Search

Abstract Introduction Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with previously treated advanced non-small cell lung cancer (NSCLC). This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine) in patients with advanced NSCLC. Methods Patients with one prior line of platinum-containing therapy were randomised in a ratio of 1:1 to CC-486 or placebo, on days 1–14, in combination with pembrolizumab on day 1 of a 21-day cycle. The primary end-point was progression-free survival (PFS). Key secondary end-points included overall survival (OS), overall response rate (ORR) and safety. Results Among 100 patients randomised (pembrolizumab + CC-486: 51; pembrolizumab + placebo: 49), most were male (57.0%), were white (87.0%) and had Eastern Cooperative Oncology Group performance status 1 (68.0%). No significant difference in PFS was observed between the pembrolizumab + CC-486 and pembrolizumab + placebo arms (median, 2.9 and 4.0 months, respectively; hazard ratio [HR], 1.374; 90% confidence interval [CI], 0.926–2.038; P = 0.1789). Median OS was 11.9 months versus not estimable (HR, 1.375; 90% CI, 0.830–2.276; P = 0.2968); ORR was 20% versus 14%. Median treatment duration was shorter (15.0 versus 24.1 weeks), and the number of cycles was lower (5.0 versus 7.0) with pembrolizumab + CC-486 versus pembrolizumab + placebo. No new safety signals for CC-486 or pembrolizumab were detected. Treatment-emergent adverse events were more common in the pembrolizumab + CC-486 arm, particularly gastrointestinal, potentially impacting treatment feasibility. Conclusions No improvement in PFS was observed with pembrolizumab + CC-486 versus pembrolizumab + placebo. Decreased treatment exposure due to adverse events may have impacted efficacy with pembrolizumab + CC-486. Highlights • Second-line pembrolizumab + CC-486 versus pembrolizumab + placebo in advanced non-small cell lung cancer. • No significant difference in progression-free survival (primary end-point). • No new safety signals were detected for either pembrolizumab or CC-486. • Gastrointestinal adverse events were more common in the pembrolizumab + CC-486 arm. • Pembrolizumab + CC-486 efficacy may have been impacted by lower treatment exposure. [ABSTRACT FROM AUTHOR]

Purpose To revise the recommendation on the use of concurrent chemotherapy (CC) with palliative thoracic external beam radiation therapy (EBRT) made in the original 2011 American Society for Radiation Oncology guideline on palliative thoracic radiation for lung cancer. Methods and materials Based on a systematic PubMed search showing new evidence for this key question, the task force felt an update was merited. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology–approved tools for grading evidence quality and recommendation strength. Results Although few randomized clinical trials address the question of CC combined with palliative thoracic EBRT for non-small cell lung cancer (NSCLC), a strong consensus was reached among the task force on recommendations for incurable stage III and IV NSCLC. For patients with stage III NSCLC deemed unsuitable for curative therapy but who are (1) candidates for chemotherapy, (2) have an Eastern Cooperative Oncology Group PS of 0 to 2, and (3) have a life expectancy of at least 3 months, administration of a platinum-containing chemotherapy doublet concurrently with moderately hypofractionated palliative thoracic radiation therapy is recommended over treatment with either modality alone. For patients with stage IV NSCLC, routine use of concurrent thoracic chemoradiation is not recommended. Conclusions Optimal palliation of patients with incurable NSCLC requires coordinated interdisciplinary care. Recent data establish a rationale for CC with palliative thoracic EBRT for a well-defined subset of patients with incurable stage III NSCLC. For all other patients with incurable NSCLC, data remain insufficient to support this treatment approach. [ABSTRACT FROM AUTHOR]

Background: Treatment options are limited for patients with thymic carcinoma. These aggressive tumours are not typically associated with paraneoplastic autoimmune disorders, and strong PD-L1 expression has been reported in thymic epithelial tumours. We aimed to assess the activity of pembrolizumab, a monoclonal antibody that targets PD-1, in patients with advanced thymic carcinoma.Methods: We completed a single-arm phase 2 study of pembrolizumab in patients with recurrent thymic carcinoma who had progressed after at least one line of chemotherapy. This was a single-centre study performed at Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. Key inclusion criteria were an Eastern Cooperative Oncology Group performance status of 0-2, no history of autoimmune disease or other malignancy requiring treatment or laboratory abnormality, and adequate organ function. Patients received 200 mg of pembrolizumab every 3 weeks for up to 2 years. The primary objective of the study was the proportion of patients who had achieved a response assessed with Response Evaluation Criteria in Solid Tumors version 1.1. Analysis was per protocol, in all eligible patients. The study is registered with ClinicalTrials.gov, number NCT02364076, and is closed to accrual; we report the final analysis.Findings: 41 patients were enrolled from March 12, 2015, to Dec 16, 2016, of whom 40 were eligible and evaluable and one was excluded because of elevated liver enzymes at screening. The median follow-up was 20 months (IQR 14-26). The proportion of patients who achieved a response was 22·5% (95% CI 10·8-38·5); one (3%) patient achieved a complete response, eight (20%) patients achieved partial responses, and 21 (53%) patients achieved stable disease. The most common grade 3 or 4 adverse events were increased aspartate aminotransferase and alanine aminotransferase (five [13%] patients each). Six (15%) patients developed severe autoimmune toxicity, including two (5%) patients with myocarditis. There were 17 deaths at the time of analysis, but no deaths due to toxicity.Interpretation: Pembrolizumab is a promising treatment option in patients with thymic carcinoma. Because severe autoimmune disorders are more frequent in thymic carcinoma than in other tumour types, careful monitoring is essential.Funding: Merck & Co. [ABSTRACT FROM AUTHOR]

Abstract: There has been a significant shift within oncology drug development away from empiric screening of cytotoxic compounds to the era of genomics and molecularly targeted agents. The drug development process is evolving with greater emphasis on proof-of-mechanism studies in both preclinical and early clinical development. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Task Force, established as a forum for academic and pharmaceutical leaders to discuss methodological issues in targeted anticancer therapy development, met in March 2010 to review what were the minimal data required to make appropriate decisions about moving new targeted cancer agents from late preclinical development into phase I and from phase I into phase II trials. A number of specific questions were posed, and responses to each developed through survey, literature review and discussion at the face to face meeting of the MDICT Task Force. Consensus emerged around the necessity to demonstrate proof-of-mechanism and obtain information on key pharmacokinetic aspects of drug behaviour in late preclinical and early clinical trials. However, controversy remains on the extent of in vivo anti-tumour efficacy required to support clinical development of targeted agents. A systematic review of the data in this area would be informative. Further, while objective response in phase I trials may be a favourable signal about the potential activity of a new agent, debate exists around the weight that should be placed on the observation of stable disease or functional imaging changes in driving drug development decisions in the absence of observing either responses or convincing pharmacodynamic data in phase I. MDICT made a number of recommendations that may aid in future development of targeted agents. [Copyright &y& Elsevier]

Abstract: The first-generation epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib have been incorporated into treatment paradigms for patients with advanced non-small cell lung cancer. These agents are particularly effective in a subset of patients whose tumors harbor activating epidermal growth factor receptor mutations. However, most patients do not respond to these tyrosine kinase inhibitors, and those who do will eventually acquire resistance that typically results from a secondary epidermal growth factor receptor mutation (e.g., T790M), mesenchymal–epithelial transition factor amplification, or activation of other signaling pathways. For patients whose tumors have wild-type epidermal growth factor receptor, there are several known mechanisms of initial resistance (e.g., Kirsten rat sarcoma viral oncogene homolog mutations) but these do not account for all cases, suggesting that unknown mechanisms also contribute. To potentially overcome the issue of resistance, next-generation tyrosine kinase inhibitors are being developed, which irreversibly block multiple epidermal growth factor receptor family members (e.g., afatinib [BIBW 2992] and PF-00299804) and/or vascular endothelial growth factor receptor pathways (e.g., BMS-690514 and XL647). In addition, drugs that block parallel signaling pathways or signaling molecules downstream of the epidermal growth factor receptor, such as the insulin-like growth factor-1 receptor and the mammalian target of rapamycin, are undergoing clinical evaluation. As drug resistance appears to be pleomorphic, combinations of drugs or drugs with multiple targets may be more effective in circumventing resistance. [Copyright &y& Elsevier]

Abstract: Malignant mesothelioma is an aggressive tumour, with a poor prognosis and an increasing incidence as a result of widespread exposure to asbestos. The results of the treatments available are poor. Surgery and radiotherapy have a limited role in highly selected patients and systemic therapy is the only potential treatment option for the majority of patients. Despite some definite activity of the novel antifolates such as pemetrexed and raltitrexed, the results, even in combination with platinating agents, are still modest, with a median survival of approximately one year. The better understanding of the biology of mesothelioma makes the assessment of a number of targeted agents particularly interesting. Unfortunately, the targeted agents imatinib, gefitinib, erlotinib and thalidomide have been shown to be ineffective in unselected patients. Studies with anti-angiogenesis agents are ongoing. An improvement of the knowledge of major molecular pathways involved in malignant mesothelioma is needed in order to define proper targets for the systemic treatment of this disease. [Copyright &y& Elsevier]

Abstract: In the past 12–18 months, there have been an incredible number of studies in lung cancer. This is partly reflected by an increased interest by drug companies to develop agents for this disease, given the large number of patients developing lung cancer, but also because the understanding of the biology of this tumor has led to significant advances in the development of targeted agents. A very large number of novel agents have been tested, especially in non-small cell lung cancer (NSCLC) either as single agents or in combination with chemotherapy. Some novel targeted agents have now shown definite activity in NSCLC, such as EGFR tyrosine kinase inhibitors and bevacizumab. As in previous years, this chapter will be divided into non-small cell lung cancer, small cell lung cancer and then mesothelioma and thymoma. [Copyright &y& Elsevier]

Summary: The family of inhibitor of apoptosis (IAP) proteins can suppress apoptosis induced by a variety of triggers. Among the IAPs, cIAP1, cIAP2, and XIAP have been characterized as inhibitors of specific caspases, and their expression, together with that of survivin, has been shown in several studies to play a role as tumor marker and prognostic factor for the survival of patients with cancer. Although survivin is usually not expressed in normal adult tissues, cIAP1, cIAP2, and XIAP have been found broadly expressed at messenger RNA level within normal cells. Here, we report an immunohistochemical study in a comprehensive panel of normal human tissues, and we confirm at the protein level the wide expression of IAPs. These results are consistent with a physiological role of IAPs in normal cells. Moreover, we show that IAPs'' expression levels and localization patterns differ depending on the cell lineage. The variable subcellular localization of the IAPs within different cell types suggests that compartmentalization may contribute to regulate their function. The physiological role of these proteins should be further investigated to help tailor IAP-targeted therapeutic strategies for patients with cancer and circumvent possible side effects. [Copyright &y& Elsevier]

The proteasome plays a central role in the regulation of many processes critical to solid tumour growth. Proteasome inhibition activates multiple mechanisms capable of arresting tumour proliferation, tumour metastasis, and angiogenesis. In preclinical testing, the novel proteasome inhibitor bortezomib displays a unique pattern of cytotoxicity against a broad spectrum of tumour cell lines. In experimental models of breast, lung, colon, prostate, pancreatic, and ovarian cancer, bortezomib shows additive or synergistic activity when combined with chemotherapeutic agents such as irinotecan, gemcitabine, 5-fluorouracil, cisplatin, paclitaxel, docetaxel, and doxorubicin. Bortezomib is currently being investigated both as a single agent and in combination regimens for the treatment of a broad range of solid tumours including non-small cell lung cancer (NSCLC), renal cell, breast, ovarian, prostate, colon, gastric, and pancreatic cancer. In an ongoing, single-agent phase II trial in NSCLC, one partial response and six instances of stable disease were documented in 15 evaluable patients. Pharmacodynamic studies showed inhibition of NF-κB. Two single-institution phase II trials in renal cell cancer showed four partial responses in 37 patients and one partial response in 21 patients, respectively. Randomised phase II trials of bortezomib with or without docetaxel in patients with NSCLC and with or without irinotecan in patients with colon cancer are ongoing, as are single-agent phase II studies in colon, breast, and ovarian cancer. Bortezomib is also being studied in combination with irinotecan in patients with gastro-oesophageal cancer, with gemcitabine in patients with pancreatic cancer, and with docetaxel in patients with breast and prostate cancer. [Copyright &y& Elsevier]

Lung cancer is one of the most frequent causes of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 80% of cases and no curative treatment is available for the advanced stages of disease (stages III and IV), which comprise the majority of cases. Current treatment regimens with standard chemotherapy offer only a limited survival benefit, and, therefore, the development of new therapeutic strategies is needed. Novel chemotherapeutic drugs such as the epothilones, MEN 10755 and S-1 are being studied in patients with advanced stages of disease. Furthermore, a large number of therapies targeted against critical biological abnormalities in NSCLC are being investigated in clinical trials. The latter approach includes inhibition of growth factors, interference with abnormal signal transduction, inhibition of angiogenesis and gene replacement therapy. Promising results have thus far been obtained with some of these therapies. This review describes the role of new therapeutic agents in the treatment of NSCLC. [Copyright &y& Elsevier]