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1. Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO)

Author

Julien Mazières, Diane Damotte, Virginie Westeel, Gérard Zalcman, Franck Morin, Marie-Ange Massiani, Jalal Assouad, Marie Wislez, Martine Antoine, Armelle Lavole, Olivier Carre, Thomas Egenod, Raffaele Caliandro, Catherine Dubos-Arvis, Gaelle Jeannin, Olivier Molinier, Alexandra Langlais, Francoise Le Pimpec Barthes, Laurent Brouchet, and Bernard Milleron

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background The IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC).Methods In a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable NSCLC received three doses of durvalumab (750 mg every 2 weeks) and underwent surgery between 2 and 14 days after the last infusion. The primary endpoint was the complete surgical resection rate. Secondary endpoints included tumor response rate, major histopathological response (MPR: ≤10% remaining viable tumor cells), disease-free survival (DFS), overall survival (OS), durvalumab-related safety, and 90-day postoperative mortality (NCT03030131).Results Forty-six patients were eligible (median age 60.9 years); 67% were male, 98% were smokers, and 41% had squamous cell carcinoma. Regarding tumor response, 9% had a partial response, 78% had stable disease, and 13% had progressive disease. Among the operated patients (n=43), 41 achieved complete resection (89%, 95% CI 80.1% to 98.1%)), and eight achieved MPR (19%). The 12-month median OS and DFS rates were 89% (95% CI 75.8% to 95.3%) and 78% (95% CI 63.4% to 87.7%), respectively (n=46). The median follow-up was 28.4 months (12.8–41.1). All patients in whom MPR was achieved were disease-free at 12 months compared to only 11% of those with >10% residual tumor cells (p=0.04). No durvalumab-related serious or grade 3–5 events were reported. The unexpected 90-day postoperative mortality of four patients led to premature study termination. None of these four deaths was considered secondary to direct durvalumab-related toxicity.Conclusions Neoadjuvant durvalumab given as monotherapy was associated with an 89% complete resection rate and an MPR of 19%. Despite an unexpectedly high rate of postoperative deaths, which prevented us from completing the trial, we were able to show a significant association between MPR and DFS.

Published
2022
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2. A Recent Advance on Partial Evaporating Organic Rankine Cycle: Experimental Results on an Axial Turbine

Author

Guillaume Lhermet, Nicolas Tauveron, Nadia Caney, Quentin Blondel, and Franck Morin

Subjects
organic Rankine cycle (ORC), partial evaporating organic Rankine cycle (PEORC), wet-to-dry cycle, axial turbine, dry fluid, Technology
Abstract

The organic Rankine cycle (ORC) technology is an efficient way to convert low-grade heat from renewable sources or waste heat for power generation. The partial evaporating organic Rankine cycle (PEORC) can be considered as a promising alternative as it can offer a higher utilization of the heat source. An experimental investigation of a small ORC system used in full or partial evaporation mode is performed. First characterized in superheated mode, which corresponds to standard ORC behavior, a semi-empirical correlative approach involving traditional non-dimensional turbomachinery parameters (specific speed, pressure ratio) can accurately describe one-phase turbine performance. In a second step, two-phase behavior is experimentally investigated. The efficiency loss caused by the two-phase inlet condition is quantified and considered acceptable. The turbine two-phase operation allows for an increase in the amount of recovered heat source. The ability to operate in two phases provides a new degree of flexibility when designing a PEORC. The semi-empirical correlative approach is then completed to take into account the partially evaporated turbine inlet condition. The qualitative description and the quantitative correlations in the one-phase and two-phase modes were applied to different pure working fluids (Novec649TM, HFE7000 and HFE7100) as well as to a zeotropic mixture (Novec649TM/HFE7000).

Published
2022
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3. Outcomes of Patients With Advanced NSCLC From the Intergroupe Francophone de Cancérologie Thoracique Biomarkers France Study by KRAS Mutation Subtypes

Author

Anne-Marie Ruppert, MD, PhD, Michèle Beau-Faller, MD, PhD, Didier Debieuvre, MD, L’Houcine Ouafik, MD, PhD, Virginie Westeel, MD PhD, Isabelle Rouquette, MD, Julien Mazières, MD, PhD, Pierre-Paul Bringuier, MD, Isabelle Monnet, MD, Fabienne Escande, MD, Charles Ricordel, MD, Jean-Philippe Merlio, MD, PDh, Henri Janicot, MD, Antoinette Lemoine, MD, PhD, Pascal Foucher, MD, Michel Poudenx, MD, Franck Morin, MSc, Alexandra Langlais, MSc, Pierre-Jean Souquet, MD, PhD, Fabrice Barlesi, MD, PhD, and Marie Wislez, MD, PhD

Subjects
KRAS mutation, Non–small cell lung cancer, NSCLC, Prognosis, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Introduction: KRAS mutations are detected in 20% to 30% of NSCLC. However, KRAS mutation subtypes may differently influence the outcome of patients with advanced NSCLC. Methods: In the Biomarkers France study, 4894 KRAS mutations (26.2%) were detected in 4634 patients from the 17,664 enrolled patients with NSCLC. Survival and treatment data on noncurative stage III to IV NSCLC were available for 901 patients. First- and second-line treatment effects on progression-free survival and overall survival were analyzed according to the KRAS mutations subtype. Results: Over 95% of patients with KRAS mutation were smokers or former smokers who were white (99.5%), presenting with adenocarcinoma (82.5%). The most common KRAS mutation subtype was G12C (374 patients; 41.5%), followed by G12V (168; 18.6%), G12D (131; 14.5%), G12A (62; 6.9%), G13C (45; 5.0%), G13D (31; 3.4%), and others (10; 1%). Approximately 21% of patients had transition mutation and 68.2% had a transversion mutation. G12D and transition mutations were predominant in never-smokers. The median overall survival for patients with KRAS-mutated NSCLC was 8.1 months (95% confidence interval [CI]: 7.5–9.5), without any differences according to the different KRAS subtypes mutations. The median progression-free survival was 4.6 months (95% CI: 4.2–5.1) for first-line treatment and 4.8 months (95% CI: 4.3–6.8) for second-line treatment, without any differences according to the different KRAS subtypes mutations. Conclusions: KRAS mutation subtypes influenced neither treatment responses nor outcomes. The KRAS G12C mutation was detected in 41.5% of patients, who are now eligible for potent and specific G12C inhibitors.

Published
2020
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4. Development and Validation of a Simplified Prognostic Score in SCLC

Author

Elodie Negre, MD, Amandine Coffy, BSc, Alexandra Langlais, BSc, Jean-Pierre Daures, MD, PhD, Armelle Lavole, MD, Elisabeth Quoix, MD, PhD, Olivier Molinier, MD, Laurent Greillier, MD, PhD, Clarisse Audigier-Valette, MD, Denis Moro-Sibilot, MD, PhD, Virginie Westeel, MD, PhD, Franck Morin, PhD, Benoît Roch, MD, and Jean-Louis Pujol, MD, PhD

Subjects
Small cell lung cancer, Prognosis, Prognostic score, Chemotherapy, Serum markers, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Introduction: This study aimed at generating a new simplified prognostic score (SPS) using common clinical and biological variables to discriminate a limited number of subgroups of patients with SCLC differing by their overall survival (OS). Methods: The SPS was developed exploring the Montpellier University Hospital retrospective database of 401 patients over a 16-year period. All patients had received etoposide - platinum-based chemotherapy as first-line treatment. The SPS development took into account significant determinants of OS in the Cox model, weighted by their regression β coefficients. Validation of the consequent SPS has been done separately in a combined population of 213 patients accrued from two different published trials (NCT03059667 and NCT00930891). Results: The significant independent determinants of OS included the following: (1) American Joint Committee on Cancer TNM stage IV (hazard ratio [HR]: 2.52; 95% confidence interval [CI]: 1.91–3.33); (2) Eastern Cooperative Oncology Group performance status greater than 1 (HR: 2.27; 95% CI: 1.79–2.87); (3) the presence of liver metastases (HR: 1.66; 95% CI: 1.29–2.15); and (4) neutrophil-to-lymphocyte ratio greater than 4 (HR: 1.39; 95% CI: 1.11–1.92). The SPS generated with these four variables, segregated three groups (good, intermediate, and poor prognosis) with respective median OS of 26.9 months (95% CI: 20.1–38.9), 11.5 months (95% CI: 9.8–13.0), and 6.8 months (95% CI: 5.8–8.3; log-rank p < 10–4). Harrell's C statistic estimate was 0.68 ± 0.012, suggesting goodness of calibration. In the validation cohort, the SPS segregated the aforementioned three subgroups in a nearly similar manner, with respective median OS: 27.2, 12.3, and 8.6 months (log-rank p < 10–3; Harrell’s C statistic: 0.58 ± 0.02). Conclusions: The SPS is easy to calculate in real-life practice and efficiently discriminates three populations with different prognoses. This study deserves further validation of this score in patients with SCLC receiving immunochemotherapy.

Published
2020
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5. Circulating Tumor DNA as a Prognostic Determinant in Small Cell Lung Cancer Patients Receiving Atezolizumab

Author

Guillaume Herbreteau, Alexandra Langlais, Laurent Greillier, Clarisse Audigier-Valette, Lionel Uwer, José Hureaux, Denis Moro-Sibilot, Florian Guisier, Delphine Carmier, Jeannick Madelaine, Josiane Otto, Pierre-Jean Souquet, Valérie Gounant, Patrick Merle, Olivier Molinier, Aldo Renault, Audrey Rabeau, Franck Morin, Marc G Denis, and Jean-Louis Pujol

Subjects
SCLC, ctDNA, atezolizumab, mutation, TP53, RB1, Medicine
Abstract

Background: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab. Methods: 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the TP53, RB1, NOTCH1, NOTCH2, and NOTCH3 genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation. Results: We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49; 65.3%) and RB1 (25/49; 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm. Conclusion: ctDNA is strongly associated with the prognosis of SCLC patients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials.

Published
2020
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6. Role of the YAP-1 Transcriptional Target cIAP2 in the Differential Susceptibility to Chemotherapy of Non-Small-Cell Lung Cancer (NSCLC) Patients with Tumor RASSF1A Gene Methylation from the Phase 3 IFCT-0002 Trial

Author

Fatéméh Dubois, Maureen Keller, Julien Hoflack, Elodie Maille, Martine Antoine, Virginie Westeel, Emmanuel Bergot, Elisabeth Quoix, Armelle Lavolé, Laurence Bigay-Game, Jean-Louis Pujol, Alexandra Langlais, Franck Morin, Gérard Zalcman, and Guénaëlle Levallet

Subjects
non-small-cell lung cancer, rassf1a, dna methylation, paclitaxel, iap2, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

RASSF1 gene methylation predicts longer disease-free survival (DFS) and overall survival (OS) in patients with early-stage non-small-cell lung cancer treated using paclitaxel-based neo-adjuvant chemotherapy compared to patients receiving a gemcitabine-based regimen, according to the randomized Phase 3 IFCT (Intergroupe Francophone de Cancérologie Thoracique)-0002 trial. To better understand these results, this study used four human bronchial epithelial cell (HBEC) models (HBEC-3, HBEC-3-RasV12, A549, and H1299) and modulated the expression of RASSF1A or YAP-1. Wound-healing, invasion, proliferation and apoptosis assays were then carried out and the expression of YAP-1 transcriptional targets was quantified using a quantitative polymerase chain reaction. This study reports herein that gemcitabine synergizes with RASSF1A, silencing to increase the IAP-2 expression, which in turn not only interferes with cell proliferation but also promotes cell migration. This contributes to the aggressive behavior of RASSF1A-depleted cells, as confirmed by a combined knockdown of IAP-2 and RASSF1A. Conversely, paclitaxel does not increase the IAP-2 expression but limits the invasiveness of RASSF1A-depleted cells, presumably by rescuing microtubule stabilization. Overall, these data provide a functional insight that supports the prognostic value of RASSF1 gene methylation on survival of early-stage lung cancer patients receiving perioperative paclitaxel-based treatment compared to gemcitabine-based treatment, identifying IAP-2 as a novel biomarker indicative of YAP-1-mediated modulation of chemo-sensitivity in lung cancer.

Published
2019
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7. Study and Evaluation of Innovative Fuel Handling Systems for Sodium-Cooled Fast Reactors: Fuel Handling Route Optimization

Author

Franck Dechelette, Franck Morin, Guy Laffont, Gilles Rodriguez, Emmanuel Sanseigne, Sébastien Christin, Xavier Mognot, and Aurélien Morcillo

Subjects
Electrical engineering. Electronics. Nuclear engineering, TK1-9971
Abstract

The research for technological improvement and innovation in sodium-cooled fast reactor is a matter of concern in fuel handling systems in a view to perform a better load factor of the reactor thanks to a quicker fuelling/defueling process. An optimized fuel handling route will also limit its investment cost. In that field, CEA has engaged some innovation study either of complete FHR or on the optimization of some specific components. This paper presents the study of three SFR fuel handling route fully described and compared to a reference FHR option. In those three FHR, two use a gas corridor to transfer spent and fresh fuel assembly and the third uses two casks with a sodium pot to evacuate and load an assembly in parallel. All of them are designed for the ASTRID reactor (1500 MWth) but can be extrapolated to power reactors and are compatible with the mutualisation of one FHS coupled with two reactors. These three concepts are then intercompared and evaluated with the reference FHR according to four criteria: performances, risk assessment, investment cost, and qualification time. This analysis reveals that the “mixed way” FHR presents interesting solutions mainly in terms of design simplicity and time reduction. Therefore its study will be pursued for ASTRID as an alternative option.

Published
2014
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8. Supplementary Table 1 from High TUBB3 Expression, an Independent Prognostic Marker in Patients with Early Non–Small Cell Lung Cancer Treated by Preoperative Chemotherapy, Is Regulated by K-Ras Signaling Pathway

Author

Gérard Zalcman, Jacques Camonis, Denis Moro-Sibilot, Jean-Louis Pujol, Isabelle Rouquette, Fatéméh Dubois, Didier Debieuvre, Elisabeth Quoix, Marie Wislez, Virginie Westeel, Franck Morin, Jérôme Levallet, Elisabeth Brambilla, Florence de Fraipont, Michelle Beau-Faller, Adriana O. Santos, Christian Creveuil, Martine Antoine, Emmanuel Bergot, and Guénaëlle Levallet

Abstract

PDF file - 56K

Published
2023

9. Data from High TUBB3 Expression, an Independent Prognostic Marker in Patients with Early Non–Small Cell Lung Cancer Treated by Preoperative Chemotherapy, Is Regulated by K-Ras Signaling Pathway

Author

Gérard Zalcman, Jacques Camonis, Denis Moro-Sibilot, Jean-Louis Pujol, Isabelle Rouquette, Fatéméh Dubois, Didier Debieuvre, Elisabeth Quoix, Marie Wislez, Virginie Westeel, Franck Morin, Jérôme Levallet, Elisabeth Brambilla, Florence de Fraipont, Michelle Beau-Faller, Adriana O. Santos, Christian Creveuil, Martine Antoine, Emmanuel Bergot, and Guénaëlle Levallet

Abstract

We assessed the prognostic and predictive value of β-tubulin III (TUBB3) expression, as determined by immunohistochemistry, in 412 non–small cell lung cancer (NSCLC) specimens from early-stage patients who received neoadjuvant chemotherapy (paclitaxel- or gemcitabine-based) in a phase III trial (IFCT-0002). We also correlated TUBB3 expression with K-Ras and EGF receptor (EGFR) mutations in a subset of 208 cryopreserved specimens. High TUBB3 protein expression was associated with nonsquamous cell carcinomas (P < 0.001) and K-Ras mutation (P < 0.001). The 127 (30.8%) TUBB3-negative patients derived more than 1 year of overall survival advantage, with more than 84 months median overall survival versus 71.7 months for TUBB3-positive patients [HR, 1.58; 95% confidence interval (CI), 1.11–2.25)]. This prognostic value was confirmed in multivariate analysis (adjusted HR for death, 1.51; 95% CI, 1.04–2.21; P = 0.031) with a bootstrapping validation procedure. TUBB3 expression was associated with nonresponse to chemotherapy (adjusted HR, 1.31; 95% CI, 1.01–1.70; P = 0.044) but had no predictive value (taxane vs. gemcitabine). Taking account of these clinical findings, we further investigated TUBB3 expression in isogenic human bronchial cell lines only differing by K-Ras gene status and assessed the effect of K-Ras short interfering RNA (siRNA) mediated depletion, cell hypoxia, or pharmacologic inhibitors of K-Ras downstream effectors, on TUBB3 protein cell content. siRNA K-Ras knockdown, inhibition of RAF/MEK (MAP–ERK kinase) and phosphoinositide 3-kinase (PI3K)/AKT signaling, and hypoxia were shown to downregulate TUBB3 expression in bronchial cells. This study is the first one to identify K-Ras mutations as determinant of TUBB3 expression, a chemoresistance marker. Our in vitro data deserve studies combining standard chemotherapy with anti-MEK or anti-PI3K drugs in patients with TUBB3-overexpressing tumors. Mol Cancer Ther; 11(5); 1203–13. ©2012 AACR.

Published
2023

10. Supplementary Figure 3 from High TUBB3 Expression, an Independent Prognostic Marker in Patients with Early Non–Small Cell Lung Cancer Treated by Preoperative Chemotherapy, Is Regulated by K-Ras Signaling Pathway

Author

Gérard Zalcman, Jacques Camonis, Denis Moro-Sibilot, Jean-Louis Pujol, Isabelle Rouquette, Fatéméh Dubois, Didier Debieuvre, Elisabeth Quoix, Marie Wislez, Virginie Westeel, Franck Morin, Jérôme Levallet, Elisabeth Brambilla, Florence de Fraipont, Michelle Beau-Faller, Adriana O. Santos, Christian Creveuil, Martine Antoine, Emmanuel Bergot, and Guénaëlle Levallet

Abstract

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

Published
2023

11. Supplementary Figure Legends 1-5 from High TUBB3 Expression, an Independent Prognostic Marker in Patients with Early Non–Small Cell Lung Cancer Treated by Preoperative Chemotherapy, Is Regulated by K-Ras Signaling Pathway

Author

Gérard Zalcman, Jacques Camonis, Denis Moro-Sibilot, Jean-Louis Pujol, Isabelle Rouquette, Fatéméh Dubois, Didier Debieuvre, Elisabeth Quoix, Marie Wislez, Virginie Westeel, Franck Morin, Jérôme Levallet, Elisabeth Brambilla, Florence de Fraipont, Michelle Beau-Faller, Adriana O. Santos, Christian Creveuil, Martine Antoine, Emmanuel Bergot, and Guénaëlle Levallet

Abstract

PDF file - 64K

Published
2023

12. Supplementary Figure 1 from High TUBB3 Expression, an Independent Prognostic Marker in Patients with Early Non–Small Cell Lung Cancer Treated by Preoperative Chemotherapy, Is Regulated by K-Ras Signaling Pathway

Author

Gérard Zalcman, Jacques Camonis, Denis Moro-Sibilot, Jean-Louis Pujol, Isabelle Rouquette, Fatéméh Dubois, Didier Debieuvre, Elisabeth Quoix, Marie Wislez, Virginie Westeel, Franck Morin, Jérôme Levallet, Elisabeth Brambilla, Florence de Fraipont, Michelle Beau-Faller, Adriana O. Santos, Christian Creveuil, Martine Antoine, Emmanuel Bergot, and Guénaëlle Levallet

Abstract

PDF file - 60K, Flow-Chart

Published
2023

13. Supplementary Figure 5 from High TUBB3 Expression, an Independent Prognostic Marker in Patients with Early Non–Small Cell Lung Cancer Treated by Preoperative Chemotherapy, Is Regulated by K-Ras Signaling Pathway

Author

Gérard Zalcman, Jacques Camonis, Denis Moro-Sibilot, Jean-Louis Pujol, Isabelle Rouquette, Fatéméh Dubois, Didier Debieuvre, Elisabeth Quoix, Marie Wislez, Virginie Westeel, Franck Morin, Jérôme Levallet, Elisabeth Brambilla, Florence de Fraipont, Michelle Beau-Faller, Adriana O. Santos, Christian Creveuil, Martine Antoine, Emmanuel Bergot, and Guénaëlle Levallet

Abstract

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

Published
2023

14. Supplementary Figure 4 from High TUBB3 Expression, an Independent Prognostic Marker in Patients with Early Non–Small Cell Lung Cancer Treated by Preoperative Chemotherapy, Is Regulated by K-Ras Signaling Pathway

Author

Gérard Zalcman, Jacques Camonis, Denis Moro-Sibilot, Jean-Louis Pujol, Isabelle Rouquette, Fatéméh Dubois, Didier Debieuvre, Elisabeth Quoix, Marie Wislez, Virginie Westeel, Franck Morin, Jérôme Levallet, Elisabeth Brambilla, Florence de Fraipont, Michelle Beau-Faller, Adriana O. Santos, Christian Creveuil, Martine Antoine, Emmanuel Bergot, and Guénaëlle Levallet

Abstract

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

Published
2023

15. Data Supplement from Noninvasive Diagnosis of Actionable Mutations by Deep Sequencing of Circulating Free DNA in Lung Cancer from Never-Smokers: A Proof-of-Concept Study from BioCAST/IFCT-1002

Author

Pierre-Jean Souquet, Magali Olivier, Gérard Zalcman, Franck Morin, Pascale Missy, James McKay, Florence Le Calvez-Kelm, Maxime Vallee, Bernard Duvert, Pascal Foucher, Sébastien Larivé, Jacques Margery, Michel Vincent, Nathalie Prim, Radj Gervais, Laurent Guilleminault, Jean Trédaniel, Nicolas Girard, Hélène Blanché, Tibor Schuster, Javier Oliver, Stéphanie Villar, Felipe Vaca-Paniagua, and Sébastien Couraud

Abstract

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

Published
2023

16. Supplementary Methods, Figures 1-2, Figure 4, Tables 1-5 from An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial

Author

Gérard Zalcman, Bernard Milleron, Franck Morin, Denis Moro-Sibilot, Pierre Hainaut, Elisabeth Brambilla, Elisabeth Quoix, Virginie Westeel, Denis Braun, Didier Debieuvre, Marie-Christine Favrot, Isabelle Rouquette, Martine Antoine, Nicolas Richard, Mounia Mounawar, Michèle Beau-Faller, Emmanuel Bergot, Christian Creveuil, Guénaëlle Levallet, and Florence de Fraipont

Abstract

PDF file - 344K, Supplementary methods, suppl. Figure 1 with with the specimens flow-chart, suppl. Figure 2 with the diagram of the clinical trial IFCT 0002 and sampling timepoints, suppl. Figure 4 with RASSF1A interactome, suppl. Table 1 & 2 with primers used in the study, suppl. Table 3 with all the molecular analyses in the bio-IFCT 0002 study, suppl. Table 4 comparing patients with or without molecular analyses, suppl. Table 5 with all the HRs and p-values forthe molecular and clinical variables in the final prognostic analysis

Published
2023

17. 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

18. 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

19. Data from Health-Related Quality of Life Impact from Adding Bevacizumab to Cisplatin-Pemetrexed in Malignant Pleural Mesothelioma in the MAPS IFCT-GFPC-0701 Phase III Trial

Author

Virginie Westeel, Gérard Zalcman, Franck Morin, Emilie Charton, Chrystelle Locher, Radj Gervais, Henri Janicot, Valérie Gounant, Isabelle Monnet, Frédéric Rivière, Hervé Léna, Olivier Molinier, Denis Moro-Sibilot, Clarisse Audigier-Valette, Laurent Greillier, Jacques Margery, Julien Mazieres, Arnaud Scherpereel, Amélie Anota, and Guillaume Eberst

Abstract

Purpose:The IFCT-GFPC-0701 MAPS phase III trial highlighted significant improvement in overall survival from adding bevacizumab to the standard first-line chemotherapy regimen [cisplatin plus pemetrexed (PC)] in advanced malignant pleural mesothelioma (MPM). We present the results of health-related quality of life (HRQoL), a secondary endpoint of MAPS.Patients and Methods:HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire QLQ-C30 and the lung cancer–specific module QLQ-LC13 at randomization and then every 9 weeks until disease progression.HRQoL deterioration–free survival (QFS), used to analyze longitudinal HRQoL data, was defined as the interval between randomization and the occurrence of the first clinically relevant definitive deterioration compared with the HRQoL score at baseline, or death.Results:A total of 448 patients were included in the MAPS trial between 2008 and 2014. At baseline, 425 patients (94.8%) completed the HRQoL questionnaire. We report that adding bevacizumab to cisplatin and pemetrexed (PCB) significantly improved QFS for the peripheral neuropathy dimension, with a median QFS of 12.09 months [95% confidence interval (CI), 9.59–13.67] in the PCB arm versus 7.59 months (95% CI, 6.57–8.61) in the PC arm [HR (PCB vs. PC) = 0.74; 95% CI, 0.61–0.91; P = 0.004]. QFS was also longer in the PCB arm for the pain dimension (HR = 0.84; 95% CI, 0.69–1.02; P = 0.08).Conclusions:This study demonstrated that adding bevacizumab to standard chemotherapy in patients with advanced MPM had no negative impact on HRQoL. A significant improvement in the peripheral neuropathy and pain HRQoL dimensions was even observed.

Published
2023

20. Acknowledgements List from An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial

Author

Gérard Zalcman, Bernard Milleron, Franck Morin, Denis Moro-Sibilot, Pierre Hainaut, Elisabeth Brambilla, Elisabeth Quoix, Virginie Westeel, Denis Braun, Didier Debieuvre, Marie-Christine Favrot, Isabelle Rouquette, Martine Antoine, Nicolas Richard, Mounia Mounawar, Michèle Beau-Faller, Emmanuel Bergot, Christian Creveuil, Guénaëlle Levallet, and Florence de Fraipont

Abstract

PDF file - 21K, Acknowledegements to IFCT staff (administrative and CRAs), to expert pathological panel, and list of investigators of the phase 3 clinical trial IFCT 0002

Published
2023

21. Data from Noninvasive Diagnosis of Actionable Mutations by Deep Sequencing of Circulating Free DNA in Lung Cancer from Never-Smokers: A Proof-of-Concept Study from BioCAST/IFCT-1002

Author

Pierre-Jean Souquet, Magali Olivier, Gérard Zalcman, Franck Morin, Pascale Missy, James McKay, Florence Le Calvez-Kelm, Maxime Vallee, Bernard Duvert, Pascal Foucher, Sébastien Larivé, Jacques Margery, Michel Vincent, Nathalie Prim, Radj Gervais, Laurent Guilleminault, Jean Trédaniel, Nicolas Girard, Hélène Blanché, Tibor Schuster, Javier Oliver, Stéphanie Villar, Felipe Vaca-Paniagua, and Sébastien Couraud

Abstract

Purpose: Tumor somatic mutation analysis is part of the standard management of metastatic lung cancer. However, physicians often have to deal with small biopsies and consequently with challenging mutation testing. Circulating free DNA (cfDNA) is a promising tool for accessing the tumor genome as a liquid biopsy. Here, we evaluated next-generation sequencing (NGS) on cfDNA samples obtained from a consecutive series of patients for the screening of a range of clinically relevant mutations.Experimental Design: A total of 107 plasma samples were collected from the BioCAST/IFCT-1002 lung cancer study (never-smokers cohort). Matched tumor DNA (tDNA) was obtained for 68 cases. Multiplex PCR-based assays were designed to target specific coding regions in EGFR, KRAS, BRAF, ERBB2, and PI3KCA genes, and amplicon sequencing was performed at deep coverage on the cfDNA/tDNA pairs using the NGS IonTorrent Personal Genome Machine Platform.Results: CfDNA concentration in plasma was significantly associated with both stage and number of metastatic sites. In tDNA, 50 mutations (36 EGFR, 5 ERBB2, 4 KRAS, 3 BRAF, and 2 PIK3CA) were identified, of which 26 were detected in cfDNA. Sensitivity of the test was 58% (95% confidence interval, 43%–71%) and the estimated specificity was 87% (62%–96%).Conclusion: These data demonstrate the feasibility and potential utility of mutation screening in cfDNA using IonTorrent NGS for the detection of a range of tumor biomarkers in patients with metastatic lung cancer. Clin Cancer Res; 20(17); 4613–24. ©2014 AACR.

Published
2023

22. Supplementary Data 1 from Health-Related Quality of Life Impact from Adding Bevacizumab to Cisplatin-Pemetrexed in Malignant Pleural Mesothelioma in the MAPS IFCT-GFPC-0701 Phase III Trial

Author

Virginie Westeel, Gérard Zalcman, Franck Morin, Emilie Charton, Chrystelle Locher, Radj Gervais, Henri Janicot, Valérie Gounant, Isabelle Monnet, Frédéric Rivière, Hervé Léna, Olivier Molinier, Denis Moro-Sibilot, Clarisse Audigier-Valette, Laurent Greillier, Jacques Margery, Julien Mazieres, Arnaud Scherpereel, Amélie Anota, and Guillaume Eberst

Abstract

Table 1

Published
2023

23. Supplementary Table 3 from An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial

Author

Gérard Zalcman, Bernard Milleron, Franck Morin, Denis Moro-Sibilot, Pierre Hainaut, Elisabeth Brambilla, Elisabeth Quoix, Virginie Westeel, Denis Braun, Didier Debieuvre, Marie-Christine Favrot, Isabelle Rouquette, Martine Antoine, Nicolas Richard, Mounia Mounawar, Michèle Beau-Faller, Emmanuel Bergot, Christian Creveuil, Guénaëlle Levallet, and Florence de Fraipont

Abstract

PDF file - 205K, Correlation between RASSF1 promoter gene methylation and RASSF1A protein expression by immunoblotting

Published
2023

24. Data from An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial

Author

Gérard Zalcman, Bernard Milleron, Franck Morin, Denis Moro-Sibilot, Pierre Hainaut, Elisabeth Brambilla, Elisabeth Quoix, Virginie Westeel, Denis Braun, Didier Debieuvre, Marie-Christine Favrot, Isabelle Rouquette, Martine Antoine, Nicolas Richard, Mounia Mounawar, Michèle Beau-Faller, Emmanuel Bergot, Christian Creveuil, Guénaëlle Levallet, and Florence de Fraipont

Abstract

Purpose: To evaluate prognostic and predictive molecular biomarkers in early-stage non–small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy.Experimental Design: The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes.Results: RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR = 1.88, 95% CI: 1.25–2.82, P = 0.0048) and shorter median overall survival (OS; adjusted HR = 2.01, 95% CI: 1.26–3.20, P = 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death = 3.85, 95% CI: 1.79–6.40) to more than 84 months for moderate (HR = 1.85, 95% CI: 0.97–3.52) and low-risk patients (reference group; P = 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR = 0.47, 95% CI: 0.23–0.97, Pinteraction = 0.042).Conclusions: Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC. Clin Cancer Res; 18(10); 2976–86. ©2012 AACR.

Published
2023

25. A defect of amphiregulin release predicted longer survival independently of <scp>YAP</scp> expression in patients with pleural mesothelioma in the <scp>IFCT</scp> ‐0701 <scp>MAPS</scp> phase 3 trial

Author

Elodie Maille, Jérôme Levallet, Fatéméh Dubois, Martine Antoine, Claire Danel, Christian Creveuil, Julien Mazieres, Jacques Margery, Laurent Greillier, Valérie Gounant, Denis Moro‐Sibilot, Olivier Molinier, Hervé Léna, Isabelle Monnet, Emmanuel Bergot, Alexandra Langlais, Franck Morin, Arnaud Scherpereel, Gérard Zalcman, and Guénaëlle Levallet

Subjects
Cancer Research, Oncology
Published
2022

26. Tailoring maintenance chemotherapy upon response to induction chemotherapy as compared with pemetrexed continuation maintenance in advanced non-squamous NSCLC patients: Results of the IFCT-GFPC-1101 multicenter randomized phase III trial

Author

Alexis B. Cortot, Didier Debieuvre, L. Moreau, Radj Gervais, Jacques Margery, Julien Mazieres, Olivier Molinier, Michel Poudenx, Alexandra Langlais, Nicolas Girard, Patrick Dumont, Gérard Zalcman, Franck Morin, Virginie Westeel, Pierre-Jean Souquet, Eric Pichon, Fabrice Barlesi, Maurice Pérol, Jérôme Dauba, Jacques Cadranel, Clarisse Audigier-Valette, and Denis Moro-Sibilot

Subjects
Adult, Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Adolescent, Pemetrexed, Maintenance Chemotherapy, Young Adult, Carcinoma, Non-Small-Cell Lung, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Aged, Maintenance chemotherapy, business.industry, Induction chemotherapy, Induction Chemotherapy, Middle Aged, Treatment Outcome, Non squamous, Cisplatin, business, medicine.drug
Abstract

Benefit from maintenance in advanced non-squamous non-small cell lung cancer (NS-NSCLC) might favor switch maintenance after disease stabilization (SD) and continuation after objective response (OR). This trial assessed a maintenance strategy conditioned by response to cisplatin-gemcitabine (CG) with G continuation for patients with OR or switch to pemetrexed (P) for patients with SD as compared with a control arm based on the Paramount regimen.Eligibility criteria: age 18-70 years, ECOG PS 0-1, untreated stage IV NS-NSCLC without EGFR or ALK alteration, ineligibility to bevacizumab. Patients were randomized 1:1 to receive either CG (4 cycles) followed by G maintenance in case of OR followed by P at progression, or switch to P for patients with SD, or 4 cycles of CP followed by P (control arm). Primary endpoint: overall Survival.Between 2012 and 2016, 932 patients were randomized (CG: 467, CP: 465) with well-balanced characteristics. 257 patients (56.7%) in the CG arm received maintenance (G: 142, P: 113) versus 277 patients (59.7%) in the CP arm. Median number of maintenance cycles was 5 for G and P (CG induction) and 4 for P (CP induction). OS adjusted HR was 0.97 (95% CI 0.84, 1.13; p = 0.71) with a median of 10.9 months (CG) versus 10.4 (CP). HR for PFS was 0.95 (95% CI 0.83, 1.09; p = 0.45) with a median of 4.8 months for CG versus 4.5 for CP. Safety profile was as expected.Adapting maintenance strategy according to response to induction chemotherapy does not improve patient outcome.NCT01631136.

Published
2022

27. Neoadjuvant durvalumab for resectable non-small-cell lung cancer (NSCLC): results from a multicenter study (IFCT-1601 IONESCO)

Author

Marie Wislez, Julien Mazieres, Armelle Lavole, Gérard Zalcman, Olivier Carre, Thomas Egenod, Raffaele Caliandro, Catherine Dubos-Arvis, Gaelle Jeannin, Olivier Molinier, Marie-Ange Massiani, Alexandra Langlais, Franck Morin, Francoise Le Pimpec Barthes, Laurent Brouchet, Jalal Assouad, Bernard Milleron, Diane Damotte, Martine Antoine, and Virginie Westeel

Subjects
Pharmacology, Male, Cancer Research, Lung Neoplasms, Immunology, Middle Aged, Neoadjuvant Therapy, Antineoplastic Agents, Immunological, Oncology, Carcinoma, Non-Small-Cell Lung, Molecular Medicine, Immunology and Allergy, Humans, Female, Neoplasm Staging
Abstract

BackgroundThe IONESCO (IFCT-1601) trial assessed the feasibility of neoadjuvant durvalumab, for early-stage resectable non-small-cell lung cancer (NSCLC).MethodsIn a multicenter, single-arm, phase II trial, patients with IB (≥4 cm)-IIIA, non-N2, resectable NSCLC received three doses of durvalumab (750 mg every 2 weeks) and underwent surgery between 2 and 14 days after the last infusion. The primary endpoint was the complete surgical resection rate. Secondary endpoints included tumor response rate, major histopathological response (MPR: ≤10% remaining viable tumor cells), disease-free survival (DFS), overall survival (OS), durvalumab-related safety, and 90-day postoperative mortality (NCT03030131).ResultsForty-six patients were eligible (median age 60.9 years); 67% were male, 98% were smokers, and 41% had squamous cell carcinoma. Regarding tumor response, 9% had a partial response, 78% had stable disease, and 13% had progressive disease. Among the operated patients (n=43), 41 achieved complete resection (89%, 95% CI 80.1% to 98.1%)), and eight achieved MPR (19%). The 12-month median OS and DFS rates were 89% (95% CI 75.8% to 95.3%) and 78% (95% CI 63.4% to 87.7%), respectively (n=46). The median follow-up was 28.4 months (12.8–41.1). All patients in whom MPR was achieved were disease-free at 12 months compared to only 11% of those with >10% residual tumor cells (p=0.04). No durvalumab-related serious or grade 3–5 events were reported. The unexpected 90-day postoperative mortality of four patients led to premature study termination. None of these four deaths was considered secondary to direct durvalumab-related toxicity.ConclusionsNeoadjuvant durvalumab given as monotherapy was associated with an 89% complete resection rate and an MPR of 19%. Despite an unexpectedly high rate of postoperative deaths, which prevented us from completing the trial, we were able to show a significant association between MPR and DFS.

Published
2022

28. Chest CT scan plus x-ray versus chest x-ray for the follow-up of completely resected non-small-cell lung cancer (IFCT-0302): a multicentre, open-label, randomised, phase 3 trial

Author

Virginie Westeel, Pascal Foucher, Arnaud Scherpereel, Jean Domas, Philippe Girard, Jean Trédaniel, Marie Wislez, Patrick Dumont, Elisabeth Quoix, Olivier Raffy, Denis Braun, Marc Derollez, François Goupil, Jacques Hermann, Etienne Devin, Hubert Barbieux, Eric Pichon, Didier Debieuvre, Gervais Ozenne, Jean-François Muir, Stéphanie Dehette, Jérôme Virally, Michel Grivaux, François Lebargy, Pierre-Jean Souquet, Faraj Al Freijat, Nicolas Girard, Emmanuel Courau, Reza Azarian, Michel Farny, Jean-Paul Duhamel, Alexandra Langlais, Franck Morin, Bernard Milleron, Gérard Zalcman, and Fabrice Barlesi

Subjects
Lung Neoplasms, Oncology, Carcinoma, Non-Small-Cell Lung, X-Rays, Antineoplastic Combined Chemotherapy Protocols, Humans, Tomography, X-Ray Computed, Early Detection of Cancer, Follow-Up Studies
Abstract

Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC.In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling.Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported.The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures.French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology.For the French translation of the abstract see Supplementary Materials section.

Published
2022

29. Switch maintenance chemotherapy versus observation after carboplatin and weekly paclitaxel doublet chemotherapy in elderly patients with advanced non–small cell lung cancer: IFCT-1201 MODEL trial

Author

Didier Debieuvre, Pierre-Jean Souquet, Jean-Louis Pujol, Jérôme Dauba, Jeannick Madelaine, Olivier Molinier, J. Otto, Jacques Le Treut, Fabrice Barlesi, Elisabeth Quoix, Patrick Aldo Renault, Eric Pichon, Alexandra Langlais, Virginie Westeel, L. Moreau, Franck Morin, Jacques Margery, Clarisse Audigier-Valette, Armelle Lavolé, Patrick Dumont, Denis Moro-Sibilot, CHU Strasbourg, Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Le Mans (CH Le Mans), Service de Pneumologie, oncologie thoracique et allergologie respiratoire [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier du Pays d'Aix, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre Hospitalier Layné, Université Côte d'Azur (UCA), Hôpital pasteur [Colmar], Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier de Chauny, Partenaires INRAE, Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Groupe hospitalier de la région de Mulhouse Sud-Alsace (GHRMSA), Centre hospitalier de Pau, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, CHU Grenoble, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, Lung Neoplasms, Time Factors, medicine.medical_treatment, NSCLC, Deoxycytidine, Carboplatin, chemistry.chemical_compound, Elderly, MESH: Aged, 80 and over, 0302 clinical medicine, Maintenance therapy, MESH: Progression-Free Survival, MESH: Carboplatin, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Aged, 80 and over, MESH: Aged, MESH: Antimetabolites, Antineoplastic, Drug Substitution, Age Factors, MESH: Neoplasm Staging, Progression-Free Survival, 3. Good health, MESH: Maintenance Chemotherapy, MESH: Antineoplastic Combined Chemotherapy Protocols, Pemetrexed, 030220 oncology & carcinogenesis, Disease Progression, Female, MESH: Disease Progression, France, medicine.drug, Antimetabolites, Antineoplastic, medicine.medical_specialty, Paclitaxel, Maintenance, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Drug Administration Schedule, Drug Administration Schedule, Maintenance Chemotherapy, 03 medical and health sciences, Internal medicine, medicine, Carcinoma, Humans, Chemotherapy, MESH: Paclitaxel, MESH: Pemetrexed, Lung cancer, Aged, Neoplasm Staging, MESH: Age Factors, MESH: Humans, Performance status, business.industry, MESH: Time Factors, MESH: Deoxycytidine, medicine.disease, Gemcitabine, MESH: Drug Substitution, MESH: Male, MESH: Lung Neoplasms, MESH: France, 030104 developmental biology, chemistry, business, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung
Abstract

International audience; Purpose: Maintenance chemotherapy is a reasonable choice for patients with metastatic non-small cell lung carcinoma (NSCLC) not progressing after induction therapy with a platinum-based doublet. Nevertheless, there have been no studies dedicated to elderly patients.Patients and methods: We conducted a randomised trial in patients aged 70-89 years, with advanced NSCLC (with neither EGFR mutation nor ALK rearrangement), who had not progressed after four cycles of monthly carboplatin and weekly paclitaxel in order to compare maintenance with either pemetrexed (500 mg/m2 d1, 22) in patients with non-squamous cell carcinoma or gemcitabine (1,150 mg/m2 d1, 8, 22) in squamous cell carcinoma to simple observation. The patients were required to have a performance status (PS) 0-2, mini-mental score >23, and creatinine clearance ≥45 mL/min. The primary end-point was overall survival (OS).Results: 632 patients were enrolled from May 2013 to October 2016. Of the 328 (52.3%) patients randomised after induction therapy, 166 patients were assigned to the observation arm, versus 162 to the switch maintenance arm, 119 of whom received pemetrexed and 43 gemcitabine. The median OS from randomisation was 14.1 months (95% confidence interval [CI]: 12.0-17.0) in the observation arm and 14 months (95% CI: 10.9-16.9) in the maintenance arm (p = 0.72). The median progression-free survival (PFS) from randomisation was 2.7 months (95% CI: 2.6-3.1) in the observation arm versus 5.7 months (95% CI: 4.8-7.1) in the maintenance arm (p < 0.001).Conclusion: Switch maintenance therapy significantly prolonged PFS but not OS and, thus, should not be proposed to elderly patients with advanced NSCLC.

Published
2020

30. Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703 R2D2 Trial

Author

Julien Mazieres, Claire Lafitte, Charles Ricordel, Laurent Greillier, Elodie Negre, Gérard Zalcman, Charlotte Domblides, Jeannick Madelaine, Jaafar Bennouna, Céline Mascaux, Denis Moro-Sibilot, François Pinquie, Alexis B. Cortot, Josiane Otto, Jacques Cadranel, Alexandra Langlais, Franck Morin, Virginie Westeel, Benjamin Besse, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Services de Pneumologie, Exploration Fonctionnelle Respiratoire et Cardiologie (Hôpital Louis Pradel), Hospices Civils de Lyon (HCL), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Multidisciplinary Oncology and Therapeutic Innovations Unit, Hôpital Nord [CHU - APHM], Thèses d'exercice et mémoires - UFR de Médecine Montpellier-Nîmes, Université de Montpellier (UM), Service d’oncologie thoracique et essais précoces [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Bordeaux [Bordeaux], Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital Foch [Suresnes], Service de Pneumologie [Strasbourg], Université de Strasbourg (UNISTRA)-Nouvel Hôpital Civil, Hospices Civils de Strasbourg, CHU de Grenoble-Alpes, Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Groupe de recherche clinique Biomarqueurs Théranostiques des Cancers Bronchiques Non à Petites Cellules (GRC 4 - Theranoscan), Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Institut Gustave Roussy (IGR), and Département de médecine oncologique [Gustave Roussy]

Subjects
MESH: Aged, MESH: Docetaxel, Cancer Research, MESH: Humans, MESH: Middle Aged, MESH: Mutation, MESH: Survival Rate, MESH: Non-Randomized Controlled Trials as Topic, MESH: Adult, [SDV.CAN]Life Sciences [q-bio]/Cancer, MESH: Follow-Up Studies, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Male, MESH: Prognosis, MESH: Lung Neoplasms, MESH: Receptor, ErbB-2, MESH: Antineoplastic Combined Chemotherapy Protocols, MESH: Aged, 80 and over, Oncology, MESH: Antibodies, Monoclonal, Humanized, MESH: Trastuzumab, MESH: Female, MESH: Carcinoma, Non-Small-Cell Lung
Abstract

PURPOSE HER2 exon 20 insertions and point mutations are oncogenic drivers found in 1%-2% of patients with non–small-cell lung cancer (NSCLC). No targeted therapy is approved for this subset of patients. We prospectively evaluated the effectiveness of the combination of two antibodies against human epidermal growth factor 2 (HER2 [HER2] trastuzumab and pertuzumab with docetaxel; trastuzumab and pertuzumab) and docetaxel. METHODS The IFCT 1703-R2D2 trial is a multicenter, nonrandomized phase II study. Patients with HER2-mutated, advanced NSCLC who progressed after ≥ 1 platinum-based treatment were enrolled. Patients received pertuzumab at a loading dose of 840 mg and 420 mg thereafter; trastuzumab at an 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at a dose of 75 mg/m2 every 3 weeks. The primary outcome was the objective response rate (ORR). Other end points included the duration of response, progression-free survival, and safety ( NCT03845270 ). RESULTS Forty-five patients were enrolled and treated. The median age was 64.5 years (range, 31-84 years), 35% were smokers, 72% were females, 15% had an Eastern Cooperative Oncology Group performance status of 2, and 30% had brain metastases. The objective response rate was 29% (n = 13), and 58% had stable disease (n = 26). The median progression-free survival was 6.8 months (95% CI, 4.0 to 8.5). The median duration of response in patients with a confirmed response (n = 13) was 11 months (95% CI, 2.9 to 14.9). Grade 3/4 treatment-related adverse events were observed in 64% of the patients. No patient discontinued treatment because of toxicity. The most frequent grade ≥ 3 treatment-related adverse events were neutropenia (33%), diarrhea (13%), and anemia (9%). CONCLUSION Triple therapy with trastuzumab, pertuzumab, and docetaxel is feasible and effective for HER2-mutated pretreated advanced NSCLC. These results highlight the effectiveness of the HER2 antibody-based strategy, which should be considered for these patients.

Published
2022

31. Somatic profile in lung cancers is associated to reproductive factors in never-smokers women: Results from the IFCT-1002 BioCAST study

Author

Bruno Coudert, Bénédicte Mastroianni, P. Foucher, Séverine Fraboulet, Adrien Dixmier, Julien Mazieres, Michel Vincent, Eric Dansin, Eric Pichon, M. Locatelli-Sanchez, Jacques Cadranel, Sébastien Couraud, N. Baize, Isabelle Monnet, Franck Morin, Catherine Dubos-Arvis, P. Missy, C. Fontaine-Delaruelle, Patrick Dumont, Denis Moro-Sibilot, Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Service de pneumologie, Département d'oncologie médicale [Centre Georges-François Leclerc], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Férération d'oncologie thoracique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université d'Angers (UA), INSAVALOR, Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Unité pneumologie et oncologie thoracique [CHU Tenon], 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
Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung Neoplasms, Multivariate analysis, [SDV]Life Sciences [q-bio], DNA Mutational Analysis, Cohort Studies, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Risk Factors, Internal medicine, Humans, Medicine, Anaplastic Lymphoma Kinase, Lung cancer, Reproductive History, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Smokers, Lung, business.industry, Oncogenes, Middle Aged, medicine.disease, 3. Good health, ErbB Receptors, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Menarche, Biomarker (medicine), Female, Observational study, France, business, Hormone
Abstract

Background Lung cancer in women is on the rise, with a higher proportion occurring in lifelong never-smokers. Lung cancer in never-smokers (LCINS) exhibits a high frequency of driver oncogene alterations. In this study, we aimed to investigate whether exposure to reproductive factors in women with LCINS may modulate the molecular pattern. Methods All newly diagnosed LCINSs were included in a prospective, observational study (IFCT-1002 BioCAST). Each patient responded to a questionnaire including reproductive factors. Biomarker test results were also collected. Results Two hundred and sixty women were included in this analysis, and 166 alterations were characterized. EGFR mutation frequency proved greater among patients with late menarche (74% in age > 14 vs. 40% and 41% for 12–14 and ≤ 12 years, respectively; P = 0.020) and tended to decrease with increasingly late age at menopause. In multivariate analysis, EGFR mutation frequency increased by 23% per increment of 1 year of age at menarche (P = 0.048), and by 9% for each year at age at first birth (P = 0.035). ALK alteration frequency was greater in women with high parity (50% in ≥ 5 vs. 12% and 7% for 1–4 and nulliparity, respectively; P = 0.021). Conclusion In a cohort of women LCINSs, female hormonal factors appear to impact molecular pattern.

Published
2020

32. Lorlatinib for advanced anaplastic lymphoma kinase-positive non-small cell lung cancer: Results of the IFCT-1803 LORLATU cohort

Author

Simon Baldacci, Benjamin Besse, Virginie Avrillon, Bertrand Mennecier, Julien Mazieres, Pascale Dubray-Longeras, Alexis B. Cortot, Renaud Descourt, Helene Doubre, Xavier Quantin, Michael Duruisseaux, Isabelle Monnet, Denis Moro-Sibilot, Jacques Cadranel, Christelle Clément-Duchêne, Sophie Cousin, Charles Ricordel, Patrick Merle, Josiane Otto, Sophie Schneider, Alexandra Langlais, Franck Morin, Virginie Westeel, and Nicolas Girard

Subjects
Male, Cancer Research, Lung Neoplasms, Lactams, Lactams, Macrocyclic, Aminopyridines, Middle Aged, Oncology, Carcinoma, Non-Small-Cell Lung, Proto-Oncogene Proteins, Humans, Pyrazoles, Anaplastic Lymphoma Kinase, Female, Protein Kinase Inhibitors
Abstract

Anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small cell lung cancer (NSCLC) represents a rare subset of lung cancer, with specific presentation, and multiple treatment options, including selective tyrosine kinase inhibitors (TKIs). Real-world evidence is insufficient regarding the actual real-life treatment sequences in the late line setting, and available clinical trials may not reflect real-world situation. Here, we took advantage of the French Expanded Access Program (EAP) of lorlatinib, a third-generation TKI targeting ALK and ROS1, to assess treatment sequencing, and lorlatinib efficacy and safety, in patients with ALK+ NSCLC.All consecutive patients with advanced ALK+ NSCLC treated between October 2015 and June 2019 with lorlatinib as part of EAP were included. Data were collected and reviewed from medical records by independent research staff of the French Thoracic Cancer Intergroup. The primary endpoint was progression-free survival (PFS).Of the 208 patients included, 117 (56%) were female, 142 (69%) were never smokers, and 180 (87%) had stage IV NSCLC at diagnosis. The most frequent histology was adenocarcinoma (94%), and the median age was 60.9 years. At the time of lorlatinib initiation, 160 (77%) patients had brain metastases, and 125 (72%) were performance status 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 4%/17%/30%/49% of patients. A total of 162 (78%) patients had previously been treated with chemotherapy, 194 (93%) with a first-generation ALK-TKI, 195 (94%) with a second-generation ALK-TKI. The median follow-up from lorlatinib initiation was 23.3 months. The median PFS, median overall survival (OS) from lorlatinib initiation and median OS from advanced NSCLC diagnosis were 9.9 months (95% confidence interval [CI] 6-12.3 months), 32.9 months (95% CI 18.7 months to not reached) and 97.3 months (95% CI 75.7-152.8 months), respectively. The median duration of treatment with lorlatinib was 11.8 months (95% CI 8.5-18.8 months). Overall response and disease control rate were 49% and 86%, respectively. Central nervous system objective response rate was 56%. Treatment was stopped due to toxicity in 28 patients (14%). The safety profile of lorlatinib was consistent with previously published data.Real-world evidence indicates that lorlatinib offers a significant clinical benefit and high intracerebral antitumour activity in heavily pretreated patients with ALK+ NSCLC.NCT03727477.

Published
2021

33. COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study

Author

Jérôme Avouac, Elodie Drumez, Eric Hachulla, Raphaèle Seror, Sophie Georgin-Lavialle, Soumaya El Mahou, Edouard Pertuiset, Thao Pham, Hubert Marotte, Amélie Servettaz, Fanny Domont, Pascal Chazerain, Mathilde Devaux, Pascal Claudepierre, Vincent Langlois, Arsène Mekinian, Alexandre Thibault Jacques Maria, Béatrice Banneville, Bruno Fautrel, Jacques Pouchot, Thierry Thomas, René-Marc Flipo, Christophe Richez, Florence Aeschlimann, Christian Agard, Nassim Ait-Abdallah, Jean-David Albert, Didier Alcais, Jean-Sébastien Allain, Yannick Allanore, Blanca Amador-Borreiro, Zahir Amoura, Emma Andre, Anaïs Arbault, Jean-Benoît Arlet, Laurent Arnaud, Denis Arniaud, Herliette Arty-Hue, Lucie Atlan, Alexandra Audemard-Verger, Christine Audoin-Pajot, Victor Audren, Maxime Bach-Bunner, Hélène Bacquet-Deschryver, Brigitte Bader-Meunier, Nathalie Balandraud, Jean-Charles Balblanc, Stéphane Bally, Frédéric Banal, Pierre Barbery, Thomas Barnetche, Audre Barrelet, André Basch, Vincent Baumier, Guillaume Bayer, Sophie Bayle, Catherine Beauvais, Rudie Beinat, Véronique Belin, Rakiba Belkhir, Ruben Benainous, Alexandre Belot, Mohammed Benammar, Mathilde Benhamou, Ygal Benhamou, Ahmed Benmansour, Pascal Bennet, Brigitte Bernoux-Manat, Elise Berthet, Emilie Berthoux, Ewa Bertolini, Adrien Bigot, Aurélia Bisson-Vaivre, Gilles Blaison, Gilles Bolla, Olivier Bonidan, Christine Bonnet, Raphaël Borie, Marie Bossert, Laurence Boudou, Françoise Bouhour, Kévin Bouiller, Bastien Bouldoires, Karima Boussoualim, Eric Bouvard, Regine Brondino, Pierre Buchlin, Laurence Cabantous, Patrice Cacoub, Simon Cadiou, Maurizio Carteni, Aurélia Carbasse, Brice Castel, Pascal Cathebras, Hervé Caumont, Annalisa Celant, Benjamin Chaigne, Benoît Chaillous, Romuald Champy, Agnès Charcot, Pierre Charles, Isabelle Charlot-Lambrecht, Caroline Charpin, Emmanuel Chatelus, Bernard Chaudier, Pascale Chertok, Xavier Chevalier, Maxime Chevreau, Emilie Chotard, Delphine Chu Miow Lin, Gaëlle Clavel, Cyril Clavel-Osorio, Fleur Cohen, Gregory Cohen, Marie-Eve Colette-Cedoz, Nived Collercandy, Antoine Colombey, Chloé Comarmond, Bernard Combe, Céline Comparon, Elodie Constant, Pascal Coquerelle, Justine Corli, Clémence Corre, Nathalie Costedoat-Chalumeau, Marie Couret, Natacha Courvoisier, Fabienne Coury-Lucas, Cécile Coutarel, Fabrice Coutier, Richard Damade, Laurence Daver-Malaterre, Sarahe Dehimat, Michel Delahousse, Emilie Barrois-Delattre, Delphine Denarie, Camille Deprouw, Emanuelle Dernis, Alban Deroux, Renaud Desbarbieux, Elise Descamps, Chantal Deslandre, Marie Desmurs, Jacques Despaux, Marie Desplats, Frédérick Detree, Valérie Devauchelle-Pensec, Robin Dhote, Philippe Dieude, Yannick Dieudonne, Elisabeth Diot, Guillaume Direz, Djamal-Dine Djeddi, Sarah Douvier, Béatrice Drouet, Catherine Duc, Angélique Ducornet, Carine Dufauret-Lombard, Alain Duhamel, Cécile Dumaine, Anne-Elisabeth Dumel, Chantal Dumoulin-Richez, Agnès Duquesne, Géraldine Durand, Mariane Durandin-Truffinet, Pierre-Marie Duret, Maïka Duval, Mikaël Ebbo, Esther Ebstein, Andra Economu-Dubosc, Stéphanie Emilie, Romain Euvrard, Philippe Evon, Sylvie Fabre, Dorothée Fagedet, Meryem Farhat, Marion Fauconier, Jacques Fechtenbaum, Renaud Felten, Fanny Fernandes, Nicole Ferreira-Maldent, Elodie Feurer, Amandine Fichet, Françoise Flaisler, Nans Florens, Violaine Foltz, Elisabeth Fontanges, Jennifer Foret, Anne-Claire Fougerousse, Anne Fouque-Aubert, Catherine Foutrier-Morello, Hélène Francois-Pradier, Léa Frantzen, Pierre Fritz, Antoine Froissart, Jean Fulpin, Piera Fuzibet, Francis Gaches, Laurence Gagneux-Lemoussu, Mélanie Penhoat-Gahier, Joris Galland, Frédérique Gandjbakhch, Nicole Garnier, Thomas Garraud, Jean-François Garrot, Romain Gastaldi, Véronique Gaud-Listrat, Maud Gauthier-Prieur, Dana Georgescu, Nathalie Gerard, Elisabeth Gervais, Christelle Gibert, Eric Gibert, Ghislaine Gill, Jérôme Gillard, Mélanie Gilson, Pauline Gimonnet, Jeanine-Sophie Giraudet-Le Quintrec, Aude Giraud-Morelet, Baptiste Glace, Camille Glanowski, Bertrand Godeau, Bruno Gombert, Camille Gonnet-Gracia, Tiphaine Goulenok, Philippe Goupille, Olivier Gourmelen, Sophie Govindaraju-Audouard, Franck Grados, Martine Grall-Lerosey, Bruno Grardel, Anne Grasland, Gilles Grateau, Monica Groza, Constance Guillaud, Séverine Guillaume, Caroline Guillibert, Xavier Guillot, Philippe Guilpain, Aline Gury, Marie-Hélène Guyot, Cécile Hacquard-Bouder, Marie-Noelle Havard, Jean-Pierre Hellier, Pascal Hennequin, Basile Henriot, Julien Henry, Véronique Hentgen, Marion Hermet, Muriel Herasse, Julie Hernandez, Miguel Hie, Pascal Hilliquin, Olivier Hinschberger, Ambre Hittinger-Roux, Jan Holubar, Christophe Hudry, Serge Huguenel, Clara Jaccard, Jean-Michel, Jacquemier, Bénédicte Jamard, Catherine Jan, Sylvie Jean, Mathieu Jouvray, Pierre-Antoine Juge, Laurent Juillard, Denis Jullien, Anna Kabala, Abdelkrim Kabchou, Ludovic Karkowski, Françoise Karman, Farid Kemiche, Jérémy Keraen, Pierre Kieffer, Isabelle Kone-Paut, Abdeldajallil Koreichi, Marie Kostine, Sylvain La Batide Alanore, Pierre Lafforgue, Sophie Lahalle, Marc Lambert, Isabelle Lambrecht, Sylvain Lanot, Aurélia Lanteri, Jean-Paul Larbre, Augustin Latourte, Christian Lavigne, Sophie Le Guen Guegan, Guillaume, Le Guenno, Diane Leguy, Agnès Lebrun, Emmanuel Ledoult, Nathalie Legoupil, Erick Legrand, Charlotte Lejeune, Olivier Leloire, Christophe Leroux, Rémi Leroy, Marie Leroy-Gouix, Tifenn Leturcq, Amélie Leurs, Céline Leveque-Michaud, François-Xavier Limbach, Frédéric Liote, Anne Lohse, Pierre Lozac'h, Virginie Lucas, Aurélie Madelon, Nadine Magy-Bertrand, Matthieu Mahevas, Hélène Maillard, Thibault Maillet, Sandrine Malochet-Guinamand, Quentin Mangon, Sylvie Marchou-Lopez, Nathalie Margarit, Thierry Marhadour, Xavier Mariette, Claire Martin, Alexis Mathian, François Maurier, Frédéric Maury, Betty Mazet-Guillaume, Arnaud Mazouyez, Hassan Mazyad, Nadia Mehsen-Cetre, Ulrich Meinzer, Isabelle Melki, Laurent Messer, Corinne Miceli, Martin Michaud, Catherine Michel, Matthias Michel, Mathilde Michon, Anne-Marie Milesi-Lecat, Anna Molto, Marie Moly, Olivier Moranne, Gautier Morel, Hugo Morel, Jacques Morel, Franck Morin, Laurence Moulinier, Guillaume Moulis, Bertrand Moura, Minh Nguyen, Sabine Nicolas-Vullierme, Hubert Nielly, Gaétane Nocturne, Aurore Nottez, Henri-Olivier Ollagnon, Isabelle Pacaud-Vitoux, Anne Pagnier, Caroline Paris, Antoine Parrot, Tristan Pascart, Yasmina Pascaud-Mansour, Lætitia Paulin, Stephan Pavy, Laurent Perard, Yves-Marie Pers, Micheline Pha, Maud Pichon, Audrey Pierreisnard, Gabrielle Pizana, Sylvaine Poignant, Elsa Poix, Agnès Portier, Antoine Poulet, Samira Plassard, Grégory Pugnet, Déborah Puyraimond-Zemmour, Pierre Quartier-Dit-Maire, Marion Quenet, Viviane Queyrel, Loïc Raffray, Philippe Remy, Myriam Renard, Jessica Rene, Sabine Revuz, Bénédicte Rey, Gaëlle Richard-Colmant, Etienne Riviere, Sébastien Riviere, Sophie Robin, Julien Rohmer, Isabelle Roitg, Mélanie Romier, Michel Rolland, Mélanie Roriz, Carole Rosenberg, Linda Rossi, Olivier Roth, Sid-Ahmed Rouidi, Mathilde Roumier, Mickaël Rousiere, Clémentine Rousselin, Bénédicte Rouviere, Christian Roux, Fabienne Roux, Marielle Roux, Nicolas Roux, Diane Rouzaud, Sylvie Rozenberg, Isabelle Sacco, Fatiha Sadji, Laurent Sailler, Carine Salliot, Jean-Hugues Salmon, Alain Saraux, Jean Schmidt, Julie Seguier, Jérémie Sellam, Eric Senbel, Thomas Sene, Patricia Senet, Pascal Seve, Aurélie Sicaud, Perrine Smets, Vincent Sobanski, Christelle Sordet, Elisabeth Sornay-Rendu, Odile Souchaud-Debouverie, Lætitia Sparsa, Lionel Spielmann, Sarah Steib, Chloé Stavris, Catherine Straus, Victor Strotz, Paulina Szafors, Séverine Taffignon-Clave, Justine Simoens, Claire Theillac, Nora Tenenbaum, Benoît Thomachot, Nathalie Tieulie, Soizic Tiriau, Alice Tison, Eric Toussirot, Ludovic Trefond, Sophie Trijau, Sébastien Trouillier, Anne-Priscille Trouvin, Marie-Elise Truchetet, Marc Ulrich, Jacques Vaquier, Eric Veillard, Laurent Veillon, Guillaume Vial, Jean-François Viallard, Judith Victor, Claire Vidon, Mathias Vidon, Camille Vigne, Alexandre Virone, Ursula Warzocha, Daniel Wendling, Claude Werle, Cécile Wibaux, Alexandra Willems, Michel Wisniewski, Juliette Woessner, Bernadette Xerri-Campano, Service de rhumatologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de médecine interne [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Tourcoing, Centre Hospitalier René Dubos [Pontoise], Assistance Publique - Hôpitaux de Marseille (APHM), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Intégrative du Tissu Osseux (LBTO), Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Pitié-Salpêtrière [AP-HP], Groupe Hospitalier Diaconesses Croix Saint-Simon, Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Epidemiology in Dermatology and Evaluation in Therapeutics (EpiDermE), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Saint-Antoine [AP-HP], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), 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 Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Bordeaux [Bordeaux], Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Médecine Interne = Hôpital de jour de médecine [CHU Tenon], INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie intégrative du tissu osseux, Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Service de rhumatologie, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, Service de Médecine Interne [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de rhumatologie [CH Gustave Dron, Tourcoing], Centre Hospitalier Gustave Dron [Tourcoing], Hopital Réné Dubos, Université Paris 1 Panthéon-Sorbonne - UFR Science Politique (UP1 UFR11), and Université Paris 1 Panthéon-Sorbonne (UP1)

Subjects
medicine.medical_specialty, Immunology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Rheumatology, immune system diseases, law, hemic and lymphatic diseases, Internal medicine, Clinical endpoint, Immunology and Allergy, Medicine, 030212 general & internal medicine, 030203 arthritis & rheumatology, business.industry, Hazard ratio, Odds ratio, Articles, medicine.disease, Intensive care unit, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Rheumatoid arthritis, Cohort, Rituximab, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Cohort study, medicine.drug
Abstract

Summary Background Various observations have suggested that the course of COVID-19 might be less favourable in patients with inflammatory rheumatic and musculoskeletal diseases receiving rituximab compared with those not receiving rituximab. We aimed to investigate whether treatment with rituximab is associated with severe COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases. Methods In this cohort study, we analysed data from the French RMD COVID-19 cohort, which included patients aged 18 years or older with inflammatory rheumatic and musculoskeletal diseases and highly suspected or confirmed COVID-19. The primary endpoint was the severity of COVID-19 in patients treated with rituximab (rituximab group) compared with patients who did not receive rituximab (no rituximab group). Severe disease was defined as that requiring admission to an intensive care unit or leading to death. Secondary objectives were to analyse deaths and duration of hospital stay. The inverse probability of treatment weighting propensity score method was used to adjust for potential confounding factors (age, sex, arterial hypertension, diabetes, smoking status, body-mass index, interstitial lung disease, cardiovascular diseases, cancer, corticosteroid use, chronic renal failure, and the underlying disease [rheumatoid arthritis vs others]). Odds ratios and hazard ratios and their 95% CIs were calculated as effect size, by dividing the two population mean differences by their SD. This study is registered with ClinicalTrials.gov, NCT04353609. Findings Between April 15, 2020, and Nov 20, 2020, data were collected for 1090 patients (mean age 55·2 years [SD 16·4]); 734 (67%) were female and 356 (33%) were male. Of the 1090 patients, 137 (13%) developed severe COVID-19 and 89 (8%) died. After adjusting for potential confounding factors, severe disease was observed more frequently (effect size 3·26, 95% CI 1·66–6·40, p=0·0006) and the duration of hospital stay was markedly longer (0·62, 0·46–0·85, p=0·0024) in the 63 patients in the rituximab group than in the 1027 patients in the no rituximab group. 13 (21%) of 63 patients in the rituximab group died compared with 76 (7%) of 1027 patients in the no rituximab group, but the adjusted risk of death was not significantly increased in the rituximab group (effect size 1·32, 95% CI 0·55–3·19, p=0·53). Interpretation Rituximab therapy is associated with more severe COVID-19. Rituximab will have to be prescribed with particular caution in patients with inflammatory rheumatic and musculoskeletal diseases. Funding None.

Published
2021

34. Shorter Survival in Malignant Pleural Mesothelioma Patients With High PD-L1 Expression Associated With Sarcomatoid or Biphasic Histology Subtype: A Series of 214 Cases From the Bio-MAPS Cohort

Author

Jacques Margery, Martine Antoine, Gérard Zalcman, Olivier Molinier, Claire Danel, Clarisse Audigier-Valette, Alexandra Langlais, Julien Mazieres, Laurent Greillier, Emmanuel Bergot, Solenn Brosseau, Franck Morin, Sylvie Lantuejoul, Isabelle Rouquette, Isabelle Monnet, Arnaud Scherpereel, Valérie Gounant, Denis Moro-Sibilot, Romain Corre, Guénaëlle Levallet, Service d'Oncologie Thoracique [ Bichat], Hôpital Bichat - Claude Bernard-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Département d'Anatomo-Pathologie [Hôpital Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pôle Cardiovasculaire et Pulmonaire [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Pneumologie, Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Département d'anatomie et cythologie pathologique, CHU Grenoble-Hôpital Michallon, Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Service d'oncologie multidisciplinaire innovations thérapeutiques [Hôpital Nord - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Département de biologie intégrée, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Association Générale des Laboratoires d'Analyse de l'Environnement (AGLAE), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche sur les Ions, les MAtériaux et la Photonique (CIMAP - UMR 6252), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Service de pneumologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Pathologie [CHU Caen], Roche, Fonds de Recherche en Santé Respiratoire, Caen University Hospital, Normandy League, CIC Hôpital Bichat, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-UFR de Médecine, CHU Lille, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie et oncologie thoracique [CH Le Mans], Centre Hospitalier Le Mans (CH Le Mans), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bichat - Claude Bernard-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), CHU, Hôpital Larrey, Hôpital Sainte-Musse, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Caen Normandie (UNICAEN), Normandie Université (NU), Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CCSD, Accord Elsevier, 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), Service d'Anatomie et cytologie pathologiques [CHU Tenon], and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Adult, Male, Mesothelioma, 0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Multivariate analysis, Pleural Neoplasms, [SDV]Life Sciences [q-bio], Clone (cell biology), [SDV.CAN]Life Sciences [q-bio]/Cancer, B7-H1 Antigen, Cohort Studies, Immune checkpoint inhibitors, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, PD-1, medicine, Humans, Lung cancer, Aged, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Proportional hazards model, Mesothelioma, Malignant, Histology, Middle Aged, Prognosis, medicine.disease, Survival Analysis, Immunohistochemistry, 3. Good health, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, Phenotype, 030104 developmental biology, 030220 oncology & carcinogenesis, Cohort, Cancer cell, Female, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

CERVOXY CLIN; International audience; Background - Anticancer immune responses are negatively regulated by programmed cell death 1 (PD-1) T-cell membrane protein interaction with its ligand, programmed death ligand 1 (PD-L1), on cancer cells. We sought to assess the prognostic role of PD-L1 expression in tumor samples from patients enrolled onto the IFCT-0701 MAPS randomized phase 3 trial (NCT00651456). Patients and methods - Tumor samples were analyzed by immunohistochemistry for percentages of PD-L1 membrane-stained tumor cells using the E1L3N clone, and data were correlated to survival by multivariate Cox models including stratification variables. Results - PD-L1 staining was assessed in 214 (47.75%) of 448 patients. Epithelioid subtype represented 83.7% (179/214). Absence of PD-L1 staining occurred in 137 (64.1%) of 214 malignant pleural mesothelioma (MPM) samples, while 77 (35.9%) of 214 were PD-L1 positive, with 50 (64.9%) of 77 showing < 50% PD-L1-expressing tumor cells. Sarcomatoid/biphasic subtypes were more commonly PD-L1 positive than epithelioid subtype (P < .001). In patients with 1% or more PD-L1-stained tumor cells, median overall survival (OS) was 12.3 months versus 22.2 months for other patients (hazard ratio [HR] = 1.25; 95% confidence interval [CI], 0.93-1.67; P = .14). OS did not differ according to PD-L1 positivity in multivariate analyses (adjusted HR = 1.10; 95% CI, 0.81-1.49; P = .55). With a 50% cutoff, PD-L1-positive patients displayed a 10.5 months median OS versus 19.3 months for patients with lower PD-L1 expression (HR = 1.93; 95% CI, 1.27-2.93; P = .002). OS did not significantly differ in adjusted Cox models (adjusted HR = 1.20; 95% CI, 0.74-1.94; P = .47). In the 179 epithelioid MPM patients, high PD-L1 staining (≥ 50% of tumor cells) negatively affected OS, although not significantly, showing a 12.3-month median OS (95% CI, 4.3-21.6) versus 23-month (95% CI, 18.5-25.2) for patients with tumor PD-L1 staining in < 50% cells (P = .071). The progression-free survival (PFS) differences were statistically significant, with a longer 9.9-month median PFS in patients with low PD-L1 staining (< 50% cells) compared to 6.7 months of median PFS in patients with high PD-L1 expression (≥ 50% cells) (P = .0047). Conclusion - Although high PD-L1 tumor cell expression was associated with poorer OS in MPM patients from the MAPS trial, its prognostic influence was lost in multivariate analyses in the whole cohort, while PD-L1 expression was strongly associated with the sarcomatoid/biphasic subtypes. In the epithelioid MPM subset of patients, high PD-L1 tumor expression (≥ 50%) negatively affected OS and PFS, with this prognostic influence remaining statistically significant for PFS after adjustment in multivariate Cox model.

Published
2019

35. A Randomized Non-Comparative Phase II Study of Anti-Programmed Cell Death-Ligand 1 Atezolizumab or Chemotherapy as Second-Line Therapy in Patients With Small Cell Lung Cancer: Results From the IFCT-1603 Trial

Author

Valérie Gounant, Delphine Carmier, Alexandra Langlais, Lionel Uwer, Denis Moro-Sibilot, Franck Morin, Olivier Molinier, José Hureaux, Pierre-Jean Souquet, Patrick Merle, Jean-Louis Pujol, Sébastien Bommart, Clarisse Audigier-Valette, Pierre Mourlanette, Florian Guisier, Aldo Renault, Martine Antoine, Jeannick Madelaine, Laurent Greillier, Marc G. Denis, Audrey Rabeau, J. Otto, Equipe Quantification en Imagerie Fonctionnelle (QuantIF-LITIS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), and Normandie Université (NU)

Subjects
Male, 0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, Lung Neoplasms, Randomization, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Phases of clinical research, Antineoplastic Agents, Antibodies, Monoclonal, Humanized, 03 medical and health sciences, 0302 clinical medicine, Atezolizumab, Internal medicine, medicine, Clinical endpoint, Chemotherapy, Humans, Aged, Aged, 80 and over, Programmed cell death ligand 1, business.industry, SCLC, Middle Aged, Small Cell Lung Carcinoma, Confidence interval, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Toxicity, Female, Topotecan, business, medicine.drug
Abstract

Introduction This randomized phase II trial aimed at evaluating the engineered programmed cell death ligand 1 (PD-L1) antibody atezolizumab in SCLC progressing after first-line platinum–etoposide chemotherapy. Methods Patients were randomized 2:1 to atezolizumab (1200 mg intravenously every 3 weeks) until progression or unacceptable toxicity, or conventional chemotherapy (up to 6 cycles of topotecan or re-induction of initial chemotherapy). Patients were not selected based on PD-L1 tissue expression. The primary endpoint was objective response rate at 6 weeks. A two-stage design with 2:1 randomization and O'Brien-Fleming stopping rules was used. The null hypothesis was rejected if more than 12 of 45 patients were responders. Results Overall, 73 patients were randomized (atezolizumab n = 49; chemotherapy n = 24). At 6 weeks, 1 of 43 eligible atezolizumab patients achieved an objective response (2.3%, 95% confidence interval [CI]: 0.0–6.8), whereas 8 others had stable disease (20.9% disease control rate; 95% CI: 8.8–33.1). Among eligible chemotherapy patients (n = 20), 10% achieved an objective response (65% disease control rate). Median progression-free survival was 1.4 months (95% CI: 1.2–1.5) with atezolizumab and 4.3 months (95% CI: 1.5–5.9) with chemotherapy. Overall survival did not significantly differ between groups. Median overall survival was 9.5 months versus 8.7 months for the atezolizumab and the chemotherapy group, respectively (adjusted hazard ratioatezolizumab : 0.84, 95% CI: 0.45–1.58; p = 0.60). Two atezolizumab patients (4.2%) experienced grade 3 fatigue, and two others grade 1 dysthyroidism. Among 53 evaluable specimens, only 1 (2%) had positive immunohistochemical PD-L1 staining (SP142 clone). Conclusions Atezolizumab monotherapy in relapsed SCLC failed to show significant efficacy. No unexpected safety concerns were observed.

Published
2019

36. Efficacy of dabrafenib-trametinib combination in BRAF V600E-mutated metastatic non–small cell lung cancer: Results of the IFCT-2004 BLaDE cohort

Author

Aurélie Swalduz, Michele Beau-Faller, David Planchard, Julien Mazieres, Sophie Bayle, Didier Debieuvre, Vincent Fallet, Margaux Geier, Alexis B Cortot, Sebastien Couraud, Catherine Daniel, Eric Pichon, Pascale Missy, Franck Morin, Virginie Westeel, Jean-Bernard Auliac, and Remi Veillon

Subjects
Cancer Research, Oncology
Abstract

9082 Background: BRAF V600E mutations occur up to 2% of advanced non-small cell lung (NSCLC). Dabrafenib-trametinib (D-T) combination was associated with improved OS rates in phase II study and was approved in the 1st-line setting and further. The IFCT-2004 BLaDE study reports the D-T combination efficacy in a large French real-world multicenter cohort of advanced BRAF V600E-mutated NSCLC. Methods: Patients (pts) with advanced NSCLC harboring BRAF V600E mutation diagnosed between 01.01.2016 and 31.12.2019 and treated with D-T combination (D 300 mg + T 2 mg daily) whatever the treatment line were included. Demographic, clinical, pathological data were collected as well as data of efficacy and reason of treatment discontinuation. The primary endpoint was 12 months-OS rate in pts receiving the D-T as 2nd-line or subsequent treatment (L2+). Results: 163 pts were included in 54 centers through 32 national testing labs: 50.3 % were female, 30.2% never-smokers, 95.1 % had adenocarcinoma and PDL1 was > 1% in 78.2%. Median age was 68.3 years. At D-T initiation, 80.8 % of pts were PS 0/1, 93.9 % were stage IIIB/C ineligible for surgery or local therapy and IV, 20.9% had brain metastases and 27% received D+T as 1st line treatment (L1). At the data cutoff (30.06.2021), median (m) follow-up was 27.4 months [95% CI 22.2-31.9] and 47 pts (28.8%) remained on study treatment. 12 months-OS rate in pts receiving D+T in L2+ (n = 119) was 67.4% [95% CI 57.8-75.3] with a median progression-free survival (mPFS) of 10.4 months [95% CI 7.3-13.1]. In the 44 pts receiving D+T in L1, 12 months-OS rate was also 67.4% [95% CI 51.2-79.3] with a mPFS of 18.2 months [95% CI 7.7-21.3]. Objective response rates were 73.8% [95% CI 65.5 - 82.2] and 82.9% [95% CI 71.4 - 94.4], disease progression was observed as best response in 3.7% [95% CI 0.1 - 7.3] and 0% in L2+ and L1, respectively. Other efficacy results are detailed in the table. D-T discontinuation for toxicity was reported in 10.3% of pts. 51.2% and 43.7% of pts received subsequent treatment in L2+ and L1 respectively. For L2+ pts, subsequent treatments were immunotherapy (IO)-based in 37.2 % and chemotherapy in 58.3%. For L1 pts, subsequent treatments were (IO)-based in 42.9% and chemotherapy in 42.7%. Conclusions: Our series confirms significant efficacy of D-T combination in BRAF V600E-mutated metastatic NSCLC. These results in real-world conditions are consistent with registration studies but also support its use in 1st line setting. [Table: see text]

Published
2022

37. A phase II randomized, open-labelled, multicenter study of safety and efficacy of combination brigatinib and carboplatin-pemetrexed therapy or brigatinib monotherapy as first-line treatment in patients with advanced ALK-positive non–small cell lung cancer (IFCT-2101 MASTERPROTOCOL ALK)

Author

Michaël Duruisseaux, Aurélie Swalduz, Julien Mazieres, Fabrice Barlesi, Elodie Amour, Franck Morin, and Virginie Westeel

Subjects
Cancer Research, Oncology
Abstract

TPS9144 Background: Second generation ALK tyrosine kinase inhibitors (ALK-TKI), including brigatinib, provide substantial therapeutic benefit in first-line treatment of ALK-positive NSCLC patients (pts) but relapse eventually occurs in all pts due to development of drug resistance, possibly caused by emergence of drug-tolerant cells (DTC). Combining chemotherapy to TKI may prevent DTC emergence in preclinical studies, and results in prolonged progression-free survival (PFS) and overall survival in EGFR-mutant NSCLC. We hypothesize that combination of second generation ALK-TKI with chemotherapy will improve clinical outcomes in advanced ALK-positive NSCLC patients. The IFCT-2101 MASTERPROTOCOL ALK trial will evaluate the efficacy and safety of brigatinib and carboplatin-pemetrexed combination in treatment-naïve metastatic ALK-positive NSCLC. Methods: The IFCT-2101 MASTERPROTOCOL ALK randomized, open-label phase II trial will enrol 110 pts in 30 French centers over 24 months. Eligible pts will have metastatic NSCLC with ALK-fusion according to local testing, be untreated for advanced disease, and have an ECOG Performance Status (PS) of 0-1 and at least one measurable lesion per RECIST 1.1. Pts with asymptomatic and stable brain metastases (BM) will be eligible. Exclusion criteria include leptomeningeal metastases. Patients will be randomized 1:1 to receive brigatinib monotherapy (Arm A) or combination brigatinib and carboplatin-pemetrexed therapy (Arm B), with PS (0 vs 1) and BM (presence vs absence) as stratification factors. Brigatinib will be administered at a dose of 90 mg QD for a 7-day lead-in period followed by 180 mg QD continuously, in 28-day cycles. In Arm B, 4 cycles of carboplatin (AUC 5) and pemetrexed (500 mg/m2) therapy every 3 weeks will be added at Day 8 of brigatinib treatment. Treatment will continue until progression, intolerable toxicity or discontinuation. The first 26 pts enrolled in Arm B will represent the population of a safety phase, during which adverse events (AE) will be closely monitored by an independent data monitoring committee. The primary endpoint is investigator-assessed 12-month PFS rate. Secondary endpoints include independently-reviewed 12-month PFS rate, overall response rate (ORR), 12-month intracranial PFS and ORR, incidence, nature and severity of AEs, and impact of ALK-fusion detection, co-mutations and clearance of circulating tumor (ct) DNA (Guardant360) on outcome. Exploratory objectives include the evaluation of early blood ctDNA decrease on patient outcome. The study is enrolling and primary completion date is March 2025. Clinical trial information: NCT05200481.

Published
2022

38. Inhibiteurs du check-point immunitaire en néo-adjuvant dans les cancers bronchiques non à petites cellules localisés : essai IoNESCO

Author

Xavier Mignard, Bertrand Mennecier, Marie Wislez, Radj Gervais, Martine Antoine, Gérard Zalcman, Bernard Milleron, Denis Moro-Sibilot, Franck Morin, E. Amour, and Charles Dayen

Subjects
Pulmonary and Respiratory Medicine, Gynecology, medicine.medical_specialty, Durvalumab, business.industry, Anti pd 1, Neo adjuvant, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Immune system, 030220 oncology & carcinogenesis, medicine, 030212 general & internal medicine, Non small cell, Stage (cooking), Lung cancer, business
Abstract

Resume Etat des connaissances Programmed cell death-ligand 1 (PD-L1) est une proteine membranaire facilitant l’echappement tumoral vis-a-vis de l’immunite. Le durvalumab est un anticorps monoclonal bloquant l’interaction PD-L1/PD-1 entre lymphocytes T et cellules tumorales, ayant montre des reponses durables et une toxicite acceptable en phase I/II dans les cancers bronchiques non a petites cellules (CBNPC) metastatiques. Methodes Dans cette etude de phase II, 3 perfusions de durvalumab (10 mg/kg a j1, j15, j29) sont administrees en neo-adjuvant a des patients ≥ 18 ans, indice de performance (PS) 0–1, ayant un CBNPC de stade clinique IB (> 4 cm) ou II. La chimiotherapie et la radiotherapie preoperatoire ne sont pas permises. L’objectif principal est la faisabilite d’une resection chirurgicale complete. Un taux de resection complete Resultats attendus L’immunotherapie neo-adjuvante est faisable et pourrait ameliorer la survie des CBNPC de stade precoce.

Published
2018

39. Assessment of nivolumab in HIV-Infected patients with advanced non-small cell lung cancer after prior chemotherapy. The IFCT-1602 CHIVA2 phase 2 clinical trial

Author

Armelle Lavolé, L. Kiakouama, Jean-Philippe Spano, Laurent Greillier, Sophie Schneider, Marine Baron, Alain Makinson, Solenn Brosseau, Franck Morin, Alexandra Langlais, Amélie Guihot, Baptiste Abbar, Julien Mazieres, Jacques Cadranel, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier de la Côte Basque (CHCB), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), and Intergroupe Francophone de Cancérologie thoracique

Subjects
0301 basic medicine, Pulmonary and Respiratory Medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Phases of clinical research, [SDV.CAN]Life Sciences [q-bio]/Cancer, HIV Infections, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Carcinoma, Non-Small-Cell Lung, Clinical endpoint, Medicine, Humans, Prospective Studies, Lung cancer, Adverse effect, MESH: Humans, MESH: Middle Aged, business.industry, HIV, Common Terminology Criteria for Adverse Events, MESH: HIV Infections, Middle Aged, medicine.disease, MESH: Male, MESH: Prospective Studies, MESH: Lung Neoplasms, 030104 developmental biology, Nivolumab, Tolerability, Response Evaluation Criteria in Solid Tumors, 030220 oncology & carcinogenesis, MESH: Nivolumab, [SDV.IMM]Life Sciences [q-bio]/Immunology, Non small cell lung cancer, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Immunotherapy, business, MESH: Carcinoma, Non-Small-Cell Lung
Abstract

Importance Therapies targeting immune checkpoints, such as the programmed cell death 1 (PD-1) receptor, have become the standard-of-care for patients with non-small cell lung cancer (NSCLC), but people living with HIV (PLWH) were excluded from these studies. Objective To evaluate the efficacy and tolerability of nivolumab in PLWH with advanced NSCLC. Design The CHIVA2 study was a nonrandomized, open-label, phase 2 clinical trial in PLWH with previously treated advanced NSCLC. Setting National multicenter prospective study. Participants patients had viral load of Intervention Nivolumab was administered in second or third line, as monotherapy intravenously at 3 mg/kg every 2 weeks, until disease progression or limiting toxicity. Main Outcomes and Measures The primary endpoint was disease control rate, evaluated using the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results Sixteen patients with advanced NSCLC were enrolled: 14 (88 %) were men, median age was 58 years (range: 44−71), and all were smokers. The median duration of nivolumab treatment was 3.5 months (range: 0.5–26.5). The median follow-up was 23.6 months. Disease control rate was 62.5 % for 15 evaluable patients at 8 weeks (2 with partial response, 8 with stable disease, and 5 with disease progression). Twelve (75 %) patients had treatment-related adverse events, which were mild or moderate, except for one patient experiencing severe pruritus, onycholysis, and pemphigoid. There were no opportunistic infections or unexpected immune-related events. HIV viral load was stable during treatment. An increase in proliferating CD8+ and CD4+ T-cells was observed after 3 nivolumab cycles in a subgroup of 9 patients. Conclusions and Relevance Second/third-line nivolumab treatment was well-tolerated and beneficial in PLWH with NSCLC. Future trials should investigate immune checkpoint inhibitors in first-line settings. Trial Registration EudraCT.ema.europa.eu registration number: 2016−003796-22

Published
2021

40. FP09.05 Driver Oncogenic Alterations and Indoor Radon in NSCLC Patients From the IFCT Biomarker Cohort: Bioradon France Study

Author

Virginie Westeel, David Planchard, Isabelle Monnet, L'Houcine Ouafik, Alexandra Langlais, C. Vignaud, Isabelle Rouquette, Jean-Philippe Merlio, K. Leuraud, Charles Ricordel, Didier Debieuvre, Jean Mosser, Benjamin Besse, Fabrice Barlesi, Jose Carlos Benitez, Dominique Laurier, Fabienne Escande, G. Ielsch, Edouard Auclin, Franck Morin, Laura Mezquita, Department of Medical Oncology [Barcelona, Spain], Hospital del Mar [Barcelona, Spain], Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bureau d'étude et d'expertise du radon (IRSN/PSE-ENV/SEREN/BERAD), Service d'expertise et d'étude en radioprotection des populations et de la radioactivité dans l'environnement (IRSN/PSE-ENV/SEREN), Institut de Radioprotection et de Sûreté Nucléaire (IRSN)-Institut de Radioprotection et de Sûreté Nucléaire (IRSN), CHU Bordeaux [Bordeaux], Groupe hospitalier de la région de Mulhouse Sud-Alsace (GHRMSA), CHU Pontchaillou [Rennes], Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Service de Transfert d’Oncologie Biologique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHI Créteil, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Institut de Radioprotection et de Sûreté Nucléaire (IRSN), 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 Régional Universitaire de Besançon (CHRU Besançon), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Ouafik, L'Houcine

Subjects
Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, business.industry, Prevention, chemistry.chemical_element, Radon, [SDV.CAN]Life Sciences [q-bio]/Cancer, Risky Behaviors, chemistry, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, Cohort, medicine, Biomarker (medicine), business, Family History
Abstract

International audience; Those with FH of LC were more likely to be obese regardless of demographic factors, and less likely to exercise 2+ times per week (Table). Those with FH of LC were more likely to have received 10+ imaging scans and to have been exposed to hydrocarbons compared to those without FH (Table). There were no reported differences in any other occupational or home exposures, including asbestos and radon in those with v. without FH of LC (Table). Conclusion: FH of LC is associated with higher-risk behaviors that increase the likelihood of developing both lung and other cancers. As such, FH can be used in cancer prevention and control programs to identify higher-risk patients and educate patients that FH of lung cancer is associated with risk-increasing behaviors that are nonetheless modifiable.

Published
2021

41. 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

42. 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

43. Circulating Tumor DNA as a Prognostic Determinant in Small Cell Lung Cancer Patients Receiving Atezolizumab

Author

Denis Moro-Sibilot, Guillaume Herbreteau, Olivier Molinier, José Hureaux, Patrick Merle, Jeannick Madelaine, Audrey Rabeau, J. Otto, Florian Guisier, Clarisse Audigier-Valette, Lionel Uwer, Valérie Gounant, Aldo Renault, Marc G. Denis, Laurent Greillier, Jean-Louis Pujol, Alexandra Langlais, Franck Morin, Pierre-Jean Souquet, Delphine Carmier, Centre hospitalier universitaire de Nantes (CHU Nantes), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Assistance Publique - Hôpitaux de Marseille (APHM), Centre Hospitalier Intercommunal Toulon-La Seyne sur Mer - Hôpital Sainte-Musse, Institut de Cancérologie de Lorraine - Alexis Vautrin [Nancy] (UNICANCER/ICL), UNICANCER, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Grenoble, Service de pneumologie, oncologie thoracique et soins intensifs respiratoires [Rouen], Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Hôpital Charles Nicolle [Rouen]-CHU Rouen, Normandie Université (NU), Hôpital Bretonneau, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de pneumologie [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d’oncologie thoracique et essais précoces [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Clermont-Ferrand, Centre Hospitalier Le Mans (CH Le Mans), Centre hospitalier de Pau, Service de pneumologie [Toulouse], CHU Toulouse [Toulouse]-Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital Charles Nicolle [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Herrada, Anthony, and Hôpital Charles Nicolle [Rouen]-CHU Rouen

Subjects
Oncology, atezolizumab, medicine.medical_specialty, medicine.medical_treatment, lcsh:Medicine, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, Article, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, [SDV.CAN] Life Sciences [q-bio]/Cancer, Atezolizumab, Internal medicine, medicine, RB1, Progression-free survival, TP53, 030304 developmental biology, 0303 health sciences, Chemotherapy, Mutation, business.industry, lcsh:R, SCLC, General Medicine, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, ctDNA, NOTCH, 3. Good health, Clinical trial, 030220 oncology & carcinogenesis, Non small cell, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, mutation, business
Abstract

Background: The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab. Methods: 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the TP53, RB1, NOTCH1, NOTCH2, and NOTCH3 genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation. Results: We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49, 65.3%) and RB1 (25/49, 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm. Conclusion: ctDNA is strongly associated with the prognosis of SCLC patients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials.

Published
2020

44. Outcomes of Patients With Advanced NSCLC From the Intergroupe Francophone de Cancérologie Thoracique Biomarkers France Study by KRAS Mutation Subtypes

Author

Fabrice Barlesi, H. Janicot, Pierre-Jean Souquet, Didier Debieuvre, Michel Poudenx, Virginie Westeel, Julien Mazieres, Michèle Beau-Faller, M. Wislez, Isabelle Monnet, Fabienne Escande, Pierre-Paul Bringuier, L'Houcine Ouafik, Pascal Foucher, Alexandra Langlais, Isabelle Rouquette, Jean-Philippe Merlio, Antoinette Lemoine, Anne-Marie Ruppert, Franck Morin, Charles Ricordel, Groupe de recherche clinique Biomarqueurs Théranostiques des Cancers Bronchiques Non à Petites Cellules (GRC 4 - Theranoscan), Sorbonne Université (SU), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Biochimie et Biologie Moléculaire [Strasbourg] (HUS), Les Hôpitaux Universitaires de Strasbourg (HUS), Univ Strasbourg, INSERM, IRFAC, UMR S1113, F-67200 Strasbourg, France, Groupe hospitalier de la région de Mulhouse Sud-Alsace (GHRMSA), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), 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 Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Pneumologie-Allergologie [CHU Toulouse], Pôle Clinique des Voies respiratoires [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Groupement Hospitalier Lyon-Est (GHE), Hospices Civils de Lyon (HCL), Centre Hospitalier Intercommunal de Créteil (CHIC), Laboratoire de Biochimie et Biologie Moléculaire [CHRU Lille] (Pôle de Biologie Pathologie Génétique), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Rennes (CHU Rennes), INSERM U1053, Université Bordeaux, Bordeaux, France., Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Clermont-Ferrand, INSERM UMR S1193, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Service de pneumologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service d'oncologie multidisciplinaire innovations thérapeutiques [Hôpital Nord - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], 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 Paris Cité (UPCité), AstraZeneca, Roche, 2011-038, Institut National Du Cancer, France, Novartis, France, Ouafik, L'Houcine, Theranoscan [CHU Tenon] (GRC 4), 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), 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), 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), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), 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), Unité pneumologie et oncologie thoracique [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), Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de pneumologie [CHU Toulouse], Groupement hospitalier lyon Est (Hospices Civils de Lyon), INSERM U1242, Université Rennes 1, and 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)

Subjects
Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, endocrine system diseases, [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease_cause, NSCLC, lcsh:RC254-282, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Non-small cell lung cancer, Internal medicine, medicine, Overall survival, Non–small cell lung cancer, Stage (cooking), neoplasms, 030304 developmental biology, 0303 health sciences, Mutation, Transition (genetics), business.industry, KRAS mutation, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, Confidence interval, digestive system diseases, 3. Good health, respiratory tract diseases, 030220 oncology & carcinogenesis, Adenocarcinoma, Original Article, KRAS, business, Kras mutation
Abstract

Introduction KRAS mutations are detected in 20% to 30% of NSCLC. However, KRAS mutation subtypes may differently influence the outcome of patients with advanced NSCLC. Methods In the Biomarkers France study, 4894 KRAS mutations (26.2%) were detected in 4634 patients from the 17,664 enrolled patients with NSCLC. Survival and treatment data on noncurative stage III to IV NSCLC were available for 901 patients. First- and second-line treatment effects on progression-free survival and overall survival were analyzed according to the KRAS mutations subtype. Results Over 95% of patients with KRAS mutation were smokers or former smokers who were white (99.5%), presenting with adenocarcinoma (82.5%). The most common KRAS mutation subtype was G12C (374 patients; 41.5%), followed by G12V (168; 18.6%), G12D (131; 14.5%), G12A (62; 6.9%), G13C (45; 5.0%), G13D (31; 3.4%), and others (10; 1%). Approximately 21% of patients had transition mutation and 68.2% had a transversion mutation. G12D and transition mutations were predominant in never-smokers. The median overall survival for patients with KRAS-mutated NSCLC was 8.1 months (95% confidence interval [CI]: 7.5–9.5), without any differences according to the different KRAS subtypes mutations. The median progression-free survival was 4.6 months (95% CI: 4.2–5.1) for first-line treatment and 4.8 months (95% CI: 4.3–6.8) for second-line treatment, without any differences according to the different KRAS subtypes mutations. Conclusions KRAS mutation subtypes influenced neither treatment responses nor outcomes. The KRAS G12C mutation was detected in 41.5% of patients, who are now eligible for potent and specific G12C inhibitors.

Published
2020

45. Lorlatinib for advanced ALK and ROS1+non-small cell lung cancer (NSCLC): Efficacy and treatment sequences in the IFCT-1803 LORLATU expanded access program (EAP) cohort

Author

Julien Mazieres, Bertrand Mennecier, Jacques Cadranel, Hélène Doubre, Renaud Descourt, Pascale Dubray-Longeras, P. Missy, Denis Moro-Sibilot, Sophie Schneider, Franck Morin, Virginie Westeel, Benjamin Besse, Michael Duruisseaux, J. Otto, Simon Baldacci, Nicolas Girard, Sigolene Galland-Girodet, Virginie Avrillon, Charles Ricordel, Isabelle Monnet, Site de Recherche Intégrée en Cancérologie (SIRIC-ONCOLille), Université de Lille, Sciences et Technologies-Université de Lille, Sciences Humaines et Sociales-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Léon Bérard [Lyon], Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [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), Sorbonne Université (SU), Sorbonne Université - Faculté de médecine Pitié Salpétrière, CHU Pitié-Salpêtrière [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 Pontchaillou [Rennes], Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie [CHI Créteil], CHI Créteil, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), Université Côte d'Azur (UCA)-UNICANCER, Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Institut Curie [Paris], IFCT, Pharmaceutical/Biotech Company, Université de Lille-UNICANCER-Université de Lille-UNICANCER-Cancéropole Nord-Ouest-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université - Faculté de médecine [CHU Pitié Salpétrière], Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNICANCER-Université Côte d'Azur (UCA), 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), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)

Subjects
Cancer Research, medicine.drug_class, business.industry, non-small cell lung cancer (NSCLC), [SDV.CAN]Life Sciences [q-bio]/Cancer, medicine.disease, Lorlatinib, Tyrosine-kinase inhibitor, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Oncology, Refractory, 030220 oncology & carcinogenesis, Expanded access, Cohort, Cancer research, medicine, ROS1, business, ComputingMilieux_MISCELLANEOUS, 030215 immunology
Abstract

9615 Background: Lorlatinib, a third-generation tyrosine kinase inhibitor targeting ALK and ROS1, has been made available in France starting October 2015 through an EAP for advanced, refractory, ALK+ NSCLC after the failure of chemotherapy and TKIs. Besides the landmark, multi-cohort phase II trial that assessed lorlatinib in ALK+ NSCLC, real-life evidence regarding the efficacy and safety, as well as treatment sequences including lorlatinib, is lacking. Methods: We report the cohort of consecutive patients with advanced, refractory, ALK or ROS1+ NSCLC enrolled in the French EAP of lorlatinib from October 2015 to October 2019. Data were collected from medical records by French Cooperative Thoracic Intergroup (IFCT) research study assistants on site. Primary endpoint was progression-free survival. Results: 200 patients were included: 143 (71.5%) ALK+, 57 (28.5%) ROS1+, 87 (44%) men, 127 (66%) never-smokers, and 167 (85%) stage IV disease. Mean age was 59 years. At the time of initiation of lorlatinib, 146 (74%) patients had Central Nervous System (CNS) disease (78 % for ALK+, 63% for ROS1+), 131 (76%) were PS 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 3%/17%/27%/53%of ALK+ patients and in 30%/30%/16%/24%of ROS1+ patients, respectively. 150 (75%), 185 (93%), 138 (69%), and 80 (40%) patients had received prior chemotherapy, crizotinib, 2nd generation TKIs, and brain radiotherapy, respectively. Median PFS and OS from the initiation of lorlatinib were 11.8 (95% CI 7.3-14.6) months and NR (95% CI 18.6-NR) months, respectively for ALK+ patients and 7.6 (95% CI 6.2-10.2) months and 20.9 (95% CI 10.0-NR) months, respectively for ROS1+ patients. ORR and DCR were 46.2% (95% CI 37.6-54.7) and 86.2% (95% CI 80.2-92.1), respectively for ALK+ patients and 47.1% (95% CI 33.4-60.8) and 88.2% (95% CI 79.4-97.1), respectively for ROS1+ patients. CNS ORR was 41.7% (95% CI 33.3-50.1) and 37.7% (95% CI 24.7-50.8), respectively. With a median follow-up of 15.6 (95% CI 14.0-17.6) months, progression under lorlatinib treatment was observed in 71 (50%) ALK+ patients and 35 (61%) ROS1+ patients, and CNS progression in 24 (34%) and 8 (23%) patients, respectively. The safety profile of lorlatinib was consistent with published data. Conclusions: These real-life results confirmed lorlatinib as a major treatment option for patients with advanced refractory ALK or ROS1+ NSCLC.

Published
2020

46. Development and Validation of a Simplified Prognostic Score in SCLC

Author

D. Moro-Sibilot, Jean-Louis Pujol, Olivier Molinier, Jean-Pierre Daurès, Laurent Greillier, Benoît Roch, Franck Morin, Armelle Lavolé, Alexandra Langlais, Elodie Negre, Elisabeth Quoix, Virginie Westeel, Clarisse Audigier-Valette, and Amandine Coffy

Subjects
Pulmonary and Respiratory Medicine, medicine.medical_specialty, medicine.medical_treatment, Population, lcsh:RC254-282, Serum markers, Prognostic score, Internal medicine, medicine, Chemotherapy, education, Etoposide, education.field_of_study, Small cell lung cancer, Proportional hazards model, business.industry, Hazard ratio, Cancer, University hospital, medicine.disease, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Oncology, Original Article, business, medicine.drug
Abstract

Introduction: This study aimed at generating a new simplified prognostic score (SPS) using common clinical and biological variables to discriminate a limited number of subgroups of patients with SCLC differing by their overall survival (OS). Methods: The SPS was developed exploring the Montpellier University Hospital retrospective database of 401 patients over a 16-year period. All patients had received etoposide - platinum-based chemotherapy as first-line treatment. The SPS development took into account significant determinants of OS in the Cox model, weighted by their regression β coefficients. Validation of the consequent SPS has been done separately in a combined population of 213 patients accrued from two different published trials (NCT03059667 and NCT00930891). Results: The significant independent determinants of OS included the following: (1) American Joint Committee on Cancer TNM stage IV (hazard ratio [HR]: 2.52; 95% confidence interval [CI]: 1.91–3.33); (2) Eastern Cooperative Oncology Group performance status greater than 1 (HR: 2.27; 95% CI: 1.79–2.87); (3) the presence of liver metastases (HR: 1.66; 95% CI: 1.29–2.15); and (4) neutrophil-to-lymphocyte ratio greater than 4 (HR: 1.39; 95% CI: 1.11–1.92). The SPS generated with these four variables, segregated three groups (good, intermediate, and poor prognosis) with respective median OS of 26.9 months (95% CI: 20.1–38.9), 11.5 months (95% CI: 9.8–13.0), and 6.8 months (95% CI: 5.8–8.3; log-rank p < 10–4). Harrell's C statistic estimate was 0.68 ± 0.012, suggesting goodness of calibration. In the validation cohort, the SPS segregated the aforementioned three subgroups in a nearly similar manner, with respective median OS: 27.2, 12.3, and 8.6 months (log-rank p < 10–3; Harrell’s C statistic: 0.58 ± 0.02). Conclusions: The SPS is easy to calculate in real-life practice and efficiently discriminates three populations with different prognoses. This study deserves further validation of this score in patients with SCLC receiving immunochemotherapy.

Published
2020

47. Weekly paclitaxel plus bevacizumab versus docetaxel as second- or third-line treatment in advanced non-squamous non-small-cell lung cancer: Results of the IFCT-1103 ULTIMATE study

Author

Olivier Raffy, Adrien Dixmier, Gérard Zalcman, Clara Fontaine-Delaruelle, Damien Pouessel, Olivier Molinier, Sandrine Hiret, Franck Morin, Patrick-Aldo Renault, Julien Mazieres, Charles Dayen, Patrick Dumont, Catherine Becht, Sylvestre Le Moulec, Eric Pichon, Benjamin Besse, Clarisse Audigier-Valette, Claire Poulet, Fabrice Barlesi, Alexis B. Cortot, Denis Moro-Sibilot, and Alexandra Langlais

Subjects
0301 basic medicine, Adult, Male, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Bevacizumab, Adolescent, Paclitaxel, medicine.medical_treatment, Population, Docetaxel, Kaplan-Meier Estimate, Neutropenia, Gastroenterology, Drug Administration Schedule, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Internal medicine, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, Lung cancer, education, Aged, Neoplasm Staging, Aged, 80 and over, Chemotherapy, education.field_of_study, Cross-Over Studies, business.industry, Hazard ratio, Middle Aged, medicine.disease, Progression-Free Survival, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Disease Progression, Female, business, medicine.drug
Abstract

Purpose Second-line chemotherapy regimens have demonstrated poor benefit after failure of platinum-based chemotherapy in advanced non-squamous non–small-cell lung cancer (nsNSCLC). Methods In this multicentre, open-label phase III trial, patients with advanced nsNSCLC treated with one or two prior lines, including one platinum-based doublet, were centrally randomised to receive 90 mg/m2 of paclitaxel (D1, D8, D15) plus 10 mg/kg of bevacizumab (D1, D15) every 28 days or docetaxel (75 mg/m2) every 21 days; crossover was allowed after disease progression. Primary end-point was progression-free survival (PFS). ClinicalTrials.gov registration number: NCT01763671 . Results One hundred sixty six patients were randomised (paclitaxel plus bevacizumab: 111, docetaxel: 55). The median PFS was longer in patients receiving paclitaxel plus bevacizumab than in patients receveing docetaxel [5·4 months versus 3·9 months, adjusted hazard ratio (HR) 0·61 (95% confidence interval [CI]: 0·44–0·86); p = 0·005]. Objective response rates (ORRs) were 22·5% (95% CI: 14·8–30·3) and 5·5% (95% CI: 0·0–11·5) (p = 0·006), respectively. Median overall survivals were similar (adjusted HR 1·17; p = 0·50). Crossover occurred in 21 of 55 (38·2%) docetaxel-treated patients. Grade III-IV adverse events (AEs) were reported in 45·9% and 54·5% of patients treated with paclitaxel and bevacizumab or docetaxel, respectively (p = NS), including neutropenia (19·3% versus 45·4%), neuropathy (8·3% versus 0·0%) and hypertension (7·3% versus 0·0%). Three patients died due to treatment-related AEs (1·8% in each group). Conclusion Weekly paclitaxel plus bevacizumab as second- or third-line improves PFS and ORR compared with docetaxel in patients with nsNSCLC, with an acceptable safety profile. These results place weekly paclitaxel plus bevacizumab as a valid option in this population. Clinical trials registration number ClinicalTrials.gov Identifier: NCT01763671 .

Published
2020

48. Independent prognostic value of ultra-sensitive quantification of tumor pre-treatment T790M subclones in EGFR mutated non-small cell lung cancer (NSCLC) treated by first/second generation TKI, depends on variant allele frequency (VAF): Results of the French cooperative thoracic intergroup (IFCT) biomarkers France project

Author

Franck Morin, Hélène Blons, Fabienne Escande, Denis Moro-Sibilot, Alexandra Langlais, Charlotte Leduc, L'Houcine Ouafik, Antoinette Lemoine, Roger Lacave, Samia Melaabi, P. Missy, Jean-Philippe Merlio, Jacques Cadranel, Fabrice Barlesi, Pierre-Paul Bringuier, Michèle Beau-Faller, Paul Hofman, Marc G. Denis, Erwan Pencreach, Florence de Fraipont, Laboratoire de Biochimie et de Biologie Moléculaire, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Interface de Recherche Fondamentale et Appliquée en Cancérologie (IRFAC - Inserm U1113), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC)-Fédération de Médecine Translationelle de Strasbourg (FMTS), Service de Pneumologie, Nouvel Hôpital Civil, Université de Strasbourg, Strasbourg, Service de Biochimie (HEGP - Biochimie), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM U1209, Institute for Advanced Biosciences, Laboratoire de Biochimie et Biologie Moléculaire (LILLE - Biochimie et Biol Moléculaire), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), INSERM UMR S1193, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Transfert d'Oncologie Biologique [Hôpital Nord - APHM], Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Laboratoire de Biochimie et Plateforme de Génétique Moléculaire des Cancers [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Biopathologie [Institut Curie, Paris], Institut Curie [Paris], Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Unité d'Oncologie Thoracique-Pneumologie, CHU de Grenoble, INSERM U823, Grenoble, France., Centre Hospitalier Universitaire [Grenoble] (CHU), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), 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), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Université Nice Sophia Antipolis (1965 - 2019) (UNS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Ouafik, L'Houcine, Progression tumorale et microenvironnement. Approches translationnelles et épidémiologie, Université de Strasbourg (UNISTRA)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Institut Régional du Cancer-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), Institut national de recherches archéologiques préventives (Inrap), 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)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Département de pathologie [Hôpital Haut Lévêque], CHU Bordeaux [Bordeaux]-CHU Bordeaux [Bordeaux], Département de biologie intégrée, CHU Grenoble-Hôpital Michallon, Microenvironnement et Physiopathologie de la Differenciation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Transfert d’Oncologie Biologique, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Laboratoire de Biochimie, Unit of Pharmacogenomics, Department of Genetics, Amplitude Systèmes, Clinique de pneumologie, CHU Grenoble, Oncologie multidisciplinaire et innovations thérapeutiques [Hôpital Nord - APHM], École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [APHP], Institut Curie, Service de pneumologie et réanimation [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Institut Régional du Cancer-Université de Strasbourg (UNISTRA)-CHU Strasbourg-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre Paul Strauss : Centre Régional de Lutte contre le Cancer (CRLCC), École pratique des hautes études (EPHE), Aix Marseille Université (AMU)- Hôpital Nord [CHU - APHM]-Assistance Publique - Hôpitaux de Marseille (APHM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), and Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, Lung Neoplasms, [SDV]Life Sciences [q-bio], non-small cell lung cancer (NSCLC), T790M, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Digital polymerase chain reaction, Variant allele frequency (VAF), ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Hazard ratio, Variant allele, Middle Aged, Prognosis, 3. Good health, ErbB Receptors, Survival Rate, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Carcinoma, Squamous Cell, Female, France, Droplet digital PCR (ddPCR), Pulmonary and Respiratory Medicine, Adult, medicine.medical_specialty, Adenocarcinoma of Lung, Non-small cell lung cancer (NSCLC), [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Biomarkers, Tumor, Humans, Clinical significance, Protein Kinase Inhibitors, Aged, Retrospective Studies, business.industry, Proportional hazards model, medicine.disease, Confidence interval, respiratory tract diseases, 030104 developmental biology, Drug Resistance, Neoplasm, Mutation, Carcinoma, Large Cell, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, EGFR mutation, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Follow-Up Studies
Abstract

T790M mutations inEGFR-mutated non-small cell lung cancer (NSCLC) account for nearly 50% of acquired resistance mechanisms to EGFR-TKIs. Earlier studies suggested that tumor T790M could also be detected in TKI-naïve EGFR-mutated NSCLC. The aim of the study is to assess the prevalence and clinical significance of quantification of tumor pre-treatment T790M subclones.We analyzed 366 EGFR-mutated NSCLC patients of the real-life IFCT Biomarkers France study with available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor DNA before treatment by first/second-generation EGFR-TKI. We used ultra-sensitive Droplet Digital Polymerase Chain Reaction (ddPCR) QX200 (BIO-RAD®, Hercules, CA, USA). All samples were tested in duplicate.ddPCR identified T790M in 19/240 specimens (8%). T790M-positive and T790M-negative populations were not different for clinical baseline characteristics. T790M Variant Allele Frequency (VAF) was 0.01% 0.1%, 0.1% 1%, 1% 10%, and10% in five (26.3%), six (31.6%), six (31.6%), and two (10.5%) patients, respectively. T790M VAF was0.1% in 11/13 (84%) patients with rapid (3 months) or usual progression (3-20 months) compared to 0/3 with low progression (20 months) (p = 0.02). In a Cox model, T790M mutation positivity was correlated with overall survival (OS) and progression-free survival (PFS) for 10%VAF1% (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.13-7.07, p = 0.03; HR=3.62, 95%CI 1.43-4.92, p = 0.007, respectively) and for VAF10% (HR = 19.14, 95%CI 4.35-84.26, p 0.001; HR = 17.89, 95%CI 2.21-144.86, p = 0.007, respectively).Ultra-sensitive detection of tumor T790M mutation concerned 8% of EGFR-mutated TKI-naïve NSCLC patients and has a negative prognostic value only for T790M VAF over 1%.

Published
2020

49. Role of the YAP-1 Transcriptional Target cIAP2 in the Differential Susceptibility to Chemotherapy of Non-Small-Cell Lung Cancer (NSCLC) Patients with Tumor RASSF1A Gene Methylation from the Phase 3 IFCT-0002 Trial

Author

Alexandra Langlais, Laurence Bigay-Game, Emmanuel Bergot, Elisabeth Quoix, Guénaëlle Levallet, Fatéméh Dubois, Jean-Louis Pujol, Elodie Maille, Martine Antoine, Franck Morin, Virginie Westeel, Julien Hoflack, Maureen Keller, Gérard Zalcman, Armelle Lavolé, Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Département de Pathologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Œstrogènes, reproduction, cancer (OeReCa), Normandie Université (NU)-Normandie Université (NU), Unité de recherche interdisciplinaire pour la prévention et le traitement des cancers (ANTICIPE), Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service de pneumologie [CHU Caen], Service de pneumologie, CHU Strasbourg-Hopital Civil, Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Intergroupe Francophone de Cancérologie Thoracique [Paris] (IFCT), Intergroupe Francophone de Cancérologie thoracique, Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’oncologie thoracique et essais précoces [CHU Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-UNICANCER, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), 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 Toulouse [Toulouse], Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Couteau, Florence, Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], 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)

Subjects
Cancer Research, medicine.medical_treatment, non-small cell lung cancer (NSCLC), [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, lcsh:RC254-282, Article, 03 medical and health sciences, chemistry.chemical_compound, paclitaxel, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Gene silencing, Lung cancer, 030304 developmental biology, 0303 health sciences, Chemotherapy, Gene knockdown, DNA methylation, business.industry, RASSF1A, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Gemcitabine, 3. Good health, Oncology, Paclitaxel, chemistry, non-small-cell lung cancer, 030220 oncology & carcinogenesis, Cancer research, IAP2, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], business, medicine.drug
Abstract

RASSF1 gene methylation predicts longer disease-free survival (DFS) and overall survival (OS) in patients with early-stage non-small-cell lung cancer treated using paclitaxel-based neo-adjuvant chemotherapy compared to patients receiving a gemcitabine-based regimen, according to the randomized Phase 3 IFCT (Intergroupe Francophone de Canc&eacute, rologie Thoracique)-0002 trial. To better understand these results, this study used four human bronchial epithelial cell (HBEC) models (HBEC-3, HBEC-3-RasV12, A549, and H1299) and modulated the expression of RASSF1A or YAP-1. Wound-healing, invasion, proliferation and apoptosis assays were then carried out and the expression of YAP-1 transcriptional targets was quantified using a quantitative polymerase chain reaction. This study reports herein that gemcitabine synergizes with RASSF1A, silencing to increase the IAP-2 expression, which in turn not only interferes with cell proliferation but also promotes cell migration. This contributes to the aggressive behavior of RASSF1A-depleted cells, as confirmed by a combined knockdown of IAP-2 and RASSF1A. Conversely, paclitaxel does not increase the IAP-2 expression but limits the invasiveness of RASSF1A-depleted cells, presumably by rescuing microtubule stabilization. Overall, these data provide a functional insight that supports the prognostic value of RASSF1 gene methylation on survival of early-stage lung cancer patients receiving perioperative paclitaxel-based treatment compared to gemcitabine-based treatment, identifying IAP-2 as a novel biomarker indicative of YAP-1-mediated modulation of chemo-sensitivity in lung cancer.

Published
2019

50. First-line carboplatin plus pemetrexed with pemetrexed maintenance in HIV-positive patients with advanced non-squamous non-small cell lung cancer: the phase II IFCT-1001 CHIVA trial

Author

Jean Philippe Spano, Jacques Cadranel, Alexandra Langlais, H. Janicot, Xavier Quantin, Clarisse Audigier-Valette, Armelle Lavolé, Lena Herve, Franck Morin, Alain Makinson, Philippe Fraisse, Isabelle Monnet, Laurent Greillier, Lize Kiakouama-Maleka, and Julien Mazieres

Subjects
Pulmonary and Respiratory Medicine, Oncology, medicine.medical_specialty, Lung Neoplasms, Anemia, medicine.medical_treatment, HIV Infections, Pemetrexed, Neutropenia, Carboplatin, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, medicine, Carcinoma, Humans, 030212 general & internal medicine, Lung cancer, business.industry, Immunotherapy, medicine.disease, Clinical trial, Treatment Outcome, chemistry, 030220 oncology & carcinogenesis, business, medicine.drug
Abstract

PurposeHIV infection is an exclusion criterion in lung cancer trials. This multicenter phase II trial aimed to assess feasibility, efficacy and safety of first-line carboplatin plus pemetrexed (CaP) followed by pemetrexed (P) maintenance in people living with HIV (PLHIV) with advanced non-squamous non-small cell lung cancer (NS-NSCLC).MethodsFour cycles of CaP were followed by P-maintenance therapy in patients with Eastern Cooperative Oncology Group performance status (PS) ≤2. The primary objective was a disease control rate (DCR) ≥30% after 12 weeks.ResultsOf the 61 PLHIV enrolled 49 (80%) had a PS 0–1, 19 (31%) brain metastases. Median CD4 lymphocyte count was 418 cells·µL−1(range: 18–1230), median CD4 lymphocyte nadir 169.5 cells·µL−1(1–822); 48 patients (80%) were virologically controlled. Four-cycle inductions were achieved by 38 patients (62%), and 31 (51%) started P maintenance [median of 4.1 cycles (range: 1–19)]. The 12-week DCR was 50.8% (95%CI: 38.3;63.4) and partial response rate 21.3%. Median PFS and OS were respectively 3.5 (95%CI: 2.7;4.4) and 7.6 months (5.7;12.8). Patients with PS 0–1 had the longest median PFS (4.3 months, 95%CI: 3.1;5.2) and OS (11.9 months, 95%CI: 6.4;14.3). During induction, CaP doublet was well tolerated apart from grade 3–4 hematologic toxicities (neutropenia, 53.8%; thrombocytopenia, 35.0%; anemia, 30.0%). Two fatal treatment-related sepsis were reported. No opportunistic infections were experienced.ConclusionIn PLHIV with advanced NS-NSCLC, first-line 4-cycle CaP induction followed by P maintenance was effective and reasonably well-tolerated. Further studies should evaluate combination strategies of CaP with immunotherapy in PLHIV.

Published
2019

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