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The ALK inhibitor crizotinib as first-line therapy was associated with a significantly better response rate, longer progression-free survival, and greater improvement in quality of life measures than standard chemotherapy in patients with ALK -positive lung cancer. Rearrangements of the anaplastic lymphoma kinase ( ALK ) gene are present in 3 to 5% of non–small-cell lung cancers (NSCLCs). 1 , 2 They define a distinct subgroup of NSCLC that typically occurs in younger patients who have never smoked or have a history of light smoking and that has adenocarcinoma histologic characteristics. 3 – 5 Crizotinib is an oral small-molecule tyrosine kinase inhibitor of ALK, MET, and ROS1 kinases. 6 In phase 1 and 2 studies, crizotinib treatment resulted in objective tumor responses in approximately 60% of patients with ALK -positive NSCLC and in progression-free survival of 7 to 10 months. 7 – 9 In . . .

Atezolizumab (a monoclonal antibody against PD-L1), which restores anticancer immunity, improved overall survival in patients with previously treated non-small-cell lung cancer and also showed clinical benefit when combined with chemotherapy as first-line treatment of non-small-cell lung cancer. IMpower130 aimed to assess the efficacy and safety of atezolizumab plus chemotherapy versus chemotherapy alone as first-line therapy for non-squamous non-small-cell lung cancer. IMpower130 was a multicentre, randomised, open-label, phase 3 study done in 131 centres across eight countries (the USA, Canada, Belgium, France, Germany, Italy, Spain, and Israel). Eligible patients were aged 18 years or older, and had histologically or cytologically confirmed stage IV non-squamous non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0 or 1, and received no previous chemotherapy for stage IV disease. Patients were randomly assigned (2:1; permuted block [block size of six] with an interactive voice or web response system) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus chemotherapy (carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m2 intravenously every week]) or chemotherapy alone for four or six 21-day cycles followed by maintenance therapy. Stratification factors were sex, baseline liver metastases, and PD-L1 tumour expression. Co-primary endpoints were investigator-assessed progression-free survival and overall survival in the intention-to-treat wild-type (ie, EGFRwt and ALKwt) population. The safety population included patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02367781. Between April 16, 2015, and Feb 13, 2017, 724 patients were randomly assigned and 723 were included in the intention-to-treat population (one patient died before randomisation, but was assigned to a treatment group; this patient was excluded from the intention-to-treat population) of the atezolizumab plus chemotherapy group (483 patients in the intention-to-treat population and 451 patients in the intention-to-treat wild-type population) or the chemotherapy group (240 patients in the intention-to-treat population and 228 patients in the intention-to-treat wild-type population). Median follow-up in the intention-to-treat wild-type population was similar between groups (18·5 months [IQR 15·2–23·6] in the atezolizumab plus chemotherapy group and 19·2 months [15·4–23·0] in the chemotherapy group). In the intention-to-treat wild-type population, there were significant improvements in median overall survival (18·6 months [95% CI 16·0–21·2] in the atezolizumab plus chemotherapy group and 13·9 months [12·0–18·7] in the chemotherapy group; stratified hazard ratio [HR] 0·79 [95% CI 0·64–0·98]; p=0·033) and median progression-free survival (7·0 months [95% CI 6·2–7·3] in the atezolizumab plus chemotherapy group and 5·5 months [4·4–5·9] in the chemotherapy group; stratified HR 0·64 [95% CI 0·54–0·77]; p<0·0001]). The most common grade 3 or worse treatment-related adverse events were neutropenia (152 [32%] of 473 in the atezolizumab plus chemotherapy group vs 65 [28%] of 232 in the chemotherapy group), anaemia (138 [29%] vs 47 [20%]), and decreased neutrophil count (57 [12%] vs 19 [8%]). Treatment-related serious adverse events were reported in 112 (24%) of 473 patients in the atezolizumab plus chemotherapy group and 30 (13%) of 232 patients in the chemotherapy group. Treatment-related (any treatment) deaths occurred in eight (2%) of 473 patients in the atezolizumab plus chemotherapy group and one (<1%) of 232 patients in the chemotherapy group. IMpower130 showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer and no ALK or EGFR mutations. No new safety signals were identified. This study supports the benefit of atezolizumab, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer. F. Hoffmann-La Roche.

Background Identification of variable epidermal growth factor receptor ( EGFR ) gene mutations in non-small cell lung cancer (NSCLC) is important for the selection of appropriate targeted therapies. This meta-analysis was conducted to provide a worldwide overview of EGFR mutation and submutation (specifically exon 19 deletions, exon 21 L858R substitutions, and others) prevalence, and identify important covariates that influence EGFR mutation status in patients with advanced NSCLC to address this clinical data gap. Methods Embase ® and MEDLINE ® in Ovid were searched for studies published between 2004 and 2019 with cohorts of ≥ 50 adults with EGFR mutations, focusing on stage III/IV NSCLC (≤ 20% of patients with stage I/II NSCLC). Linear mixed-effects models were fitted to EGFR mutation endpoints using logistic transformation (logit), assuming a binomial distribution. The model included terms for an intercept reflecting European studies and further additive terms for other continents. EGFR submutations examined were exon 19 deletions, exon 21 L858R substitutions, and others. Results Of 3969 abstracts screened, 57 studies were included in the overall EGFR mutation analysis and 74 were included in the submutation analysis relative to the overall EGFR mutation population (Europe, n  = 12; Asia, n = 51; North America, n = 5; Central America, n = 1; South America, n = 1; Oceania, n = 1; Global, n = 3). The final overall EGFR mutations model estimated Asian and European prevalence of 49.1% and 12.8%, respectively, and included an additive covariate for the proportion of male patients in a study. There were no significant covariates in the submutation analyses. Most submutations were actionable: exon 19 deletions (49.2% [Asia]; 48.4% [Europe]); exon 21 L858R substitutions (41.1% [Asia]; 29.9% [Europe]). Conclusions Although EGFR mutation prevalence was higher in Asian than Western countries, data support worldwide testing for EGFR overall and submutations to inform appropriate targeted treatment decisions.

There is the urgent need to study the effects of immunomodulating agents as therapy for Covid-19. An observational, cohort, prospective study with 30 days of observation was carried out to assess clinical outcomes in 88 patients hospitalized for Covid-19 pneumonia and treated with canakinumab (300 mg sc). Median time from diagnosis of Covid-19 by viral swab to administration of canakinumab was 7.5 days (range 0–30, IQR 4–11). Median PaO 2 /FiO 2 increased from 160 (range 53–409, IQR 122–210) at baseline to 237 (range 72–533, IQR 158–331) at day 7 after treatment with canakinumab ( p  < 0.0001). Improvement of oxygen support category was observed in 61.4% of cases. Median duration of hospitalization following administration of canakinumab was 6 days (range 0–30, IQR 4–11). At 7 days, 58% of patients had been discharged and 12 (13.6%) had died. Significant differences between baseline and 7 days were observed for absolute lymphocyte counts (mean 0.60 vs 1.11 × 10 9 /L, respectively, p  < 0.0001) and C-reactive protein (mean 31.5 vs 5.8 mg/L, respectively, p  < 0.0001).Overall survival at 1 month was 79.5% (95% CI 68.7–90.3). Oxygen-support requirements improved and overall mortality was 13.6%. Confirmation of the efficacy of canakinumab for Covid-19 warrants further study in randomized controlled trials.

First-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) is usually limited to four to six cycles. Maintenance therapy can delay progression and prolong survival. The oral epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor erlotinib has proven efficacy and tolerability in second-line NSCLC. We designed the phase 3, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study to assess use of erlotinib as maintenance therapy in patients with non-progressive disease following first-line platinum-doublet chemotherapy. Between December, 2005, and May, 2008, 1949 patients were included in the run-in phase (four cycles of platinum-based chemotherapy). At the end of the run-in phase, 889 patients who did not have progressive disease were entered into the main study, and were randomly allocated using a 1:1 adaptive randomisation method through a third-party interactive voice response system to receive erlotinib (150 mg/day; n=438) or placebo (n=451) until progression or unacceptable toxicity. Patients were stratified by EGFR immunohistochemistry status, stage, Eastern Cooperative Oncology Group performance status, chemotherapy regimen, smoking history, and region. Co-primary endpoints were progression-free survival (PFS) in all analysable patients irrespective of EGFR status, and PFS in patients whose tumours had EGFR protein overexpression, as determined by immunohistochemistry. This study is registered with www.ClinicalTrials.gov, number NCT00556712. 884 patients were analysable for PFS; 437 in the erlotinib group and 447 in the placebo group. After a median follow-up of 11·4 months for the erlotinib group and 11·5 months for the placebo group, median PFS was significantly longer with erlotinib than with placebo: 12·3 weeks for patients in the erlotinib group versus 11·1 weeks for those in the placebo group (HR 0·71, 95% CI 0·62–0·82; p<0·0001). PFS was also significantly longer in patients with EGFR-positive immunohistochemistry who were treated with erlotinib (n=307) compared with EGFR-positive patients given placebo (n=311; median PFS 12·3 weeks in the erlotinib group vs 11·1 weeks in the placebo group; HR 0·69, 0·58–0·82; p<0·0001). The most common grade 3 or higher adverse events were rash (37 [9%] of 443 patients in the erlotinib group vs none of 445 in the placebo group) and diarrhoea (seven [2%] of 443 patients vs none of 445). Serious adverse events were reported in 47 patients (11%) on erlotinib compared with 34 patients (8%) on placebo. The most common serious adverse event was pneumonia (seven cases [2%] with erlotinib and four [<1%] with placebo). Maintenance therapy with erlotinib for patients with NSCLC is well tolerated and significantly prolongs PFS compared with placebo. First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy. F Hoffmann-La Roche Ltd.

BackgroundThe efficacy of atezolizumab (A) and/or bevacizumab (B) with carboplatin/paclitaxel (CP) chemotherapy was explored in the phase III, randomized IMpower150 study in patients with non-squamous non-small cell lung cancer (NSCLC) according to KRAS mutations (mKRAS) and co-occurring STK11, KEAP1, or TP53 mutations.MethodsMutation status was determined by circulating tumor DNA next-generation sequencing. Overall survival (OS) and progression-free survival (PFS) were analyzed in a mutation-evaluable intention-to-treat population (MEP; n=920) and SP263 (programmed cell death ligand 1 (PD-L1)) biomarker-evaluable population (n=774).ResultsWithin the mKRAS population (24.5% of MEP), ABCP showed numerical improvements vs BCP in median OS (19.8 vs 9.9 months; HR 0.50; 95% CI 0.34 to 0.72) and PFS (8.1 vs 5.8 months; HR 0.42; 95% CI 0.29 to 0.61)—greater than with ACP (OS: 11.7 vs 9.9 months; HR 0.63; 95% CI 0.43 to 0.91; PFS: 4.8 vs 5.8 months; HR 0.80; 95% CI 0.56 to 1.13) vs BCP. Across PD-L1 subgroups in mKRAS patients, OS and PFS were longer with ABCP vs BCP, but OS with ACP was similar to BCP in PD-L1-low and PD-L1-negative subgroups. Conversely, in KRAS-WT patients, OS was longer with ACP than with ABCP or BCP across PD-L1 subgroups. KRAS was frequently comutated with STK11, KEAP1, and TP53; these subgroups conferred different prognostic outcomes. Within the mKRAS population, STK11 and/or KEAP1 mutations were associated with inferior OS and PFS across treatments compared with STK11-WT and/or KEAP1-WT. In mKRAS patients with co-occurring mSTK11 and/or mKEAP1 (44.9%) or mTP53 (49.3%), survival was longer with ABCP than with ACP or BCP.ConclusionsThese analyses support previous findings of mutation of STK11 and/or KEAP1 as poor prognostic indicators. While clinical efficacy favored ABCP and ACP vs BCP in these mutational subgroups, survival benefits were greater in the mKRAS and KEAP1-WT and STK11-WT population vs mKRAS and mKEAP1 and mSTK11 population, suggesting both prognostic and predictive effects. Overall, these results suggest that atezolizumab combined with bevacizumab and chemotherapy is an efficacious first-line treatment in metastatic NSCLC subgroups with mKRAS and co-occurring STK11 and/or KEAP1 or TP53 mutations and/or high PD-L1 expression.

Inspired by the limited battery life of multi-rotor unmanned aerial vehicles (UAVs), this research investigated hierarchical real-time control of UAVs with the generation of energy-optimal reference trajectories. The goal was to design a reference generator and controller based on optimal-control theory that would guarantee energy consumption close to optimal with lower computational cost. First, a least-squares-estimation-(LSE) algorithm identified the parameters of the UAV mathematical model. Then, by considering a precise electrical model for the brushless DC motors and rest-to-rest maneuvers, the extraction of clear rules to compute the optimal mission time and generate ’energetic trajectories’ was performed. These rules emerged from analyzing the optimal-control strategy results that minimized the consumption over many simulations. Afterward, a hierarchical controller tracked those desired energetic trajectories identified as sub-optimal. Numerical experiments compared the results regarding trajectory tracking, energy performance index, and battery state of charge (SOC). A co-simulation framework consisting of commercial software tools, Simcenter Amesim for the physical modeling of the UAV, and Matlab-Simulink executed numerical simulations of the implemented controller.

BackgroundBone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy.MethodsPretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM.ResultsCohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p <  0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p <  0.0001; Cohort B: 2.7 versus 5.2 months, p <  0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p <  0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78).ConclusionsBoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy.

Objectives Subsolid nodules emerged as frequent radiological variants of lung adenocarcinoma. Radiological features including solid-component prevalence and larger tumour dimensions prompt tumoral invasiveness guiding prognosis and management. Thus, we aimed to clarify the molecular grounds that dictate these radiological appearances and clinical behaviour in a real-life European-cohort. Additionally, following the growing interest toward targeted-therapies in early-stage diseases, we aimed to present real-life epidemiological data of actionable mutations in these patients. Methods In this retrospective single-centre study, targeted next-generation sequencing was performed continuatively in all the resected subsolid lung adenocarcinomas in the period between May 2016 and December 2023. Clinico-radiological data were collected. The genetic landscape of our real-life European subsolid adenocarcinoma population is defined. Common and actionable mutations (frequency > 5%) relation to key clinico-radiological features are evaluated. Results Overall, 156 subsolid adenocarcinomas were analysed. KRAS -mutations, mostly KRAS p.G12C , were the most prevalent followed by EGFR , including 25% uncommon EGFR -mutations, TP53 and MET mutations. Amongst the clinico-radiological variables, KRAS -mutations and KRAS p.G12C -mutation were associated to smoking history (≥ 20 pack/years), aggressive histologic subtype and higher consolidation-to-tumor ratio (CTR). Moreover, KRAS -mutated nodules had faster tumour-doubling-time. Conversely, EGFR -mutations were associated to female sex and lower CTR. The latter not being confirmed in common EGFR -mutations. Additionally, in common EGFR -mutated nodules, aggressive histological components were rarer. Conclusion Our study presents the molecular profile of subsolid lung adenocarcinoma in a real-life European-cohort. KRAS -mutations were the most prevalent, and were related to smoking history, higher CTR and faster growth. Conversely, common EGFR -mutations were rarer than expected and unrelated to smoking history and radiological features.

Background Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood. Methods A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and Kaplan–Meier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirus–meditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression. Results The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumor–node–metastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration. Conclusions Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy.