•This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing non-oncogene-addicted mNSCLC.•ESMO-MCBS scores are given to describe the levels of evidence for ...treatment choices.•ESCAT scores are given to describe the evidence level for genomic alterations as biomarkers for using targeted therapies.•Recommendations are based on available scientific data and the authors’ collective expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach.
•This Clinical Practice Guideline provides management recommendations for patients with brain metastases from solid tumours.•The guideline covers clinical and pathological diagnosis, staging and risk ...assessment, treatment and follow-up.•Treatment and management algorithms are provided.•The author panel encompasses a multidisciplinary group of experts from different institutions and countries in Europe.•Recommendations are based on available scientific data and the authors’ collective expert opinion.
To conduct a comprehensive examination of the association between women's reproductive health factors and measures of body adiposity in a contemporary Western population.
A cross-sectional analysis ...of 502 664 individuals from the UK Biobank was conducted. Multivariable linear regression models were used to examine the association of age at menarche, age at first birth, parity and age at menopause with measures of general and central body adiposity, adjusted for age, smoking and socioeconomic status. The association between number of children and body adiposity in men was also assessed.
Age at menarche was inversely associated with body mass index (BMI); adjusted mean BMI was 29.0 kg m(-2) in women with menarche before the age of 12 years, compared with 26.5 kg m(-2) in those who had menarche after 14 years of age. Age at first birth was linearly and inversely associated with BMI: 0.16 kg m(-2) lower BMI per year increase in age of first birth. Each additional live birth or child fathered was associated with a 0.22 kg m(-2) higher BMI in women and a 0.14 kg m(-2) higher BMI in men. There was no evidence for an association between age at menopause and BMI. Corresponding associations for other markers of general or abdominal adiposity were similar to those for BMI. Findings were broadly similar in analyses stratified by age, smoking status, socioeconomic status, ethnic background, and history of diabetes or cardiovascular disease.
In women from a contemporary Western population, earlier age at menarche and age at first birth, and higher number of total live births were associated with higher levels of body adiposity. Prospective evaluations of the association between reproductive health factors, adiposity and the onset of cardiometabolic diseases are needed to assess causality, and to explore the mechanisms involved.
•Investigator-assessed PFS data in the ALEX study are now mature (53% of events in the alectinib arm).•Alectinib significantly prolonged PFS vs crizotinib (stratified HR 0.43, 95% CI 0.32–0.58; ...median 34.8 vs 10.9 months).•OS data are immature (37% of events); median NR alectinib vs 57.4 months crizotinib (stratified HR 0.67, 95% CI 0.46–0.98).•5-year OS rate of 62.5% with alectinib and 45.5% with crizotinib.•Median treatment duration was longer with alectinib (28.1 vs 10.8 months crizotinib), with no new safety signals seen.
The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019).
Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n = 152) or crizotinib 250 mg (n = 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety.
Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32–0.58; median PFS 34.8 versus 10.9 months crizotinib. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46–0.98). The 5-year OS rate was 62.5% (95% CI 54.3–70.8) with alectinib and 45.5% (95% CI 33.6–57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline HR 0.58 (95% CI 0.34–1.00) and those without HR 0.76 (95% CI 0.45–1.26). Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed.
Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALK-positive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC.
NCT02075840.
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