Publications by authors named "Herve Lena"

60 Publications

Carboplatin plus etoposide versus topotecan as second-line treatment for patients with sensitive relapsed small-cell lung cancer: an open-label, multicentre, randomised, phase 3 trial.

Lancet Oncol 2020 09;21(9):1224-1233

Service de Pneumologie, CHI Créteil, Créteil, France; Institut Mondor de Recherche Biomédicale, U955 Inserm-Université Paris Est Créteil, Créteil, France. Electronic address:

Background: Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer.

Methods: In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m from day 1 to day 3]) or oral topotecan (2·3 mg/m from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346.

Findings: Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0-37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73; p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group.

Interpretation: Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer.

Funding: Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie).
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http://dx.doi.org/10.1016/S1470-2045(20)30461-7DOI Listing
September 2020

Coeliac-Like Disease Is a Rare Immune-Related Complication Induced by Nivolumab in NSCLC.

J Thorac Oncol 2020 08;15(8):e147-e148

CHU Rennes, Service de Pneumologie, CHU Rennes, Rennes, France; INSERM U1242, Chemestry Oncogenesis Stress and Signaling, CLCC Eugène Marquis, Rennes, France. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2019.12.119DOI Listing
August 2020

Final overall survival and safety update for durvalumab in third- or later-line advanced NSCLC: The phase II ATLANTIC study.

Lung Cancer 2020 09 30;147:137-142. Epub 2020 Jun 30.

Columbia University Medical Center, New York, NY, USA.

Introduction: In the phase II ATLANTIC study, durvalumab provided durable responses with acceptable tolerability in heavily pretreated patients with advanced NSCLC, across three independent patient cohorts defined by EGFR/ALK status and tumour PD-L1 expression. Preliminary overall survival (OS) data were encouraging. We now report final OS and updated safety data.

Methods: Patients with advanced NSCLC with disease progression following ≥2 previous systemic regimens received durvalumab 10 mg/kg every 2 weeks. The primary endpoint was objective response rate among patients with increased PD-L1 expression (defined as ≥25 % or ≥90 % of tumour cells [TCs], cohort-dependent). Secondary endpoints included OS and safety.

Results: 444 patients received durvalumab: 111 in Cohort 1 (EGFR+/ALK+), 265 in Cohort 2 (EGFR-/ALK-), and 68 in Cohort 3 (EGFR-/ALK-; TC ≥ 90 %). Median (95 % CI) OS was 13.3 months (6.3-24.5) in patients with EGFR+/ALK+ NSCLC with TC ≥ 25 %, 10.9 months (8.6-13.6) in patients with EGFR-/ALK- NSCLC with TC ≥ 25 %, and 13.2 months (5.9-not reached) in patients with EGFR-/ALK- NSCLC with TC ≥ 90 %. Median (95 % CI) OS was slightly shorter in patients with TC < 25 % (9.9 months [4.2-13.3] in patients with EGFR+/ALK+ NSCLC and 9.3 months [5.9-10.8] in those with EGFR-/ALK- NSCLC). Treatment-related adverse events of special interest occurred with similar incidences as reported previously.

Conclusions: After additional follow-up, final OS data remain encouraging across all cohorts, further supporting the clinical activity of durvalumab in patients with heavily pretreated advanced NSCLC, including those with EGFR+/ALK+ tumours. There were no new safety signals.
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http://dx.doi.org/10.1016/j.lungcan.2020.06.032DOI Listing
September 2020

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.

Eur Respir J 2020 08 27;56(2). Epub 2020 Aug 27.

Service de Pneumologie, Assistance Publique - Hôpitaux de Paris (Hôpital Tenon) and Sorbonne Université, Paris, France.

HIV infection is an exclusion criterion in lung cancer trials. This multicentre 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).Four cycles of CaP were followed by P-maintenance therapy in patients with Eastern Cooperative Oncology Group performance status ≤2. The primary objective was a disease control rate (DCR) ≥30% after 12 weeks.Of the 61 PLHIV enrolled, 49 (80%) had a performance status of 0-1, and 19 (31%) had brain metastases. Median CD4 lymphocyte count was 418 cells·µL (range 18-1230), median CD4 lymphocyte nadir was 169.5 cells·µL (1-822); 48 (80%) patients were virologically controlled. Four-cycle inductions were achieved by 38 (62%) patients, 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 progression-free survival and overall survival were 3.5 (95% CI 2.7-4.4) and 7.6 months (5.7-12.8), respectively. Patients with a performance status of 0-1 had the longest median progression-free survival (4.3 months, 95% CI 3.1-5.2) and overall survival (11.9 months, 95% CI 6.4-14.3). During induction, CaP doublet was well tolerated apart from grade 3-4 haematological toxicities (neutropenia 53.8%; thrombocytopenia 35.0%; anaemia 30.0%). Two fatal treatment-related sepses were reported. No opportunistic infections were experienced.In PLHIV with advanced NS-NSCLC, first-line four-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.
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http://dx.doi.org/10.1183/13993003.02066-2019DOI Listing
August 2020

Immune-related Encephalitis in Two Patients Treated With Immune Checkpoint Inhibitor.

Clin Lung Cancer 2020 09 20;21(5):e474-e477. Epub 2020 Mar 20.

Respiratory Medicine Department, CHU Rennes, Rennes, France; INSERM U1242, Chemistry Oncogenesis Stress and Signaling, CLCC Eugène Marquis, Rennes, France. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2020.03.006DOI Listing
September 2020

High Prevalence of Somatic Oncogenic Driver Alterations in Patients With NSCLC and Li-Fraumeni Syndrome.

J Thorac Oncol 2020 07 14;15(7):1232-1239. Epub 2020 Mar 14.

Thoracic Oncology Group, Cancer Medicine Department, Gustave Roussy, Villejuif, France; INSERM, Gustave Roussy Cancer Campus, Université Paris Saclay, Saint-Aubin, France.

Introduction: Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its somatic molecular profile is unknown.

Methods: Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants.

Results: Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation.

Conclusions: Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.
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http://dx.doi.org/10.1016/j.jtho.2020.03.005DOI Listing
July 2020

Eosinophilic Fasciitis Triggered by Nivolumab: A Remarkable Efficacy of the mTOR Inhibitor Sirolimus.

J Thorac Oncol 2020 02;15(2):e29-e30

Department of Internal Medicine, South Hospital, Rennes, France; Rennes 1 University, Rennes, France. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2019.09.011DOI Listing
February 2020

First-line pembrolizumab for non-small cell lung cancer patients with PD-L1 ≥50% in a multicenter real-life cohort: The PEMBREIZH study.

Cancer Med 2020 04 5;9(7):2309-2316. Epub 2020 Feb 5.

Oncology Department, CHRU Brest, Brest, France.

Background: The KEYNOTE-024 trial demonstrated that pembrolizumab, a PD-1 inhibitor, significantly improves progression-free survival (PFS) and overall survival (OS) in selected patients with previously untreated advanced non-small cell lung cancer (NSCLC) with a PD-L1 tumor proportion score (TPS) ≥50% and without EGFR/ALK aberrations. The main aim of this study was to report the efficacy and safety profile of pembrolizumab in real-life conditions.

Method: This was a French retrospective multicenter longitudinal study of 108 consecutive patients with advanced NSCLC, a PD-L1 TPS ≥50% and without EGFR/ALK aberrations who were treated by pembrolizumab, in first line. Patient data were obtained from medical files.

Results: The main characteristics of the cohort were: median age [range] 66.7 [37-87] years, 64.8% male, 23.1% with a performance status (PS) of 2, and 88.9% current or former smokers. Eighty-seven percent had stage IV NSCLC at diagnosis, 9.2% untreated brain metastases at inclusion,. With a median follow-up of 8.2 months, the median PFS was 10.1 months (95% CI, 8.8-11.4). The objective response rate was 57.3% (complete response 2.7%, partial response 54.6%). Disease control rate was 71.1%. At 6 months, the OS rate estimated was 86.2%. Treatment-related adverse events (AE) of grade 3 occurred in 8% of patients. There were no grade 4 or 5 AEs.

Conclusion: In a real-life cohort of advanced NSCLC patients (including PS 2 and untreated brain metastases), with PD-L1 TPS ≥50%, pembrolizumab demonstrates similar PFS to the pivotal clinical trial.
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http://dx.doi.org/10.1002/cam4.2806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7131849PMC
April 2020

Open-label Phase II trial to evaluate safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination for stage-IV non-small-cell lung cancer - VinMetAtezo trial, (GFPC 04-2017).

Future Oncol 2020 Feb 2;16(4):5-10. Epub 2020 Jan 2.

Department of Pneumology, Centre Hospitalier Universitaire Brest, Brest France.

Metronomic chemotherapy is defined as frequent low-dose administration without prolonged drug-free breaks. Combining immune-checkpoint inhibitors and metronomic chemotherapy is a new approach to improve responses and delay onset of resistance to immune-checkpoint inhibitors. This multicenter, Phase II, open-label, single-arm study was designed to assess the safety and efficacy of metronomic oral vinorelbine in combination with immune-checkpoint inhibitors in advanced non-small-cell lung cancers progressing after first-line platinum-based chemotherapy. The recommended metronomic oral vinorelbine dose will be determined during a safety run-in period including 12 patients; the main study will include 59 additional patients. The primary outcome is progression-free survival at 4 months. Secondary outcomes are safety of the combination, median overall survival, objective response rate, disease-control rate at 4 months and quality of life (NCT03801304).
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http://dx.doi.org/10.2217/fon-2019-0730DOI Listing
February 2020

Pooled overall survival and safety data from the pivotal phase II studies (NP28673 and NP28761) of alectinib in ALK-positive non-small-cell lung cancer.

Lung Cancer 2020 01 14;139:22-27. Epub 2019 Oct 14.

Massachusetts General Hospital Cancer Center, Yawkey 7B, 32 Fruit Street, Boston, MA, USA. Electronic address:

Objectives: A pooled analysis of two open-label phase II studies of alectinib (NP28673 [NCT01801111] and NP28761 [NCT01871805]) demonstrated clinical activity in patients with advanced, anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) previously treated with crizotinib. Longer-term and final pooled analyses of overall survival (OS) and safety data from the two studies are presented here.

Patients And Methods: The pooled population totaled 225 patients (NP28673: n = 138, NP28761: n = 87) who received 600 mg oral alectinib twice daily until disease progression, death, or withdrawal. OS was defined as the time from date of first treatment to date of death, regardless of cause. OS was estimated using Kaplan-Meier methodology, with 95% confidence intervals (CIs) determined using the Brookmeyer-Crowley method. Safety was assessed through adverse event (AE) reporting.

Results: Baseline characteristics were generally comparable between the studies. At final data cutoff (October 27, 2017 [NP28673], October 12, 2017 [NP28761]; median pooled follow-up time, ∼21 months), 53.3% of patients had died, 39.1% were alive and in follow-up, and 7.6% had withdrawn consent or were lost to follow-up. Alectinib demonstrated a median OS of 29.1 months (95% CI 21.3-39.0). No new or unexpected safety findings were observed. The most common all-grade AEs included constipation (39.1%), fatigue (35.1%), peripheral edema (28.4%), myalgia (26.2%), and nausea (24.0%).

Conclusion: Updated results from this pooled analysis further demonstrate that alectinib has robust clinical activity and a manageable safety profile in patients with advanced, ALK+ NSCLC pretreated with crizotinib.
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http://dx.doi.org/10.1016/j.lungcan.2019.10.015DOI Listing
January 2020

Phase II Study Evaluating the Mechanisms of Resistance on Tumor Tissue and Liquid Biopsy in Patients With EGFR-mutated Non-pretreated Advanced Lung Cancer Receiving Osimertinib Until and Beyond Radiologic Progression: The MELROSE Trial.

Clin Lung Cancer 2020 01 1;21(1):e10-e14. Epub 2019 Oct 1.

Department of Biochemistry, Centre Hospitalier Universitaire Nantes, Nantes, France.

Background: Osimertinib, a third-generation tyrosine kinase inhibitor, is a new therapeutic option in epidermal growth factor receptor (EGFR)-mutated non-pretreated advanced non-small-cell lung cancer (NSCLC). The tumor escape mechanisms after first-line treatment with osimertinib are partially known; most of the data being obtained by analysis of circulating tumor DNA (ctDNA) from the FLAURA phase III trial.

Study Design: The MELROSE study, a French multicentric, open label, phase II trial (ClinicalTrials.govNCT03865511) plans to enroll 150 patients with treatment-naive advanced EGFR-mutated (L858R or exon 19 deletion) NSCLC, age ≥ 18 years, with an Eastern Cooperative Oncology Group performance status 0 or 1. All patients will receive osimertinib at the dose of 80 mg/d. Tumor assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria will be performed every 3 months, with brain and thoracoabdominal computed tomographic scan. The continuation of osimertinib is at the discretion of the referring physician, particularly if clinical benefit is observed. The primary objective is the genetic tumor profile, both on tissue biopsy and ctDNA analyses, at the time of disease progression. Other endpoints include kinetic studies of ctDNA, biological progression-free survival (bPFS) (time from first study dose to first biological event on ctDNA), median PFS according to RECIST criteria 1.1 (called radiological [r] PFS), and median clinical (c) PFS (time from the first study dose to off-osimertinib). This study started in April 2019, and 18 centers in France are participants.
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http://dx.doi.org/10.1016/j.cllc.2019.09.007DOI Listing
January 2020

Clinical outcomes of non-small-cell lung cancer patients with BRAF mutations: results from the French Cooperative Thoracic Intergroup biomarkers France study.

Eur J Cancer 2019 07 8;116:86-97. Epub 2019 Jun 8.

Department of Medical Oncology, Thoracic Unit, Gustave Roussy, Villejuif, France. Electronic address:

Introduction: Patients with stage IV non-small-cell lung cancer (NSCLC) and BRAF V600 mutations may benefit from targeted therapies. Chemotherapy outcomes are little known in this population.

Methods: The French Cooperative Thoracic Intergroup (IFCT) Biomarkers France study was a national prospective cohort study aiming to describe the molecular characteristics and clinical outcome of all consecutive NSCLC patients (N = 17,664) screened for molecular alterations. We used this data set to set up a case-control analysis. Cases had stage IV BRAF-mutated (BRAF-MT) NSCLC, whereas controls had NSCLC that was wild-type for EGFR, KRAS, HER2, BRAF, PIK3CA and ALK. Each case was matched for sex, age at diagnosis and smoking status to two controls randomly selected.

Results: Overall, 83 cases with BRAF mutant disease (66.3% V600E) were matched to 166 controls. Five cases received tyrosine kinase inhibition in the first-line and 16 in the second-line. All others were treated with standard chemotherapy. There was no significant difference in first-line and second-line progression-free survival (PFS) between the groups, as well as in the disease control rate, BRAF mutation was not found to be prognostic of overall survival. We found no significant difference in outcome between the treatment types used in first-line or second-line in patients with BRAF-MT disease compared with controls nor between BRAF V600E or non-V600E compared with controls.

Conclusions: BRAF mutation is not a strong prognostic factor in NSCLC. Although taxan-based therapy shows poorest PFS in first-line, no chemotherapy regimen was associated with prognosis.
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http://dx.doi.org/10.1016/j.ejca.2019.04.016DOI Listing
July 2019

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.

Clin Cancer Res 2019 10 7;25(19):5759-5765. Epub 2019 Jun 7.

Department of Thoracic Oncology, Centre d'investigation clinique Institut national de la santé et de la recherche médicale 1425, Hospital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Paris-Diderot University (Paris 7), Paris, France.

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; = 0.004]. QFS was also longer in the PCB arm for the pain dimension (HR = 0.84; 95% CI, 0.69-1.02; = 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2860DOI Listing
October 2019

Systemic Capillary Leak Syndrome (Clarkson's Disease) as a Complication of Anti-Programmed Death 1 Immunotherapy.

J Thorac Oncol 2019 06;14(6):e131-e132

Service de Pneumologie, CHU de Rennes, Rennes, France; Chemistry Oncogenesis and Stress Signaling, INSERM U1242, Rennes, France.

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http://dx.doi.org/10.1016/j.jtho.2019.02.003DOI Listing
June 2019

Clinical efficacy and cost-effectiveness of endobronchial ultrasound-guided transbronchial needle aspiration for preoperative staging of non-small-cell lung cancer: Results of a French prospective multicenter trial (EVIEPEB).

PLoS One 2019 7;14(1):e0208992. Epub 2019 Jan 7.

Department of Pneumology, CHU de Rouen, Rouen, France.

This two-step study evaluated the cost-effectiveness of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for presurgery staging of non-small cell lung cancer (NSCLC) in France (EVIEPEB; ClinicalTrial.gov identifier NCT00960271). Step 1 consisted of a high-benchmark EBUS-TBNA-training program in participating hospital centers. Step 2 was a prospective, national, multicenter study on patients with confirmed or suspected NSCLC and an indication for mediastinal staging with at least one lymph node > 1 cm in diameter. Patients with negative or uninformative EBUS-TBNA and positron-emission tomography-positive or -negative nodes, respectively, underwent either mediastinoscopy or surgery. Direct costs related to final diagnosis of node status were prospectively recorded. Sixteen of 22 participating centers were certified by the EBUS-TBNA-training program and enrolled 163 patients in Step 2. EBUS-TBNA was informative for 149 (91%) patients (75 malignant, 74 non-malignant) and uninformative for 14 (9%). Mediastinoscopy was avoided for 80% of the patients. With a 52% malignant-node rate, EBUS-TBNA positive- and negative-predictive values, respectively, were 100% and 90%. EBUS-TBNA was cost-effective, with expected savings of €1,450 per patient, and would have remained cost-effective even if all EBUS-TBNAs had been performed under general anesthesia or the cost of the procedure had been 30% higher (expected cost-saving of €994 and €1,427 per patient, respectively). After EBUS-TBNA training and certification of participating centers, the results of this prospective multicenter study confirmed EBUS-TBNA cost-effectiveness for NSCLC staging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0208992PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322724PMC
September 2019

An Original Case of an Association of Eosinophilic Fasciitis with Cholangitis Induced by Nivolumab.

J Thorac Oncol 2019 01;14(1):e13-e15

Department of Internal Medicine, South Hospital, Rennes, France; Rennes 1 University, Rennes, France.

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http://dx.doi.org/10.1016/j.jtho.2018.09.016DOI Listing
January 2019

Systemic Therapy in Advanced Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort.

J Thorac Oncol 2018 11 21;13(11):1762-1770. Epub 2018 Aug 21.

University of Lyon, University Claude Bernard Lyon 1, Lyon, France; Thorax Institute Curie-Montsouris, Curie Institute, Paris, France. Electronic address:

Introduction: Thymic epithelial tumors (TETs) are rare malignancies that may be aggressive and difficult to treat. In the advanced setting, systemic treatments may be delivered as primary therapy before surgery or definitive radiotherapy, as exclusive treatment when no focal treatment is feasible, or in the setting of recurrences. Réseau tumeurs THYMIques et Cancer (RYTHMIC) is the nationwide network for TETs in France. The objective of the study was to describe the modalities and analyze the efficacy of systemic treatments for patients with advanced TETs included in the RYTHMIC prospective database hosted by the French Thoracic Cancer Intergroup.

Methods: All consecutive patients for whom systemic treatment was discussed at the RYTHMIC multidisciplinary tumor board from 2012 to 2015 and who received at least one cycle of treatment were included. The main end points were objective response and progression-free survival (PFS).

Results: A total of 236 patients were included in this analysis. Of those 236 patients, 91 received primary chemotherapy, leading to response rates of 83% for thymomas and 75% for thymic carcinomas and a median PFS of 23.2 months. A strong predictor of longer PFS was histologic type of thymoma (p < 0.001). Exclusive chemotherapy was delivered to 54 patients. The response rates were 31% for thymomas and 37% for thymic carcinomas. The median PFS was 6.2 months, and it was correlated to response rate (p = 0.001). Systemic therapy for a first, second, third, and fourth recurrence was delivered to 114, 81, 51, and 27 patients, respectively. The response rates ranged between 15% and 39% for thymomas and 4% to 21% for thymic carcinomas. The median PFS times were 7.7, 6.2, 5.9, and 6.5 months, respectively.

Conclusion: Patients with advanced thymic malignancies may receive multiple lines of systemic therapy, with an opportunity for clinically relevant PFS rates for which objective response may be a surrogate. Our real-life study provides landmark efficacy data that are needed when designing clinical trials to assess innovative agents.
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http://dx.doi.org/10.1016/j.jtho.2018.08.005DOI Listing
November 2018

Optimized radiotherapy to improve clinical outcomes for locally advanced lung cancer.

Radiat Oncol 2018 Aug 13;13(1):147. Epub 2018 Aug 13.

Département de Radiothérapie, Centre Eugène Marquis, Rue de la Bataille Flandres Dunkerque, Rennes, France.

Background: We aimed to evaluate the toxicity, loco-regional control (LRC) and overall survival (OS) associated with accelerated intensity-modulated radiotherapy (IMRT) for locally advanced lung cancer.

Methods: Seventy-three patients were consecutively treated with IMRT from November 2011 to August 2016. A total dose of 66 Gy was delivered using two different schedules of radiotherapy: simultaneous modulated accelerated radiotherapy (SMART) (30 × 2.2 Gy, across 6 weeks) with or without chemotherapy, or moderate hypofractionated radiotherapy (HRT) (24 × 2.75 Gy, across 4 weeks) in patients unfit to receive concomitant chemotherapy. Data on esophageal and pulmonary toxicities, LRC and OS were prospectively collected.

Results: The median follow-up duration was 44 months. Severe pneumonitis and esophagitis (grade 3-4) were observed in 7% and 1% of patients respectively, with only one case of grade 4 (pneumonitis). Overall, the 1-year and 2-year LRCs were 76% [95 confidence interval (CI)%: 66-87%] and 62% [95 CI%: 49-77%] respectively. The 1 and 2-year OS rates were 72% [95% CI: 63-83%] and 54% [95 CI%: 43-68%] respectively. None parameters were correlated with LRC or OS. In particular, no difference was observed between patients treated with SMART and H-RT (p = 0.26 and 0.6 respectively), with a 1-year LRC of 74% [95 CI%: 62-86%] for SMART and 91% [95 CI%: 74-100%] for H-RT. No significant differences were observed in the toxicity rates associated with each of the RT schedules.

Conclusions: Accelerated IMRT for locally advanced lung cancer is associated with low toxicities and high LRC. Moderate hypofractionated RT, by decreasing the total treatment time, may be promising in improving clinical outcomes.
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http://dx.doi.org/10.1186/s13014-018-1094-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6090773PMC
August 2018

30 Immunotherapy in advanced NSCLC-from the 'tsunami' of therapeutic knowledge to a clinical practice algorithm: results from an international expert panel meeting of the Italian Association of Thoracic Oncology (AIOT).

ESMO Open 2018 31;3(4):e000298. Epub 2018 May 31.

Division of Medical Oncology, 'S.G. Moscati' Hospital, Avellino, Italy.

Although lung cancer remains the leading cause of death from cancer worldwide, the advent of immunotherapy is changing the survival of patients affected by non-small cell lung cancer (NSCLC). A multitude of clinical trials are evaluating different immune checkpoints inhibitors in this new field of thoracic oncology. At the beginning of the immunotherapy era, nivolumab, pembrolizumab and atezolizumab showed high efficacy in patients with advanced NSCLC in second-line setting, receiving approvals for clinical practice. Nivolumab and atezolizumab are approved independently from programmed death lig and 1 (PD-L1) expression, while pembrolizumab is currently approved only for patients with PD-L1 expression ≥1%. The role of PD-L1 expression acquired more interest considering first-line clinical trials, in which the role of immunotherapy as monotherapy was confirmed only for pembrolizumab in patients with PD-L1 expression ≥50%. These data were analysed in this paper, focusing on the implications in clinical practice and how to use them to an accurate clinical benefit of patients with advanced NSCLC. We report a review based on a MEDLINE/PubMed, searched for randomised phase 2/3 trials evaluating immune checkpoint inhibitors and NSCLC, that moved to an approval from Food and Drug Administration (FDA) and European Medicine Agency (EMA). The evidence discussed in this manuscript and the final therapeutic algorithm, coming out from an International Experts Panel Meeting of the Italian Association of Thoracic Oncology.
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http://dx.doi.org/10.1136/esmoopen-2017-000298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6012561PMC
May 2018

Cost-effectiveness of , and testing for decision making in advanced nonsmall cell lung carcinoma: the French IFCT-PREDICT.amm study.

Eur Respir J 2018 03 15;51(3). Epub 2018 Mar 15.

Service de Pneumologie, Assistance Publique Hôpitaux de Paris, Hôpital Tenon, Sorbonne Universités, UPMC Université Paris 06, GRC 04, Theranoscan, Paris, France.

rearrangement and / mutations constitute the primary biomarkers tested to provide targeted or nontargeted therapies in advanced nonsmall cell lung cancer (NSCLC) patients. Our objective was to assess the cost-effectiveness of biomarker testing for NSCLC.Between 2013 and 2014, 843 treatment-naive patients were prospectively recruited at 19 French hospitals into a longitudinal observational cohort study. Two testing strategies were compared, with "at least one biomarker status known" and "at least status known", in addition to "no biomarker testing" as the reference strategy. The Kaplan-Meier approach was employed to assess restricted mean survival time. Direct medical costs incurred by hospitals were estimated with regard to treatment, inpatient care and biomarker testing.Compared with "no biomarker testing", the "at least one biomarker status known" strategy yielded an incremental cost-effectiveness ratio of EUR13 230 per life-year saved, which decreased to EUR7444 per life-year saved with the "at least status known" testing strategy. In sensitivity analyses, biomarker testing strategies were less costly and more effective in 41% of iterations.In summary, molecular testing prior to treatment initiation proves to be cost-effective in advanced NSCLC management and may assist decision makers in defining conditions for further implementation of these innovations in general practice.
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http://dx.doi.org/10.1183/13993003.01467-2017DOI Listing
March 2018

Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.

Lancet Oncol 2018 04 12;19(4):521-536. Epub 2018 Mar 12.

Columbia University Medical Center, New York, NY, USA.

Background: Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1.

Methods: ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR-/ALK- NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423.

Findings: Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7-21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8-23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2-43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines.

Interpretation: In patients with advanced and heavily pretreated NSCLC, the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts; the proportion of patients with EGFR-/ALK- NSCLC (cohorts 2 and 3) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(18)30144-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771363PMC
April 2018

Real-life experience of ceritinib in crizotinib-pretreated advanced non-small cell lung cancer patients.

ERJ Open Res 2018 Jan 13;4(1). Epub 2018 Feb 13.

Institut d'Oncologie Thoracique, Institut Gustave Roussy, Villejuif, France.

Here we report our experience of ceritinib in crizotinib-pretreated patients with anaplastic lymphoma kinase () positive () non-small cell lung cancer (NSCLC) in a French temporary authorisation for use (TAU) study. The French TAU study included crizotinib-pretreated patients with advanced or ROS proto-oncogene 1 positive () tumours. Patients received oral ceritinib (750 mg·day as a starting dose) and best tumour response (as evaluated by the investigator) and safety were reported every 3 months. A total of 242 TAUs were granted from March 12, 2013 to August 05, 2015. Of the 242 patients, 228 had NSCLC and 13 had NSCLC. The median age of patients (n=214) was 58.5 years, 51.9% were female, 70.8% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and 50.0% had brain metastases. Of the 149 efficacy evaluable NSCLC patients, 5.4% had a complete response (CR), 47.0% had a partial response (PR) and 22.8% had stable disease (SD). At September 05, 2015, the median duration of ceritinib treatment (n=182) was 3.9 months but 5.5 months for patients (n=71) with a follow-up of ≥12 months. Higher objective response rate (ORR) was observed for patients with ECOG PS 0 to 1 (55.0% 42.4%) and those receiving prior crizotinib for >5 months (51.6% 36.1%). Treatment-related adverse events (AEs) were reported in 118 of 208 patients (56.7%), the most common being diarrhoea (22.1%) and hepatic toxicity (19.7%). Ceritinib (750 mg·day) demonstrated efficacy similar efficacy to ASCEND-1, ASCEND-2 and phase 3 ASCEND-5 trials with manageable safety in crizotinib-pretreated patients with NSCLC.
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http://dx.doi.org/10.1183/23120541.00058-2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810621PMC
January 2018

Spontaneous splenic rupture as a rare complication of G-CSF injection.

BMJ Case Rep 2018 Jan 12;2018. Epub 2018 Jan 12.

Centre Hospitalier Universitaire de Rennes, Rennes, France.

Splenic rupture is an infrequent and underdiagnosed side effect of granylocyte colony-stimulating factor (G-CSF). We report the case of a 54-year-old woman with brain and bone metastasis in a lung adenocarcinoma who was admitted for faintness 28 days after a G-CSF injection. Abdominal CT scan confirmed the diagnosis of splenic rupture. A conservative treatment was chosen using a peritoneal cleansing during laparoscopic surgery. Clinicians should be aware of this rare toxicity as it could be severe, but easily reversible using appropriate surgical treatment. Even if prognosis remains poor for patients with lung cancer, invasive procedures could be considered in this rapidly evolving setting, especially in case of reversible adverse event.
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http://dx.doi.org/10.1136/bcr-2017-222561DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780587PMC
January 2018

Mutational Landscape of DDR2 Gene in Lung Squamous Cell Carcinoma Using Next-generation Sequencing.

Clin Lung Cancer 2018 03 19;19(2):163-169.e4. Epub 2017 Oct 19.

Department of Respiratory Medicine, Pontchaillou Hospital, Rennes 1 University, Rennes, France; Chemistry, Oncogenesis, and Stress Signaling, INSERM U1242, Centre Eugène Marquis, Rennes, France.

Background: Lung cancer represents the leading cause of cancer-related death worldwide. Despite great advances in lung cancer management with the recent emergence of molecular targeted therapies for non-squamous non-small-cell lung cancer, no dramatic improvements have been achieved in lung squamous cell carcinoma (SCC). Mutations in discoidin domain receptor 2 (DDR2) gene were recently identified as promising molecular targets in this histology. The aim of this study is to describe the DDR2 mutational landscape of lung SCC and investigate the associated clinical factors.

Methods: Next-generation sequencing of the DDR2 gene was performed on 271 samples of lung SCC. Patients followed in our institution from January 2011 to August 2014 were retrospectively selected for data collection. Other driver gene alterations (EGFR, KRAS, BRAF, HER2, and PI3KCA) were analyzed using pyrosequencing.

Results: A total of 11 patients harboring a DDR2 mutation was detected among the 271 sequenced lung SCC samples (4%). We describe 10 unreported mutations, comprising a novel DDR2 exon 7 splice mutant. DDR2 mutations were not mutually exclusive with other driver gene alterations. One hundred thirty-six patients were included for clinical comparison and logistic regression analysis. No difference was detected between DDR2-mutant and DDR2 wild-type lung SCC regarding clinical characteristics or survival.

Conclusion: DDR2 mutations were observed in 4% of cases of lung SCC of European descent. DDR2-mutated tumors can exhibit other driver gene alterations. No clinical characteristics were significantly associated with DDR2 mutation.
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http://dx.doi.org/10.1016/j.cllc.2017.10.006DOI Listing
March 2018

Large Cell Neuroendocrine Lung Carcinoma Transformation as an Acquired Resistance Mechanism to Osimertinib.

J Thorac Oncol 2017 11;12(11):e184-e186

Department of Respiratory Medicine, Pontchaillou Hospital, Rennes, France; Chemistry, Oncogenesis, and Stress Signaling, INSERM U1242, Rennes 1 University, Centre Eugène Marquis, Rennes, France.

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http://dx.doi.org/10.1016/j.jtho.2017.07.019DOI Listing
November 2017

Efficacy and safety of long-acting pasireotide or everolimus alone or in combination in patients with advanced carcinoids of the lung and thymus (LUNA): an open-label, multicentre, randomised, phase 2 trial.

Lancet Oncol 2017 12 23;18(12):1652-1664. Epub 2017 Oct 23.

Endocrine Oncology and Nuclear Medicine, Institut Gustave Roussy, Villejuif, France.

Background: There are no data from prospective studies focused exclusively on patients with advanced lung and thymic carcinoids. We aimed to assess the efficacy and safety of long-acting pasireotide and everolimus, administered alone or in combination, in patients with advanced carcinoids of the lung or thymus.

Methods: LUNA was a prospective, multicentre, randomised, open-label, phase 2 trial of adult patients (aged >18 years) with advanced (unresectable or metastatic), well differentiated carcinoid tumours of the lung or thymus, with radiological progression within 12 months before randomisation, and a WHO performance status of 0-2. At each centre, the investigator or their designee registered each patient using an interactive voice recognition system into one of the three treatment groups. The randomisation allocation sequence was generated by an external company; patients were randomly assigned (1:1:1) to receive treatment with long-acting pasireotide (60 mg intramuscularly every 28 days), everolimus (10 mg orally once daily), or both in combination, for the core 12-month treatment period. Patients were stratified by carcinoid type (typical vs atypical) and line of study treatment (first line vs others). The primary endpoint was the proportion of patients progression-free at month 9, defined as the proportion of patients with overall lesion assessment at month 9 showing a complete response, partial response, or stable disease according to local Response Evaluation Criteria in Solid Tumors, version 1.1, assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment. The trial is registered with ClinicalTrials.gov, number NCT01563354. The extension phase of the study is ongoing.

Findings: Between Aug 16, 2013, and Sept 30, 2014, 124 patients were enrolled from 36 centres in nine countries: 41 were allocated to the long-acting pasireotide group, 42 to the everolimus group, and 41 to the combination group. At month 9, the proportion of patients with an overall lesion assessment of complete response, partial response, or stable disease was 16 of 41 patients (39·0%, 95% CI 24·2-55·5) in the long-acting pasireotide group, 14 of 42 patients (33·3%, 19·6-49·5) in the everolimus group, and 24 of 41 patients (58·5%, 42·1-73·7) in the combination group. The most common grade 1-2 adverse events with a suspected association with long-acting pasireotide monotherapy were diarrhoea (15 [37%] of 41), hyperglycaemia (17 [41%]), and weight loss (8 [20%]); those with a suspected association with everolimus monotherapy were stomatitis (26 [62%] of 42) and diarrhoea (16 [38%]); and those suspected to be associated with combination treatment were hyperglycaemia (27 [66%] of 41]), diarrhoea (19 [46%]), and asthenia (8 [20%]). The most common grade 3-4 adverse events with a suspected association with long-acting pasireotide monotherapy were γ-glutamyltransferase increased (four [10%] of 41 patients), diarrhoea (three [7%]), and hyperglycaemia (three [7%]); those for everolimus were hyperglycaemia (seven [17%] of 42 patients), stomatitis (four [10%]), and diarrhoea (three [7%]); those for combination treatment were hyperglycaemia (nine [22%] of 41 patients) and diarrhoea (four [10%]). 11 patients died during the core 12-month treatment phase or up to 56 days after the last study treatment exposure date: two (5%) of 41 in the long-acting pasireotide group, six (14%) of 42 in the everolimus group, and three (7%) of 41 in the combination group. No deaths were suspected to be related to long-acting pasireotide treatment. One death in the everolimus group (acute kidney injury associated with diarrhoea), and two deaths in the combination group (diarrhoea and urinary sepsis in one patient, and acute renal failure and respiratory failure in one patient) were suspected to be related to everolimus treatment. In the latter patient, acute renal failure was not suspected to be related to everolimus treatment, but respiratory failure was suspected to be related.

Interpretation: The study met the primary endpoint in all three treatment groups. Safety profiles were consistent with the known safety profiles of these agents. Further studies are needed to confirm the antitumour efficacy of the combination of a somatostatin analogue with everolimus in lung and thymic carcinoids.

Funding: Novartis Pharma AG.
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http://dx.doi.org/10.1016/S1470-2045(17)30681-2DOI Listing
December 2017

Clinicopathological characteristics of and rearranged NSCLC in caucasian patients: Data from a cohort of 713 non-squamous NSCLC lacking KRAS/EGFR/HER2/BRAF/PIK3CA/ALK alterations.

Oncotarget 2017 Aug 8;8(32):53336-53351. Epub 2017 Jun 8.

Department of Cytogenetics and Cell Biology, CHU de Rennes, Rennes, France.

Targeted therapies have substantially changed the management of non-small cell lung cancer (NSCLC) patients with driver oncogenes. Given the high frequency, and aberrations were the first to be detected and paved the way for tyrosine kinase inhibitor (TKI) treatments. Other kinases such as and more recently have emerged as promising targets, and ROS1 and RET TKIs are already available for precision medicine. We screened a large cohort of 713 Caucasian non-squamous NSCLC patients lacking ///// aberrations for and rearrangements using fluorescence hybridization to determine the frequency and clinicopathological characteristics of ROS1- and RET-positive patients. Frequencies of and rearrangements were 2.1% and 2.52%, respectively. Contrary to common belief, both and rearrangements were detected in patients with a history of smoking, and the -positive patients were not younger than the negative patients. Moreover, but not rearrangement was associated with the female gender. Nearly half of the -rearranged patients were successfully treated with ROS1 TKIs. In contrast, only 5/18 RET-positive patients received off-label RET TKIs. Two patients had stable disease, and three experienced disease progression. In addition to the 18 RET-positive cases, 10 showed isolated 5' signals. The clinical relevance is unknown but if the frequency is confirmed by other groups, the question whether these patients are eligible to TKIs will arise. More potent RET TKIs are under development and may improve the response rate in RET-positive patients. Therefore, we recommend the routine implementation of RET testing in non-squamous NSCLC patients, including those with a history of smoking.
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http://dx.doi.org/10.18632/oncotarget.18408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581114PMC
August 2017

Multidisciplinary Tumor Board Decision Making for Postoperative Radiotherapy in Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort.

J Thorac Oncol 2017 11 31;12(11):1715-1722. Epub 2017 Jul 31.

Respiratory Department, Hospices Civils of Lyon, Lyon, France. Electronic address:

Introduction: Thymic epithelial tumors (TETs) are rare intrathoracic malignancies for which surgery represents the mainstay of the treatment. Current practice for postoperative radiotherapy (PORT) is highly variable, and there is a lack of prospective, high level evidence. Réseau Tumeurs Thymiques et Cancer (RYTHMIC) is the nationwide network for TETs in France. Established in 2012, it prospectively collects data on all TET patients, for whom management is discussed at a national multidisciplinary tumor board (MTB). We assessed whether PORT decisions at the MTB were in accordance with RYTHMIC guidelines and ultimately implemented in patients.

Methods: All consecutive patients for whom PORT was discussed at the MTB from 2012 to 2015 were identified from the RYTHMIC prospective database, and a complete review of their medical records was performed.

Results: A total of 274 patients, including 243 with thymoma (89%) and 31 with thymic carcinoma (11%), were analyzed. The decision of the MTB was in accordance with guidelines in 221 patients (92%) of the 241 with stage I or III TET. An MTB decision to deliver PORT was made for 117 patients (43%). PORT was ultimately initiated in 101 patients. The most frequent reason for not delivering PORT was excessive (>3 months) delay after surgery. Dose-volume constraints defined by the International Thymic Malignancy Interest Group were followed in all but four patients.

Conclusion: Our data provide a unique insight into the decision-making process for PORT in TETs, highlighting the need for systematic discussion at an expert MTB, while stressing the value of current available guidelines.
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http://dx.doi.org/10.1016/j.jtho.2017.07.023DOI Listing
November 2017

Pooled Systemic Efficacy and Safety Data from the Pivotal Phase II Studies (NP28673 and NP28761) of Alectinib in ALK-positive Non-Small Cell Lung Cancer.

J Thorac Oncol 2017 10 6;12(10):1552-1560. Epub 2017 Jul 6.

Massachusetts General Hospital Cancer Centre, Harvard Medical School, Boston, Massachusetts.

Introduction: Alectinib demonstrated clinical efficacy and an acceptable safety profile in two phase II studies (NP28761 and NP28673). Here we report the pooled efficacy and safety data after 15 and 18 months more follow-up than in the respective primary analyses.

Methods: Enrolled patients had ALK receptor tyrosine kinase gene (ALK)-positive NSCLC and had progressed while taking, or could not tolerate, crizotinib. Patients received oral alectinib, 600 mg twice daily. The primary end point in both studies was objective response rate assessed by an independent review committee (IRC) using the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included disease control rate, duration of response, progression-free survival, overall survival, and safety.

Results: The pooled data set included 225 patients (n = 138 in NP28673 and n = 87 in NP28761). The response-evaluable population included 189 patients (84% [n = 122 in NP28673 and n = 67 in NP28761]). In the response-evaluable population, objective response rate as assessed by the IRC was 51.3% (95% confidence interval [CI]: 44.0-58.6 [all PRs]), the disease control rate was 78.8% (95% CI: 72.3-84.4), and the median duration of response was 14.9 months (95% CI: 11.1-20.4) after 58% of events. Median progression-free survival as assessed by the IRC was 8.3 months (95% CI: 7.0-11.3) and median overall survival was 26.0 months (95% CI: 21.4-not estimable). Grade 3 or higher adverse events (AEs) occurred in 40% of patients, 6% of patients had treatment withdrawn on account of AEs, and 33% had AEs leading to dose interruptions/modification.

Conclusions: This pooled data analysis confirmed the robust systemic efficacy of alectinib in ALK-positive NSCLC with a durable response rate. Alectinib also had an acceptable safety profile with a longer duration of follow-up.
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http://dx.doi.org/10.1016/j.jtho.2017.06.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886236PMC
October 2017

Efficacy of alectinib in central nervous system metastases in crizotinib-resistant ALK-positive non-small-cell lung cancer: Comparison of RECIST 1.1 and RANO-HGG criteria.

Eur J Cancer 2017 09 10;82:27-33. Epub 2017 Jul 10.

Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

Background: Central nervous system (CNS) progression is common in patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) receiving crizotinib. Next-generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria.

Methods: Both studies enrolled patients aged ≥18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee.

Results: Baseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2-77.1; 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7-68.8; eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate).

Conclusion: Alectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used.
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http://dx.doi.org/10.1016/j.ejca.2017.05.019DOI Listing
September 2017