Additional significant differences in circulating chemokines.

Cytotoxic response in tumor biopsies of patients with No DCB upon combination treatment.

Immuno-Histo-Chemistry scoring of baseline tumor biopsies according to their DCB status.

PARP inhibitors (PARPi) are used in the treatment of ovarian, breast, pancreatic, and prostate cancers. Pneumonitis has been identified as a potential side effect, with a higher meta-analysis-assessed risk for olaparib versus other PARPi. Olaparib-induced interstitial lung disease (O-ILD) was first described within the Japanese population, with few information available for Caucasian patients. We performed a retrospective study by pooling data from the French and Belgian pharmacovigilance databases from 2018 to 2022. Patients with O-ILD were included following a central review by: 1) pharmacologists using the French drug causality assessment method; 2) senior pneumologists or radiologists, using the Fleischner Society’s recommendations. Five patients were identified and analysed. All were females, with ovarian or breast cancer. Median age at O-ILD diagnosis was 71 (38–72) years old, with no smoking history. Median delay between treatment initiation and symptom occurrence was 12 (6–33) weeks. Pneumonitis severity assessed using the Common Terminology Criteria for Adverse Events V5 was Grade 3 (n = 4) or 2 (n = 1). CT-scan review (n = 3) described hypersensitivity pneumonitis reaction as a common pattern. Bronchioalveolar lavage (n = 4) revealed lymphocytic alveolitis. Treatments relied on olaparib discontinuation (n = 5) and glucocorticoid intake (n = 4), with no fatal issue. Safe re-challenge with PARPi occurred in two patients. Forty additional O-ILD cases were identified in the WHO VigiBase database, including one fatal case. PARPi-ILD is a rare but potentially life-threatening disease, presenting as a hypersensitivity pneumonitis pattern within 3 months of PARPi initiation. Treatment primarily relies on medication discontinuation. Re-challenging with another PARPi could be considered. CEPRO #2023–010.

Background Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [18F]fluorodeoxyglucose 18 F]fluorodeoxyglucose ([18F]FDG)-PET 18 F]FDG)-PET results. Methods In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative- intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 08]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [18F]FDG-PET 18 F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 65 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 65 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m2 2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m2 2 intravenously once every 3 weeks and vinorelbine 30 mg/m2 2 intravenously on day 1 and 60 mg/m2 2 orally [or 30 mg/m2 2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m2 2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m2 2 intravenously and vinorelbine 20 mg/m2 2 intravenously on day 1 and 40 mg/m2 2 orally (or 20 mg/m2 2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing. Findings From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 Interpretation A thoracic radiotherapy boost, based on interim [18F]FDG-PET, 18 F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [18F]FDG-PET-guided 18 F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC. Funding Programme Hospitalier de Recherche Clinique National 2014. Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies. [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [18F]FDG-PET 18 F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 451 months (95% CI 393-483). The 15-month local control rate was 776% (95% CI 676-876%) in group A and 712% (95% CI 608-816%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment). Interpretation A thoracic radiotherapy boost, based on interim [18F]FDG-PET, 18 F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [18F]FDG-PET-guided 18 F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC.

8022 Background: Immune checkpoint inhibitors (ICI) are currently included in the peri-operative standard of care for NSCLC with the objective of a curative strategy. In early stages of NSCLC, biomarkers predicting ICI efficacy should be more stringent than PD-L1 tumoral expression in order to improve the benefit-toxicity ratio. We deeply analyzed the tumor microenvironment of patients included in the IONESCO multicenter phase 2 trial (stage IB > 4cm–IIIA, non N2 resectable NSCLC). Diagnostic biopsies and surgical resection specimen after 3 cycles of Durvalumab were available. We previously showed that the % of residual viable tumor cells (RVT) was associated with disease free survival (DFS) and overall survival (OS). PD-L1 tumor positive score was not correlated to RVT nor survival. Methods: 46 patients were included in the IONESCO trial. Among them, diagnostic biopsy (n = 32), surgical resection specimen post durvalumab (n = 39) and paired tumor samples (n = 31) were analyzed. Immune environment was assessed using 7 quantitative 7-plex immunofluorescence panels generating 349 different cellular phenotypes in 3 different compartments (whole tumor, intra cytokeratin and stroma), focusing on T and B lymphocytes, macrophages, immune checkpoint, NK cells, apoptosis, innate and adaptive immunity, dendritic cells. Densities of cells were quantified using Fluorescent Multiplex immunohistochemistry performed on Leica Bond RX, using OpalTM technology. A fisher's exact test or chi2 test was used for demographics variables and RVT. HRs and 95% CIs were estimated using a Cox model. NCT number: NCT03030131. Results: With median follow-up of 4.5 years, 16/31 patients had a disease recurrence. Histology, sex, stage and survival were significantly associated with intra-tumor densities of CD3, CD8, PD1, TIM3, and CD163 cells in the diagnostic biopsy, and with the delta of CD3, FoxP3, CD4, CD163PD1, TIM3, PDL1 on immune cells and TIM3PDL1 cells, between biopsy and surgical specimen. DFS was significantly associated with high density of CD8+TIM3+ in biopsies (HR = 0.25 [0.09-0.71], p = 0.0092) and with the high density of CD20+ cells in surgical specimen (HR = 0.36 [0.13-0.97], p = 0.04). The RVT was significantly associated with CK+Caspase3- cells and CK+PDL1+ cells in the surgical specimen. No biomarker was associated with OS. Conclusions: Multiparameter analysis of the immune NSCLC environment of patients treated with neoadjuvant anti-PDL1 allows identification of markers associated with clinical, pathological parameters and DFS. Our findings highlight the substantial impact of high CD8+TIM3+ cell density pre-durvalumab and of high CD20+ cell density post-durvalumab on DFS. These findings deserve to be assessed in patients treated with neoadjuvant combined immunotherapy chemotherapy. Clinical trial information: NCT03030131 .

8583 Background: Epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-MET) are dysregulated in many tumors, including NSCLC. In particular, splice-site alterations resulting in the loss of transcription of exon 14 in the oncogenic driver c-MET ( METex14 skipping mutations) occur in ~3% of NSCLC and lead to oncogenic MET activation. MCLA-129 is a bispecific antibody that targets EGFR and c-MET with multiple mechanisms of action, including inhibition of EGFR and c-MET signaling, antibody-dependent cellular phagocytosis and enhanced antibody-dependent cellular cytotoxicity. In the dose escalation part of a phase 1/2 trial (NCT04868877), the initial recommended phase 2 dose of MCLA-129 monotherapy was determined to be 1500 mg every 2 weeks (Q2W) with 28-day cycles. Significant tumor shrinkage was observed in one patient with METex14 NSCLC previously treated with multiple chemotherapy agents and the c-MET tyrosine kinase inhibitor (TKI) capmatinib. Preliminary data are presented of patients (pts) with advanced or metastatic METex14 NSCLC treated with MCLA-129 in the dose expansion phase of the trial. Methods: Pts with advanced/metastatic METex14 NSCLC Pts received MCLA-129 1500 mg IV Q2W, until disease progression or unacceptable toxicity. Tumor imaging was conducted every 8 weeks. Primary endpoint: investigator-assessed ORR (RECIST v1.1), in pts with measurable disease, ≥2 MCLA-129 cycles, and ≥1 post-baseline scan. Secondary endpoints: DCR and safety. Biomarker analyses of EGFR/c-MET expression and ctDNA mutation status are planned. Results: As of December 1, 2023, 15 pts were dosed. The median age was 72 years (range 61-83), 40% were male, and 13%/87% of pts had ECOG performance status 0/1 respectively. The trial is ongoing; further analysis of safety and efficacy is planned with a later data cutoff date and will be presented at the meeting. Conclusions: MCLA-129 is being evaluated as monotherapy for the treatment of patients with locally advanced/metastatic c-MET exon 14 skipping NSCLC. Clinical trial information: NCT04868877 .

PDF file - 59K, IHC score according probability of response to chemo

PDF file - 352K, TUBB3 mRNA and protein expression according to K-RAs Si-RNA

Supplemental Figure S1. Sample inclusion flow chart. Supplemental Figure S2. Boxplot of circulating free DNA concentration in plasma (in ng/microl) regarding M stage (up), and number of metastatic sites (down) in all samples (n=106). Y axis is in logarithmic scale. Supplemental Table S1. Processes used in the different participating labs for tumor DNA extraction, storage, shipment, and biomarker analysis. Supplemental Table S2. Primers used for amplicon sequencing by IonTorrent next-generation sequencing Supplemental Table S3. Multiplex reaction conditions. Supplemental Table S4. NGS mutation screening results in the 68 paired samples Supplemental Table S5. IonTorrent NGS test results in cfDNA, for each individual amplicon and overall, taking tDNA as a reference and restricted to stage IV samples (n=50). Supplemental Table S6. NGS test results in tDNA and cfDNA for all amplicons concomitantly using the ITVC strategy (5A), or the in-house strategy (5B); and corresponding calculated sensitivity for all matched samples analyzed by NGS (n=68)

Abstract Purpose Because modern medical treatments of lung cancer had a potential efficacy on brain metastases, the optimal timing of stereotactic radiosurgery (SRT) could be discussed. The aim of this retrospective study is to evaluate the outcomes according to the timing of SRT during the course of the disease. Materials and Methods all patients receiving SRT for BM of a lung cancer were included in the study, except those receiving whole brain radiotherapy (WBRT). We defined three groups of patients, according to the timing of SRT: L1 for those receiving SRT during the first line of medical treatment, L2 during the second line and L3 for others line. We analyzed local control of the treated metastases (LC), occurrence of new BM and overall survival (OS). For the two last variables, we calculated the probability of event from the date of SRT and from the first day of medical treatment (D1L1). Results 109 patients were included in the study and 102 evaluable for all parameters. LC did not differ if SRT was performed during L1, L2 or L3. Occurrence of new BM is delayed when SRT is performed in L1 and the initial point the time of SRT, but this difference disappeared when the probability of new BM is calculated from D1L1. No difference in OS was observed according to the timing of SRT. Conclusion this study underlines the important role of medical treatment to prevent new BM. In view of our results, SRT could be delayed if the medical treatment has a good probability of controlling BM progression.

PDF file - 252K, TUBB3 protein expression in HBEC cells is reduced by hypoxia cells culture conditions

PDF file - 144K, Representative SiRNA K-Ras depletion in HBEC and A549 (K-Ras mutated) cells

Introduction: BRCA1 and BRCA2 (BReast CAncer susceptibility genes) are two tumor-suppressor genes associated with the hereditary breast and ovarian cancer susceptibility syndrome. Recent studies also suggest an increased lung adenocarcinoma risk in carriers. Methods: We conducted a multi-center retrospective study in 18 different French pulmonology and/or oncology departments on medico-administrative and clinical data prospectively collected in the Clinical Data Warehouse (CDW) of Greater Paris University Hospitals (Assistance Publique-Flemitaux de Paris, AP-HP). Clinical characteristics and outcomes of patients with LC and a previously known BRCA1/2gl variant were retrospectively evaluated. Results: 17 patients with LC and known BRCA1/2gl variant were included. Patients were most women, former smokers with localized disease and BRCA2 variants. All LC were adenocarcinoma. For patients with medical history of cancer, median time from the first cancer in the BRCA spectrum and the LC occurrence was 20 years. Median disease-free survival (DFS) and overall survival (OS) in localized tumor (Stage I and II) was not reached and 78.6 months, respectively. In advanced cancer (Stade III and IV) median progression free survival was 9.7 months and median OS was 17.8 months. Univariate OS and DFS/PFS analyses by BRCA status did not find significant differences. Conclusion: Results seem to show particular LC features in carriers of BRCA2 variants: adenocarcinoma subtype, woman, former or non-smoker.

L’indice de performance ou « Performance Status (PS) » est une mesure de l’état général du patient. Les échelles de Karnofsky et de l’ECOG (Eastern Cooperative Oncology Group) sont les plus utilisées. La meilleure corrélation est obtenue en utilisant 3 points : ECOG 0-1 = Karnofsky 100-80 %, ECOG 2 = Karnofsky 60-70 %, ECOG 3-4 = Karnofsky 50-10 %. De nombreux facteurs, liés au cancer ou aux comorbidités peuvent influencer le PS. Malgré une évaluation dont la reproductibilité n’est pas parfaite et le caractère hétérogène des patients au PS altéré, le PS est un facteur pronostique indépendant majeur des CBNPC (cancers bronchiques non à petites cellules) et des CPC (cancers à petites cellules). Il doit donc être un facteur de stratification dans les études. Toutes les recommandations tiennent compte du PS dans la décision thérapeutique, en particulier pour la chimiothérapie des CBNPC métastatiques. Les thérapies ciblées, en cas de tumeur métastatique avec altération moléculaire ciblable, doivent être proposées quel que soit le PS du fait d’un profil efficacité / tolérance très favorable. Les données concernant l’immunothérapie sont plus parcellaires. La tolérance semble bonne. Les résultats concernant l’efficacité incitent à sélectionner les patients qui pourraient bénéficier du traitement. Comme nous y encourage l’European Medicines Agency, construisons des études dédiées aux patients fragiles et incluons-les dans les essais, afin qu’ils bénéficient, comme les autres, de l’innovation thérapeutique. Pour que les résultats de la recherche clinique soient applicables à une large population, les populations dites particulières doivent être représentées plus largement.1877-1203/© 2022 SPLF. Publié par Elsevier Masson SAS. Tous droits réservés.

BackgroundWe report the results from the advanced malignant mesothelioma (aMM) expansion cohort of the PEMBIB Phase Ib trial (NCT02856425) evaluating the safety, efficacy & biomarkers of an antiangiogenic tyrosine kinase inhibitor (nintedanib) with an anti-PD1 immunotherapy (pembrolizumab).MethodsPatients with aMM relapsing after at least one line of platinum doublet chemotherapy and not previously pre-exposed to IO were treated with a combination of oral nintedanib (150mg BID) & IV pembrolizumab (200mg Q3W) with a 7 days nintedanib lead-in preceding pembrolizumab initiation. Baseline and on-treatment (cycle D2, day 1 [C2D1]) fresh tumor & blood samples were prospectively phenotyped by flow cytometry (FC). RNAseq was run on tumor samples. Immune factors were titrated on tumor secretome and plasma.Results30 aMM patients were treated and 29 evaluable for response. Median age was 68 years old (38–85) and 86% of aMM were epithelioid. The most frequent adverse events (AE) (grades 1–3) related to the combination were liver enzymes increase, fatigue, nausea, and diarrhea. 4 (13.3%) patients developed grade 3–5 immune- related AE. Patients died of cancer progression (n=14, 46.7%), myocarditis with thrombo-embolic event (n=1, 3.3%) and COVID-19 (n=1, 3.3%). Median follow-up was 14.8 months (95%CI [9.70–18.2]). Best Overall Response Rates (BORR) per RECISTv1.1 were Partial Response (PR, n=7/29; 24.1%), Stable Disease (SD, n=17/29; 58.6%) and Progressive Disease (n=5/29; 17.2%). Disease Control Rate (DCR) (defined as PR + SD) was 46.6% at 6 months. Patients with DCR at 6 months had significantly higher percentage of PDL1 expression on tumor cells (by Immuno-Histo-Chemistry, antibody clone SP263) and higher CD8+ T cells infiltrate in tumor biopsies (by FC) at screening. Upon treatment, soluble plasma rate of CXCL9 and CXCL13 increased in all patients, as well as tumor immune infiltrates estimated by deconvolution of tumor biopsies RNA-seq. But deconvoluted estimates of NK cells, T cells and myeloid dendritic cells infiltrates on baseline tumors and C2D1 biopsies were higher in patients with DCR at 6 months. Pre & on-treatment IL6 and IL8 rates in tumor secretome & plasma were higher in patients without DCR. Gene Set Enrichment Analyses on RNA-seq from screening biopsies highlighted an enrichment in E2F, MYC and KRAS gene pathways and lower expression of type 1 interferon signature in patients without DCR than those with DCR at 6 months.ConclusionsWith a BORR of 24% and a DCR of 47% at 6 months, pembrolizumab and nintedanib combination provided valuable therapeutic benefits for patients with aMM.Trial RegistrationClinicalTrialsgov, NCT02856425. Registered August 4, 2016 — Prospectively registered,https://clinicaltrials.gov/ct2/show/NCT02856425?term=PEMBIB&draw=2&rank=1.Ethics ApprovalThe protocol was first approved by the Agence Nationale de Sécurité du Médicament (ANSM) on June 24th 2016 (Ref #160371A-12). The protocol was also approved by the Ethical Committee (Comité de Protection des Personnes Ile de France 1) on Jul 12th 2016 (Ref #2016-mai-14236ND).

Immune checkpoint inhibitors (ICI) have improved patient outcomes in a variety of cancers but with variable efficacy. In the past 24 months, several observational studies, mostly retrospective, suggested that antibiotic (ABX) use may be associated with a lowered efficacy of ICI and survival of patients. ABX-induced disruption of the gut microbiota and the complex interplay between the immune system and the microbiota have been advanced as the likely mechanisms underlying the observed effect. We aim at reviewing the meta-analyses that summarized the findings reported in literature. We systematically searched Medline, the Cochrane Library, and oncology conferences proceedings to identify the systematic reviews and meta-analyses as well as all the recent studies that were not included in them. We identified 4 meta-analyses published since 2019 studying the overall survival (OS) and progression-free survival (PFS) of cancer patients treated with ICI (mainly anti-PD(L)1 antibodies as monotherapy or combined with anticancer drugs) and ABX. In all, ABX use is reported to have a negative impact on the survival of patients treated with ICI regardless of cancer type. The pooled hazard ratio (HR) ranged from 1.47 to 1.84 for PFS and 1.69 to 2.37 for OS, revealing a significantly reduced survival in patients with cancer exposed to ABX. In all meta-analyses, the use of ABX around the ICI treatment start appeared to be most detrimental to the outcomes.Table: 1043P1st AuthorHuangWilsonLurienneXuCancerNon-small-cell lung cancer (NSCLC), Melanoma, Renal cell carcinoma (RCC), Urothelial Carcinoma (UC), MixedNSCLC, Melanoma, RCC, UC, MixedNSCLCNSCLC, Melanoma, RCC, MixedHR OS [95% CI]2.37 [2.05; 2.75]1.92 [1.37; 2.68]1.69 [1.25; 2.29]1.90 [1.55; 2.34]HR PFS [95% CI]1.84 [1.49; 2.26]1.65 [1.30; 2.10]1.47 [1.13; 1.90]1.53 [1.30; 1.79] Open table in a new tab The independently-developed meta-analyses vary in the scope of studies included and their methodology but they commonly conclude on a significant deleterious effect of ABX use on the survival of patients treated with ICI. The topic deserves further research to understand the mechanisms at stake and improve care of patients.

Immune checkpoint inhibitors (ICIs) have dramatically improved patient outcomes in a variety of tumor types, but with variable ef ficacy. Recent research has suggested that antibiotic-induced disruption of the microbiota may impact ICI ef ficacy. We performed a systematic review and meta-analysis of studies that assessed the impact of antibiotic use on the survival of patients diagnosed with NSCLC and treated with ICI. We systematically searched Medline, the Cochrane Library, and major oncology conferences pro-ceedings. Eligible studies mentioned hazard ratio or Kaplan-Meier curves for progression-free survival (PFS) or overall survival (OS) based on antibiotic exposure before or during ICI treatment. We identi fied 23 eligible studies. The impact of antibiotics was then evaluated in 2208 patients for PFS and 5560 for OS. For both PFS and OS meta-analyses, the between-study heterogeneity was high (Hig-gins and Thompson I 2 of 69% and 80%, respectively). The pooled hazard ratio was 1.47 (95% con fidence interval [CI]: 1.13-1.90) for PFS and 1.69 (95% CI: 1.25-2.29) for OS revealing a signi ficantly reduced survival in patients with NSCLC exposed to antibiotics. The median OS was reduced on average by 6.7 months (95% CI: 5.1-8.4) in the patients exposed to antibiotics. The effect seems to depend on the time window of exposure with stronger effects reported when the patients took antibiotics [-60 days; +60 days] around ICI initiation. In patients with NSCLC, the findings of the meta-analysis indicate that antibiotic use before or during treatment with ICI leads to a median OS decreased by more than 6 months. Speci fically, exposure shortly before or after ICI initiation seems to be particularly detrimental, whereas antibiotic use later during disease course does not seem to alter survival. Because PFS and OS were dif ficult to compare between studies owing to het-erogeneity and the multiple confounding factors identi fied, further studies are needed to strengthen the understanding of this phenomenon. (C) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.