BackgroundBlocking programmed cell death protein 1 (PD-1) has become a standard cancer immunotherapy, increasingly used in kidney, liver, or heart transplant recipients who develop skin cancer or hepatocellular carcinoma, despite the increased risk of graft failure or rejection. The mechanism of action of PD-1 blockade relies on stimulating CD8+ T cell activity, but its impact on humoral immunity in general and on alloimmunization in particular remains uncertain.ObjectiveThe aim of this study was to investigate the impact on anti-PD-1 treatment on alloimmunization.MethodsThe effect of anti-PD-1 treatment on the generation of anti-HLA (Human Leucocyte Antigen) antibodies was investigated in 72 patients with non-small cell lung cancer vaccinated with an allogeneic plasmacytoid dendritic cell line (PDC*line; six weekly injections), with or without pembrolizumab administered every three weeks. The kinetics and functionality of the anti-HLA generated were analyzed.ResultsThe results show that 51.4% of the patients developed anti-HLA antibodies, primarily dependent on the vaccine dose. In 60% of cases, the antibody response appeared after the sixth injection, peaked after one month, and then gradually declined over two years. Anti-HLA class II antibodies appeared earlier than class I antibodies. Functional assays demonstrated complement-dependent cytotoxicity against allogeneic B lymphocytes and PDC*line cells in the serum of some patients, with no difference related to treatment. PD-1 blockade did not alter the magnitude, kinetics, or cytotoxic potential of the vaccine-induced humoral response. ConclusionThese results indicate that, during allogeneic human vaccination, PD-1 signaling exerts a limited effect on antibody production and effector function, suggesting a more complex regulatory role in humoral immunity than previously thought.

Abstract We have developed an innovative cancer vaccine for the treatment of advanced NSCLC patients in combination with checkpoint inhibitors. This PDC*lung01 product based on an irradiated plasmacytoid dendritic cell line loaded with HLA-A*02:01 restricted peptides (NY-ESO-1, MAGE-A3, MAGE-A4, Multi-MAGE-A, MUC1, Survivin and Melan-A) is able to prime and expand peptide-specific CD8+ T cells in vitro and in vivo, and is synergistic with anti-Programmed Death (PD)-1 (Plumas et al, 2022; Hannani et al, 2023, NCT03970746). In study PDC-LUNG-101 with EudraCT number 2018-002382-19, PDC*lung01 is injected intravenously and subcutaneously for 6 times at two dose levels, 14 million, or 140 million cells in stage II/IIIA (cohort A1 & A2, monotherapy) or stage IV with TPS≥50% (cohort B1 & B2; in combination with pembrolizumab) patients. We report here the analysis of immune response of 3 cohorts (A1, A2, B1) of patients and the first 19 patients out of 42 (cohort B2) treated with high dose of PDC*lung01 in combination with Pembrolizumab at baseline and 3 timepoints post injection. Several circulating immune parameters have been evaluated at different times before and after vaccination using different assays we have developed: leukocyte count and determination of circulation peptide specific CD8+ T cells by flow cytometry using multimer tools without prior in vitro culture. The assay made on purified CD8+ T-cells allowed us to define a limit of quantification (LOQ) to accurately assess the fold changes of the cell expansion. In addition, tumor microenvironment (TME) was analyzed by multiplex fluorescence immunochemistry. The data of 42 patients for who an immune response has been evaluated (cohorts A and B) will be presented. No major changes in circulating main lymphocyte frequencies (B cells, NK cells, CD4+, CD8+, or Treg T cells) were observed during treatment. In addition, no major cell activation (CD25+, CD54, or DR+) was noted. In contrast, in a significant number of patients, PDC*lung01 induced circulating peptide-specific CD8+ T cell expansion in all 4 cohorts at different levels and time points against at least one out of seven peptides used. The percentages of patients for who an expansion of antigen-specific T-cell were observed were 50%, 64%, 66.7% and 68.4% in A1, A2, B1 and B2 cohorts respectively. The intensity of the immune response was proportional to the dose of PDC*lung01 and to the combination with pembrolizumab. When possible, total and peptide-specific CD8+ T cells were sorted for analysis of TCR repertoire, illustrating the modelling and dynamics of the immune response. The TME features will also be illustrated. To conclude, treatment with PDC*lung01 induces an anti-tumor immune response in a significant number of patients which appears to be enhanced by the combination with pembrolizumab. Citation Format: Joel Plumas, Anne Sibille, Ingel Demedts, Elvire Pons-Tostivint, Charlotte Van de Kerkhove, Sofie Derijcke, Willemijn Theelen, Bonne Biesma, Frank Borm, Els Wauters, Mike Collodoro, Kays Al Badawy, Camille Duchayne, Channa Debruyne, Beatrice Devos, Benoit Colinet, Denis Moro-Sibilot, Maurice Perol, Eva-Lotte Buchmeier, Marcin Skrzypski, Kristof Cuppens, Johan Vansteenkiste. PDC*lung01: An innovative therapeutic cancer vaccine induces specific immune responses in combination with anti- PD-1 treatment in patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1182.

IntroductionSelective tyrosine kinase inhibitors are proven effective in patients with non-small lung cancer (NSCLC) with a MET exon 14 skipping mutation. Case presentationThe patient developed a metastatic lung adenocarcinoma with a MET exon 14 skipping mutation. She was treated with a first 1b MET inhibitor, Capmatinib, but had to stop the drug because of major hepatotoxicity. A few months later, she started Tepotinib, another 1b MET inhibitor with this time, no sign of hepatotoxicity. DiscussionAdverse events are frequent with 1b MET inhibitors. However, there is a wide interpatient variability. Absence of cross-toxicity between Capmatinib and Tepotinib is misunderstood but can be explained by slight differences in phamarcodynamics and pharmacokinetics. Practitionners have to be warned about severe adverse events to stop or change the drug if necessary. ConclusionThis is the first case showing the absence of cross-toxicity between 1b MET inhibitors.

Abstract Background PDC*lung01 (IMP) is a therapeutic cancer vaccine based on an irradiated plasmacytoid dendritic cell line loaded with HLA-A*02:01-restricted peptides (NY-ESO-1, MAGE-A3, MAGE-A4, Multi-MAGE-A, MUC1, Survivin and Melan-A), able to prime and expand peptide-specific CD8+ T cells in vitro and in vivo, and is synergistic with anti-PD-1. Methods In this phase I/II study, HLA-A*02 positive NSCLC pts were enrolled in 4 cohorts: resected stage II/IIIA in adjuvant setting treated with low dose (A1) or high dose (A2) of IMP following SOC; or untreated stage IV NSCLC with measurable disease, PD-L1≥50% and no targetable driver mutation, treated with low dose (B1) or high dose (B2) of IMP in combination to pembrolizumab 200mg q3w, continuously. IMP was simultaneously administered by SC and IV route weekly for 6 consecutive doses. Objective response rate (ORR) and progression-free survival (PFS) were assessed in cohort B2. We report herein preliminary efficacy results of the first 21 pts analysed when the 19th evaluable patient reached the 9-months PFS and the safety of 38 pts. Results Out of 21, 19 pts receiving at least 5 doses of IMP and having 1 post-baseline radiological evaluation were evaluated. The median follow-up was 12.5 months. The best objective response (BOR) included 12 PR (63.2%) and 7 SD (36.8%) with ORR of 63.2% (80% CI 45.9% - 78.2%) and a disease control rate (DCR) of 94.7%. The 9mPFS according to the Kaplan-Meier estimate was 52.1% (80% CI 36.5% - 65.56%). The mPFS was 10.9 months. The median duration of response was 9.49 months. An antigen-specific CD8+ T-cell response was induced against the lung antigens of the IMP in 68.4% of pts. Immune responses with remarkable expanded anti-tumor CD8+ T-cells were observed both in PR and SD. More immune response results will be available in the final analysis of the 45 pts of cohort B2. Treatment-related AEs (TRAEs) were mostly Grade 1-2. Only 1 severe TRAE occurred, a Grade 4 allergic infusion-related reaction, leading to IMP discontinuation. Thirteen pts experienced a serious AE, of which 3 were considered causally related to the IMP. Conclusions The BOR, ORR, DCR, PFS, duration of response and safety of PDC*lung01 in combination with anti-PD-1 showed encouraging signals suggesting that this combination may provide a clinical meaningful tumour response in stage IV NSCLC population with a mild safety profile. Interestingly, the immune response observed confirms the mechanism of action of the IMP in relation to clinical activity. Citation Format: Willemijn Theelen, Maurice Perol, Kristof Cuppens, Ingel Demedts, Frank Borm, Bonne Biesma, Els Wauters, Benoit Colinet, Eva-Lotte Buchmeier, Friederike Althoff, Elvire Pons-Tostivint, Charlotte Van de Kerkhove, Denis Moro-Sibilot, Anne Sibille, Sofie Derijcke, Marcin Skrzypski, Joel Plumas, Beatrice De Vos, Channa Debruyne, Frederique Cantero, Stefanie Adriaenssens, Florence Renard, Johan Vansteenkiste. Preliminary clinical results of a therapeutic cancer vaccine PDC*lung01 in combination with anti-PD-1 in patients (pts) with stage IV NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT021.

Anne Sibille, Frederique Bustin, Luciano Carestia, Gaetan Catala, Christophe Comp ere, Kristof Cuppens , Benoit Colinet, Stephanie Coulon, Nele De Brucker, Lore Decoster, Lynn Decoster, Ingel Demedts, Sofie Derijcke, Koen Deschepper, Danny Galdermans, Annelies Janssens, Sebahat Ocak, Christel Oyen, Karin Pat, Thierry Pieters, Vincent Pruniau, Veerle Surmont, Saar Vandekeere and Johan Vansteenkiste Department of Pulmonology, University Hospital of Li ege, Li ege, Belgium; Department of Pulmonology, CHR de la Citadelle, Li ege, Belgium; Department of Pulmonology, Clinique Saint-Pierre Ottignies, Ottignies, Belgium; Department of Oncology, CH Jolimont, Haine-StPaul, La Louvi ere, Belgium; Department of Pulmonology, CCI (CHIREC Cancer Institute), CHIREC Hospital, Brussels, Belgium; Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium; Department of Pulmonology, Grand Hôpital de Charleroi, Gilly, Belgium; Medical Affairs Department, MSD Belgium, Brussels, Belgium; Department of Pneumonology, Imelda Hospital, Bonheiden, Belgium; Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium; Department of Pulmonology, AZ Turnhout, Turnhout, Belgium; Department of Pulmonary Diseases, AZ Delta, Roeselare, Belgium; Department of Pulmonology, AZ Groeninge, Kortrijk, Belgium; Algemeen Ziekenhuis Nikolaas, Sint-Niklaas, Belgium; Department of Pulmonology, ZNA Middelheim, Antwerp, Belgium; MOCA Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium; Division of Pulmonology, CHU UCL Namur, Godinne Site, Yvoir, Belgium; Pole of Pneumology, ENT, and Dermatology (PNEU), Institut de Recherche Exp erimentale et Clinique (IREC), Universit e Catholique de Louvain (UCLouvain), Brussels, Belgium; Respiratory Oncology Unit, University Hospitals KU Leuven, Leuven, Belgium; Department of Pulmonology, Cliniques Universitaires Saint-Luc, Brussels, Belgium; Department of Respiratory Medicine, Ghent University, Ghent, Belgium

Mahiat, Cédric MD; Jacquerie, Alexandre MD; Beniuga, Gabriela MD; Weynand, Birgit MD, PhD; Dermesropian, François MD; Colinet, Benoît MD Author Information

Introduction: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, an atypical Notch ligand expressed in SCLC tumors. We evaluated the efficacy of Rova-T versus placebo as maintenance therapy in patients with extensive-stage-SCLC after platinum-based chemotherapy. Methods: MERU was a phase 3 randomized, double blinded, placebo-controlled study. Patients without disease progression after four cycles of platinum-based, front-line chemotherapy were randomized in a 1:1 ratio to receive 0.3 mg/kg Rova-T or placebo (every 6 wk, omitted every third cycle). Primary efficacy end points were progression-free survival (PFS) evaluated by the Central Radiographic Assessment Committee and overall survival (OS) in patients with DLL3-high tumors. Results: Median age of all randomized patients (N = 748) was 64 years; 78% had TNM stage IV disease. At futility analysis of the subset with DLL3-high tumors, the hazard ratio for OS was 1.07 (95% confidence interval: 0.84-1.36) favoring the placebo arm, with median OS of 8.5 and 9.8 months in the Rova-T and placebo arms, respectively; futility criteria were met. Rova-T signifi-cantly improved PFS versus placebo by investigator assessment (4.0 versus 1.4 mo, hazard ratio = 0.48, p < 0.001). Any-grade adverse events (>20%) in the Rova-T arm were pleural effusion (27%), decreased appetite (27%), peripheral edema ( 26%), photosensitivity reaction (25%), fatigue ( 25%), nausea (22%), and dyspnea (21%). Conclusions: Because of the lack of survival benefit in the Rova-T arm, the study did not meet its primary end point and was terminated early. As a result, the Central Radiographic Assessment Committee evaluation of PFS was not performed. The frequency of grade greater than or equal to 3 and drug-related toxicities were higher with Rova-T versus placebo. Rova-T was associated with unique toxicities, such as pleural and pericardial effusions, photosensitivity reaction, and peripheral edema, which should be carefully considered in the population with extensive-stage- SCLC. (c) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

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

Objectives: The aim of ASTRIS, a real-world study, was to assess the safety and efficacy of osimertinib in patients with locally advanced or metastatic (stage IIIB-IV) epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC) who had received prior EGFR-tyrosine kinase inhibitor (TKI) therapy. Here, we describe the Belgian subset of the global ASTRIS study.Methods: Patients received osimertinib orally as one 80 mg tablet once daily until disease progression or unacceptable toxicity. Socio-demographic data, medical history, disease progression and survival status were collected and molecular testing for EGFR status was performed. Safety was also assessed. All collected data were summarized using descriptive statistics.Results: Of the 31 Belgian patients enrolled in the study, 9 (29.0%) discontinued treatment for disease progression and 5 (16.1%) due to other reasons. Among the 31 patients treated with osimertinib, 16 (51.6%, 95% CI 33.1-69.8) had a clinical response and 13 (41.9%) had stable disease as best response assessed by the investigator, with a disease control rate of 93.5%. The clinical response rate was 66.7% (6/9) in patients with brain/leptomeningeal metastases and 50.0% (4/8) in patients without brain/leptomeningeal metastases. About one third of the patients (11/31) reported at least one adverse event (AE) (35.5%) or serious AE (10/31; 32.3%) and 3/31 (9.7%) patients discontinued treatment due to AEs.Conclusion: We here demonstrate the effectiveness of osimertinib in a real-world setting in Belgian patients with locally advanced or metastatic T790M-positive NSCLC who had received previous EGFR-TKI treatment. No new safety signals were identified.

Introduction Idiopathic chronic eosinophilic pneumonia (ICEP) is an orphan lung disease characterized by concomitant systemic and local eosinophilia, along with bilateral lung infiltrates. Symptoms include dyspnea of subacute/chronic onset, cough, and general systemic signs. Although all patients do respond to oral corticosteroids, relapse rate is very high, which highlights the need for alternative therapies in case of relapsing ICEP. Mepolizumab is a fully humanized antibody directed against interleukin 5, a key growth factor of eosinophils. In the present study, we retrospectively studied the effect of off-label use of mepolizumab for relapsing ICEP. Materials and Methods All data from patients treated with mepolizumab for relapsing ICEP were included in our database and diagnoses were reviewed. We analyzed the effect of treatment on relapse rate, oral corticosteroids (OCS) use, and lung lesions on high-resolution computed tomography (HRCT). Results We included ten patients in the final analysis, with a median follow-up of 9 months after initiation of mepolizumab. Beside its expected effect on circulating eosinophils, treatment with mepolizumab was associated with a significant reduction of annual rate of exacerbations and a reduced consumption of corticosteroids. We also observed a remission of lung lesions on follow-up HRCT. Conclusions In this open-label retrospective study, treatment of ICEP with mepolizumab was associated with a reduction of relapses, OCS use, and the disappearance of lung infiltrates.

A flow-volume curve with a flattening of the inspiratory and expiratory limb suggests a proximal obstruction of the upper airways. Plasma cell neoplasms need to be considered in the differential diagnosis of an invasion of the upper respiratory tract. https://bit.ly/2K9lOXj.

s presented at the 24th Annual Congress of the Belgian Society of Internal Medicine, 13–14 December 2019, Dolce La Hulpe, La Hulpe, Belgium Oral Communication – Case Reports 24 IgA nephropathy associated with thrombotic microangiopathy and diffuse alveolar hemorrhage. Quentin Binet, Christian Miesse, Benoît Colinet, Selda Aydin, Jean-Philippe Lengelé, JeanFrançois Cambier, Grand Hôpital de Charleroi, Gilly, Belgium, Cliniques Universitaires Saint-Luc,

OBJECTIVES:To assess if induction radiochemotherapy followed by consolidation chemotherapy (arm A) will improve survival in comparison with the same chemotherapy given as induction followed by consolidation concurrent radiochemotherapy (arm B) in patients with unresectable non-metastatic non-small cell lung cancer (NSCLC).PATIENTS AND METHODS:Chemotherapy consisted in a combination of cisplatin with docetaxel, with one initial course for each patient, two courses in single modality therapy and weekly administration during chest irradiation (66 Gy).RESULTS:A total of 125 patients were randomised before early closure of the study because of poor accrual and an unplanned blind interim analysis which suggested that the continuation of the study would have been futile. Mature survival results showed no significant difference between both modalities with median survival times, respectively in arms A and B, of 19.6 months and 18.3 months, two years survival rates of 44% and 44% and five years survival rates of 23% and 26%. Toxicity was acceptable.CONCLUSIONS:Our randomised study did not demonstrate survival difference between induction concurrent radiochemotherapy followed by consolidation chemotherapy and induction chemotherapy followed by consolidation concurrent radiochemotherapy.

INTRODUCTION:Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibition is the preferred first-line treatment of advanced adenocarcinoma of the lung that harbors EGFR activating tyrosine kinase domain mutations. Most data available pertain to Asian populations in which such mutations are more prevalent. We report on the long-term results of first-line treatment with erlotinib in Caucasian patients with advanced adenocarcinoma of the lung that have a somatic EGFR mutation in their tumor.METHODS:Multicenter academic prospective phase II study with erlotinib in patients with an activating EGFR tyrosine kinase (TK) domain somatic mutation (any exon encoding the kinase domain) in the tumor and no prior treatment for their advanced disease.RESULTS:Phenotypic preselecting of 229 patients led to a high EGFR mutation detection rate of 24% of which 46 patients were included in the phase II study. With a progression free survival (PFS) of 81% at three months the study met its primary endpoint for presumed superiority over chemotherapy. With an overall median PFS of 11 months and a median overall survival (OS) of 23 months, the results compare favorably with results obtained in randomized studies using TKI in first line in EGFR mutation positive adenocarcinoma of the lung.CONCLUSION:The present study reinforces the use of EGFR tyrosine kinase inhibition (TKI) as a first line treatment of choice for advanced adenocarcinoma of the lung carrying an activating EGFR mutation. The mutation rate in preselected Caucasian patients is higher than previously reported. Issues relevant for clinical practice are discussed.TRIAL REGISTRATION:ClinicalTrials.gov NCT00339586.