The advent of immunotherapy, and in particular the use of immune-checkpoint inhibitors, has profoundly revolutionized the treatment of different cancers, including lung cancer. The use of ...immune-checkpoint inhibitors has prolonged survival in lung cancer with a strong benefit in a significant percentage of patients with non-small-cell lung cancer. Here, a clinical case of a patient who, despite testing negative for PD-L1, displayed a sustained complete response to immunotherapy treatment in advanced metastatic non-small-cell lung cancer is presented. Additionally, recent findings concerning the application of immunotherapy in this context are reviewed.The advent of immunotherapy, and in particular the use of immune-checkpoint inhibitors, has profoundly revolutionized the treatment of different cancers, including lung cancer. The use of immune-checkpoint inhibitors has prolonged survival in lung cancer with a strong benefit in a significant percentage of patients with non-small-cell lung cancer. Here, a clinical case of a patient who, despite testing negative for PD-L1, displayed a sustained complete response to immunotherapy treatment in advanced metastatic non-small-cell lung cancer is presented. Additionally, recent findings concerning the application of immunotherapy in this context are reviewed.
The therapeutic approach for the second-line treatment of patients with advanced non-small cell lung cancer (NSCLC) without actionable mutations has been revolutionized by the recent approval of new ...effective drugs with various mechanisms of action, including nintedanib, ramucirumab, nivolumab, pembrolizumab, atezolizumab, and afatinib. The recent network meta-analysis of Créquit et al. (BMC Medicine, 15:193, 2017) compared the effectiveness and tolerability of the second-line treatments for advanced NSCLC with wild-type or unknown status for EGFR. The authors found that immunotherapy might be more efficacious than the currently recommended treatments. However, their meta-analysis does not take into account the role of predictive biomarkers - this is indeed a crucial point in the decision-making process considering that only a fraction of advanced NSCLC patients might derive a long-term benefit from second-line immunotherapy. The identification of molecular biomarkers that can predict a response to immune checkpoints, angiogenesis, and EGFR inhibitors remains an important goal of clinical research in order to maximize the benefit of these agents and to aid clinicians in the decision-making process.Please see related article: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-017-0954-x.
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, has robust efficacy in patients with ALK-positive non-small-cell lung cancer (NSCLC) that is refractory to crizotinib. The ...efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear.
In an open-label, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced ALK-positive NSCLC who had not previously received ALK inhibitors to receive brigatinib at a dose of 180 mg once daily (with a 7-day lead-in period at 90 mg) or crizotinib at a dose of 250 mg twice daily. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included the objective response rate and intracranial response. The first interim analysis was planned when approximately 50% of 198 expected events of disease progression or death had occurred.
A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% 95% confidence interval {CI}, 56 to 75 vs. 43% 95% CI, 32 to 53; hazard ratio for disease progression or death, 0.49 95% CI, 0.33 to 0.74; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted.
Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501 .).
Information about symptomatic toxicities of anticancer treatments is not based on direct report by patients, but rather on reports by clinicians in trials. Given the potential for under-reporting, ...our aim was to compare reporting by patients and physicians of six toxicities (anorexia, nausea, vomiting, constipation, diarrhea, and hair loss) within three randomized trials.
In one trial, elderly patients with breast cancer received adjuvant chemotherapy; in two trials, patients with advanced non-small-cell lung cancer received first-line treatment. Toxicity was prospectively collected by investigators (graded by National Cancer Institute Common Toxicity Criteria version 2.0 or Common Terminology Criteria for Adverse Events version 3). At the end of each cycle, patients completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaires, including toxicity-related symptom items. Possible answers were "not at all," "a little," "quite a bit," and "very much." Analysis was limited to the first three cycles. For each toxicity, agreement between patients and physicians and under-reporting by physicians (ie, toxicity reported by patients but not reported by physicians) were calculated.
Overall, 1,090 patients (2,482 cycles) were included. Agreement between patients and physicians was low for all toxicities. Toxicity rates reported by physicians were always lower than those reported by patients. For patients who reported toxicity (any severity), under-reporting by physicians ranged from 40.7% to 74.4%. Examining only patients who reported "very much" toxicity, under-reporting by physicians ranged from 13.0% to 50.0%.
Subjective toxicities are at high risk of under-reporting by physicians, even when prospectively collected within randomized trials. This strongly supports the incorporation of patient-reported outcomes into toxicity reporting in clinical trials.
Summary Background There is a major unmet need for effective treatments in patients with squamous cell carcinoma of the lung. LUX-Lung 8 compared afatinib (an irreversible ErbB family blocker) with ...erlotinib (a reversible EGFR tyrosine kinase inhibitor), as second-line treatment for patients with advanced squamous cell carcinoma of the lung. Methods We did this open-label, phase 3 randomised controlled trial at 183 cancer centres in 23 countries worldwide. We enrolled adults with stage IIIB or IV squamous cell carcinoma of the lung who had progressed after at least four cycles of platinum-based-chemotherapy. Participants were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. The randomisation was done centrally with an interactive voice or web-based response system and stratified by ethnic origin (eastern Asian vs non-eastern Asian). Clinicians and patients were not masked to treatment allocation. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). The key secondary endpoint was overall survival. This trial is registered with ClinicalTrials.gov , NCT01523587. Findings 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). Median follow-up at the time of the primary analysis of progression-free survival was 6·7 months (IQR 3·1–10·2), at which point enrolment was not complete. Progression free-survival at the primary analysis was significantly longer with afatinib than with erlotinib (median 2·4 months 95% CI 1·9–2·9 vs 1·9 months 1·9–2·2; hazard ratio HR 0·82 95% CI 0·68–1·00, p=0·0427). At the time of the primary analysis of overall survival (median follow-up 18·4 months IQR 13·8–22·4), overall survival was significantly greater in the afatinib group than in the erloinib group (median 7·9 months 95% CI 7·2–8·7 vs 6·8 months 5·9–7·8; HR 0·81 95% CI 0·69–0·95, p=0·0077), as were progression-free survival (median 2·6 months 95% CI 2·0–2·9 vs 1·9 months 1·9–2·1; HR 0·81 95% CI 0·69–0·96, p=0·0103) and disease control (201 51% of 398 patients vs 157 40% of 397; p=0·0020). The proportion of patients with an objective response did not differ significantly between groups (22 6% vs 11 3%; p=0·0551). Tumour shrinkage occurred in 103 (26%) of 398 patients versus 90 (23%) of 397 patients. Adverse event profiles were similar in each group: 224 (57%) of 392 patients in the afatinib group versus 227 (57%) of 395 in the erlotinib group had grade 3 or higher adverse events. We recorded higher incidences of treatment-related grade 3 diarrhoea with afatinib (39 10% vs nine 2%), of grade 3 stomatitis with afatinib (16 4% vs none), and of grade 3 rash or acne with erlotinib (23 6% vs 41 10%). Interpretation The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung. Funding Boehringer Ingelheim.
Background: Targeted therapies changed the treatment of advanced oncogene-addicted non-small cell lung cancer and could also improve outcomes in resectable disease. Results: The ALINA trial evaluated ...the clinical benefit of adjuvant alectinib compared with standard chemotherapy and met the primary endpoint with a significant increase in disease-free survival at 2 years among anaplastic lymphoma kinase positive patients with stage IB-IIIA disease; two phase II trials (ALNEO and NAUTIKA1) are currently evaluating perioperative treatment with alectinib, and the results of the case reports published to date are encouraging. Conclusion: In resectable anaplastic lymphoma kinase-positive lung cancer, adjuvant alectinib represents the new standard of care and could soon be used in perioperative treatment.
Angiogenesis Inhibitors in NSCLC Manzo, Anna; Montanino, Agnese; Carillio, Guido ...
International journal of molecular sciences,
09/2017, Letnik:
18, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Angiogenesis is a complex biological process that plays a relevant role in sustaining the microenvironment, growth, and metastatic potential of several tumors, including non-small cell lung cancer ...(NSCLC). Bevacizumab was the first angiogenesis inhibitor approved for the treatment of patients with advanced NSCLC in combination with chemotherapy; however, it was limited to patients with non-squamous histology and first-line setting. Approval was based on the results of two phase III trials (ECOG4599 and AVAIL) that demonstrated an improvement of about two months in progression-free survival (PFS) in both trials, and in the ECOG4599 trial, an improvement in overall survival (OS) also. Afterwards, other antiangiogenic agents, including sunitinib, sorafenib, and vandetanib have been unsuccessfully tested in first and successive lines. Recently, two new antiangiogenic agents (ramucirumab and nintedanib) produced a significant survival benefit in second-line setting. In the REVEL study, ramucirumab plus docetaxel prolonged the median OS of patients with any histology NSCLC when compared with docetaxel alone (10.4 versus 9.1 months, hazard ratio (HR) 0.857,
= 0.0235). In the LUME-Lung 1 study, nintedanib plus docetaxel prolonged the median PFS of patients with any tumor histology (
= 0.0019), and improved OS (12.6 versus 10.3 months) in patients with adenocarcinoma. As a result, it became a new option for the second-line treatment of patients with advanced NSCLC and adenocarcinoma histology. Identifying predictive biomarkers to optimize the benefit of antiangiogenic drugs remains an ongoing challenge.
To avoid the geographical and topographical prerequisites of the conventional pumped hydro energy storage, the use of underground cavities as water reservoirs allows countries without steep ...topography, such as Belgium, to increase the potential of the energy storage capacity. Belgium abounds in disused mines and quarries convertible into water basins. In this article, two Belgian case studies are presented and discussed for their singularity. A slate quarry in Martelange is discussed in technical aspects proposing three operating scenarios. Moreover, a preliminary economic analysis of the underground pumped storage system and a greenhouse gas emission evaluation for the storage system’s lifetime are presented. The analysis for a 100 MW power plant estimates a total initial investment of over 12 million euros and two million of CO2 avoided over its lifetime. This article also proposes the use of the coal mine 500 m deep of Pérronnes-lez-Binche. The mine representation discussed here offers a high energy capacity, but the substantial head drop (from about 500 to 200 m) challenges the selection of the hydraulic turbomachinery. A 1D simulation computed in SIMSEN draws out the behaviour of the unusual hydraulic configuration of turbines in series.
The epithelial-mesenchymal transition (EMT) plays a key role in tumor progression, drug resistance and metastasis. Recently, numerous microRNA (miRNA) have been described to regulate EMT in tumor ...progression. In this study, we found that conditioned medium from the LC212 non-small-cell lung cancer (NSCLC) cell line (LC212-CM) induces morphological changes and overexpression of Vimentin, CD90, SMAD 2/3, SLUG and TWIST in A549 NSCLC cells, consistent with a mesenchymal phenotype. To identify the soluble mediators in LC212-CM involved in this phenomenon, we performed miRNA profiling and TGF-β1 quantification. We found that LC212-CM contains high levels of TGF-β1 as well as different secreted miRNAs. We focused our attention on Homo sapiens-microRNA21 (hsa-miR21), one of most relevant miRNA associated with lung cancer progression, metastasis and EMT. An hsa-miR21 antagomiR was able to prevent the LC212-CM-induced EMT phenotype in A549 cells. Furthermore, we found that TGF-β1 and hsa-miR21 cooperate in the induction of EMT in A549 cells. Intriguingly, TGF-β1 was found to induce hsa-miR21 expression in A549 cell, thus suggesting that the hsa-miR21 mediates at least in part the pro-EMT effects of TGF-β1. In conclusion, hsa-miR21 and TGF-β1 are involved in autocrine and paracrine circuits that regulate the EMT status of lung cancer cells.
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