NUT carcinoma (NC) is a rare, aggressive tumor with poor prognosis and no standard treatment. NC arises from NUTM1 gene rearrangements, which drive epigenetic dysregulation and uncontrolled proliferation via enhanced RNA polymerase II (RNA-pol II) activity. An analysis of our registry (70 patient) revealed limited benefits from current systemic therapies. Among patients on first-line (26), progression-free survival was modest: immunotherapy (5.4months-mo-, 95%CI 3.6-7.1), chemo-immunotherapy(CTIO) (4.8mo, 95%CI 0.2-8.8), BET inhibitors (4.3mo, 95%CI 1-17.1), and chemotherapy (3.9mo, 95%CI 1.7-52.1). Given Lurbinectedin’s (LUR) RNA-pol II-dependent mechanism and its regulation of BRD4, a critical partner of NUTM1, we investigated its potential therapeutic value in NC. LUR efficacy was assessed in three settings. First, in vitro studies by 4 BRD4:NUTM1 cell lines treated with escalating doses of LUR for 72 hours, and cell viability evaluated by MTT assays. Second, in vivo, with 2 patient-derived xenograft (PDX) models. Finally, under compassionate use, 3 patients with BRD4:NUTM1. NC cell lines demonstrated high sensitivity to LUR, with IC50: 22-122nM. Ongoing PDX model experiments are evaluating in vivo sensitivity. Clinically, a 54-year-old woman with metastatic thoracic NC pretreated with CTIO, showed rapid clinical and radiological response to second-line LUR, with a 3mo duration of response. A 20-year-old man with head and neck metastatic NC pretreated with VDC/IE, had clinical improvement (ECOG-PS, weight gain, and reduced morphine use) after a first cycle (imaging pending for response confirmation). The third patient, recently initiated second-line LUR. Preliminary results suggest that LUR shows promising activity in NC, both in vitro and in early clinical cases. LUR offers a biologically informed therapeutic strategy in NC. These findings highlight the importance of leveraging tumor biology to guide treatment development for rare and aggressive cancers Maria Virginia Sanchez-Becerra, Carmen Escudero-Iriarte, Ludovic Bigot, Tian V Tian, Pablo Aviles-Marin, Magdalena Knetki-Wróblewska, Sinead Oreilly, Mateo Bover, José Carlos Benitez-Montañez, Paloma Martin-Martorell, Sergio Sandiego Contreras, Maria Rosa Ghigna, Christos Markellos, Mickael Burgy, Camille Travert, Pauline Hulo, Mangon Quentin, Rodrigo Motta Guerrero, Jeanne Chapron, Nathalie Cozic, Luc Friboulet, Yohann Loriot, Antoine Italiano, Benjamin Besse. New therapeutic approaches in NUT carcinoma: An unmet need [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5996.

OBJECTIVE:Recent evidence suggests that elevated levels of PD-L1 expression may be linked to early resistance to TKI and reduced survival in NSCLC with EGFR mutations. This study aimed to characterize the clinical and molecular features of EGFR-mutated lung adenocarcinomas and determine the prognostic significance associated with high PD-L1 expression. MATERIALS AND METHODS:We conducted a retrospective chart review of 103 consecutive patients with advanced EGFR-mutated NSCLC, who received treatment between 01/01/2016 and 30/12/2020, at our institution. RESULTS:Among the tumors, 17% (n = 18) exhibited high PD-L1 expression (≥50% tumor proportion score), which was associated with a lower prevalence of common EGFR mutations (56% vs. 82%, p = 0.03) and a higher frequency of complex EGFR mutations (28% vs. 7%, p = 0.02). Univariate analysis did not reveal any significant differences in first-line response, progression-free survival, or overall survival between the PD-L1 ≥50% and <50% groups. However, multivariate analysis demonstrated that PD-L1 ≥50% was independently associated with shorter survival (HR = 2.57; 95%CI[1.20-5.55]; p = 0.02), along with male gender (HR = 2.77; 95%CI[1.54-4.19]; p<0.005), presence of liver metastases (HR = 5.80; 95%CI[2.86-11.75]; p<0.005) or brain metastases (HR = 1.99; 95%CI[1.13-3.52]; p = 0.02), and poor general condition at diagnosis (ECOG 3 and 4) (HR = 10.69; 95% CI[4.42-25.85]; p<0.005). Additionally, a trend towards a higher frequency of de novo resistance was observed in the PD-L1 >50% group (7% vs. 17%, p = 0.19). CONCLUSION:High PD-L1 expression was more commonly found in lung adenocarcinomas with uncommon and complex EGFR mutations. Furthermore, high PD-L1 expression independently predicted poor survival. These findings warrant validation through prospective studies.

Background:Pulmonary sarcomatoid carcinomas (PSC) are notorious for their poor prognosis and resistance to chemotherapy. The literature suggests that immunotherapy might be effective against this aggressive tumor. This study aims to evaluate the efficacy of immunotherapy, either alone or combined with chemotherapy, as first-line treatment for PSC patients. Methods:In a retrospective, multicentric, real-world study conducted between July 2017 and April 2021, patients with stage III (ineligible for surgery or radio-chemotherapy) or stage IV PSC were enrolled. These patients received their first-line treatment with immunotherapy and were categorized into two groups based on their treatment modality: the immuno-chemotherapy (IO CT) group or the immunotherapy-alone (IO) group. Results:This study analyzed a population of 34 patients from eight different hospital centers. In this cohort, the objective response rate (ORR) was 56%, median duration of response was 20.5 months, median progression-free survival (PFS) was 5.11 months, and median overall survival (OS) 13.9 months. Demographic characteristics remained consistent among the treatment groups except for the age (54.0- and 71.0-year-old in the IO CT and IO group, respectively, P=0.02). The IO CT group demonstrated an ORR of 64.0%, a median PFS at 8.72 months, and a median OS of 16.08 months, while the IO group displayed respective values of 52.0%, 3.45 months, and 13.11 months. Conclusions:This study showed the potential efficacy of immunotherapy as a first-line treatment for PSC. While acknowledging the retrospective nature of the study, our findings suggest a trend favoring the combination of IO CT over IO alone in these patients.

NC represents a rare malignancy with a devastating prognosis. It's produced by the rearrangement of the NUTM1 gene, affecting people of all ages and arising from different localisations, the thoracic being the most common. Due to its rarity and heterogeneity, there is no standard of care for NC and most of the evidence comes from retrospective series. Ambispect multicentric international study for the clinical and therapeutic characterisation of NC. The primary endpoint is to describe first-line treatment and survival in a non-curative and curative setting. Secondary endpoints are to describe baseline characteristics and prognostic. Characteristics will be defined in terms of frequency, median with confidence intervals. The Kaplan-Meier estimate stratified by treatment type will be applied. 51 patients (28 from France, 10 Spain, 6 Poland, 5 United States, 1 Greece, and 1 Peru) have been included. The median age was 34 years and 60% were men. The most common partner of fusion was BRD4 (23%), and the thoracic area was the most frequent primary site (51%), followed by the head and neck (45%). 16% of the patients had localised disease, 37% locally advanced, and 47% metastatic. 51% of the patients were in the poor prognostic group, while 10% and 4% had intermediate and good prognostic. 25 patients underwent a curative intention approach and 26 underwent palliative treatment. The median number of treatment lines was 2. With a median follow-up of 27 months, in the whole population, median overall survival (OS) was 9 months (95%CI 6.4-20.4). OS and Progression Free Survival (PFS) for each type of treatment is summarized in the table. Table: 147ONPFS (months)OS (months)Median (95%CI)Median (95%CI)Curative253.8 (2.5-7.4)8.7 (4.8-20.4)Surgery42.1 (0.4-2.5)NRChemoradiotherapy106.7 (1.2-7.6)9.0 (3.9-NR)Multimodal approach115.2 (2.9-8.7)5.7 (2.1-9.3)Palliative264.0 (3.6-8.1)9.4 (5.6-22.0)Chemotherapy83.9 (1.7-52.1)6.4 (1.9-22.0)BET inhibitors84.3 (1.0-17.1)5.6 (1.1-29.4)Chemo-immunotherapy84.8 (0.2-8.8)21.3 (6.7-26.5)Immunotherapy25.4 (3.6-7.1)19.4 (9.4-29.3) Open table in a new tab The multidisciplinary approach represents a cornerstone of curative treatment. Chemoimmunotherapy could have a potential role in the metastatic setting. The International Registry is a powerful tool in rare tumours such as NC.

Lung cancer is the leading cause of cancer death in France and worldwide (20 % of cancer deaths). This mortality is partly linked to an overrepresentation of metastatic stages at diagnosis (approximately 55 % of lung cancers at diagnosis). Low-dose chest CT in a target population to detect early forms accessible to radical treatment has been evaluated through multiple rando-mized trials (NLST, NELSON, MILD, DANTE. . .). These trials demonstrated a reduction in lung cancer specific mortality. The current problem is to integrate a CT screening policy CT at a national level, which should be both efficient and cost-effective, while presenting the least harms for the eligible population. Finally, it is necessary to optimize the participation of the eligible population and particularly in the most deprived areas and ensure the proper implementation of smoking cessation measures.

Des mutations activatrices du gène EGFR (Epidermal Growth Factor) sont mises en évidence dans 10 à 12 % des cancers bronchiques non à petites cellules (CBNPC) non épidermoïdes, Le développement des inhibiteurs de tyrosine kinase (ITK) représente une avancée majeure dans la prise en charge de ces cancers. Programmed Death-Ligand (PD-L1) est faiblement exprimé dans les CBNPC avec mutation de l’EGFR [1]. Des données récentes suggèrent qu’un taux élevé (> 50 %) pourrait être associé à une résistance précoce aux ITK et à une survie globale diminuée [2]. Les objectifs de cette étude étaient (1) la caractérisation des adénocarcinomes pulmonaires mutés EGFR et avec forte expression de PD-L1, (2) l’impact de PD-L1 sur la réponse et la survie. Une analyse exploratoire a également évalué l’évolution de l’expression de PD-L1 à progression après une première ligne de traitement. Analyse rétrospective des patients de plus de 18 ans, atteints d’un CBNPC de stade avancé ayant bénéficié d’une analyse histologique, moléculaire par NGS et de l’expression de PD-L1 par immunohistochimie entre le 01/01/2016 et 30/12/2020. Étaient inclus les patients avec une tumeur mutée EGFR, avec analyse de l’expression de PD-L1 en immunohistochimie au diagnostic. Les données ont été recueillies par analyse du dossier, la dernière date de point était le 30/06/2022. L’avis favorable du comité d’éthique CERAPHP. Centre a été obtenu le 03/06/2021. Au total, 103 patients étaient inclus. Un taux de PD-L1 fortement exprimé (≥ 50 %) était observé chez 17 % des patients et était associé à une plus faible fréquence des mutations communes (56 % vs 82 %, p = 0,03), à une plus grande fréquence des mutations complexes (28 % contre 7 %, p = 0,02) et à l’absence de co-mutation de CTNNB1 (0 sur 18 contre 8 sur 85 patients, p = 0,34). Il n’y avait pas de différence significative de réponse à la première ligne de traitement (84 % contre 76 % de maladie contrôlée), ni de survie sans progression (SSP 10 mois vs 11 mois), ni de survie globale (SG médiane 28 mois vs 29 mois) respectivement entre les groupes PD-L1 ≥ 50 % et < 50 %. Néanmoins, le taux de PD-L1 ≥ 50 % était associé en analyse multivariée à une survie plus courte (HR = 2,09 ; IC95 % [1,06–4,12] ; p = 0,03), ainsi que le sexe masculin (HR = 2,12 ; IC95 % [1,09–4,14] ; p = 0,03), la présence de métastases hépatiques (HR = 3,94 ; IC95 % [2,76–8,80] ; p < 0,005) ou cérébrales (HR = 2,07 ; IC95 % [1,20–3,57] ; p = 0,01), l’état général au diagnostic (HR = 18,89 ; IC95 % [4,92–72,61] ; p < 0,005) et la présence d’une mutation complexe d’EGFR (HR = 2,59 ; IC95 % [1,29–5,18] ; p = 0,01). Il existait une modification significative (variation absolue de 30 %) du taux de PD-L1 à la progression chez 30 % (6/20) des patients, avec une augmentation de l’expression de PD-L1 chez 15 % (3/20) des patients. Une forte expression de PDL1 était plus fréquemment observée dans le cas de mutation EGFR non commune et/ou complexe. Une forte expression de PD-L1 était un facteur indépendant de mauvais pronostic sur la survie. Ces résultats méritent d’être confirmés sur des études prospectives, afin de préciser la place de ce biomarqueur pour orienter la stratégie thérapeutique dans les CBNPC EGFR muté.

Introduction Lung cancer remains the leading cause of cancer mortality in France, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of lung cancer cases. Several studies have highlighted the role of neutrophils (PMN) in immune tolerance and tumor progression in NSCLC, but their functions and phenotypes are poorly characterized. Our hypothesis is that defined PMN subpopulations endowed with specific activities are involved in NSCLC progression. Methods Blood from 25 patients with metastatic NSCLC was collected. Ficoll gradient separates low-density neutrophils (LDN) from conventional normal density neutrophils. Membrane phenotype was examined using a 24 markers panel with an Aurora spectral cytometer. Functional analysis of NADPH oxidase-dependent ROS production has been determined in whole blood PMN by luminol-amplified luminescence. We recruited 24 healthy donors (HD) from the Établissement Français du Sang. All data have been collected according to ethics rules (CPP number 22.04.07). Results PMN counts showed a significant increase in NSCLC patients compared to HD. Analysis of markers in whole blood shows a significant decrease in surface antigen related to differentiation and maturity, especially the expression of CD10, CD13 and CD16 in PMN from NSCLCs compared to HD. No significant difference was observed in activation markers such as CD11b, CD66b and FPR1 between NSCLC PMN compared to HD. Regarding metabolic markers, a significant increase in the membrane expression of GLUT1 was observed in NSCLC PMN compared to HD. Analysis of PMN subsets was next performed according to the double labelling CD16/CD62L which allows discriminating nuclear morphology, function and phenotype of neutrophils according to an established method. In HD, the subset of CD16high/CD62Lhigh represents the majority of the PMN (Fig. 1). A new subset characterized by CD16high/CD62Llow was observed in NSCLC patients, indicative of chronic inflammatory state. Interestingly, the percentage of LDN was significantly increased in NSCLC patients compared to HD. In addition, the major difference between HD and NSCLC patients was the presence of subsets within the LDN fraction with an immature (CD16low/CD62Llow) phenotype. Concerning PMN function, NADPH oxidase-dependent ROS production measured in whole blood was significantly increased in NSCLC patients compared to HD. Conclusion We discovered new subpopulations in NSCLC normal and low density neutrophils which represent a disturbance in PMN phenotype, function, and metabolism which could open to new therapeutic or prognostic strategies.

Le cancer du poumon est la principale cause de mortalité par cancer en France et dans le monde (20 % des décès par cancer). Cette mortalité élevée est liée en partie à une sur-représentativité des stades métastatiques au diagnostic (environ 55 % des cancers du poumon au diagnostic). Le scanner thoracique à faible dose d’irradiation dans une population cible pour détecter les formes précoces accessibles à un traitement radical a été évalué à travers de multiples essais randomisés (NLST, NELSON, MILD, DANTE…). Ces essais ont démontré une réduction de la mortalité spécifique par cancer du poumon. La problématique actuelle est d’intégrer une politique de dépistage par scanner thoracique à un échelon national, qui serait à la fois efficiente et coût-efficace, tout en présentant le moins de risques pour la population éligible. Enfin, il est nécessaire d’optimiser la participation de la population éligible et notamment des populations les plus précaires sur le plan socio-économique et de s’assurer de la mise en place des mesures d’aide au sevrage tabagique nécessaires.

NC represents an ultra-rare underdiagnosed malignancy, with a devastating prognosis. It is caused by the rearrangement of NUTM1, that through epigenetic changes enhances cell proliferation and dedifferentiation. Due to its low frequency and heterogeneity, few clinical trials have been conducted, mainly with BET inhibitors. Since there is no standard of care, we conducted a retrospective study of patients with NC treated in Institut Gustave Roussy and Hôpital Cochin.

Rationale: Malnutrition is associated with immune dysfunction and inflammatory processes. Immune checkpoint inhibitors (ICI) provide an immense breakthrough in cancer therapeutics, especially for lung cancer. However, a significant proportion of patients (pts) experienced disease progression shortly after starting single-agent ICI treatment even after biomarker selection, such as programmed cell death-ligand 1(PD-L1). We studied the relationship between nutritional biomarkers and benefit from ICI among pts with mNSCLC.

Anti PD1(L)1 show improved overall survival (OS) benefits over conventional treatments in several cancer types. However, the optimal therapy duration for responder patients is still debated. This study aimed to provide real-life data across different tumor types after anti PD(L)1 discontinuation for patients who stopped immunotherapy without disease progression. Data from patients treated at Cochin Hospital and Georges Pompidou European Hospital between January 2015 and December 2019 with anti PD(L)1 monotherapy, for whom treatment was discontinued within the first 2 years without disease progression were retrospectively analyzed. Long term outcomes and clinical and biological factors associated with survival were assessed. Cox proportional hazard regression models were used for survival analyses. At the time of analysis, 69 patients (51% NSCLC) treated with anti PD(L)1 had stopped therapy without disease progression, because of controlled disease (54%, including 26% of complete response (CR)), or adverse event (46%). The median treatment duration was 6.9 months (0.5-24.6). Median progression free survival after therapy discontinuation (dPFS) was 11.9 months, 95%CI [10.3-NA] and the median OS was not reached after a median follow up of 29 months. In univariate analysis, the type of response seemed to have an impact on OS (CR vs PR: HR 9.01, p = 0.036). A longer therapy duration was significantly associated with longer OS (HR 0.908, p=0.047). Discontinuation after 6 months was associated with longer dPFS (HR 0.506, p =0.0471) and OS (HR 0.3, p = 0.031) than within the first 6 months. Similar results were found among complete responders. Discontinuation because of adverse event rather than controlled disease was associated with shorter OS (HR 2.9; p=0.048). Secondary progression occurred in 36 patients (56%), of whom 21 received treatment rechallenge, with 33% ORR and 21% CR rate. These results suggest that patients who do not experience disease progression and discontinue antiPD(L)1 therapy before 2 years may have long term benefits and can benefit from treatment rechallenge. Patients treated for less than 6 months seem to have poorer prognosis, even among complete responders.

BACKGROUND:The occurrence of severe, acute limiting toxicity in patients receiving anti-programmed cell death receptor-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found to be associated with anti-cytotoxic T-lymphocyte-associated protein 4 acute toxicity. We explore the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition. METHODS:From June 2015 to January 2017, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship between muscle mass assessed by computed tomography, nivolumab trough level (Cmin) at day 14 assessed using the enzyme-linked immunosorbent assay method, and the occurrence of immune grade III or IV toxicity or any toxicity leading to treatment discontinuation (immune-related acute limiting toxicity [irALT]). RESULTS:In our population (n = 92) with a majority of lung cancer (72%), forty-five (51.7%) patients were sarcopenic. The median plasma nivolumab Cmin at day 14 was 15.4 μg/mL (interquartile range = 11.8-21.0). In multivariate analysis, hypoalbuminaemia (<35 g/L) was independently associated with low nivolumab Cmin on day 14 (odds ratio [OR] = 0.09; 95% confidence interval [CI] = 0.01-0.59, p = 0.01) and overweight/obesity with high nivolumab Cmin on day 14 (OR = 5.94; 95% CI = 1.25-28.29, p = 0.03). We observed 22 irALTs in 19 patients (21%). The most frequent irALT was respiratory (6.5%) disorders and gastrointestinal (4.3%) disorders. Patients with sarcopenia were at significantly increased risk of experiencing an irALT (OR = 3.84; 95% CI = 1.02-14.46, p = 0.047). No association was found between toxicity and nivolumab plasma Cmin at day 14. CONCLUSIONS:Our results highlight the importance of assessing body composition and suggest that sarcopenia could predict severe immune-related toxicity of nivolumab in real life.

Background & aims: Metastatic non-small cell lung cancer (NSCLC) is the first cause of cancer death worldwide. Increased resting energy expenditure (REE) is frequent among cancer patients and may contribute to cancer cachexia. The aim of this study was to examine the prognostic value of increased REE in metastatic NSCLC patients. Methods: This observational study was conducted between June 2012 and November 2017 in the outpatient unit of the oncology department of Cochin hospital, Paris. Consecutive patients with newly diagnosed stage IV NSCLC underwent measurement of REE by indirect calorimetry before treatment initiation. Uni- and multivariate analysis of overall survival (OS, Cox models) included age, sex, smoking habit, histological subtype, performance status, body mass index, weight loss, albumin and CRP levels and the ratio of measured REE to the REE predicted by the Harris Benedict formula (mREE/pREE). Results: 144 patients were enrolled: mean age 64 years, 63% male, 90% non-squamous carcinoma, including 17% with ALK/EGFR alteration. In univariate analysis, tobacco consumption (p = 0.007), histomolecular subtype (p < 10(-3)), performance status (p = 0.04), weight loss (p < 10(-4)), albumin (p < 10(-4)), CRP (p = 0.001) and mREE/pREE ratio (>vs <= 120%: HR = 2.16, p < 10(-3)) were significant prognostic factors of OS. Median OS were 6.1 and 17.3 months in patients with mREE/pREE ratio > and <= 120%, respectively. In multivariate analysis, histomolecular subtype (non-squamous ALK/EGFR mutated vs squamous carcinoma: HR = 0.25, p = 0.006), weight loss (>vs <= 5%: HR = 1.98, p = 0.004), albumin (>= vs < 35 g/L: HR = 0.56, p = 0.02) and mREE/pREE ratio (> vs <= 120%: HR = 1.90, p = 0.004) were identified as independent prognostic factors. Conclusions: Elevated resting energy expenditure emerges as an independent prognostic factor in metastatic NSCLC. (C) 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Pharmacokinetic/pharmacodynamic data from real-world cohort are sparse in non small–cell lung cancer (NSCLC) patients treated with nivolumab. The aim of this prospective observational study was to explore the exposure-response relationship for effectiveness and toxicity of nivolumab in 81 outpatients with metastatic lung cancer. Nivolumab plasma trough concentrations (Cmin) were assayed at days 14, 28, and 42. Prognostic factors (including Cmin) regarding progression-free survival (PFS) and overall survival (OS) were explored using a multivariate Cox model. A Spearman’s rank test was used to investigate the relationship between Cmin and grade >2 immune-related adverse events (irAE). Mean nivolumab Cmin was 16.2 ± 6.0 µg/mL (n = 76), 25.6 ± 10.2 µg/mL (n = 64) and 33.4 ± 11.3 µg/mL (n = 53) at days 14, 28, and 42, respectively. No pharmacokinetic/pharmacodynamic (PK/PD) relationship was observed with either survival or onset of irAE. Multivariable Cox regression analysis identified Eastern Cooperative Oncology Group Performance Status (hazard ratio 1.85, 95%confidence interval 1.02–3.38, p-value = 0.043) and baseline use of corticosteroids (HR 8.08, 95%CI 1.78–36.62, p-value = 0.007) as independent risk factor for PFS and only baseline use of corticosteroids (HR 6.29, 95%CI 1.46–27.08, p-value = 0.013) for OS. No PK/PD relationship for nivolumab was observed in real-world NSCLC patients. This supports the recent use of flat dose regimens without plasma drug monitoring.

Le cancer bronchique est la première cause de décès par cancer en France, avec environ 30 000 décès par an. La très grande majorité (90 %) des cancers bronchiques est liée au tabac. Le pronostic est sombre mais de grandes avancées thérapeutiques ont été réalisées avec le développement des thérapies ciblées d’abord puis de l’immunothérapie ensuite. Ces médicaments sont conditionnés à l’expression de biomarqueurs qui nécessitent des outils spécifiques en routine pour les mesurer. Nous détaillerons dans ce chapitre plusieurs techniques d’anatomopathologie, de cytogénétique et de biologie moléculaire nécessaires à la détection des biomarqueurs dans les cancers du poumon, et leurs applications en oncologie thoracique en 2018.

Les inhibiteurs des points de contrôle (IPC) sont des anticorps monoclonaux qui bloquent l’interaction entre un point de contrôle et son ligand, afin de lever l’inhibition du système immunitaire issue de cette interaction, et de favoriser une réponse anti-tumorale. Les principaux points de contrôle sont PD-1 (Programmed Death 1) et CTLA-4 (Cytotoxic T-lymphocyte Associated 4).

Abstract Background: Immune evasion and deregulation of energy metabolism play a pivotal role in cancer progression. Immunosuppression in the tumor microenvironment can be based on the mutual metabolic requirements of immune and tumor cells. We evaluated the value of resting energy expenditure (REE) as a predictor of outcome, in mNSCLC patients under Nivolumab, an immune checkpoint inhibitor. Methods: We studied the relation between REE, clinical and biological markers of cachexia and inflammation, and response to Nivolumab in 82 consecutive mNSCLC patients. Efficacy was assessed every 2 months according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. REE was measured using indirect calorimetry, before the initiation of Nivolumab. According to their REE and with the use of Boothby's standard, patients were categorized as hypermetabolic, normometabolic and hypometabolic. Body mass index (BMI), performance status (PS), C-reactive protein (CRP), albumin, Neutrophil Lymphocyte R Ratio (NLR) and PD-L1 tumor expression were also recorded. Results: Patients characteristics were: 62% males, median age of 65 years (range 37-78), 61% PS 0-1, median BMI of 24 kg.m-² (range 17-39), 78% nonsquamous NSCLC. The analysis of REE was available for 69 out of 82 consecutive pts: 37.7% were hypermetabolic, 47.8% were normometabolic, and 14.5% were hypometabolic. In univariate analysis, hypometabolism was a strong predictive marker of disease progression (Table 1), with positive and negative predictive values of 0.80 and 0.52 respectively. In multivariate analysis, independent parameters associated with disease progression were baseline hypometabolism (vs normometabolism: OR 1.77 [1.31-2.39] p= 0.0004) and albumin (per 1pt increase: OR 0.96 [0.94-0.99] p= 0.005). Conclusion: Rest energy expenditure assessed by calorimetry appears as a biomarker of nivolumab clinical activity independently of PD1/PDL1 status. Table 1Disease control (best response) n (%)<85% calculated REE n=10 (14.5%) Hypometabolic85-115% calculated REE n=33 (47.8%) Normometabolic>115% calculated REE n=26 (37.7%) Hypermetabolicunivariate OR (Hypometabolic vs normometabolic)pProgression8 (80%)11 (33%)17 (65%)8 [1.4-44.2]0.0007Disease control rate2 (20%)22 (67%)9 (35%) Citation Format: Claire Gervais, Pascaline Boudou-Rouquette, Anne Jouinot, Jeanne Chapron, Jennifer Arrondeau, Marco Alifano, Frédérique Giraud, Olivier Huillard, Jérôme Alexandre, Clara Vazeille, Jean-Philippe Durand, Karen Leroy, Marie-Pierre Revel, Jean-Pascal de Bandt, Luc Cynober, Diane Damotte, Audrey Lupo-Mansuet, François Goldwasser. Prediction of the efficacy of nivolumab using resting energy expenditure in metastatic non-small cell lung cancer (mNSCLC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1693.

3066 Background: The occurrence of severe, acute limiting toxicity in patients receiving anti-PD-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found associated with anti-CTLA4 acute toxicity (Daly LE et al, Br J Cancer 2017). We studied the clinical and pharmacological parameters influencing nivolumab toxicity, including body composition. Methods: From June 2015 to December 2016, all consecutive patients treated with nivolumab in our institution were prospectively included. We studied the relationship, using logistic regression, between muscle mass, assessed by computed tomography and by Janmahasatian formula, nivolumab trough levels (Cmin) assayed using ELISA method, and the occurrence of grade 3 or 4 toxicity or any toxicity leading to treatment discontinuation (ALT). Univariate and multivariate analysis were made for parameters associated with nivolumab concentration. Results: Out of 92 patients, 81 were analyzable for body composition and 84 for nivolumab pharmacokinetics. The population included 63% males, median age 65 years, a majority had lung cancer (72%). We observed 20 ALT including 4 pneumonitis and 4 colitis in 20 (21.7%) patients and 825 (2.4%) nivolumab infusions. The ALT events were more frequent in sarcopenic patients (OR = 3.29, 95% CI: 0.96-11.28, p = 0.06). Sarcopenic overweight patients were the most susceptible to experience ALT (OR = 5.08, CI: 0.53-48.9; p = 0,16), as already reported by our group in melanoma patients (Heidelberger V et al, Invest N Drugs, 2017). The nivolumab Cmin was 17.0 ± 5.9 μg/mL on day 14. In multivariate analysis, low nivolumab Cmin was independently associated with hypoalbuminemia ( < 35g/L) (OR = 0.03, 95% CI: 0.002-0.34, p = 0.005) and sarcopenia (OR = 0.13, 95% CI: 0.03-0.54, p = 0.005). The recycling of albumin and nivolumab is both mediated by the neonatal Fc receptor (FcRn) and therefore albumin levels may reflect the abundance and efficiency of FcRn. Conclusions: Body composition influences both nivolumab pharmacokinetics and acute toxicity.