A randomized, phase 2 study of deoxyuridine triphosphatase inhibitor, TAS-114, in combination with S-1 versus S-1 alone in patients with advanced non-small-cell lung cancer

Summary Introduction TAS-114 is a potent inhibitor of deoxyuridine triphosphatase, which is a gatekeeper protein preventing uracil and 5-fluorouracil (5-FU) misincorporation into DNA. TAS-114 has been suggested to enhance the antitumor activity of 5-FU. This randomized, phase 2 study investigated TAS-114 plus S-1 (TAS-114/S-1) vs. S-1 in non-small-cell lung cancer (NSCLC) patients. Methods Patients with advanced NSCLC, previously treated with ≥ 2 regimens, were randomized 1:1 to receive TAS-114 (400 mg)/S-1 (30 mg/m2) or S-1 (30 mg/m2). Progression-free survival (PFS, independent central review) was the primary endpoint. Secondary endpoints included disease control rate (DCR), overall survival (OS), overall response rate (ORR), and safety. Results In total, 127 patients received treatment. Median PFS was 3.65 and 4.17 months in the TAS-114/S-1 and S-1 groups, respectively (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.71–1.88; P = 0.2744). DCR was similar between groups (TAS-114/S-1 80.3%, S-1 75.9%) and median OS was 7.92 and 9.82 months for the TAS-114/S-1 and S-1 groups, respectively (HR 1.31, 95% CI 0.80–2.14; P = 0.1431). The ORR was higher in the TAS-114/S-1 group than the S-1 group (19.7% vs. 10.3%), and more patients with tumor shrinkage were observed in the TAS-114/S-1 group. Incidence rates of anemia, skin toxicities, and Grade ≥ 3 treatment-related adverse events were higher in the TAS-114/S-1 group compared with the monotherapy group. Conclusions Although the TAS-114/S-1 combination improved the response rate, this did not translate into improvements in PFS. Clinical Trial Registration No. NCT02855125 (ClinicalTrials.gov) registered on 4 August 2016

Activity of HSP90 Inhibiton in a Metastatic Lung Cancer Patient With a Germline BRCA1 Mutation

Heat shock proteins (HSPs) are molecular chaperones that maintain proteins in their correct conformation to ensure stability and protect carcinoma cells from apoptosis. HSP90 inhibitors (HSP90i) block multiple targets simultaneously, and despite responses in a selected population, no HSP90i have yet been approved. We present a patient with a lung tumor with an exceptional response to cisplatin/gemcitabine in combination with HSP90i, which nowadays continues with HSP90i maintenance after three years. Whole-exome sequencing of the lung tumor unveiled a BRCA1/2 deficiency mutational signature, and mutation analysis confirmed a germline BRCA1 mutation. The striking efficacy of HSP90i plus chemotherapy vs chemotherapy alone was reproduced in a patient-derived xenograft (PDX) model from a breast cancer patient with a BRCA1 mutation (mean tumor volume [SD], No. of tumors: vehicle 8.38 [7.07] mm 3, n = 3; HSP90i 4.18 [1.93] mm 3, n = 5; cisplatin plus gemcitabine 3.31 [1.95] mm 3, n = 5; cisplatin plus gemcitabine plus HSP90i 0.065 [0.076] mm 3, n = 6). This case and the PDX demonstrate the efficacy for therapeutic inhibition of HSP90 in a BRCA- mutated patient, opening a new potential avenue for better identifying patients who might benefit most from HSP90i

Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer

Altres ajuts: This work was supported by the Fundacion Cientifica Asociación Española Contra el Cancer-AECC [grant number GCB14142170 to LMM, MS-C, and EF].Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs

Análisis de la expresión de PD-L1 en una serie de pacientes con mesotelioma pleural maligno

Introducción El mesotelioma pleural maligno (MPM) es un tumor que se caracteriza por su mal pronóstico y escasa respuesta al tratamiento, con una mediana de supervivencia de 12 meses. Se ha relacionado el asbesto como principal causante de esta enfermedad aunque recientemente se apunta a que los factores genéticos pueden tener importancia en el desarrollo del mesotelioma. Numerosos estudios han demostrado que el mesotelioma es un tumor inmunogénico, que induce reconocimiento inmune, infiltración de células inmunes y muerte mediada por inmunidad. La vía del PD1-PD-L1 es responsable de controlar la muerte celular , el daño tisular y mantener la tolerancia periférica. Estudios recientes que evalúan esta vía en cáncer de pulmón, renal y melanoma entre otros han encontrado que está activada en aproximadamente un 50% de los pacientes. Nosotros analizamos el papel de la vía de PD-L1 en el MPM. Material y métodos Analizamos 119 pacientes diagnosticados de MPM entre el periodo 2000-2014 con material archivado en el servicio de anatomía patológica del Hospital Unuversitario Vall de H´ebron y el Hospital Universitario 12 de Octubre. Se recogió la información de los pacientes y seleccionamos los casos que disponían de al menos dos laminillas no teñidas para hacer el estudio de inmunohistoquímica. Utilizamos el anticuerpo E1L3N™para realizar la tinción de PD-L1y el resultado lo consideramos positivo si teñían más del 1% de las células en cualquier localización (membrana celular, infiltrado inflamatorio y citoplasma). Los datos de supervivencia se analizaron por medio de las curvas de Kaplan Meier. Resultados Características de los 119 pacientes: edad media 69 años (rango 42-90), la mayoría eran hombres (71.4%), fumadores (51%), referían contacto con el amianto (44.5%), tenían el subtipo epitelioide (65%) y presentaban buen estado general con ECOG 1 el 64.8% de pacientes. Se disponía de material suficiente para realizar el análisis de inmunohistoquimica en 77 pacientes y encontramos que PD-L1 es positivo en 16 pacientes (20.7%).Respecto a la intensidad de la tinción 9 pacientes presentaban una intensidad leve, 4 pacientes moderada y 3 intensa. La supervivencia global de todos los pacientes fue de 9.8 meses. Los pacientes con histología epitelioide presentaban significativamente mejor pronóstico (16.8 meses frente a 5.2 meses los bifásicos y 0.8 meses los sarcomatoides, p<0.001). Cuando analizamos los pacientes evaluados para PD-L1 encontramos que su expresión es más frecuente en los tumores no epitelioides (p=0.033). En nuestra serie PD-L1 es un factor pronóstico desfavorable. Los pacientes PD-L1 positivo tenían una mediana de supervivencia de 4.7 meses frente a 16.3 los pacientes los PD-L1 negativos, (p=0.012). En el análisis multivariado el valor pronóstico desfavorable de PD-L1 se mantiene independiente del subtipo histológico (p=0.021). Conclusiones En nuestra serie encontramos que PD-L1 se expresa en el 20% de los pacientes con MPM medido por inmunohistoquímica. La presencia de PD-L1 en el tumor es un factor pronóstico desfavorable significativo e independiente de la histología.Introduction Malignant pleural mesothelioma (MPM) is a rare tumor with poor prognosis and low response to treatment, with a median survival of 12 months. Asbestos has been linked as one of the main causes of the disease but recently genetics factors has been suggested play a role in MPM. Several studies have shown that MPM is an immunologic tumor that induces immune recognition, immune cells infiltration and death mediated by immunity. PD1-PD-L1 pathway is responsible to control cell death, tissue damage and to keep peripheral tolerance. Recent studies analyzing this pathway in lung cancer, renal cancer and melanoma and other cancer have shown that is activated in more than 50% of patients. We analyzed the role of PD-L1 in MPM. Material and methods We studied 119 patients diagnosed of MPM between 2000 and 2014 with archival material in pathologic department of Vall d´Hebron University Hospital and 12 October University Hospital. The clinical information was recorded and we selected cases with at least 3 unstained slides for the immunohistoquemical analysis. We use the antibody E1L3N™ for the PD-L1 staining and the result was considered positive if more than 1% of tumor cells were stained in any localization (membrane, cytoplasm and inflammatory infiltrate). Kaplan Meier curves were used for survival analysis. Results Patients characteristics: median age 69 years (range 42-90), the majority of patients were males (71.4%), smokers (51%), had previous asbestos exposure (44.5%), epithelial subtype (65%) and had ECOG 1 64.8% of patients. Archival samples with sufficient quality to perform the immunhistoquemical analysis were available in 77 patients and we found PD-L1 positive in 16 patients (20.7%). In relation to the intensity of the staining 9 patients had low intensity, 4 patients moderate and 3 patients strong intensity. The overall survival of all the patients was 9.8 months. Patients with epitheial histology had significant better prognosis (16.8 months versus 5.2 months biphasic and 0.8 months sarcomatoid, p<0.001). When we analyzed patients evaluated for PD-L1 we found that the expression is more frequent in no epithelial tumor (p=0.03). In our series PD-L1 is an unfavorable prognostic factor .PD-L1 positive patients had median survival of 4.7 months versus 16.3 months PD-L1 negative patients (p=0.012). In the multivariate analysis the unfavorable prognostic of PD-L1 was independent of the histological subtype (p=0.021). Conclusions In our series we found that PD-L1 is expressed in 20% of MPM patients assessed by inmunhistochemistry. PD-L1 is an unfavorable prognostic factor independent of the histolog

Análisis de la expresión de PD-L1 en una serie de pacientes con mesotelioma pleural maligno

Introducción El mesotelioma pleural maligno (MPM) es un tumor que se caracteriza por su mal pronóstico y escasa respuesta al tratamiento, con una mediana de supervivencia de 12 meses. Se ha relacionado el asbesto como principal causante de esta enfermedad aunque recientemente se apunta a que los factores genéticos pueden tener importancia en el desarrollo del mesotelioma. Numerosos estudios han demostrado que el mesotelioma es un tumor inmunogénico, que induce reconocimiento inmune, infiltración de células inmunes y muerte mediada por inmunidad. La vía del PD1-PD-L1 es responsable de controlar la muerte celular , el daño tisular y mantener la tolerancia periférica. Estudios recientes que evalúan esta vía en cáncer de pulmón, renal y melanoma entre otros han encontrado que está activada en aproximadamente un 50% de los pacientes. Nosotros analizamos el papel de la vía de PD-L1 en el MPM. Material y métodos Analizamos 119 pacientes diagnosticados de MPM entre el periodo 2000-2014 con material archivado en el servicio de anatomía patológica del Hospital Unuversitario Vall de H'ebron y el Hospital Universitario 12 de Octubre. Se recogió la información de los pacientes y seleccionamos los casos que disponían de al menos dos laminillas no teñidas para hacer el estudio de inmunohistoquímica. Utilizamos el anticuerpo E1L3N™para realizar la tinción de PD-L1y el resultado lo consideramos positivo si teñían más del 1% de las células en cualquier localización (membrana celular, infiltrado inflamatorio y citoplasma). Los datos de supervivencia se analizaron por medio de las curvas de Kaplan Meier. Resultados Características de los 119 pacientes: edad media 69 años (rango 42-90), la mayoría eran hombres (71.4%), fumadores (51%), referían contacto con el amianto (44.5%), tenían el subtipo epitelioide (65%) y presentaban buen estado general con ECOG 1 el 64.8% de pacientes. Se disponía de material suficiente para realizar el análisis de inmunohistoquimica en 77 pacientes y encontramos que PD-L1 es positivo en 16 pacientes (20.7%).Respecto a la intensidad de la tinción 9 pacientes presentaban una intensidad leve, 4 pacientes moderada y 3 intensa. La supervivencia global de todos los pacientes fue de 9.8 meses. Los pacientes con histología epitelioide presentaban significativamente mejor pronóstico (16.8 meses frente a 5.2 meses los bifásicos y 0.8 meses los sarcomatoides, p 0.001). Cuando analizamos los pacientes evaluados para PD-L1 encontramos que su expresión es más frecuente en los tumores no epitelioides (p=0.033). En nuestra serie PD-L1 es un factor pronóstico desfavorable. Los pacientes PD-L1 positivo tenían una mediana de supervivencia de 4.7 meses frente a 16.3 los pacientes los PD-L1 negativos, (p=0.012). En el análisis multivariado el valor pronóstico desfavorable de PD-L1 se mantiene independiente del subtipo histológico (p=0.021). Conclusiones En nuestra serie encontramos que PD-L1 se expresa en el 20% de los pacientes con MPM medido por inmunohistoquímica. La presencia de PD-L1 en el tumor es un factor pronóstico desfavorable significativo e independiente de la histología.Introduction Malignant pleural mesothelioma (MPM) is a rare tumor with poor prognosis and low response to treatment, with a median survival of 12 months. Asbestos has been linked as one of the main causes of the disease but recently genetics factors has been suggested play a role in MPM. Several studies have shown that MPM is an immunologic tumor that induces immune recognition, immune cells infiltration and death mediated by immunity. PD1-PD-L1 pathway is responsible to control cell death, tissue damage and to keep peripheral tolerance. Recent studies analyzing this pathway in lung cancer, renal cancer and melanoma and other cancer have shown that is activated in more than 50% of patients. We analyzed the role of PD-L1 in MPM. Material and methods We studied 119 patients diagnosed of MPM between 2000 and 2014 with archival material in pathologic department of Vall d'Hebron University Hospital and 12 October University Hospital. The clinical information was recorded and we selected cases with at least 3 unstained slides for the immunohistoquemical analysis. We use the antibody E1L3N™ for the PD-L1 staining and the result was considered positive if more than 1% of tumor cells were stained in any localization (membrane, cytoplasm and inflammatory infiltrate). Kaplan Meier curves were used for survival analysis. Results Patients characteristics: median age 69 years (range 42-90), the majority of patients were males (71.4%), smokers (51%), had previous asbestos exposure (44.5%), epithelial subtype (65%) and had ECOG 1 64.8% of patients. Archival samples with sufficient quality to perform the immunhistoquemical analysis were available in 77 patients and we found PD-L1 positive in 16 patients (20.7%). In relation to the intensity of the staining 9 patients had low intensity, 4 patients moderate and 3 patients strong intensity. The overall survival of all the patients was 9.8 months. Patients with epitheial histology had significant better prognosis (16.8 months versus 5.2 months biphasic and 0.8 months sarcomatoid, p 0.001). When we analyzed patients evaluated for PD-L1 we found that the expression is more frequent in no epithelial tumor (p=0.03). In our series PD-L1 is an unfavorable prognostic factor .PD-L1 positive patients had median survival of 4.7 months versus 16.3 months PD-L1 negative patients (p=0.012). In the multivariate analysis the unfavorable prognostic of PD-L1 was independent of the histological subtype (p=0.021). Conclusions In our series we found that PD-L1 is expressed in 20% of MPM patients assessed by inmunhistochemistry. PD-L1 is an unfavorable prognostic factor independent of the histolog

Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM).

The increasing incidence and poor outcome associated with MPM requires finding effective treatment for this disease. PD1/PD-L1 pathway plays a central role in tumor immune evasion and appears to be predictive and prognostic marker. PD-L1 is expressed in many different human cancers but its role in MPM has yet to be established. The aim of this study is to evaluate the expression of PD-L1 in MPM.119 MPM patients (p) from two institutions between November 2002 and February 2014 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained with anti-PD-L1 (clone E1L3N). Cases showing more than 1% of tumor cells expression of PD-L1 were considered positive.PD-L1 was analyzed in 77 p with tumor tissue available and was positive in 20.7% p (14 samples in membrane, 16 in cytoplasm and 4 in immune infiltrate). PD-L1 intensity was weak in 56.2%, moderate in 25% and strong in 18.7% p. There was a significant relationship between PD-L1 expression and histology (PD-L1 expression 37.5% in no-epithelioid tumor and 13.2% in epithelioid; p=0.033). The median survival in p PD-L1 positive was 4.79 vs 16.3 months in p PD-L1 negative (p=0.012).We have shown PD-L1 is expressed in 20% of patients, associated with no epithelioid histology and poor prognostic in MPM. Our results suggest PD-L1 warrants further exploration in selecting p for immunotherapy

Representatives examples of Hematoxylin eosin immunohistochemical PD-L1 staining in cytoplasm, membrane and inflammatory infiltrate

<p>Representatives examples of Hematoxylin eosin immunohistochemical PD-L1 staining in cytoplasm, membrane and inflammatory infiltrate</p

Fluorescence in situ hybridization and immunohistochemistry as diagnostic methods for ALK positive non-small cell lung cancer patients.

BACKGROUND: Anaplastic Lymphoma Kinase (ALK) positivity represents a novel molecular target in a subset of Non-Small Cell Lung Cancers (NSCLC). We explore Fluorescence in situ Hybridization (FISH) and Immunohistochemistry (IHC) as diagnostic methods for ALK positive patients and to describe its prevalence and outcomes in a population of NSCLC patients. METHODS: NSCLC patients previously screened for Epidermal Growth Factor Receptor (EGFR) at our institution were selected. ALK positive patients were identified by FISH and the value of IHC (D5F3) was explored. RESULTS: ninety-nine patients were identified. Median age was 61.5 years (range 35-83), all were caucasians, eighty percent were adenocarcinomas, fifty-one percent were male and thirty-eight percent were current smokers. Seven (7.1%) patients were ALK positive by FISH, thirteen (13.1%) were EGFR mutant, and 65 (65.6%) were negative/Wild Type (WT) for both ALK and EGFR. ALK positivity and EGFR mutations were mutually exclusive. ALK positive patients tend to be younger than EGFR mutated or wt patients. ALK positive patients were predominantly never smokers (71.4%) and adenocarcinoma (71.4%). ALK positive and EGFR mutant patients have a better outcome than negative/WT. All patients with ALK FISH negative tumours were negative for ALK IHC. Out of 6 patients positive for ALK FISH with more tissue available, 5 were positive for ALK IHC and 1 negative. CONCLUSIONS: ALK positive patients represent 7.1% of a population of selected NSCLC. ALK positive patients have different clinical features and a better outcome than EGFR WT and ALK negative patients. IHC is a promising method for detecting ALK positive NSCLC patients

Patients characteristics according PD-L1 expression.

<p>Patients characteristics according PD-L1 expression.</p