nab-paclitaxel plus durvalumab in patients with previously treated advanced stage non-small cell lung cancer (ABOUND.2L+)

Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab-paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC. Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab-paclitaxel 100 mg/m2 (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety. Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred. Conclusions: The nab-paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted. Clinical Trial Registration: ClinicalTrials.gov registration (NCT02250326). EudraCT number: 2014-001105-41.This work was supported by Bristol Myers Squibb Company, Princeton, New Jersey. The sponsor was involved in the design of the study as well as in the collection, analysis, and interpretation of the data. The sponsor agreed to the decision to submit the article for publication.Ye

Fluorometric Quantification of Total Cell-Free DNA as a Prognostic Biomarker in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Blockade.

The present study aimed to investigate the potential of basal cell-free fluorometric DNA (cfDNA) quantification as a prognostic biomarker in advanced non-small cell lung cancer (NSCLC) patients treated with an Immune Checkpoint Blockade (ICB). A discovery and validation cohort of 61 and 31 advanced lung cancer patients treated with ICB were included in this study. Quantification of cfDNA concentration was performed before the start of the treatment and patients were followed up for a median of 34 (30–40) months. The prognostic predicted value of cfDNA was evaluated based on ROC, and Cox regression was conducted via univariate and multivariate analyses to estimate the hazard ratio. We observed that a cfDNA cut-off of 0.55 ng/ L before the ICB determines the overall survival of patients with a log rank p-value of 3.3 104. That represents median survivals of 3.8 vs. 17.5 months. Similar results were obtained in the validation cohort being the log rank p-value 3.8 102 with median survivals of 5.9 vs. 24.3. The univariate and multivariate analysis revealed that the cut-off of 0.55 ng/ L before ICB treatment was an independent predictive factor and was significantly associated with a better survival outcome. High cfDNA concentrations identify patients with advanced NSCLC who do not benefit from the ICB. The determination of cfDNA is a simple test that could select a group of patients in whom new therapeutic strategies are needed.Partial funding for open access charge: Universidad de Málag

Efficacy of naloxegol on symptoms and quality of life related to opioid-induced constipation in patients with cancer: a 3-month follow-up analysis

Objectives: Opioid-induced constipation (OIC) can affect up to 63% of all patients with cancer. The objectives of this study were to assess quality of life as well as efficacy and safety of naloxegol, in patients with cancer with OIC. Methods: An observational study was made of a cohort of patients with cancer and with OIC exhibiting an inadequate response to laxatives and treated with naloxegol. The sample consisted of adult outpatients with a Karnofsky performance status score ≥50. The Patient Assessment of Constipation Quality of Life Questionnaire (PAC-QOL) and the Patient Assessment of Constipation Symptoms (PAC-SYM) were applied for 3 months. Results: A total of 126 patients (58.2% males) with a mean age of 61.3 years (range 34-89) were included. Clinically relevant improvements (>0.5 points) were recorded in the PAC-QOL and PAC-SYM questionnaires (p<0.0001) from 15 days of treatment. The number of days a week with complete spontaneous bowel movements increased significantly (p<0.0001) from 2.4 to 4.6 on day 15, 4.7 after 1 month and 5 after 3 months. Pain control significantly improved (p<0.0001) during follow-up. A total of 13.5% of the patients (17/126) presented some gastrointestinal adverse reaction, mostly of mild (62.5%) or moderate intensity (25%). Conclusions: Clinically relevant improvements in OIC-related quality of life, number of bowel movements and constipation-related symptoms were recorded as early as after 15 days of treatment with naloxegol in patients with cancer and OIC, with a good safety profile

High IGKC-Expressing Intratumoral Plasma Cells Predict Response to Immune Checkpoint Blockade.

Este artículo ha sido publicado en la revista International Journal of Molecular Sciences. Esta versión tiene Licencia Creative Commons CC-BYResistance to Immune Checkpoint Blockade (ICB) constitutes the current limiting factor for the optimal implementation of this novel therapy, which otherwise demonstrates durable responses with acceptable toxicity scores. This limitation is exacerbated by a lack of robust biomarkers. In this study, we have dissected the basal TME composition at the gene expression and cellular levels that predict response to Nivolumab and prognosis. BCR, TCR and HLA profiling were employed for further characterization of the molecular variables associated with response. The findings were validated using a single-cell RNA-seq data of metastatic melanoma patients treated with ICB, and by multispectral immunofluorescence. Finally, machine learning was employed to construct a prediction algorithm that was validated across eight metastatic melanoma cohorts treated with ICB. Using this strategy, we have unmasked a major role played by basal intratumoral Plasma cells expressing high levels of IGKC in efficacy. IGKC, differentially expressed in good responders, was also identified within the Top response-related BCR clonotypes, together with IGK variants. These results were validated at gene, cellular and protein levels; CD138+ Plasma-like and Plasma cells were more abundant in good responders and correlated with the same RNA-seq-defined fraction. Finally, we generated a 15-gene prediction model that outperformed the current reference score in eight ICB-treated metastatic melanoma cohorts. The evidenced major contribution of basal intratumoral IGKC and Plasma cells in good response and outcome in ICB in metastatic melanoma is a groundbreaking finding in the field beyond the role of T lymphocytes

Emerging noninvasive methylation biomarkers of cancer prognosis and drug response prediction.

Cancer is the second leading cause of death worldwide being responsible for 9.6 million deaths in 2018. Epigenetic alterations are key in directing the aberrant expression of tumor-associated genes that drive cellular malignant transformation and cancer progression. Among epigenetic alterations, DNA methylation is the most deeply studied one in relation to environmental exposure. Tissue biopsies have traditionally been the main procedure by which a small sample of body tissue is excised to confirm cancer diagnosis or to indicate the primary site when cancer has spread. In contrast, the analysis of circulating tumor-derived material, or tumor circulome, by means of liquid biopsy of peripheral blood, urine, saliva or sputum is a noninvasive, fast and reproducible alternative to tissue biopsy. Recently, the assessment of epigenetic alterations such as DNA methylation and hydroxymethylation in circulating free DNA has been proved possible. These marks can be associated to prognosis and response to a variety of treatments including chemotherapy, hormonotherapy or immunotherapy. Epigenetic biomarkers may offer some advantages over RNA or genetic biomarkers given their stability in bodily fluids and their high tissue-specificity. While many challenges are still ahead, the unique advantages of these types of biomarkers is urging the scientific community to persevere in their clinical validation and integration into reliable prediction models. This review aims at recapitulating the emerging noninvasive DNA methylated biomarkers of importance for prediction of prognosis and drug response in cancer

Construction of miRNA-mRNA networks for the identification of lung cancer biomarkers in liquid biopsies.

Lung cancer (LC) is the most common cause of cancer death worldwide mostly due to the low survival rate: 75% of cases are identified in advanced stages. In this study, the list of useful biomarkers to make an early diagnosis using liquid biopsies was expanded. A total of 30 samples of LC were analyzed to define potential miRNA biomarkers in liquid biopsies for LC. The biomarkers have been identified in interaction networks miRNA-mRNA. The potential biomarkers have been then validated in large cohorts. A total of 15 candidate miRNAs, that regulate the repression of 30 mRNAs, have been identified as a specific functional interaction network for squamous carcinoma, while the specific functional interaction network of adenocarcinoma consists of four candidate miRNAs that seem to handle the repression of five mRNA. Inspection of expression levels in larger cohorts validates the usefulness of the 11 candidates as biomarkers in liquid biopsies. The 11 candidate miRNAs found could be utilized to form diagnostic predictive biomarkers for LC in liquid biopsies

Prognostic factors for survival in patients with metastatic lung adenocarcinoma: An analysis of the SEER database

Background: Lung adenocarcinoma (ADC) is the main cause of death related to lung cancer. The aim of this study was to identify poor prognostic factors for overall survival (OS) in patients with stage IV lung ADC in real-world clinical practice. Methods: Patients were selected from the Surveillance Epidemiology and End Results (SEER) database. Chi-square bivariate analysis was used for the association of binary qualitative variables. A multivariate Cox regression analysis was performed to determine the impact of these prognostic factors on OS. Results: A total of 46 030 patients were included (51.3% men, mean age 67.03 ± 11.6), of whom 41.3% presented with metastases in bone, 28.9% in brain, 17.1% in liver and 31.8% in lung. Patients with liver metastases presented with two or more metastatic sites more frequently than patients without liver metastases (P < 0.001). Male sex (HR 0.78, 95% CI: 0.76-0.80), age ≥ 65 years (HR 1.37, 95% CI: 1.33-1.40), lack of family support (HR 0.80, 95% CI: 0.78-0.81) and presence of liver (HR 1.45, 95% CI: 1.40-1.50), bone (HR 1.21, 95% CI: 1.18-1.24) or brain metastases (HR 1.18, 95% CI: 1.15-1.21) were identified as poor prognostic factors for OS. Patients with liver metastasis showed the highest hazard ratio value (P < 0.001). Conclusions: The presence of liver metastases was the worst prognostic factor for patients with metastatic lung ADC. This factor should be considered as a stratification factor for future studies evaluating new cancer treatments including immunotherapy.Ye

A Randomized, Placebo-Controlled, Phase 1b/2 Study of Rilotumumab or Ganitumab in Combination With Platinum-Based Chemotherapy as First-Line Treatment for Extensive-Stage Small-Cell Lung Cancer

In this randomized, double-blind, placebo-controlled phase 1b/2 study we assessed the efficacy/safety of rilotumumab or ganitumab combined with etoposide and carboplatin or cisplatin as first-line treatment in patients with extensive stage small-cell lung cancer (ES-SCLC).status: publishe