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).

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).

Safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination in stage IV non-small-cell lung cancer: An open-label phase II trial (VinMetAtezo).

OBJECTIVE: To evaluate the safety and efficacy of second-line metronomic oral vinorelbine-atezolizumab combination for stage IV non-small-cell lung cancer. METHODS: This was a multicenter, open-label, single-arm Phase II study performed in patients with advanced NSCLC without activating EGFR mutation or ALK rearrangement who progressed after first-line platinum-doublet chemotherapy. Combination treatment was atezolizumab (1200 mg IV day 1, every 3 weeks) and oral vinorelbine (40 mg, 3 times by week). The primary outcome was progression-free survival (PFS) during the 4-month follow-up from the first dose of treatment. Statistical analysis was based on the exact single-stage Phase II design defined by A'Hern. Based on literature data, the Phase III trial threshold was set at 36 successes in 71 patients. RESULTS: 71 patients were analyzed (median age, 64 years; male, 66.2%; ex-smokers/active smokers, 85.9%; ECOG performance status 0-1, 90.2%; non-squamous NSCLC, 83.1%; PD-L1 ≥ 50%, 4.4%). After a median follow-up of 8.1 months from treatment initiation, 4-month PFS rate was 32% (95% CI, 22-44), i.e. 23 successes out 71 patients. OS rate was 73.2% at 4 months and 24.3% at 24 months. Median PFS and OS were 2.2 (95% CI, 1.5-3.0) months and 7.9 (95% CI, 4.8-11.4) months, respectively. Overall response rate and disease control rate at 4 months were 11% (95% CI, 5-21) and 32% (95% CI, 22-44), respectively. No safety signal was evidenced. CONCLUSION: Metronomic oral vinorelbine-atezolizumab in the second-line setting did not achieve the predefined PFS threshold. No new safety signal was reported for vinorelbine-atezolizumab combination.

Clinical Characteristics of Patients with Advanced ALK-Translocated Non-small Cell Lung Cancers and Long-Term Responses to Crizotinib (CRIZOLONG GFPC 05-19 Study).

BACKGROUND: Although ALK-translocated (ALK+) advanced non-small cell lung cancers (aNSCLCs) are currently treated with second- or third-generation ALK inhibitors (ALK-TKIs), some patients respond durably to the first-generation ALK-TKI crizotinib. OBJECTIVE: This study aimed to describe the clinical characteristics of these long-term responders. PATIENTS AND METHODS: This national, multicenter, retrospective, non-interventional study included patients with ALK+ aNSCLCs and long-term responses to first (L1)- or subsequent (≥ L2)-line crizotinib, defined, respectively, as treatments lasting > 18 and > 10 months. Median treatment duration (mDOT) was the primary endpoint. RESULTS: A total of 85 patients (32 L1 and 53 ≥ L2 responders) from 23 centers were included (receiving crizotinib between 10/24/2011-10/02/2018): median age of 59 years, 83.6% non-smokers or ex-smokers, 85.9% performance status (PS) 0/1, 94.1% with adenocarcinomas, median of one metastatic site, and 22.4% with brain metastases (BMs). After median follow-up of 73.4 [95% confidence interval, 67.5-79.9] months, respective L1 and ≥ L2 mDOTs were 43.3 [26.7-56.8] and 29.6 [22.6-35.8] months, with overall survival (OS) not reached (NR) and 116.2 [83.4-NR] months. BM presence or absence did not affect mDOT (31.4 versus 32.9 months) but significantly impacted median OS (70.6 versus 158.6 months; p = 0.0008). Progression on crizotinib was paucisymptomatic (74.1%) and oligometastatic (34.8%), especially BMs (42.4%). After crizotinib discontinuation, 65 (76.5%) patients received subsequent systemic therapy: 57 (67.1%) with second-generation ALK-TKIs. Respective mDOTs of first- and second-line post-crizotinib ALK-TKIs lasted 19.4 [14.9-25.6] and 11.1 [4.8-17.9] months, respectively. CONCLUSIONS: Most ALK+ aNSCLC patients with prolonged crizotinib efficacy had paucisymptomatic and oligometastatic disease without BMs. They subsequently benefited from a sequential strategy with other ALK-TKIs.

Management of patients with synchronous head-and-neck and lung cancers: SYNCHRON GFPC 15-01 study.

Purpose: Few data have been published on the management of patients with synchronous head-and-neck cancer (HNC) and lung cancer (LC). This observational study was undertaken to describe the management of these patients in multiple centers. Materials and Methods: All patients consecutively diagnosed with synchronous HNC and LC in 26 French centers were included. Information was collected on patients' clinical characteristics, management, and outcomes. Those characteristics and treatments were analyzed descriptively. Kaplan-Meier progression-free and overall survival probabilities were estimated. Results: The study included 132 patients: 83% male; median age: 63.7 (range: 62.1-65.4) years; all current or former smokers; Eastern Cooperative Oncology Group performance status: 0 or 1 for 21.9% or 65.9% of the patients, respectively; cardiovascular comorbidities: 63%; chronic obstructive pulmonary disease: 33%; and previous cancer: 11%. HNC histology was 98% squamous: 23.5% oral cavity, 26.5% oropharyngeal, 22.0% hypopharyngeal, and 28.0% laryngeal. LCs were mainly localized (47.7% Stage I and 9.9% Stage II): 38% squamous, 49% adenocarcinomas, and 13% others. LC diagnosis impacted HNC management for 38% of the patients, with a median time from HNC diagnosis to first HNC treatment of 40 days. HNC impacted LC management for 48% of the patients, with a median time from LC diagnosis-to-LC treatment interval of 41 days. Conclusions: Synchronous LC at HNC diagnosis impacted management and outcomes of both cancers. Specific recommendations should be elaborated to improve the management of these patients.

Mid-term pulmonary sequelae after hospitalisation for COVID-19: The French SISCOVID cohort.

BACKGROUND: Even though COVID-19 clinical features, pathogenesis, complications, and therapeutic options have been largely described in the literature, long-term consequences in patients remain poorly known. METHODS: The French, multicentre, non-interventional SISCOVID study evaluated lung impairment three (M3) and six months (M6) after hospital discharge in patients recovered from COVID-19. Evaluation was based on clinical examination, pulmonary function tests, and chest computed tomography (CT-scan). RESULTS: Of the 320 included patients (mean age: 61 years; men: 64.1%), 205 had had a severe form of COVID-19, being hospitalised in an intensive care unit (ICU), and requiring high flow nasal cannula, non-invasive ventilation, or invasive mechanical ventilation. At M6, 54.1% of included patients had persistent dyspnoea (mMRC score ≥1), 20.1% severe impairment in gas diffusing capacity (DLCO <60% pred.), 21.6% restrictive ventilatory pattern (total lung capacity <80% pred.), and 40% a fibrotic-like pattern at CT-scan. Fibrotic-like pattern and restrictive ventilatory pattern were significantly more frequent in patients recovered from severe than non-severe COVID-19. Improved functional and radiological outcomes were observed between M3 and M6. At M6, age was an independent risk factor for severe DLco impairment and fibrotic-like pattern and severe COVID-19 form was independent risk factor for restrictive ventilatory profile and fibrotic-like pattern. CONCLUSION: Six months after discharge, patients hospitalised for COVID-19, especially those recovered from a severe form of COVID-19, frequently presented persistent dyspnoea, lung function impairment, and persistent fibrotic-like pattern, confirming the need for long-term post-discharge follow-up in these patients and for further studies to better understand long-term COVID-19 lung impairment.

Multicenter phase II trial of nintedanib plus docetaxel in second-line treatment in advanced non-squamous non-small cell lung cancer patients refractory to first-line platin-based chemotherapy (REFRACT GFPC 02-15 study).

INTRODUCTION: Advanced non-squamous non-small cell lung cancer (NsqNSCLC) progressing at the induction of a first-line of platin-based chemotherapy is a subgroup of patients with poor prognosis and few second-line treatment options. MATERIALS AND METHODS: This single-stage phase II prospective multicenter open-label trial performed in platin-based refractory (i.e. progressing during induction phase of first-line platin-based chemotherapy) advanced NsqNSCLC assessed the efficacy of the nintedanib-docetaxel combination in second-line treatment. The primary endpoint was progression-free survival (PFS) rates at 12 weeks with a cut-off at 30% for ineffectiveness and 50% for minimal efficacy. RESULTS: A total of 59 patients from 23 centers were included (mean age, 58.5 years; male gender, 73.6%; performance status 0-1, 100%; former/current smokers, 92.5%; adenocarcinoma, 92.5%, median platin-based first-line chemotherapy, 2). Nintedanib-docetaxel combination was administered for a median of 4 cycles. The rate of PFS at 12 weeks was 39.6% (95% CI, 28.2-56.8). Median PFS was 2.7 (95% CI, 1.4-4.1) months and one-year PFS was 11.8% (95% CI, 4.8-22.2). Median overall survival (OS) was 6.9 (95% CI, 4.3-8.2) months and 12-month OS was 32.1% (95% CI, 19.8-45.0); 18-month OS was 27.6% (95% CI, 16,1-40.4). Twenty-nine (53.7%) patients reported at least one serious treatment-related adverse events leading to permanent discontinuation of at least one study drug in 12 (22.2%) patients. CONCLUSION: The predefined minimal efficacy was not demonstrated. However, a number of NsqNSCLC patients refractory to first-line platin-based chemotherapy appeared to benefit from this combination.

Impact of Programmed Death Ligand 1 Expression in Advanced Non-Small-Cell Lung Cancer Patients, Treated by Chemotherapy (GFPC 06-2015 Study).

BACKGROUND: Few data have been published on the clinical and histopathological characteristics of advanced non-small-cell lung cancer (NSCLC) patients with high PD-L1 expression versus intermediate or none and the prognostic value of PD-L1 expression for patients treated with chemotherapy is unknown. This study was undertaken to prospectively assess the prognostic value of tumor-cell (TC) and immune-cell (IC) PD-L1 expressions for advanced NSCLC patients. METHODS: It was a prospective, multicenter study on advanced NSCLC patients, with performance status 0/1, scheduled, consecutively, to receive first-line platin-based chemotherapy. PD-L1 expression was determined immunochemically (Dako Autostainer and monoclonal antibody 22C3) and its impact on progression-free survival (PFS) and overall survival (OS) assessed. RESULTS: Among 198 patients screened in 19 centers, 140 were included median age: 66.5 ± 10 years; 76.4% men; 79.3% Caucasians; 10.7% nonsmokers; 63.6% adenocarcinomas; <1%, 1-50% and ≥50% TC PD-L1-expression rates were 47.1%, 25.7% and 27.2% of patients, respectively; respective null, intermediate and high rates on ICs were 35.7%, 38.6% and 25.7%. Second- and third-line chemotherapies were administered to 58.6% and 26.4% of the patients, respectively. None received immunotherapy. First-, second- and third-line median (95% CI) PFS lasted 4.6 (3.6-5.2), 3.7 (2.3-4.7) and 2.2 (1.5-4.3) months, respectively; median OS was 16.9 (11.4-19.9) months. No significant PFS and OS differences were observed according to TC or IC PD-L1 expression. CONCLUSION: According to the results of this prospective, multicenter study, neither TC nor IC PD-L1 expression appears to be prognostic for chemotherapy-managed advanced NSCLC patients.

Non-Small-Cell Lung Cancer (NSCLC) Harboring ALK Translocations: Clinical Characteristics and Management in a Real-Life Setting: a French Retrospective Analysis (GFPC 02-14 Study).

BACKGROUND: Chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK) are rare oncogenic events found in 3-5% of non-small-cell lung cancers (NSCLC). Limited data have been published on the management of these patients outside clinical trials. OBJECTIVE: To investigate the clinical characteristics and management of patients with NSCLC harboring ALK translocations (ALK+) in a real-life setting in France. METHODS: This multicenter, observational, retrospective study included all NSCLC patients harboring ALK translocations diagnosed in participating centers between January 2012 and December 2014. Patient data include clinical characteristics, disease management, and outcomes [progression-free survival (PFS) and overall survival (OS)]. RESULTS: The 31 participating centers reported data on 132 patients, of whom 51% (n = 67) were male. The median age was 60.1 ± 14.5 (standard deviation) years; 89% (n = 106/119) had performance status 0/1 at diagnosis; 79% (n = 103/130) were non- or former smokers; 93% (n = 120/129) had adenocarcinomas and 74%(n = 97)/19%(n = 25)/7%(n = 10) had disease stages IV/III/I-II at diagnosis, respectively; co-mutations included EGFR (n = 2), BRAF (n  = 2), KRAS (n = 1), and HER2 (n = 1). Of the patients with stage IV NSCLC (n = 97), 96% received first-line treatment [75% chemotherapy-based, 21% ALK tyrosine kinase inhibitor (TKI)], with an associated response rate (RR), disease-control rate (DCR), and PFS of 42%, 64%, and 7.5 [95% confidence interval (CI) 5.9-9.5] months, respectively; 62% received second-line treatment (28% chemotherapy, 72% ALK TKI) with an associated RR, DCR, and PFS of 43.4%, 70%, and 4.7 (95% CI 4.0-8.1) months, respectively. The 2-year OS was 56.7% (95% CI 45.5-70.4%); median OS was not reached. CONCLUSION: The results of this real-life analysis suggest that the prognosis of NSCLC patients with theALK translocation may be better than that of the overall NSCLC population, but the outcomes were poorer than those of ALK+ NSCLC patients included in clinical studies.