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1. Real-World Outcomes of Pralsetinib in RET Fusion-Positive NSCLC

Author

Francesca Lucibello, MD, Valérie Gounant, MD, PhD, Mihaela Aldea, MD, PhD, Michaël Duruisseaux, MD, PhD, Maurice Perol, MD, Christos Chouaid, MD, Jaafar Bennouna, MD, PhD, Vincent Fallet, MD, Aldo Renault, MD, Florian Guisier, MD, PhD, Etienne Giroux-Leprieur, MD, PhD, Marie Wislez, MD, PhD, Anne-Claire Toffart, MD, PhD, Julien Mazieres, MD, PhD, Clémence Basse, MD, PhD, Nadia Hegarat, PhD, Matthieu Carton, MD, and Nicolas Girard, MD, PhD

Subjects
Pralsetinib, Lung Cancer, RET, Second-Line, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Introduction: Pralsetinib is a RET inhibitor found to have antitumor activity in advanced, metastatic, RET fusion-positive NSCLC. Objective: To assess real-world efficacy of pralsetinib and treatment sequences in patients with RET fusion-positive NSCLC. Design: Retrospective study of consecutive patients enrolled in the French expanded-access program for pralsetinib from December 1, 2019, to December 31, 2021. Participants: A total of 41 patients with advanced, refractory, RET fusion-positive NSCLC were included. Pralsetinib was administered at a daily dose of 400 mg based on safety and pharmacokinetic outcomes from previous phase 1/2 study. Results: Pralsetinib was administered as second line in 23 patients (56%) and as third line and beyond in 15 patients (37%). After a median follow-up of 26.3 months, pralsetinib was ongoing in 13 patients. Median real-world progression-free survival was 11.8 (95% confidence interval [CI]: 9.3–15.5) months. Objective response rate was 68% (95% CI: 50%–82%), and disease control rate was 89% (95% CI: 75%–97%). Subsequent line of systemic therapy was initiated in 11 patients. Median overall survival from pralsetinib initiation was 23.8 (95% CI: 16.5–not reached) months. Conclusion: In this extensive real-world cohort of patients with advanced or metastatic NSCLC harboring RET fusions, we highlight the antitumor efficacy of pralsetinib, particularly when administered in later treatment lines. We also observe the aggressive nature of disease progression, frequent utilization of chemotherapy and antiangiogenic agents as initial subsequent therapies, and limited insight into resistance mechanisms due to infrequent rebiopsy and genomic profiling at progression.

Published
2025
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2. Acute generalized exanthematous pustulosis caused by gemcitabine after nivolumab in metastatic lung adenocarcinoma followed by a dramatic tumor response: A case report

Author

Pierre Magdelaine, Adrien Costantini, Lucie Fabre, and Etienne Giroux‐Leprieur

Subjects
acute generalized exanthematous pustulosis, gemcitabine, lung adenocarcinoma, nivolumab, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Herein, we report a case of a 73‐year‐old female patient diagnosed with cT4N0M1a lung adenocarcinoma with KRAS G12C mutation, PDL1

Published
2022
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3. Corrigendum: High Circulating Sonic Hedgehog Protein Is Associated With Poor Outcome in EGFR-Mutated Advanced NSCLC Treated With Tyrosine Kinase Inhibitors

Author

Paul Takam Kamga, Aurélie Swalduz, Adrien Costantini, Catherine Julié, Jean-François Emile, Maurice Pérol, Virginie Avrillon, Sandra Ortiz-Cuaran, Pierre De Saintigny, and Etienne Giroux-Leprieur

Subjects
non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR), Sonic Hedgehog (Shh), biomarker, tyrosine kinase inhibitor (TKI), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2022
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4. High Circulating Sonic Hedgehog Protein Is Associated With Poor Outcome in EGFR-Mutated Advanced NSCLC Treated With Tyrosine Kinase Inhibitors

Author

Paul Takam Kamga, Aurélie Swalduz, Adrien Costantini, Catherine Julié, Jean-François Emile, Maurice Pérol, Virginie Avrillon, Sandra Ortiz-Cuaran, Pierre de Saintigny, and Etienne Giroux-Leprieur

Subjects
non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR), Sonic Hedgehog (Shh), biomarker, tyrosine kinase inhibitor (TKI), Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

IntroductionGrowing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). However, little is known concerning the prognostic value of this pathway in this context.Materials and MethodsWe investigated the relationship between plasma levels of Shh and EGFRm NSCLC patients’ outcome with EGFR TKIs. We included 74 consecutive patients from two institutions with EGFRm advanced NSCLC treated by EGFR TKI as first-line therapy. Plasma samples were collected longitudinally for each patient and were analyzed for the expression of Shh using an ELISA assay. The activation of the Shh–Gli1 pathway was assessed through immunohistochemistry (IHC) of Gli1 and RT-qPCR analysis of the transcripts of Gli1 target genes in 14 available tumor biopsies collected at diagnosis (baseline).ResultsAmong the 74 patients, only 61 had baseline (diagnosis) plasma samples, while only 49 patients had plasma samples at the first evaluation. Shh protein was detectable in all samples at diagnosis (n = 61, mean = 1,041.2 ± 252.5 pg/ml). Among the 14 available tumor biopsies, nuclear expression of Gli1 was observed in 57.1% (8/14) of patients’ biopsies. Shh was significantly (p < 0.05) enriched in youth (age < 68), male, nonsmokers, patients with a PS > 1, and patients presenting more than 2 metastatic sites and L858R mutation. Higher levels of Shh correlated with poor objective response to TKI, shorter progression-free survival (PFS), and T790M-independent mechanism of resistance. In addition, the rise of plasma Shh levels along the treatment was associated with the emergence of drug resistance in patients presenting an initial good therapy response.ConclusionThese data support that higher levels of plasma Shh at diagnosis and increased levels of Shh along the course of the disease are related to the emergence of TKI resistance and poor outcome for EGFR-TKI therapy, suggesting that Shh levels could stand both as a prognostic and as a resistance biomarker for the management of EGFR-mutated NSCLC patients treated with EGFR-TKI.

Published
2021
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5. Efficacy of next treatment received after nivolumab progression in patients with advanced nonsmall cell lung cancer

Author

Adrien Costantini, Jennifer Corny, Vincent Fallet, Sophie Renet, Sylvie Friard, Christos Chouaid, Boris Duchemann, Etienne Giroux-Leprieur, Laurent Taillade, Ludovic Doucet, Marina Nguenang, Stéphane Jouveshomme, Marie Wislez, Jean Tredaniel, and Jacques Cadranel

Subjects
Medicine
Abstract

Nivolumab for the treatment of advanced nonsmall cell lung cancer (NSCLC) evaluated in phase III trials showed 50% progression at first evaluation, but better overall survival (OS), suggesting regained efficacy of treatments given thereafter. We aimed to evaluate the efficacy of nivolumab and of next treatment received after nivolumab progression in patients with advanced NSCLC. Our multicentre retrospective study included all patients receiving nivolumab between January and December 2015. The primary end-point was progression-free survival (PFS) of treatment given after nivolumab. The 303 patients had the following characteristics: median age 63 years, 69% males, 92% smokers, 67% performance status 0–1 and 61% adenocarcinoma. Nivolumab was given as second-line treatment in 40% of patients. With 13.7 months of median follow-up, nivolumab PFS and OS were 2.6 and 11.3 months, respectively. At the cut-off analysis 18% were controlled under nivolumab, 14% were deceased and 5% were lost to follow-up under nivolumab. Among the 191 (63%) patients eligible for post-nivolumab (PN) treatment, 115 (38%) received further treatment and were characterised by better performance status (p=0.028) and by receiving more injections of nivolumab (p=0.001). Global PN-OS and PN-PFS were 5.2 and 2.8 months, respectively. Drugs most frequently used after nivolumab were gemcitabine (23%), docetaxel (22%) and erlotinib (16%), with median PFS of 2.8, 2.7 and 2.0 months, respectively. Nivolumab produced similar efficacy as in phase III trials, although patients received nivolumab later and had worse performance status. 38% received treatment after nivolumab progression with efficacy comparable to historical second-line trials.

Published
2018
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6. EMX2 Is a Predictive Marker for Adjuvant Chemotherapy in Lung Squamous Cell Carcinomas.

Author

Dongsheng Yue, Hui Li, Juanjuan Che, Yi Zhang, Bhairavi Tolani, Minli Mo, Hua Zhang, Qingfeng Zheng, Yue Yang, Runfen Cheng, Joy Q Jin, Thomas W Luh, Cathryn Yang, Hsin-Hui K Tseng, Etienne Giroux-Leprieur, Gavitt A Woodard, Xishan Hao, Changli Wang, David M Jablons, and Biao He

Subjects
Medicine, Science
Abstract

Squamous cell carcinomas (SCC) account for approximately 30% of non-small cell lung cancer (NSCLC). Current staging methods do not adequately predict outcome for this disease. EMX2 is a homeo-domain containing transcription factor known to regulate a key developmental pathway. This study assessed the significance of EMX2 as a prognostic and predictive marker for resectable lung SCC.Two independent cohorts of patients with lung SCC undergoing surgical resection were studied. EMX2 protein expression was examined by immunohistochemistry, Western blot, or immunofluorescence. EMX2 expression levels in tissue specimens were scored and correlated with patient outcomes. Chemo-sensitivity of lung SCC cell lines stably transfected with EMX2 shRNAs to cisplatin, carboplatin, and docetaxel was examined in vitro.EMX2 expression was down-regulated in lung SCC tissue samples compared to their matched adjacent normal tissues. Positive EMX2 expression was significantly associated with improved overall survival in stage I lung SCC patients, and in stage II/IIIA lung SCC patients receiving adjuvant chemotherapy. EMX2 expression was also associated with expression of EMT markers in both lung SCC cell lines and tissue samples. Knock-down of EMX2 expression in lung SCC cells promoted chemo-resistance and cell migration.EMX2 expression is down-regulated in lung SCC and its down-regulation is associated with chemo-resistance in lung SCC cells, possibly through regulation of Epithelial-to-Mesenchymal Transition (EMT). EMX2 may serve as a novel prognostic marker for stage I lung SCC patients and a prediction marker for stage II/IIIA lung SCC patients receiving adjuvant chemotherapy.

Published
2015
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7. Gli as a novel therapeutic target in malignant pleural mesothelioma.

Author

Hui Li, Natalie Lui, Tiffany Cheng, Hsin-Hui K Tseng, Dongsheng Yue, Etienne Giroux-Leprieur, Hanh T Do, Qing Sheng, Joy Q Jin, Thomas W Luh, David M Jablons, and Biao He

Subjects
Medicine, Science
Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis. Current treatment is rarely curative, thus novel meaningful therapies are urgently needed. Inhibition of Hedgehog (Hh) signaling at the cell membrane level in several cancers has shown anti-cancer activity in recent clinical studies. Evidence of Hh-independent Gli activation suggests Gli as a more potent therapeutic target. The current study is aimed to evaluate the potential of Gli as a therapeutic target to treat MPM. The expression profiles of Gli factors and other Hh signaling components were characterized in 46 MPM patient tissue samples by RT-PCR and immunohistochemistry. Cultured cell lines were employed to investigate the requirement of Gli activation in tumor cell growth by inhibiting Gli through siRNA or a novel small molecule Gli inhibitor (Gli-I). A xenograft model was used to evaluate Gli-I in vivo. In addition, a side by side comparison between Gli and Smoothened (Smo) inhibition was conducted in vitro using siRNA and small molecule inhibitors. Our study reported aberrant Gli1 and Gli2 activation in a large majority of tissues. Inhibition of Gli by siRNAs or Gli-I suppressed cell growth dramatically both in vitro and in vivo. Inhibition of Gli exhibited better cytotoxicity than that of Smo by siRNA and small molecule inhibitors vismodegib and cyclopamine. Combination of Gli-I and pemetrexed, as well as Gli-I and vismodegib demonstrated synergistic effects in suppression of MPM proliferation in vitro. In summary, Gli activation plays a critical role in MPM. Inhibition of Gli function holds strong potential to become a novel, clinically effective approach to treat MPM.

Published
2013
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8. Role of antibiotic use, plasma citrulline and blood microbiome in advanced non-small cell lung cancer patients treated with nivolumab

Author

Julia Ouaknine Krief, Pierre Helly de Tauriers, Coraline Dumenil, Nathalie Neveux, Jennifer Dumoulin, Violaine Giraud, Sylvie Labrune, Julie Tisserand, Catherine Julie, Jean-François Emile, Thierry Chinet, and Etienne Giroux Leprieur

Subjects
Non-small cell lung cancer, Antibiotic, Plasma, Blood, Microbiome, Citrulline, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Recent data suggested a role of gut microbiota and antibiotic use on immune checkpoint inhibitors efficacy. We aimed to evaluate the impact of early use of antibiotic (EUA), blood microbiome and plasmatic citrulline (marker of the intestinal barrier) on nivolumab efficacy in non-small cell lung cancer (NSCLC). Methods We included all consecutive patients with advanced NSCLC treated with nivolumab in our Department between 2014 and 2017. Blood microbiome was analyzed at month (M) M0 and M2. Citrulline rates were evaluated at M0, M2, M4 and M6. Results Seventy-two patients were included (EUA in 42%). Overall survival (OS) was longer without EUA (median 13.4 months) than with EUA (5.1 months, p = 0.03). Thirty-five patients (49%) had plasma samples available. High citrulline rate (≥20 μM) at M0 was associated with tumor response (p = 0.084) and clinical benefit (nivolumab > 6 months) (p = 0.002). Median progression-free survival (PFS) was 7.9 months (high citrulline) vs 1.6 months (low citrulline) (p

Published
2019
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9. Histomolecular Resistance Mechanisms to First-Line Osimertinib in EGFR-Mutated Advanced Non-Small Cell Lung Cancer: A Multicentric Retrospective French Study

Author

Assya Akli, Nicolas Girard, Vincent Fallet, Gaelle Rousseau-Bussac, Valérie Gounant, Sylvie Friard, Jean Trédaniel, Cécile Dujon, Marie Wislez, Boris Duchemann, and Etienne Giroux-Leprieur

Subjects
ErbB Receptors, Cancer Research, Aniline Compounds, Lung Neoplasms, Oncology, Drug Resistance, Neoplasm, Carcinoma, Non-Small-Cell Lung, Mutation, Humans, Pharmacology (medical), Protein Kinase Inhibitors, Retrospective Studies
Abstract

Osimertinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) used in first line for the treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC).The identification of related histomolecular resistance mechanisms to first-line osimertinib is a critical step to define the optimal treatment strategy beyond progression.All consecutive patients treated in the first line with osimertinib for advanced EGFR-mutated NSCLC at 10 hospitals in the Greater Paris area between April 2015 and January 2021 were included. Histomolecular data from plasma and tissue samples taken at progression under osimertinib were collected, and all samples were analyzed using DNA next-generation sequencing. Data on objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and time to treatment discontinuation (TTD) were also collected.Overall, 104 patients were included. Most patients had adenocarcinoma (n = 102, 98%) with an exon 19 EGFR deletion (n = 54, 52%). Forty-two patients (50%) had central nervous system (CNS) metastasis at the time of osimertinib initiation. ORR was 76%, median PFS and OS were 12.6 months and 52 months, respectively, and TTD was 33 months. At the time of analysis, 44 patients (42%) had tumor progression, and among these patients, 27 (61%) contributive samples were available. The most frequent molecular alterations at progression were mesenchymal epithelial transition factor (MET) amplification (15%; n = 4) and EGFR C797S mutation (11%; n = 3). Histological transformation was found in one patient (4%). RNA next-generation sequencing was performed in eight patients and showed a CCDC6-RET fusion in one patient (12%).We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation-positive NSCLC. At progression, the most frequent histomolecular alterations were MET amplification and EGFR C797S mutation.

Published
2022
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10. Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial

Author

Fabrice Barlesi, Pascale Tomasini, Maryam Karimi, Stefan Michiels, Judith Raimbourg, Catherine Daniel, Henri Janicot, Anne Madroszyk, Clarisse Audigier-Valette, Elisabeth Quoix, Julien Mazieres, Denis Moro-Sibilot, Eric Dansin, Olivier Molinier, Hugues Morel, Eric Pichon, Alexis Cortot, Josiane Otto, François Chomy, Pierre-Jean Souquet, Nicolas Cloarec, Etienne Giroux-Leprieur, Ivan Bieche, Ludovic Lacroix, Sandrine Boyault, Valery Attignon, Isabelle Soubeyran, Alain Morel, Alicia Tran-Dien, Alexandra Jacquet, Filippo Gustavo Dall'Olio, Marta Jimenez, Jean-Charles Soria, and Benjamin Besse

Subjects
Cancer Research, Oncology
Abstract

Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. Patients and Methods: SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS). Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Published
2022
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11. Severe sotorasib-related hepatotoxicity and non-liver adverse events associated with sequential anti-PD(L)1 and sotorasib therapy in KRASG12C-mutant lung cancer

Author

Ali Chour, Julie Denis, Céline Mascaux, Maeva Zysman, Laurence Bigay-Game, Aurélie Swalduz, Valérie Gounant, Alexis Cortot, Marie Darrason, Vincent Fallet, Edouard Auclin, Clémence Basse, Claire Tissot, Chantal Decroisette, Pierre Bombaron, Etienne Giroux-Leprieur, Luc Odier, Solenn Brosseau, Quentin Creusot, Marina Gueçamburu, Corentin Meersseman, Adrien Rochand, Adrien Costantini, Claire Marine Gaillard, Eric Wasielewski, Nicolas Girard, Jacques Cadranel, Claire Lafitte, Fanny Lebossé, and Michael Duruisseaux

Subjects
Pulmonary and Respiratory Medicine, Oncology
Published
2023
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12. Supplementary Figure S2 from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Supplementary Figure 2. Forest plot with subgroup analysis for PFS in substudy 1.

Published
2023
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13. Supplementary Table TS1 from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Supplementary Table S1. Representativeness of Study Participants

Published
2023
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14. Data from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Purpose:Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods:SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results:Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036).Conclusions:Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Published
2023
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15. Supplementary Figure Legends SL1 from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Supplementary Figure legends 1-5

Published
2023
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16. Supplementary Material SM1 from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Supplementary materials - substudy 1 statistical report

Published
2023
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17. Study Protocol from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung/IFCT 1301 Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Study protocol

Published
2023
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18. Gene expression profile of high PD-L1 non-small cell lung cancers refractory to pembrolizumab

Author

Jamila, Talb, Paul, Takam Kamga, Marie, Mayenga, Adrien, Costantini, Catherine, Julié, Coraline, Dumenil, Jennifer, Dumoulin, Julia, Ouaknine, Violaine, Giraud, Cécile, Dujon, Reza, Azarian, Claire, Glaser, Jean-François, Emile, and Etienne, Giroux Leprieur

Subjects
Male, Cancer Research, Lung Neoplasms, Programmed Cell Death 1 Receptor, Immunology, Antibodies, Monoclonal, Humanized, B7-H1 Antigen, Interferon-gamma, Oncology, Drug Resistance, Neoplasm, Albumins, Carcinoma, Non-Small-Cell Lung, Toll-Like Receptor 9, Humans, Immunology and Allergy, Female, Transcriptome, Retrospective Studies
Abstract

Despite high expression of PD-L1, around half of advanced non-small cell lung cancer (NSCLC) will not experience tumor response with pembrolizumab. There is an need for a better understanding of the resistance mechanisms in this setting.This bi-centric retrospective study included all consecutive patients with PDL1 ≥ 50% advanced NSCLC treated with pembrolizumab in first-line treatment between 2016 and 2020. We compared the clinical characteristics of patients with early progression (refractory) vs others. We performed a comprehensive gene expression profile screening by RNAseq capture on tumor samples.We included 46 patients. Twenty-two patients were refractory to pembrolizumab, mainly women, with poor performance status and lower albumin concentration. RNAseq analysis was performed on 19 samples. Hierarchical clustering allowed the identification of 3 clusters with various proportion of refractory tumors: intermediate (C1: 57%), high (C2: 71%) and low proportion (C3: 40%). Comparative analysis between C2 and C3 allowed the identification of overexpressed (n = 137) and underexpressed (n = 40) genes. Among the genes of interest, C2 exhibits higher activation of pathways associated with stemness phenotype (Hedgehog, Notch and Hippo pathways) and pathways associated with loss of PTEN and JAK2. In C2, genes associated with PD-1, toll-like receptor-9 (TLR-9), major histocompatibility complex (MHC) and interferon-γ pathways were underexpressed.This study gives an overview of activated and downregulated pathways in high PD-L1 NSCLC refractory to pembrolizumab. These tumors showed activation of pathways associated with cancer stem cells, loss of PTEN and JAK2, and inhibition of both priming and effector phases of the immune response.

Published
2022
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19. Supplementary Figure from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Supplementary Figure from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Published
2023
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20. Supplementary Data from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Supplementary Data from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Published
2023
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21. Data from Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with BRAF-Mutant Metastatic Non–Small Cell Lung Cancer

Author

David Planchard, Pierre Saintigny, Jean-Yves Blay, Benjamin Besse, Maurice Perol, Jean-François Guichou, Sylvie Chabaud, Luc Friboulet, Emma Green, Clive Morris, Karen Howarth, Frank de Kievit, Natalie Hoog-Labouret, Celine Mahier-Aït Oukhatar, Caroline Caramella, Etienne Giroux Leprieur, Isabelle Monnet, Etienne Brain, Radj Gervais, Christine Raynaud, Claire Tissot, Maud Ngo-Camus, Virginie Westeel, Yohann Loriot, Ludovic Lacroix, Washington R. Chumbi Flores, Virginie Avrillon, Anne Pradines, Cecile Jovelet, Camille Leonce, Julien Mazieres, Mihalea Aldea, Aurélie Swalduz, Laura Mezquita, and Sandra Ortiz-Cuaran

Abstract

Purpose:The limited knowledge on the molecular profile of patients with BRAF-mutant non–small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAF-mutant NSCLC.Experimental Design:This was a prospective study of 78 patients with advanced BRAF-mutant NSCLC, enrolled in 27 centers across France. Blood samples (n = 208) were collected from BRAF-TT–naïve patients (n = 47), patients nonprogressive under treatment (n = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.Results:BRAFV600E ctDNA was detected in 74% of BRAF-TT–naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as BRAF-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1, and CTNNB1.Conclusions:ctDNA sequencing is clinically relevant for the detection of BRAF-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAF-mutant NSCLC.

Published
2023
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22. Data from First-Line Afatinib plus Cetuximab for EGFR-Mutant Non–Small Cell Lung Cancer: Results from the Randomized Phase II IFCT-1503 ACE-Lung Study

Author

Jacques Cadranel, Marc G. Denis, Sandrine Charpentier, Benjamin Huret, Eric Pichon, Aldo Renault, Hugues Morel, Didier Debieuvre, Lionel Moreau, José Hureaux, Franck Morin, Elodie Amour, Judith Raimbourg, Denis Moro-Sibilot, Isabelle Rault, Josiane Otto, Henri Bérard, Elisabeth Quoix, Olivier Molinier, Etienne Giroux-Leprieur, Anne Madroszyk, and Alexis B. Cortot

Abstract

Purpose:Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non–small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advanced EGFR-mutant NSCLC.Patients and Methods:In this phase II, randomized, open-label study, patients with stage III/IV EGFR-positive NSCLC were randomly assigned (1:1) to receive afatinib (group A) or afatinib + cetuximab (group A + C). Oral afatinib 40 mg was given once daily; cetuximab 250 mg/m² was administered intravenously on day 15 of cycle 1, then every 2 weeks at 500 mg/m² for 6 months. The primary endpoint was time to treatment failure (TTF) rate at 9 months. Exploratory analysis of EGFR circulating tumor DNA in plasma was performed.Results:Between June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5–14.1) and 12.9 (9.2–14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of the EGFR gene mutation in circulating tumor DNA at baseline was associated with shorter PFS, regardless of the treatment received.Conclusions:These results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced EGFR-mutant NSCLC.

Published
2023
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23. Data from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Purpose:Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non–small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown.Patients and Methods:SAFIR02-Lung was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS).Results:Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6–2.9] with TT versus 2.7 months (1.6–4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7–1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3–4.4) with durvalumab versus 3.0 months (2.0–5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62–1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11–0.75) as compared with PD-L1 n = 31; HR, 0.71; 95% CI, 0.31–1.60; Pinteraction = 0.036).Conclusions:Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients.

Published
2023
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24. Supplementary Tables from First-Line Afatinib plus Cetuximab for EGFR-Mutant Non–Small Cell Lung Cancer: Results from the Randomized Phase II IFCT-1503 ACE-Lung Study

Author

Jacques Cadranel, Marc G. Denis, Sandrine Charpentier, Benjamin Huret, Eric Pichon, Aldo Renault, Hugues Morel, Didier Debieuvre, Lionel Moreau, José Hureaux, Franck Morin, Elodie Amour, Judith Raimbourg, Denis Moro-Sibilot, Isabelle Rault, Josiane Otto, Henri Bérard, Elisabeth Quoix, Olivier Molinier, Etienne Giroux-Leprieur, Anne Madroszyk, and Alexis B. Cortot

Abstract

Supplementary Tables

Published
2023
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25. Supplementary Table from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Author

Benjamin Besse, Jean-Charles Soria, Marta Jimenez, Filippo Gustavo Dall'Olio, Alexandra Jacquet, Alicia Tran-Dien, Alain Morel, Isabelle Soubeyran, Valery Attignon, Sandrine Boyault, Ludovic Lacroix, Ivan Bieche, Etienne Giroux-Leprieur, Nicolas Cloarec, Pierre-Jean Souquet, François Chomy, Josiane Otto, Alexis Cortot, Eric Pichon, Hugues Morel, Olivier Molinier, Eric Dansin, Denis Moro-Sibilot, Julien Mazieres, Elisabeth Quoix, Clarisse Audigier-Valette, Anne Madroszyk, Henri Janicot, Catherine Daniel, Judith Raimbourg, Stefan Michiels, Maryam Karimi, Pascale Tomasini, and Fabrice Barlesi

Abstract

Supplementary Table from Comprehensive Genome Profiling in Patients With Metastatic Non–Small Cell Lung Cancer: The Precision Medicine Phase II Randomized SAFIR02-Lung Trial

Published
2023
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26. Respiratory recovery trajectories after severe-to-critical COVID-19: a 1-year prospective multicentre study

Author

Frédéric Schlemmer, Simon Valentin, Laurent Boyer, Anne Guillaumot, François Chabot, Clairelyne Dupin, Pierre Le Guen, Gwenael Lorillon, Anne Bergeron, Damien Basille, Julia Delomez, Claire Andrejak, Valentine Bonnefoy, Hélène Goussault, Jean-Baptiste Assié, Pascaline Choinier, Anne-Marie Ruppert, Jacques Cadranel, Maria Chiara Mennitti, Mehdi Roumila, Charlotte Colin, Sven Günther, Olivier Sanchez, Thomas Gille, Lucile Sésé, Yurdagul Uzunhan, Morgane Faure, Maxime Patout, Capucine Morelot-Panzini, Pierantonio Laveneziana, Maeva Zysman, Elodie Blanchard, Chantal Raherison-Semjen, Violaine Giraud, Etienne Giroux-Leprieur, Stéfanie Habib, Nicolas Roche, Anh Tuan Dinh-Xuan, Islem Sifaoui, Pierre-Yves Brillet, Camille Jung, Emmanuelle Boutin, Richard Layese, Florence Canoui-Poitrine, Bernard Maitre, Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Département Universitaire de Psychiatrie - [Hôpital Sainte Marguerite - APHM] (Hôpitaux Sud), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpitaux Universitaires de Genève (HUG), CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Université de Picardie Jules Verne (UPJV), Service de Pneumologie [CHI Créteil], CHI Créteil, Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), 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 Paris Cité (UPCité), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Centre Hospitalier de Versailles André Mignot (CHV), 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), Hôpital Avicenne [AP-HP], Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), UFR SMBH-Université Sorbonne Paris Nord, CHU Pitié-Salpêtrière [AP-HP], Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier de Basse-Terre [Guadeloupe], Hôpital Ambroise Paré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de physiologie et explorations fonctionelles [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Service de radiologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, Centre Hospitalier Intercommunal de Créteil (CHIC), IMRB - CEPIA/'Clinical Epidemiology And Ageing : Geriatrics, Primary Care and Public Health' [Créteil] (U955 Inserm - UPEC), and Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)

Subjects
Pulmonary and Respiratory Medicine, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

BackgroundSurvivors of severe-to-critical coronavirus disease 2019 (COVID-19) may have functional impairment, radiological sequelae and persistent symptoms requiring prolonged follow-up. This pragmatic study aimed to describe their clinical follow-up and determine their respiratory recovery trajectories, and the factors that could influence them and their health-related quality of life.MethodsAdults hospitalised for severe-to-critical COVID-19 were evaluated at 3 months and up to 12 months post-hospital discharge in this prospective, multicentre, cohort study.ResultsAmong 485 enrolled participants, 293 (60%) were reassessed at 6 months and 163 (35%) at 12 months; 89 (51%) and 47 (27%) of the 173 participants initially managed with standard oxygen were reassessed at 6 and 12 months, respectively. At 3 months, 34%, 70% and 56% of the participants had a restrictive lung defect, impaired diffusing capacity of the lung for carbon monoxide (DLCO) and significant radiological sequelae, respectively. During extended follow-up, bothDLCOand forced vital capacity percentage predicted increased by means of +4 points at 6 months and +6 points at 12 months. Sex, body mass index, chronic respiratory disease, immunosuppression, pneumonia extent or corticosteroid use during acute COVID-19 and prolonged invasive mechanical ventilation (IMV) were associated withDLCOat 3 months, but not its trajectory thereafter. Among 475 (98%) patients with at least one chest computed tomography scan during follow-up, 196 (41%) had significant sequelae on their last images.ConclusionsAlthough pulmonary function and radiological abnormalities improved up to 1 year post-acute COVID-19, high percentages of severe-to-critical disease survivors, including a notable proportion of those managed with standard oxygen, had significant lung sequelae and residual symptoms justifying prolonged follow-up.

Published
2023
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27. Discontinuation of immune checkpoint inhibitor (ICI) above 18 months of treatment in real-life patients with advanced non-small cell lung cancer (NSCLC): INTEPI, a multicentric retrospective study

Author

Hélène Doubre, Matteo Giaj Levra, Geoffroy Bilger, Matthieu Carton, Frederique Giraud, Chantal Decroisette, Nicolas Girard, Marie Ange Massiani, and Etienne Giroux-Leprieur

Subjects
Cancer Research, medicine.medical_specialty, Lung Neoplasms, medicine.medical_treatment, Immunology, non-small cell lung cancer (NSCLC), Gastroenterology, Stable Disease, Carcinoma, Non-Small-Cell Lung, Positron Emission Tomography Computed Tomography, Internal medicine, medicine, Humans, Immunology and Allergy, Immune Checkpoint Inhibitors, Retrospective Studies, business.industry, Retrospective cohort study, Immunotherapy, medicine.disease, Discontinuation, Clinical trial, Oncology, Tumor progression, Toxicity, Neoplasm Recurrence, Local, business
Abstract

The optimal treatment duration of ICIs for patients with advanced NSCLC remains uncertain. In phase 3 clinical trials, treatment continued for 2 years or until disease progression with similar long-term survival rates. Real-life data are missing. This academic multicentric retrospective study aims at analyzing the characteristics of patients who discontinued treatment after at least 18 months of ICI monotherapy, in the setting of controlled disease. Of the 1127 patients treated with immunotherapy in the given period in six centers, 107 patients had their tumor controlled after at least 18 months of treatment and 54 (50%) of them had discontinued ICI. The median duration of treatment was 26 months. Treatment was stopped due to prescriber choice or toxicity in 46% and 22% of cases, respectively. After a median follow-up of 21 months from ICI discontinuation (95% CI 15.0–26.1 months), 18 (33%) patients experienced tumor progression after a median time of 10.0 months (range 2–33). From discontinuation, 12-month overall survival (OS) and progression-free survival (PFS) were 90% (95% CI 77.7–95.7) and 71% (95% CI 56.8–81.5), respectively; 24-month OS and PFS were 84% (95% CI 68.7–92.2) and 63% (95% CI 46.1–76.2), respectively. Duration of disease control after ICI discontinuation was correlated with tumor response at treatment discontinuation: PFS rate at 12 months was 76% after complete response (CR n = 11) or partial response (PR n = 37) and 22% after only stable disease (SD n = 6) as best response, p-value = 0.0002. PFS rate at 12 months was 80% for CR and/or complete metabolic response with 18F-FDG PET/CT (CMR) and 65% for others. Fourteen patients out of the 18 relapse patients received a subsequent treatment: seven with ICI rechallenge (best response 14% PR and 86% SD) and five with localized therapy with 60% CR. This real-life study provides new insight into long-term outcomes of patients with advanced NSCLC treated with ICI for at least 18 months before treatment discontinuation in the absence of PD. Tumor response and CMR with FDG PET just before therapy discontinuation may be a predictive factor of prolonged disease control upon discontinuation. These results call for caution in discontinuing treatment in patients with stable disease as the best response.

Published
2021
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28. Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients withBRAF-Mutant Metastatic Non–Small Cell Lung Cancer

Author

Yohann Loriot, Celine Mahier Ait Oukhatar, Benjamin Besse, S. Ortiz-Cuaran, Washington René Chumbi Flores, Jean-Yves Blay, Etienne Giroux Leprieur, Ludovic Lacroix, Mihaela Aldea, Claire Tissot, Clive Morris, Caroline Caramella, Julien Mazieres, Radj Gervais, Karen Howarth, Maurice Perol, Emma Green, Pierre Saintigny, Isabelle Monnet, C. Raynaud, Virginie Westeel, V. Avrillon, Etienne Brain, Jean-François Guichou, Camille Leonce, Maud Ngo-Camus, Anne Pradines, Frank de Kievit, Laura Mezquita, Sylvie Chabaud, Aurélie Swalduz, Cécile Jovelet, David Planchard, Luc Friboulet, and N. Hoog-Labouret

Subjects
0301 basic medicine, MAPK/ERK pathway, Cancer Research, IDH1, endocrine system diseases, Combination therapy, In silico, 03 medical and health sciences, 0302 clinical medicine, Medicine, skin and connective tissue diseases, Lung cancer, Prospective cohort study, neoplasms, PI3K/AKT/mTOR pathway, Kinase, business.industry, medicine.disease, digestive system diseases, 3. Good health, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, business
Abstract

Purpose:The limited knowledge on the molecular profile of patients with BRAF-mutant non–small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAF-mutant NSCLC.Experimental Design:This was a prospective study of 78 patients with advanced BRAF-mutant NSCLC, enrolled in 27 centers across France. Blood samples (n = 208) were collected from BRAF-TT–naïve patients (n = 47), patients nonprogressive under treatment (n = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.Results:BRAFV600E ctDNA was detected in 74% of BRAF-TT–naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as BRAF-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1, and CTNNB1.Conclusions:ctDNA sequencing is clinically relevant for the detection of BRAF-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAF-mutant NSCLC.

Published
2020
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29. FDG-PET biomarkers associated with long-term benefit from first-line immunotherapy in patients with advanced non-small cell lung cancer

Author

Romain-David Seban, Etienne Giroux-Leprieur, Nicolas Girard, Boris Duchemann, Laurence Champion, Christos Chouaid, Gérald Bonardel, Lucas Goldfarb, Margot Playe, Michael Soussan, Marie-Ange Massiani, and Jean-Baptiste Assié

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Lung Neoplasms, Multivariate analysis, medicine.medical_treatment, Pembrolizumab, Logistic regression, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Stable Disease, Fluorodeoxyglucose F18, Carcinoma, Non-Small-Cell Lung, Positron Emission Tomography Computed Tomography, Internal medicine, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Lung cancer, Aged, medicine.diagnostic_test, business.industry, Proportional hazards model, General Medicine, Immunotherapy, Middle Aged, medicine.disease, Tumor Burden, Positron emission tomography, 030220 oncology & carcinogenesis, Female, business
Abstract

To determine FDG-PET biomarkers associated with long-term benefit (LTB) and survival in advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy. In this multicenter study, we retrospectively analyzed advanced NSCLC patients with a PD-L1 tumor proportion score (TPS) ≥ 50%, who underwent FDG-PET/CT before first-line pembrolizumab, received from August 2017 to September 2019. Parameters extracted were SUVmax, SUVmean, TMTV (total metabolic tumor volume) and TLG (total lesion glycolysis). LTB was defined as objective (complete or partial) response or stable disease as best overall response, maintained for ≥ 12 months. A multivariate prediction model was developed using logistic regression for LTB and Cox models for progression-free survival (PFS) and overall survival (OS). On the 63 eligible patients, with a median follow-up of 13.4 (range, 1.5–29.1) months, 17 (27%) had LTB. Median PFS and OS were 7.7 months (95%CI 5.0–10.5) and 12.1 months (95%CI 8.6–15.6). In multivariate analyses, high TMTV (> 84cm3) and high tumor SUVmean (> 10.1) remained independent factors for predicting LTB (OR 0.2; p = 0.03 and OR 3.7; p = 0.04) and PFS (HR 2.2; p = 0.02 and HR 0.5; p = 0.045). High TMTV was significantly associated with poor OS (HR 3.1; p = 0.03). No association was observed between tumor SUVmax or TLG and clinical outcomes. In patients with advanced NSCLC and PD-L1 TPS ≥ 50%, baseline low TMTV and high tumor SUVmean correlate with survival and LTB from upfront pembrolizumab. Beyond the initial staging, FDG-PET/CT scan could provide relevant biomarkers associated with clinical outcomes that should be taken into account when considering first-line treatment options.

Published
2020
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30. First-line afatinib plus cetuximab for EGFR-mutant non–small cell lung cancer: Results from the randomized phase II IFCT-1503 ACE-lung study

Author

Franck Morin, Judith Raimbourg, Didier Debieuvre, Denis Moro-Sibilot, Elisabeth Quoix, Hugues Morel, Elodie Amour, Olivier Molinier, José Hureaux, Etienne Giroux-Leprieur, Isabelle Rault, Alexis B. Cortot, Benjamin Huret, Josiane Otto, Aldo Renault, L. Moreau, Anne Madroszyk, Sandrine Charpentier, Marc G. Denis, Eric Pichon, Henri Berard, Jacques Cadranel, Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Centre Hospitalier Le Mans (CH Le Mans), CHU Strasbourg, Hopital d'instruction des armées Sainte-Anne [Toulon] (HIA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Amiens-Picardie, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC René Gauducheau, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Université Bretagne Loire (UBL), Hôpitaux Civils de Colmar, Centre Hospitalier Régional d'Orléans (CHRO), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Bristol-Myers Squibb, BMS, Pfizer, AstraZeneca, Merck, Novartis, Roche, Meso Scale Diagnostics, MSD, Boehringer Ingelheim, Takeda Pharmaceutical Company, TPC, and nonfinancial support from MSD, Takeda, and AbbVie outside the submitted work. E. Pichon reports nonfinancial support from Takeda, personal fees from Roche and AstraZeneca, and nonfinancial support from BMS outside the submitted work. B. Huret reports personal fees from Roche, AstraZeneca, BMS, and Boehringher Ingelheim outside the submitted work. M.G. Denis reports grants and personal fees from AstraZeneca and Takeda, grants from BluePrint Medicines, and personal fees from BMS, Boehringer Ingelheim, Roche Diagnostics, and Amgen outside the submitted work. J. Cadranel reports personal fees from BI, grants and personal fees from AstraZeneca, Pfizer, and Novartis, and personal fees from Roche, MSD, BMS, and Takeda outside the submitted work. No disclosures were reported by the other authors., A.B. Cortot reports grants from Boeringher-Ingelheim during the conduct of the study, as well as personal fees and nonfinancial support from AstraZeneca and Pfizer, grants, personal fees, and nonfinancial support from Roche and Novartis, personal fees and nonfinancial support from MSD, BMS, and Takeda, and grants from Merck, outside the submitted work. A. Madroszyk reports other support from Boehringer and MSD during the conduct of the study, as well as other support from Roche, Pfizer, AstraZeneca, BMS, and Prostrakan outside the submitted work. E. Giroux-Leprieur reports grants, personal fees, and nonfinancial support from AstraZeneca, Bristol Myers Squibb, and Roche, personal fees and nonfinancial support from Boehringer Ingelheim, MSD, and Takeda, and personal fees from Novartis outside the submitted work. O. Molinier reports personal fees from AstraZeneca, MSD, BMS, Amgen, Takeda, and Menarini outside the submitted work. E. Quoix reports grants from Boehringer Ingelheim and Ligue Nationale contre le Cancer during the conduct of the study, as well as personal fees and other from BMS and Chugai, other from Roche and Takeda, and personal fees from Novartis outside the submitted work. H. Bérard reports other from MSD, Roche, and Novartis outside the submitted work. D. Moro-Sibilot reports grants, personal fees, and nonfinancial support from Boehringer Ingelheim, Roche, BMS, Pfizer, AstraZeneca, and Merck, as well as personal fees, Medical writing assistance was provided by Dr Sarah Hopwood (Scinopsis, France), funded by IFCT. We thank the participating patients and their families as well as the study teams involved in the trial, the clinical research assistants, study coordinators, and IFCT operations staff. We thank the staff of the department of Biochemistry, CHU de Nantes. We also thank all the participating investigators: Dr Anne Madroszyk (institut Paoli Calmette, Marseille), Dr Etienne Giroux-Leprieur (hôpital Ambroise Paré, Boulogne), Dr Olivier Molinier (CHG, Le Mans), Pr Elisabeth Quoix (NHC, Strasbourg), Pr Jacques Cadranel (hôpital Tenon, Paris), Dr Henri Bérard (HIA Sainte-Anne, Toulon), Dr Josiane Otto (centre Antoine Lacassagne, Nice), Dr Isabelle Rault (CH, Saint Quentin), Pr Denis Moro-Sibilot (CHU, Grenoble), Pr Alexis B. Cortot (hôpital Calmette, Lille), Dr Judith Raimbourg (Institut de Cancérologie de l’Ouest, Nantes), Dr José Hureaux (CHU Angers), Lionel Moreau (CH Colmar), Dr Didier Debieuvre (GHRMSA, Mulhouse), Dr Hugues Morel (CHR, Orléans), Dr Valérie Gounant (hôpital Bichat, Paris), Dr Ludovic Doucet (hôpital Saint-Louis, Paris), Dr Aldo Renault (CHG, Pau), Dr Eric Pichon (CHU, Tours), Dr Benjamin Huret (hôpital privé, Villeneuve d’Asq), Dr Nadine Dohollou (Polyclinique Bordeaux Nord), Dr Clarisse Audigier-Valette (CHI, Toulon), Dr Chantal Decroisette (CH, Annecy), Dr Mathilde Cabart (Institut Bergonié, Bordeaux), Dr Patrick Merle (CHU, Clermont-Ferrand), Dr Catherine Becht (clinique du Parc, Castelnau le Lez), and Dr Luc Odier (CH, Villefranche sur Saône)., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)

Subjects
Oncology, Cancer Research, medicine.medical_specialty, medicine.drug_class, Afatinib, [SDV.CAN]Life Sciences [q-bio]/Cancer, EGFR Gene Mutation, Tyrosine-kinase inhibitor, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Clinical endpoint, Epidermal growth factor receptor, Adverse effect, Lung cancer, 030304 developmental biology, 0303 health sciences, Cetuximab, biology, business.industry, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, biology.protein, business, medicine.drug
Abstract

Purpose: Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non–small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advanced EGFR-mutant NSCLC. Patients and Methods: In this phase II, randomized, open-label study, patients with stage III/IV EGFR-positive NSCLC were randomly assigned (1:1) to receive afatinib (group A) or afatinib + cetuximab (group A + C). Oral afatinib 40 mg was given once daily; cetuximab 250 mg/m² was administered intravenously on day 15 of cycle 1, then every 2 weeks at 500 mg/m² for 6 months. The primary endpoint was time to treatment failure (TTF) rate at 9 months. Exploratory analysis of EGFR circulating tumor DNA in plasma was performed. Results: Between June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5–14.1) and 12.9 (9.2–14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of the EGFR gene mutation in circulating tumor DNA at baseline was associated with shorter PFS, regardless of the treatment received. Conclusions: These results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced EGFR-mutant NSCLC.

Published
2021
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31. EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy

Author

Marie Wislez, Marie-Ange Massiani, Nathalie Théou-Anton, Jacques Cadranel, Xavier Mignard, Boris Duchemann, Isabelle Monnet, Elizabeth Fabre, Sylvie Friard, Karen Leroy, Solenn Brosseau, Etienne Giroux-Leprieur, Samy Chelabi, Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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), 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), Centre Hospitalier Intercommunal de Créteil (CHIC), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Curie [Paris], Hôpital Foch [Suresnes], Hôpital Avicenne [AP-HP], Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Ambroise Paré [AP-HP], Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Unité pneumologie et oncologie thoracique [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Theranoscan [CHU Tenon] (GRC 4), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 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), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université

Subjects
Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, EGFR, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, NSCLC, chemotherapy, survival, Article, exon 20 insertion, 03 medical and health sciences, Exon, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Medicine, Clinical efficacy, Lung cancer, education, RC254-282, 030304 developmental biology, 0303 health sciences, Chemotherapy, education.field_of_study, Lung, business.industry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, TKI, 3. Good health, respiratory tract diseases, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Non small cell, business, Progressive disease
Abstract

Simple Summary EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs), but data is limited about this population. We aim to describe clinical features, survival, and response to chemotherapy and TKIs in this patient population. Abstract EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patients (controls). Between 2012 and 2017, 35 Exon20ins patients were included. These patients were younger at diagnosis than the controls. All Exon20ins patients who were treated with first-line EGFR TKIs (n = 6) showed progressive disease as the best tumor response. There was no significant difference in the tumor response or the disease control rate with first-line platinum-based chemotherapy between the two groups. A trend towards shorter overall survival was observed in Exon20ins vs. controls (17 months (14—not reach(NR) 95% confidence interval(CI) vs. 29 months (17–NR 95%CI), p = 0.09), respectively. A significant heterogeneity in amino acid insertion in EGFR exon 20 was observed. EGFR exon 20 insertions are heterogeneous molecular alterations in NSCLC that are resistant to classic EGFR TKIs, which contraindicates their use as a first-line treatment.

Published
2021
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32. Resistance mechanisms to osimertinib in EGFR-mutated advanced non-small-cell lung cancer: A multicentric retrospective French study

Author

Camille Mehlman, Etienne Giroux Leprieur, Valérie Gounant, Pierre Olivier Schischmanoff, Gaelle Rousseau-Bussac, Thierry Chinet, B. Duchemann, Jean Trédaniel, Cécile Dujon, Nicolas Girard, Jacques Cadranel, Céline Callens, Roger Lacave, Anaïs Pujals, Nathalie Théou-Anton, Hélène Blons, Sylvie Friard, CCSD, Accord Elsevier, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Hôpital Ambroise Paré [AP-HP], Centre Constitutif de Référence des Maladies Pulmonaires Rares [AP-HP Tenon], Centre national de référence des maladies pulmonaires rares [Lyon] (CRMPM)-Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Intercommunal de Créteil (CHIC), Unité Génomique des tumeurs solides [CHU Tenon], Service d'Histologie - Embryologie - Cytogénétique biologie tumorale et génétique moléculaire [CHU Tenon], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Curie [Paris], Université Paris sciences et lettres (PSL), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Foch [Suresnes], Centre hospitalier Saint-Joseph [Paris], Médecine Personnalisée, Pharmacogénomique, Optimisation Thérapeutique (MEPPOT - U1147), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre Hospitalier de Versailles André Mignot (CHV), Hôpital Avicenne [AP-HP], Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse (AMMICa), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut Gustave Roussy (IGR), Adaptateurs de signalisation en hématologie (ASIH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Nord, Centre national de référence des maladies pulmonaires rares [Lyon] (CRMPM)-Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, Lung Neoplasms, [SDV]Life Sciences [q-bio], Resistance, 0302 clinical medicine, Non-small cell lung cancer, Carcinoma, Non-Small-Cell Lung, Osimertinib, Aged, 80 and over, Aniline Compounds, Middle Aged, Prognosis, 3. Good health, ErbB Receptors, Survival Rate, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Cohort, Carcinoma, Squamous Cell, MET, Female, Non small cell, Adult, C797S, Pulmonary and Respiratory Medicine, medicine.medical_specialty, EGFR, Met amplification, Adenocarcinoma of Lung, 03 medical and health sciences, Internal medicine, Biomarkers, Tumor, medicine, Humans, In patient, Progression-free survival, Lung cancer, Protein Kinase Inhibitors, Aged, Retrospective Studies, Acrylamides, business.industry, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Tumor progression, Mutation, business, Follow-Up Studies
Abstract

International audience; Objectives: The understanding of histo-molecular mechanisms associated with resistance to osimertinib is a critical step to define the optimal treatment strategy in advanced EGFR-mutated Non-Small-Cell-Lung-Cancer (NSCLC).Materials and methods: We performed a multicentric retrospective analysis on a cohort of consecutive patients treated with osimertinib for an advanced EGFR-mutated NSCLC and collected histo-molecular data from plasma and tumor samples at the time of progression. Next-generation sequencing (NGS) was performed for all samples. Best Overall Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS) and data on treatment post-progression efficacy were also collected.Results: Two-hundred and twenty-six patients were included from 9 Academic French Hospitals between April 2015-October 2018. Osimertinib was given in second-line or more in 219 patients (97%). Best ORR was 52% and best central nervous system ORR was 56%. Median PFS and OS were 9.5 months (IQR 4.0-17.2) and 24 months (IQR 12.4-NR) respectively. At the time of analysis, 150 patients (66%) had tumor progression. Among them, 73 contributive samples (56 tumor biopsies) were available. The most frequent molecular alterations were C797S mutation (n = 9 (13%)) and MET amplification (n = 8 (11%)). Histologic transformation occurred in 5 patients (9% of tumor biopsies). In T790M + NSCLC, loss of T790 M occurred in 68% of cases. Median PFS and OS with treatment beyond progression were 6.0 months (IQR 2.0-10.4) and 15.1 months (IQR 6.7-NR) respectively and longer in case of osimertinib continuation beyond progression.Conclusion: We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation positive NSCLC. At progression, the most frequent molecular alterations were MET amplification and C797S mutation.

Published
2019
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33. Editorial: Emerging Biomarkers for NSCLC: Recent Advances in Diagnosis and Therapy

Author

Umberto Malapelle, Etienne Giroux Leprieur, Paul Takam Kamga, Marius Tresor Chiasseu, Christian Rolfo, Malapelle, U., Leprieur, E. G., Kamga, P. T., Chiasseu, M. T., and Rolfo, C.

Subjects
Oncology, Cancer Research, medicine.medical_specialty, therapy, business.industry, diagnosis, biomarkers, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, NSCLC, diagnosi, Internal medicine, NGS, biomarker, Medicine, business, RC254-282
Published
2021
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34. Prognostic value of inflammatory response biomarkers using peripheral blood and [18F]-FDG PET/CT in advanced NSCLC patients treated with first-line chemo- or immunotherapy

Author

Romain-David Seban, Etienne Giroux-Leprieur, Gérald Bonardel, Marie-Ange Massiani, Jean-Baptiste Assié, Nicolas Girard, Christos Chouaid, Capucine Richard, Laurence Champion, Laura Mezquita, and Nicolas Deleval

Subjects
Pulmonary and Respiratory Medicine, Cancer Research, medicine.medical_specialty, Lung Neoplasms, First line, medicine.medical_treatment, Inflammatory response, Gastroenterology, Fluorodeoxyglucose F18, Internal medicine, Carcinoma, Non-Small-Cell Lung, Positron Emission Tomography Computed Tomography, Medicine, Humans, Retrospective Studies, Chemotherapy, business.industry, Immunotherapy, Prognosis, Peripheral blood, medicine.anatomical_structure, Oncology, Cohort, Fdg pet ct, Bone marrow, business, Biomarkers
Abstract

Objectives We aimed to compare the prognostic value of inflammatory biomarkers extracted from pretreatment peripheral blood and [18F]-FDG PET for estimating outcomes in non-small cell lung cancer (NSCLC) patients treated with first-line immunotherapy (IT) or chemotherapy (CT). Materials and methods In this retrospective multicenter study, we evaluated 111 patients with advanced NSCLC who underwent baseline [18F]-FDG PET/CT before IT or CT between 2016 and 2019. Several blood inflammatory indices were evaluated: derived neutrophil-to-lymphocyte ratio (dNLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP) and systemic immune-inflammation index (SII). FDG-PET inflammatory parameters were extracted from lymphoid tissues (BLR and SLR: bone marrow or spleen-to-Liver SUVmax ratios). Association with survival and relationships between parameters were evaluated using Cox prediction models and Spearman's correlation respectively. Results Overall, 90 patients were included (IT:CT) (51:39pts). Median PFS was 8.6:6.6 months and median OS was not reached:21.2 months. In the IT cohort, high dNLR (>3), high SII (≥1,270) and high SLR (0.77) were independent statistically significant prognostic factors for one-year progression-free survival (1y-PFS) and two-year overall survival (2y-OS) on multivariable analysis. In the CT cohort, high BLR (≥0.80) and high dNLR (>3) were associated with shorter 1y-PFS (HR 2.2, 95% CI 1.0–4.9) and 2y-OS (HR 3.4, 95CI 1.1–10.3) respectively, on multivariable analysis. Finally, BLR significantly but moderately correlated with most blood-based inflammatory indices (CRP, PLR and SII) while SLR was only associated with CRP (p Conclusion In advanced NSCLC patients undergoing first-line IT or CT, pretreatment blood and inflammatory factors evaluating the spleen or bone marrow on [18F]-FDG PET/CT provided prognostic information for 1y-PFS and 2y-OS. These biomarkers should be further evaluated for potential clinical application.

Published
2021

35. Baseline hedgehog pathway activation and increase of plasma wnt1 protein are associated with resistance to immune checkpoint inhibitors in advanced non-small-cell lung cancer

Author

Thierry Chinet, Camille Mehlman, Violaine Giraud, Adrien Costantini, Coraline Dumenil, Jean-François Emile, J. Ouaknine, Jennifer Dumoulin, Etienne Giroux Leprieur, Paul Takam Kamga, Catherine Julie, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, and Hôpital Ambroise Paré [AP-HP]

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Gli1, Resistance, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immune checkpoint inhibitor, lcsh:RC254-282, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Article, 03 medical and health sciences, Wnt, Plasma, 0302 clinical medicine, Non-small cell lung cancer, GLI1, WNT2, Interquartile range, Internal medicine, medicine, Sonic hedgehog, Lung cancer, Hedgehog, 030304 developmental biology, 0303 health sciences, biology, business.industry, Wnt signaling pathway, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hedgehog signaling pathway, 3. Good health, Sonic Hedgehog, 030220 oncology & carcinogenesis, Beta-catenin, biology.protein, business
Abstract

Simple Summary Wnt and Hedgehog (Hh) pathways are associated with stemness profile and with resistance to anti-tumor therapies. Pre-clinical data have suggested a role of these pathways in resistance to immune checkpoint inhibitors (ICIs). Here we evaluated the expression and levels of Shh and Wnt molecules both in plasma and tumor samples in a prospective cohort of 63 consecutive NSCLC patients treated with ICIs. We found that baseline Hh activation as assessed by nuclear staining of Gli1 was associated with poor outcome and high primary resistance rate. Increase of plasma Wnt1 during treatment was associated with resistance to ICIs. This is the first study to our knowledge to find an association between the Hh and Wnt pathways and resistance to ICIs in advanced NSCLC patients. We believe that these results are important to understand the molecular mechanisms associated with resistance to ICIs, and ultimately to improve future treatment strategies. Abstract Hedgehog (Hh) and Wingless-type (Wnt) pathways are associated with resistance to immune checkpoint inhibitors (ICIs) in preclinical studies. This study aimed to assess the association between expression and activation levels of Wnt and Sonic Hedgehog (Shh) pathways and resistance to ICIs in advanced NSCLC patients treated with ICI. Hh and Wnt pathways activation was assessed by immunohistochemistry (Gli1 and beta-catenin) on corresponding tumor tissues, and by plasma concentrations of Shh and Wnt (Wnt1, Wnt2 and Wnt3) at ICI introduction and at the first clinical evaluation. Sixty-three patients were included, with 36 patients (57.1%) with available tissue. Response rate was lower in Gli1+ NSCLC (20.0%) compared to Gli1 negative (Gli-) NSCLC (55.6%) (p = 0.015). Rate of primary resistance was 69.8%, vs. 31.2%, respectively (p = 0.04), and median progression-free survival (PFS) was 1.9 months (interquartile range (IQR) 1.2–5.7) vs. 6.1 months (1.6–26.0), respectively (p = 0.08). Median PFS and overall survival were shorter in case of increase of Wnt1 concentration during ICI treatment compared to other patients: 3.9 months vs. 11.2 months (p = 0.008), and 15.3 months vs. not reached (p = 0.003). In conclusion, baseline activation of Hh pathway and increase of Wnt1 concentrations during ICI treatment were associated with poor outcome in NSCLC patients treated with ICIs.

Published
2021
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36. Risk factors for Coronavirus Disease 2019 (COVID-19) severity and mortality among solid cancer patients and impact of the disease on anticancer treatment: A French nationwide cohort study (GCO-002 CACOVID-19)

Author

Astrid Lièvre, Anthony Turpin, Isabelle Ray-Coquard, Karine Le Malicot, Juliette Thariat, Guido Ahle, Cindy Neuzillet, Xavier Paoletti, Olivier Bouché, Kais Aldabbagh, Pierre Michel, Didier Debieuvre, Anthony Canellas, Marie Wislez, Lucie Laurent, May Mabro, Raphael Colle, Anne-Claire Hardy-Bessard, Laura Mansi, Emeline Colomba, Jean Bourhis, Philippe Gorphe, Yoann Pointreau, Ahmed Idbaih, Renata Ursu, Anna Luisa Di Stefano, Gérard Zalcman, Thomas Aparicio, Solenne Moulin, Olivier Leleu, Sylvie Leparree, Henri Goasdoue, Christine Piprot, Gerald Tourneur, Vincent Bayart, Delphine Lignier, Emma Lachaier, Marwa Khamari, Alexandre Coutte, Nicolas Siembida, Aline Houessinon, Jean Marc Regimbeau, Bruno Chauffert, Aurélie Moreira, Vincent Hautefeuille, Christine Hee, Mathieu Boone, Céline Bihan, Emilie Chive, Stéphane Poulet-Potriquier, Rachida Fahem, Dominique Luet, Guillaume Roquin, Carole Vitellius, Nathanaëlle Cornet-Trichereau, François-Xavier Caroli-Bosc, Anne Thirot-Bidault, Stanislas Ropert, Julie Gachet - Masson, Mélanie Dehais, Gwen-Ael L'helgoualc'h, Ibrahim Ali-Mahamadou, Safia Talfi, Laure Belmont, Dieudonné Kilendo, Nasro Benrezzak, Emeline Dubief, Guillaume Conroy, Laurence Delique, Maud Basso, Isabelle Pons, Karine Salignon, Anne-Laure Villing, Emmanuelle Mougenot, Cassandra Porebski, Asma Guiatni, Nicolas Cloarec, Laurent Mineur, Marie Bouchaud, Céleste David, Annie Peytier, Thomas Greletty, Franck Audemar, Emanuelle Vignes, Floriane Minne, Guillaume Goldzak, Fabienne Huysman, Fayçal Hocine, Zaher Lakkis, Guillaume Meynard, Hamadi Almotlak, Elodie Klajer, Xu-Shan Sun, Julie Wasselin, Pascale Catala, Claire Mazuy, Hélène Vandamme, Jean-Briac Prevost, Aurélie Fadin, Laurent Basson, Jean-Baptiste Huguet, Emmanuelle Dos Santos, Bérangère Jany, Alain Saad, Frédéric Goutorbe, Eric Oziol, Mohamed Ramdani, Ouafae Kadiri, Delphine Garbay, Clotilde Huet, Etienne Giroux Leprieur, Wen Teng, Justine Monvoisin, Patrick Arnaud Coffin, Sylvie Roux, Hubert Orfeuvre, Mélanie Chagros, Didier Pillon, Agathe Rassoul, Pierre Guillaume Poureau, Cécile Novello, François Ducray, Cécile Trouba, Vianney Bastit, Emmanuel Babin, Vincent Leon, Anne-Catherine Courtecuisse, Julie Vambre, Vincent Tack, Christophe Desauw, Fatima Meniai, Christina Peres, Aurélie Esparcieux, Hervé Perrier, Nathalie Doux, Régis Kaphan, Bertrand Roques, Christine Rebischung, Dominique Mille, Gaëlle Fernandes, Naceur Abdelli, Natacha Jousset, Pierre Combe, Eric Jonveaux, Patrick Dumont, Marc Kanaan, Corinne Berthelot Gras, Valérie Panis, Laure Kaluzinski, Marjolène Venant-Valery, You-Heng Lam, Laura Vallee, Frédéric Riviere, Muriel Durand, Dihya Benghadid, Emilie Villeneuve, Olivia Hentic Dhome, Zedjiga Bounouar, Louis De Mestier, Jacqueline Dubois, Magali Eyriey, Lionel Moreau, Dib Baihas, Kaïs Aldabbagh, Dominique Degriffolet, Virginie Sebbagh, Jean-Christophe Seghezzi, Marion Lozach-Brugirard, Julie Mandrou, Loubna Mavier, Florence Hennetier, Jean-Philippe Wagner, Elisabeth Carola, Karthiga Chandirakumaran, Sandrine Loutski, Isabelle Cojean-Zelek, Amina Bouras, Sandrine Lacour, Fahem Froura, Hadjer Ben Nadji, Sophie Cattelain, Franck Darloy, Geneviève Jolimoy Boilleau, Cyrielle Maissiat, Ariane Darut-Jouve, Véronique Lorgis, Ikram Charifi-Alaoui, François Ghiringhelli, Antoine Drouillard, Marie Chaix, Sylvain Manfredi, Côme Lepage, Alice Gagnaire, Marianne Latournerie, Sofia jourdan, Nora Perrot, Mireille folia, Anne Minello, Jean-Louis Jouve, Marielle Fery, Alain Landau, Diane Evrard, Bruno Valenza, Jean-François Paitel, Laetitia Chablais, Thomas Kreitmann, Laurence Lancry-Lecomte, Adrien Monard, Eve Faugeras, Paul Boucheret, Cécile Glommeau, Christine Tchikladze, Claire Garnier Tixidre, Jérôme Long, Manel Zaidi, Véronique Delabarre, Juliette Meyzenc, Loïc Ferrand, Denis Moro-Sibilot, Paul Bouheret, Cécile Leyronnas, Camille Herve, Audrey Thoor, Emanuelle Jacquet, Gaël Roth, Videsheka Madapathage-Senanyake, Peggy Chupeau, Elsa Bieber, Maud Rosso, Isabelle Lepage, Frank Priou, Margot Laly, Sylvie Aprelon, Natacha Sobolak, Helen Homokos, Fabienne Watelle, Alice Pham-Becker, Géraldine Lauridant, Charlotte Dujardin, Etienne Lenglin, Aimée Nienguet Tsota, Sophie Dominguez, Alexandra Forestier, Franck Nouvel, Justine Lerooy, Céline Ratajczak, Olivier Romano, Dorothéee Brzyski, Aurélien Barriere, Dominique Genet, Julien Tisse, Xavier Zasadny, Adeline Grelet, Amélie Hennion-Imbault, Eglantine Haustraete, Samy Louafi, Manal Awad, Younes Zekri, Caroline Cheneau, Nolwen Leissen, Joëlle Egreteau, Alexandra Breant, Matthieu Sarabi, Stéphanie Labonne, Julien Forestier, Céline Leclercq, Florence Prunier-Bossion, Isabelle Ray Coquard, Marielle Guillet, Aurélie Theillaumas, Emilie Prome, Thomas Walter, Pierre Philouze, Melody Lawo, Solène De Talhouet, Johanne Beuvelot, Yann Molin, Marie Bellecoste Martin, Maud Saussereau, Lauren Agnelli, Nicolas Fakhry, Christophe Laplace, Emmanuelle Norguet Monnereau, Céline Boucard, Kahina Djenad, Catherine Fontaine, Jean-François Seitz, Laétitia Dahan, Julie Sigrand, Muriel Duluc, Christophe Locher, Marjory Fleury, Ange Brou Marie, Ramdane Berkane, Séverine Poupblanc, Dominique Auby, Daniela Petran, Patrick Texereau, Elodie Guerineau, Morgan Andre, Linda Mahjoubi, Fanny Sarrazin, Sonia Jeanson, Anthony Gschwend, Virginie Birr, Mathieu Fore, Monique Noirclerc, Sihem Dahou, Dominique Spaeth, Mélanie Lambotin, Thomas Lelu, Benjamin Linot, Nathalie Hugon, Dominique Rousseau, Hélène Castanie, Carole Lenne, Alain Lortholary, Anatole Cessot, Messaouda Merzoug, Cécile Naudin, Jean-Michel Vannetzel, Ghina Aziz, Yacine Hadj Arab, Stéphanie Pernes, Isabelle Roche-Lachaise, Frédéric Fiteni, Hadjer Yahiaoui, Gwendoline Marel Lopez, Jeanne Oddoz, Fabienne Peira, Olivier Michel, Jérôme Meunier, Brahim Ouahrani, Antoine Roger, Sonia Branco, Van Nguyen, Mathilde Gisselbrecht, Ghania Hammad, Pierre Mordant, Magda Stroksztejn, Marc Pocard, Luc Nlo Meyengue, Emmanuelle Sacco, Sophie Simon Anne, Elizabeth Fabre-Guillevin, Marine Slim, Aziz Zaanan, Jacques Cadranel, Johan Pluvy, Rénata Ursu, Amyrath Geraldo, Rime Lihi, Maryline Vo, Zohra Brouk, Raphaël Colle, Mostefa Bennamoun, Fabrice Lacan, Christophe Louvet, Soraya Mebarki, Marianne Veyri, Elena Paillaud, Christelle Lucas, Olivier Dubreuil, Jamila Lyamani, Hanane Agguini, Emilie Soularue, Clément Jourdaine, Benjamin Verillaud, Hakima Herzine, Eric Raymond, Nathalie Mathiot, Lola Jade Palmieri, Christian Epanya, Julien Taieb, Eliane Bertrand, Gaël Goujon, Céline Namour, Benoit Gazeau, Biljana Zafirova, Haitham Mirghani, Catherine Belin, Kahina Belkhir, Myriam Gharib, Aurore Vozy, Karim Amrane, Jean-Philippe Spano, Johanna Wassermann, Loic Feuvret, Jean-Baptiste Bachet, Sara Philonenko, Laetitia Guillot, Marion Zabbe, Stéphanie Gibiat, Camille Baylot, Aude Jouinot, Nicolas Leduc, Sabine Vieillot, Laurie James, Camille Ducerf, Jean-Frédéric Blanc, Claire Falandry Leger, Virginie Wautot, Marion Chauvenet, Aude Vincent, David Tougeron, Sandrine Goulvent, Etienne Suc, Anne-Pascale Laurenty, Eric Marquis, Margaux Bonnaire, Maxime Dewolf, Esteban Brenet, Delphine Billard, Claude-Fabien Litre, Antoine Dumazet, Damien Botsen, Marion Vazel, Claire Carlier, David Bonnerave, Charles Marchand-Crety, Olivier Bouche, Patricia Fosse, David Sefrioui, Sarah Watson, Fatah Torche, Thierry Muron, Stéphane Natur, Romain Desgrippes, Véronique Bihel, François-Régis Ferrand, Caroline Leiterer, Julie Lavole, Claire Moquet, Nathalie Pressoir, Catherine Dziukala, Catherine Ligeza Poisson, Abdelhalim Naji, Nicolas Williet, Jean-Marc Phelip, Fabrice Di Palma, Amina Kherrour Mehdi, Julien Langrand-Escure, Pierre Fournel, Grégoire Pigne, Léa Saban-Roche, Nicolas Magne, Cécile Vassal, Jean-Philippe Jacquin, Carole Ramirez, Alexis Vallard, Olivier Collard, Romain Rivoirard, Ivan Graber, Stéphanie Trager Maury, Elodie Duboisset, Jorge Ayllon Ugarte, Dalilia Rami, Christine Saler, Manon Reinbolt, Clara Le Fevre, Meher Ben Abdelghani, Louis-Marie Dourthe, Joffrey Perruisseau-Carrier, Marlène Nguimpi-Tambou, Flavie Barret, Luisa Di Stefano Anna, Annie Balthazard, Camille Vassord-Dang, Mathilde Le Marchand, Julien Vergniol, Iulia Pripon, Axelle Daemaegdt, Vanessa Latry, Muna Larrieu, Gaëlle Landry, Laetitia Touihri Maximin, Francesco Del Piano, Agnès Barlet, Mylène Vernisse, Sophie Lafond, Charline Genin, Camille Sibertin-Blanc, Emilien Chabrillac, Caroline Gregoire, Sébastien Vergez, Quentin Panouille, Rosine Guimbaud, Floriane Richa, Loïc Lebellec, Sophie Gounin, Guillaume Buiret, Marine Baudin, Hervé Hamon, Anne-Claire Deshorgue, Eduardo Barrascout, Stéphanie Legrand, Morgane Houlze, Linda Cambula, Anthony Lopez, Guillaume Fouquet, Kahina Touabi, Adeline GermaIn, Benoit Godbert, Florence Voivret, Julie Perrin, Rosa Da Silva, Emilie Bernichon, GCO-002 CACOVID-19 collaborators/investigators, Moulin, S., Leleu, O., Leparree, S., Goasdoue, H., Piprot, C., Tourneur, G., Bayart, V., Lignier, D., Lachaier, E., Khamari, M., Coutte, A., Siembida, N., Houessinon, A., Regimbeau, J.M., Chauffert, B., Moreira, A., Hautefeuille, V., Hee, C., Boone, M., Bihan, C., Chive, E., Poulet-Potriquier, S., Fahem, R., Luet, D., Roquin, G., Vitellius, C., Cornet-Trichereau, N., Caroli-Bosc, F.X., Thirot-Bidault, A., Ropert, S., Gachet-Masson, J., Dehais, M., L'helgoualc'h, G.A., Ali-Mahamadou, I., Talfi, S., Belmont, L., Kilendo, D., Benrezzak, N., Dubief, E., Conroy, G., Delique, L., Basso, M., Pons, I., Salignon, K., Villing, A.L., Mougenot, E., Porebski, C., Guiatni, A., Cloarec, N., Mineur, L., Bouchaud, M., David, C., Peytier, A., Greletty, T., Audemar, F., Vignes, E., Minne, F., Goldzak, G., Huysman, F., Hocine, F., Lakkis, Z., Mansi, L., Meynard, G., Almotlak, H., Klajer, E., Sun, X.S., Wasselin, J., Catala, P., Mazuy, C., Vandamme, H., Prevost, J.B., Fadin, A., Basson, L., Huguet, J.B., Dos Santos, E., Jany, B., Saad, A., Goutorbe, F., Oziol, E., Ramdani, M., Kadiri, O., Garbay, D., Huet, C., Giroux Leprieur, E., Teng, W., Monvoisin, J., Arnaud Coffin, P., Roux, S., Orfeuvre, H., Chagros, M., Pillon, D., Rassoul, A., Poureau, P.G., Novello, C., Ducray, F., Trouba, C., Bastit, V., Babin, E., Thariat, J., Leon, V., Courtecuisse, A.C., Vambre, J., Tack, V., Desauw, C., Meniai, F., Peres, C., Esparcieux, A., Perrier, H., Doux, N., Kaphan, R., Roques, B., Rebischung, C., Mille, D., Fernandes, G., Abdelli, N., Jousset, N., Combe, P., Jonveaux, E., Dumont, P., Kanaan, M., Berthelot Gras, C., Panis, V., Kaluzinski, L., Venant-Valery, M., Lam, Y.H., Vallee, L., Riviere, F., Durand, M., Benghadid, D., Villeneuve, E., Hentic Dhome, O., Laurent, L., Bounouar, Z., De Mestier, L., Dubois, J., Eyriey, M., Moreau, L., Ahle, G., Baihas, D., Aldabbagh, K., Degriffolet, D., Sebbagh, V., Seghezzi, J.C., Lozach-Brugirard, M., Mandrou, J., Mavier, L., Hennetier, F., Wagner, J.P., Carola, E., Chandirakumaran, K., Loutski, S., Cojean-Zelek, I., Bouras, A., Lacour, S., Froura, F., Ben Nadji, H., Cattelain, S., Darloy, F., Jolimoy Boilleau, G., Maissiat, C., Darut-Jouve, A., Lorgis, V., Charifi-Alaoui, I., Ghiringhelli, F., Drouillard, A., Chaix, M., Manfredi, S., Lepage, C., Gagnaire, A., Latournerie, M., Jourdan, S., Perrot, N., Folia, M., Minello, A., Jouve, J.L., Fery, M., Landau, A., Evrard, D., Valenza, B., Paitel, J.F., Chablais, L., Kreitmann, T., Lancry-Lecomte, L., Monard, A., Faugeras, E., Boucheret, P., Glommeau, C., Tchikladze, C., Garnier Tixidre, C., Long, J., Zaidi, M., Delabarre, V., Meyzenc, J., Ferrand, L., Moro-Sibilot, D., Bouheret, P., Leyronnas, C., Herve, C., Thoor, A., Jacquet, E., Roth, G., Madapathage-Senanyake, V., Chupeau, P., Bieber, E., Rosso, M., Lepage, I., Priou, F., Laly, M., Aprelon, S., Sobolak, N., Homokos, H., Pointreau, Y., Watelle, F., Pham-Becker, A., Lauridant, G., Turpin, A., Dujardin, C., Lenglin, E., Nienguet Tsota, A., Dominguez, S., Forestier, A., Nouvel, F., Lerooy, J., Ratajczak, C., Romano, O., Brzyski, D., Barriere, A., Genet, D., Tisse, J., Zasadny, X., Grelet, A., Hennion-Imbault, A., Haustraete, E., Louafi, S., Awad, M., Zekri, Y., Cheneau, C., Leissen, N., Egreteau, J., Breant, A., Sarabi, M., Labonne, S., Forestier, J., Leclercq, C., Prunier-Bossion, F., Ray Coquard, I., Guillet, M., Theillaumas, A., Prome, E., Walter, T., Philouze, P., Lawo, M., De Talhouet, S., Beuvelot, J., Molin, Y., Bellecoste Martin, M., Saussereau, M., Agnelli, L., Fakhry, N., Laplace, C., Norguet Monnereau, E., Boucard, C., Djenad, K., Fontaine, C., Seitz, J.F., Dahan, L., Sigrand, J., Duluc, M., Locher, C., Fleury, M., Brou Marie, A., Berkane, R., Poupblanc, S., Auby, D., Petran, D., Texereau, P., Guerineau, E., Andre, M., Mahjoubi, L., Sarrazin, F., Jeanson, S., Gschwend, A., Birr, V., Debieuvre, D., Fore, M., Noirclerc, M., Dahou, S., Spaeth, D., Lambotin, M., Lelu, T., Linot, B., Hugon, N., Rousseau, D., Castanie, H., Lenne, C., Lortholary, A., Cessot, A., Merzoug, M., Naudin, C., Vannetzel, J.M., Aziz, G., Hadj Arab, Y., Pernes, S., Roche-Lachaise, I., Fiteni, F., Yahiaoui, H., Marel Lopez, G., Oddoz, J., Peira, F., Michel, O., Meunier, J., Ouahrani, B., Roger, A., Branco, S., Nguyen, V., Gisselbrecht, M., Hammad, G., Mordant, P., Stroksztejn, M., Pocard, M., Nlo Meyengue, L., Aparicio, T., Sacco, E., Simon Anne, S., Fabre-Guillevin, E., Wislez, M., Slim, M., Zaanan, A., Cadranel, J., Pluvy, J., Ursu, R., Geraldo, A., Lihi, R., Vo, M., Brouk, Z., Colle, R., Bennamoun, M., Lacan, F., Louvet, C., Mebarki, S., Veyri, M., Paillaud, E., Lucas, C., Dubreuil, O., Lyamani, J., Idbaih, A., Agguini, H., Soularue, E., Canellas, A., Zalcman, G., Jourdaine, C., Verillaud, B., Herzine, H., Raymond, E., Mathiot, N., Palmieri, L.J., Epanya, C., Taieb, J., Bertrand, E., Goujon, G., Namour, C., Gazeau, B., Zafirova, B., Mirghani, H., Belin, C., Belkhir, K., Gharib, M., Vozy, A., Amrane, K., Spano, J.P., Wassermann, J., Feuvret, L., Bachet, J.B., Philonenko, S., Guillot, L., Zabbe, M., Gibiat, S., Baylot, C., Jouinot, A., Leduc, N., Vieillot, S., James, L., Ducerf, C., Blanc, J.F., Falandry Leger, C., Wautot, V., Chauvenet, M., Vincent, A., Tougeron, D., Goulvent, S., Suc, E., Laurenty, A.P., Marquis, E., Bonnaire, M., Dewolf, M., Brenet, E., Billard, D., Litre, C.F., Dumazet, A., Botsen, D., Vazel, M., Carlier, C., Bonnerave, D., Marchand-Crety, C., Bouche, O., Fosse, P., Sefrioui, D., Michel, P., Watson, S., Neuzillet, C., Torche, F., Muron, T., Natur, S., Desgrippes, R., Bihel, V., Ferrand, F.R., Leiterer, C., Lavole, J., Moquet, C., Pressoir, N., Dziukala, C., Ligeza Poisson, C., Naji, A., Williet, N., Phelip, J.M., Di Palma, F., Kherrour Mehdi, A., Langrand-Escure, J., Fournel, P., Pigne, G., Saban-Roche, L., Magne, N., Vassal, C., Jacquin, J.P., Ramirez, C., Vallard, A., Collard, O., Rivoirard, R., Graber, I., Trager Maury, S., Duboisset, E., Ayllon Ugarte, J., Rami, D., Saler, C., Reinbolt, M., Le Fevre, C., Ben Abdelghani, M., Dourthe, L.M., Perruisseau-Carrier, J., Nguimpi-Tambou, M., Barret, F., Di Stefano Anna, L., Balthazard, A., Mabro, M., Vassord-Dang, C., Le Marchand, M., Vergniol, J., Pripon, I., Daemaegdt, A., Latry, V., Larrieu, M., Landry, G., Touihri Maximin, L., Del Piano, F., Barlet, A., Vernisse, M., Lafond, S., Genin, C., Sibertin-Blanc, C., Chabrillac, E., Gregoire, C., Vergez, S., Panouille, Q., Guimbaud, R., Richa, F., Lebellec, L., Gounin, S., Buiret, G., Baudin, M., Hamon, H., Deshorgue, A.C., Barrascout, E., Legrand, S., Houlze, M., Cambula, L., Lopez, A., Fouquet, G., Touabi, K., GermaIn, A., Godbert, B., Voivret, F., Perrin, J., Da Silva, R., Bernichon, E., Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 (CANTHER), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Centre Léon Bérard [Lyon], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), CH Colmar, Institut Curie [Paris], Centre Hospitalier Universitaire de Reims (CHU Reims), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Beaujon, Hôpital Foch [Suresnes], CHU Saint-Antoine [AP-HP], ARCAGY-GINECO, 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), Département de médecine nucléaire [Rennes], CRLCC Eugène Marquis (CRLCC), Département de médecine oncologique [Gustave Roussy], Département de cancérologie cervico-faciale [Gustave Roussy] (CCF), Centre Jean Bernard [Institut Inter-régional de Cancérologie - Le Mans], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), AbbVie, Merck, Carthera, Transgene, Nutritheragene, Roche, Air Liquide, Eli Lilly Japan, LEO Pharma Research Foundation, Bayer, Novartis, Sanofi, Biogen, Institut National de la Santé et de la Recherche Médicale (INSERM)-CRLCC Eugène Marquis (CRLCC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, 0301 basic medicine, Cancer Research, medicine.medical_treatment, Disease, law.invention, Cohort Studies, 0302 clinical medicine, Mechanical ventilation, Risk Factors, law, Neoplasms, Medicine, Prospective Studies, Prospective cohort study, Original Research, Cancer, Intensive care unit, 3. Good health, Death, Oncology, 030220 oncology & carcinogenesis, Female, France, Immunotherapy, Cohort study, medicine.medical_specialty, chemotherapy. radiotherapy, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, Internal medicine, Humans, Chemotherapy, Mortality, Pandemics, Aged, Retrospective Studies, Radiotherapy, SARS-CoV-2, business.industry, COVID-19, Retrospective cohort study, Odds ratio, medicine.disease, Antineoplastic Agents/adverse effects, Antineoplastic Agents/therapeutic use, COVID-19/mortality, France/epidemiology, Neoplasms/mortality, Neoplasms/therapy, Neoplasms/virology, SARS-CoV-2/isolation & purification, 030104 developmental biology, business
Abstract

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.

Published
2020
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37. First-Line Afatinib plus Cetuximab for

Author

Alexis B, Cortot, Anne, Madroszyk, Etienne, Giroux-Leprieur, Olivier, Molinier, Elisabeth, Quoix, Henri, Bérard, Josiane, Otto, Isabelle, Rault, Denis, Moro-Sibilot, Judith, Raimbourg, Elodie, Amour, Franck, Morin, José, Hureaux, Lionel, Moreau, Didier, Debieuvre, Hugues, Morel, Aldo, Renault, Eric, Pichon, Benjamin, Huret, Sandrine, Charpentier, Marc G, Denis, and Jacques, Cadranel

Subjects
Adult, Aged, 80 and over, Male, Lung Neoplasms, Cetuximab, Middle Aged, Afatinib, ErbB Receptors, Treatment Outcome, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Mutation, Humans, Female, Aged
Abstract

Double inhibition of epidermal growth factor receptor (EGFR) using a tyrosine kinase inhibitor plus a monoclonal antibody may be a novel treatment strategy for non-small cell lung cancer (NSCLC). We assessed the efficacy and toxicity of afatinib + cetuximab versus afatinib alone in the first-line treatment of advancedIn this phase II, randomized, open-label study, patients with stage III/IVBetween June 2016 and November 2018, 59 patients were included in group A and 58 in group A + C. The study was ended early after a futility analysis was performed. The percentage of patients without treatment failure at 9 months was similar for both groups (59.3% for group A vs. 64.9% for group A + C), and median TTF was 11.1 (95% CI, 8.5-14.1) and 12.9 (9.2-14.5) months, respectively. Other endpoints, including progression-free survival and overall survival, also showed no improvement with the combination versus afatinib alone. There was a slight numerical increase in grade ≥3 adverse events in group A + C. Allele frequency of theThese results suggest that addition of cetuximab to afatinib does not warrant further investigation in treatment-naïve advanced

Published
2020

38. Plasma Biomarkers Screening by Multiplex ELISA Assay in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors

Author

Jennifer Dumoulin, Adrien Costantini, Violaine Giraud, Catherine Julie, Coraline Dumenil, Thierry Chinet, Jean-François Emile, Alexandre Corjon, Martin Rottman, J. Ouaknine, Etienne Giroux Leprieur, Paul Takam Kamga, Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), HAL UVSQ, Équipe, Hôpital Ambroise Paré [AP-HP], and Hôpital Raymond Poincaré [AP-HP]

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Fibroblast growth factor, immune checkpoint inhibitor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Pembrolizumab, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, lcsh:RC254-282, Article, resistance, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Medicine, Multiplex, 030212 general & internal medicine, Adverse effect, Lung cancer, non-small cell lung cancer, plasma, interleukine-12, business.industry, toxicity, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, respiratory tract diseases, hepatocyte growth factor, 030220 oncology & carcinogenesis, Toxicity, Biomarker (medicine), [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, biomarker, Nivolumab, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business
Abstract

Immune checkpoint inhibitors (ICIs) are commonly used in patients with advanced non-small cell lung cancer (NSCLC). An unmet need remains for new biomarkers associated with ICIs. In this study, consecutive patients with advanced NSCLC treated with nivolumab or pembrolizumab were included. Plasma at ICIs initiation was prospectively collected and a multiplex ELISA assay testing 48 cytokines and growth factors was performed. Exploratory endpoints were the association between plasma biomarkers with outcome and grade III&ndash, IV immune related adverse events (irAEs). Thirty-five patients were included. Patients without clinical benefit (n = 22) had higher pre-ICI soluble Hepatocyte Growth Factor (sHGF) (210.9 vs. 155.8 pg/mL, p = 0.010), lower pre-ICI soluble Fibroblast Growth Factor (sFGF) (4.0 vs. 4.8 pg/mL, p = 0.043) and lower pre-ICI interleukine-12 (IL-12) (1.3 vs. 2.2 pg/mL, p = 0.043) concentrations. Patients with early progression (n = 23) had higher pre-ICIs sHGF (206.2 vs. 155.8 pg/mL, p = 0.025) concentrations. Patients with low sHGF levels at ICIs initiation had longer progression-free survival and overall survival than those with high sHGF levels: respectively 2.5 vs. 8.0 months (p = 0.002), and 5.5 vs. 35.0 months (p = 0.001). TNF-&alpha, IL-16, IL-12p40 and MCP3 were associated with high grade irAEs. This study shows the potential association between several plasma biomarkers with outcome and grade 3&ndash, 4 IrAEs in advanced NSCLC treated with ICIs.

Published
2020
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39. Sequential ctDNA whole-exome sequencing in advanced lung adenocarcinoma with initial durable tumor response on immune checkpoint inhibitor and late progression

Author

Adrien Costantini, Paul Takam Kamga, Thierry Chinet, Jean-François Emile, Etienne Giroux Leprieur, Simon Garinet, Sylvie Labrune, Alexandre Corjon, Zofia Hélias-Rodzewicz, Coraline Dumenil, Catherine Julie, Violaine Giraud, Jennifer Dumoulin, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Ambroise Paré [AP-HP], Service de pathologie [CHU Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, Lung Neoplasms, Time Factors, DNA Mutational Analysis, Programmed Cell Death 1 Receptor, Pembrolizumab, B7-H1 Antigen, Circulating Tumor DNA, 0302 clinical medicine, biomarkers, tumor, Carcinoma, Non-Small-Cell Lung, Immunology and Allergy, Immune Checkpoint Inhibitors, Lung, Exome sequencing, RC254-282, Clinical/Translational Cancer Immunotherapy, Aged, 80 and over, biology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Middle Aged, Progression-Free Survival, 3. Good health, Nivolumab, 030220 oncology & carcinogenesis, Disease Progression, Molecular Medicine, Adenocarcinoma, Female, Microsatellite Instability, Drug Monitoring, Adult, tumor, medicine.medical_specialty, DNA Copy Number Variations, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, Immune system, Internal medicine, Exome Sequencing, medicine, Humans, PTEN, Lung cancer, Aged, Neoplasm Staging, Retrospective Studies, Pharmacology, business.industry, biomarkers, medicine.disease, 030104 developmental biology, Drug Resistance, Neoplasm, Tumor progression, Mutation, biology.protein, business
Abstract

BackgroundDespite prolonged tumor response to immune checkpoint inhibitors (ICIs) for a subset of patients with advanced non-small cell lung cancer (NSCLC), a secondary resistance will occur for a majority of these patients. The understanding of late progression mechanisms with ICIs is important to improve future treatment strategies.MethodsWe performed whole-exome sequencing (WES) on circulating tumor DNA and compared molecular profiles between the beginning of ICI treatment and tumor progression in patients with advanced NSCLC treated with ICIs and who had initial and prolonged tumor response with secondary progression, after at least 6 months of treatment.ResultsWe identified eight patients who experienced initial and durable tumor response, and secondary tumor progression after 6 months of treatment, with available paired blood samples (diagnosis and progression). All had lung adenocarcinoma, three had programmed-death ligand-1 expression ≥50% in immunohistochemistry and all presented low blood tumor mutational burden (bTMB). Seven patients received nivolumab in second-line or more, and one received pembrolizumab as first-line treatment. WES at progression showed clonal selection with molecular alterations of Wnt pathway-related genes, increase of copy number aberrations in cancer-related genes and loss of tumor-suppressor genes (such as PTEN) or of genes associated with immune response (such as B2M). No difference in term of bTMB was observed at progression.ConclusionsThis is the first study describing putative molecular mechanisms associated with late progression under ICI in lung cancer. Studies on treatment strategies adapted to these mechanisms are needed.

Published
2020
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40. Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with

Author

Sandra, Ortiz-Cuaran, Laura, Mezquita, Aurélie, Swalduz, Mihalea, Aldea, Julien, Mazieres, Camille, Leonce, Cecile, Jovelet, Anne, Pradines, Virginie, Avrillon, Washington R, Chumbi Flores, Ludovic, Lacroix, Yohann, Loriot, Virginie, Westeel, Maud, Ngo-Camus, Claire, Tissot, Christine, Raynaud, Radj, Gervais, Etienne, Brain, Isabelle, Monnet, Etienne, Giroux Leprieur, Caroline, Caramella, Celine, Mahier-Aït Oukhatar, Natalie, Hoog-Labouret, Frank, de Kievit, Karen, Howarth, Clive, Morris, Emma, Green, Luc, Friboulet, Sylvie, Chabaud, Jean-François, Guichou, Maurice, Perol, Benjamin, Besse, Jean-Yves, Blay, Pierre, Saintigny, and David, Planchard

Subjects
Proto-Oncogene Proteins B-raf, Lung Neoplasms, Genomics, Prognosis, Circulating Tumor DNA, Survival Rate, Drug Resistance, Neoplasm, Carcinoma, Non-Small-Cell Lung, Mutation, Biomarkers, Tumor, Humans, Molecular Targeted Therapy, Prospective Studies, Protein Kinase Inhibitors, Follow-Up Studies
Abstract

The limited knowledge on the molecular profile of patients withThis was a prospective study of 78 patients with advancedctDNA sequencing is clinically relevant for the detection of

Published
2020

41. Predictive Value of Soluble PD-1, PD-L1, VEGFA, CD40 Ligand and CD44 for Nivolumab Therapy in Advanced Non-Small Cell Lung Cancer: A Case-Control Study

Author

Jérôme Alexandre, Jennifer Arrondeau, Marie Wislez, Etienne Giroux-Leprieur, Audrey Mansuet-Lupo, Diane Damotte, Audrey Thomas-Schoemann, F. Goldwasser, Michel Vidal, Camille Tlemsani, Nihel Khoudour, Pascaline Boudou-Rouquette, Elizabeth Fabre, Benoit Blanchet, Marco Alifano, Manuela Tiako Meyo, Anne Jouinot, Karen Leroy, and Hélène Blons

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, NSCLC, lcsh:RC254-282, Article, 03 medical and health sciences, Immune checkpoint inhibitors, 0302 clinical medicine, Internal medicine, PD-L1, mental disorders, PD-1, Medicine, Epidermal growth factor receptor, Lung cancer, nivolumab, biology, business.industry, CD44, Case-control study, biomarkers, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Vascular endothelial growth factor A, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Biomarker (medicine), Nivolumab, business
Abstract

A large interindividual variability has been observed in anti Programmed cell Death 1 (anti-PD1) therapies efficacy. The aim of this study is to assess the correlation of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1), Vascular Endothelial Growth Factor A (VEGFA), soluble CD40 ligand (sCD40L) and soluble CD44 (sCD44), with survival in nivolumab-treated metastatic non-small cell lung cancer (NSCLC) patients. Plasma biomarkers were assayed at baseline and after two cycles of nivolumab. A cut-off of positivity for sPD-1, sPD-L1 and sCD40L expressions was defined as a plasma level above the lower limit of quantification. Baseline sPD-1 and sPD-L1 levels were subsequently analyzed in a control group of EGFR-mutated (Epidermal Growth Factor Receptor) NSCLC patients. Association between survival and biomarkers was investigated using Cox proportional hazard regression model. Eighty-seven patients were included (51 nivolumab-treated patients, 36 in EGFR-mutated group). In nivolumab group, baseline sPD-1, sPD-L1 and sCD40L were positive for 15(29.4%), 27(52.9%) and 18(50%) patients, respectively. We defined a composite criteria (sCombo) corresponding to sPD-1 and/or sPD-L1 positivity for each patient. In nivolumab group, baseline sCombo positivity was associated with shorter median progression-free survival (PFS) (78 days 95%CI (55&ndash, 109) vs. 658 days (222-not reached), HR: 4.12 (1.95&ndash, 8.71), p = 0.0002) and OS (HR: 3.99(1.63&ndash, 9.80), p = 0.003). In multivariate analysis, baseline sCombo independently correlated with PFS (HR: 2.66 (1.17&ndash, 6.08), p = 0.02) but not OS. In EGFR-mutated group, all patients were baseline sCombo positive, therefore this factor was not associated with survival. After two cycles of nivolumab, an increased or stable sPD-1 level independently correlated with longer PFS (HR: 0.49, 95%CI (0.30&ndash, 0.80), p = 0.004) and OS (HR: 0.39, 95%CI (0.21&ndash, 0.71), p = 0.002). VEGFA, sCD40L and sCD44 did not correlate with survival. We propose a composite biomarker using sPD-1and sPDL-1 to predict nivolumab efficacy in NSCLC patients. A larger validation study is warranted.

Published
2020
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42. Immune Checkpoint Inhibitors Rechallenge Efficacy in Non-Small-Cell Lung Cancer Patients

Author

Chantal Decroisette, Etienne Giroux Leprieur, Olivier Molinier, Elisa Gobbini, Catherine Dubos, Denis Moro-Sibilot, Eric Dansin, Jean-Baptiste Assié, Dahna Coupez, Remi Veillon, Boris Duchemann, Anne Claire Toffart, Valérie Gounant, Nouha Chaabane, Matteo Giaj Levra, Laura Mezquita, François-Roger Vanel, Virginie Westeel, Youssef Oulkhouir, Vincent Alcazer, Michael Duruisseaux, A. Canellas, Fabrice Barlesi, Maurice Pérol, Myriam Delaunay, Florian Guisier, Pierre Fournel, Hélène Babey, and Catherine Daniel

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Multivariate analysis, Lung Neoplasms, Adenocarcinoma of Lung, Disease, 03 medical and health sciences, 0302 clinical medicine, Interquartile range, Internal medicine, Carcinoma, Non-Small-Cell Lung, medicine, Humans, Lung cancer, Immune Checkpoint Inhibitors, Aged, Retrospective Studies, Performance status, business.industry, Middle Aged, medicine.disease, Prognosis, Confidence interval, Discontinuation, Survival Rate, 030104 developmental biology, 030220 oncology & carcinogenesis, Toxicity, Retreatment, Carcinoma, Squamous Cell, Female, business, Follow-Up Studies
Abstract

Background Immune checkpoint inhibitor (ICPi) rechallenge could represent an attractive option in non–small-cell lung cancer (NSCLC), yet no sufficient data supporting this strategy are available. This retrospective observational multicenter national study explored the efficacy of anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) rechallenge in advanced NSCLC patients, looking for potential clinical features associated with greater outcomes. Patients and Methods We retrospectively collected data from 144 advanced NSCLC patients whose disease was rechallenged with ICPis after ≥ 12 weeks of discontinuation. The progression-free survival (PFS) and overall survival (OS) were calculated from first or second ICPi initiation to disease progression (PFS1 and PFSR, respectively), death, or last follow-up (OS1, OSR), respectively. Results The median (interquartile range) age was 63 (58-70) years. Most patients were male (67%) and smokers (87%). Most had adenocarcinomas (62%) and/or stage IV disease at diagnosis (66%). The best response at rechallenge was not associated with that under the first ICPi (P = 1.10−1). The median (95% confidence interval) PFS1 and PFSR were 13 (10-16.5) and 4.4 (3-6.5) months, respectively. The median (95% confidence interval) OS1 and OSR were 3.3 (2.9-3.9) and 1.5 (1.0-2.1) years, respectively. Longer PFSR and OSR were found in patients discontinuing first ICPi because of toxicity or clinical decision, those not receiving systemic treatment between the two ICPis, and those with good Eastern Cooperative Oncology Group performance status at rechallenge. Only performance status proved to affect outcomes at multivariate analysis. Conclusion Patients discontinuing first ICPi because of toxicity or clinical decision, those able to maintain a treatment-free period, and those with good performance status may be potential candidates for rechallenge.

Published
2020

43. Paclitaxel–bevacizumab combination in advanced non-squamous non-small-cell lung cancer (NSCLC): AVATAX, a retrospective multicentric study

Author

Geoffroy Bilger, Anne-Claire Toffart, Marie Darrason, Michaël Duruisseaux, Lucie Ulmer, Pascal Wang, Etienne Giroux Leprieur, Nicolas Girard, Marie Ange Massiani, Paul Bore, Renaud Descourt, Julian Pinsolle, Solene Valery, Isabelle Monnet, Aurélie Swalduz, Claire Tissot, Pierre Fournel, Anne Baranzelli, Alexis B. Cortot, and Chantal Decroisette

Subjects
Oncology
Abstract

Introduction: Compared with docetaxel, the phase-III trial, ULTIMATE, showed a significant improvement of progression-free survival (PFS) with paclitaxel–bevacizumab combination (PB) as second- or third-line treatment in advanced non-small cell lung cancer (NSCLC). With the increase of immunotherapy treatment in first-line settings, the optimal treatment after first-line failure must be redefined. Methods: This multicentric retrospective study identified all advanced NSCLC patients treated with PB as second-line therapy and beyond. The main efficacy outcomes assessed were objective response rate (ORR), disease control rate (DCR), PFS, and overall survival (OS). The adverse events were reported according to Common Terminology Criteria for Adverse Events (CTCAE). Results: From January 2010 to February 2020, 314 patients in 16 centers received the PB combination. Most patients were male (55%), with a median age of 60 years (19–82), 95% had adenocarcinoma, 27% had a performance status ⩾2, 45% had brain metastases at the time of inclusion. They mostly received the PB combination either in second (20%) or in third-line (39%), and 28% were treated just after ICI failure. ORR and DCR were 40% and 77%, respectively; median PFS and OS were 5.7 [interquartile range (IQR): 3.2–9.6] and 10.8 [IQR: 5.3–19.6] months, respectively. All grade adverse events concerned 82% of patients, including 53% asthenia and 39% neurotoxicity, and 25% of patients continued monotherapy (mostly with bevacizumab) alone due to toxicity. Median PFS for patients treated after ICI failure (ICI+) was significantly superior compared with those not previously treated with ICI (ICI−): 7.0 [IQR: 4.2–11.0] versus 5.2 [IQR: 2.9–8.8] months, p = 0.01, without statistically significant difference for OS between these two groups. In multivariate analysis, factors associated with superior PFS were previous ICI treatment and performance status of 0–1. Only a performance status of 0–1 was associated with superior OS. Conclusion: PB combination as second-line treatment or beyond for advanced non-squamous NSCLC had acceptable toxicity and a clinically relevant efficacy and is an option as salvage treatment for these patients, more particularly after ICI progression.

Published
2022
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44. Validity of Targeted Next-Generation Sequencing in Routine Care for Identifying Clinically Relevant Molecular Profiles in Non–Small-Cell Lung Cancer

Author

Pierre Laurent-Puig, Véronique Giraudet, Alice Guyard, Anne Tallet, Françoise Le Pimpec-Barthes, Etienne Giroux-Leprieur, William Digan, Catherine Julié, Bastien Rance, Hélène Blons, Jean Pastre, Antoine Legras, Alain Cazier, Véronique Duchatelle, Nicolas Pécuchet, Stéphane Jouveshomme, Laure Gibault, Elizabeth Fabre, and Marc Barritault

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Mutation, business.industry, STK11, medicine.disease, medicine.disease_cause, DNA sequencing, Pathology and Forensic Medicine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, TaqMan, Molecular Medicine, KRAS, Non small cell, Lung cancer, business, Routine care
Abstract

Theranostic assays are based on single-gene testing, but the ability of next-generation sequencing (NGS) to interrogate numerous genetic alterations will progressively replace single-gene assays. Although NGS was evaluated to screen for theranostic mutations, its usefulness in clinical practice on large series of samples remains to be demonstrated. NGS performance was assessed following guidelines. TaqMan probes and NGS were compared for their ability to detect EGFR and KRAS mutations, and NGS mutation profiles were analyzed on a large series of non–small-cell lung cancers (n = 1343). The R2 correlation between expected and measured allelic ratio, using commercial samples, was >0.96. Mutation detection threshold was 2% for 10 ng of DNA input. κ Scores for TaqMan versus NGS were 0.99 (95% CI, 0.97–1.00) for EGFR and 0.98 (95% CI, 0.97–1.00) for KRAS after exclusion of rare EGFR (n = 40) and KRAS (n = 60) mutations. NGS identified 693 and 292 mutations in validated and potential oncogenic drivers, respectively. Significant associations were found between EGFR and PI3KCA or CTNNB1 and between KRAS and STK11. Potential oncogenic driver mutations or gene amplifications were more frequent in validated oncogenic driver nonmutated samples. This work is a proof of concept that targeted NGS is accessible in routine screening, including large screening, at reasonable cost. Clinical data should be collected and implemented in specific databases to make molecular data meaningful for direct patients' benefit.

Published
2018
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45. Molecular characterization of circulating tumor cells in lung cancer: moving beyond enumeration

Author

Violaine Giraud, Biao He, Coraline Dumenil, Sylvie Labrune, Catherine Julié, Jennifer Dumoulin, Jean-François Emile, Thierry Chinet, Etienne Giroux Leprieur, and Lei Wang

Subjects
0301 basic medicine, Review, circulating tumor cells, Tumor heterogeneity, 03 medical and health sciences, 0302 clinical medicine, Circulating tumor cell, molecular diagnosis, medicine, Lung cancer, Predictive marker, business.industry, Optimal treatment, Early disease, medicine.disease, Molecular diagnostics, lung cancer, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Immunology, Cancer research, prognosis, Non small cell, business, predictive marker
Abstract

Molecular characterization of tumor cells is a key step in the diagnosis and optimal treatment of lung cancer. However, analysis of tumor samples, often corresponding to small biopsies, can be difficult and does not accurately reflect tumor heterogeneity. Recent studies have shown that isolation of circulating tumor cells (CTCs) is feasible in non-small cell lung cancer patients, even at early disease stages. The amount of CTCs corresponds to the metastatic potential of the tumor and to patient prognosis. Moreover, molecular analyses, even at the single-cell level, can be performed on CTCs. This review describes the technologies currently available for detecting and capturing CTCs, the potential for downstream molecular diagnostics, and the clinical applications of CTCs isolated from lung cancer patients as screening, prognostic, and predictive tools. Main limitations of CTCs are also discussed.

Published
2017
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46. Membrane-bound full-length Sonic Hedgehog identifies cancer stem cells in human non-small cell lung cancer

Author

Bhairavi Tolani, Biao He, Changli Wang, Marie Wislez, Fleur Leguay, Hui Li, Hsin Hui Tseng, Il-Jin Kim, David M. Jablons, Luis A. Acevedo, Joy Q. Jin, Ngoc T. Hoang, Dongsheng Yue, and Etienne Giroux Leprieur

Subjects
0301 basic medicine, animal structures, cancer stem cells (CSCs), Population, non-small cell lung cancer (NSCLC), chemo-resistance, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, Sonic Hedgehog (Shh), In vivo, Cancer stem cell, medicine, GDC0449, Sonic hedgehog, education, education.field_of_study, biology, Chemistry, medicine.disease, In vitro, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, embryonic structures, biology.protein, Cancer research, Antibody, Research Paper
Abstract

The mechanism of Sonic Hedgehog (Shh) pathway activation in non-small cell lung cancer (NSCLC) is poorly described. Using an antibody against the Shh C-terminal domain, we found a small population of Shh-positive (Shh+) cells in NSCLC cells. The objective of this study was to characterize these Shh+ cells. Shh+ and Shh- cells were sorted by using Fluorescence Activated Cell Sorting (FACS) on 12 commercial NSCLC cell lines. Functional analyses on sorted cells were performed with gene expression assays (qRT-PCR and microarray) and cells were treated with cytotoxic chemotherapy and a targeted inhibitor of Shh signaling (GDC0449). We used in vivo models of nude mice inoculated with Shh+ and Shh- sorted cells and drug-treated cells. Finally, we confirmed our results in fresh human NSCLC samples (n=48) paired with normal lung tissue. We found that Shh+ cells produced an uncleaved, full-length Shh protein detected on the membranes of these cells. Shh+ cells exerted a paracrine effect on Shh- cells, inducing their proliferation and migration. Shh+ cells were chemo-resistant and showed features of cancer stem cells (CSCs) in vitro and in vivo. Pharmacological inhibition of the Shh pathway suppressed their CSC features. A high percentage of Shh+ cells was associated with poor prognosis in early-stage NSCLC patients. In conclusion, we describe for the first time the presence of an abnormal membrane-bound full-length Shh protein in human cancer cells that allows the identification of CSCs in vitro and in vivo.

Published
2017
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47. Immunotherapy revolutionises non-small-cell lung cancer therapy: Results, perspectives and new challenges

Author

Sylvie Labrune, Jennifer Dumoulin, Thierry Chinet, Etienne Giroux Leprieur, C. Julié, Coraline Dumenil, and Violaine Giraud

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, medicine.medical_treatment, Docetaxel, Pembrolizumab, Antibodies, Monoclonal, Humanized, B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Atezolizumab, Carcinoma, Non-Small-Cell Lung, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Lung cancer, Clinical Trials as Topic, Chemotherapy, business.industry, Hazard ratio, Antibodies, Monoclonal, Immunotherapy, Programmed Cell Death 1 Ligand 2 Protein, medicine.disease, Surgery, Nivolumab, 030104 developmental biology, 030220 oncology & carcinogenesis, Taxoids, business, medicine.drug
Abstract

Immune checkpoint inhibitors (ICIs) are antibodies that target key signalling pathways such as programmed death 1 (PD1)/programmed death-ligands 1 and 2 (PDL1 and PDL2) to improve anti-tumour immune responses. Until recently, nivolumab was the only ICI validated for advanced non-small-cell lung cancer (NSCLC) in a second-line treatment setting. Results from recent phase II and phase III randomised trials testing other ICIs have been presented. In Keynote-024, pembrolizumab, an anti-PD1 antibody, was reported to have great efficacy in the first-line treatment of PDL1 ≥ 50% tumours (30% of screened tumours), with a progression-free survival (PFS, median) of 10.4 months versus 6.0 months with chemotherapy (CT; hazard ratio [HR] = 0.50; 95% confidence interval [95% CI] 0.37–0.68, P < 0.001), overall response rate (ORR) of 45% versus 28% with CT (P = 0.0011), and a 1-year overall survival (OS) of around 70%. In contrast, Checkmate-026 reported that nivolumab failed to show any benefit compared with standard platinum-based CT, with a PFS (median) in the PDL1 ≥ 5% NSCLC group of 4.2 months (nivolumab) versus 5.9 months (CT; HR = 1.15: 95% CI 0.91–1.45, P = 0.25). No benefit was observed in the PDL1 ≥ 50% subgroup. An encouraging report of the efficacy of pembrolizumab in addition to CT in first-line treatment in unselected NSCLC was also presented (Keynote-021) with an ORR of 55% versus 29% with CT alone (P = 0.0016). Atezolizumab, an anti-PDL1 antibody, showed efficacy for second-line treatment compared with docetaxel (OAK phase III study) with an OS (median) of 13.8 months versus 9.6 months with docetaxel. These results suggest a new paradigm for the treatment of advanced NSCLC using pembrolizumab for the first-line treatment of PDL1 ≥ 50% tumours.

Published
2017
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48. Combination of Crizotinib and Osimertinib or Erlotinib Might Overcome MET-Mediated Resistance to EGFR Tyrosine Kinase Inhibitor in EGFR-Mutated Adenocarcinoma

Author

Thierry Chinet, Etienne Giroux-Leprieur, and Coraline Dumenil

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Crizotinib, business.industry, medicine.disease, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, medicine, Cancer research, Adenocarcinoma, Osimertinib, Erlotinib, business, Egfr tyrosine kinase, medicine.drug
Published
2018
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49. Efficacy of Immune Checkpoint Inhibitors in Lung Sarcomatoid Carcinoma

Author

Simon Baldacci, Olivier Molinier, Etienne Giroux-Leprieur, Valérie Gounant, Anne-Marie Ruppert, M. Wislez, Gilles Robinet, Charles Ricordel, Anne-Claire Toffart, Eric Pichon, Bertrand Mennecier, Dorine Templement-Grangerat, Clarisse Audigier-Valette, Julien Mazieres, Charlotte Domblides, Ludovic Doucet, Florian Guisier, Karen Leroy, Nathalie Rabbe, Fabrice Barlesi, Martine Antoine, Maurice Pérol, and Isabelle Monnet

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, Male, medicine.medical_specialty, Lung Neoplasms, medicine.medical_treatment, Clone (cell biology), B7-H1 Antigen, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, PD-L1, medicine, Humans, Prospective Studies, Sarcomatoid carcinoma, Lung cancer, Immune Checkpoint Inhibitors, Lung, Retrospective Studies, biology, business.industry, Lung Sarcomatoid Carcinoma, Carcinoma, Immunotherapy, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, biology.protein, Immunohistochemistry, Nivolumab, business
Abstract

Introduction Immune checkpoint inhibitors (ICIs) have improved cancer prognosis but have not been evaluated specifically in sarcomatoid carcinoma (SC), a rare lung cancer subtype with poor prognosis. As such, our study sought to retrospectively assess the efficacy of ICI in SC. Methods All consecutive patients with centrally confirmed SC treated using ICI as a second-line treatment or beyond between 2011 and 2017 were enrolled. Programmed death-ligand 1 (PD-L1) tumor expression was assessed using immunohistochemistry (SP263 clone) and the tumor mutational burden (TMB) with the Foundation One panel. TMB was considered high if it was greater than or equal to 10 mutations per megabase. Results Overall, 37 patients with SC were evaluated, predominantly men (73%) with a median age of 63.2 years (36.8–79.7) and who were current or former smokers (94.6%). Immunotherapy (nivolumab, 86.5% of cases) was given as a second-line treatment in 54% of the patients and as third-line treatment or beyond in 46% of the patients. The objective response rate was 40.5% and disease control rate was 64.8%, regardless of PD-L1 status. Median overall survival was 12.7 months (range: 0.3–45.7). One-third of patients exhibited early progression. The median PD-L1 expression was 70% (0–100). There was a trend toward higher PD-L1 expression in responsive diseases, with an objective response rate of 58.8% in patients with PD-L1+ and 0% in the one patient with PD-L1- (p = 0.44). The median TMB was 18 (4–39) mutations per megabase, with 87.5% of the cases displaying a high TMB. There was a trend toward higher TMB in responders versus stable or progressive diseases (p = 0.2). Conclusions Patients with SC exhibited high response rates and prolonged overall survival under ICI treatment. These data support the prospective investigation of ICI in patients with SC who are under first-line treatment.

Published
2019

50. Efficacy of osimertinib and histomolecular profile at progression in EGFR-mutated lung cancer

Author

Roger Lacave, Thierry Chinet, Hélène Blons, Ivan Bièche, Nicolas Girard, Jacques Cadranel, Pierre-Olivier Schischmanoff, Valérie Gounant, Sylvie Friard, Cécile Dujon, G. Rousseau-Bussac, Etienne Giroux Leprieur, Boris Duchemann, Nathalie Théou-Anton, Anaïs Pujals, Jean Trédaniel, and Camille Mehlman

Subjects
Oncology, medicine.medical_specialty, business.industry, Internal medicine, medicine, Osimertinib, Lung cancer, medicine.disease, business
Published
2019
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