Summary Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Funding Bristol-Myers Squibb.

Hospitalizations for acute exacerbation in patients with chronic obstructive pulmonary disease (COPD) have a great impact on health care expenditure. The aim of this study was to look at predictive factors of hospitalization for acute exacerbation in a group of patients with moderate to severe COPD. During the year 1994, we included 64 patients with COPD in this study. At inclusion, the patients being in a stable state, we performed a complete evaluation of their clinical, spirometric, gasometric, and pulmonary hemodynamic characteristics. All patients were followed during a period of at least 2.5 yr. We recorded the intervals free of hospitalization for exacerbation and realized an analysis of the proportional hazards not to be hospitalized using the Kaplan-Meier method. Univariate analysis using the log-rank test showed that the risk of being hospitalized was significantly increased in patients with COPD with a low body mass index (BMI <= 20 kg/m2, p = 0.015) and in patients with a limited 6-min walk distance (<= 367 m, p = 0. 045). But above all, the risk of hospitalization for acute exacerbation was significantly increased by gas exchange impairment and pulmonary hemodynamic worsening: PaO2 <= 65 mm Hg versus PaO2 > 65 mm Hg, p = 0.005; PaCO2 > 44 mm Hg versus PaCO2 <= 44 mm Hg, p = 0.005; and mean pulmonary artery pressure ( Ppa) at rest > 18 mm Hg versus Ppa <= 18 mm Hg, p = 0.0008. Neither age, nor the association of one or more comorbidities with COPD, nor the smoking habits had a significant impact on the risk of hospitalization in our study. Multivariate analysis showed that only PaCO2 and Ppa were independently related to the risk of hospitalization for acute exacerbation of COPD. We conclude that chronic hypercapnic respiratory insufficiency and pulmonary hypertension are predictive factors of hospitalization for acute exacerbation in COPD patients.

Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics. Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progressionfree survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated. Conclusion:In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.

Overall survival (OS) with the anaplastic lymphoma kinase (ALK) inhibitor (ALKi) crizotinib in a large population of unselected patients with ALK-positive non-smallcell lung cancer (NSCLC) is not documented. We sought to assess OS with crizotinib in unselected ALK-positive NSCLC patients and whether post-progression systemic treatments affect survival outcomes.ALK-positive NSCLC patients receiving crizotinib in French expanded access programs or as approved drug were enrolled. We collected clinical and survival data, RECIST-defined progressive disease (PD) and post-PD systemic treatment efficacy. We performed multivariable analysis of OS from crizotinib initiation and PD under crizotinib. Unselected ALK-positive NSCLC patients achieve good survival outcomes with crizotinib therapy. Next-generation ALKi may provide survival improvement after PD under crizotinib.

In EGFR-TKIs naive NSCLC patients, MET amplification is a frequent event, which could be associated with EGFR amplification, but not with K-Ras mutation. MET amplification may identify a subset of NSCLC for new targeted therapy. It will also be important to evaluate MET copy number to properly interpret future clinical trials.

Introduction: Immune checkpoint inhibitors (ICIs) have improved cancer prognosis but have not been evaluated specifically in sarcomatoid carcinoma (SC), a rare lung cancer subtype with poor prognosis. As such, our study sought to retrospectively assess the efficacy of ICI in SC.Methods: All consecutive patients with centrally confirmed SC treated using ICI as a second-line treatment or beyond between 2011 and 2017 were enrolled. Programmed deathligand 1 (PD-L1) tumor expression was assessed using immunohistochemistry (SP263 clone) and the tumor mutational burden (TMB) with the Foundation One panel. TMB was considered high if it was greater than or equal to 10 mutations per megabase.Results: Overall, 37 patients with SC were evaluated, predominantly men (73%) with a median age of 63.2 years (36.8-79.7) and who were current or former smokers (94.6%). Immunotherapy (nivolumab, 86.5% of cases) was given as a second-line treatment in 54% of the patients and as third-line treatment or beyond in 46% of the patients. The objective response rate was 40.5% and disease control rate was 64.8%, regardless of PD-L1 status. Median overall survival was 12.7 months (range: 0.3-45.7). One-third of patients exhibited early progression. The median PD-L1 expression was 70% (0-100). There was a trend toward higher PD-L1 expression in responsive diseases, with an objective response rate of 58.8% in patients with PD-L1þ and 0% in the one patient with PD-L1-(p ¼ 0.44). The median TMB was 18 (4-39) mutations per megabase, with 87.5% of the cases displaying a high TMB. There was a trend toward higher TMB in responders versus stable or progressive diseases (p ¼ 0.2).Conclusions: Patients with SC exhibited high response rates and prolonged overall survival under ICI treatment. These data support the prospective investigation of ICI in patients with SC who are under first-line treatment.

Background: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC).Patients and methods: Advanced NSCLC patients with c-MET 6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance.Results: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET 6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET 6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET 6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported.Conclusions: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET 6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified.

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.