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IMPORTANCE Arginine deprivation using ADI-PEG20 (pegargiminase) combined with chemotherapy is untested in a randomized study among patients with cancer. ATOMIC-Meso (ADI-PEG20 Targeting of Malignancies Induces Cytotoxicity-Mesothelioma) is a pivotal trial comparing standard first-line chemotherapy plus pegargiminase or placebo in patients with nonepithelioid pleural mesothelioma. OBJECTIVE To determine the effect of pegargiminase-based chemotherapy on survival in nonepithelioid pleural mesothelioma, an arginine-auxotrophic tumor. DESIGN, SETTING, AND PARTICIPANTS Thiswas a phase 2-3, double-blind randomized clinical trial conducted at 43 centers in 5 countries that included patients with chemotherapy-naive nonepithelioid pleural mesothelioma from August 1, 2017, to August 15, 2021, with at least 12 months' follow-up. Final follow-up was on August 15, 2022. Data analysis was performed from March 2018 to June 2023. INTERVENTION Patients were randomly assigned (1:1) to receive weekly intramuscular pegargiminase (36.8mg/m2) or placebo. All patients received intravenous pemetrexed (500mg/m2) and platinum (75-mg/m2 cisplatin or carboplatin area under the curve 5) chemotherapy every 3 weeks up to 6 cycles. Pegargiminase or placebo was continued until progression, toxicity, or 24 months. MAIN OUTCOMES AND MEASURES The primary end pointwas overall survival, and secondary end points were progression-free survival and safety. Response rate by blinded independent central review was assessed in the phase 2 portion only. RESULTS Among 249 randomized patients (mean [SD] age, 69.5 [7.9] years; 43 female individuals [17.3%] and 206 male individuals [82.7%]), all were included in the analysis. The median overall survival was 9.3 months (95%CI, 7.9-11.8 months) with pegargiminase-chemotherapy as compared with 7.7 months (95%CI, 6.1-9.5 months) with placebo-chemotherapy (hazard ratio [HR] for death, 0.71; 95%CI, 0.55-0.93; P = .02). The median progression-free survival was 6.2 months (

Background MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation.Materials and Methods Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received <= 3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction.Results At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or <= 3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response.Conclusions Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice.Clinical Trial Registration Eudract No. 2019-001146-17, NCT04028050.This analysis is based on interim data from the MAURIS study, an Italian multicenter, phase IIIb ongoing trial to evaluate treatment with atezolizumab plus carboplatin/etoposide in patients with newly diagnosed extensive-stage small-cell lung cancer.

Background: Hypofractionated proton beam radiotherapy (PBT) is gaining attention in early-stage non-small cell lung cancer (ES-NSCLC). However, there is a large unmet need to define indications, prescription doses and potential adverse events of protons in this clinical scenario. Hence, the present work aims to provide a critical literature revision, and to investigate associations between fractionation schedules/ biological effective doses (BEDs), oncological outcomes and toxicities.Materials and methods: This systematic review and meta-analysis complied with the PRISMA recommendations. Inclusion criteria were: 1) curative-intent hypofractionated PBT for ES-NSCLC (>= 3 Gy(RBE)/fraction), 2) report of the clinical outcomes of interest, 3) availability of full-text written in English. The bibliographic search was performed on the NCBI Pubmed, Embase and Scopus in September 2021; no other limitations were applied. The BED was calculated for each included study (alpha/beta = 10 Gy); the median BED for all studies was used as a threshold for stratifying selected evidence into "high" and "low"-dose subgroups. Heterogeneity was tested using chi-square statistics; inconsistency was measured with the I2 index. Pooled estimate was obtained by fitting both the fixed-effect and the DerSimonian and Laird random-effect model.Results: Eight studies and 401 patients were available for the meta-analysis; median follow-up was 32.8 months. The median delivered BED was 105.6 Gy(RBE). A BED >= 105.6 Gy(RBE) consistently provided superior OS, CSS, DFS and LC rates (i.e.: 4-year OS: 0.56 [0.34-0.76] for BED < 105.6 Gy(RBE) and 0.78 [0.64-0.88] for BED >= 105.6 Gy(RBE)). The meta-analysis of proportions showed a comparable probability of developing acute grade >= 2 toxicity between the two groups, while the probability of any late grade >= 2 event was almost three-times greater for BED >= 105.6 Gy(RBE), with rib fractures being more common in the high dose group.Concl

Background: Alectinib, a highly selective next generation ALK-inhibitor, has exhibited potent anti-tumour activity in RET-rearranged NSCLC in the preclinical stage. Methods: ALERT-lung is a single-arm, phase II trial evaluating the activity of alectinib for the treatment of pretreated RET-rearranged advanced NSCLC. Alectinib was administered orally, 600 mg, twice per day until progression, refusal or unacceptable toxicity (treatment could continue beyond progression, if patient was deriving clinical benefit). Patient recruitment closed prematurely due to discouraging results for alectinib in a phase I/II study in the same indication. Results: All 14 patients who enrolled until the premature accrual closure, received at lease one dose of alectinib. Among them, median age was 61 years, majority (71 %) was female, never smokers, of ECOG PS 1. No objective response (complete or partial response) was recorded. Of the 13 evaluable patients, three (23 %) achieved and maintained disease stabilisation for 24 weeks. Up to 31 March 2021 (median follow-up 15.9 months), 12 PFS-events (92 %) were observed, with median PFS of 3.7 months (95 % C.I.: 1.8 - 7.3 months). Overall, three deaths (23 %) were reported. Seven patients (50 %) experienced grade = 3 adverse events, while three discontinued treatment due to erythema multiforme of grade 3, related to alectinib. No treatment-related serious adverse event was reported. Conclusions: Accrual into our trial was terminated early in response to other reports of limited activity of alectinib in patients with RET-fusion NSCLC and the emergence of more potent selective RET-inhibitors. Also in our trial, alectinib did not show the expected potential for anti-tumour activity in NSCLC.

Lesion segmentation is a crucial step of the radiomic workflow. Manual segmentation requires long execution time and is prone to variability, impairing the realisation of radiomic studies and their robustness. In this study, a deep-learning automatic segmentation method was applied on computed tomography images of non-small-cell lung cancer patients. The use of manual vs automatic segmentation in the performance of survival radiomic models was assessed, as well. METHODS A total of 899 NSCLC patients were included (2 proprietary: A and B, 1 public datasets: C). Automatic segmentation of lung lesions was performed by training a previously developed architecture, the nnU-Net, including 2D, 3D and cascade approaches. The quality of automatic segmentation was evaluated with DICE coefficient, considering manual contours as reference. The impact of automatic segmentation on the performance of a radiomic model for patient survival was explored by extracting radiomic hand-crafted and deep-learning features from manual and automatic contours of dataset A, and feeding different machine learning algorithms to classify survival above/below median. Models' accuracies were assessed and compared. RESULTS The best agreement between automatic and manual contours with DICE=0.78 +(0.12) was achieved by averaging predictions from 2D and 3D models, and applying a post-processing technique to extract the maximum connected component. No statistical differences were observed in the performances of survival models when using manual or automatic contours, hand-crafted, or deep features. The best classifier showed an accuracy between 0.65 and 0.78. CONCLUSION The promising role of nnU-Net for automatic segmentation of lung lesions was confirmed, dramatically reducing the time-consuming physicians' workload without impairing the accuracy of survival predictive models based on radiomics.

Alectinib, a highly selective next generation ALK-inhibitor, has exhibited potent anti-tumour activity in RET-rearranged NSCLC in the preclinical stage., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND No evidence supports the choice of specific imaging filtering methodologies in radiomics. As the volume of the primary tumor is a well-recognized prognosticator, our purpose is to assess how filtering may impact the feature/volume dependency in computed tomography (CT) images of non-small cell lung cancer (NSCLC), and if such impact translates into differences in the performance of survival modeling. The role of lesion volume in model performances was also considered and discussed. METHODS Four-hundred seventeen CT images NSCLC patients were retrieved from the NSCLC-Radiomics public repository. Pre-processing and features extraction were implemented using Pyradiomics v3.0.1. Features showing high correlation with volume across original and filtered images were excluded. Cox proportional hazards (PH) with least absolute shrinkage and selection operator (LASSO) regularization and CatBoost models were built with and without volume, and their concordance (C-) indices were compared using Wilcoxon signed-ranked test. The Mann Whitney U test was used to assess model performances after stratification into two groups based on low- and high-volume lesions. RESULTS Radiomic models significantly outperformed models built on only clinical variables and volume. However, the exclusion/inclusion of volume did not generally alter the performances of radiomic models. Overall, performances were not substantially affected by the choice of either imaging filter (overall C-index 0.539-0.590 for Cox PH and 0.589-0.612 for CatBoost). The separation of patients with high-volume lesions resulted in significantly better performances in 2/10 and 7/10 cases for Cox PH and CatBoost models, respectively. Both low- and high-volume models performed significantly better with the inclusion of radiomic features (P<0.0001), but the improvement was largest in the high-volume group (+10.2% against +8.7% improvement for CatBoost models and +10.0% against +5.4% in Cox PH models). CONCLUSIONS Rad

Background: The potential value of patient preference studies has been recognized in clinical individual treatment decision-making between clinicians and patients, as well as in upstream drug decision-making. Drug developers, regulators, reimbursement and Health Technology Assessment (HTA) bodies are exploring how the use of patient preference studies could inform drug development, regulatory benefit risk-assessment and reimbursement decisions respectively. Understanding patient preferences may be especially valuable in decisions regarding Non-Small Cell Lung Cancer (NSCLC) treatment options, where a variety of treatment options with different characteristics raise uncertainty about which features are most important to NSCLC patients. As part of the Innovative Medicines Initiative PREFER project, this qualitative study aimed to identify patient-relevant lung cancer treatment characteristics. Methods: This study consisted of a scoping literature review and four focus group discussions, 2 in Italy and 2 in Belgium, with a total of 24 NSCLC patients (Stages III-IV). The focus group discussions sought to identify which treatment characteristics patients find most relevant. The discussions were analyzed thematically using a thematic inductive analysis. Results: Patients highlighted themes reflecting: 1) positive effects or expected gains from treatment such as greater life expectancy and maintenance of daily functioning, 2) negative effects or adverse events related to therapy that negatively impact patients’ daily functioning such as fatigue and 3) uncertainty regarding the duration and type of treatment effects. These overarching themes were consistent among patients from Belgium and Italy, suggesting that treatment aspects related to efficacy and safety as well as the psychological impact of lung cancer treatment are common areas of concern for patients, regardless of cultural background or country. Discussion: Our findings illustrate the value of using qualitative me, IMI-PREFER

Purpose: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC. Experimental Design: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti–PD-1/anti–PD-L1 drugs. Results: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell–excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti–PD-1/PD-L1 drugs. Conclusions: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.

The COVID-19 pandemic, characterised by a fast and global spread during the first months of 2020, has prompted the development of a structured set of recommendations for cancer care management, to maintain the highest possible standards. Within this framework, it is crucial to ensure no disruption to essential oncological services and guarantee the optimal care.This is a structured proposal for the management of lung cancer, comprising three levels of priorities, namely: tier 1 (high priority), tier 2 (medium priority) and tier 3 (low priority)-defined according to the criteria of the Cancer Care Ontario, Huntsman Cancer Institute and Magnitude of Clinical Benefit Scale.The manuscript emphasises the impact of the COVID-19 pandemic on lung cancer care and reconsiders all steps from diagnosis, staging and treatment.These recommendations should, therefore, serve as guidance for prioritising the different aspects of cancer care to mitigate the possible negative impact of the COVID-19 pandemic on the management of our patients.As the situation is rapidly evolving, practical actions are required to guarantee the best patients' treatment while protecting and respecting their rights, safety and well-being. In this environment, cancer practitioners have great responsibilities: provide timely, appropriate, compassionate and justified cancer care, while protecting themselves and their patients from being infected with COVID-19. In case of shortages, resources must be distributed fairly. Consequently, the following recommendations can be applied with significant nuances, depending on the time and location for their use, considering variable constraints imposed to the health systems. An exceptional flexibility is required from cancer caregivers.

BACKGROUND Among patients with non-small-cell lung cancer (NSCLC),METexon 14 skipping mutations occur in 3 to 4% andMETamplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients withMET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy andMETstatus (METexon 14 skipping mutation orMETamplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with aMETexon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients withMETamplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients withMETamplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS Capmatinib showed substantial antitu

BACKGROUND Among patients with non-small-cell lung cancer (NSCLC),METexon 14 skipping mutations occur in 3 to 4% andMETamplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation. METHODS We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients withMET-dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy andMETstatus (METexon 14 skipping mutation orMETamplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments. RESULTS A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with aMETexon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients withMETamplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients withMETamplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. CONCLUSIONS Capmatinib showed substantial antitu

Background: Brain metastases (BM) are common in patients with small cell lung cancer (SCLC). In recent years, the role of whole brain radiotherapy (WBRT) for brain metastases in lung cancer is being reevaluated, especially in the context of new systemic treatments available for SCLC. With this analysis, we investigate decision-making in SCLC patients with BM among European experts in medical oncology and radiation oncology. Methods: We analyzed decision-making from 13 medical oncologists (selected by IASLC) and 13 radiation oncologists (selected by ESTRO) specialized in SCLC. Management strategies of individual experts were converted into decision trees and analyzed for consensus. Results and conclusion: In asymptomatic patients, chemotherapy alone is the most commonly recommended first line treatment. In asymptomatic patients with limited volume of brain metastases, a higher preference for chemotherapy without WBRT among medical oncologists compared to radiation oncologists was observed. For symptomatic patients, WBRT followed by chemotherapy was recommended most commonly. For limited extent of BM in symptomatic patients, some experts chose stereotactic radiotherapy as an alternative to WBRT. Significant variation in clinical decision-making was observed among European SCLC experts for the first line treatment of patients with SCLC and BM., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are established therapies for previously untreated advanced/metastatic non-small cell lung cancer (NSCLC) EGFR-mutated patients. Osimertinib, a third-generation TKI, has recently received the same first-line indication. This study aims at investigating management costs and potential productivity losses in Italy in this patient setting, given all the available therapeutic options. Two analyses were performed. The first evaluates first-line yearly management costs and potential productivity losses per patient, for each first-line treatment. The second, performed nationally and regionally, models all lines of treatments and costs over a five-year period, through different market-share scenarios – considering osimertinib adoption as new therapy in 60% of patients as the most probable one – and line-switch/mortality probabilities. Using this model, patients’ total months of treatment and development/progression of brain metastases were also analyzed. The first analysis shows that first-line management costs and potential productivity losses are minimized by osimertinib (first-line yearly expenditure of €25.942, 8%-12% less than TKIs). The second analysis, based on a five-year horizon and on all therapy lines, shows that total management costs and potential productivity losses decrease by increasing the adoption of osimertinib as a first-line therapy (€7.4m cumulative lower cost with osimertinib at 60% compared to 0%). Considering the average month of therapy, where results are not affected by the length of the therapy, with osimertinib at 60% on naïve patients, monthly management costs and productivity losses are 10% lower than in the non-osimertinib scenario. In advanced, metastatic EGFR-mutated NSCLC, the use of osimertinib as the first-line treatment could reduce patient management costs and potential productivity losses.

We previously showed that therapy with anti-checkpoints T-lymphocyte-associated protein 4 (anti-CTLA-4) or antiprogrammed cell death protein 1 (anti-PD-1) agents was more effective for men as compared with women. However, because the sex-dimorphism of the immune system is complex, involving multiple elements of immune responses, it is possible that women could derive larger benefit than men from strategies other than therapy with immune checkpoint inhibitors (ICIs) alone. Here we investigated whether women could derive larger benefit than men from the combination of chemotherapy and anti-PD-1 or anti-PD-L1. Methods: We performed two meta-analyses. The first included all randomized controlled trials (RCTs) testing anti-PD1 and anti-PD-L1 plus chemotherapy vs chemotherapy to assess different efficacy between men and women. The second included all RCTs of first-line systemic treatment in advanced non-small cell lung cancer testing anti-PD-1/PD-L1 given either alone or combined with chemotherapy to assess the different efficacy of these two immunotherapeutic strategies according to patients' sex. For each RCT included in the two meta-analyses, first, a trial-specific ratio of hazard ratios (HRs) was calculated from the ratio of the reported hazard ratios in men and in women; second, these trial-specific ratios of hazard ratios were combined across trials using a random-effects model to obtain a pooled hazard ratios ratio. A pooled HRs ratio estimate lower than 1 indicates a greater treatment effect in men, and higher than 1 a greater effect in women. Results: Eight RCTs were included in the first meta-analysis. The pooled overall survival hazard ratios (OS-HRs) comparing anti-PD-1/PD-L1 plus chemotherapy vs chemotherapy was 0.76 (95% confidence interval [CI] = 0.66 to 0.87) for men and 0.48 (95% CI = 0.35 to 0.67) for women. The pooled ratio of the overall survival hazard ratios reported in men vs women was 1.56 (95% CI = 1.21 to 2.01), indicating a statistically signif

Background: The role of consolidative thoracic radiotherapy (TRT) in stage IV small cell lung cancer (SCLC) is not uniformly accepted. Methods: We obtained a list of 13 European medical oncologists from the International Association for the Study of Lung Cancer (IASLC) and 13 European radiation oncologists from the European Society for Therapeutic Radiation Oncology (ESTRO). The strategies in decision making for TRT in stage IV SCLC were collected. Decision trees were created representing these strategies. Frequencies of recommending TRT were analysed for various parameter combinations based on the objective consensus methodology. Results: The factors associated with the recommendation for TRT included fitness of the patient, limited extrathoracic tumour burden, initial bulky thoracic disease and response to chemotherapy. The highest consensus for TRT was in fit patients with limited extrathoracic tumour burden and initial bulky disease with either a complete extrathoracic response or partial thoracic response (92% recommend TRT). For these patients the recommendations were the same for medical and radiation oncologists. In the setting of partial response (intra- and extra-thoracically) without initial bulky thoracic disease radiation oncologists were more likely to recommend TRT than medical oncologists. For unfit patients or for patients with poor overall response to chemotherapy, the majority did not recommend TRT. Conclusion: European radiation and medical oncologists specializing in lung cancer recommend TRT in selected patients with stage IV SCLC and restrict its use primarily to fit patients who responded to chemotherapy with limited extrathoracic tumour burden., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

Background: Due to conflicting results between major trials the role of prophylactic cranial irradiation (PCI) in stage IV small cell lung cancer (SCLC) is controversial. Methods: We obtained a list of 13 European experts from both the European Society for Therapeutic Radiation Oncology (ESTRO) and the International Association for the Study of Lung Cancer (IASLC). The strategies in decision making for PCI in stage IV SCLC were collected. Decision trees were created representing these strategies. Analysis of consensus was performed with the objective consensus methodology. Results: The factors associated with the recommendation for the use of PCI included the fitness of the patient, young age and good response to chemotherapy. PCI was recommended by the majority of experts for non-elderly fit patients who had at least a partial response (PR) to chemotherapy (for complete remission (CR) 85% of radiation oncologists and 69% of medical oncologists, for PR: 85% of radiation oncologists and 54% of medical oncologists). For patients with stable disease after chemotherapy, PCI was recommended by 6 out of 13 (46%) radiation oncologists and only 3 out of 13 medical oncologists (23%). For elderly fit patients with CR, a majority recommended PCI (62%) and no consensus was reached for patients with PR. Conclusion: European radiation and medical oncologists specializing in lung cancer recommend PCI in selected patients and restrict its use primarily to fit, non-elderly patients who responded to chemotherapy., SCOPUS: ar.j, DecretOANoAutActif, info:eu-repo/semantics/published

The publisher regrets that in the abovementioned article, an author name was listed incorrectly. The correct author listing is presented above. The publisher would like to apologise for any inconvenience caused., SCOPUS: er.j, DecretOANoAutActif, info:eu-repo/semantics/published

Shirish Gadgeel,1 Alice T Shaw,2 Fabrice Barlesi,3 Lucio Crino,4 James CH Yang,5 Anne-Marie Dingemans,6 Dong-Wan Kim,7 Filippo de Marinis,8 Mathias Schulz,8 Shiyao Liu,9 Ravindra Gupta,9 Vlatka Smoljanovic,10 Sai-Hong Ignatius Ou11 1Department of Internal Medicine, Division of Hematology and Oncology, The University of Michigan, Ann Arbor, MI 48109, USA; 2Center for Thoracic Cancers, Massachusetts General Hospital, Boston, MA, USA; 3Multidisciplinary Oncology and Therapeutic Innovations Department, Aix-Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille 13005, France; 4Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) Srl I.R.C.C.S., Meldola, FC 47014, Italy; 5National Taiwan University Hospital and National Taiwan University Cancer Centre, Taipei City, Taiwan; 6Department of Pulmonology, Maastricht University Medical Centre, Maastricht 6229 HX, The Netherlands; 7Department of Internal Medicine, Seoul National University Hospital, Jongno-Gu, Seoul 03080, South Korea; 8Division of Thoracic Oncology, European Institute of Oncology IRCCS, Milan 20146, Italy; 9Genentech Inc., South San Francisco, CA, USA; 10F. Hoffmann-La Roche Ltd., Basel CH-4070, Switzerland; 11Division of Hematology-Medical Oncology, Department of Internal Medicine, University of California, Irvine School of Medicine, Orange, CA 92617, USACorrespondence: Sai-Hong Ignatius OuUniversity of California, Irvine School of Medicine, 1001 Health Sciences Road, Irvine, Orange, CA 92617, USATel +1 714 456 8104Email siou@uci.eduIntroduction: Alectinib is a highly selective and potent ALK inhibitor, approved for the treatment of patients with metastatic ALK+ NSCLC based on results from the Phase II global NP28673 (NCT01801111) and North American NP28761 (NCT01871805) studies.Methods: This exploratory analysis of two Phase II studies of alectinib (NP28673/NP28761) investigated time to systemic response (TTR) and time to centra

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are established therapies for previously untreated advanced/metastatic non-small cell lung cancer (NSCLC) EGFR-mutated patients. Osimertinib, a third-generation TKI, has recently received the same first-line indication. This study aims at investigating management costs and potential productivity losses in Italy in this patient setting, given all the available therapeutic options. Two analyses were performed. The first evaluates first-line yearly management costs and potential productivity losses per patient, for each first-line treatment. The second, performed nationally and regionally, models all lines of treatments and costs over a five-year period, through different market-share scenarios – considering osimertinib adoption as new therapy in 60% of patients as the most probable one – and line-switch/mortality probabilities. Using this model, patients’ total months of treatment and development/progression of brain metastases were also analyzed. The first analysis shows that first-line management costs and potential productivity losses are minimized by osimertinib (first-line yearly expenditure of €25.942, 8%-12% less than TKIs). The second analysis, based on a five-year horizon and on all therapy lines, shows that total management costs and potential productivity losses decrease by increasing the adoption of osimertinib as a first-line therapy (€7.4m cumulative lower cost with osimertinib at 60% compared to 0%). Considering the average month of therapy, where results are not affected by the length of the therapy, with osimertinib at 60% on naïve patients, monthly management costs and productivity losses are 10% lower than in the non-osimertinib scenario. In advanced, metastatic EGFR-mutated NSCLC, the use of osimertinib as the first-line treatment could reduce patient management costs and potential productivity losses.

OBJECTIVES: To assess the effect of long-term pemetrexed maintenance therapy on patients' renal function. METHODS: In the PARAMOUNT phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays and treatment discontinuations associated with impaired renal function. RESULTS: Creatinine clearance ≥45 mL/min was required before the start of any cycle. Patients on pemetrexed maintenance had a significantly higher percentage maximum increase in sCr over baseline versus placebo for the range of ≥10% to ≥90% increase (p < .05). The risk of experiencing renal events leading to dose delays and discontinuations was higher with higher increases in sCr but reversible in most patients. sCr increases of ≥30% and ≥40% were associated with gender (female), age (<70 years) and longer exposure to pemetrexed compared with placebo. Sixteen (4%) pemetrexed patients and 1 (1%) placebo patient discontinued treatment due to drug-related renal events; 13/16 (81%) of those pemetrexed patients had sCr increases ≥30% and 7/13 (54%) had pre-existing conditions and/or were receiving nephrotoxic drugs. CONCLUSIONS: The appearance of renal events leading to dose delays and/or treatment discontinuations was associated with sCr increase of at least 30%. However, it was difficult to identify patients at a higher risk of treatment discontinuation due to a drug-related renal event based only on changes in pre-maintenance laboratory values.

BackgroundAtezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer.MethodsWe did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m2 every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227.FindingsBetween March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT popul

Angiogenesis, one of the hallmarks of cancer, occurs when new blood vessels feed malignant cells, providing oxygen and nutrients, promoting tumor growth, and allowing tumor cells to escape into the circulation, thus leading to metastases. To date, a series of antiangiogenic drugs (either monoclonal antibodies or small molecules) have been approved by regulatory agencies for the treatment of advanced non-small cell lung cancer, and they are currently available for both first- and second-line therapy. The overall benefit of these drugs seems modest (although clearly significant), especially when administered as a single agent, and there is no clear consensus with regard to which patients should be candidates to receive these drugs across the different disease settings. From the biological perspective, angiogenesis represents a difficult and complex process to explore, given the interference with other key pathways and the dynamic evolution during the disease's history. Indeed, this process is complicated by the presence of multiple targets to hit, polymorphisms, hypoxiadependent modifications, and epigenetics. These difficulties do not allow capture of which specific key pathways can be identified as biomarkers of efficacy so as to maximize to overall benefit of such drugs. An International Experts Panel Meeting was inspired by the absence of clear recommendations to address which patients should receive antiangiogenic drugs in the context of advanced non-small cell lung cancer so as to support decisions for clinical practice on a daily basis and determine priorities for future research. After a literature review and panelists consensus, a series of recommendations were defined to support decisions for the daily clinical practice and to indicate a potential road map for translational research.

Antonio Passaro,1 Chiara Lazzari,1,2 Niki Karachaliou,3 Gianluca Spitaleri,1 Alessia Pochesci,1 Chiara Catania,1 Rafael Rosell,4 Filippo de Marinis1 1Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy; 2Department of Medical Oncology, Division of Experimental Medicine, San Raffaele Scientific Institute, Milan, Italy; 3Oncology Institute Dr Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain; 4Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain Abstract: The discovery of anaplastic lymphoma kinase (ALK) gene rearrangements and the development of tyrosine kinase inhibitors (TKI) that target them have achieved unprecedented success in the management of patients with ALK-positive non-small cell lung cancer (NSCLC). Despite the high efficacy of crizotinib, the first oral ALK TKI approved for the treatment of ALK-positive NSCLC, almost all patients inevitably develop acquired resistance, showing disease progression in the brain or in other parenchymal sites. Second- or third-generation ALK TKIs have shown to be active in crizotinib-pretreated or crizotinib-naïve ALK-positive patients, even in those with brain metastases. In this review, the current knowledge regarding ALK-positive NSCLC, focusing on the biology of the disease and the available therapeutic options are discussed. Keywords: ALK, NSCLC, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, brain metastases

In recent years, the treatment landscape in advanced non-squamous non-small-cell lung cancer (nsNSCLC) has changed. New therapies (e.g., bevacizumab indicated in first line) have become available and other therapies (e.g., pemetrexed in first line and second line) moved into earlier lines in the treatment paradigm. While there has been an expansion of the available treatment options, it is still a key research question which therapy sequence results in the best survival outcomes for patients with nsNSCLC.

Gianluca Spitaleri,1 Roberto Biffi,2 Massimo Barberis,3 Caterina Fumagalli,3 Francesca Toffalorio,1 Chiara Catania,1 Cristina Noberasco,1 Chiara Lazzari,1 Filippo de Marinis,1 Tommaso De Pas41Division of Chest Medical Oncology, 2Division of Abdominal Surgery, 3Division of Pathology, 4Oncology Unit of Thymic cancer, Rare Tumors and Sarcomas, European Institute of Oncology, Milan, ItalyAbstract: The development of gastrointestinal stromal tumors (GISTs) is largely driven by mutations in the KIT and PDGFRα genes. Imatinib mesylate is an oral small molecular tyrosine kinase inhibitor that mainly targets abl, c-KIT, and PDGFRα. Imatinib achieves disease control in approximately 70%–85% of patients with advanced GIST, and the median progression-free survival is 20–24 months. The efficacy of imatinib correlates with tumor kinase mutational status (exon 11 mutations mainly), and some mutations are known to be responsible for primary and secondary imatinib resistance. Beyond these, there are many other mutations that are considered rare and are associated with unknown clinical behavior. In the literature, there are poor and inconsistent data about the inhibitor sensitivity of mutations occurring in the activation-loop domain encoded by exon 17. In this article, we focus on a case of a patient suffering from GIST, harboring an extremely rare KIT activation-loop domain mutation (exon 17 mutation pN822K) treated with imatinib. A review of the literature is also presented. Keywords: GIST, KIT activation-loop domain mutation, drug resistance, imatinib

Chiara Catania,1 Fabio Conforti,1 Gianluca Spitaleri,1 Massimo Barberis,2 Lorenzo Preda,3 Cristina Noberasco,1 Chiara Lazzari,1 Francesca Toffalorio,1 Filippo de Marinis,1 Michela Manzotti,2 Tommaso Martino De Pas11Division of Thoracic Oncology, 2Division of Pathology, 3Division of Radiology, European Institute of Oncology, Milan, ItalyAbstract: We report the case of a man with an advanced nonkeratinizing squamous cell thymic carcinoma harboring c-KIT exon 13 missense mutation K642E. This aberration is rare and has never been described previously in patients with thymic cancers. It has been found in a small number of cases of gastrointestinal stromal tumor and also in several cases of acral and mucosal melanomas. Some of the patients with gastrointestinal stromal tumor or melanoma harboring this rare mutation have had a tumor response when treated with imatinib. In contrast, in our case, the mutation was associated with primary resistance to full doses of imatinib but, at the same time, it was not a cause of resistance to sorafenib.Keywords: sorafenib, imatinib, thymic carcinoma

The FLEX study demonstrated that the addition of cetuximab to chemotherapy significantly improved overall survival in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). In the FLEX intention to treat (ITT) population, we investigated the prognostic significance of particular baseline characteristics. Individual patient data from the treatment arms of the ITT population of the FLEX study were combined. Univariable and multivariable Cox regression models were used to investigate variables with potential prognostic value. The ITT population comprised 1125 patients. In the univariable analysis, longer median survival times were apparent for females compared with males (12.7 vs 9.3 months); patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 compared with 1 compared with 2 (13.5 vs 10.6 vs 5.9 months); never smokers compared with former smokers compared with current smokers (14.6 vs 11.1 vs 9.0); Asians compared with Caucasians (19.5 vs 9.6 months); patients with adenocarcinoma compared with squamous cell carcinoma (12.4 vs 9.3 months) and those with metastases to one site compared with two sites compared with three or more sites (12.4 months vs 9.8 months vs 6.4 months). Age (<65 vs ≥65 years), tumor stage (IIIB with pleural effusion vs IV) and percentage of tumor cells expressing EGFR (<40% vs ≥40%) were not identified as possible prognostic factors in relation to survival time. In multivariable analysis, a stepwise selection procedure identified age (<65 vs ≥65 years), gender, ECOG PS, smoking status, region, tumor histology, and number of organs involved as independent factors of prognostic value. In summary, in patients with advanced NSCLC enrolled in the FLEX study, and consistent with previous analyses, particular patient and disease characteristics at baseline were shown to be independent factors of prognostic value. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. © 20

Background: Findings from the phase 3 First-Line ErbituX in lung cancer (FLEX) study showed that the addition of cetuximab to first-line chemotherapy significantly improved overall survival compared with chemotherapy alone (hazard ratio [HR] 0·871, 95% CI 0·762-0·996; p=0·044) in patients with advanced non-small-cell lung cancer (NSCLC). To define patients benefiting most from cetuximab, we studied the association of tumour EGFR expression level with clinical outcome in FLEX study patients. Methods: We used prospectively collected tumour EGFR expression data to generate an immunohistochemistry score for FLEX study patients on a continuous scale of 0-300. We used response data to select an outcome-based discriminatory threshold immunohistochemistry score for EGFR expression of 200. Treatment outcome was analysed in patients with low (immunohistochemistry score <200) and high (≥200) tumour EGFR expression. The primary endpoint in the FLEX study was overall survival. We analysed patients from the FLEX intention-to-treat (ITT) population. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Tumour EGFR immunohistochemistry data were available for 1121 of 1125 (99·6%) patients from the FLEX study ITT population. High EGFR expression was scored for 345 (31%) evaluable patients and low for 776 (69%) patients. For patients in the high EGFR expression group, overall survival was longer in the chemotherapy plus cetuximab group than in the chemotherapy alone group (median 12·0 months [95% CI 10·2-15·2] vs 9·6 months [7·6-10·6]; HR 0·73, 0·58-0·93; p=0·011), with no meaningful increase in side-effects. We recorded no corresponding survival benefit for patients in the low EGFR expression group (median 9·8 months [8·9-12·2] vs 10·3 months [9·2-11·5]; HR 0·99, 0·84-1·16; p=0·88). A treatment interaction test assessing the difference in the HRs for overall survival between the EGFR expression groups suggested a predictive value for EGFR expression (p=

Background: The randomised phase 3 First-Line Erbitux in Lung Cancer (FLEX) study showed that the addition of cetuximab to cisplatin and vinorelbine significantly improved overall survival compared with chemotherapy alone in the first-line treatment of advanced non-small-cell lung cancer (NSCLC). The main cetuximab-related side-effect was acne-like rash. Here, we assessed the association of this acne-like rash with clinical benefit. Methods: We did a subgroup analysis of patients in the FLEX study, which enrolled patients with advanced NSCLC whose tumours expressed epidermal growth factor receptor. Our landmark analysis assessed if the development of acne-like rash in the first 21 days of treatment (first-cycle rash) was associated with clinical outcome, on the basis of patients in the intention-to-treat population alive on day 21. The FLEX study is registered with ClinicalTrials.gov, number NCT00148798. Findings: 518 patients in the chemotherapy plus cetuximab group-290 of whom had first-cycle rash-and 540 patients in the chemotherapy alone group were alive on day 21. Patients in the chemotherapy plus cetuximab group with first-cycle rash had significantly prolonged overall survival compared with patients in the same treatment group without first-cycle rash (median 15·0 months [95% CI 12·8-16·4] vs 8·8 months [7·6-11·1]; hazard ratio [HR] 0·631 [0·515-0·774]; p<0·0001). Corresponding significant associations were also noted for progression-free survival (median 5·4 months [5·2-5·7] vs 4·3 months [4·1-5·3]; HR 0·741 [0·607-0·905]; p=0·0031) and response (rate 44·8% [39·0-50·8] vs 32·0% [26·0-38·5]; odds ratio 1·703 [1·186-2·448]; p=0·0039). Overall survival for patients without first-cycle rash was similar to that of patients that received chemotherapy alone (median 8·8 months [7·6-11·1] vs 10·3 months [9·6-11·3]; HR 1·085 [0·910-1·293]; p=0·36). The significant overall survival benefit for patients with first-cycle rash versus without was seen in all histology subg

Bruno Gori1, Serena Ricciardi1, Alberto Fulvi1, Salvatore Intagliata2, Ester Del Signore1, Filippo de Marinis11Oncological-Pulmonary Unit 1st, San Camillo Hospital, Rome, Italy; 2Department of Medical Oncology, University Campus Bio-Medico, Rome, ItalyAbstract: Lung cancer is the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the metastatic disease, the standard therapy is a platinum-based combination chemotherapy; however, in spite of available treatment options for patients who progress beyond first-line therapy, prognosis remains poor. Angiogenesis is a tightly regulated process which comprises a complex, complementary, and overlapping network. Inhibition of tumor-related angiogenesis has become an attractive target for anticancer therapy. Antiangiogenic strategy includes: monoclonal antibodies against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), small molecule inhibitors of VEGF tyrosine kinase activity, VEGF Trap, and a new class named “vascular disrupting agents,” tested in ongoing clinical trials which will further define their role in the management of NSCLC. BIBF 1120 is an investigational orally administered receptor tyrosine kinase inhibitor that has shown antiangiogenic and antineoplastic activity, inhibiting VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor tyrosine kinases, preventing tumor growth and interfering with the angiogenesis-signaling cascade and overcoming drug resistances.Keywords: NSCLC, angiogenesis, oral antiangiogenic agents, VEGF, PDGF, FGF

Serena Ricciardi1, Silverio Tomao2, Filippo de Marinis11Thoracic-Oncology Unit 1st, Lung Diseases Department, San Camillo-Forlanini High Specialization Hospitals, Rome, Italy; 2Sperimental Medicine Department, La Sapienza University, Rome, ItalyAbstract: Lung cancer is the leading cause of cancer deaths worldwide. Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing non-small-cell lung cancer (NSCLC) research, treatment, and patient outcome over the last few years. Erlotinib is a human epidermal growth factor receptor Type 1/EGFR tyrosine kinase inhibitor. Erlotinib monotherapy is indicated for the treatment of patients with locally advanced or metastatic NSCLC after the failure of at least one prior chemotherapy regimen. We present the results of phase I, II, III, and IV trials. Erlotinib monotherapy has shown a significant improvement in median survival, quality of life, and related symptoms in an unselected population of patients in second- and third-line therapy as a single agent. Most commonly reported erlotinib-related adverse effects were rash and diarrhea. In general, patients with adenocarcinoma histology, female gender, Asian ethnicity, and nonsmokers have a better response when treated with erlotinib. Ongoing trials seek to improve therapy with this agent in monotherapy or in combination regimens and better understanding of predictors of benefit with therapy.Keywords: erlotinib, NSCLC, targeted therapy

BACKGROUND: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer. METHODS: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (>or=18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m(2) intravenous infusion on day 1, and vinorelbine 25 mg/m(2) intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m(2) intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m(2) over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11.3 months vs 10.1 months; hazard ratio for death 0.871 [95% CI 0.762-0.996]; p=0.044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3). INTERPRETATION: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer.

Background: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer. Methods: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (≥18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m 2 intravenous infusion on day 1, and vinorelbine 25 mg/m 2 intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m 2 intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m 2 over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798. Findings: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11·3 months vs 10·1 months; hazard ratio for death 0·871 [95% CI 0·762-0·996]; p=0·044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3). Interpretation: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer. Funding: Merck KGaA. © 2009 Elsevier Ltd. All rights reserved.

Udgivelsesdato: 2009-Oct, INTRODUCTION: Bisphosphonates (BPs) are effective in preventing, reducing the incidence, and delaying the onset of skeletal-related events in patients with bone metastases in a variety of solid tumors, including lung cancer. The purpose of this article is to review the current evidence for the use of BPs in lung cancer and to provide specific European recommendations to support the clinical practice of using BPs to treat patients with lung cancer with bone metastases. METHODS: An expert panel of European clinical oncologists and lung cancer specialists convened for two face-to-face meetings designed to review available evidence on the efficacy of BPs in lung cancer and to develop recommendations based on published literature and clinical practice experiences. RESULTS: The panel recommends screening patients with lung cancer for bone metastases at the initial staging of disease to assess symptomatic bone metastases and screen for asymptomatic bone metastases and to allow accurate monitoring of bone disease progression and initiate bone-specific therapy. Bone assessment should be based on positron emission tomography (if available) or bone scan. BPs should be added to the treatment of patients with lung cancer (with non-small cell lung cancer or small cell lung cancer) who develop bone metastases. In such patients, BPs must be considered part of metastatic lung cancer treatment to prevent and delay the occurrence of further bone metastases and skeletal-related events and to relieve pain where present. BP treatment should continue for as long as it is practically feasible in the absence of any significant adverse effects.

Serena Ricciardi1, Silverio Tomao2, Filippo de Marinis11Thoracic-Oncology Unit 1st, Lung Diseases Department, San Camillo-Forlanini High Specialization Hospitals, Rome, Italy; 2Sperimental Medicine Department, Rome, ItalyAbstract: Pemetrexed is a new cytotoxic agent that is a standard of care for the second-line treatment of non-small cell lung cancer (NSCLC) and in combination with cisplatin in treatment of malignat pleural mesothelioma. It has been studied in numerous phase II and III trials in combination with different drugs or as single agent. Recently, pemetrexed has been approved in combination with cisplatin for the first-line treatment of patients with locally advanced or metastatic NSCLC other than squamous cell histology. The toxicity is acceptable and similar to that of other NSCLC regimens. The postinduction maintenance therapy with pemetrexed is being evaluated in a phase III, double-blind, placebo-controlled study.Keywords: pemetrexed, non-small cell lung cancer, non-squamous carcinoma, first-line setting