate differentiated adenocarcinoma (100% vs. 43.6%, p=0.008). A total of 122 patients (17.1 %) had a brain metastasis at diagnosis and 37.4% had baseline carcinoembryonic levels above 20 pg/ml.By Kaplan-Meier method 6.45% and 12.10% of patients developed BM at 12 and 24 months. The factors associated with a high incidence of BM were: female gender (40.9% vs. 34.4%; p=0.036), age < 60 years (44.4% vs. 32.1%, p=<0.001), EGFR activating mutation (53.9% vs. 39.3%; p=0.001), advanced metastatic disease (IIIB vs IV 42.8% vs. 20.3%; p=<0.0001), serological carcinoembryonic level >20pg/ml (47.2% vs. 32.8%; p=<0.0001) Finally, brain metastases were more likely to be found among patients with moderate and poorly-differentiated adenocarcinomas in comparison with highly differentiated adenocarcinomas (54.2, and 48.1% vs. 7.7%; p=0.050). In the multivariate analysis EGFR (HR:0.63;95%CI 0.44-0.92, p=0.017) and highly differentiated adenocarcinomas EGFR (HR:1.59;95%CI 1.03-2.44, p=0.034) were found to be independent factors for the development of BM.
Conclusion:
Adenocarcinoma histological-architectural-grade differentiation according to ERS/ATC/IASCL classification was found to be a predictive factor for development of BM like other previously described clinically characteristics (e.g. gender, age, EGFR activating mutations and carcinoembryonic-antigen).
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P2.03b-062 - Association of the FAACT Total Score and Subscales with Clinical Characteristics and Survival in Advanced Lung Cancer (ID 5209)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Survival of lung cancer (LC) patients has increased and it is important to assess disease and treatment related symptoms that could negatively impact on prognosis and health-related quality of life (HRQL). The FAACT questionnaires have been proposed as a useful tool to measure HRQL, it includes 5 subscales: physical (PWB), emotional (EWB), functional (FWB) and social well-being (SWB), and AC/S-12 which is used to diagnose anorexia cachexia syndrome (CACS). The aim of this study was to associate the FAACT total score and subscales with clinical outcomes and survival.
Methods:
A cohort of patients with LC completed the FAACT instrument; regardless of age, gender, line of treatment, number of cycle, performance status, or histopathology subtype. Clinical and biochemical variables were collected. Survival was estimated from the day of questionnaire application until death or last follow-up.
Results:
The study included 200 patients. FAACT subscales had association with several clinical and biochemical data that are show in Table 1. PWB, FWB, AC/S-12 and FAACT total score were strongly associated to overall survival (Figure 1). Figure 1 Figure 2
Conclusion:
The FAACT questionnaire is reliable and valid for the assessment of HRQL and CACS in patients with LC and can be used liberally in clinical trials.
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P2.03b-083 - Soluble Angiogenic Factors as Predictive Biomarkers of Response to Docetaxel plus Nintedanib as Second Line Therapy in NSCLC (ID 5199)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Angiogenesis is fundamental for progression in non-small cell lung cancer (NSCLC). Nintedanib is a potent, triple angiokinase inhibitor of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF). We evaluated the association between plasma levels of VEGF, FGF, and PDGF, both baseline and after treatment with Nintedanib plus Docetaxel, as well as disease control rate (DCR), progression-free survival (PFS) and overall survival (OS), among patients with NSCLC.
Methods:
Thirty-eight patients were enrolled from July 2014 through October 2015. Stage IIIB/IV NSCLC patients who had progression after first-line chemotherapy with adenocarcinoma histology were included. Patients received Docetaxel 75mg/m2 on day 1 plus 200mg of Nintedanib orally twice daily on days 2-21 every three weeks until unacceptable adverse events or disease progression. Peripheral blood samples were taken at baseline and after completion of the second cycle of Docetaxel plus Nintedanib therapy to measure angiogenic factors.
Results:
Mean age at diagnosis was 58.7 years. Eighty-two percent of the patients had metastatic disease, and a good (<2) ECOG performance status (97.4%). Acinar (21.1%) and papillary (15.8%) sub-histological types were the most common adenocarcinoma predominant patterns. Overall response rate and DCR were of 7.9% and 47.3%, respectively. Baseline values of FGF, VEGF and PDGF were 27.6 pg/ml; 122.7 pg/ml and 8,655 pg/ml. Patients with DCR were more likely to have lower median serological values of FGF at follow-up (33.1 vs. 88.1 pg/ml; p=0.0017). Median PFS was 3.7 months. Both in the univariate and multivariate analyses, a higher percentage change reduction in PDGF after treatment was associated with a longer PFS (6.37 vs. 3.58 months, p=0.059; Hazard ratio (HR): 3.15, p=0.024). OS of patients was 8.8 months. Both in the univariate and mutivariate analysis a higher percentage change in FGF was associated with a longer OS (13.8 vs. 7.16 months, p=0.006; HR: 3.63, p=0.033].
Conclusion:
A higher reduction of plasma levels of FGF and PDGF was associated with better clinical outcomes.
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P2.03b-088 - PET-CT with 68Ga-RGD as Biomarker of Response to Nintedanib plus Docetaxel as Second Line Therapy in NSCLC (ID 5196)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Nintedanib, an approved second-line treatment for NSCLC in combination with docetaxel, is an oral angiokinase inhibitor against pro-angiogenic pathways. Advanced techniques in nuclear medicine have developed new radiotracers, such as Ga68-RGD for assessment of tumor vascularity and therapy response. The αVβ3 integrin is a transmembrane protein of great importance in tumor angiogenesis, due to its massive overexpression. Peptides containing the RGD sequence have high affinity for αVβ3 integrin receptors overexpressed in tumor cells. We evaluate objective-response rate (ORR), disease-control rate (DCR) by RECIST v.1.1, progression-free survival benefit (PFS) and overall survival (OS) obtained by Nintedanib plus Docetaxel therapy, and its response measured by PET-CT with Ga68-RGD biomarker.
Methods:
Study enrollment from July 2014 to October 2015. Inclusion criteria were confirmed adenocarcinoma histology, and disease progression after platinum-based-chemotherapy. Thirty-eight patients were assigned to receive Docetaxel (75mg/m2, IV) on day 1 plus Nintedanib (200mg, orally twice daily) on days 2-21 every three weeks until unacceptable adverse events or disease progression. All patients underwent a PET-CT with IV tracer Ga68-RGD and measurements at three time points (30, 60 and 120 mins) prior treatment start and after completing 2 therapy cycles.
Results:
Mean age at diagnosis was 58.7±11.4 years. Of the 38 patients, 31 had complete data for analysis. After 2 treatment cycles, the PET-CT assessment response, based on baseline Lung/Spleen SUVmax index, showed an ORR of 7.9% and DCR of 47.3%. Median PFS of 3.7 months and median Hypertensive patients were more likely to have a higher PFS (6.3 vs. 3.3 months; p=0.023), as well as patients with a larger baseline tumoral-volume by Ga68-RGD PET-CT (2.1 vs. 6.1 months; p=0.007). Global OS was of 8.8 months. Non-smokers were more likely to have larger OS (9.3 vs 4.2; p=0.008). Also a median OS was longer among patients with higher Lung/Spleen SUVmax index percentage change after treatment (9.4 vs. 4.9 months; p=0.05) was found.
Conclusion:
A larger baseline tumoral-volume can be associated to a higher progression-free survival due to the major cellular component to target with antiangiogenic therapy, as well as a strong association of larger survival assessed by the Lung/Spleen SUVmax index after treatment, marked by the Ga68-RGD radiotracer.
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P2.06 - Poster Session with Presenters Present (ID 467)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Scientific Co-Operation/Research Groups (Clinical Trials in Progress should be submitted in this category)
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.06-022 - First-Line Durvalumab plus Tremelimumab vs Platinum-Based Chemotherapy for Advanced/Metastatic NSCLC: Phase 3 NEPTUNE Study (ID 4610)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Current first-line therapy for advanced EGFR and ALK wild-type NSCLC is associated with poor survival and there remains a significant need for more effective treatments in this population. Blockade of immune checkpoints programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) represents a promising anticancer therapeutic strategy. In preclinical models, targeting both PD-1 and CTLA-4 provides for non-redundant pathway blockade and potential synergy. Durvalumab (MEDI4736) is a selective, high-affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 (IC~50~ 0.1 nM) and CD80 (IC~50~ 0.04 nM). Tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4. A Phase 1b study of durvalumab + tremelimumab demonstrated encouraging clinical activity and a manageable tolerability profile in advanced NSCLC, with activity observed in patients with high and low/no tumour PD-L1 expression (NCT02000947).
Methods:
NEPTUNE (NCT02542293) is a randomised, open-label, multicentre, global, Phase 3 study. Immunotherapy- and chemotherapy-naïve patients with advanced/metastatic EGFR and ALK wild-type NSCLC (with either PD-L1 high expression [≥25% tumour cells staining for PD-L1 at any intensity] or PD-L1 low/negative expression [<25% tumour cells staining for PD-L1 at any intensity] ) will be randomised (1:1) to durvalumab (20 mg/kg i.v. every 4 weeks [q4w] for up to 12 months) + tremelimumab (1 mg/kg i.v. q4w for up to 4 doses); or standard-of-care platinum-based doublet chemotherapy. The primary endpoint is overall survival (OS). Secondary endpoints are progression-free survival (PFS), objective response rate (ORR), duration of response and proportion of patients alive and progression free at 12 months by investigator assessment (RECIST v1.1); time from randomisation to second progression; OS, PFS and ORR in patients with PD-L1 low/negative NSCLC; safety (CTCAE v4.03) and tolerability; pharmacokinetics; and immunogenicity. Exploratory outcomes include potential biomarkers of response to treatment and impact of subsequent anticancer therapies on OS. Recruitment is ongoing. Figure 1
Results:
Not-applicable
Conclusion:
Not-applicable
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P3.01 - Poster Session with Presenters Present (ID 469)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.01-014 - Differential Gene Expression of Lung Adenocarcinoma Histology Subtypes According to the IASLC/ATS/ERS Classification (ID 4946)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
The current lung cancer classification from the IASLC/ATS/ERS integrates lung invasive adenocarcinoma subtypes accounting for the clinical, radiological, molecular and prognostic differences with its implications within the clinical practice. We analyzed the differences in genetic expression of the adenocarcinoma subtypes according to the new WHO 2015 classification.
Methods:
A cohort of 29 NSCLC patients treated at the Instituto Nacional de Cancerología of Mexico from 2008 to 2011. All patients had an available biopsy sample and were classified in four different subtypes of adenocarcinoma (2015 WHO classification). All the tissue samples were analyzed by microarrays to characterize the different expressed genes. IPA Software was used to identify biological processes, functions and biomarkers.
Results:
Lepidic predominant adenocarcinoma subtype was the only pattern that showed a marked gene expression difference against all predominant histologic patterns, revealing genes with significant (p < 0.01) expression. For all the histological predominant pattern subtype comparisons the top functional networks were related to eight different biological categories as follows: DNA replication; Recombination and Repair; Cell Cycle; Cell Death and Survival; RNA Post-Transcriptional Modification; Cancer; Organismal Injury and Abnormalities; Cellular Development. Moreover, we observed 13 genes with specific differential expression in the Lepidic predominant adenocarcinoma subtype.
Conclusion:
Lepidic predominant histological pattern subtype has a differential gene expression profile when compared against all predominant histological patterns subtypes. Moreover, we found a gene expression signature of 13 genes that has a unique behavior in the Lepidic histologic pattern subtype that could be used as a specific gene expression signature, biomarker or therapeutic target.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-125 - Failure to Tyrosine Kinase Inhibitors and Patterns of Progression in Patients with Advanced Non-Small Cell Lung Cancer (ID 5089)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Some studies have evaluated the impact of patterns of progression after treatment with tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). We evaluated the patterns of progression and prognosis of NSCLC patients that received TKI.
Methods:
Using the criteria established by Yang to define models of progression to TKI we did a retrospective analysis. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis.
Results:
Eighty-three NSCLC patients were included: 43 patients with dramatic-progression (51.8%), 26 with gradual-progression (31.3%), and 17 with local-progression (16.9%); demographic and clinical characteristics were similar in all subgroups. There was a significant difference in the median Progression-Free Survival (PFS) among the three groups, for the group with dramatic-progression it was 9.1 months, 16 months for gradual-progression and 11.9 for local-progression (P: 0.044). The overall survival (OS) was different among the three groups, for patients in gradual-progression 56 months, for patients in dramatic-progression 30 months and local-progression 36.4 months (figure A). Additionally 41.7% were treated with afatinib after progression to erlotinib and gefitinib. PFS in all patients was 8.08 months. Patients that present asymptomatic progression have a longer OS compared to those who present symptomatic progression (42 vs 31.9 months; p = 0.048). Figure 1
Conclusion:
There is a subgroup of patients with NSCLC and EGFR mutations with better prognosis and they can be identified according to the pattern of progression and presence of symptoms, as well as the duration of response during treatment. These could help decide which patients will benefit from continuing the anti-EGFR therapy beyond progression or to prescribe an aggressive approach when there is oligometastatic disease or local progression, especially in countries where access to third-generation TKIs is limited.
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P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 4
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.03-035 - Prognostic Role of hENT1 and RRM1 in Patients with Advanced Pleural Mesothelioma Treated with Second Line Gemcitabine Based Regimens (ID 6328)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Nucleoside transporter proteins mediates the transport of nucleosides and nucleoside analog drugs across the plasma membrane. The human equilibrative nucleoside transporter 1 (hENT1) is a nucleoside transporter protein that mediates cellular entry of gemcitabine, cytarabine, and fludarabine. The hENT1 expression has been demonstrated to be related with prognosis and activity of gemcitabine-based therapy in breast, ampullary, lung, and pancreatic cancer. In the same way, RRM1 encodes the regulatory subunit of ribonucleotide reductase and is a molecular target of gemcitabine. Previous studies showed increased RRM1 expression on continuous exposure of cell lines to gemcitabine and suggested improved survival for patients with low RRM1 expression.
Methods:
We measured hENT1 and RRM1 messenger RNA (mRNA) levels by quantitative real-time reverse transcription-polymerase chain reaction in tumor samples from 29 patients with advanced pleural mesothelioma (APM) treated in second line with gemcitabine based chemotherapy correlating these data with clinical parameters and disease outcomes (overall response rate-ORR, progression free survival-PFS and overall survival-OS).
Results:
The median age was 60-yo (r, 33-70 years), 15 patients were males (51%), 34% of cases undergone debulking surgery and the median follow-up was 13.4 months (95%CI 6.4-34). All patients were treated with Pem based chemotherapy in first line achieving a PFS of 8.1 months (95%CI 3.7-12.6), while PFS with second-line Gem based chemotherapy was 6.3 months (95%CI 3.6-8.8). 62% and 34.5% of patients had low levels of mRNA for hENT1 and RRM1, respectively. On univariate survival analysis, the hENT1 expression was associated with OS (p=0.001) and PFS (p=0.022). Specifically, those patients with overexpression of hENT1 showed a shorter OS p=0.021) and a shorter PFS (p=0.033). In contrast, mRNA expression of RRM1 did not influence the OS (p = 0.44) but it modifies positively the PFS (p=0.034). Multivariate analysis found that combined hENT1 (p=0.001) and RMM1 (p=0.012) predict survival in patients with APM treated with Gem based regimens.
Conclusion:
hENT1 mRNA expression carries prognostic information in patients with APM and combined with RRM1 holds promise as a predictive biomarkers in gemcitabine treated patients.
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P3.03-045 - Treatment of Malignant Pleural Mesothelioma beyond First-Line among Hispanics (MeSO-CLICaP) (ID 6271)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Platinum/Pemetrexed chemotherapy is standard of care in first-line (FL) treatment of malignant pleural mesothelioma (MPM). Different second and third lines regimens are also considered, but the optimal treatment has not yet been defined.
Methods:
The aim of this study was to evaluate clinical outcomes of second (SL) and third line (TL) therapies in a series of MPMs included in a retrospective multinational database (MeSO-CLICaP). Clinical records of MPM-patients who received treatment beyond FL from 2008 to 2016 were reviewed. Study endpoints were response, overall-survival (OS), and progression-free-survival (PFS) for SL and TL, stratified for patient characteristics, FL-outcomes, and type of regimen. Out of 124 patients, 79 received SL/TL and had sufficient clinical data.
Results:
Of the 124 patients included in the MeSO-CLICaP registry, 79 (64%) received some treatment after first line. Median age was 59 years (range 33-81), 42 (53%) were men, 74% were current or former smokers and 77% had a baseline ECOG 0-1. After FL, 57 patients (76%) achieved disease-control (PR 24/32% and SD 33/44%) and 18 had a time-to-progression ≥8 months. Median PFS and OS to SL were 6.2 (95%CI 4.9-7.4) and 16.1 (95%CI 14.5-17.6) months, respectively. According to a multivariate analysis, disease control after SL-therapy was significantly related to pemetrexed-based treatment (OR 2.46; p=0.017) and FL-TTP≥12 months (OR 3.50; p=0.006). Improved PFS to SL was related to younger age (<65 years, HR: 0.60; p=0.045), ECOG 0-1 (HR 0.72; p=0.02), and FL-TTP≥12 months (HR 0.48; p<0.001). OS was significantly related to ECOG 0-1 (HR 0.43; p=0.011) and to FL-TTP≥12 months (HR 0.66; p=0.05). Fifty-two patients (42%) receive a TL achieving a disease control rate of 62% with a PFS of 5.9 months (95%CI 5.0-6.8).
Conclusion:
SL-chemotherapy appears to be active in Hispanic MPM-patients, particularly in younger patients with good PS and prolonged disease control with FL chemotherapy. Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues.
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P3.03-048 - Profiling Response to Chemotherapy in Malignant Pleural Mesothelioma among Hispanics (MeSO-CLICaP) (ID 6319)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is a rare malignant disease, and the understanding of molecular pathogenesis has lagged behind other malignancies.
Methods:
A series of 53 formalin-fixed, paraffin-embedded tissue samples with clinical annotations were retrospectively tested for BAP1 and PI3K mutations and for mRNA expression of TS and EGFR. Immunohistochemistry staining for CD26 (dipeptidyl-peptidase IV, DPP-IV) and Fibulin3 (Fib3) proteins were also performed. Outcomes like progression free survival (PFS), overall survival (OS) and response rate (ORR) were recorded and evaluated according to biomarkers. Cox model was applied to determine variables associated with survival.
Results:
Median age was 58 years (range 36-76), 27 (51%) were men, 89% were current or former smokers, and six patients had previous contact with asbestos. 77% had a baseline ECOG 0-1 and almost all patients (n=52/98%) received cisplatin or carboplatin plus pemetrexed (Pem) as first line; 58% of them were treated with Pem as maintenance for a mean of 4.7 +/-2.8 cycles. 53.5% and 41.5% of patients were positive for CD26 and fibulin-3, while 49% and 43.4% had low levels of EGFR and TS mRNA, respectively. The majority of epithelioid and biphasic types expressed CD26 (p=0.008), Fibulin3 (0.013) and had lower levels of TS mRNA (p=0.008). Mutations in PI3K (c.1173A> G, c.32G> C and c.32G> T) were found in 5 patients and only one patient had a mutation in BAP1 (c.241T> G). First line PFS were significantly longer in CD26+ (p=0.0001), in those with low EGFR mRNA expression (p=0.001), in patients with positive Fib3 (p=0.006) and lower TS mRNA expression (p=0.0001). OS were significantly higher in patients with CD26+ (p=0.0001), EGFR- (p=0.001), Fib3 + (p=0.0002) and low TS mRNA expression level (p=0.0001). Multivariate analysis found that CD26+ (p=0.012), Fib3 (p=0.020) and TS mRNA levels (p=0.05) were independent prognostic factors.
Conclusion:
CD26, Fib3 and TS were prognostic factors significantly associated with improved survival in patients with advanced MPM.
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P3.03-060 - Characteristics and Long Term Outcomes of Advanced Pleural Mesothelioma in Latin America (MeSO-CLICaP) (ID 6265)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor, usually associated with a poor prognosis. MPM is a heterogeneous disease often associated with different clinical courses. Palliative platinum-based chemotherapy may help to improve symptoms and prolong life.
Methods:
The MeSO-CLICaP registry identified 124 patients with advanced MPM from 5 Latin American countries diagnosed and treated between January 2008 and March 2016. Data collected included age, gender, asbestos exposure, presenting signs/symptoms, performance status, histology, stage, treatment modalities including chemotherapy, and date of death or last follow-up. Outcomes like progression free survival (PFS), overall survival (OS) and response rate (ORR) were recorded. Cox model was applied to determine variables associated with survival.
Results:
median age was 59.5 years (range 33-84), 72 (58%) were men, 69% were current or former smokers and 37 patients (30%) had previous exposure to asbestos. Ninety-six patients (77%) had a baseline ECOG 0-1, 102 (82%) were epithelioid tumors, 47 (38%) and 77 (62%) cases had stage III or IV MPM. Only 20% (n=25) underwent pleurectomy, 28% (n=35) received radiotherapy and 123 patients received platinum-based chemotherapy in first line (plus Pem 68/54% and Gem 55/44%). ORR to first line chemotherapy was 48% (CR 3.2%/PR 43%), PFS was 10.5 months (95%CI 8.2-12.8) and 47 patients had Pem maintenance (mean number of cycles 4.4+/-3). Median OS was 25.3 months (95%CI 22.3-28.3) and according to a univariate analysis, stage (p=0.03), histology (p=0.005), and Pem manteinance (p=0.014) were associated with better OS. Multivariate analysis found that stage (p=0.002), histology (p=0.021), smoking history (p=0.001) and Pem manteinance (p=0.002) were independent prognostic factors.
Conclusion:
Our study identifies factors associated with a clinical benefit from chemotherapy among Hispanic patients with advanced MPM, and emphasizes the impact of histology and clinical benefit of chemotherapy on outcomes.
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P3.05 - Poster Session with Presenters Present (ID 475)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Palliative Care/Ethics
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.05-002 - Malnutrition is an Independent Risk Factor on Survival on EGFR Mutated Patients Diagnosed with Non-Small Cell Lung Cancer (ID 5300)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Lung cancer continues to be the leading cause of cancer-related death worldwide. In Mexico, EGFR mutation is around 31%. Malnutrition is a common problem among patients with cancer, affecting up to 85% of end-stage cancer patients, and 50-56% advanced NSCLC patients. Malnutrition poses an unfavorable prognosis and has also been associated with higher incidence of treatment related toxicity. No evidence about malnutrition in EGFR mutated patients has been described. The objective of the study is to asses the relation between malnutrition and survival of patients with NSCLC and EGFR mutation.
Methods:
One hundred-five patients diagnosed with NSCLC haring EGFR mutation undergoing any line of treatment were assessed from January 2015 to June 2016. Malnutrition was measured using the Subjective Global Assessment tool (SGA), patients were classified as without malnourishment (SGA=A) or malnourished (SGA=B+C). Overall survival was compared with the Kaplan-Meier method.
Results:
Baseline characteristics are shown in Table 1, 51.9% of patients were malnourished by the time of evaluation. Overall survival (OS) was 13.6 months (95% CI:12.7-14.4 months). Patients without malnutrition at the time of treatment initiation had a better OS than malnourished patients 14.2 vs 10.5 months (p=0.003) (Figure 1). Malnutrition is a risk factor for death independently of age, sex and treatment with TKIs versus chemotherapy (OR=8.7, 95% CI: 1.01-75.4, p=0.049).
Conclusion:
Patients harbouring EGFR mutations benefit from more effective treatments, and usually have better prognosis. Malnutrition is an independent risk factor for mortality in this population, thus assessment of nutritional status and a timely referral to a nutrition expert could result a better prognosis and health related quality of life.
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P3.05-003 - Anxiety and Depression in Patients with EGFR+ NSCLC Receiving Treatment with TKIs (ID 6152)
14:30 - 14:30 | Author(s): O. Arrieta
- Abstract
Background:
Patients with lung cancer (LC) report higher levels of anxiety and depression than cancer patients in general. Targeted therapies, such as tyrosine kinase inhibitors (TKIs) offer patients with EGFR mutations improved survival outcomes with less associated toxicity. This type of treatment has been associated with improvement on quality of life and lower symptomatic burden, which influence emotional status. The aim of this study is to report anxiety and depression prevalence and severity on patients with EGFR mutation on the course of the first four months of treatment with TKIs.
Methods:
A cohort of 76 LC patients receiving TKIs was evaluated. Hospital Anxiety and Depression Scale (HADS) and Quality of Life (QLQ-30) scores were registered at baseline (T0), and after treatment (two cycles [T2] and four cycles [T4]). For each subscale of HADS, scores were rated: <7 as negative, 8-10 as low and 11-21 as severe. Score changes on emotional subscales were analyzed with Wilcoxon test.
Results:
Most patients reported normal levels of anxiety and depression at all times of the evaluation. Anxiety reduced significantly at T2 (p=0.007) and T4 (p=0.001). Depression rates remained stable, but were associated with worse global QoL scores (p=0.001), fatigue (p=0.010), emotional distress (p=0.001) and social distress (p=0.011).
Conclusion:
Anxiety and depression rates are highly prevalent in patients with EGFR mutations. The changes found on subscales scores may be due to several factors such as quality of life, performance status, response to treatment, a heightened perception of control and the expectation of having a better prognosis, among other factors. Since the needs of the patients vary according to treatment type, further studies on the emotional status of patients treated with novel therapeutic agents are warranted in order to understand factors that stimulate emotional well-being.
