Search

Introduction: Atezo (anti-PD-L1) + bev + chemo prolonged PFS vs bev + chemo in patients (pts) with 1L non-squamous mNSCLC in the randomized Ph 3 IMpower150 study regardless of PD-L1 expression. This analysis aims to further understand the efficacy of atezo + bev + chemo in key subgroups: PD-L1 expression subgroups defined by the SP142 and SP263 IHC assays, patients with EGFR/ALK genetic alterations and patients with liver metastases at baseline. Methods: Pts received atezo 1200 mg + bev 15 mg/kg + carboplatin (C) AUC 6 + paclitaxel (P) 200 mg/m2 (Arm B) or bev + C + P (Arm C) IV q3w. A co-primary endpoint (EP) was PFS in the ITT-WT (EGFR or ALK wild-type pts); a secondary EP was PFS in subgroups defined by PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) with SP142. Retrospective analysis with SP263 was a prespecified exploratory EP. Results: In Arms B and C of the ITT-WT (n = 692), 503 pts had available tumor sections for SP263 testing (BEP). Pt characteristics in the ITT-WT and BEP were similar. A similar PFS benefit was observed for Arm B vs C across all PD-L1 expression subgroups defined by either assay, including pts with PD-L1-negative and PD-L1-low tumors (Table). PFS benefit with Arm B vs C was also observed in patients with EGFR or ALK genomic alterations, including patients with actionable EGFR mutations, and in patients with liver metastases at baseline (Table). Conclusion: PFS benefit with atezo + bev + chemo was observed across all PD-L1 subgroups, regardless of the IHC assay used. Additionally, clinically meaningful PFS benefit was observed in patients with EGFR/ALK genomic alterations, and in patients with liver metastases with this combination. Table. PFS in Biomarker Subgroups and Other Subgroups of Interest in IMpower150Median PFS, moPFSan (%)HRb (95% CI)P ValueArm BArm CITT-WT692 (100%)0.62 (0.52, 0.74) Citation Format: Marcin Kowanetz, Mark A. Socinski, Wei Zou, Mark McCleland, Nancy Yang, Ariel Lopez Chavez, Alexander Spira, Julien Mazières, Fadi Braiteh, David Shames, Alan Sandler, Martin Reck. IMpower150: Efficacy of atezolizumab (atezo) plus bevacizumab (bev) and chemotherapy (chemo) in 1L metastatic nonsquamous NSCLC (mNSCLC) across key subgroups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT076.

9047Background: Atezo (anti–PD-L1) + bev (anti-VEGF) + chemo prolonged PFS vs bev + chemo in patients (pts) with 1L nonsquamous mNSCLC in the randomized, Phase III IMpower150 study. PRO data, inclu...

9002Background: Atezo (anti–PD-L1) inhibits PD-L1 to restore anticancer immunity; bev may enhance atezo efficacy by inhibiting VEGF immunosuppression and promoting T-cell tumor infiltration. IMpower150 is the first randomized Ph 3 trial evaluating atezo + chemo (carboplatin [C] + paclitaxel [P]) ± bev vs CP + bev in 1L NSQ NSCLC. PFS benefit was observed with atezo + CP + bev vs CP + bev regardless of PD-L1 expression. Here we present the IMpower150 interim OS results. Methods: 1202 patients (pts) received atezo 1200 mg + C AUC 6 + P 200 mg/m2 (Arm A) or atezo + CP + bev 15 mg/kg (Arm B) vs CP + bev (Arm C) IV q3w for 4 or 6 cycles per investigator (INV); then maintenance atezo, atezo + bev, or bev, respectively. Co-primary endpoints were INV-assessed PFS in the ITT-WT (EGFR/ALK WT) and in WT pts with expression of a tumor T-effector gene signature (Teff-high WT) and OS in the ITT-WT. Data cutoff: 1/22/2018. Results: 349, 359, and 337 ITT-WT pts were enrolled in Arms A, B, and C, respectively, with median...

Basket trials investigate the effects of targeted therapies against specific molecular alterations across multiple histologic subtypes, including tumors arising in parallel from different primary organs. The rationale is that the presence of a specific molecular aberration would predict the response to a targeted therapy regardless of the histologic subtype. Patient enrollment in basket trials is based on the molecular profiles of their tumors. The CUSTOM (Molecular Profiling and Targeted Therapies in Advanced Thoracic Malignancies) trial used a basket trial design to simultaneously evaluate targeted therapies in patients with advanced non–small-cell lung cancer, small-cell lung cancer, and thymic malignancies; patients were grouped by molecular alterations along with tumor histology. Stenzinger et al raise concerns about the viability of basket trial designs in their current form: directing targeted treatments of patients with disparate histologies on the basis of single genetic alterations to address the mutational complexity of cancer. We fully agree. As Stenzinger et al point out, the biologic relevance of molecular drivers has been reported to vary between tumors arising from different primary sites; for example, the effect of BRAF V600E is different in nevi, malignant melanoma, and colorectal cancer. Further extending these observations are reports that show the effect of coexisting mutations in determining response to the same targeted therapy, even among primary cancers that harbor identical genetic mutations. In KRAS-mutant non–small-cell lung cancer, for example, therapeutic response to a combination of the MEK inhibitor selumetinib and docetaxel has been reported to vary, depending on concurrent alterations in tumor suppressor genes, including P53 and LKB1; in KRAS-/P53-mutant mice, selumetinib plus docetaxel led to responses in 61% of mice whereas only 33% of mice with KRAS-/ LKB1-mutant cancers achieved a partial response with the combination. Indeed, most basket trial designs ignore the biologic context not only with respect to coexisting mutations but also with respect to other interactions that may have an impact on the clinical response, including the proteome, epigenome, and the immune milieu. Basket trials are a relatively new and evolving area in oncology trial design. Treatment arms of basket trials will show clinical efficacy only when the tumor depends on the target pathway and the targeted therapy reliably inhibits the target. Basket trial designs are therefore best used to identify early signals of clinical activity of targeted therapies with a small number of patients and to validate a clinical target. This is particularly useful when the cancer type or the mutation is rare. So where do we go from here with basket trials? Future basket trials, as indicated by Stenzinger et al, should use more comprehensive characterization of molecular alterations to overcome limitations of existing histology-based and single genetic alteration–based approaches. The CUSTOM trial is a necessary first step toward identifying better clinical trial designs to investigate in parallel the clinical efficacy of multiple targeted therapies in multiple cancers.

TPS8584 Background: The first-line standard of care for the majority of patients (pts) with extensive-stage small-cell lung cancer (ES-SCLC) is platinum-based chemotherapy with etoposide, but survival outcomes remain poor (median OS, < 1 year) despite initial response rates ranging from 50-70%. Atezolizumab (atezo), an anti–PD-L1 mAb, prevents the binding of PD-L1 with its receptors PD-1 and B7.1 and restores anticancer T-cell activity. Tolerable safety with promising durability of response has been shown with atezo in pts with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 mo) by RECIST v1.1 and 24% by immune-related response criteria (irRC; n = 4/17, with 2 pts on atezo for ≥ 12 mo). Preliminary data also indicate the potential synergy between atezo and platinum-based chemotherapy in NSCLC, whereby durable responses may translate into improved survival over atezo alone. IMpower133 (NCT02763579), a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial will evaluate the efficacy and safety of 1L atezo + carboplatin + etoposide compared with placebo + carboplatin + etoposide in treatment-naive pts with ES-SCLC. Methods: Pts with measurable (RECIST v1.1) ES-SCLC, who have ECOG PS 0-1 and no prior systemic anticancer treatment, are eligible for the study. Exclusion criteria include untreated CNS metastases and history of autoimmune disease. The study requires submission of tumor tissue, but pts will be enrolled regardless of biomarker status. Pts will be stratified by sex, ECOG PS and presence of treated brain metastases. Eligible pts will be randomized 1:1 to receive four 21-day cycles of atezo (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, d 1) and etoposide (100 mg/m2 IV, d 1-3), followed by maintenance therapy with atezo or placebo until PD per RECIST v1.1. Pts can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints are investigator-assessed PFS per RECIST v1.1 and OS. Secondary efficacy endpoints include investigator-assessed ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 pts will be enrolled. Clinical trial information: NCT02763579.

Platinum-based chemotherapy has been the standard first-line treatment for patients with advanced non-small-cell lung cancer for decades. However, a recent study has shown the superiority of gefitinib treatment in comparison with chemotherapy in a molecularly selected cohort of patients harboring sensitizing EGFR mutations. These results demonstrate the importance of incorporating molecular selection into the design of lung cancer trials that use EGFR tyrosine kinase inhibitors.

Summary Background No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. Methods Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. Findings 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1–46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3–36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5–29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0–26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3–4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions during treatment (five were new-onset disorders), the most common of which was pure red-cell aplasia. Two (4%) patients died; one was attributed to disease progression and the other to disease-related complications (respiratory failure, myositis, and an acute coronary event), which could have been precipitated by treatment with cixutumumab. Interpretation Cixutumumab monotherapy is well-tolerated and active in relapsed thymoma. Development of autoimmunity during treatment needs further investigation. Funding Division of Cancer Treatment and Diagnosis at the National Cancer Institute (National Institutes of Health), ImClone Systems.

Improved understanding of the molecular mechanisms involved in development, growth and spread of cancer have led to develpment of targeted therapies for many cancers. Based on their superior tolerability and efficacy, targeted therapies with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) or crizotinib are preferred first-line treatments over platinum-based chemotherapies in patients whose tumours harbour EGFR-activating mutations and anaplastic lymphoma kinase (ALK) translocations, respectively. Active areas of research in EGFR-mutant and ALK-translocated NSCLC include identification of mechanisms of resistance and overcoming them. Therapeutic targeting of several other targets including ROS, RET and discoidin domain receptor 2 (DDR2) tyrosine kinases are in early phases of clinical evaluation. Despite the advances in tumour genomic sequencing, a substantial fraction of patients with non-small cell lung cancer (NSCLC) do not have any targetable genetic alteration. Ongoing research is focused on identifying mechanisms of carcinogenesis in these patients. Targeted therapies in small cell lung cancer (SCLC) and thymic malignancies have not yielded meaningful clinical benefits, and platinum-based therapies remain the cornerstone of treating patients with advanced disease.

NO TIENE RESUMEN

Aims Among lung cancer patients, depression has been associated with increased mortality, although the mechanisms are unknown. We evaluated the association of depression with mortality and receipt of cancer therapies among depressed veterans with lung cancer. Materials and methods A retrospective, cohort study of lung cancer patients in the Veterans Affairs-Northwest Health Network from 1995 to 2010. Depression was defined by ICD-9 coding within 24 months before lung cancer diagnosis. Multivariable Cox proportional analysis and logistic regression were used. Results In total, 3869 lung cancer patients were evaluated; 14% had a diagnosis of depression. A diagnosis of depression was associated with increased mortality among all stage lung cancer patients (hazard ratio = 1.14, 95% confidence interval: 1.03–1.27, P = 0.01). Among early-stage (I and II) non-small cell lung cancer (NSCLC) patients, the hazard ratio was 1.37 (95% confidence interval: 1.12–1.68, P = 0.003). There was no association of depression diagnosis with surgery (odds ratio = 0.83, 95% confidence interval: 0.56–1.22, P = 0.34) among early-stage NSCLC patients. A depression diagnosis was not associated with mortality (hazard ratio = 1.02, 95% confidence interval: 0.89–1.16, P = 0.78) or chemotherapy (odds ratio = 1.07, 95% confidence interval: 0.83–1.39, P = 0.59) or radiation (odds ratio = 1.04, 95% confidence interval: 0.81–1.34, P = 0.75) receipt among advanced-stage (III and IV) NSCLC patients. Increased utilisation of health services for depression was associated with increased mortality among depressed patients. Conclusions Depression is associated with increased mortality in lung cancer patients and this association is higher among those with increased measures of depression care utilisation. Differences in lung cancer treatment receipt are probably not responsible for the observed mortality differences between depressed and non-depressed patients. Clinicians should recognise the significant effect of depression on lung cancer survival.

Although tumor molecular-profile-directed therapy appears promising in early clinical studies, there are many practical challenges to its successful clinical application in non-small-cell lung cancer (NSCLC). These challenges may be broadly classified as those relating to tumor (heterogeneity), tissue (acquisition and processing), testing (assays for molecular profiling) and trials (clinical evaluation of molecular markers and drugs). Strategies to overcome these challenges include (i) understanding the biological basis of tumor heterogeneity and of carcinogenesis in the large subset of patients with no currently evident driver events; (ii) technological advances in minimally invasive acquisition of tumor and next-generation sequencing (NGS) which would enable single-platform analysis of molecular alterations in limited tissue at a reasonable turnaround time (TAT); (iii) deliberation in early stages of drug development as well as clinical trial design to identify, validate and assess the clinical utility of biomarkers in conjunction with drugs and (iv) collaboration to improve understanding of and accrual to trials enrolling patients with rare molecular alterations.

A partir de la información facilitada por el Instituto Nicaragüense de Estudios Territoriales (INETER) se procedió a analizar los datos pluviográficos de cada estación, con el propósito de obtener las intensidades máximas por año, para los distintos períodos de retorno 5, 10,15, 20, 30, 40 y 50 años y duración de 5, 10, 20, 30, 60 y 120 minutos para la construcción de las curvas Intensidad-Duración-Frecuencia (IDF), en la región central de Nicaragua, en base al comportamiento de los registros pluviográ ficos para 15 años en 5 estaciones, en la quinta región se seleccionaron los departamentos que poseen estaciones con registros pluviográficos, estos son los siguientes: Estación de Juigalpa Latitud 12° 06' 00" y Longitud 85° 22' 00", Estación de aeropuerto de Managua Latitud 12° 08' 36" y Longitud 86° 09' 49",Estación Raúl González (San Isidro) Latitud 12° 54' 48" y Longitud 86° 11'30", Estación de Muy Muy Latitud 12° 45'48" y Longitud 85° 37' 36", Estación de Boaco Latitud 12 ̊ 28' 12"N y Longitud 85 ̊ 39' 18"W. En dicha selección se tomo como criterio la periodicidad de los datos de precipitaciones, el período entre 1972-1986, en lo referente a los años de estadísticas seleccionados para la investigación, es importante hacer mención que la estación pluviográfica de Juigalpa, los registros de las precipitaciones se encontraban con algunos datos faltantes producto del paso del tiempo lo que provocaría errores en la estimación de eventos futuros, por ende se implemento el método de promedio aritmético para calcular las intensidades de precipitaciones faltantes con la siguiente fórmula: Px = pa+ pb+ pc =/n Durante el desarrollo de esta investigación se estudiaron distintos métodos o formas analíticas para desarrollar las curvas IDF; sin embargo el método que se ajusto más a las condiciones topográficas de la zona fue el método de Gumbel tipo I ya que el método de Aparicio 1997, sobre estima los valores de las precipitaciones.

Purpose Thymic epithelial tumors are rare malignancies, and there is no standard treatment for patients with advanced disease in whom chemotherapy has failed. Antitumor activity of histone deacetylase (HDAC) inhibitors in this disease has been documented, including one patient with thymoma treated with the pan-HDAC inhibitor belinostat. Patients and Methods Patients with advanced thymic epithelial malignancies in whom at least one line of platinum-containing chemotherapy had failed were eligible for this study. Other eligibility criteria included adequate organ function and good performance status. Belinostat was administered intravenously at 1 g/m2 on days 1 to 5 of a 21-day cycle until disease progression or development of intolerance. The primary objective was response rate in patients with thymoma. Results Of the 41 patients enrolled, 25 had thymoma, and 16 had thymic carcinoma; patients had a median of two previous systemic regimens (range, one to 10 regimens). Treatment was well tolerated, with nausea, vomiting, and fatigue being the most frequent adverse effects. Two patients achieved partial response (both had thymoma; response rate, 8%; 95% CI, 2.2% to 25%), 25 had stable disease, and 13 had progressive disease; there were no responses among patients with thymic carcinoma. Median times to progression and survival were 5.8 and 19.1 months, respectively. Survival of patients with thymoma was significantly longer than that of patients with thymic carcinoma (median not reached v 12.4 months; P = .001). Protein acetylation, regulatory T-cell numbers, and circulating angiogenic factors did not predict outcome. Conclusion Belinostat has modest antitumor activity in this group of heavily pretreated thymic malignancies. However, the duration of response and disease stabilization is intriguing, and additional testing of belinostat in this disease is warranted.

Survivin (BIRC5), a member of the inhibitor of apoptosis protein (IAP) family that inhibits caspases and blocks cell death is highly expressed in cancer and is associated with a poorer clinical outcome. Functioning simultaneously during cell division and apoptosis inhibition, survivin plays a pivotal role in determining cell survival. Survivin has consistently been identified by molecular profiling analysis to be associated with higher tumor grade, more advanced disease, abbreviated survival, accelerated rates of recurrence, and chemotherapy and radiation resistance. Survivin's differential expression in cancer compared to normal tissue and its role as a nodal protein in a number of cellular pathways make it a highly flexible therapeutic target, suitable for small-molecule inhibitiors, molecular antagonists, and vaccination-based therapies. By targeting survivin it is hoped that multiple tumor signaling circuitries may be simultaneously disabled. This effect may be applicable to many tumor histologies irrespective of specific genetic makeup. To date, survivin inhibitors have shown modest activity as single agents, but it is anticipated that when given in combination with cytotoxic chemotherapy or monoclonal antibodies they may exhibit enhanced efficacy. This review discusses the complex circuitry of survivin in human cancers and highlights clinical trials involving novel agents that target this important protein.

Epidermal growth factor receptor (EGFR) mutations are predictive markers for response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). The most common mutations, exon 19 short deletions and exon 20 point mutation (L858R), activate the tyrosine kinase and confer sensitivity to EGFR-TKIs. However, the function and sensitivity of rare mutations to EGFR-TKIs are unknown. In this study, we found five EGFR mutations out of 16 patients with NSCLC of African-American descent. The frequency of such mutations in this patient population appears to be significantly higher than previously reported. Two of them (N771GY and A767-V769dup) are rare insertion mutations located in exon 20. Using YFP-tagged EGFR mutants, we demonstrated that the mutations confer increased kinase activity, but no sensitivity to erlotinib at clinically available concentrations. In addition, we examined efficacy of PF00299804, an irreversible EGFR-TKI. Although the drug failed to show efficacy to T790M and S768N mutations, the exon 20 insertion mutations were sensitive to PF00299804. These data suggest that rare mutations in exon 20 are resistant to erlotinib but may be sensitive to irreversible inhibitors.

El procedimiento de trabajo seguro para realizar un hot tap en tanques y líneas de procesos tiene como finalidad, establecer directrices que sirvan como guía para identificar, analizar y evaluar los diferentes aspectos en seguridad industrial y cumplir con normas establecidas, garantizando que la integridad del personal involucrado en el desarrollo de la actividad no se vea afectada., Pregrado, Profesional en Seguridad y Salud en el Trabajo