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Cet article de formation médicale continue s’attache à résumer les principaux éléments d’un workshop tenu à l’institut Jules Bordet le 30 septembre 2023. Le sujet portait sur le rôle de la double immunothérapie dans les cancers de la cage thoracique. Après trois exposés introductifs, deux ateliers destinés aux médecins et un troisième à destination des infirmières coordinatrices de soins en oncologie (ICSO) ont été tenus. Une présentation des principales conclusions a été faite par chaque coordinateur d’atelier et discutée en séance plénière, info:eu-repo/semantics/published

Biomarkers of systemic inflammation/nutritional status have been associated with outcomes in advanced-stage non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs). However, most of them were not tested in cohorts of patients treated with ICIs in combination with chemotherapy (CT) (ICI + CT) or with CT alone, making it impossible to discriminate a predictive from a prognostic effect. We conducted a single-center retrospective study to search for associations between various baseline biomarkers/scores that reflected the systemic inflammation/nutritional status (Lung Immune Prognostic Index, Modified Lung Immune Prognostic Index, Scottish Inflammatory Prognostic Score, Advanced Lung Cancer Inflammation Index, EPSILoN, Prognostic Nutritional Index, Systemic Immune-Inflammation Index, Gustave Roussy Immune Score, Royal Marsden Hospital Prognostic Score, Lung Immuno-oncology Prognostic Score 3, Lung Immuno-oncology Prognostic Score 4, score published by Holtzman et al., and Glasgow Prognostic Score) and outcomes in metastatic NSCLC treated in a first-line setting either with ICI in monotherapy (cohort 1; n = 75), ICI + CT (cohort 2; n = 56), or CT alone (cohort 3; n = 221). In the three cohorts, the biomarkers/scores were moderately associated with overall survival (OS) and progression-free survival (PFS). Their prognostic performance was relatively poor, with a maximum c-index of 0.66. None of them was specific to ICIs and could help to choose the best treatment modality. The systemic inflammation/nutritional status, associated with outcomes independently of the treatment, is therefore prognostic but not predictive in metastatic NSCLC.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved the prognosis of advanced-stage non-small cell lung cancer (NSCLC) with ALK rearrangement, but resistance mechanisms limit their efficacy. We describe the case of a 63-year-old man with a stage cIVA -rearranged lung adenocarcinoma who developed a A598-T599insV mutation as a potential resistance mechanism to alectinib, a second-generation ALK TKI. He was treated with an association of BRAF and MEK inhibitors but death occurred two months after treatment initiation in a context of tumor progression and toxicity. Based on this first report of A598-T599insV mutation occurring in lung cancer, we discuss resistance mechanisms to ALK TKIs, implications of mutation in NSCLC, and A598-T599insV mutation in other cancers.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have improved the prognosis of advanced-stage non-small cell lung cancer (NSCLC) with ALK rearrangement, but resistance mechanisms limit their efficacy. We describe the case of a 63-year-old man with a stage cIVA ALK-rearranged lung adenocarcinoma who developed a BRAF A598-T599insV mutation as a potential resistance mechanism to alectinib, a second-generation ALK TKI. He was treated with an association of BRAF and MEK inhibitors but death occurred two months after treatment initiation in a context of tumor progression and toxicity. Based on this first report of BRAF A598-T599insV mutation occurring in lung cancer, we discuss resistance mechanisms to ALK TKIs, implications of BRAF mutation in NSCLC, and BRAF A598-T599insV mutation in other cancers., SCOPUS: ar.j, info:eu-repo/semantics/published

Treatment of patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) continues to evolve expeditiously. This retrospective study investigated real-world treatment patterns and EGFR mutation testing in patients with EGFRm advanced NSCLC in Belgium. Data were extracted from medical records of adults diagnosed with EGFRm locally advanced/metastatic NSCLC between 1 September 2015 and 31 December 2017. Patients were followed retrospectively from diagnosis until 1 September 2018, end of clinical activity or death. Data on demographics, patient outcomes and disease characteristics, treatment patterns and EGFR mutation testing at diagnosis and progression were analyzed descriptively. A total of 141 patients were enrolled. At diagnosis, median age was 69 years, 63.1% were female, 88.7% had metastatic disease, 94.3% had adenocarcinoma histology, 76.6% had ECOG 0/1, 70.9% had common EGFR mutations and 29.1% had only rare mutations. In first line, 73.8% of patients received first/second-generation EGFR-tyrosine kinase inhibitors (1G/2G EGFR-TKIs), while 21.9% received other systemic treatments. Among 61 patients progressing on and discontinuing a first 1G/2G EGFR-TKI, 45 (73.8%) received subsequent systemic treatment while 16 (26.2%) did not; 20 (32.8%) received osimertinib. Among 65 patients progressing on a first 1G/2G EGFR-TKI, 47 (72.3%) were tested for T790M, of whom 25 (53.2%) were positive. These real-world data from Belgium show that a substantial fraction of patients with EGFRm NSCLC do not receive 1G/2G EGFR-TKIs in first line and do not receive subsequent systemic treatment after progression on 1G/2G EGFR-TKIs. Only a third receive osimertinib upon progression on 1G/2G EGFR-TKIs. These observations should be considered in first-line treatment decisions. ClinicalTrials.gov: NCT03761901-December 3, 2018.

Cet article décrit les avancées récentes relatives à la prise en charge diagnostique et thérapeutiques des cancers bronchiques à petites cellules. Une place particulière est faite au développement des inhibiteurs des protéines de contrôle de l’immunité. Il cite aussi les points encore débattus autour des explorations préthérapeutiques, de la radiothérapie thoracique, et de l’irradiation prophylactique cérébrale. Enfin, les pistes de thérapie ciblant les anomalies de réparation des dommages de l’ADN sont évoquées., This article describes recent advances in the diagnostic and therapeutic management of small cell lung cancer, particularly, the development of immune checkpoint inhibitors. He also cites still debatable issues such as pre-therapeutic explorations, thoracic radiotherapy, and prophylactic cerebral irradiation. Finally, therapeutic approaches targeting DNA damage repair abnormalities are discussed.

Multiple nonspecific symptoms in a patient treated by pembrolizumab Immune checkpoint inhibitors, such as the receptor programmed cell death protein 1 (PD-1) or PD-1 ligand 1 (PD-L1), which are new therapeutic weapons against cancer, which are increasingly sed nowadays. This case report concerns a 72-year-old man treated by pembrolizumab (Keytruda®), a PD-1 inhibitor, in first-line systemic treatment of an Stage IVA lung adenocarcinoma. Three weeks before his eighth cure, the patient’s general condition deteriorated, including loss of appetite, fatigue, nausea, and a slight weigh loss. He also reported headaches. As an adrenal insufficiency was suspected, a substitution treatment consisting of hydrocortisone was initiated. The originality of this case lies in the relevance of also considering non-specific symptoms in cancer patients under immunotherapy, the emergency of the diagnosis, and the recommended medical management. The aim of this article is direct your attention to this rare but potentially fatal adverse event of immunotherapy, with its new treatments that you will encounter increasingly often in your practice, and to revise some cases already published in the literature , in addition to another personal case.

Introduction : Lung cancer is the most frequent and the deadliest cancer in the world. In non-small cell lung cancer (NSCLC), which represents 85% of all lung cancers, up to 55% patients relapse following surgery alone or in combination with chemotherapy or radiotherapy. Tumor-infiltrating lymphocytes play a key role in the control of the malignancy and display different phenotypes whilst interacting with cancer cells. Hence, immunoglobulin-A (IgA)-producing cells have been described to have an immunosuppressive function, promoting tumor development and growth in hepatocarcinoma and prostate cancer. Due to the important role of IgA in the lung, we aimed to study the prognostic significance of IgA+ cell infiltration in the epithelial and stromal compartments of resected NSCLCs. [...]

Airway stenting offers good palliation and improves the quality of life in patients with inoperable bronchotracheal stenosis. However, in some cases, the management of stenting can be life-threatening. Hence, a strategy for maintaining oxygenation and hemodynamic stability should be anticipated to avoid critical situations. Herein, we report the use of extracorporeal membrane oxygenation (ECMO) in bronchotracheal stenting management to secure oxygenation and facilitate interventions. We retrospectively reviewed all patients who underwent rigid bronchoscopy under ECMO support for the management of bronchotracheal stenting at CHU UCL Namur hospital (Belgium), between January 2009 and December 2019. We included 14 bronchoscopy cases performed on 11 patients (3 patients underwent 2 bronchoscopies) in this study; 12 were performed on males and 2 on females. The median age was 54 years. There were 11 benign and 3 malignant etiologies for the central airway obstruction/stenosis. Eight cases were supported by venovenous ECMO and six by venoarterial ECMO. The median ECMO time was 267 minutes. The weaning of ECMO support was successful in all cases. In most cases, the procedures were performed effectively and safely. Only two local complications caused by the cannulation of ECMO were reported, and anticoagulation was adapted to avoid bleeding at the operating site and clot formation in the system. Elective ECMO support was helpful and safe for the high-risk management of bronchotracheal stenting with rigid bronchoscopy and was not associated with any additional significant complications.

Osimertinib has become a standard of care in the first-line treatment of advanced-stage non-small-cell lung cancer (NSCLC) harboring exon 19 and 21 activating mutations in the gene. Nevertheless, the 18.9-month median progression-free survival emphasizes the fact that resistance to osimertinib therapy is inevitable. Acquired resistance mechanisms to osimertinib in EGFR-driven NSCLC include amplification, C797S mutation, neuroendocrine differentiation, small-cell lung carcinoma histologic transformation, and amplifications and and translocations, as well as V600 mutation. This last one represents 3% of the acquired resistance mechanisms to osimertinib. In this review, we discuss the rationale for EGFR/BRAF/MEK co-inhibition in the light of a clinical case of -mutant NSCLC developing a V600 mutation as an acquired resistance mechanism to osimertinib and responding to the association of osimertinib plus dabrafenib and trametinib. Additionally, we discuss the acquired resistance mechanisms to osimertinib plus dabrafenib and trametinib combination in that context.

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Treatment with pembrolizumab, an anti-programmed cell death-1 (PDCD-1) monoclonal antibody for the treatment of non-small cell lung cancers (NSCLCs) requires prior immunohistochemical (IHC) analysis of the expression of the programmed death-ligand 1 (PD-L1) (also known as CD274 molecule) which is a heterogeneous and complex marker. The present study aimed to investigate how pathological and technical factors (such as tumor location and sampling type, respectively) may affect the PD-L1 evaluation in patients with NSCLC in the daily practice of pathology laboratories. The current study was retrospective, and included 454 patients with NSCLC, for whom PD-L1 expression analysis by IHC was prospectively performed between November 2016 and January 2018. The association between PD-L1 expression and the clinicopathological characteristics of patients was statistically investigated using either the χ2 and Fisher exact tests or the Mann-Whitney and Kruskal-Wallis tests, depending on whether PD-L1 expression was assessed in three large categories (<1, 1-49, ≥50%) or in more precise percentages. Furthermore, the same statistical methodology was used to analyze the heterogeneity of PD-L1 expression according to its sampling type (cytology, biopsy or surgical specimen) and its location (primary tumor, lymph node or distant metastasis). Intra- and inter-observer discrepancies were also studied using double-blind evaluation and concordance analyses based on the weighted κ coefficient. The results demonstrated a significant association between PD-L1 expression and sample location (P=0.005), histological type (P=0.026), total number of mutations (P=0.004) and KRAS proto-oncogene, GTPase mutations (P=0.024). In addition, sampling type did not influence PD-L1 expression. The inter- and intra-observer discrepancies were 15% and between 16 and 17.5%, respectively. The present study confirmed that evaluation of PD-L1 expression by IHC can be performed on all types of samples. In addition, info:eu-repo/semantics/published

RATIONALE: Accumulation of B cells and lymphoid follicles (LFs) has been described in chronic obstructive pulmonary disease (COPD) airways, but the functional status of lung B cells remains poorly known. OBJECTIVES: To characterize LFs for expression of IgA, the main mucosal antibody. METHODS: The presence of B cells and LFs, including intrafollicular IgA expression, were determined in the lung from patients with COPD (n = 37) versus control subjects (n = 34) by immunohistochemistry. We also evaluated follicular IgA responses in the lungs from mice infected with Pseudomonas aeruginosa (PAO1) (n = 10 per group) and in smoking mice. MEASUREMENTS AND MAIN RESULTS: Whereas in smokers B-cell numbers slightly increased, robust increases in B-cell and LF numbers (mainly in distal airways) were only observed in severe COPD. Most follicular B cells were IgM+ (70-80%), but IgA+ (and not IgG+) B-cell numbers were increased in LFs from severe COPD compared with control subjects (twofold, 44.7% vs. 25.2%), and this was significant in distal but not proximal airways. Follicular IgA response was also observed in PAO1-infected mouse lungs, but not after smoke exposure. Moreover, follicular IgA expression associated with expression of IL-21, which was very potent to activate immunoglobulin production in vitro. CONCLUSIONS: This study shows that IgA production occurs in peribronchiolar LFs from severe COPD, where IL-21-producing T cells are present, and presumably represents a feature of exacerbated mucosal adaptive immune responses against microbial and/or self-antigens.

Lung large-cell neuroendocrine carcinoma (L-LCNEC) is a rare subset of lung carcinoma associated with poor overall survival. Due to its rarity, little has been established about its optimal treatment in the advanced stage. We report the case of a 41-year-old woman diagnosed with an unresectable locally advanced L-LCNEC who presented an impressive tumor response to immunotherapy with nivolumab after non-curative thoracic radiotherapy. Salvage surgery was then performed, and pathologic analysis of the resected piece revealed the absence of residual viable tumor cells. Based on this case report, we discuss the literature regarding the efficacy of inhibitors of programmed death-1 protein (PD-1) in L-LCNEC and their use in association with radiotherapy and in the neoadjuvant setting.

BACKGROUND: To evaluate the outcome of patients treated with stereotactic ablative body radiotherapy (SABR) with curative intent for stage I non-small cell lung cancer (NSCLC) with regard to local, regional and distant tumor control, disease-free survival (DFS), overall survival (OS) and toxicity. METHODS: Data of 300 patients treated with SABR for NSCLC cancer for the period of November 2007 to June 2016 were retrospectively analyzed. Of which, 189 patients had single primary lung lesion and were included in the study. The prescribed dose for the tumor was 48 Gy, given in 12 Gy × 4 fractions for all patients. In 2010, an improved protocol was established in advanced technology for the planning CT, dose calculation and imaging. Cumulative incidence function (CIF) of local, regional, distant or any recurrences were computed using competing risk analysis with death as a competing event. Survivals (DFS and OS) were estimated using the Kaplan-Meier method and Cox proportional regression was used for comparisons. Toxicities were graded according to the common terminology criteria for adverse events version 4.0 (CTCAE v.4). RESULTS: Diagnosis was histologically confirmed in 42% of the patients (N = 80). At 1, 2 and 4 years, the cumulative incidence function (CIF) of local relapses were 8% [4-13%], 15% [10-21%] and 18% [12-25%], the CIF of regional relapses were 4% [2-8%], 10% [6-16%] and 12% [8-19%], the CIF of distant relapses were 9% [5-14%], 15% [11-22%] and 20% [15-28%] and the CIF of any relapses were 14% [10-20%], 28% [22-36%], 34% [27-43%], respectively. After 1, 2 and 4 years, the OS rates were 83% [95% CI: 78-89%] (N = 128), 65% [95% CI: 57-73%] (N = 78) and 37% [95% CI: 29-47%] (N = 53), respectively. The median survival time was 37 months. The DFS after 1, 2 and 4 years reached 75% [95% CI: 68-81%] (N = 114), 49% [95% CI: 42-58%] (N = 60) and 31% [95% CI: 24-41%] (N = 41), respectively. No grade 4 or 5 toxicity was observed. CONCLUSIONS: We observed a long-term