437 results on '"Jaafar, Bennouna"'
Search Results
2. Use of non-small cell lung cancer multicellular tumor spheroids to study the impact of chemotherapy
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Pauline Hulo, Sophie Deshayes, Judith Fresquet, Anne-Laure Chéné, Stéphanie Blandin, Nicolas Boisgerault, Jean-François Fonteneau, Lucas Treps, Marc G Denis, Jaafar Bennouna, Delphine Fradin, Elvire Pons-Tostivint, and Christophe Blanquart
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Lung cancer ,Chemotherapies ,Spheroids ,Co-culture and PD-L1 ,Diseases of the respiratory system ,RC705-779 - Abstract
Abstract Background Lung cancers represent the main cause of cancer related-death worldwide. Recently, immunotherapy alone or in combination with chemotherapy has deeply impacted the therapeutic care leading to an improved overall survival. However, relapse will finally occur, with no efficient second line treatment so far. New therapies development based on the comprehension of resistance mechanisms is necessary. However, the difficulties to obtain tumor samples before and after first line treatment hamper to clearly understand the consequence of these molecules on tumor cells and also to identify adapted second line therapies. Methods To overcome this difficulty, we developed multicellular tumor spheroids (MCTS) using characterized Non-Small Cell Lung Cancer (NSCLC) cell lines, monocytes from healthy donors and fibroblasts. MCTS were treated with carboplatin-paclitaxel or -gemcitabine combinations according to clinical administration schedules. The treatments impact was studied using cell viability assay, histological analyses, 3’RNA sequencing, real-time PCR, flow cytometry and confocal microscopy. Results We showed that treatments induced a decrease in cell viability and strong modifications in the transcriptomic profile notably at the level of pathways involved in DNA damage repair and cell cycle. Interestingly, we also observed a modification of genes expression considered as hallmarks of response to immune check point inhibitors and immunogenicity, particularly an increase in CD274 gene expression, coding for PD-L1. This result was validated at the protein level and shown to be restricted to tumor cells on MCTS containing fibroblasts and macrophages. This increase was also observed in an additional cell line, expressing low basal CD274 level. Conclusions This study shows that MCTS are interesting models to study the impact of first line therapies using conditions close to clinical practice and also to identify more adapted second line or concomitant therapies for lung cancer treatment.
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- 2024
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3. Vaccination against HPV: Easier said than done?
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Henri-Corto Stoeklé, Sakina Sekkate, Jean-Marc Ayoubi, Jaafar Bennouna, Philippe Beuzeboc, and Christian Hervé
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Immunologic diseases. Allergy ,RC581-607 ,Therapeutics. Pharmacology ,RM1-950 - Published
- 2023
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4. PROPERTY: study protocol for a randomized, double-blind, multicenter placebo-controlled trial assessing neurotoxicity in patients with metastatic gastrointestinal cancer taking PHYCOCARE® during oxaliplatin-based chemotherapy
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Christele Le Gouill-Jaijarat, Yann Péréon, Maxime Leroy, Olivier Lépine, Aymeric Loloum, Claire Peluchon, Christelle Volteau, Anne-Sophie Martineau, Simon Korner, Caroline Perrault, Asmahane Benmaziane, Paul Girot, Caroline Petorin, Clément Perret, Catherine Ligeza-Poisson, Didier Mayeur, Laurent Flet, Anne Chiffoleau, Alexandra Poinas, and Jaafar Bennouna
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Chemotherapy-induced peripheral neuropathy ,Sensory neuropathy ,Neurotoxicity ,Spirulina extract ,Phycocyanin ,Oxaliplatin ,Medicine (General) ,R5-920 - Abstract
Abstract Background Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse effects of antineoplastic agents, ranging in prevalence from 19% to over 85%. Clinically, CIPN is a predominantly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. The high prevalence of CIPN among cancer patients makes it a major problem for both patients and survivors, as well as for their health care providers, especially because there is currently no single effective method of preventing CIPN; moreover, the options for treating this syndrome are very limited. Phycocyanin, a biliprotein pigment and an important constituent of the blue-green algae Spirulina platensis, has been reported to possess significant antioxidant and radical-scavenging properties, offering protection against oxidative stress, which is one of the hypothetic mechanisms, between others, of CIPN occurrence. Methods Our hypothesis is that phycocyanin may give protection against oxaliplatin-induced neuropathy in the treatment of gastrointestinal cancers. Our trial will be a randomized double-blind placebo-controlled study with 110 randomized patients suffering from metastatic gastrointestinal adenocarcinoma including esogastric, colorectal, and pancreatic cancers. Patients are being followed up in the gastroenterology or oncology departments of seven French hospitals. Discussion Due to the neuropathy, patients need to avoid injury by paying careful attention to home safety; patients’ physicians often prescribe over-the-counter pain medications. If validated, our hypothesis should help to limit neurotoxicity without the need to discontinue chemotherapy. Trial registration ClinicalTrials.gov NCT05025826. First published on August 27, 2021.
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- 2023
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5. 'Emergency' multidisciplinary team meeting in cancer: a first feedback from a care team
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Henri-Corto Stoeklé, David Billard, Jaafar Bennouna, Philippe Beuzeboc, and Christian Hervé
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Medicine - Published
- 2023
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6. HRAS Q61L Mutation as a Possible Target for Non-Small Cell Lung Cancer: Case Series and Review of Literature
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Laurent Mathiot, Guillaume Herbreteau, Siméon Robin, Charlotte Fenat, Jaafar Bennouna, Christophe Blanquart, Marc Denis, and Elvire Pons-Tostivint
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non-small cell lung cancer ,HRAS Gln61Leu ,tipifarnib ,oncogenic driver ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction: Assessment of actionable gene mutations and oncogene fusions have made a paradigm shift in treatment strategies of non-small cell lung cancer (NSCLC). HRAS mutations involved around 0.2–0.8% of NSCLC patients, mostly on codon 61. For these patients, few data are available regarding clinical characteristics and response to therapies. Methods: Next-Generation Sequencing (NGS) done routinely at Nantes University Hospital was used to identify HRAS molecular alterations in NSCLC patients. We identified and described four HRAS p.GlnQ61Leu mutated patients. Literature of previously HRAS-mutant NSCLC cases was reviewed, and available data in solid tumour with the most advanced H-Ras specific inhibitor, tipifarnib, were presented. Results: Of 1614 patients diagnosed with advanced NSCLC from January 2018 to December 2020, four (0.25%) had HRAS p.Gln61Leu mutation. Three of them died during the first-line systemic therapy. Furthermore, three additional cases were identified in literature. All cases were current or former smokers, most of them had pleural or pericardial effusion at diagnosis. Conclusions: The clinical course of patients with HRAS-mutant NSCLC remains unclear. Furthers cases should be identified in order to clarify prognosis and response to therapies. Tipifarnib, a farnesyl transferase inhibitor, is a promising candidate to target HRAS-mutant tumours and should be explored in NSCLC patients.
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- 2022
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7. Treatments for Non-Small-Cell Lung Cancer: The Multiple Options for Precision Medicine
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Elvire Pons-Tostivint and Jaafar Bennouna
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n/a ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
In recent years, advances in molecular diagnostics have transformed the management of advanced non-small-cell lung cancer (NSCLC), allowing for increasingly personalized approaches [...]
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- 2022
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8. Predictive value of vascular endothelial growth factor polymorphisms for maintenance bevacizumab efficacy in metastatic colorectal cancer: an ancillary study of the PRODIGE 9 phase III trial
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Bernadette de Rauglaudre, Camille Sibertin-Blanc, Aurélie Fabre, Karine Le Malicot, Jaafar Bennouna, François Ghiringhelli, Julien Taïeb, Valérie Boige, Olivier Bouché, Thierry Chatellier, Roger Faroux, Eric François, Stéphane Jacquot, Dominique Genet, Claire Mulot, Sylviane Olschwang, Jean-François Seitz, Thomas Aparicio, and Laetitia Dahan
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Several studies have reported the impact of single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor ( VEGF ) pathway genes on the efficacy of bevacizumab in metastatic colorectal cancer (mCRC), but results are still inconsistent. The PRODIGE 9 phase III study compared bevacizumab maintenance versus observation alone after induction chemotherapy with FOLFIRI plus bevacizumab. Objective: We evaluated the impact of SNPs of VEGF-A , VEGF receptors ( VEGFR-1, VEGFR-2 ), and hypoxia inducible factor-1α ( HIF-1α ) on tumor control duration (TCD), overall survival (OS), progression-free survival (PFS), and duration of first chemotherapy free-intervals (CFI). Patients and methods: We included 314/491 patients from PRODIGE 9 with a DNA blood sample available. Nine SNPs were genotyped on germline DNA using real-time Polymerase Chain Reaction TaqMan TM (Thermo Fisher Scientific, Waltham, MA , USA 02451). Results: In the bevacizumab arm, patients with the VEGFR-1 rs9582036 CC genotype ( n = 14) had significantly longer TCD [22.4 months (95% confidence interval (CI): 14.75-not reached)] than patients with the AA or CA genotype [14.4 months (95% CI: 11.7–17.1)] ( p = 0.036), whereas there was no significant difference in the observation arm. In the bevacizumab arm, no significant difference was found between the CC, and AA or CA genotype for OS [28.2 (95% CI: 18.1–42.8) versus 22.5 (95% CI: 18.6–24.6) months, p = 0.5], PFS [9.4 (95% CI: 7.2–11.3) versus 9.2 (95% CI: 8.71–10.1)], and duration of the first CFI [4.6 (95% CI: 1.6–13.3) versus 4.14 (95% CI: 0.5–29.0) months, p = 0.3]. Conclusion: Among mCRC patients treated with bevacizumab maintenance, those with the VEGFR-1 rs9582036 CC genotype experienced longer TCD. The presence of this genotype may thus predict a benefit of bevacizumab maintenance in mCRC.
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- 2022
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9. Carcinoembryonic Antigen Increase in a Patient with Colon Cancer Who Have Achieved Complete Remission and Negative 18F-FDG PET/CT: Don’t Forget the Thyroid!
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Alexandre Lugat, Pauline Hulo, Catherine Ansquer, Yann Touchefeu, Eric Mirallié, Jaafar Bennouna, and Delphine Drui
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carcinoembryonic antigen ,medullary thyroid carcinoma ,colon adenocarcinoma ,calcitonin ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Serum carcinoembryonic antigen (CEA) is a tumor marker especially used to follow a patient with colorectal cancer. However, it is non-specific and could be increased in several cancers and some benign conditions. We report the case of a 70-year-old man followed since 2014 for a left colon adenocarcinoma with the persistence of an increased CEA. There was no evidence of recurrence, but a right lobar thyroid nodule without a significantly increased uptake was incidentally discovered on the CT scan of 18F-fluorodeoxyglucose (18F-FDG) PET/CT. We suspected a medullary thyroid carcinoma (MTC) explaining the persistent elevation of CEA. Plasma calcitonin levels were 47 ng/L (N < 10). Fine needle aspiration cytology found atypia of undetermined significance and the patient was reluctant to undergo surgery without any further exploration. We performed a 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT preoperatively which revealed a punctiform focus of the right thyroid lobe corresponding to a pT1aN1aMxR0 medullary thyroid carcinoma, histopathologically confirmed. This case highlights that despite the potential usefulness of 18F-FDG PET/CT in case of an unknown source of elevated CEA this imaging may be falsely negative as in the case of MTC and should lead to further explorations.
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- 2021
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10. A fatal case associated with Catabacter hongkongensis bacteremia in lung cancer patient: A case report
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Valentin Mandin, Stéphane Corvec, Anne-Laure Chéné, Aurélie Guillouzouic, Stéphanie Dirou, Jaafar Bennouna, Pascale Bémer, and Elvire Pons-Tostivint
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Catabacter hongkongensis ,Thoracic malignancy ,Fatal infection ,Infectious and parasitic diseases ,RC109-216 - Abstract
Catabacter hongkongensis is a bacterium first isolated in 2007 and has since been detected in the blood of about fifteen patients with disease such as gastrointestinal malignancy, intestinal obstruction, or acute intestinal infection. We describe herein the case of a patient newly diagnosed with metastatic lung cancer, who died from a fatal infection possibly related to Catabacter hongkongensis bacteremia. By reviewing all cases reported in the literature, our case report supports that this infection is associated with a very high mortality in cancer patients.
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- 2022
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11. Carcinoembryonic antigen kinetics predict response to first-line treatment in metastatic colorectal cancer: Analysis from PRODIGE 9 trial
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Delphine Salfati, Margaux Huot, Thomas Aparicio, Come Lepage, Julien Taieb, Olivier Bouché, Valérie Boige, Jean-Marc Phelip, Laetitia Dahan, Jaafar Bennouna, Karine Le Malicot, Olayide Boussari, and Jean-Marc Gornet
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Hepatology ,Gastroenterology - Published
- 2023
12. Homozygous Co-Deletion of Type I Interferons and CDKN2A Genes in Thoracic Cancers: Potential Consequences for Therapy
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Marion Grard, Camille Chatelain, Tiphaine Delaunay, Elvire Pons-Tostivint, Jaafar Bennouna, and Jean-François Fonteneau
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lung cancer ,mesothelioma ,type I interferon ,CDKN2A (p16) ,homozygous deletion ,immunotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Homozygous deletion (HD) of the tumor suppressor gene CDKN2A is the most frequent genetic alteration in malignant pleural mesothelioma and is also frequent in non-small cell lung cancers. This HD is often accompanied by the HD of the type I interferons (IFN I) genes that are located closed to the CDKN2A gene on the p21.3 region of chromosome 9. IFN I genes encode sixteen cytokines (IFN-α, IFN-β…) that are implicated in cellular antiviral and antitumor defense and in the induction of the immune response. In this review, we discuss the potential influence of IFN I genes HD on thoracic cancers therapy and speak in favor of better taking these HD into account in patients monitoring.
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- 2021
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13. The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancerResearch in context
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Delphine Le Corre, Alexandre Ghazi, Ralyath Balogoun, Camilla Pilati, Thomas Aparicio, Séverine Martin-Lannerée, Laetitia Marisa, Fatima Djouadi, Virginie Poindessous, Carole Crozet, Jean-François Emile, Claire Mulot, Karine Le Malicot, Valérie Boige, Hélène Blons, Aurélien de Reynies, Julien Taieb, François Ghiringhelli, Jaafar Bennouna, Jean-Marie Launay, Pierre Laurent-Puig, and Sophie Mouillet-Richard
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Comprehensive transcriptomic analyses have shown that colorectal cancer (CRC) is heterogeneous and have led to the definition of molecular subtypes among which the stem-cell, mesenchymal-like group is associated with poor prognosis. The molecular pathways orchestrating the emergence of this subtype are incompletely understood. In line with the contribution of the cellular prion protein PrPC to stemness, we hypothesize that deregulation of this protein could lead to a stem-cell, mesenchymal-like phenotype in CRC. Methods: We assessed the distribution of the PrPC-encoding PRNP mRNA in two large CRC cohorts according to molecular classification and its association with patient survival. We developed cell-based assays to explore the impact of gain and loss of PrPC function on markers of the mesenchymal subtype and to delineate the signalling pathways recruited by PrPC. We measured soluble PrPC in the plasmas of 325 patients with metastatic CRC and probed associations with disease outcome. Findings: We found that PRNP gene expression is enriched in tumours of the mesenchymal subtype and is associated with poor survival. Our in vitro analyses revealed that PrPC controls the expression of genes that specify the mesenchymal subtype through the recruitment of the Hippo pathway effectors YAP and TAZ and the TGFß pathway. We showed that plasma levels of PrPC are elevated in metastatic CRC and are associated with poor disease control. Interpretation: Our findings define PrPC as a candidate driver of the poor-prognosis mesenchymal subtype of CRC. They suggest that PrPC may serve as a potential biomarker for patient stratification in CRC. Funding: Grant support was provided by the following: Cancéropôle Ile de France (grant number 2016-1-EMERG-36-UP 5-1), Association pour la Recherche sur le Cancer (grant number PJA 20171206220), SATT Ile de France Innov (grant number 415) as well as INSERM. Keywords: Colorectal cancer, Molecular classification, Prion protein, Hippo pathway, TGFß pathway
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- 2019
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14. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in metastatic non-small cell lung cancer: CheckMate 9LA 2-year patient-reported outcomes
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Martin Reck, Tudor-Eliade Ciuleanu, Manuel Cobo, Michael Schenker, Bogdan Zurawski, Juliana Menezes, Eduardo Richardet, Jaafar Bennouna, Enriqueta Felip, Oscar Juan-Vidal, Aurelia Alexandru, Ying Cheng, Hiroshi Sakai, Luis Paz-Ares, Shun Lu, Thomas John, Xiaowu Sun, Aniela Moisei, Fiona Taylor, Rachael Lawrance, Xiaoqing Zhang, Judi Sylvester, Yong Yuan, Steven I. Blum, John R. Penrod, and David P. Carbone
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Cancer Research ,Oncology - Published
- 2023
15. First-Line Nivolumab Plus Ipilimumab With Chemotherapy Versus Chemotherapy Alone for Metastatic NSCLC in CheckMate 9LA: 3-Year Clinical Update and Outcomes in Patients With Brain Metastases or Select Somatic Mutations
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Luis G. Paz-Ares, Tudor-Eliade Ciuleanu, Manuel Cobo, Jaafar Bennouna, Michael Schenker, Ying Cheng, Oscar Juan-Vidal, Hideaki Mizutani, Alejo Lingua, Felipe Reyes-Cosmelli, Niels Reinmuth, Juliana Menezes, Jacek Jassem, Svetlana Protsenko, Eduardo Richardet, Enriqueta Felip, Kynan Feeney, Bogdan Zurawski, Aurelia Alexandru, Emmanuel de la Mora Jimenez, Shaker Dakhil, Shun Lu, Martin Reck, Thomas John, Nan Hu, Xiaoqing Zhang, Judi Sylvester, Laura J. Eccles, Diederik J. Grootendorst, David Balli, Jaclyn Neely, David P. Carbone, Institut Català de la Salut, [Paz-Ares LG] Medical Oncology Department, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain. [Ciuleanu TE] Department of Medical Oncology, Institutul Oncologic Prof Dr Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania. [Cobo M] Department of Medical Oncology, Unidad de Gestión Clínica Intercentros de Oncología Médica, Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga, Spain. [Bennouna J] Department of Pneumology, Thoracic Oncology, University Hospital of Nantes and INSERM, CRCINA, Nantes, France. [Schenker M] Department of Medical Oncology, SF Nectarie Oncology Center, Craiova, Romania. [Cheng Y] Department of Oncology, Jilin Cancer Hospital, Changchun, Jilin, People’s Republic of China. [Felip E] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Pulmonary and Respiratory Medicine ,Otros calificadores::/uso terapéutico [Otros calificadores] ,terapéutica::terapéutica::farmacoterapia::protocolos antineoplásicos::terapéutica::farmacoterapia::protocolos de quimioterapia antineoplásica combinada [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms::Bronchial Neoplasms::Carcinoma, Bronchogenic::Carcinoma, Non-Small-Cell Lung [DISEASES] ,neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares::neoplasias de los bronquios::carcinoma broncogénico::carcinoma de pulmón de células no pequeñas [ENFERMEDADES] ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Quimioteràpia combinada ,Oncology ,Therapeutics::Therapeutics::Drug Therapy::Antineoplastic Protocols::Therapeutics::Drug Therapy::Antineoplastic Combined Chemotherapy Protocols [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,Avaluació de resultats (Assistència sanitària) ,Other subheadings::/therapeutic use [Other subheadings] ,Pulmons - Càncer - Tractament - Abstract
Non–small cell lung cancer; Brain metastases; Somatic mutations Càncer de pulmó de cèl·lules no petites; Metàstasis cerebrals; Mutacions somàtiques Cáncer de pulmón de células no pequeñas; Metástasis cerebrales; Mutaciones somáticas Introduction In the phase 3 CheckMate 9LA study, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy alone. We report updated efficacy and safety (≥3 y of follow-up), clinical outcomes in patients with baseline brain metastases, and exploratory somatic mutation analyses. Methods Adults with stage IV or recurrent NSCLC, no known sensitizing EGFR or ALK alterations, and Eastern Cooperative Oncology Group performance status less than or equal to 1 were randomized 1:1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with chemotherapy (two cycles) or chemotherapy alone (four cycles). Assessments included OS, progression-free survival (PFS), and objective response rate. Exploratory analyses included systemic and intracranial efficacy in patients with or without baseline brain metastases, in addition to OS and PFS by KRAS, TP53, STK11, and KEAP1 somatic mutation status in patients with nonsquamous NSCLC. Results With a minimum follow-up of 36.1 months, nivolumab plus ipilimumab with chemotherapy continued to prolong OS versus chemotherapy alone in the intent-to-treat population (median [hazard ratio; 95% confidence interval] OS: 15.8 versus 11.0 mo [0.74; 0.62–0.87]; 3-y OS: 27% versus 19%). Efficacy outcomes were improved in patients with pretreated baseline brain metastases (median [hazard ratio; 95% confidence interval] OS: 19.3 versus 6.8 mo [0.45; 0.29–0.70]; systemic PFS: 9.7 versus 4.1 mo [0.44; 0.28–0.69]; intracranial PFS: 11.4 versus 4.6 mo [0.42; 0.26–0.68]). A trend of OS benefit was observed in patients treated with nivolumab plus ipilimumab with chemotherapy versus chemotherapy alone, despite KRAS, TP53, and STK11 tumor mutations. Extended follow-up revealed no new safety signals. Conclusions With a 3-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy continued to have long-term, durable efficacy versus chemotherapy alone; a manageable safety profile; and survival benefit in patients with or without baseline brain metastases or select somatic mutations, further supporting the regimen as first-line treatment for patients with metastatic NSCLC. This study was supported by Bristol Myers Squibb (Princeton, NJ).
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- 2023
16. nab-Paclitaxel Plus Durvalumab in Patients With Previously Treated Advanced Stage Non-small Cell Lung Cancer (ABOUND.2L+)
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Daniel Morgensztern, Manuel Cobo Dols, Santiago Ponce Aix, Pieter E. Postmus, Jaafar Bennouna, Jürgen R. Fischer, Oscar Juan-Vidal, David J. Stewart, Andrea Ardizzoni, Rafia Bhore, Marianne Wolfsteiner, Martin Reck, Denis Talbot, Ramaswamy Govindan, and Teng Jin Ong
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advanced stage non-small cell lung cancer ,durvalumab ,immune checkpoint blocker plus chemotherapy ,nab-paclitaxel ,second-line therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: The standard therapy for advanced stage non-small cell lung cancer (NSCLC) with no actionable gene alterations is a platinum-based chemotherapy doublet and immune checkpoint blocker (ICB), either concurrently or sequentially, followed by docetaxel at the time of tumor progression. However, more effective treatments are needed. We evaluated the nab-paclitaxel and durvalumab combination in patients with previously treated advanced stage NSCLC.Methods: Patients with advanced stage NSCLC previously treated with one line of platinum-based doublet with or without an ICB and no activating EGFR mutations or ALK translocations received nab-paclitaxel 100 mg/m2 (days 1 and 8) plus durvalumab 1,125 mg (day 15) every 21 days. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall survival (OS) and safety.Results: Between February 2016 and December 2016, 79 patients were enrolled. The median age was 63 years. Most patients were males (68.4%), had non-squamous histology (69.6%), and had no prior ICB treatment (88.6%). The median PFS was 4.5 months; median OS was 10.1 months. A post hoc analysis of survival by prior ICB treatment revealed a median PFS and OS of 4.4 and 9.9 months, respectively, in ICB-naive patients and 6.9 months and not estimable, respectively, in patients previously treated with ICB. The most common treatment-emergent adverse events were asthenia (46.2%) and diarrhea (34.6%); four treatment-related deaths (5.1%) occurred.Conclusions: The nab-paclitaxel and durvalumab combination is feasible and demonstrated antitumor activity without new safety signals. Additional studies using taxanes and ICB in patients with previously treated NSCLC are warranted.Clinical Trial Registration:ClinicalTrials.gov registration (NCT02250326).EudraCT number: 2014-001105-41
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- 2021
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17. RECIST and iRECIST criteria for the evaluation of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the GERCOR NIPICOL phase II study
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Christelle de La Fouchardière, Jaafar Bennouna, David Tougeron, Magali Svrcek, Thierry André, Christophe Tournigand, Christophe Borg, Romain Cohen, Marie-Line Garcia-Larnicol, Thibault Mazard, Yves Menu, Dewi Vernerey, Aurélia Meurisse, and Benoist Chibaudel
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background Immune checkpoint inhibitors (ICIs) are highly effective in patients with microsatellite instability/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC). Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria may underestimate response to ICIs due to the pseudoprogression phenomenon. The GERCOR NIPICOL phase II study aimed to evaluate the frequency of pseudoprogressions in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab.Methods Patients with MSI/dMMR mCRC previously treated with fluoropyrimidines, oxaliplatin, and irinotecan with/without targeted therapies received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles then nivolumab 3 mg/kg every 2 weeks until progression or a maximum of 20 cycles. Computed tomography scan tumor assessments were done every 6 weeks for 24 weeks and then every 12 weeks. The primary endpoint was disease control rate at 12 weeks according to RECIST 1.1 and iRECIST by central review.Results Of 57 patients included between December 2017 and November 2018, 48.0% received ≥3 prior lines of chemotherapy, 18.0% had BRAFV600E mutation, and 56.0% had Lynch syndrome-related cancer. Seven patients (12.0%) discontinued treatment due to adverse events; one died due to a treatment-related adverse event. The disease control rate (DCR) at 12 weeks was 86.0% with RECIST 1.1% and 87.7% with iRECIST. Two pseudoprogressions (3.5%) were observed, at week 6 and at week 36, representing 18% of patients with disease progression per RECIST 1.1 criteria. With a median follow-up of 18.4 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The 12-month PFS rate was 72.9% with RECIST 1.1% and 76.5% with iRECIST. The 12-month OS rate was 84%. Overall response rate was 59.7% with both criteria. RAS/BRAF status, sidedness, Lynch syndrome, and other baseline parameters were not associated with PFS.Conclusion Pseudoprogression is rare in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab. This combined ICI therapy confirms impressive DCR and survival outcomes in these patients.Trial registration number NCT03350126.
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- 2020
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18. Efficacy and safety of first-line avelumab in patients with advanced non-small cell lung cancer: results from a phase Ib cohort of the JAVELIN Solid Tumor study
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Jaafar Bennouna, Guy Jerusalem, Karen Kelly, David Spigel, Marcis Bajars, Claire F Verschraegen, Edward F McClay, Nicholas Iannotti, Charles H Redfern, Franklin L Chen, John C Morris, Hans Juergen Grote, Dongli Zhou, and Neru Munshi
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Introduction Avelumab, an antiprogrammed death ligand-1 antibody, is approved as a monotherapy for treatment of metastatic Merkel cell carcinoma and advanced urothelial carcinoma, and in combination with axitinib for advanced renal cell carcinoma. We report the efficacy and safety of first-line avelumab in advanced non-small cell lung cancer (NSCLC).Methods In a phase I expansion cohort of the JAVELIN Solid Tumor trial, patients with treatment-naive, metastatic, or recurrent NSCLC received 10 mg/kg avelumab intravenously every 2 weeks. Endpoints included best overall response, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.Results Overall, 156 patients were enrolled and treated. Median duration of follow-up was 18.6 months (range, 15 to 23 months). The objective response rate was 19.9% (95% CI, 13.9 to 27.0), including complete response in 3 (1.9%) and partial response in 28 (17.9%). Median DOR was 12.0 months (95% CI, 6.9 to not estimable). Median PFS was 4.0 months (95% CI, 2.7 to 5.4) and the 6-month PFS rate was 38.5% (95% CI, 30.7 to 46.3). Median OS was 14.1 months (95% CI, 11.3 to 16.9) and the 12-month OS rate was 56.6% (95% CI, 48.2 to 64.1). Treatment-related adverse events (TRAEs) occurred in 107 patients (68.6%), including grade ≥3 TRAEs in 19 (12.2%). Immune-related adverse events and infusion-related reactions occurred in 31 (19.9%) and 40 patients (25.6%), respectively. No treatment-related deaths occurred.Conclusion Avelumab showed antitumor activity with a tolerable safety profile as a first-line treatment in patients with advanced NSCLC. These data support further investigation of avelumab in the phase III JAVELIN Lung 100 study.Trial registration details ClinicalTrials.gov NCT01772004; registered January 21, 2013.
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- 2020
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19. STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact
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Elvire Pons-Tostivint, Alexandre Lugat, Jean-François Fontenau, Marc Guillaume Denis, and Jaafar Bennouna
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STK11/LKB1 ,non-small cell lung cancer ,immunotherapy ,biomarker ,KRAS ,Cytology ,QH573-671 - Abstract
The STK11/LKB1 gene codes for liver kinase B1 (STK11/LKB1), a highly conserved serine/threonine kinase involved in many energy-related cellular processes. The canonical tumor-suppressive role for STK11/LKB1 involves the activation of AMPK-related kinases, a master regulator of cell survival during stress conditions. In pre-clinical models, inactivation of STK11/LKB1 leads to the progression of lung cancer with the acquisition of metastatic properties. Moreover, preclinical and clinical data have shown that inactivation of STK11/LKB1 is associated with an inert tumor immune microenvironment, with a reduced density of infiltrating cytotoxic CD8+ T lymphocytes, a lower expression of PD-(L)1, and a neutrophil-enriched tumor microenvironment. In this review, we first describe the biological function of STK11/LKB1 and the role of its inactivation in cancer cells. We report descriptive epidemiology, co-occurring genomic alterations, and prognostic impact for lung cancer patients. Finally, we discuss recent data based on pre-clinical models and lung cancer cohorts analyzing the results of STK11/LKB1 alterations on the immune system and response or resistance to immune checkpoint inhibitors.
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- 2021
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20. Docetaxel, Cisplatin, and 5-fluorouracil (DCF) chemotherapy in the treatment of metastatic or unresectable locally recurrent anal squamous cell carcinoma: a phase II study of French interdisciplinary GERCOR and FFCD groups (Epitopes-HPV02 study)
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Stefano Kim, Marine Jary, Thierry André, Véronique Vendrely, Bruno Buecher, Eric François, François-Clément Bidard, Sarah Dumont, Emmanuelle Samalin, Didier Peiffert, Simon Pernot, Nabil Baba-Hamed, Farid El Hajbi, Olivier Bouché, Jérôme Desrame, Aurélie Parzy, Mustapha Zoubir, Christophe Louvet, Jean-Baptiste Bachet, Thierry Nguyen, Meher Ben Abdelghani, Denis Smith, Christelle De La Fouchardière, Thomas Aparicio, Jaafar Bennouna, Jean-Marc Gornet, Marion Jacquin, Franck Bonnetain, and Christophe Borg
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Anal carcinoma ,Advanced ,Metastatic ,Docetaxel ,And chemotherapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background The squamous cell carcinoma of the anus (SCCA) is a rare disease, but its incidence is markedly increasing. About 15% of patients are diagnosed at metastatic stage, and more than 20% with a localized disease treated by chemoradiotherapy (CRT) will recur. In advanced SCCA, cisplatin and 5-fluorouracil (CF) combination is the standard option but complete response is a rare event and the prognosis remains poor with most disease progression occurring within the first 12 months. We have previously published the potential role of the addition of docetaxel (D). Among 8 consecutive patients with advanced recurrent SCCA after CRT, the DCF regimen induced a complete response in 4 patients, including 3 pathological complete responses. Then, the Epitopes-HPV02 study was designed to confirm the interest of DCF regimen in SCCA patients. Methods This multicentre phase II trial assesses the DCF regimen in advanced SCCA patients. Main eligibility criteria are: histologically proven SCCA, unresectable locally advanced recurrent or metastatic disease, Eastern Cooperative Oncology Group-performance status (ECOG-PS) vs. ≤ 75 years-old) and ECOG-PS (0 vs. 1). The trial was set up based on a Simon’s optimal two-stage design for phase II trials, allowing an early futility interim analysis. The primary endpoint is the observed progression-free survival (PFS) rate at 12 months from the first DCF cycle. A PFS rate below 10% is considered uninteresting, while a PFS rate above 25% is expected. With a unilateral alpha error of 5% and a statistical power of 90%, 66 evaluable patients should be included. Main secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and the correlation of biomarkers with treatment efficacy. Discussion Since the recommended CF regimen is based in a small retrospective analysis and generates a low rate of complete responses, the Epitopes-HPV02 study will establish a new standard in case of a positive result. Associated biomarker studies will contribute to understand the underlying mechanism of resistance and the role of immunity in SCCA. Trial registration NCT02402842 , EudraCT: 2014–001789-81.
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- 2017
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21. Health-Related Quality of Life Analysis in Metastatic Colorectal Cancer Patients Treated by Second-Line Chemotherapy, Associated With Either Cetuximab or Bevacizumab: The PRODIGE 18 Randomized Phase II Study
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Christophe Borg, Olivier Bouché, Antoine Adenis, Jaafar Bennouna, Yann Touchefeu, François Ghiringhelli, Aurélie Bertaut, Julie Blanc, Thierry Conroy, Eric Francois, Jessica Gobbo, and Pascal Artru
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Diarrhea ,Oncology ,medicine.medical_specialty ,Bevacizumab ,Colorectal cancer ,Cetuximab ,Quality of life ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Rectal Neoplasms ,Proportional hazards model ,business.industry ,Gastroenterology ,Cancer ,Common Terminology Criteria for Adverse Events ,medicine.disease ,humanities ,Colonic Neoplasms ,Quality of Life ,FOLFIRI ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
Background and objectives : We have previously showed that for patients with wild-type RAS metastatic colorectal cancer (mCRC) progressing after bevacizumab plus chemotherapy, bevacizumab continuation plus a switch of chemotherapy is the most appropriate option (PRODIGE 18 phase II study). Here we aimed to determine treatment impact in patient's Health-Related Quality Of Life (HRQoL) in PRODIGE18 study. Methods : HRQoL was evaluated in two arms bevacizumab or cetuximab – combined with chemotherapy (modified FOLFOX6 [mFOLFOX6] or FOLFIRI) using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 at baseline, first and third tumour evaluation and at the end of the study. The temporal evolution of quality of life scores was investigated using longitudinal linear mixed models of variance. The time until definitive deterioration (TUDD) was estimated using the Kaplan-Meier method and the long-rank test. A univariate Cox model was used to calculate HR with 95% CI. A multivariate Cox model was applied to determine association of TUDD with age and gender. Safety was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events. Results : HRQoL QLQ-C30 questionnaire compliance was high at baseline (>90%) and declined over time (∼ 70% in tumour evaluation 1 and ∼ 60% in tumour evaluation 3), but remained similar in both treatment arms. Patient reported mean diarrhoea QLQ-C30 score is significantly higher in bevacizumab treatment arm. Clinician reported mild diarrhoea was more frequently declared in bevacizumab treatment arm. Cox multivariate analyses showed no statistically significant differences in TUDD for all QLQ-C30 scales between treatments. TUDD of appetite loss was significantly associated to age. Conclusions : Our study shows that no relevant impairment of patients HRQoL between the two treatment arms. So, the analysis of the HRQoL with equal effectiveness does not make it possible to favor one treatment over another. ClinicalTrials.gov : NCT01442649; Clinicaltrialsregister.eu EUDRACT 2009-012942-22.
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- 2022
22. Management of cancer disease in Burundi, a health challenge
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Bagorane, Justin, primary, Negamiyimana, Gustave, additional, Kwizera, Juvénal, additional, Morillon, Manon, additional, Déo, Ntukamazina, additional, Fadli, Mohamed El, additional, Jaafar, Bennouna, additional, and Belbaraka, Rhizlane, additional
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- 2023
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23. The density of Tbet+ tumor-infiltrating T lymphocytes reflects an effective and druggable preexisting adaptive antitumor immune response in colorectal cancer, irrespective of the microsatellite status
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Eva Ott, Linda Bilonda, Delphine Dansette, Cécile Deleine, Emilie Duchalais, Juliette Podevin, Christelle Volteau, Jaafar Bennouna, Yann Touchefeu, Pierre Fourquier, Wassila El Alami Thomas, Jérome Chetritt, Stéphane Bezieau, Marc Denis, Claire Toquet, Jean-François Mosnier, Anne Jarry, and Céline Bossard
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colorectal cancer ,medullary carcinoma ,tbet ,microsatellite instability ,ifnγ response ,explant culture ,pd1/pdl1 ,ido-1 ,pd1 blockade ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Purpose: The recent success of anti-PD1 antibody in metastatic colorectal cancer (CRC) patients with microsatellite instability (MSI), known to be associated with an upregulated Th1/Tc1 gene signature, provides new promising therapeutic strategies. However, the partial objective response highlights a crucial need for relevant, easily evaluable, predictive biomarkers. Here we explore whether in situ assessment of Tbet+ tumor infiltrating lymphocytes (TILs) reflects a pre-existing functional antitumor Th1/Tc1/IFNγ response, in relation with clinicopathological features, microsatellite status and expression of immunoregulatory molecules (PD1, PDL1, IDO-1). Methodology: In two independent cohorts of CRC (retrospective n = 80; prospective n = 27) we assessed TILs density (CD3, Tbet, PD1) and expression profile of PDL1 and IDO-1 by immunohistochemistry/image analysis. Furthermore, the prospective cohort allowed to perform ex vivo CRC explant cultures and measure by Elisa the IFNγ response, at baseline and upon anti-PD1 treatment. Results: The density of Tbet+ TILs was significantly higher in MSI CRC, especially in the medullary subtype but also in a subgroup of MSS (microsatellite stable), and positively correlated with PD1 and PDL1 expression, but not with IDO-1. Finally, a high number of Tbet+ TILs was associated with a favorable overall survival. These Tbet+ TILs were functional as their density positively correlated with basal IFNγ levels. In addition, the combined score of Tbet+ PD1+ TILs coupled with IDO-1 expression predicted the magnitude of the IFNγ response upon anti-PD1. Conclusion: Altogether, immunohistochemical quantification of Tbet+ TILs is a reliable and accurate tool to recapitulate a preexisting Th1/Tc1/IFNγ antitumor response that can be reinvigorated by anti-PD1 treatment.
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- 2019
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24. Supplementary figures and table from Sensitization of EGFR Wild-Type Non–Small Cell Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitor Erlotinib
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Lisenn Lalier, François M. Vallette, Jaafar Bennouna, Didier Decaudin, Ariel Savina, Fanny Bouquet, Ludmilla de Plater, Mathilde Cabart, Marie-Pierre Joalland, and Judith Raimbourg
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Supplementary figures and table described in the manuscript
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- 2023
25. Data from Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France Trial
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Pierre Laurent-Puig, Thierry André, Dewi Vernerey, Aimery de Gramont, Thibault Mazard, Kariman Chaba, Katia Hormigos, Claire Mulot, Olivier Bouche, Joëlle Egreteau, May Mabro, Céline Lepere, Christophe Louvet, Jérôme Desrame, Jaafar Bennouna, Laurent Mineur, Camille Bourreau, Julie Henriques, Valérie Taly, and Julien Taieb
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Purpose:Circulating tumor DNA (ctDNA) has been suggested as a major prognostic factor in resected stage-III colon cancer. We analyzed ctDNA of patients randomized in the phase III IDEA-France trial.Experimental Design:ctDNA was tested for WIF1 and NPY by droplet digital PCR with method developed and validated for colorectal cancer. Disease-free survival (DFS) and overall survival (OS) were analyzed via multivariable analysis in patients with ctDNA samples and in sub-groups according to treatment duration (3/6 months) and disease stage (high/low-risk stage III).Results:Of 2,010 randomized patients, 1,345 had available ctDNA samples (1,017 collected both post-surgery and pre-chemotherapy). More Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 (78% versus 69%) and T4 and/or N2 (40% versus 36%) were observed in patients studied (n = 1017) versus not analyzed (n = 993). There were 877 ctDNA-negative (86.2%) and 140 ctDNA-positive (13.8%) patients; their baseline characteristics were similar. With a median follow-up of 6.6 years, the 3-year DFS rate was 66.39% for ctDNA-positive patients and 76.71% for ctDNA-negative patients (P = 0.015). ctDNA was confirmed as an independent prognostic marker for DFS (adjusted HR = 1.55, 95% CI 1.13–2.12, P = 0.006) and OS (HR = 1.65, 95% CI 1.12–2.43, P = 0.011). ctDNA was prognostic in patients treated for 3 months and with T4 and/or N2 tumors, but not in those treated for 6 months and with T1–3/N1 tumors.Conclusions:In this first ctDNA assessment of a large series of patients with stage III colon cancer enrolled in phase III trial, post-surgery ctDNA was found in 13.8% of them and was confirmed as an independent prognostic marker.See related commentary by Bent and Kopetz, p. 5449
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- 2023
26. Supplementary Data from Prognostic Value and Relation with Adjuvant Treatment Duration of ctDNA in Stage III Colon Cancer: a Post Hoc Analysis of the PRODIGE-GERCOR IDEA-France Trial
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Pierre Laurent-Puig, Thierry André, Dewi Vernerey, Aimery de Gramont, Thibault Mazard, Kariman Chaba, Katia Hormigos, Claire Mulot, Olivier Bouche, Joëlle Egreteau, May Mabro, Céline Lepere, Christophe Louvet, Jérôme Desrame, Jaafar Bennouna, Laurent Mineur, Camille Bourreau, Julie Henriques, Valérie Taly, and Julien Taieb
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Supplementary Data
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- 2023
27. Supplementary Table 2 from Human TH17 Immune Cells Specific for the Tumor Antigen MAGE-A3 Convert to IFN-γ–Secreting Cells as They Differentiate into Effector T Cells In Vivo
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Danila Valmori, Maha Ayyoub, Jaafar Bennouna, Jean-Yves Douillard, Sandrine Hiret, Hélène Senellart, Karine Duperrier-Amouriaux, Isabelle Raimbaud, Pascale Pignon, and Ahmed Hamaï
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PDF file - 49K
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- 2023
28. Supplementary Figure Legend from Human TH17 Immune Cells Specific for the Tumor Antigen MAGE-A3 Convert to IFN-γ–Secreting Cells as They Differentiate into Effector T Cells In Vivo
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Danila Valmori, Maha Ayyoub, Jaafar Bennouna, Jean-Yves Douillard, Sandrine Hiret, Hélène Senellart, Karine Duperrier-Amouriaux, Isabelle Raimbaud, Pascale Pignon, and Ahmed Hamaï
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Supplementary Figure Legend from Human TH17 Immune Cells Specific for the Tumor Antigen MAGE-A3 Convert to IFN-γ–Secreting Cells as They Differentiate into Effector T Cells In Vivo
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- 2023
29. Supplementary Methods from Human TH17 Immune Cells Specific for the Tumor Antigen MAGE-A3 Convert to IFN-γ–Secreting Cells as They Differentiate into Effector T Cells In Vivo
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Danila Valmori, Maha Ayyoub, Jaafar Bennouna, Jean-Yves Douillard, Sandrine Hiret, Hélène Senellart, Karine Duperrier-Amouriaux, Isabelle Raimbaud, Pascale Pignon, and Ahmed Hamaï
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- 2023
30. Supplementary Table 1 from Human TH17 Immune Cells Specific for the Tumor Antigen MAGE-A3 Convert to IFN-γ–Secreting Cells as They Differentiate into Effector T Cells In Vivo
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Danila Valmori, Maha Ayyoub, Jaafar Bennouna, Jean-Yves Douillard, Sandrine Hiret, Hélène Senellart, Karine Duperrier-Amouriaux, Isabelle Raimbaud, Pascale Pignon, and Ahmed Hamaï
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PDF file - 49K
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- 2023
31. Supplementary Figure 1 from Human TH17 Immune Cells Specific for the Tumor Antigen MAGE-A3 Convert to IFN-γ–Secreting Cells as They Differentiate into Effector T Cells In Vivo
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Danila Valmori, Maha Ayyoub, Jaafar Bennouna, Jean-Yves Douillard, Sandrine Hiret, Hélène Senellart, Karine Duperrier-Amouriaux, Isabelle Raimbaud, Pascale Pignon, and Ahmed Hamaï
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- 2023
32. The Expression of Anti-Müllerian Hormone Type II Receptor (AMHRII) in Non-Gynecological Solid Tumors Offers Potential for Broad Therapeutic Intervention in Cancer
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Jean-Marc Barret, André Nicolas, Anne Jarry, Olivier Dubreuil, Didier Meseure, Tilda Passat, Emeline Perrial, Cécile Deleine, Gabriel Champenois, Solenne Gaillard, Emilie Duchalais, Isabelle Ray-Coquard, Mehdi Lahmar, Charles Dumontet, Jaafar Bennouna, Céline Bossard, Sergio Roman-Roman, and Jean-François Prost
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AMHRII ,oncofetal antigen ,colorectal cancer ,protein expression ,murlentamab ,Biology (General) ,QH301-705.5 - Abstract
The anti-Müllerian hormone (AMH) belongs to the TGF-β family and plays a key role during fetal sexual development. Various reports have described the expression of AMH type II receptor (AMHRII) in human gynecological cancers including ovarian tumors. According to qRT-PCR results confirmed by specific In-Situ Hybridization (ISH) experiments, AMHRII mRNA is expressed in an extremely restricted number of normal tissues. By performing ISH on tissue microarray of solid tumor samples AMHRII mRNA was unexpectedly detected in several non-gynecological primary cancers including lung, breast, head and neck, and colorectal cancers. AMHRII protein expression, evaluated by immunohistochemistry (IHC) was detected in approximately 70% of epithelial ovarian cancers. Using the same IHC protocol on more than 900 frozen samples covering 18 different cancer types we detected AMHRII expression in more than 50% of hepato-carcinomas, colorectal, lung, and renal cancer samples. AMHRII expression was not observed in neuroendocrine lung tumor samples nor in non-Hodgkin lymphoma samples. Complementary analyses by immunofluorescence and flow cytometry confirmed the detection of AMHRII on a panel of ovarian and colorectal cancers displaying comparable expression levels with mean values of 39,000 and 50,000 AMHRII receptors per cell, respectively. Overall, our results suggest that this embryonic receptor could be a suitable target for treating AMHRII-expressing tumors with an anti-AMHRII selective agent such as murlentamab, also named 3C23K or GM102. This potential therapeutic intervention was confirmed in vivo by showing antitumor activity of murlentamab against AMHRII-expressing colorectal cancer and hepatocarcinoma Patient-Derived tumor Xenografts (PDX) models.
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- 2021
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33. Long-term avelumab in advanced non-small-cell lung cancer: summaries and post hoc analyses from JAVELIN Solid Tumor
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Borys Hrinczenko, Nicholas Iannotti, Sanjay Goel, David Spigel, Howard Safran, Matthew H Taylor, Jaafar Bennouna, Deborah J Wong, Karen Kelly, Claire Verschraegen, Marcis Bajars, Juliane Manitz, Mary Ruisi, and James L Gulley
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Cancer Research ,Oncology ,General Medicine - Abstract
Background: This study examined patients with advanced non-small-cell lung cancer who received long-term avelumab (anti-PD-L1) in a large phase Ib trial (JAVELIN Solid Tumor). Methods: Patients receiving >2 years of avelumab were reviewed and exploratory descriptive analyses were conducted. Results: Individuals with varying baseline characteristics who had received up to 6 years of avelumab were reviewed. Overall, 37/340 (10.9%) had received ≥2 years of treatment; in this subgroup, best response was complete response in 5.4%, partial response in 59.5% and stable disease in 29.7%; 51.4% had continued treatment beyond disease progression. Conclusions: In this study, 11% of patients with advanced non-small-cell lung cancer received ≥2 years of avelumab treatment and experienced prolonged response or continued clinical benefit. Clinical Trial Registration: NCT02395172 ( ClinicalTrials.gov )
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- 2022
34. Phase II study of afatinib plus pembrolizumab in patients with squamous cell carcinoma of the lung following progression during or after first-line chemotherapy (LUX-Lung-IO)
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Benjamin Levy, Fabrice Barlesi, Luis Paz-Ares, Jaafar Bennouna, Mustafa Erman, Enriqueta Felip, Dolores Isla, Hye Ryun Kim, Sang-We Kim, Jeannick Madelaine, Olivier Molinier, Mustafa Özgüroğlu, Delvys Rodríguez Abreu, Abidemi Adeniji, Robert M. Lorence, Isabelle Voccia, Michael J. Chisamore, Jonathan W. Riess, Institut Català de la Salut, [Levy B] Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital, Washington, DC, USA. [Barlesi F] Aix Marseille University, CNRS, INSERM, CRCM, Assistance Publique Hôpitaux de Marseille, Marseille, France. Gustave Roussy Cancer Campus, Villejuif, France. [Paz-Ares L] Department of Medical Oncology, University Hospital 12 De Octubre, Madrid, Spain. [Bennouna J] Department of Pneumology, Thoracic Oncology, University Hospital - Nantes, Nantes, France. [Erman M] Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey. [Felip E] Servei d’Oncologia Mèdica, Vall d'Hebron Hospital Universitari, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Isla D] Department of Medical Oncology, University Hospital Lozano Blesa, Zaragoza, Spain, Vall d'Hebron Barcelona Hospital Campus, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Hôpital Foch [Suresnes], Hacettepe University = Hacettepe Üniversitesi, Vall d'Hebron University Hospital [Barcelona], Yonsei University College of Medicine [Séoul, Corée du Sud], Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), and Centre Hospitalier Le Mans (CH Le Mans)
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Male ,Pulmonary and Respiratory Medicine ,Neoplasms::Neoplasms by Site::Thoracic Neoplasms::Respiratory Tract Neoplasms::Lung Neoplasms [DISEASES] ,Cancer Research ,Lung Neoplasms ,[SDV]Life Sciences [q-bio] ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Middle Aged ,Afatinib ,Antibodies, Monoclonal, Humanized ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Quimioteràpia combinada ,ErbB Receptors ,neoplasias::neoplasias por localización::neoplasias torácicas::neoplasias del tracto respiratorio::neoplasias pulmonares [ENFERMEDADES] ,Oncology ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma, Squamous Cell ,Avaluació de resultats (Assistència sanitària) ,Humans ,Female ,Pulmons - Càncer - Tractament - Abstract
Afatinib; Carcinoma, Squamous Cell; Pembrolizumab Afatinib; Carcinoma de células escamosas; Pembrolizumab Afatinib; Carcinoma de cèl·lules escamoses; Pembrolizumab Introduction Afatinib and pembrolizumab have separately shown survival benefit in patients with squamous cell carcinoma (SqCC) of the lung, and there is biological rationale for concurrent inhibition of the programmed death ligand-1 and epidermal growth factor receptor (EGFR) pathways in this patient population. Materials and Methods This open-label, single-arm study enrolled patients with SqCC of the lung who had progressed during/after first-line chemotherapy and comprised two parts: a safety run-in to establish the recommended phase II dose (RP2D; afatinib 40 mg or 30 mg once daily with pembrolizumab 200 mg every 3 weeks); and the main part assessing efficacy and safety of the RP2D. The primary endpoint was objective response rate (ORR); secondary endpoints included the RP2D, progression-free survival (PFS) and overall survival (OS). Results Twenty-four patients were treated in the safety run-in (afatinib 40 mg/30 mg cohorts: n = 12/12). Median age was 63.5 years; 79.2% of patients were male. All patients discontinued afatinib and pembrolizumab, most commonly due to disease progression (58.3% and 75.0%, respectively) or adverse events (AEs; 37.5% and 25.0%, respectively). The study was discontinued early after completion of the safety run-in, and no patients entered the main part. ORR was 12.5%; median PFS and OS were 13.1 and 29.3 weeks, respectively. All patients had ≥ 1 drug-related AE (grade ≥ 3: 45.8%). Conclusion While there were no new or unexpected safety findings, exploratory analysis of antitumor activity indicated limited efficacy with afatinib plus pembrolizumab in patients with SqCC of the lung who had progressed during/after first-line chemotherapy. This work was supported by Boehringer Ingelheim International GmbH and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Both study sponsors participated in the design of the study, the collection, analysis, and interpretation of the data, writing this article, and the decision to submit the article for publication.
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- 2022
35. Réévaluation du score Pronopall : une étude rétrospective multicentrique
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Lucie Duval, You-Heng Lam, Elvire Pons-Tostivint, Jaafar Bennouna, Tamara Matysiak-Budnik, Aurélie Lepeintre, Paul Girot, and Yann Touchefeu
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Cancer Research ,Oncology ,Radiology, Nuclear Medicine and imaging ,Hematology ,General Medicine - Published
- 2022
36. Bringing Greater Accuracy to Europe’s Healthcare Systems: The Unexploited Potential of Biomarker Testing in Oncology
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Denis Horgan, Gennaro Ciliberto, Pierfranco Conte, David Baldwin, Luis Seijo, Luis M. Montuenga, Luis Paz-Ares, Marina Garassino, Frederique Penault-Llorca, Fabrizia Galli, Isabelle Ray-Coquard, Denis Querleu, Ettore Capoluongo, Susana Banerjee, Peter Riegman, Keith Kerr, Benjamin Horbach, Reinhard Büttner, Hein Van Poppel, Anders Bjartell, Giovanni Codacci-Pisanelli, Benedikt Westphalen, Fabien Calvo, Jasmina Koeva-Balabanova, Stephen Hall, Angelo Paradiso, Dipak Kalra, Christa Cobbaert, Rocio Varea Menendez, Zorana Maravic, Vassiliki Fotaki, Jaafar Bennouna, Estelle Cauchin, Nuria Malats, Iñaki Gutiérrez-Ibarluzea, Benjamin Gannon, Ken Mastris, Chiara Bernini, William Gallagher, Simonetta Buglioni, Alastair Kent, Elisabetta Munzone, Ivica Belina, Jan Van Meerbeeck, Michael Duffy, Elżbieta Sarnowska, Beata Jagielska, Sarah Mee, and Giuseppe Curigliano
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biomarkers ,cancer plan ,companion diagnostics ,comprehensive genomic profiling ,diagnostic tests ,million european genome ,molecular diagnostics ,personalised healthcare ,public health ,reimbursement challenges ,Medicine (General) ,R5-920 - Abstract
Rapid and continuing advances in biomarker testing are not being matched by take-up in health systems, and this is hampering both patient care and innovation. It also risks costing health systems the opportunity to make their services more efficient and, over time, more economical. This paper sets out the potential of biomarker testing, the unfolding precision and range of possible diagnosis and prediction, and the many obstacles to adoption. It offers case studies of biomarker testing in breast, ovarian, prostate, lung, thyroid and colon cancers, and derives specific lessons as to the potential and actual use of each of them. It also draws lessons about how to improve access and alignment, and to remedy the data deficiencies that impede development. And it suggests solutions to outstanding issues – notably including funding and the tangled web of obtaining reimbursement or equivalent coverage that Europe’s fragmented health system implies. It urges a European evolution towards an initial minimum testing scenario, which would guarantee universal access to a suite of biomarker tests for the currently most common conditions, and, further into the future, to an optimum testing scenario in which a much wider range of biomarker tests would be introduced and become part of a more sophisticated health system articulated around personalised medicine. For exploiting genomics to the full, it argues the need for a new policy framework for Europe. Biomarker testing is not an issue that can be treated in isolation, since the purpose of testing is to improve health. Its use is therefore always closely linked to specific health challenges and needs to be viewed in the broader policy context in the EU and more widely. The paper is the result of extensive engagement with experts and decision makers to develop the framework, and consequently represents a wide consensus of views on how healthcare systems should respond from push and pull factors at local, national and cross-border and EU level. It contains strong views and clear recommendations springing from the convictions of patients, clinicians, academics, medicines authorities, HTA bodies, payers, the diagnostic, pharmaceutical and ICT industries, and national policy makers.
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- 2020
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37. Predictive factors of severe early treatment-related toxicity in patients receiving first-line treatment for metastatic colorectal cancer: Pooled analysis of 2190 patients enrolled in Fédération Francophone de Cancérologie Digestive (FFCD) trials
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Clémence Breton, Jean-Baptiste Bachet, Jaafar Bennouna, Sylvain Manfredi, Jean-Louis Legoux, Aimery de Gramont, Karine Le Malicot, Thomas Aparicio, Thierry Lecomte, Olivier Bouché, Michel Ducreux, Olayidé Boussari, Julien Taieb, and Jean-Marc Gornet
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Male ,0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Bevacizumab ,Colorectal cancer ,medicine.medical_treatment ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Neoplasm Metastasis ,Aged ,Aflibercept ,Chemotherapy ,Performance status ,business.industry ,Middle Aged ,Prognosis ,medicine.disease ,Oxaliplatin ,Irinotecan ,Treatment Outcome ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,Female ,Colorectal Neoplasms ,business ,medicine.drug - Abstract
Few studies have explored the association between baseline characteristics and the occurrence of early toxicities in patients treated with first-line chemotherapy for metastatic colorectal cancer (mCRC).Individual patient data of 2190 patients enrolled in 10 prospective FFCD (Fédération Francophone de Cancérologie Digestive) trials were analysed. Severe early toxicity was defined as the occurrence of grade ≥III toxicity within 3 months after initiation of chemotherapy (ET3).Patients received monotherapy based on 5-FU (n = 1068), a cytotoxic doublet (n = 395) or tritherapy with a cytotoxic doublet plus anti-VEGF agent or a cytotoxic triplet (n = 727). The patients received 5-FU (100%), Irinotecan (39.6%), Oxaliplatin (13.4%), Bevacizumab (29.6%) or Aflibercept (1.8%). ET3 occurred in 244 patients (22.8%) with monotherapy, 248 patients (62.8%) with doublet and 392 patients (53.9%) with tritherapy. The most frequent ET3s were related to biological abnormalities and/or gastrointestinal, general and vascular disorders. The prognostic factors for the occurrence of an ET3 in multivariate analysis were a performance status of 2 rather than 0-1 (OR 2.57; 95% CI [1.16, 5.73]; p = 0.02), tritherapy versus monotherapy (OR 2.31; 95% CI [0.84, 6.33]; p = 0.02), alkaline phosphatase 300 UI/l (OR 3.07; 95% CI [1.79, 5.27]; p 0.001) and non-resected primary tumour versus resection (OR 1.59; 95% CI [1.06, 2.39]; p = 0.02). Median overall survival in patients without ET3 was significantly longer than that in patients with ET3 (HR 0.87; 95% CI [0.80-0.96]; p = 0.004).ET3 is frequent whatever the treatment regimen and is associated with certain baseline characteristics. The clinical impact of ET3 on prognosis in mCRC warrants further investigation.
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- 2021
38. Prognostic factors of colorectal cancer patients with brain metastases
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Christophe Locher, Vincent Hautefeuille, Marianne Maillet, Lysiane Marthey, Astrid Lièvre, Jaafar Bennouna, Cedric Lecaille, Violaine Randrian, Romain Chautard, Pascal Artru, Yann Touchefeu, Aziz Zaanan, Pauline Roussille, Thierry Lecomte, David Tougeron, Sheik Emambux, May Mabro, Antoine Berger, Eugénie Rigault, Marie Auvray, Valérie Moulin, Damien Vansteene, Samy Louafi, Marie Dior, Département d'oncologie digestive [Hôpital Européen Georges Pompidou - APHP], Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université de Paris (UP), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
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Oncology ,medicine.medical_specialty ,Multivariate analysis ,Colorectal cancer ,[SDV]Life Sciences [q-bio] ,Rectum ,ECOG Performance Status ,Recursive partitioning ,Radiosurgery ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,ComputingMilieux_MISCELLANEOUS ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Brain Neoplasms ,business.industry ,Proportional hazards model ,Retrospective cohort study ,Hematology ,Nomogram ,Prognosis ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Colorectal Neoplasms ,business - Abstract
Introduction Brain metastases (BMs) from colorectal cancer (CRC) are rare (≈2%) but are increasing with the improvement of CRC prognosis. The main objective of this study was to evaluate the prognostic factors of BM from CRC. Materials and methods This multicenter retrospective study included all consecutive patients with BM from CRC diagnosed between 2000 and 2017. Theory/calculation Prognostic factors of OS were evaluated in univariate (log-rank test) and multivariate analyses (Cox regression model). These prognostic factors could help the management of patients with BM from CRC. Results A total of 358 patients were included with a median age of 65.5 years. Primary tumors were mostly located in the rectum (42.4%) or left colon (37.2%) and frequently KRAS-mutated (56.9%). The median time from metastatic CRC diagnosis to BM diagnosis was 18.5 ± 2.5 months. BMs were predominantly single (56.9%) and only supratentorial (54.4%). BM resection was performed in 33.0% of the cases and 73.2% of patients had brain radiotherapy alone or after surgery. Median OS was 5.1 ± 0.3 months. In multivariate analysis, age under 65 years, ECOG performance status 0–1, single BM and less than 3 chemotherapy lines before BM diagnosis were associated with better OS. Prognostic scores, i.e. recursive partitioning analysis (RPA), Graded Prognostic Assessment (GPA), Disease Specific-Graded Prognostic Assessment (DS-GPA), Gastro-Intestinal-Graded Prognostic Assessment (GI-GPA) and the nomogram were statistically significantly associated with OS but the most relevant prognosis criteria seemed the ECOG performance status 0–1. Conclusions ECOG performance status, number of BM and number of chemotherapy lines are the most relevant factors in the management of patients with BM from CRC.
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- 2021
39. Prediction of Response to Immune Checkpoint Blockade in Patients with Metastatic Colorectal Cancer with Microsatellite Instability
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Alex Duval, Toky Ratovomanana, Remy Nicolle, Romain Cohen, Aurélien Diehl, Aurélie Siret, Quentin Letourneur, Olivier Buhard, Alexandre Perrier, Erell Guillerm, Florence Coulet, Raphaël Colle, Ada Collura, Emmanuelle Despras, Philippe Le Rouzic, Florence Renaud, Agusti Alentorn, Mehdi Touat, Mira Ayadi, Pierre Bourgoin, Celine Prunier, Vincent Jonchère, Jaafar Bennouna, Aurélien de Reynies, Jean-François Fléjou, Magali Svrcek, and Thierry André
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Tumors with microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). To date however, tools for predicting efficacy of these new therapies are lacking. Here we combined high-throughput DNA and RNA sequencing of tumors from 117 patients with MSI mCRC treated with anti-PD-1 +/- anti-CTLA-4 and enrolled into two cohorts, i.e., the NIPICOL clinical trial (NCT03350126) and the ImmunoMSI prospective cohort that were used as discovery and validation cohorts in this ancillary study, respectively. All analyses based on previously suggested DNA/RNA biomarkers of resistance failed to identify robust predictors of treatment response in patients, e.g., the level of MSI, mutational burden, the presence of specific somatic DNA variants as assessed by exome-sequencing and the activity of canonical signaling pathways or the presence of specific cellular contingents within the tumor bulk as estimated by RNA-sequencing. By contrast, resistance to ICI was found to depend both on a small subset of somatic DNA variants located in microsatellite-containing genes with very diverse biological functions and the expression of a stromal-oriented RNA component. Testing of these predictors in 5 large additional independent retrospective and prospective cohorts (IDEA and MOSAIC clinical trials) regrouping 446 patients with nonmetastatic or metastatic MSI CRC untreated with ICI allowed us to validate the specificity of the predictive nature of these indicators regarding ICI-treated MSI mCRC patients. The use of these DNA/RNA predictors will help to refine the ICI-based precision therapy of patients with metastatic MSI mCRC.
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- 2022
40. KEYNOTE-975 study design: a Phase III study of definitive chemoradiotherapy plus pembrolizumab in patients with esophageal carcinoma
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Markus Moehler, Chie Schin Shih, Jaafar Bennouna, Lin Shen, Anjali Desai, Xiaolong Fu, Manish A. Shah, Antoine Adenis, Pooja Bhagia, Sonal Bordia, Peter C. Enzinger, Harvey J. Mamon, Ken Kato, Toshihiko Doi, and Byoung Chul Cho
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Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Clinical Trial Protocol ,Esophageal Neoplasms ,esophageal adenocarcinoma ,medicine.medical_treatment ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,chemotherapy ,03 medical and health sciences ,0302 clinical medicine ,Clinical Protocols ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Carcinoma ,Humans ,esophageal cancer ,radiotherapy ,Chemotherapy ,business.industry ,Cancer ,Chemoradiotherapy ,General Medicine ,Esophageal cancer ,medicine.disease ,Combined Modality Therapy ,esophageal squamous cell carcinoma ,Radiation therapy ,Clinical trial ,030104 developmental biology ,Research Design ,030220 oncology & carcinogenesis ,Female ,immunotherapy ,pembrolizumab ,business - Abstract
Despite curative-intent treatment, most patients with locally advanced esophageal cancer will experience disease recurrence or locoregional progression, highlighting the need for new therapies. Current guidelines recommend definitive chemoradiotherapy in patients ineligible for surgical resection, but survival outcomes are poor. Pembrolizumab is well tolerated and provides promising antitumor activity in patients with previously treated, advanced, unresectable esophageal/esophagogastric junction cancer. Combining pembrolizumab with chemoradiotherapy may further improve outcomes in the first-line setting. Here, we describe the design and rationale for the double-blind, Phase III, placebo-controlled, randomized KEYNOTE-975 trial investigating pembrolizumab in combination with definitive chemoradiotherapy as first-line treatment in patients with locally advanced, unresectable esophageal/gastroesophageal junction cancer. Overall survival and event-free survival are the dual primary end points. Clinical trial registration: NCT04210115 (ClinicalTrials.gov)
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- 2021
41. KEYMAKER-U06 substudy 06A trial in progress: A phase 1/2 study of investigational agents with pembrolizumab (pembro) plus chemotherapy (chemo) or lenvatinib in PD-1/L1 treatment-naïve advanced esophageal cancer
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Ken Kato, Toshihiko Doi, Jaafar Bennouna, Jong-Mu Sun, Thomas Jemielita, Kanu Sharan, Pooja Bhagia, and Antoine Adenis
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Cancer Research ,Oncology - Abstract
TPS487 Background: Immunotherapy has improved clinical outcomes in esophageal carcinoma; however, patients with advanced esophageal cancer that progresses after first-line chemo continue to have limited treatment options and poor prognosis. KEYMAKER-U06 substudy 06A (NCT05342636) is evaluating pembro (anti–PD-1) + investigator choice of chemo (irinotecan or paclitaxel), MK-4280A, a coformulation of pembro and favezelimab (anti-LAG3) + chemo, pembro + MK-4830 (anti-ILT4) + chemo, and pembro + MK-4830 + lenvatinib (multitargeted RTK inhibitor) for the second-line treatment of patients with PD-1/L1 treatment-naive advanced esophageal squamous cell carcinoma (ESCC). Methods: KEYMAKER-U06 substudy 06A is a phase 1/2, multicenter, open-label study comprising a safety lead-in phase and an efficacy phase. Adults with histologically or cytologically confirmed metastatic or locally advanced ESCC, who experienced disease progression on 1 prior line of therapy, have not received anti-PD-1/L1 therapy, any immune-modulating therapy, and/or VEGF targeted therapy, have measurable disease per RECIST v1.1 confirmed by blinded independent central review (BICR), and have an Eastern Cooperative Oncology Group performance status of 0 or 1 are eligible. Patients are being allocated to 1 of 4 treatment arms: pembro 200 mg IV Q3W + investigator choice of chemo (paclitaxel 80-100 mg/m2 IV days 1, 8, and 15 of every 28-day cycle or irinotecan 180 mg/m2 day 1 of every 14-day cycle) (arm 1), MK-4280A (pembro 200 mg/favezelimab 800 mg IV day 1 then Q3W) + investigator choice of chemo (arm 2), pembro 200 mg IV Q3W + MK-4830 800 mg IV Q3W + investigator choice of chemo (arm 3), or pembro 200 mg IV Q3W + MK-4830 800 mg IV Q3W + lenvatinib 20 mg orally once daily (arm 4). Arms 2-4 will have a safety lead-in phase; arm 1 will not have a safety lead-in phase because the safety and tolerability of pembro + chemo has been established in multiple phase 3 studies in the first-line treatment setting. The safety lead-in phase includes 10 patients who will be closely monitored for dose-limiting toxicities (DLTs) for 21 days after the first dose of study intervention. If ≥4 patients experience DLTs in any treatment arm, then enrollment in the efficacy phase may be delayed to allow for examination of safety data and to consider design changes. If ≤3 patients experience DLTs, up to 30 patients per arm will be enrolled (inclusive of the 10 patients from the safety lead-in) for efficacy assessment. In the safety lead-in phase, the primary end point is safety/tolerability assessed by DLTs, adverse events (AEs), and discontinuation of treatment due to AEs. In the efficacy phase, the primary end point is ORR per RECIST v1.1 by BICR, and secondary end points are PFS and DOR, per RECIST v1.1 by BICR, and OS and safety/tolerability. Enrollment in this study is ongoing. Clinical trial information: NCT05342636 .
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- 2023
42. Osimertinib for Front-Line Treatment of Locally Advanced or Metastatic EGFR-Mutant NSCLC Patients: Efficacy, Acquired Resistance and Perspectives for Subsequent Treatments
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Jaafar Bennouna and Marc G. Denis
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0301 basic medicine ,Mutation ,biology ,business.industry ,Immunogenicity ,medicine.medical_treatment ,medicine.disease_cause ,medicine.disease ,Precision medicine ,respiratory tract diseases ,3. Good health ,Targeted therapy ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Tumor Escape ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,medicine ,Osimertinib ,Epidermal growth factor receptor ,Lung cancer ,business - Abstract
Non-small cell lung cancer (NSCLC) is one of the most efficient models for precision medicine in oncology. The most appropriate therapeutic for the patient is chosen according to the molecular characteristics of the tumor, schematically distributed between immunogenicity and oncogenic addiction. For this last concept, advanced NSCLC with epidermal growth factor receptor (EGFR) mutation is one of the most illustrative models. EGFR-tyrosine kinase inhibitors (TKIs) are the therapeutic backbone for this type of tumor. The recent development of a third-generation TKI, osimertinib, has been a new step forward in the treatment of NSCLC patients. In this article, we first review the clinical development of osimertinib and highlight its efficacy results. We then present the most frequent tumor escape mechanisms when osimertinib is prescribed in first line: off-target (MET amplification, HER2 amplification, BRAF mutation, gene fusions, histologic transformation) and on-target mechanisms (EGFR mutation). Finally, we discuss subsequent biomarker-driven treatment strategies.
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- 2020
43. Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703 R2D2 Trial
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Julien Mazieres, Claire Lafitte, Charles Ricordel, Laurent Greillier, Elodie Negre, Gérard Zalcman, Charlotte Domblides, Jeannick Madelaine, Jaafar Bennouna, Céline Mascaux, Denis Moro-Sibilot, François Pinquie, Alexis B. Cortot, Josiane Otto, Jacques Cadranel, Alexandra Langlais, Franck Morin, Virginie Westeel, Benjamin Besse, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Services de Pneumologie, Exploration Fonctionnelle Respiratoire et Cardiologie (Hôpital Louis Pradel), Hospices Civils de Lyon (HCL), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Multidisciplinary Oncology and Therapeutic Innovations Unit, Hôpital Nord [CHU - APHM], Thèses d'exercice et mémoires - UFR de Médecine Montpellier-Nîmes, Université de Montpellier (UM), Service d’oncologie thoracique et essais précoces [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Foch [Suresnes], Service de Pneumologie [Strasbourg], Université de Strasbourg (UNISTRA)-Nouvel Hôpital Civil, Hospices Civils de Strasbourg, CHU de Grenoble-Alpes, Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Groupe de recherche clinique Biomarqueurs Théranostiques des Cancers Bronchiques Non à Petites Cellules (GRC 4 - Theranoscan), Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Gustave Roussy (IGR), and Département de médecine oncologique [Gustave Roussy]
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MESH: Aged ,MESH: Docetaxel ,Cancer Research ,MESH: Humans ,MESH: Middle Aged ,MESH: Mutation ,MESH: Survival Rate ,MESH: Non-Randomized Controlled Trials as Topic ,MESH: Adult ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,MESH: Follow-Up Studies ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,MESH: Male ,MESH: Prognosis ,MESH: Lung Neoplasms ,MESH: Receptor, ErbB-2 ,MESH: Antineoplastic Combined Chemotherapy Protocols ,MESH: Aged, 80 and over ,Oncology ,MESH: Antibodies, Monoclonal, Humanized ,MESH: Trastuzumab ,MESH: Female ,MESH: Carcinoma, Non-Small-Cell Lung - Abstract
PURPOSE HER2 exon 20 insertions and point mutations are oncogenic drivers found in 1%-2% of patients with non–small-cell lung cancer (NSCLC). No targeted therapy is approved for this subset of patients. We prospectively evaluated the effectiveness of the combination of two antibodies against human epidermal growth factor 2 (HER2 [HER2] trastuzumab and pertuzumab with docetaxel; trastuzumab and pertuzumab) and docetaxel. METHODS The IFCT 1703-R2D2 trial is a multicenter, nonrandomized phase II study. Patients with HER2-mutated, advanced NSCLC who progressed after ≥ 1 platinum-based treatment were enrolled. Patients received pertuzumab at a loading dose of 840 mg and 420 mg thereafter; trastuzumab at an 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at a dose of 75 mg/m2 every 3 weeks. The primary outcome was the objective response rate (ORR). Other end points included the duration of response, progression-free survival, and safety ( NCT03845270 ). RESULTS Forty-five patients were enrolled and treated. The median age was 64.5 years (range, 31-84 years), 35% were smokers, 72% were females, 15% had an Eastern Cooperative Oncology Group performance status of 2, and 30% had brain metastases. The objective response rate was 29% (n = 13), and 58% had stable disease (n = 26). The median progression-free survival was 6.8 months (95% CI, 4.0 to 8.5). The median duration of response in patients with a confirmed response (n = 13) was 11 months (95% CI, 2.9 to 14.9). Grade 3/4 treatment-related adverse events were observed in 64% of the patients. No patient discontinued treatment because of toxicity. The most frequent grade ≥ 3 treatment-related adverse events were neutropenia (33%), diarrhea (13%), and anemia (9%). CONCLUSION Triple therapy with trastuzumab, pertuzumab, and docetaxel is feasible and effective for HER2-mutated pretreated advanced NSCLC. These results highlight the effectiveness of the HER2 antibody-based strategy, which should be considered for these patients.
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- 2022
44. Investigating beam matching for multi-room pencil beam scanning proton therapy
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Jaafar Bennouna and Suresh Rana
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Range (particle radiation) ,Materials science ,Radiological and Ultrasound Technology ,Proton ,business.industry ,Biomedical Engineering ,Biophysics ,Dose profile ,Scintillator ,Optics ,Beam matching ,Radiology, Nuclear Medicine and imaging ,Pencil-beam scanning ,business ,Instrumentation ,Proton therapy ,Beam (structure) ,Biotechnology - Abstract
The purpose of this study was to investigate the proton beam matching for a multi-room ProteusPLUS pencil beam scanning (PBS) proton therapy system and quantify the agreement among three beam-matched treatment rooms (GTR1, GTR2, and GTR3). In-air spot size measurements were acquired using a 2D scintillation detector at various gantry angles. Range and absolute dose measurements were performed in water at gantry angle 0°. Patient-specific quality assurance (QA) plans of four different disease sites (brain, mediastinum, sacrum, and prostate) and machine QA fields with uniform dose were delivered for various beam conditions. The results from GTR1 were considered as reference values. The average difference in spot sizes between GTR2 and GTR1 was − 0.3% ± 2.2% (range, − 5.9 to 5.8%). For GTR3 vs. GTR1, the average difference in spot sizes was 0.6% ± 1.7% (range, − 4.8 to 4.6%). The spot symmetry was found to be ≤ 4.4%. For proton range, the difference among three rooms was within ± 0.5 mm. On average, the difference in absolute dose was − 0.1 ± 0.7% (range, − 1.3 to 2.1%) for GTR2 vs. GTR1 and 0.7 ± 0.6% (range, − 0.1 to 2.1%) for GTR3 vs. GTR1. The average gamma passing rate of patient-specific QA measurements (n = 29) was ≥ 98.6%. The average gamma passing rate of machine QA fields was 99.9%. In conclusion, proton beam matching was quantified for three beam-matched rooms of an IBA ProteusPLUS system with a PBS dedicated nozzle. It is feasible to match the spot size and absolute dose within ± 5% and ± 2%, respectively. Proton range can be matched within ± 0.5 mm.
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- 2020
45. Impact of magnetic field regulation in conjunction with the volumetric repainting technique on the spot positions and beam range in pencil beam scanning proton therapy
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Jaafar Bennouna, Suresh Rana, Anatoly B. Rosenfeld, and A. Gutierrez
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Proton ,87.55.Qr ,87.56.Fc ,magnetic field regulation ,030218 nuclear medicine & medical imaging ,proton energy ,03 medical and health sciences ,0302 clinical medicine ,Optics ,Proton Therapy ,Radiation Oncology Physics ,Humans ,Radiology, Nuclear Medicine and imaging ,Pencil-beam scanning ,Instrumentation ,Proton therapy ,Physics ,Range (particle radiation) ,volumetric repainting ,Radiation ,Spots ,business.industry ,87.56.bd ,Radiotherapy Planning, Computer-Assisted ,Isocenter ,pencil beam scanning ,Radiotherapy Dosage ,Magnetic Fields ,030220 oncology & carcinogenesis ,Ionization chamber ,spot position ,business ,Beam (structure) - Abstract
Purpose The objective of this study was to evaluate the impact of the magnetic field regulation in conjunction with the volumetric repainting technique on the spot positions and range in pencil beam scanning proton therapy. Methods “Field regulation” — a feature to reduce the switching time between layers by applying a magnetic field setpoint (instead of a current setpoint) has been implemented on the proton beam delivery system at the Miami Cancer Institute. To investigate the impact of field regulation for the volumetric repainting technique, several spot maps were generated with beam delivery sequence in both directions, that is, irradiating from the deepest layer to the most proximal layer (“down” direction) as well as irradiating from the most proximal layer to the deepest layer (“up” direction). Range measurements were performed using a multi‐layer ionization chamber array. Spot positions were measured using two‐dimensional and three‐dimensional scintillation detectors. For range and central‐axis spot position, spot maps were delivered for energies ranging from 70–225 MeV. For off‐axis spot positions, the maps were delivered for high‐, medium, and low‐energies at eight different gantry angles. The results were then compared between the “up” and “down” directions. Results The average difference in range for given energy between “up” and “down” directions was 0.0 ± 0.1 mm. The off‐axis spot position results showed that 846/864 of the spots were within ±1 mm, and all off‐axis spot positions were within ±1.2 mm. For spots (n = 126) at the isocenter, the evaluation between “up” and “down” directions for given energy showed the spot position difference within ±0.25 mm. At the nozzle entrance, the average differences in X and Y positions for given energy were 0.0 ± 0.2 mm and −0.0 ± 0.4 mm, respectively. At the nozzle exit, the average differences in X and Y positions for given energy were 0.0 ± 0.1 mm and −0.1 ± 0.1 mm, respectively. Conclusion The volumetric repainting technique in magnetic field regulation mode resulted in acceptable spot position and range differences for our beam delivery system. The range differences were found to be within ±1 mm (TG224). For the spot positions (TG224: ±1 mm), the central axis measurements were within ±1 mm, whereas for the off‐axis measurements, 97.9% of the spots were within ±1 mm, and all spots were within ±1.2 mm.
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- 2020
46. Reply to: Oncolytic Viral Therapy for Malignant Pleural Mesothelioma
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Clément Meiller, Nicolas Boisgerault, Tiphaine Delaunay, Marc Grégoire, Marion Grard, Stefano Caruso, Jean-François Fonteneau, Jaafar Bennouna, Didier Jean, Frédéric Tangy, Emanuela Felley-Bosco, Christophe Blanquart, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Immunogenic Cell Death and Mesothelioma Therapy (CRCINA-ÉQUIPE 4), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), University hospital of Zurich [Zurich], Service de pneumologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), ANR-16-CE18-0016,OncoMeVax,Un virus de la rougeole modifié pour traiter le cancer(2016), ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), Bernardo, Elizabeth, Un virus de la rougeole modifié pour traiter le cancer - - OncoMeVax2016 - ANR-16-CE18-0016 - AAPG2016 - VALID, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of Zurich, Jean, Didier, and École Pratique des Hautes Études (EPHE)
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Mesothelioma ,Pulmonary and Respiratory Medicine ,Lung Neoplasms ,10255 Clinic for Thoracic Surgery ,Pleural Neoplasms ,610 Medicine & health ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Measles virus ,03 medical and health sciences ,0302 clinical medicine ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,MESH: Oncolytic immunotherapy ,Humans ,Medicine ,Viral therapy ,ComputingMilieux_MISCELLANEOUS ,Sequence Deletion ,030304 developmental biology ,0303 health sciences ,MESH: Type I interferon ,MESH: Mesothelioma ,biology ,business.industry ,Pleural mesothelioma ,Homozygote ,MESH: Gene homozygous deletion ,biology.organism_classification ,Oncolytic virus ,Oncolytic Viruses ,Oncology ,2740 Pulmonary and Respiratory Medicine ,030220 oncology & carcinogenesis ,Interferon Type I ,Cancer research ,2730 Oncology ,business ,MESH: Measles virus ,Interferon type I ,medicine.drug - Abstract
International audience
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- 2020
47. Efficacy and safety of necitumumab and pembrolizumab combination therapy in patients with Stage IV non-small cell lung cancer
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Anas Gazzah, Pilar Garrido, Alexis B. Cortot, Jaafar Bennouna, Melissa Lynne Johnson, Maciej Gil, Haruyasu Murakami, and Benjamin Besse
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Adult ,Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,Combination therapy ,Adenocarcinoma of Lung ,Pembrolizumab ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,B7-H1 Antigen ,03 medical and health sciences ,0302 clinical medicine ,Stable Disease ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Humans ,Medicine ,Aged ,Neoplasm Staging ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Cancer ,Middle Aged ,medicine.disease ,Confidence interval ,ErbB Receptors ,Survival Rate ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Toxicity ,Carcinoma, Squamous Cell ,Female ,business ,Progressive disease ,Follow-Up Studies ,Necitumumab - Abstract
Objectives Efficacy and safety of necitumumab when combined with pembrolizumab was assessed in patients with Stage IV non-small cell lung cancer (NSCLC) of squamous and nonsquamous histology, who had progressed after treatment with a platinum-based doublet. Materials and methods This single-arm, multicenter, phase Ib study had a dose-finding phase, in which escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W, and expansion cohorts. Patients were treated until progressive disease (PD), toxicity requiring cessation, protocol noncompliance, or withdrawal of consent. Efficacy was evaluated by overall response rate (ORR). Results In 64 treated patients (32 patients [50 %] were programmed death-ligand 1 [PD-L1] negative), confirmed ORR was 23.4 % (95 % confidence interval [CI] 13.8 %–35.7 %). Two patients (3.1 %) had complete response (CR), 13 patients (20.3 %) had partial response (PR), 26 patients (40.6 %) had stable disease, 17 patients (26.6 %) had PD, and 6 patients (9.4 %) were not evaluable. Regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95 % CI 2.4–6.9 months) and OS at 6 months was 74.7 % (61.5%–83.9%). Confirmed disease control rate was 64.1 % (95 % CI 51.5–75.7). Patients with programmed death-ligand 1 (PD-L1) ≥1% had numerically improved ORR and median progression-free survival when compared with patients with PD-L1 negative cancer. No dose-limiting toxicities were recorded and the combination of necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable. Conclusion Results suggest modest benefits of second-line necitumumab and pembrolizumab combination therapy in patients with Stage IV NSCLC. Safety profiles were consistent with class effects typical of epidermal growth factor receptor inhibitors and immunotherapies with no additive toxicities.
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- 2020
48. Predictive factors for early progression during induction chemotherapy and chemotherapy-free interval: analysis from PRODIGE 9 trial
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Jean-Marc Phelip, Valérie Boige, Karine Le Malicot, Julien Taieb, Jean-Marc Gornet, Jaafar Bennouna, Olivier Bouché, Eric Francois, for Prodige investigators, Veronique Guerin-Meyer, Oana Cojocarasu, Marie-Christine Kaminsky, Joëlle Egreteau, Laetitia Dahan, Jean-Baptiste Bachet, François Ghiringhelli, Roger Faroux, Mohamed Gasmi, Thomas Aparicio, Christian Borel, and Côme Lepage
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Colorectal cancer ,medicine.medical_treatment ,Logistic regression ,Article ,law.invention ,Free interval ,Prognostic markers ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,medicine ,Humans ,Aged ,030304 developmental biology ,0303 health sciences ,Chemotherapy ,business.industry ,Induction chemotherapy ,Induction Chemotherapy ,medicine.disease ,Clinical trial ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Colorectal Neoplasms ,business - Abstract
Background Identifying patients with metastatic colorectal cancer who will have an early disease progression during induction chemotherapy (IC) and identifying patients who may have a chemotherapy-free interval (CFI) after IC are two major challenges. Methods A logistic model was used to identify factors associated with early progression during IC and with short duration of the first CFI in 488 patients enrolled in the PRODIGE 9 trial. Independent factors were defined with a threshold 0.10. Results In multivariate analysis, baseline leukocytes >10 × 109/L (OR = 1.98 [1.02–3.8], p = 0.04), and stable or increasing CEA at 2 months (OR = 3.61 [1.68–7.75], p = 0.01) were independent factors associated with progression during IC. Male gender (OR = 1.725 [0.92–3.325], p = 0.09) and no tumour response at first evaluation (OR = 1.90 [0.96–3.76], p = 0.07) were significantly associated with a short CFI. The presence of BRAF V600E mutation was also associated with short CFI (OR = 4.59 [0.95; 22.3], p = 0.058). Conclusion High baseline leukocyte count and the lack of CEA decrease level at first evaluation were associated with early progression, and could be in favour of early chemotherapy intensification. Male gender, no tumour response at first evaluation and BRAF mutation are associated with a short CFI, and may be considered for maintenance chemotherapy after IC. Clinical trial number NCT00952029.
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- 2020
49. Quantification of radiation and imaging isocenter coincidence of a multi-room PBS proton therapy system
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Jaafar Bennouna, Suresh Rana, Alonso N. Gutierrez, and E. James Jebaseelan Samuel
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Physics ,Radiological and Ultrasound Technology ,business.industry ,Detector ,Biomedical Engineering ,Biophysics ,Isocenter ,Radiation ,Scintillator ,Coincidence ,030218 nuclear medicine & medical imaging ,Pencil (optics) ,03 medical and health sciences ,0302 clinical medicine ,Optics ,030220 oncology & carcinogenesis ,Radiology, Nuclear Medicine and imaging ,Pencil-beam scanning ,business ,Instrumentation ,Proton therapy ,Biotechnology - Abstract
Alignment between the radiation isocenter and imaging isocenter is critical to ensure accurate proton dose deposition in the patient. The purpose of the current study is to perform a comprehensive evaluation of the coincidence (planar kV X-rays vs. pencil proton beam) among three, beam-matched pencil beam scanning (PBS) gantries of a ProteusPLUS proton therapy system. For proton radiation isocenter measurement, a cone-shaped scintillator detector, XRV-124, was utilized. To test the impact of gantry angle on the beam coincidence, measurements at 12 different gantry angles were performed in the study. Additionally, the energy dependency on beam coincidence was investigated by acquiring measurements for a total of 63 different energies ranging from 70─225 MeV at increments of 2.5 MeV. The measurements were performed in all three beam-matched gantries (GTR1, GTR2, and GTR3). A correction of ≤ 0.3 mm was applied in the imaging system to account for the imaging isocenter shift as the gantry rotates from 0° to 330°. The beam coincidences in X, Y, and Z were within ± 1.0 mm for 63 different energies at 12 different gantry angles in all three beam-matched gantries. The beam coincidence results among three gantries (GTR1, GTR2, and GTR3) ranged from − 0.9 to 0.7 mm in the lateral (X), − 0.8 to 0.5 mm in the longitudinal (Y), and − 0.7 to 0.7 mm in the vertical (Z) directions. Overall, the mean isofocus of radiation isocenter was 0.4 ± 0.2 mm in GTR1, 0.5 ± 0.2 mm in GTR2, and 0.4 ± 0.2 mm in GTR3. Given the consistent agreement (
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- 2020
50. A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)
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Guillem Argilés, Nuria Mulet, Manuel Valladares-Ayerbes, José M. Viéitez, Cristina Grávalos, Pilar García-Alfonso, Cristina Santos, María Tobeña, Beatriz García-Paredes, Manuel Benavides, María T. Cano, Fotios Loupakis, Mercedes Rodríguez-Garrote, Fernando Rivera, Richard M. Goldberg, Chiara Cremolini, Jaafar Bennouna, Fortunato Ciardiello, Josep M. Tabernero, Enrique Aranda, Josep Tabernero, Alfredo Falcone, Richard Goldberg, null Argilés, J. Tabernero, N. Mulet, M.L. Limón, M. Valladares, P. Jiménez, J. Ma Vieitez, C. Grávalos, P. García-Alfonso, C. Santos, D. Páez, M. Tobeña, J. Sastre, B. García Paredes, M. Benavides, E. Aranda, M.T. Cano, F. Loupakis, M. Rguez Garrote, C. Guillén, Ma F. Rivera, J. Safont, S. Hiret, J. Bennouna, D. Pannier, D. Malka, A. Falcone, C. Cremolini, Argilés, Guillem, Mulet, Nuria, Valladares-Ayerbes, Manuel, Viéitez, José M, Grávalos, Cristina, García-Alfonso, Pilar, Santos, Cristina, Tobeña, María, García-Paredes, Beatriz, Benavides, Manuel, Cano, María T, Loupakis, Fotio, Rodríguez-Garrote, Mercede, Rivera, Fernando, Goldberg, Richard M, Cremolini, Chiara, Bennouna, Jaafar, Ciardiello, Fortunato, Tabernero, Josep M, Aranda, Enrique, Tabernero, Josep, Institut Català de la Salut, [Argilés G] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain. Memorial Sloan Kettering Cancer Center, New York, USA. [Mulet N, Tabernero JM] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. CIBERONC, Barcelona, Spain. [Valladares-Ayerbes M] Virgen del Rocío University Hospital and Institute of Biomedicine (IBIS), Sevilla, Spain. [Viéitez JM] Hospital Universitario Central de Asturias, Oviedo, Spain. [Grávalos C] Universitary Hospital 12 de Octubre, Madrid, Spain. [García-Alfonso P] Gregorio Marañón Hospital, Madrid, Spain, and Vall d'Hebron Barcelona Hospital Campus
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Cancer Research ,Pyridines ,Colorectal cancer ,Drug administration schedule ,Metastasis ,Regorafenib ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Metastasi ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors [CHEMICALS AND DRUGS] ,Còlon - Càncer - Tractament ,Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms::Intestinal Neoplasms::Colorectal Neoplasms [DISEASES] ,Metàstasi ,Càncer colorectal ,Recte - Càncer - Tractament ,Humans ,Other subheadings::/therapeutic use [Other subheadings] ,Administration of drugs ,acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas [COMPUESTOS QUÍMICOS Y DROGAS] ,Otros calificadores::/uso terapéutico [Otros calificadores] ,Rectal Neoplasms ,Phenylurea Compounds ,neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales::neoplasias intestinales::neoplasias colorrectales [ENFERMEDADES] ,Oncology ,Colonic Neoplasms ,Administració de medicaments ,Colorectal Neoplasms ,Proteïnes quinases - Inhibidors - Ús terapèutic - Abstract
Purpose: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients.Patients and methods: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm.Results: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: pop-ulation for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 pa-tients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C.Conclusions: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher nu-merical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifier: NCT02835924.(C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
- Published
- 2022
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