Publications by authors named "Christos CHOUAID"

174 Publications

Phase III randomized study of carboplatin pemetrexed with or without bevacizumab with initial "at progression" cerebral radiotherapy in advanced non squamous non-small cell lung cancer with asymptomatic brain metastasis.

Ther Adv Med Oncol 2021 16;13:17588359211006983. Epub 2021 Apr 16.

Service de Pneumologie, CHI Créteil, 40 avenue de Verdun, Créteil, 94010, France.

Background: The role and timing of whole or stereotaxic brain radiotherapy (BR) in patients with advanced non-small cell lung cancer (aNSCLC) and asymptomatic brain metastases (aBMs) are not well established. This study investigates whether deferring BR until cerebral progression was superior to upfront BR for patients with aNSCLC and aBM.

Methods: This open-label, multicenter, phase III trial, randomized (1:1) aNSCLC patients with aBMs to receive upfront BR and chemotherapy: platin-pemetrexed and bevacizumab in eligible patients, followed by maintenance pemetrexed with or without bevacizumab, BR arm, or the same chemotherapy with BR only at cerebral progression, chemotherapy (ChT) arm. Primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), global, extra-cerebral and cerebral objective response rate (ORR), toxicity, and quality of life [ClinicalTrials.gov identifier: NCT02162537].

Results: The trial was stopped early because of slow recruitment. Among 95 included patients, 91 were randomized in 24 centers: 45 to BR and 46 to ChT arms (age: 60 ± 8.1, men: 79%, PS 0/1: 51.7%/48.3%; adenocarcinomas: 92.2%, extra-cerebral metastases: 57.8%, without differences between arms.) Significantly more patients in the BR-arm received BR compare with those in the ChT arm (87% 20%;  < 0.001); there were no significant differences between BR and ChT arms for median PFS: 4.7, 95% confidence interval (CI):3.4-7.5 4.8, 95% CI: 2.4-6.5 months, for median OS: 8.5, 95% CI:.6-11.1 8.3, 95% CI:4.5-11.5 months, cerebral and extra-cerebral ORR (27% 13%, = 0.064, and 30% 41%,  = 0.245, respectively). The ChT arm had more grade 3/4 neutropenia than the BR arm (13% 6%,  = 0.045); others toxicities were comparable.

Conclusion: The significant BR rate difference between the two arms suggests that upfront BR is not mandatory in aNSCLC with aBM but this trial failed to show that deferring BR for aBM is superior in terms of PFS from upfront BR.
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http://dx.doi.org/10.1177/17588359211006983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053829PMC
April 2021

Development of a Questionnaire for the Search for Occupational Causes in Patients with Non-Hodgkin Lymphoma: The RHELYPRO Study.

Int J Environ Res Public Health 2021 Apr 11;18(8). Epub 2021 Apr 11.

Service des Pathologies Professionnelles et de l'Environnement, CHI Créteil, F-94010 Créteil, France.

Non-Hodgkin lymphoma (NHL), multiple myeloma and chronic lymphocytic leukemia are possibly related to environmental and/or occupational exposure. The primary objective of this study was to develop a questionnaire for screening patients with these blood disorders who might benefit from a specialized consultation for possible recognition of the disease as an occupational disease. The study included 205 subjects (male gender, 67.3%; mean age, 60 years; NHL, 78.5%). The questionnaire performed very satisfactorily in identifying the exposures most frequently retained by experts for their potential involvement in the occurrence of NHL. Its sensitivity and specificity in relation to the final expertise were 96% and 96% for trichloroethylene, 85% and 82% for benzene, 78% and 87% for solvents other than trichloroethylene and dichloromethane, 87% and 95% for pesticides, respectively. Overall, 15% of the subjects were invited to ask National Social Insurance for compensation as occupational disease. These declarations concerned exposure to pesticides (64%), solvents (trichloroethylene: 29%; benzene: 18%; other than chlorinated solvents: 18%) and sometimes multiple exposures. In conclusion, this questionnaire appears as a useful tool to identify NHL patients for a specialized consultation, in order to ask for compensation for occupational disease.
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http://dx.doi.org/10.3390/ijerph18084008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068898PMC
April 2021

Does Very Poor Performance Status Systematically Preclude Single Agent Anti-PD-1 Immunotherapy? A Multicenter Study of 35 Consecutive Patients.

Cancers (Basel) 2021 Mar 2;13(5). Epub 2021 Mar 2.

Department of Thoracic Oncology, Bichat Claude Bernard Hospital, APHP, CIC Inserm 1425, Université de Paris, 75018 Paris, France.

Anti-PD-1 antibodies prolong survival of performance status (PS) 0-1 advanced non-small-cell lung cancer (aNSCLC) patients. Their efficacy in PS 3-4 patients is unknown. Conse- cutive PS 3-4 aNSCLC patients receiving compassionate nivolumab were accrued by 12 French thoracic oncology departments, over 24 months. Overall survival (OS) was calculated using the Kaplan-Meier method. Prognostic variables were assessed using Cox proportional hazards models. Overall, 35 PS 3-4 aNSCLC patients (median age 65 years) received a median of 4 nivolumab infusions (interquartile range [IQR], 1-7) as first- ( = 6) or second-line ( = 29) therapy. At a median of 52-month follow-up (95%CI, 41-63), 32 (91%) patients had died. Median progression-free survival was 2.1 months (95%CI, 1.1-3.2). Median OS was 4.4 months (95%CI, 0.5-8.2). Overall, 20% of patients were alive at 1 year, and 14% at 2 years. Treatment-related adverse events occurred in 8/35 patients (23%), mostly of low-grade. After adjustment, brain metastases (HR = 5.2; 95%CI, 9-14.3, = 0.001) and <20 pack-years (HR = 4.8; 95%CI, 1.7-13.8, = 0.003) predicted worse survival. PS improvement from 3-4 to 0-1 ( = 9) led to a median 43-month (95%CI, 0-102) OS. Certain patients with very poor general condition could derive long-term benefit from nivolumab salvage therapy.
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http://dx.doi.org/10.3390/cancers13051040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958129PMC
March 2021

Impact on All-Cause and Cardiovascular Mortality Rates of Coronary Artery Calcifications Detected during Organized, Low-Dose, Computed-Tomography Screening for Lung Cancer: Systematic Literature Review and Meta-Analysis.

Cancers (Basel) 2021 Mar 28;13(7). Epub 2021 Mar 28.

UCOG, Hôpital René Muret, APHP, 93270 Sevran, France.

Although organized, low-dose, computed-tomography (CT) scan lung-cancer screening has been shown to lower all-cause and lung-cancer-specific mortality, the primary cause of death for subjects eligible for such screening remains cardiovascular (CV) mortality. This meta-analysis study was undertaken to evaluate the impact of screening-scan-detected coronary artery calcifications (CACs) on CV and all-cause mortality. We conducted a systematic review and meta-analysis of studies reporting CV mortality according to the Agatson CAC score for participants in a lung-cancer screening program of randomized clinical or cohort studies. PubMed, Embase, and Cochrane databases were screened in June 2020. Two authors independently selected articles and extracted data. Six studies, including 20,175 subjects, were retained. CV and all-cause mortality rates were higher for subjects with CAC scores >0, with respective relative risks of 2.02 [95% CI 1.23-3.32] and 2.29 [95% CI 1.00-5.21]. Both mortality rates were even higher for those with high CAC scores (>400 or >1000). CACs are more common in men than in women, with an odds ratio of 1.49 [95% CI 1.40-1.59]. The presence of CAC is associated with CV mortality with an RR of 2.05 [95% CI 1.20-3.57] in men and 2.37 [CI 95% 1.29-5.09] in women, respectively. Analysis of lung-cancer-screening scans for CACs is a tool able to predict CV mortality. Prospective studies within those programs are needed to assess the benefit of primary CV prevention based on CAC detection.
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http://dx.doi.org/10.3390/cancers13071553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036563PMC
March 2021

Impact of Programmed Death Ligand 1 Expression in Advanced Non-Small-Cell Lung Cancer Patients, Treated by Chemotherapy (GFPC 06-2015 Study).

Onco Targets Ther 2020 30;13:13299-13305. Epub 2020 Dec 30.

Pneumology Department, Centre Hospitalier Intercommunal de Créteil, Créteil, France.

Background: Few data have been published on the clinical and histopathological characteristics of advanced non-small-cell lung cancer (NSCLC) patients with high PD-L1 expression versus intermediate or none and the prognostic value of PD-L1 expression for patients treated with chemotherapy is unknown. This study was undertaken to prospectively assess the prognostic value of tumor-cell (TC) and immune-cell (IC) PD-L1 expressions for advanced NSCLC patients.

Methods: It was a prospective, multicenter study on advanced NSCLC patients, with performance status 0/1, scheduled, consecutively, to receive first-line platin-based chemotherapy. PD-L1 expression was determined immunochemically (Dako Autostainer and monoclonal antibody 22C3) and its impact on progression-free survival (PFS) and overall survival (OS) assessed.

Results: Among 198 patients screened in 19 centers, 140 were included median age: 66.5 ± 10 years; 76.4% men; 79.3% Caucasians; 10.7% nonsmokers; 63.6% adenocarcinomas; <1%, 1-50% and ≥50% TC PD-L1-expression rates were 47.1%, 25.7% and 27.2% of patients, respectively; respective null, intermediate and high rates on ICs were 35.7%, 38.6% and 25.7%. Second- and third-line chemotherapies were administered to 58.6% and 26.4% of the patients, respectively. None received immunotherapy. First-, second- and third-line median (95% CI) PFS lasted 4.6 (3.6-5.2), 3.7 (2.3-4.7) and 2.2 (1.5-4.3) months, respectively; median OS was 16.9 (11.4-19.9) months. No significant PFS and OS differences were observed according to TC or IC PD-L1 expression.

Conclusion: According to the results of this prospective, multicenter study, neither TC nor IC PD-L1 expression appears to be prognostic for chemotherapy-managed advanced NSCLC patients.
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http://dx.doi.org/10.2147/OTT.S288825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779294PMC
December 2020

Nivolumab treatment in advanced non-small cell lung cancer: real-world long-term outcomes within overall and special populations (the UNIVOC study).

Ther Adv Med Oncol 2020 26;12:1758835920967237. Epub 2020 Oct 26.

Service de Pneumologie, CHI Créteil, UPEC, Créteil, France.

Objective: To describe long-term outcomes of patients treated with nivolumab for advanced non-small cell lung cancer (aNSCLC) in everyday clinical practice in France, with a focus on patients aged ⩾80 years, patients with renal impairment and patients with brain metastases.

Methods: The study included all patients with aNSCLC recorded in the French national hospital database, starting nivolumab in 2015-2016 and followed until December 2018. Patients were stratified by age, the presence of renal impairment and brain metastasis, as documented in the hospital discharge summaries. Information was retrieved on demographics, comorbidities and treatment history at baseline. Time to discontinuation of nivolumab treatment and overall survival were estimated using Kaplan-Meier survival analysis.

Results: Overall, 10,452 patients were included, of whom 514 were octogenarians, 479 had renal impairment and 1800 had brain metastases at baseline. Median duration of nivolumab treatment was 2.8 months in the overall population and in both the octogenarian and renally impaired subgroups, and 2.3 months in patients with brain metastases. Median overall survival in these patient groups was 11.7 months (95% confidence interval: 11.3-12.2), 11.7 months (11.3-12.1), 11.7 months (11.3-12.2) and 9.9 months (9.0-10.9) respectively. Three-year overall survival rates were 19.1% (18.1-20.2) in the overall population, 16.5% (11.6-23.4) in octogenarians, 15.9% (11.8-21.4) in patients with renal impairment and 21.7% (19.4-24.2) in those with brain metastases.

Conclusion: This large nationwide retrospective real-life cohort provided narrow estimates of long-term overall survival, which reached 19% at 3 years, consistent with data from phase III trials of nivolumab. Survival rates were comparable in the three special populations of interest and the overall population.
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http://dx.doi.org/10.1177/1758835920967237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745546PMC
October 2020

First-line immune-checkpoint inhibitor plus chemotherapy chemotherapy alone for extensive-stage small-cell lung cancer: a meta-analysis.

Ther Adv Med Oncol 2020 9;12:1758835920977137. Epub 2020 Dec 9.

Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil, France.

Introduction: Platin-based chemotherapy (CT) has long been the first-line standard-of-care for patients with extensive-stage small-cell lung cancer (ES-SCLC). Adding immune-checkpoint inhibitor(s) to CT (ICI+CT) in this setting is an option of interest, although its benefit is apparently modest.

Methods: This meta-analysis was conducted on randomized trials comparing first-line ICI+CT CT alone for ES-SCLC. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), response at 12 months and adverse events (AEs). Subgroup analyses were computed according to the immunotherapy used, performance status (PS), age, platinum salt, liver metastases and brain metastases at diagnosis.

Results: The literature search identified one randomized phase II (ECOG-ACRIN-5161) and four phase III trials (CASPIAN, IMPOWER-133, KEYNOTE-604 and Reck 2016) that included 2775 patients (66% males, 95% smokers, median age: 64 years, PS = 0 or 1). ICI+CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS [0.82 (0.75-0.89);  <  0.00001] and PFS [0.81 (0.75-0.87);  <  0.00001], with OS benefits for anti-PD-L1 [0.73 (0.63-0.85);  < 0.0001] or anti-PD-1 [0.76 (0.63-0.93);  < 0.006] but not for anti-CTLA-4 [0.90 (0.80-1.01),  = 0.07]. ORRs for ICI+CT or CT alone were comparable [odds ratio 1.12 (0.97-1.00);  = 0.12], but responses at 12 months favored ICI+CT [4.16 (2.81-6.17),  < 0.00001]. Serious grade-3/4 AEs were more frequent with ICI+CT [odds ratio 1.18 (1.02-1.37);  = 0.03]. Compared with CT, no ICI+CT benefit was found for ES-SCLC with brain metastases at diagnosis [HR 1.14 (0.87-1.50); =0.34].

Conclusions: First-line ICI+CT appears to be superior to CT alone for ES-SCLC except for patients with brain metastases at diagnosis.
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http://dx.doi.org/10.1177/1758835920977137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731693PMC
December 2020

Economic analyses of immune-checkpoint inhibitors to treat lung cancer.

Expert Rev Pharmacoecon Outcomes Res 2020 Dec 24:1-7. Epub 2020 Dec 24.

Service De Pathologie Respiratoire, Centre Hospitalier Intercommunal De Créteil , Créteil Cedex, France.

: Total lung-cancer-management costs are increasing dramatically. The widespread use of immune-checkpoint inhibitors (ICIs) explains this rise in large part and financially impacts healthcare systems. Economic assessment has been adapted to this new challenge. : This review provides an overview of the economic literature on the use of ICIs to treat lung cancer. Numerous papers have been published over the last few years. Cancers analyzed were non-squamous non-small-cell lung cancer (NSCLC), squamous NSCLC, locally advanced NSCLC, or small-cell lung cancer. : For the majority of patients, ICIs are cost-effective for lung cancer management. However, these results are influenced by the threshold chosen by each of the different countries. Patient selection, treatment duration, and factors predictive of efficacy are mandatory to decrease costs.
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http://dx.doi.org/10.1080/14737167.2021.1863790DOI Listing
December 2020

Efficacy of Dabrafenib Plus Trametinib Combination in Patients with V600E-Mutant NSCLC in Real-World Setting: GFPC 01-2019.

Cancers (Basel) 2020 Dec 2;12(12). Epub 2020 Dec 2.

Department of Pneumology, CHI de Créteil, 94000 Créteil, France.

Dabrafenib plus trametinib combination is approved in Europe for V600E-mutant metastatic non-small-cell lung cancer (NSCLC). The objective of this study was to assess efficacy and safety of this combination in a real-world setting. This retrospective multicentric study included 40 patients with advanced NSCLC harboring V600E mutation and receiving dabrafenib plus trametinib. The median progression-free survival (PFS) and overall survival (OS) were 17.5 (95% CI 7.1-23.0) months and 25.5 (95% CI 16.6-not reached) months in the entire cohort, respectively. For the 9 patients with first-line treatment, median PFS was 16.8 (95% CI 6.1-23.2) months and median OS was 21.8 (95% CI 1.0-not reached) months; for the 31 patients with second-line or more treatments, median PFS and OS were 16.8 (95% CI 6.1-23.2) months and 25.5 (95% CI 16.6-not reached) months, respectively. Adverse events led to permanent discontinuation in 7 (18%) patients, treatment interruption in 8 (20%) and dose reduction in 12 (30%). In conclusion, these results suggest that efficacy and safety of dabrafenib plus trametinib combination in patients with V600E metastatic NSCLC are comparable in a real-world setting and in clinical trials for both previously untreated and treated patients.
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http://dx.doi.org/10.3390/cancers12123608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761573PMC
December 2020

Carboplatin plus etoposide for sensitive relapsed small-cell lung cancer - Authors' reply.

Lancet Oncol 2020 12;21(12):e546

Service de Cancérologie, Centre Hospitalier Universitaire d'Angers, Angers, France.

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http://dx.doi.org/10.1016/S1470-2045(20)30689-6DOI Listing
December 2020

Second-line therapy for disseminated small-cell lung cancer: optimal management remains to be defined.

Transl Lung Cancer Res 2020 Oct;9(5):1732-1735

Univ Paris Est Créteil, INSERM, IMRB, Equipe CEpiA, 94010 Créteil, France.

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http://dx.doi.org/10.21037/tlcr-20-362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653159PMC
October 2020

FDG-PET biomarkers associated with long-term benefit from first-line immunotherapy in patients with advanced non-small cell lung cancer.

Ann Nucl Med 2020 Dec 18;34(12):968-974. Epub 2020 Oct 18.

Department of Nuclear Medicine, Institut Curie, Saint-Cloud, 92210, Saint-Cloud, France.

Objective: To determine FDG-PET biomarkers associated with long-term benefit (LTB) and survival in advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy.

Methods: In this multicenter study, we retrospectively analyzed advanced NSCLC patients with a PD-L1 tumor proportion score (TPS) ≥ 50%, who underwent FDG-PET/CT before first-line pembrolizumab, received from August 2017 to September 2019. Parameters extracted were SUVmax, SUVmean, TMTV (total metabolic tumor volume) and TLG (total lesion glycolysis). LTB was defined as objective (complete or partial) response or stable disease as best overall response, maintained for ≥ 12 months. A multivariate prediction model was developed using logistic regression for LTB and Cox models for progression-free survival (PFS) and overall survival (OS).

Results: On the 63 eligible patients, with a median follow-up of 13.4 (range, 1.5-29.1) months, 17 (27%) had LTB. Median PFS and OS were 7.7 months (95%CI 5.0-10.5) and 12.1 months (95%CI 8.6-15.6). In multivariate analyses, high TMTV (> 84cm) and high tumor SUVmean (> 10.1) remained independent factors for predicting LTB (OR 0.2; p = 0.03 and OR 3.7; p = 0.04) and PFS (HR 2.2; p = 0.02 and HR 0.5; p = 0.045). High TMTV was significantly associated with poor OS (HR 3.1; p = 0.03). No association was observed between tumor SUVmax or TLG and clinical outcomes.

Conclusions: In patients with advanced NSCLC and PD-L1 TPS ≥ 50%, baseline low TMTV and high tumor SUVmean correlate with survival and LTB from upfront pembrolizumab. Beyond the initial staging, FDG-PET/CT scan could provide relevant biomarkers associated with clinical outcomes that should be taken into account when considering first-line treatment options.
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http://dx.doi.org/10.1007/s12149-020-01539-7DOI Listing
December 2020

Durable responses to immunotherapy of non-small cell lung cancers harboring MET exon-14-skipping mutation: A series of 6 cases.

Lung Cancer 2020 12 16;150:21-25. Epub 2020 Sep 16.

Department of Pulmonology, Hôpital Foch, 40, rue Worth, 92151, Suresnes, France. Electronic address:

Introduction: About 2-3% of non-small-cell lung cancers (NSCLCs) harbor MET exon-14-skipping (METex14) mutations. Efficacy of the MET-inhibitor crizotinib has been reported, but progression-free survival (PFS) was very short. Immune-checkpoint inhibitors (ICIs) have become a cornerstone of NSCLC treatment but appear to be less effective in non-smokers and against tumors exhibiting oncogenic addiction. We describe 6 remarkable (PFS exceeding 18 months) and durable responses to ICIs of NSCLCs harboring a METex14 mutation.

Methods: Each patient's clinical and biological characteristics, and tumor responses after ICIs were examined. Complete tumor-DNA sequencing was available after starting second-line ICIs, which followed first-line chemotherapy. Tumor-cell programmed cell-death protein-1 ligand-1 (PD-L1) expression on tumor cells was evaluated using antibody clone E1L3N (Cell Signaling Technology).

Results: Among 25 patients with METex14-mutated NSCLCs, 13 of whom were ICI-treated, 6 had prolonged responses: 5 women, 1 man; 57-80 years old; 3 never-smokers, 1 ex-smoker and 2 smokers; 5 adenocarcinomas, 1 sarcomatoid carcinoma; 5 received nivolumab, 1 pembrolizumab. No EGFR, BRAF or KRAS mutations (only 1 minority KRAS mutation), or ALK or ROS translocations were detected. No concurrent MET amplification was observed. Tumor-mutation burden was low (<10 mutations/Mb) in 3 tested tumors. Four partial and 2 complete responses were obtained during the first 3 months for 5 patients, while pseudoprogression was initially observed in 1. Tolerance was excellent, with only 1 grade-3 immune-related adverse event. Response was maintained for 18-49 months.

Conclusion: ICIs could be considered to treat patients whose NSCLCs harbor a METex14 mutation. More biological marker data are needed to identify which patients are most likely to benefit from ICIs.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.008DOI Listing
December 2020

Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial.

Lancet Oncol 2020 09;21(9):1224-1233

Service de Pneumologie, CHI Créteil, Créteil, France; Institut Mondor de Recherche Biomédicale, U955 Inserm-Université Paris Est Créteil, Créteil, France. Electronic address:

Background: Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer.

Methods: In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m from day 1 to day 3]) or oral topotecan (2·3 mg/m from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346.

Findings: Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0-37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73; p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group.

Interpretation: Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer.

Funding: Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie).
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http://dx.doi.org/10.1016/S1470-2045(20)30461-7DOI Listing
September 2020

Association of the Metabolic Score Using Baseline FDG-PET/CT and dNLR with Immunotherapy Outcomes in Advanced NSCLC Patients Treated with First-Line Pembrolizumab.

Cancers (Basel) 2020 Aug 10;12(8). Epub 2020 Aug 10.

Department of Nuclear Medicine, Institut Curie, 92210 Saint-Cloud, France.

: We aimed to assess the clinical utility of a previously published score combining the total metabolic tumor volume (TMTV) on baseline FDG-PET/CT and pretreatment derived from the neutrophils to lymphocytes ratio (dNLR) for prognostication in NSCLC patients undergoing first-line immunotherapy (IT). : In this multicenter retrospective study, 63 advanced NSCLC patients with a PD-L1 tumor proportion score (TPS) ≥50%, who underwent FDG-PET/CT before first-line IT, treated from January 2017 to September 2019, were enrolled. Associations between this score and the progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and overall response rate (ORR) were evaluated. : The median (m) PFS and mOS were 7.7 (95% CI 4.9-10.6) and 12.1 (8.6-15.6) months, respectively, and DCR and ORR were 65% and 58%, respectively. mOS was 17.9 months (14.6 not reached) for the good group versus 13.8 (95%CI 8.4-18.9) and 6.6 (CI 2.0-11.2) months for the intermediate and poor groups, respectively. mPFS was 15.1 (95%CI 12.1-20.0) months for the good group versus 5.2 (1.9-8.5) and 1.9 (95%CI 1.3-2.5) months for the intermediate and poor groups, respectively. The poor prognosis group was associated with DCR and ORR ( < 0.05). : The metabolic score combining TMTV on the baseline FDG-PET/CT scan and pretreatment dNLR was associated with the survival and response in a cohort of advanced NSCLC patients with ≥50% PD-L1 receiving frontline IT.
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http://dx.doi.org/10.3390/cancers12082234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463532PMC
August 2020

Monitoring Subsolid Pulmonary Nodules in High-Risk Patients Is Even More Cost-Effective When Combined With a Stop-Smoking Program.

J Thorac Oncol 2020 08;15(8):1268-1270

Pneumology Department, Centre Hospitalier Intercommunal de Créteil, Créteil, France; Inserm U955, Paris Est Créteil University, Institut Mondor de Recherche Biomédicale, CEpiA Team, Créteil, France. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2020.04.023DOI Listing
August 2020

Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: The phase II ATLANTIC study.

Lung Cancer 2020 09 30;147:137-142. Epub 2020 Jun 30.

Columbia University Medical Center, New York, NY, USA.

Introduction: In the phase II ATLANTIC study, durvalumab provided durable responses with acceptable tolerability in heavily pretreated patients with advanced NSCLC, across three independent patient cohorts defined by EGFR/ALK status and tumour PD-L1 expression. Preliminary overall survival (OS) data were encouraging. We now report final OS and updated safety data.

Methods: Patients with advanced NSCLC with disease progression following ≥2 previous systemic regimens received durvalumab 10 mg/kg every 2 weeks. The primary endpoint was objective response rate among patients with increased PD-L1 expression (defined as ≥25 % or ≥90 % of tumour cells [TCs], cohort-dependent). Secondary endpoints included OS and safety.

Results: 444 patients received durvalumab: 111 in Cohort 1 (EGFR+/ALK+), 265 in Cohort 2 (EGFR-/ALK-), and 68 in Cohort 3 (EGFR-/ALK-; TC ≥ 90 %). Median (95 % CI) OS was 13.3 months (6.3-24.5) in patients with EGFR+/ALK+ NSCLC with TC ≥ 25 %, 10.9 months (8.6-13.6) in patients with EGFR-/ALK- NSCLC with TC ≥ 25 %, and 13.2 months (5.9-not reached) in patients with EGFR-/ALK- NSCLC with TC ≥ 90 %. Median (95 % CI) OS was slightly shorter in patients with TC < 25 % (9.9 months [4.2-13.3] in patients with EGFR+/ALK+ NSCLC and 9.3 months [5.9-10.8] in those with EGFR-/ALK- NSCLC). Treatment-related adverse events of special interest occurred with similar incidences as reported previously.

Conclusions: After additional follow-up, final OS data remain encouraging across all cohorts, further supporting the clinical activity of durvalumab in patients with heavily pretreated advanced NSCLC, including those with EGFR+/ALK+ tumours. There were no new safety signals.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.032DOI Listing
September 2020

PD-L1-expression patterns in large-cell neuroendocrine carcinoma of the lung: potential implications for use of immunotherapy in these patients: the GFPC 03-2017 "EPNEC" study.

Ther Adv Med Oncol 2020 7;12:1758835920937972. Epub 2020 Jul 7.

Department of Pathology, Cochin Hospital APHP, Paris, France.

Background: Few data are available on programmed cell-death-protein-1-ligand-1 (PD-L1) expression on large-cell neuroendocrine carcinomas of the lung (LCNECs). We analyzed PD-L1 expression on tumor (TCs) and inflammatory cells (ICs) from LCNEC patients to assess relationships between this expression, clinical characteristics, and disease outcomes.

Methods: PD-L1 expression was determined by immunohistochemistry with monoclonal antibody 22C3 in consecutive LCNEC patients managed in 17 French centers between January 2014 and December 2016.

Results: After centralized review, only 68 out of 105 (64%) patients had confirmed LCNEC diagnoses. Median overall survival (OS) (95% CI) was 11 (7-16) months for all patients, 7 (5-10), 21 (10-not reached) and not reached months for metastatic, stage III and localized forms ( = 0.0001). Respectively, 11% and 75% of the tumor samples were TC+ and IC+, and 66% had a TC-/IC+ profile. Comparing IC+ IC- metastatic LCNEC, the former had significantly longer progression-free survival [9 (4-13) 4 (1-8) months;  = 0.03], with a trend towards better median OS [12 (7-18) 9.5 (4-14) months;  = 0.21]. Compared to patients with TC- tumors, those with TC+ LCNECs tended to have non-significantly shorter median OS [4 (1-6.2) 11 (8-18) months, respectively]. Median OS was significantly shorter for patients with TC+/IC- metastatic LCNECs than those with TC-IC+ lesions (2 8 months, respectively;  = 0.04).

Conclusion: TC-/IC+ was the most frequent PD-L1-expression profile for LCNECs, a pattern quite specific compared with non-small-cell lung cancer and small-cell lung cancer. IC PD-L1 expression seems to have a prognostic role.
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http://dx.doi.org/10.1177/1758835920937972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343361PMC
July 2020

Factors Associated With Aggressiveness of End-of-Life Care for Lung Cancer Patients and Associated Costs of Care.

Clin Lung Cancer 2020 May 23. Epub 2020 May 23.

University Paris, Est Créteil (UPEC), CEpiA (Clinical Epidemiology and Ageing), EA 7376-IMRB, Paris-Est University UPEC, Créteil, France; Département de Pneumologie, CHI de Créteil, Créteil, France.

Background: Results of previous studies demonstrated that high-intensity end-of-life (EOL) care improves neither cancer patients' survival nor quality of life. Our objective was to assess the incidence of and factors associated with aggressiveness of care during the last 30 days of life (DOL) of lung cancer (LC) patients and the impacts of aggressiveness of care in EOL-care costs.

Patients And Methods: Using French national hospital database, all patients with LC who died between January 1, 2010, and December 31, 2011, or between January 1, 2015, and January 31, 2016, were included. EOL-care aggressiveness was assessed using the following criteria: chemotherapy administered within the last 14 DOL; more than one hospitalization within the last 30 DOL; admission to the intensive care unit within the last 30 DOL; and palliative care initiated < 3 days before death. Expenditures were limited to direct costs, from a health care payer's perspective.

Results: Among 79,746 adult LC patients identified; 57% had at least one indicator of EOL-care aggressiveness (49% repeated hospitalizations, 12% intensive care unit admissions, 9% chemotherapy, 5% palliative care). It increased significantly between the 2 periods (56% vs. 58%, P < .001). Young age, male sex, shorter time since diagnosis, comorbidities, no malnutrition, type of care facility other than general hospital, social deprivation, and low-density population were independently associated with having one or more indicator of aggressive EOL care. The mean EOL cost was €8152 ± 5117 per patient, but the cost was significantly higher for patients with at least one EOL-care aggressiveness criterion (€9480 vs. €6376, P < .001).

Conclusion: In France, a majority of LC patients had at least one criterion of aggressive EOL care that had a major economic impact on the health care system.
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http://dx.doi.org/10.1016/j.cllc.2020.05.017DOI Listing
May 2020

First-line angiogenesis inhibitor plus erlotinib versus erlotinib alone for advanced non-small-cell lung cancer harboring an EGFR mutation.

J Cancer Res Clin Oncol 2020 Dec 7;146(12):3333-3339. Epub 2020 Jul 7.

Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil, France.

Purpose: Erlotinib is indicated as first-line treatment for patients with non-small-cell lung cancer (NSCLC) harboring an epidermal growth-factor-receptor (EGFR) mutation. Addition of a vascular endothelial growth factor (VEGF) inhibitor (anti-VEGF) in combination with the tyrosine-kinase inhibitor erlotinib in this setting is controversial.

Methods: We conducted a meta-analysis of randomized trials comparing anti-VEGF plus erlotinib vs erlotinib alone as first-line therapy for advanced NSCLC harboring an EGFR mutation. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and median duration of response (DOR). A fixed-effect model was used.

Results: Four studies evaluated bevacizumab + erlotinib (ARTEMIS, NEJ026, J025667, Stinchcombe et al.), and another evaluated ramucirumab + erlotinib (RELAY). These five eligible studies included 1230 non-squamous NSCLC patients, 654 (53.2%) with exon 19 deletion (ex19del) and 568 (46.8%) with EGFR. Patients were predominantly women (63%), Asians (85%) and non-smokers (60%); the median age was 64 years. The combination (anti-VEGF + erlotinib) was significantly associated with prolonged PFS (hazards ratio [HR] 0.59 [95% confidence interval (CI) 0.51-0.69]; p < 0.00001). The combination achieved significantly longer median DOR (p < 0.005). Based on interim analyses, OS (HR 0.90 [0.68-1.19]; p = 0.45) and ORR (odds ratio 1.19 [95% CI 0.91-1.55]; p = 0.21 were comparable.

Conclusions: For patients with untreated, advanced, EGFR-mutation-harboring NSCLCs, the anti-VEGF + erlotinib combination, compared to erlotinib alone, was associated with significantly prolonged PFS but mature data for OS are needed to confirm the benefit of this strategy.
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http://dx.doi.org/10.1007/s00432-020-03311-wDOI Listing
December 2020

Targeting the MET-Signaling Pathway in Non-Small-Cell Lung Cancer: Evidence to Date.

Onco Targets Ther 2020 17;13:5691-5706. Epub 2020 Jun 17.

University Paris-Est Créteil (UPEC), CEpiA (Clinical Epidemiology and Ageing), EA 7376- IMRB, UPEC, Créteil, France.

The c-MET proto-oncogene (MET) plays an important role in lung oncogenesis, affecting cancer-cell survival, growth and invasiveness. The MET receptor in non-small-cell lung cancer (NSCLC) is a potential therapeutic target. The development of high-output next-generation sequencing techniques has enabled better identification of anomalies in the MET pathway, like the MET exon-14 (METex14) mutation. Moreover, analyses of epidermal growth factor-receptor (EGFR) and mechanisms of resistance to tyrosine-kinase inhibitors (TKIs) demonstrated the importance of MET amplification as an escape mechanism in patients with TKI-treated EGFR-mutated NSCLCs. This review summarizes the laboratory findings on MET and its anomalies, trial results on METex14 alterations and MET amplification in non-EGFR mutated NSCLCs, and acquired resistance to TKI in EGFR-mutated NSCLCs. The outcomes of the first trials with anti-MET agents on non-selected NSCLC patients or those selected for MET overexpression were disappointing. Two situations seem the most promising today for the use of anti-MET agents to treat these patients: tumors harboring METex14 and those EGFR-sensitive mutation mutated under TKI-EGFR with a MET-amplification mechanism of resistance or EGFR-resistance mutation.
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http://dx.doi.org/10.2147/OTT.S219959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306460PMC
June 2020

Duration of nivolumab for pretreated, advanced non-small-cell lung cancer.

Cancer Med 2020 10 15;9(19):6923-6932. Epub 2020 May 15.

Department of Oncology, CHRU Morvan, University Hospital of Brest, Brest, France.

Background: A standard of care for pretreated, advanced non-small-cell lung cancers (NSCLCs), nivolumab has demonstrated long-term benefit when administered for 2 years. We aimed to better discern an optimized administration duration by retrospectively analyzing real-life long-term efficacy in a prospective cohort.

Methods: All nivolumab-treated adults with advanced NSCLCs (01/09/2015 to 30/09/2016) from nine French centers were eligible. On 31/12/2018, patients who are alive ≥ 2 years after starting nivolumab were defined as long-term survivors (LTSs) and were divided into three nivolumab treatment groups: <2, 2, or > 2 years. Co-primary endpoints were LTSs' progression-free survival (PFS) and overall survival (OS).

Results: The median follow-up was 32 months (95% CI, 31.0 to 34.0). The 3-year OS rate for the 259 cohort patients was 16.6%. Among them, 65 were LTSs: 47 treated < 2 years, 7 for 2 years, and 11 > 2 years. Their respective characteristics were: median age: 59, 52, and 58 years; smoking history: 92.9, 100, and 100%; adenocarcinomas: 66, 57.1, and 54.5%. LTSs' median (m)PFS was 28.4 months; mOS was not reached. LTSs' objective response rate was 61.6%. mOS was 32.7 months for those treated < 2 years and not reached for the others. The > 2-year group's 3-year OS was longer. Twenty-eight LTSs experienced no disease progression; 7 had durable complete responses. However, LTSs had more frequent and more severe adverse events.

Conclusion: In real-life, prolonged nivolumab use provided long-term benefit with 16.6% 3-year OS and 25% LTSs. Survival tended to be prolonged with nivolumab continued beyond 2 years. Prospective randomized trials with adequate design are needed.
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http://dx.doi.org/10.1002/cam4.3120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541160PMC
October 2020

Treatment sequence of first and second generation tyrosine kinase inhibitor followed by osimertinib in -mutated non-small-cell lung cancer: a real life study.

Future Oncol 2020 Jun 30;16(16):1115-1124. Epub 2020 Apr 30.

Service de Pneumologie, CHI Créteil, Créteil, France.

We aimed to assess the effectiveness and cost of patients with first line tyrosine kinase inhibitors (TKIs) sequence of first (1G) and second generation (2G) followed by osimertinib. Using the French nationwide claims and hospitalization database, we analyzed non-small-cell lung cancer patients who had been treated with osimertinib between April 2015 and December 2017, after a first line treatment with a TKI-1G/2G. The median time on treatment for sequential TKI-1G/2G followed by osimertinib was 34 months (95% CI: 31-46); 13 and 12months, respectively for TKI 1G or 2G and TKI 3G, respectively. The median overall survival for sequential TKI 1G or 2G followed by osimertinib was 37 months (95% CI: 34-42). The mean monthly costs per patient was €5162. These results, in line with those observed during clinical trials, confirm the effectiveness of the sequence TKI-1G/2G followed by osimertinib in -mutated non-small-cell lung cancer.
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http://dx.doi.org/10.2217/fon-2020-0084DOI Listing
June 2020

Encephalitis related to immunotherapy for lung cancer: Analysis of a multicenter cohort.

Lung Cancer 2020 05 17;143:36-39. Epub 2020 Mar 17.

Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, 40, avenue de Verdun, 94010 Créteil, France.

Introduction: Using immune-checkpoint inhibitors (ICIs) to manage cancer is associated with various immune-related adverse events. Central and/or peripheral neurological disorders are rare and potentially serious. We analyzed the characteristics of non-small-cell lung cancer (NSCLC) patients who developed immune-related encephalitis under anti-programmed-death protein-1 or its ligand (PD-1/PD-L1).

Methods: Clinical, biological and radiological characteristics of ICI-treated NSCLC patients with immune-related encephalitis, from 6 centers, were evaluated retrospectively.

Results: The 6 centers included 9 patients: all men, all smokers, median (range) age 67 (48-77) years, 78% adenocarcinomas, first- or second-line ICI for 5 and 4 patients, respectively. Two patients had non-active cerebral metastases at ICI onset. A median of 5 (1-22) ICI infusions preceded neurological symptoms, the most frequent being confusion (78%), fever (45%) and cerebellar ataxia (33%). CSF analyses revealed a median white blood cell count of 22/mm (1-210/mm), with hyperlymphocytosis in 8 patients and high protein levels in all. All bacteriological and virological analyses were negative. Cerebral MRI was considered normal for 5 patients; 4 patients had FLAIR hypersignals consistent with brain parenchyma inflammation. Three patients required intensive care. All patients received corticosteroids (different doses), a median of 8.5 (6-18) days post-onset. Corticosteroids achieved rapid symptom regression without sequelae in 8 patients. The last patient, with the longest time until corticosteroid introduction, died. ICIs were never restarted in any patient.

Conclusion: Immune encephalitis, a rare but serious complication of anti-PD-1/PD-L1 therapy, carries a good prognosis when managed with early corticosteroids.
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http://dx.doi.org/10.1016/j.lungcan.2020.03.006DOI Listing
May 2020

Interstitial Lung Disease Associated with Lung Cancer: A Case-Control Study.

J Clin Med 2020 Mar 5;9(3). Epub 2020 Mar 5.

Service de Pneumologie, Site constitutif du centre de référence des maladies pulmonaires rares OrphaLung, APHP, Hôpital Tenon, 75020 Paris, France.

Interstitial lung disease (ILD) seems to be associated with an increased risk of lung cancer (LC) and to have a poorer prognosis than LC without ILD. The frequency of ILD in an LC cohort and its prognosis implication need to be better elucidated. This retrospective, observational, cohort study evaluated the frequency of ILD among LC patients (LC-ILD) diagnosed over a 2-year period. LC-ILD patients' characteristics were compared to those with LC without ILD (LC-noILD). Lastly, we conducted a case-control study within this cohort, matching three LC-noILDs to each LC-ILD patient, to evaluate the ILD impact on LC patients' prognoses. Among 906 LC patients, 49 (5.4%) also had ILD. Comparing LC-ILD to LC-noILD patients, respectively, more were men (85.7% vs. 66.2%; = 0.02); adenocarcinomas were less frequent (47.1% vs. 58.7%, = 0.08); median [range] and overall survival was shorter: (9 [range: 0.1-39.4] vs. 17.5 [range: 0.8-50.4] months; = 0.01). Multivariate analysis (hazard ratio [95% confidence interval]) retained two factors independently associated with LC risk of death: ILD (1.79 [1.22-2.62]; = 0.003) and standard-of-care management (0.49 [0.33-0.72]; < 0.001). Approximately 5% of patients with a new LC diagnosis had associated ILD. ILD was a major prognosis factor for LC and should be taken into consideration for LC management. Further studies are needed to determine the best therapeutic strategy for the LC-ILD population.
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http://dx.doi.org/10.3390/jcm9030700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141363PMC
March 2020

First-line pembrolizumab for non-small cell lung cancer patients with PD-L1 ≥50% in a multicenter real-life cohort: The PEMBREIZH study.

Cancer Med 2020 04 5;9(7):2309-2316. Epub 2020 Feb 5.

Oncology Department, CHRU Brest, Brest, France.

Background: The KEYNOTE-024 trial demonstrated that pembrolizumab, a PD-1 inhibitor, significantly improves progression-free survival (PFS) and overall survival (OS) in selected patients with previously untreated advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumor proportion score (TPS) ≥50% and without EGFR/ALK aberrations. The main aim of this study was to report the efficacy and safety profile of pembrolizumab in real-life conditions.

Method: This was a French retrospective multicenter longitudinal study of 108 consecutive patients with advanced NSCLC, a PD-L1 TPS ≥50% and without EGFR/ALK aberrations who were treated by pembrolizumab, in first line. Patient data were obtained from medical files.

Results: The main characteristics of the cohort were: median age [range] 66.7 [37-87] years, 64.8% male, 23.1% with a performance status (PS) of 2, and 88.9% current or former smokers. Eighty-seven percent had stage IV NSCLC at diagnosis, 9.2% untreated brain metastases at inclusion,. With a median follow-up of 8.2 months, the median PFS was 10.1 months (95% CI, 8.8-11.4). The objective response rate was 57.3% (complete response 2.7%, partial response 54.6%). Disease control rate was 71.1%. At 6 months, the OS rate estimated was 86.2%. Treatment-related adverse events (AE) of grade 3 occurred in 8% of patients. There were no grade 4 or 5 AEs.

Conclusion: In a real-life cohort of advanced NSCLC patients (including PS 2 and untreated brain metastases), with PD-L1 TPS ≥50%, pembrolizumab demonstrates similar PFS to the pivotal clinical trial.
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http://dx.doi.org/10.1002/cam4.2806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131849PMC
April 2020

Efficacy and safety of programmed cell-death-protein-1 and its ligand inhibitors in pretreated patients with epidermal growth-factor receptor-mutated or anaplastic lymphoma kinase-translocated lung adenocarcinoma.

Medicine (Baltimore) 2020 Jan;99(3):e18726

Service de Pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil.

Immune-checkpoint inhibitor (ICI) efficacy in patients with non-small cell lung cancer (NSCLC) harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against epidermal growth-factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1)-mutated NSCLC patients in the real-world setting.In this retrospective, multicenter study on adults with ICI-treated EGFR-mutated or ALK- or ROS1-translated NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, and progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS) from immunotherapy initiation.Fifty-one NSCLC patients (mean age, 58.0 years) were included from 20 French centers: 61% were never-smokers and 59% were women. Among them, 82% had EGFR-activating mutations, 16% ALK translocations, or 2% ROS1 translocations. Before ICI therapy, patients had received a median of 3 treatment lines (including tyrosine-kinase inhibitor). The median PFS was 2.1 (95% confidence interval [CI], 1.5-3.2) months for the entire cohort, 2.2 (95% CI, 1.4-3.2) for EGFR-mutated patients, and 2.4 (95% CI, 2.1-not reached) months for ALK-translocated patients. The median OS was 14.7 (95% CI, 12.1-19.2) months for the entire population and 13.9 (95% CI, 8.8-20.0) and 19.2 (95% CI, 13.1-not reached) months for EGFR-mutated and ALK-translocated patients, respectively. Seven (13.7%) patients were treated with ICI for >9 months. Toxicities were reported in 22% (11/51), including 8% (4/51) grade ≥3.In this real-world setting, analysis of ICI PFS against EGFR-mutated or ALK-translocated NSCLC patients appeared close to that observed in pretreated unselected NSCLC patients. The more promising OS probably linked to post-ICI treatments. Large prospective studies on these patient subsets are needed.
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http://dx.doi.org/10.1097/MD.0000000000018726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220079PMC
January 2020

Efficacy and Safety of Anti-PD-1 Immunotherapy in Patients With Advanced NSCLC With BRAF, HER2, or MET Mutations or RET Translocation: GFPC 01-2018.

J Thorac Oncol 2020 04 13;15(4):628-636. Epub 2020 Jan 13.

Pneumology Department, Hôpital d'Instruction des Armées Percy, Clamart, France.

Introduction: Immune-checkpoint inhibitor (ICI) efficacy in patients with NSCLC harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against BRAF-, HER2-, MET-, and RET-NSCLC in a real-world setting.

Methods: In this retrospective, multicenter study in ICI-treated BRAF-, HER2-, MET- or RET-NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS).

Results: There were 107 patients with NSCLC (mean age, 65.5 y) included from 21 centers: 37% were never-smokers, 54% were men, and 93% had adenocarcinoma. Among them, 44 had BRAF mutation (V600: 26), 23 had HER2 mutation, 30 had MET mutation, and nine had RET translocation. Programmed cell death ligand 1 (PD-L1) status was known for 70 patients and was greater than or equal to 1% in 34 patients. Before ICI, patients had received a median of one treatment line. Median duration of response, PFS, and OS were 15.4 (95% confidence interval [CI]: 12.6-not reached [NR]) months, 4.7 (95% CI: 2.3-7.4) months, and 16.2 (95% CI: 12.0-24.0) months, respectively, for the entire cohort. The response rates for BRAF-V600, BRAF-non-V600, HER2, MET, and RET-altered NSCLC were 26%, 35%, 27%, 36%, and 38%, respectively. For patients who were PD-L1 negative and those who were PD-L1 positive, PFS was 3.0 (95% CI: 1.2-NR) and 4.3 (95% CI: 2.1-8.5) months, respectively, and OS was 11.7 (95% CI: 4.1-NR) and 35.8 (95% CI: 9.0-35.2) months, respectively. Toxicities were reported in 28 patients (26%), including 11 patients (10%) with a grade greater than or equal to three.

Conclusions: In this real-world setting, ICI efficacy against patients with BRAF-, HER2-, MET-, or RET-NSCLC seemed close to that observed in unselected patients with NSCLC. Large prospective studies on these subsets of patients are needed.
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http://dx.doi.org/10.1016/j.jtho.2019.12.129DOI Listing
April 2020

Immunotherapy rechallenge after nivolumab treatment in advanced non-small cell lung cancer in the real-world setting: A national data base analysis.

Lung Cancer 2020 02 31;140:99-106. Epub 2019 Dec 31.

GRC OncoThoParisEst, Service de Pneumologie, CHI Créteil, UPEC, Créteil, France.

Objectives: Nivolumab is now a reference treatment for patients with advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. Little data are available on treatment approaches following discontinuation of nivolumab and on the interest of a second course of immunotherapy after nivolumab discontinuation. The aims of this study were to describe treatment pathways following nivolumab discontinuation and to describe survival following retreatment with immunotherapy.

Materials And Methods: The analysis includes all patients with NSCLC recorded in a national hospital database, starting nivolumab in 2015-2016. Nivolumab treatment was considered discontinued if ≥3 infusions were missed. Patients starting a second course of PD-1 inhibitor following nivolumab discontinuation were analysed according to the duration of their initial nivolumab treatment course.

Results: 10,452 patients were included (71 % men; mean age: 63.8 ± 9.6 years; squamous histology: 44 %). Median nivolumab treatment duration was 2.8 months [IQR :1.4-6.9]. Median OS was 11.5 months [95 %CI: 11.1-11.9]; 5118 (53.4 %) patients received post nivolumab therapy lines: 1517 (29.6 %) of these received a second course of PD-1 inhibitor, either after a treatment-free interval (resumption: n = 1127) or after intervening chemotherapy (rechallenge: n = 390). Median OS after nivolumab discontinuation was 15.0 months [13.9-16.7] in the resumption group and 18.4 months [14.8-21.9] in the rechallenge group. Median OS was significantly longer in patients with an initial nivolumab treatment duration ≥3 months.

Conclusion: In this real-world setting, outcome after retreatment with a PD-1 inhibitor following a first course of nivolumab was significantly better in patients with a longer duration of initial nivolumab treatment.
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http://dx.doi.org/10.1016/j.lungcan.2019.12.017DOI Listing
February 2020

Impact of Therapy Persistence on Exacerbations and Resource Use in Patients Who Initiated COPD Therapy.

Int J Chron Obstruct Pulmon Dis 2019 16;14:2905-2915. Epub 2019 Dec 16.

PELyon, PharmacoEpidemiology, Lyon, France.

Purpose: This study assessed therapy persistence in patients with chronic obstructive pulmonary disease (COPD) in France, and the impact of non-persistence on exacerbations and described COPD-related healthcare resource use (HRU).

Methods: Patients aged ≥45 years who received ≥1 dispensed bronchodilator per quarter over three consecutive quarters between 2007 and 2014 and initiated specific COPD therapy were selected from the Echantillon Généraliste des Bénéficiaires (EGB) database. Persistence, defined as the absence of dispensing gaps of >90 days, was measured at 12 months. Exacerbations were compared between persistent and non-persistent patients during follow-up after patient matching and adjustment for confounding factors. COPD-related HRU during follow-up was described.

Results: Among 4020 patients with COPD, 2164 initiated a specific therapy. Of these, 54.4% stopped treatment within 12 months. Persistence with all COPD therapy regimens was low, particularly for inhaled corticosteroid (ICS; 25.6%) and ICS/twice-daily long-acting beta-agonist (39.4%) regimens. Among 721 persistent patients who were matched with 721 non-persistent patients, there was no difference in the number of moderate or severe exacerbations at 12 months. However, medical procedures (for instance, pulmonary function testing and chest X-rays) were more frequently observed among persistent patients than among non-persistent patients, suggesting worse disease severity.

Conclusion: Patients receiving specific treatment(s) for COPD demonstrated low persistence for all examined therapy regimens, with no clear impact of persistence status on the frequency of exacerbations at 12 months.
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http://dx.doi.org/10.2147/COPD.S222762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927267PMC
July 2020