Facteurs prédictifs de progression d' emblée sous inhibiteurs de tyrosine kinase du récepteur de l' épidermal growth factor

Les ITK de l EGFR sont utilisés depuis plus de 10 ans dans le traitement des cancers pulmonaires non à petites cellules. Nous avons cherché des facteurs prédictifs de progression d emblée sous ITK de l EGFR. Nous avons étudié rétrospectivement une cohorte de 269 patients traités par gefitinib ou erlotinib que nous avons classés selon leur statut au 45è jour du traitement : maladie en progression ou maladie contrôlée. Nous avons comparé ces 2 groupes.Le statut maladie en progression ou contrôlée a pu être déterminé pour 240 patients (n=76 et n=164). On trouvait dans le groupe progression d emblée des patients plus jeunes (p=0,006), avec une fréquence accrue de tabagisme non sevré (p=0,001), un performans status de l Eastern Cooperative Oncology Group plus mauvais (p=0,008) et un amaigrissement plus important (p=0,03). Leur diagnostic était plus récent (p<0,0001). Leur cancer était plus souvent d histologie indifférenciée (p=0,001), avec des métastases abdominales (p=0,008) et/ou un plus grand nombre de sites métastatiques (p=0,018). Ces facteurs, sauf le dernier, étaient prédictifs d une progression d emblée en analyse uni-variée. La présence de métastases abdominales était prédictive d une progression d emblée en analyse multi-variée (odds-ratio 0,463 ; p=0,022). Parmi les 38,3% de patients pour qui le statut mutationnel était connu, un gène EGFR sauvage était plus fréquent dans le groupe progression d emblée (p=0,013).La présence de métastases abdominales est prédictive d une progression d emblée sous ITK de l EGFR. Une étude des bio-marqueurs moléculaires sur les patients de cette cohorte est en cours.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

La réintroduction de chimiothérapie est-elle faisable au cours du traitement du cancer pulmonaire non à petites cellules de stade avancé ?

International audienceBackground: Despite recent progress, non-small cell lung cancer (NSCLC) first-line treatment remains a platinum-based doublet in most cases. No guidelines exist beyond third line. Chemotherapy rechallenge is an option, but little data is available in NSCLC. Our study aims to describe patients who underwent chemotherapy rechallenge while assessing its efficacy and safety.Methods: Consecutive patients with advanced-stage NSCLC receiving first-line treatment in Tenon hospital in 2011 were included, with a 5-year follow-up. Patients were analyzed according to chemotherapy rechallenge or not. Chemotherapy rechallenge was defined as re-initiation of a previously administered chemotherapy agent at any point in the treatment sequence, with at least one treatment regimen between first use and rechallenge.Results: Of 149 patients, 18 underwent chemotherapy rechallenge (12%). They were younger (56 vs. 61 years, P = 0.04), mostly women (61% vs. 30%, P = 0.02), with lepidic adenocarcinoma (23% vs. 3.5%, P = 0.03), a better general state of health (100% performance status 0–1 vs. 74%, P = 0.04), and fewer cardiovascular comorbidities (16% vs. 42%, P = 0.04). They were more likely to have received a receptor tyrosine kinase inhibitor treatment (89% vs. 43%, P = 0.0003). Progression-free survival was longer at first use than at rechallenge (median 9.2 vs. 2.7 months, P = 0.002). No increased toxicity was observed at rechallenge compared to first use. Finally, a subsequent line of treatment was given after rechallenge in 61% of the patients.Conclusion: Patients eligible for chemotherapy rechallenge were those with good prognostic factors. Chemotherapy rechallenge may provide a well-tolerated additional line of treatment, with decreased efficacy compared to its first application.Introduction: Malgré des progrès récents, le traitement de première ligne des cancers bronchopulmonaires non à petites cellules (CBNPC) reste majoritairement un doublet à base de platine. Il n’existe pas de recommandations après la troisième ligne. La réintroduction de chimiothérapie est une option, mais peu de données sont disponibles. Notre étude vise à décrire les patients ayant eu une réintroduction de chimiothérapie, ainsi que sa faisabilité et sa tolérance.Méthodes: Les patients consécutifs avec un CBNPC de stade avancé ayant reçu un traitement de première ligne à l’hôpital Tenon en 2011 ont été inclus. Ceux ayant eu une réintroduction de chimiothérapie ont été comparés aux autres. Celle-ci était définie par la réutilisation d’un agent de chimiothérapie utilisé antérieurement, avec au moins une ligne entre la primo-utilisation et la réutilisation.Résultats: Parmi 149 patients, 18 ont eu une réintroduction de chimiothérapie (12 %). Ils étaient plus jeunes (56 ans vs 61 ans, p = 0,04), de sexe féminin (61 % vs 30 %, p = 0,02), avec un adénocarcinome lépidique (23 % vs 35 %, p = 0,03), un meilleur état général (PS 0–1 : 100 % vs 74 %, p = 0,04) et moins de comorbidités cardiovasculaires (16 % vs 42 %, p = 0,04). La survie sans progression était plus longue à la primo-utilisation qu’à la réintroduction (médiane 9,2 mois vs 2,7, p = 0,002). Il n’y avait pas de surcroît de toxicité à la réintroduction. Enfin, une ligne supplémentaire était possible après réintroduction chez 61 % des patients.Conclusion: La réintroduction de chimiothérapie fournit une ligne supplémentaire de traitement bien tolérée, avec une efficacité moindre par rapport à la primo-utilisation

Sonic Hedgehog pathway activation is associated with resistance to platinum-based chemotherapy in advanced non-small cell lung carcinoma

International audienceIntroduction : Chemoresistance is a major challenge in the treatment of advanced non-small cell lung cancer (NSCLC). As the Sonic Hedgehog (Shh) pathway is reactivated in NSCLC, we investigated an association between chemoresistance and Shh activation.Materials and Methods : From a cohort of 178 patients with advanced NSCLC treated with platinum-based chemotherapy as first-line treatment, we selected all surgical tumor samples at diagnosis (n=36). Shh activation was evaluated through Gli1 and Gli2 expression by immunohistochemistry (IHC) (quantitative score). In vitro treatment studies with cisplatin, vismodegib (Shh-pathway inhibitor) or both were performed on NSCLC cell lines (H322 and A549) and on primary cultures from patients with sarcomatoid carcinoma (n=4).Results : Twelve patients were refractory to chemotherapy (r-patients, 33.3%) and 24 had controlled disease (c-patients). Gli1 expression did not differ between the r- and c-patients (p=0.35). Gli2 expression was more often positive in the r-patients (41.7% versus 8.3%, p=0.02). Progression-free survival (PFS) and overall survival (OS) in patients with Gli2-positive score were 2.1 and 8.0 months, respectively, versus 6.7 and 18.0 months in patients with Gli2-negative score (p=0.03; p=0.002). In multivariate analysis, Gli2 score was independently correlated with PFS (hazard ratio [HR]=2.64; 95% confidence interval [CI]: 1.05-6.63; p=0.04) and OS (HR=4.36; 95% CI: 1.67-11.36; p=0.003). The sarcomatoid carcinoma cell lines were more resistant to cisplatin than the H838 and A549 cell lines. The cisplatin - vismodegib combination displayed a synergistic cytotoxic effect in the most chemoresistant cells in vitro.Conclusion : The Shh pathway is associated with resistance to platinum-based chemotherapy in NSCLC

Factors associated with early progression of non-small-cell lung cancer treated by epidermal growth factor receptor tyrosine-kinase inhibitors

International audienceEpidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKI) are a therapeutic option as second-line therapy in non-small-cell lung carcinoma (NSCLC), regardless of the EGFR gene status. Identifying patients with early progression during EGFR-TKI treatment will help clinicians to choose the best regimen, TKI or chemotherapy. From a prospective database, all patients treated with gefitinib or erlotinib between 2001 and 2010 were retrospectively reviewed. Patients were classified into two groups according to their tumor response by RECIST after 45 days of treatment, progressive disease (PD) or controlled disease (CD). Two hundred and sixty-eight patients were treated with EGFR-TKI, among whom 239 were classified as PD (n = 75) and CD (n = 164). Median overall survival was 77 days (95% CI 61–109) for PD and 385 days (95% CI 267–481) for CD. Patients with PD were of younger age (P = 0.004) and more frequently current smokers (P = 0.001) had more frequently a performance status ≥2 (P = 0.012), a weight loss ≥10% (P = 0.025), a shorter time since diagnosis (P < 0.0001), a pathological classification as non-otherwise-specified NSCLC (P = 0.01), and the presence of abdominal metasta-ses (P = 0.008). In multivariate analysis, abdominal metastases were the only factor associated with early progression (odds ratio (OR) 2.17, 95% CI [1.12– 4.19]; P = 0.021). Wild-type EGFR versus mutated EGFR was associated with early progression. The presence of abdominal metastasis was independently associated with early progression in metastatic NSCLC receiving EGFR-TKI

Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia

International audienceImportance Severe pneumonia with hyperinflammation and elevated interleukin-6 is a common presentation of coronavirus disease 2019 (COVID-19).Objective To determine whether tocilizumab (TCZ) improves outcomes of patients hospitalized with moderate-to-severe COVID-19 pneumonia.Design, Setting, and Particpants This cohort-embedded, investigator-initiated, multicenter, open-label, bayesian randomized clinical trial investigating patients with COVID-19 and moderate or severe pneumonia requiring at least 3 L/min of oxygen but without ventilation or admission to the intensive care unit was conducted between March 31, 2020, to April 18, 2020, with follow-up through 28 days. Patients were recruited from 9 university hospitals in France. Analyses were performed on an intention-to-treat basis with no correction for multiplicity for secondary outcomes.Interventions Patients were randomly assigned to receive TCZ, 8 mg/kg, intravenously plus usual care on day 1 and on day 3 if clinically indicated (TCZ group) or to receive usual care alone (UC group). Usual care included antibiotic agents, antiviral agents, corticosteroids, vasopressor support, and anticoagulants.Main Outcomes and Measures Primary outcomes were scores higher than 5 on the World Health Organization 10-point Clinical Progression Scale (WHO-CPS) on day 4 and survival without need of ventilation (including noninvasive ventilation) at day 14. Secondary outcomes were clinical status assessed with the WHO-CPS scores at day 7 and day 14, overall survival, time to discharge, time to oxygen supply independency, biological factors such as C-reactive protein level, and adverse events.Results Of 131 patients, 64 patients were randomly assigned to the TCZ group and 67 to UC group; 1 patient in the TCZ group withdrew consent and was not included in the analysis. Of the 130 patients, 42 were women (32%), and median (interquartile range) age was 64 (57.1-74.3) years. In the TCZ group, 12 patients had a WHO-CPS score greater than 5 at day 4 vs 19 in the UC group (median posterior absolute risk difference [ARD] −9.0%; 90% credible interval [CrI], −21.0 to 3.1), with a posterior probability of negative ARD of 89.0% not achieving the 95% predefined efficacy threshold. At day 14, 12% (95% CI −28% to 4%) fewer patients needed noninvasive ventilation (NIV) or mechanical ventilation (MV) or died in the TCZ group than in the UC group (24% vs 36%, median posterior hazard ratio [HR] 0.58; 90% CrI, 0.33-1.00), with a posterior probability of HR less than 1 of 95.0%, achieving the predefined efficacy threshold. The HR for MV or death was 0.58 (90% CrI, 0.30 to 1.09). At day 28, 7 patients had died in the TCZ group and 8 in the UC group (adjusted HR, 0.92; 95% CI 0.33-2.53). Serious adverse events occurred in 20 (32%) patients in the TCZ group and 29 (43%) in the UC group (P = .21).Conclusions and Relevance In this randomized clinical trial of patients with COVID-19 and pneumonia requiring oxygen support but not admitted to the intensive care unit, TCZ did not reduce WHO-CPS scores lower than 5 at day 4 but might have reduced the risk of NIV, MV, or death by day 14. No difference on day 28 mortality was found. Further studies are necessary for confirming these preliminary results.Trial Registration ClinicalTrials.gov Identifier: NCT0433180

Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial

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Sarilumab in adults hospitalised with moderate-to-severe COVID-19 pneumonia (CORIMUNO-SARI-1): An open-label randomised controlled trial

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