Overall survival in advanced epidermal growth factor receptor mutated non-small cell lung cancer using different tyrosine kinase inhibitors in The Netherlands: a retrospective, nationwide registry study.

Background: Clinical guidelines advise osimertinib as preferred first line treatment for advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with deletions in exon 19 (del19) or exon 21 L858R mutation. However, for first-line osimertinib the real world overall survival (OS) in mutation subgroups remains unknown. Therefore, the aim of this study was to evaluate the real-world OS of those patients treated with different generations of EGFR-tyrosine kinase inhibitors (TKI), and to identify predictors of survival. Methods: Using real-world data from the Netherlands Cancer Registry (NCR) we assessed patients diagnosed with stage IV NSCLC with del19 or L858R mutation between January 1, 2015, and December 31, 2020, primarily treated with then regularly available TKIs (including osimertinib). Findings: Between January 1, 2015, and December 31, 2020, 57,592 patients were included in the NCR. Within this cohort we identified 1109 patients, 654 (59%) with del19 and 455 (41%) with L858R mutations, respectively; 230 (21%) patients were diagnosed with baseline brain metastases (BM). Patients were treated with gefitinib (19%, 213/1109), erlotinib (42%, 470/1109), afatinib (15%, 161/1109) or osimertinib (24%, 265/1109). Median OS was superior for del19 versus L858R (28.4 months (95% CI 25.6-30.6) versus 17.7 months (95% CI 16.1-19.5), p < 0.001. In multivariable analysis, no difference in survival was observed between various TKIs in both groups. Only in the subgroup of patients with del19 and baseline BM, a benefit was observed for treatment with osimertinib. Interpretation: In this nationwide real-world cohort, survival of Dutch patients with advanced NSCLC and an EGFR del19 mutation was superior versus those harboring an L858R mutation. Osimertinib performed only better as first-line treatment in patients with del19 and BM. Funding: None.

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer.

Introduction: Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods: Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0-3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2-16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results: Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2-18.8) for CPE and 10.3 months (95% CI 7.1-15.5; hazard ratio (HR) 0.62, 95% CI 0.25-1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07-0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8-61.9 months) for CPE compared to 17.2 months (95% CI 11.5-45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22-1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion: Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity.

Nationwide Real-world Cohort Study of First-line Tyrosine Kinase Inhibitor Treatment in Epidermal Growth Factor Receptor-mutated Non-small-cell Lung Cancer.

BACKGROUND: Only a few randomized trials directly compared the relative efficacy of tyrosine kinase inhibitors (TKIs) in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), and most trials comprised selected series from Asian populations. Therefore, the aim of this study was to assess the overall survival (OS) of advanced EGFR-mutated NSCLC in a large white population and to evaluate variation between different TKIs and identify predictors of survival. PATIENTS AND METHODS: Information about clinical characteristics, treatment, and survival for 873 patients with stage IV EGFR + NSCLC, diagnosed from 2015 through 2017, was derived from the Netherlands Cancer Registry. OS was evaluated by actuarial analysis and multivariable Cox regression. Prognostic factors are reported as hazard ratios and 95% confidence intervals. RESULTS: A total of 596 (68%) patients received first-line treatment with regular TKIs, providing a median survival of 20.2 months. Forty-five percent of patients were 70 years and older, and 54% of patients had distant metastasis in multiple organs. In the multivariate analysis, survival was significantly worse for men, and patients with higher age, poorer performance, and ≥ 3 organs with metastasis. Compared with erlotinib, OS was worse for gefitinib users (adjusted hazard ratio, 1.30; 95% confidence interval, 1.02-1.64), predominantly in patients with brain metastasis. CONCLUSION: Dutch patients with EGFR-mutated NSCLC who received first-line treatment with regular TKIs have a median OS of 20.2 months in a nationwide real-world cohort. In patients with brain metastasis, erlotinib showed superior results compared with gefitinib and was similar to afatinib.

RSV infection among children born moderately preterm in a community-based cohort.

UNLABELLED: We aimed to determine the rates of proven respiratory syncytial virus (RSV) hospitalization and disease severity among children born moderately preterm (MP, gestational age [GA] 32-36 weeks, n = 964), children born full-term (FT, GA 38-42 weeks, n = 572), and children born early preterm (EP, GA <32 weeks, n = 524). Our second aim was to identify risk factors for RSV hospitalization among MP. We extracted data from parental questionnaires and medical records, retrieved from a community-based cohort of children aged 43-49 months. The RSV hospitalization rates of MP were higher than FT (3.9 vs. 1.2 %, relative rate 3.2; 95 % confidence interval (CI) 1.4-7.1) and equal to EP (3.9 vs. 3.2 %, relative rate 1.2; 95 % CI 0.7-2.1). MP were hospitalized at an earlier age than EP. Disease severity (based on the type of treatment and hospitalization length) was equal in all groups. Risk factors for RSV hospitalization in MP were younger age and lower birth weight. In multivariable analyses, shorter GA and passive smoking independently increased the likelihood of RSV hospitalization in MP. CONCLUSION: The rates of hospitalization due to proven RSV infection are higher in MP than FT and not different between MP and EP. No difference in disease severity was observed. Among MP, the rates of RSV hospitalization are higher for lower GA and when exposed to passive smoking.