The
gene plays a major role in the oncogenesis of numerous tumors.
rearrangement is found in 0.9-2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas, with a significantly higher ...rate of women, non-smokers, and a tendency to a younger age. It has been demonstrated that
is a true oncogenic driver, and tyrosine kinase inhibitors (TKIs) targeting ROS-1 can block tumor growth and provide clinical benefit for the patient. Since 2016, crizotinib has been the first-line reference therapy, with two-thirds of the patients' tumors responding and progression-free survival lasting ~20 months. More recently developed are ROS-1-targeting TKIs that are active against resistance mechanisms appearing under crizotinib and have better brain penetration. This review summarizes current knowledge on
rearrangement in NSCLCs, including the mechanisms responsible for
oncogenicity, epidemiology of
-positive tumors, methods for detecting rearrangement, phenotypic, histological, and molecular characteristics, and their therapeutic management. Much of this work is devoted to resistance mechanisms and the development of promising new molecules.
HER2 mutations are identified in approximately 2%of non-small-cell lung cancers (NSCLC). There are few data available that describe the clinical course of patients with HER2-mutated NSCLC.
We ...retrospectively identified 65 NSCLC, diagnosed with a HER2 in-frame insertion in exon 20. We collected clinicopathologic characteristics, patients' outcomes, and treatments.
HER2 mutation was identified in 65 (1.7%) of 3,800 patients tested and was almost an exclusive driver, except for one single case with a concomitant KRAS mutation. Our population presented with a median age of 60 years (range, 31 to 86 years), a high proportion of women (45 women v 20 men; 69%), and a high proportion of never-smokers (n= 34; 52.3%). All tumors were adenocarcinomas and 50% were stage IV at diagnosis. For these latter cases, 22 anti-human epidermal growth factor receptor 2 (HER2) treatments were administered after conventional chemotherapy in 16 patients. Subsequently, four patients experienced progressive disease, seven experienced disease stabilizations, and 11 experienced partial responses (overall response rate, 50%; disease control rate DCR, 82%). Specifically, we observed a DCR of 93% for trastuzumab-based therapies (n = 15) and a DCR of 100% for afatinib (n = 3) but no response to other HER2-targeted drugs (n = 3). Progression-free survival for patients with HER2 therapies was 5.1 months. Median survival was of 89.6 and 22.9 months for early-stage and stage IV patients, respectively.
This study, the largest to date dedicated to HER2-mutated NSCLC, reinforces the importance of screening for HER2 mutations in lung adenocarcinomas and suggests the potential efficacy of HER2-targeted drugs in this population.
Chronic obstructive pulmonary disease (COPD) is predicted to become a major cause of death worldwide. Studies on the variability in the estimates of key epidemiological parameters of COPD may ...contribute to better assessment of the burden of this disease and to helpful guidance for future research and public policies. In the present study, we examined differences in the main epidemiological characteristics of COPD derived from studies across countries of the European Union, focusing on prevalence, severity, frequency of exacerbations and mortality, as well as on differences between the studies' methods.
This systematic review was based on a search for the relevant literature in the Science Citation Index database via the Web of Science and on COPD mortality rates issued from national statistics. Analysis was finally based on 65 articles and Eurostat COPD mortality data for 21 European countries.
Epidemiological characteristics of COPD varied widely from country to country. For example, prevalence estimates ranged between 2.1% and 26.1%, depending on the country, the age group and the methods used. Likewise, COPD mortality rates ranged from 7.2 to 36.1 per 10(5) inhabitants. The methods used to estimate these epidemiological parameters were highly variable in terms of the definition of COPD, severity scales, methods of investigation and target populations. Nevertheless, to a large extent, several recent international guidelines or research initiatives, such as GOLD, BOLD or PLATINO, have boosted a substantial standardization of methodology in data collection and have resulted in the availability of more comparable epidemiological estimates across countries. On the basis of such standardization, severity estimates as well as prevalence estimates present much less variation across countries. The contribution of these recent guidelines and initiatives is outlined, as are the problems remaining in arriving at more accurate COPD epidemiological estimates across European countries.
The accuracy of COPD epidemiological parameters is important for guiding decision making with regard to preventive measures, interventions and patient management in various health care systems. Therefore, the recent initiatives for standardizing data collection should be enhanced to result in COPD epidemiological estimates of improved quality. Moreover, establishing international guidelines for reporting research on COPD may also constitute a major contribution.
The association between lung cancer (LC) and interstitial lung disease (ILD) can be explained by the shared risk factors like smoking and physiopathology of fibrogenesis and cancerogenesis. The ...relative LC risk is shown to be 3.5- to 7.3-times higher in ILD, with LC occurrence estimated at 10-20% in ILD, with >15% of ILD patients likely to die from LC. ILD incidence upon LC diagnosis varied from 2.4-10.9%. Primary radiological presentations consist of peripheral lesions, mostly in the inferior pulmonary lobes, either close to or within the ILD areas. There is a trend towards inverted proportion of adenocarcinomas and squamous-cell carcinomas, with EGFR mutations very rarely found. ILD negatively impacted LC prognosis, with surgery associated with increased morbidity-mortality, particularly due to acute exacerbation (AE) of ILD. Limited resection reduced this risk, whilst increasing that of cancer mortality. Studies on radiotherapy that can induce AE-ILD are scarce. Chemotherapy was associated with similar response rates to those in LC patients without ILD, yet worse survival. This difference may be accounted for by ILD patients' poorer health and higher risk of drug-induced pneumonitis. Further studies are warranted to better understand cancer physiopathology within the fibrotic areas, along with the therapeutic strategies required.
Characteristics of patients at risk of developing severe forms of COVID-19 disease have been widely described, but very few studies describe their evolution through the following waves. Data was ...collected retrospectively from a prospectively maintained database from a University Hospital in Paris area, over a year corresponding to the first three waves of COVID-19 in France. Evolution of patient characteristics between non-severe and severe cases through the waves was analyzed with a classical multivariate logistic regression along with a complementary Machine-Learning-based analysis using explainability methods. On 1076 hospitalized patients, severe forms concerned 29% (123/429), 31% (66/214) and 18% (79/433) of each wave. Risk factors of the first wave included old age (≥ 70 years), male gender, diabetes and obesity while cardiovascular issues appeared to be a protective factor. Influence of age, gender and comorbidities on the occurrence of severe COVID-19 was less marked in the 3rd wave compared to the first 2, and the interactions between age and comorbidities less important. Typology of hospitalized patients with severe forms evolved rapidly through the waves. This evolution may be due to the changes of hospital practices and the early vaccination campaign targeting the people at high risk such as elderly and patients with comorbidities.
Highlights • Re-biopsy is a major challenge for lung cancer management. • We performed an observational multi-center study in real world. • The feasibility, the patients’ acceptance are the main ...outcomes. • Re-biopsy remains a difficult procedure in thoracic malignancy. • Biological analyses are not always productive.
The medico-economic impact of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (COPD) is poorly documented.
To estimate the effectiveness and cost-effectiveness of ...pulmonary rehabilitation in a hypothetical cohort of COPD patients.
We used a multi-state Markov model, adopting society's perspective. Simulated cohorts of French GOLD stage 2 to 4 COPD patients with and without pulmonary rehabilitation were compared in terms of life expectancy, quality-adjusted life years (QALY), disease-related costs, and the incremental cost-effectiveness ratio (ICER). Sensitivity analyses included variations of key model parameters.
At the horizon of a COPD patient's remaining lifetime, pulmonary rehabilitation would result in mean gain of 0.8 QALY, with an over disease-related costs of 14 102 € per patient. The ICER was 17 583 €/QALY. Sensitivity analysis showed that pulmonary rehabilitation was cost-effective in every scenario (ICER <50 000 €/QALY).
These results should provide a useful basis for COPD pulmonary rehabilitation programs.
This phase III study investigated whether continuation maintenance with gemcitabine or switch maintenance with erlotinib improves clinical outcome compared with observation in patients with advanced ...non-small-cell lung cancer (NSCLC) whose disease was controlled after cisplatin-gemcitabine induction chemotherapy.
Four hundred sixty-four patients with stage IIIB/IV NSCLC without tumor progression after four cycles of cisplatin-gemcitabine were randomly assigned to observation or to gemcitabine (1,250 mg/m(2) days 1 and 8 of a 3-week cycle) or daily erlotinib (150 mg/day) study arms. On disease progression, patients in all three arms received pemetrexed (500 mg/m(2) once every 21 days) as predefined second-line therapy. The primary end point was progression-free survival (PFS).
PFS was significantly prolonged by gemcitabine (median, 3.8 v 1.9 months; hazard ratio HR, 0.56; 95% CI, 0.44 to 0.72; log-rank P < .001) and erlotinib (median, 2.9 v 1.9 months; HR, 0.69; 95% CI, 0.54 to 0.88; log-rank P = .003) versus observation; this benefit was consistent across all clinical subgroups. Both maintenance strategies resulted in a nonsignificant improvement in overall survival (OS); patients who received second-line pemetrexed or with a performance status of 0 appeared to derive greater benefit. Exploratory analysis showed that magnitude of response to induction chemotherapy may affect the OS benefit as a result of gemcitabine maintenance. Maintenance gemcitabine and erlotinib were well tolerated with no unexpected adverse events.
Gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduces disease progression in patients with advanced NSCLC treated with cisplatin-gemcitabine as first-line chemotherapy. Response to induction chemotherapy may affect OS only for continuation maintenance.
Purpose
Consolidation immunotherapy with the PD-L1 inhibitor durvalumab following concurrent chemoradiotherapy (cCRT) has shown a significant survival improvement and is now a standard of care in ...patients with unresectable stage III or non-operable non-small cell lung cancer (NSCLC).
Methods
In this early access program cohort, demographic, disease characteristics and safety data were collected for 576 patients from 188 centers, who received durvalumab 10 mg/kg intravenous infusion every 2 weeks, until disease progression or unacceptable toxicity or for a maximum of 12 months following cCRT. Durvalumab exposure data were available for 402 patients.
Results
Overall, 576 patients were included, 72.9% were men, median age 64.0 years, 52.3% had a stage IIIB disease. PD-L1 status captured in 445 (77%) patients was positive (48.1%), negative (32.6%), unknown (19.3%). At the end of cCRT, adverse events (AEs) all grade ≤ 2, were reported in 22.7% of patients, mainly esophagitis (6.3%). The main reasons of discontinuation were completion of the planned 12 months of consolidation treatment (42.1% patients), disease progression (28.6%) and adverse events (19.5%). Treatment completion was similar in PDL-1 positive and PDL-1 negative patients groups. 20.7% patients had a SAE drug reaction and 17.7% stopped treatment mainly due to SAE. ADR rate and early treatment discontinuation were higher in patients > 70 years old. Death due to AEs occurred in 7 patients, 2 had interstitial lung disease.
Conclusion
Safety data with durvalumab consolidation after cCRT in a large cohort of patients with stage III NSCLC are reported in this real-life cohort. Consistent data were reported both in the PD-L1 positive and PD-L1 negative NSCLC patients in daily practice.
Immune checkpoint inhibitors, notably antibodies targeting programmed death–1 (PD-1) and programmed death ligand–1 (PD-L1), have modified the management of patients with locally advanced or ...metastatic non-small-cell lung cancer (NSCLC). Several PD-1/PD-L1 inhibitors have been approved by health authorities for this indication and others are in clinical development. However, only a subset of patients truly benefits from these agents. For patients with mutated
EGFR
or translocated
ALK
NSCLC, for whom an immune checkpoint inhibitor can be prescribed after progression on tyrosine kinase inhibitors and chemotherapy, information is scarce and sometimes contradictory. Phase III randomized clinical trials have evaluated different immune checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab) vs. chemotherapy as second- or subsequent-line therapy in NSCLC, but included very few patients with
EGFR/ALK
-positive disease. Subgroup analyses found that these patients did not benefit from immune checkpoint inhibitors. Retrospective data show progression-free survival lasting only 1.2–2.1 months. Preclinical data suggested a lower expression of PD-L1 in
EGFR/ALK
-positive patients compared to
EGFR/ALK
-negative patients. Our objective herein is to provide an up-to-date review of available data from the various publications on the impact of immune checkpoint inhibitors in patients with
EGFR
/
ALK
-positive NSCLC.
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