The treatment paradigm of NSCLC underwent a major revolution during the course of 2017. Immune checkpoint inhibitors (ICIs) brought remarkable improvements in response and overall survival both in ...unselected pretreated patients and in untreated patients with programmed death ligand 1 expression of 50% or more. Furthermore, compelling preliminary results were reported for new combinations of anti–programmed cell death 1/programmed death ligand 1 agents with chemotherapy or anti–cytotoxic T-lymphocyte associated protein 4 inhibitors. The success of the ICIs appeared to extend to patients with SCLC, mesothelioma, or thymic tumors. Furthermore, in SCLC, encouraging activity was reported for an experimental target therapy (rovalpituzumab teserine) and a new chemotherapeutic agent (lurbinectedin). For oncogene-addicted NSCLC, next-generation tyrosine kinase inhibitors (TKIs) (such as osimertinib or alectinib) have demonstrated increased response rates and progression-free survival compared with first-generation TKIs in patients with both EGFR-mutated and ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC. However, because of the lack of mature overall survival data and considering the high efficacy of these drugs in patients with NSCLC previously exposed to first- or second-generation TKIs, definitive conclusions concerning the best treatment sequence cannot yet be drawn. In addition, new oncogenes such as mutant BRAF, tyrosine-protein kinase met gene (MET) and erb-b2 receptor tyrosine kinase 2 gene (HER2), and ret proto-oncogene (RET) rearrangements have joined the list of potential targetable drivers. In conclusion, the field of thoracic oncology is on the verge of a breakthrough that will open up many promising new therapeutic options for physicians and patients. The characterization of biomarkers predictive of sensitivity or resistance to immunotherapy and the identification of the optimal therapeutic combinations (for ICIs) and treatment sequence (for oncogene-addicted NSCLC) represent the toughest upcoming challenges in the domain of thoracic oncology.
Lung cancer is a public health problem and the first cause of cancer death worldwide. Radon is a radioactive gas that tends to accumulate inside homes, and it is the second lung cancer risk factor ...after smoking, and the first one in non-smokers. In Europe, there are several radon-prone areas, and although the 2013/59 EURATOM directive is aimed to regulate indoor radon exposition, regulating measures can vary between countries. Radon emits alpha-ionizing radiation that has been linked to a wide variety of cytotoxic and genotoxic effects; however, the link between lung cancer and radon from the genomic point of view remains poorly described. Driver molecular alterations have been recently identified in non-small lung cancer (NSCLC), such as somatic mutations (EGFR, BRAF, HER2, MET) or chromosomal rearrangements (ALK, ROS1, RET, NTRK), mainly in the non-smoking population, where no risk factor has been identified yet. An association between radon exposure and oncogenic NSCLC in non-smokers has been hypothesised. This paper provides a practical, concise and updated review on the implications of indoor radon in lung cancer carcinogenesis, and especially of its potential relation with NSCLC with driver genomic alterations.
In the past 10 years, a deeper understanding of the immune landscape of cancers, including immune evasion processes, has allowed the development of a new class of agents. The reactivation of host ...antitumor immune response offers the potential for long-term survival benefit in a portion of patients with thoracic malignancies.
The advent of programmed cell death protein 1/programmed death ligand-1 immune checkpoint inhibitors (ICIs), both as single agents and in combination with chemotherapy, and more recently, the combination of ICI, anti–programmed cell death protein 1, and anticytotoxic T-lymphocyte antigen 4 antibody, have led to breakthrough therapeutic advances for patients with advanced NSCLC, and to a lesser extent, patients with SCLC. Encouraging activity has recently emerged in pretreated patients with thymic carcinoma (TC). Conversely, in malignant pleural mesothelioma, pivotal positive signs of activity have not been fully confirmed in randomized trials. The additive effects of chemoradiation and immunotherapy suggested intriguing potential for therapeutic synergy with combination strategies. This has led to the introduction of ICI consolidation therapy in stage III NSCLC, creating a platform for future therapeutic developments in earlier-stage disease. Despite the definitive clinical benefit observed with ICI, primary and acquired resistance represent well-known biological phenomena, which may affect the therapeutic efficacy of these agents.
The development of innovative strategies to overcome ICI resistance, standardization of new patterns of ICI progression, identification of predictive biomarkers of response, optimal treatment duration, and characterization of ICI efficacy in special populations, represent crucial issues to be adequately addressed, with the aim of improving the therapeutic benefit of ICI in patients with thoracic malignancies.
In this article, an international panel of experts in the field of thoracic malignancies discussed these topics, evaluating currently available scientific evidence, with the final aim of providing clinical recommendations, which may guide oncologists in their current practice and elucidate future treatment strategies and research priorities.
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), specifically designed to inhibit EGFR sensitizing and T790M acquired mutations, minimizing ...exposure in EGFR-wild-type tissues. Areas covered: Osimertinib use in EGFR-mutated non-small cell lung cancer patients is described, focusing on safety and tolerability from studies supporting its approval. Expert opinion: Osimertinib demonstrated greater efficacy, including CNS activity, compared to chemotherapy, with a manageable safety profile in pretreated T790M+ EGFR-mutated patients, leading to FDA approval in 2015 within record time in the oncology field. However, the therapeutic strategy in the EGFR-mutated population is changing, following the FLAURA study in untreated EGFR-mutated patients, in which osimertinib improved progression-free survival compared to other TKIs, with a similar toxicity profile but a lower serious adverse event rate. In April 2018, the FDA and EMA approved osimertinib as first-line therapy for EGFR-mutated patients. Long-term survival data will ultimately establish the true benefit of upfront versus sequential strategies guided by T790M status. These studies favor osimertinib for tolerability and safety, except for the slightly higher rate of interstitial lung disease, but which was nonetheless manageable. In the coming years, osimertinib will be consolidated as standard therapy in the EGFR population and in naïve and pretreated patients, based on mature survival data and the toxicity profile.
Abstract
TGF-β is secreted in the tumour microenvironment in a latent, inactive form bound to latency associated protein and activated by the integrin α
V
subunit. The activation of latent TGF-β by ...cancer-cell-expressed α
V
re-shapes the tumour microenvironment, and this could affect patient responses to PD-1-targeting therapy. Here we show, using multiplex immunofluorescence staining in cohorts of anti-PD-1 and anti-PD-L1-treated lung cancer patients, that decreased expression of cancer cell α
V
is associated with improved immunotherapy-related, progression-free survival, as well as with an increased density of CD8
+
CD103
+
tumour-infiltrating lymphocytes. Mechanistically, tumour α
V
regulates CD8 T cell recruitment, induces CD103 expression on activated CD8
+
T cells and promotes their differentiation to granzyme B-producing CD103
+
CD69
+
resident memory T cells via autocrine TGF-β signalling. Thus, our work provides the underlying principle of targeting cancer cell α
V
for more efficient PD-1 checkpoint blockade therapy.
Aging is an important risk factor for cancers and is associated with poor prognosis. Weakness of the immune system, also called immunosenescence may occur with older age. The impact of aging on ...efficacy and safety of immune checkpoint blockers, such as anti-programmed death (ligand) PD-(L)1, remains undetermined. This study aims to evaluate the incidence of immune-related adverse events (irAEs) in patients aged 70 years or older than their younger counterparts.
Patients with advanced solid tumors treated at Gustave Roussy with an anti–PD-(L)1 monotherapy between June 2014 and October 2017 were prospectively included within the dedicated irAEs pharmacovigilance registry REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie). The incidence of irAEs of grade ≥II was compared between patients aged ≥70 (old patients, OP) versus patients aged < 70 years (young patients, YP) using a chi-squared test. Survivals were estimated using the Kaplan-Meier method.
Among the 603 patients treated by anti-PD(L)1, 191 were ≥70 y.o (OP) and 424 < 70 y.o (YP). The median (range) age of OP and YP were respectively 77 (70–93) and 59 years old (17–69). A total of 165 irAEs occurred in these patients (103 grade II and 58 grade III–IV). The overall incidence of grade ≥II irAEs was higher in OP than in YP (33% versus 25%, p = 0.03). In addition, OP were more prone of having multiples irAEs compared with YP (p = 0.037). Skin toxicities were more frequent in OP than in YP (p = 0.007) but endocrine toxicities were less frequent in OP than in YP (p = 0.044). This higher level of irAEs seems to be responsible for a higher rate of treatment discontinuation in OP (p = 0.2). There was no statistical difference in median time to toxicity, exposure to steroids or survival between the two groups.
Although anti-PD-(L)1 immunotherapies remain an acceptable treatment option for older patients, prescribers should be aware that irAEs are more frequent in the elderly. Further translational studies are warranted to better understand the relationship between aging and irAEs.
•Incidence of grade ≥ II immune related adverse events (irAEs) is higher in older.•Older patients are more prone to having multiple irAEs.•Prescribers should monitor closely older patients during anti-PD(L)1 treatment.
Gaming motives are important factors for explaining individual differences in videogame-related behaviors. The aim of the present study was to develop a new comprehensive but brief instrument-the ...Videogaming Motives Questionnaire (VMQ)-which embraces some of the most relevant gaming motives. In a first study, a pilot exploratory factor analysis (EFA) with data from 140 undergraduates was performed on items from twelve potential motives. This identified eight main factors: recreation, social interaction, coping, violent reward, fantasy, cognitive development, customization, and competition. In Studies 2 and 3, an EFA and a confirmatory factor analysis were performed on two independent samples of 407 adolescents and 260 young adults, respectively. The VMQ presented a robust eight-factor structure, with all scales showing adequate reliability indices. In reference to criterion validity, all motives presented specific associations with hours spent playing videogames, disordered gaming, and game genre preferences. More specifically, and in both adolescents and young adults, social interaction was the main motive related to time spent gaming, whereas disordered gaming was related to both coping and social interaction motives. Based on these findings, it is concluded that the VMQ is a brief and psychometrically appropriate tool for assessing the most relevant videogaming motives.
Mindful individuals are able to acknowledge mind wandering and live in the present moment in a nonjudgmental way. Previous studies have found that both mind wandering and mindfulness are associated ...with subjective well-being. However, the main predictor of happiness is personality; more specifically, happier people are emotionally stable and extraverted. The present study aimed to explore the contribution of the five factors of personality, dispositional mindfulness facets and a mindfulness intervention to happiness. A sample of 372 university students was assessed with the NEO-Five Factor Inventory, and another sample of 217 community adults answered the Big Five Personality Trait Short Questionnaire. Both samples, 589 participants in all, completed the Five Facet Mindfulness Questionnaire and the Subjective Happiness Scale. Furthermore, 55 participants from the general population sample took a 6-week training course in meditation and developing mindfulness. The regression analyses showed that emotional stability and extraversion traits were the strongest predictors of subjective well-being. Nonetheless, the nonjudging facet, which is nonevaluative/acceptance awareness of thoughts and feelings, still remained a significant predictor of happiness when personality was accounted for. Finally, mindfulness training did not increase subjective well-being. Being nonjudgmental of one's inner thoughts, feelings and sensations contributes to happiness even when personality is taken into account. Accordingly, it seems reasonable that mindfulness training that intends to improve subjective well-being should focus on noticing thoughts without judging them.
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