Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer

BACKGROUND: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone. METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety. RESULTS: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P CONCLUSIONS: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.)

Profil étiologique et évolutif des hyperéosinophilies sanguines modérées à majeures au sein d'un hôpital général (une série rétrospective de 170 cas)

L'hyperéosinophilie sanguine (HS) est une anomalie biologique fréquemment retrouvée au cours de bilan systématique dans. les services hospitaliers. L'HS est classée en légère (500-1500/mm3), modérée (1500-5000/mm3) et majeure (>5000/mm3). Les causes d'HS sont multiples regroupant principalement les allergies, les parasitoses à tropisme tissulaire, les médicaments. Notre étude se propose d'étudier les étiologies, la prise en charge et l'évolution des HS supérieures à 1500/mm3 au sein d'un hôpital général. A partir d'une requête informatique, nous avons réalisé une étude rétrospective exhaustive des patients hospitalisés présentant une HS supérieure à 1500/mm3 entre le 01/01/2005 et le 31/12/2010 au sein d'un hôpital général comptant 290 lits. Un total de 199 patients répondaient aux critères d'inclusion pour lesquels 170 dossiers ont pu être analysés et 29 exclus. L'âge moyen était de 62,6 ans (16-98 ans) avec 69% d'hommes. L'HS au diagnostic était en moyenne de 2287/mm3, avec une valeur maximale moyenne de 2775/mm3. L'étiologie principale était iatrogène d'origine médicamenteuse (46 cas, 27%) suivi des causes dermatologiques (24 cas, 14 %) puis parasitaires (22 cas, 13 %). Pour 30 patients (18%}, I'HS n'était pas prise en compte par le praticien et donc aucune cause n'était recherchée. Les médicaments le plus souvent incriminés étaient les antibiotiques. Le diagnostic de certitude d'une cause parasitaire n'a été possible que dans 11 des 22 cas. L'évolution à 6 mois était connue chez 140 des 170 patients (79.5%) avec 93 guérisons ou rémission, 12 rechutes ou poursuites évolutives et 35 décès. Une sensibilisation de l'ensemble des praticiens des services médicaux et des urgences est nécessaire pour ne pas négliger les HS > 1500, ce d'autant que le taux de mortalité apparaît très élevé dans notre sérieLYON1-BU Santé (693882101) / SudocSudocFranceF

Efficacité du Pemetrexed en 2ème ligne dans les CBNPC avancés après un intervalle libre ou un traitement de maintenance par Gemcitabine ou Erlotinib dans l'étude IFCT-GFPC 05-02

L'exposition continue des cellules tumorales à un traitement de maintenance dans les CBNPC avancé pourrait conduire à une résistance aux traitements ultérieurs. L'essai IFCT-GFPC 0502 comprenait un traitement de 2ème ligne prédéfinie par pemetrexed, permettant une évaluation post hoc de l'efficacité du P en fonction d'un traitement de maintenance par gemcitabine ou par erlotinb ou une simple observation. Méthodes: Les pts atteints d'un CBNPC de stade IIIB/IV ont été randomisés après 4 cycles de cisplatine- gemcitabine en 3 bras: observation, gemcitabine et erlotinb. Le pemetrexed a été donné comme traitement de 2ème ligne après progression de la maladie dans chaque bras. La SSP et SG ont été évalués à partir du début de traitement par pemetrexed en fonction de bras de randomisation.Résultats: sur les 464 pts randomisés, 360 pts (78%) ont reçu du pemetrexed, soit 130(84%), 114(74%) et 116 (75%)dans les bras observation, gemcitabine, erlotinb respectivement. Le taux de réponse était de 19%, 7% et 15% pour les types non-épidermoide dans les bras observation, gemcitabine, erlotinb. La durée médiane de SSP ne différaient pas entre le bras gemcitabine et observation ( 4,2 vs 3,9 mois, HR 0,81 [0,62 à 1.06]) ou entre erlotinb et observation ( 4,2 vs 3,9 mois, HR 0,83 [0,64 à 1.09]). Les données sur la SG ont montré une amélioration non significative avec la gemcitabine vs observation (HR 0,81 [de 0,61 à 1.07]) ou de erlotinb vs observation (HR 0,80 [0,61 à 1,05]), avec une médiane de 7,5, 8,3 et 9,1 mois pour les bras 0, gemcitabine, erlotinb. Les résultats étaient similaires lorsque l'analyse a été limitée au type non épidermoide. Conclusions: Le traitement de maintenance par gemcitabine ou erlotinb n'a pas altéré l'efficacité de la 2ème ligne par pemetrexed comparativement à l'utilisation après un intervalle libre.Introduction: Maintenance therapy in advanced NSCLC might lead to resistance to subsequent treatments. IFCTGFPC 0502 study showed a progression-free survival (PFS) benefit with gemcitabine or erlotinib maintenance compared to observation after cisplatin-gemcitabine chemotherapy. The trial included a pre-defined pemetrexed secondUne therapy, allowing post-hoc assessment ofits efficacy according to previous maintenance treatment or treatment-free interval. Methods: Stage IIIB/IV NSCLC patients were randomized after 4 cycles of cisplatin-gemcitabine chemotherapy to either observation or to receive maintenance therapy with gemcitabine or erlotinib. Pemetrexed was given as secondline treatment on disease progression in ail arms. PFS and overall survival (OS) were assessed from the beginning of pemetrexed therapy according to randomization arm. Results: Of the 464 randomized patients, 360 (78 %) received second-line pemetrexed (130 (84%], 114 [74%] and 116 [75%] in observation, gemcitabine and erlotinib arm, respectively). Median number ofpernetrexed cycles was 3 (1-40) in ali arms. Median PFS did not differ between gemcitabine and observation arms (4.2 vs. 3.9 months, HR [95% CI] 0.81 [0.62-1.06]) or between erlotinib and observation arms (4.2 vs. 3.9 months, HR 0.83 (0.64-1.09]). OS data showed a non-significant improvement with gemcitabine arm vs. observation arm (8.3 vs 7.5 months, HR 0.81 [0.61-1.07]) or erlotinib arm vs. observation arm (9.1 vs. 7.5 months, HR 0.80 [0.61-1.05]). Results were similar for non-squamous patients. Grade 3-4 treatment-related AEs were comparable in ali arms. Conclusions: Maintenance therapy with gemcitabine continuation or erlotinib did not impair efficacy of second-Une pemetrexed comparatively to administration after a treatment-free interval.LYON1-BU Santé (693882101) / SudocPARIS-Bib. Serv.Santé Armées (751055204) / SudocSudocFranceF

ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date

The ROS-1 gene plays a major role in the oncogenesis of numerous tumors. ROS-1 rearrangement is found in 0.9–2.6% of non-small-cell lung cancers (NSCLCs), mostly lung adenocarcinomas, with a significantly higher rate of women, non-smokers, and a tendency to a younger age. It has been demonstrated that ROS-1 is a true oncogenic driver, and tyrosine kinase inhibitors (TKIs) targeting ROS-1 can block tumor growth and provide clinical benefit for the patient. Since 2016, crizotinib has been the first-line reference therapy, with two-thirds of the patients’ tumors responding and progression-free survival lasting ~20 months. More recently developed are ROS-1-targeting TKIs that are active against resistance mechanisms appearing under crizotinib and have better brain penetration. This review summarizes current knowledge on ROS-1 rearrangement in NSCLCs, including the mechanisms responsible for ROS-1 oncogenicity, epidemiology of ROS-1-positive tumors, methods for detecting rearrangement, phenotypic, histological, and molecular characteristics, and their therapeutic management. Much of this work is devoted to resistance mechanisms and the development of promising new molecules

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

International audienceThe 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

New PDL1 inhibitors for non-small cell lung cancer: focus on pembrolizumab

The advent of immune-checkpoint inhibitors during the past decade represents a major advancement in the treatment of non-small cell lung cancer (NSCLC) with personalized treatment. Platinum-based chemotherapy has reached its efficacy threshold, with its use remaining limited by its toxicity. For NSCLC, inhibitors of the PD1 protein and its ligand PDL1 show promising clinical activity and induce durable responses in patients with advanced disease. The US Food and Drug Administration has approved pembrolizumab for treatment-naïve metastatic NSCLC with $50$1% PDL1 expression after progression following first-line platinum-based doublet chemotherapy. In 2017, it also authorized the first-line combination of pembrolizumab and carboplatin-pemetrexed chemotherapy without selection based on PDL1 expression, but European health authorities are still waiting for the results of a Phase III trial. In this review, the clinical results of published and ongoing studies evaluating pembrolizumab for advanced NSCLC are analyzed and the potential role of PDL1 as a factor predictive of overall responses addressed