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

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

Effect of Ruxolitinib on Lung Function after Allogeneic Stem Cell Transplantation.

Ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor, has recently been proposed for steroid-refractory chronic graft-versus host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT), particularly in severe skin cGVHD. Lung function impairment is common in severe skin cGVHD through concomitant bronchiolitis obliterans syndrome (BOS) or restrictive lung disease (RLD) from skin sclerosis. To date, no treatment has shown a benefit on lung function in this context. We retrospectively assessed the effect of ruxolitinib on lung function in a cohort of 70 patients diagnosed with sclerotic-type skin cGVHD between March 2015 and April 2018. Among these patients, 36 received ruxolitinib. To handle confounding by indication bias, exposure groups were matched on the propensity score to receive ruxolitinib, incorporating age, myeloablative conditioning, total body irradiation, BOS, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and tobacco use at the time of cohort entry, as well as the time from transplantation. The 1:1 matching used a greedy-matching algorithm with replacement, with a caliper of 0.10. FVC and FEV1 trajectories during follow-up were compared in the matched samples, using linear mixed-effects models. The median duration of follow-up of the 46 matched patients was 58 months (interquartile range, 32 to 84 months). Ten patients had an RLD (6 exposed, 4 unexposed), and 13 patients were diagnosed with BOS (8 exposed, 5 unexposed). FEV1 decreased significantly over time independent of exposure to ruxolitinib (P < .0001). The FEV1 trajectory was similar in the exposed patients and the unexposed patients (P = .11). In conclusion, ruxolitinib administration did not demonstrate any improvement in the course of respiratory function in allogeneic HSCT recipients with sclerotic-type skin cGVHD.

Immunotherapy: a new standard of care in thoracic malignancies? A summary of the European Respiratory Society research seminar of the Thoracic Oncology Assembly.

In May 2017, the second European Respiratory Society research seminar of the Thoracic Oncology Assembly entitled "Immunotherapy, a new standard of care in thoracic malignancies?" was held in Paris, France. This seminar provided an opportunity to review the basis of antitumour immunity and to explain how immune checkpoint inhibitors (ICIs) work. The main therapeutic trials that have resulted in marketing authorisations for use of ICIs in lung cancer were reported. A particular focus was on the toxicity of these new molecules in relation to their immune-related adverse events. The need for biological selection, currently based on immunohistochemistry testing to identify the tumour expression of programmed death ligand (PD-L)1, was stressed, as well as the need to harmonise PD-L1 testing and techniques. Finally, sessions were dedicated to the combination of ICIs and radiotherapy and the place of ICIs in nonsmall cell lung cancer with oncogenic addictions. Finally, an important presentation was dedicated to the future of antitumour vaccination and of all ongoing trials in thoracic oncology.

Hedgehog Signaling in Lung Cancer: From Oncogenesis to Cancer Treatment Resistance.

Hedgehog signaling pathway is physiologically activated during embryogenesis, especially in lung development. It is also reactivated in many solid tumors. In lung cancer, Hedgehog pathway is closely associated with cancer stem cells (CSCs). Recent works have shown that CSCs produced a full-length Sonic Hedgehog (Shh) protein, with paracrine activity and induction of tumor development. Hedgehog pathway is also involved in tumor drug resistance in lung cancer, as cytotoxic chemotherapy, radiotherapy, and targeted therapies. This review proposes to describe the activation mechanisms of Hedgehog pathway in lung cancer, the clinical implications for overcoming drug resistance, and the perspectives for further research.

Colony stimulating factor-1 (CSF-1) signalling is predictive of response to immune checkpoint inhibitors in advanced non-small cell lung cancer.

The identification of biomarkers related to treatment in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) represents a significant challenge. The aim of this study was to determine the predictive value of macrophage-related markers assessed in plasma and tissue samples of patients with NSCLC undergoing ICI treatment. This bicentric study included a prospective cohort of 88 patients with advanced NSCLC who received first-line therapy with ICI (either as monotherapy or in combination with chemotherapy) or chemotherapy alone (CT). Samples were collected from the patients at baseline and during follow-up. Plasma levels of CSF-1 and IL-34 were measured using ELISA, while expression levels of the macrophage receptors CD163 and CSF-1-R were evaluated using immunohistochemistry on lung biopsies. At baseline, the median plasma CSF-1 expression was higher in patients who did not respond to immunotherapy compared to those who responded (8898 pg/mL vs. 14031 pg/mL, p = 0.0005). Importantly, high CSF-1 levels at the initial assessment were associated with disease progression regardless of the treatment received. Furthermore, high CSF-1 levels were associated with shorter progression-free survival (PFS) and overall survival (OS) in patients receiving ICI therapy, but not in those treated with chemotherapy. There was no correlation between IL-34, CSF-1R, CD163 and therapeutic response. We observed in vitro that the activation of lymphocytes mediated by pembrolizumab was hindered by the treatment of PBMC with recombinant CSF-1, suggesting that CSF-1 creates a systemic immunosuppressive state that interferes with ICI treatment. In conclusion, baseline CSF-1 levels represent a potential predictive marker to ICI treatment in NSCLC.

Brief Report: Severe Sotorasib-Related Hepatotoxicity and Non-Liver Adverse Events Associated With Sequential Anti-Programmed Cell Death (Ligand)1 and Sotorasib Therapy in KRASG12C-Mutant Lung Cancer.

INTRODUCTION: Sequential anti-programmed cell death protein 1 (PD-1) or anti-programmed death-ligand 1 (PD-L1) followed by small targeted therapy use is associated with increased prevalence of adverse events (AEs) in NSCLC. KRASG12C inhibitor sotorasib may trigger severe immune-mediated hepatotoxicity when used in sequence or in combination with anti-PD-(L)1. This study was designed to address whether sequential anti-PD-(L)1 and sotorasib therapy increases the risk of hepatotoxicity and other AEs. METHODS: This is a multicenter, retrospective study of consecutive advanced KRASG12C-mutant NSCLC treated with sotorasib outside clinical trials in 16 French medical centers. Patient records were reviewed to identify sotorasib-related AEs (National Cancer Institute Common Classification Criteria for Adverse Events-Version 5.0). Grade 3 and higher AE was considered as severe. Sequence group was defined as patients who received an anti-PD-(L)1 as last line of treatment before sotorasib initiation and control group as patients who did not receive an anti-PD-(L)1 as last line of treatment before sotorasib initiation. RESULTS: We identified 102 patients who received sotorasib, including 48 (47%) in the sequence group and 54 (53%) in the control group. Patients in the control group received an anti-PD-(L)1 followed by at least one treatment regimen before sotorasib in 87% of the cases or did not receive an anti-PD-(L)1 at any time before sotorasib in 13% of the cases. Severe sotorasib-related AEs were significantly more frequent in the sequence group compared with those in the control group (50% versus 13%, p < 0.001). Severe sotorasib-related AEs occurred in 24 patients (24 of 48, 50%) in the sequence group, and among them 16 (67%) experienced a severe sotorasib-related hepatotoxicity. Severe sotorasib-related hepatotoxicity was threefold more frequent in the sequence group compared with that in the control group (33% versus 11%, p = 0.006). No fatal sotorasib-related hepatotoxicity was reported. Non-liver severe sotorasib-related AEs were significantly more frequent in the sequence group (27% versus 4%, p < 0.001). Severe sotorasib-related AEs typically occurred in patients who received last anti-PD-(L)1 infusion within 30 days before sotorasib initiation. CONCLUSIONS: Sequential anti-PD-(L)1 and sotorasib therapy are associated with a significantly increased risk of severe sotorasib-related hepatotoxicity and severe non-liver AEs. We suggest avoiding starting sotorasib within 30 days from the last anti-PD-(L)1 infusion.

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

Herein, we report a case of a 73-year-old female patient diagnosed with cT4N0M1a lung adenocarcinoma with KRAS G12C mutation, PDL1 < 1% and treated in fourth-line setting with gemcitabine after progression under nivolumab. After one infusion of gemcitabine, the patient presented with an acute worsening of general condition (performance status 4) with extensive skin lesions and fever, leading to hospitalization and diagnosis of acute generalized exanthematous pustulosis. Initial blood work revealed multiple organ failures with an important inflammatory syndrome. Patient state improved after intravenous hydration and local and systemic corticosteroids. The decision was made to stop systemic cancer treatment. Two months follow-up showed a remarkable response on all cancer localizations. Although immunotherapy is transforming cancer care, predicting response to immunotherapy remains challenging and resistant mechanisms remain mostly unknown. This case underlines that important immune-stimulation can lead to tumor response in a patient previously refractory to all antitumor treatments.

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

[This corrects the article DOI: 10.3389/fonc.2021.747692.].

Electrocardiogram abnormalities and prognosis in COVID-19.

Background: COVID-19 is a major pandemic with potential cardiovascular complications. Few studies have focused on electrocardiogram (ECG) modifications in COVID-19 patients. Method and results: We reviewed from our database all patients referred to our hospital for COVID-19 between January 1st, 2020, and December 31st, 2020: 669 patients were included and 98 patients died from COVID-19 (14.6%). We systematically analyzed ECG at admission and during hospitalization if available. ECG was abnormal at admission in 478 patients (71.4%) and was more frequently abnormal in patients who did not survive (88.8 vs. 68.5%, p < 0.001). The most common ECG abnormalities associated with death were left anterior fascicular block (39.8 vs. 20.0% among alive patients, p < 0.001), left and right bundle branch blocks (p = 0.002 and p = 0.02, respectively), S1Q3 pattern (14.3 vs. 6.0%, p = 0.006). In multivariate analysis, at admission, the presence of left bundle branch block remained statistically related to death [OR = 3.82, 95% confidence interval (CI): 1.52-9.28, p < 0.01], as well as S1Q3 pattern (OR = 3.17, 95% CI: 1.38-7.03, p < 0.01) and repolarization abnormalities (OR = 2.41, 95% CI: 1.40-4.14, p < 0.01).On ECG performed during hospitalization, the occurrence of new repolarization abnormality was significantly related to death (OR = 2.72, 95% CI: 1.14-6.54, p = 0.02), as well as a new S1Q3 pattern (OR = 13.23, 95% CI: 1.49-286.56, p = 0.03) and new supraventricular arrhythmia (OR = 3.8, 95% CI: 1.11-13.35, p = 0.03). Conclusion: The presence of abnormal ECG during COVID-19 is frequent. Physicians should be aware of the usefulness of ECG for risk stratification during COVID-19.

Associations of aspirin, statins and metformin with lung cancer risk and related mortality.

Given the poor survival of lung cancer patients and the promising observations herein, future studies (RCTs) should further investigate both time- and dose-dependent effects of combination therapies across all categories of prevention of lung cancer. https://bit.ly/3hlYTtY.

Baseline Hedgehog Pathway Activation and Increase of Plasma Wnt1 Protein Are Associated with Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer.

Hedgehog (Hh) and Wingless-type (Wnt) pathways are associated with resistance to immune checkpoint inhibitors (ICIs) in preclinical studies. This study aimed to assess the association between expression and activation levels of Wnt and Sonic Hedgehog (Shh) pathways and resistance to ICIs in advanced NSCLC patients treated with ICI. Hh and Wnt pathways activation was assessed by immunohistochemistry (Gli1 and beta-catenin) on corresponding tumor tissues, and by plasma concentrations of Shh and Wnt (Wnt1, Wnt2 and Wnt3) at ICI introduction and at the first clinical evaluation. Sixty-three patients were included, with 36 patients (57.1%) with available tissue. Response rate was lower in Gli1+ NSCLC (20.0%) compared to Gli1 negative (Gli-) NSCLC (55.6%) (p = 0.015). Rate of primary resistance was 69.8%, vs. 31.2%, respectively (p = 0.04), and median progression-free survival (PFS) was 1.9 months (interquartile range (IQR) 1.2-5.7) vs. 6.1 months (1.6-26.0), respectively (p = 0.08). Median PFS and overall survival were shorter in case of increase of Wnt1 concentration during ICI treatment compared to other patients: 3.9 months vs. 11.2 months (p = 0.008), and 15.3 months vs. not reached (p = 0.003). In conclusion, baseline activation of Hh pathway and increase of Wnt1 concentrations during ICI treatment were associated with poor outcome in NSCLC patients treated with ICIs.

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

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

ERS International Congress, Madrid, 2019: highlights from the Thoracic Oncology Assembly.

Lung cancer is a devastating disease affecting hundreds of thousands of patients in Europe. Despite recent advances in treatment, its prognosis remains poor. This is mainly attributed to the late stages that diagnoses are usually established at, consequently excluding curative treatment options. During the 2019 European Respiratory Society International Congress in Madrid, Spain, lung cancer experts presented the most recent aspects of lung cancer early detection with low-dose computed tomography.

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

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

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

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

Plasma Biomarkers and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer: New Tools for Better Patient Selection?

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with non-small cell lung cancer (NSCLC). Although some patients can experience important response rates and improved survival, many others do not benefit from ICIs developing hyper-progressive disease or immune-related adverse events. This underlines the need to select biomarkers for ICIs use in order to better select patients. There is currently no universally validated robust biomarker for daily use of ICIs. Programmed death-ligand 1 (PD-L1) or tumor mutational burden (TMB) are sometimes used but still have several limitations. Plasma biomarkers are a promising approach in ICI treatment. This review will describe the development of novel plasma biomarkers such as soluble proteins, circulating tumor DNA (ctDNA), blood TMB, and blood microbiome in NSCLC patients treated with ICIs and their potential use in predicting response and toxicity.

The electronic nose: emerging biomarkers in lung cancer diagnostics.

Lung cancer is very common and the most common cause of cancer death worldwide. Despite recent progress in the systemic treatment of lung cancer (checkpoint inhibitors and tyrosine kinase inhibitors), each year, >1.5 million people die due to this disease. Most lung cancer patients already have advanced disease at the time of diagnosis. Computed tomography screening of high-risk individuals can detect lung cancer at an earlier stage but at a cost of false-positive findings. Biomarkers could lead towards a reduction of these false-positive findings and earlier lung cancer diagnosis, and have the potential to improve outcomes and treatment monitoring. To date, there is a lack of such biomarkers for lung cancer and other thoracic malignancies, although electronic nose (e-nose)-derived biomarkers are of interest. E-nose techniques using exhaled breath component measurements can detect lung cancer with a sensitivity ranging from 71% to 96% and specificity from 33 to 100%. In some case series, such results have been validated but this is mostly using internal validation and hence, more work is needed. Furthermore, standardised sampling and analysis methods are lacking, impeding interstudy comparison and clinical implementation. In this narrative review, we provide an overview of the currently available data on E-nose technology for lung cancer detection.

Positive plasma cotinine during platinum-based chemotherapy is associated with poor response rate in advanced non-small cell lung cancer patients.

INTRODUCTION: Patients with advanced non-small cell lung cancer (NSCLC) are most of the time treated with a first-line cytotoxic chemotherapy. Tobacco use is responsible for 90% of lung cancer. The aim of this study was to evaluate the impact of smoking continuation during first-line chemotherapy on tumor response in advanced-stage NSCLC. MATERIALS AND METHODS: All patients with an advanced-stage NSCLC (IIIb or IV), treated with first-line platinum-based chemotherapy in our Department between June 2013 and July 2017 were included. Smoking status was assessed at inclusion by self-report, then at the tumor assessment consultation after 2 months of treatment, by both self-report and plasmatic cotinine measurement. Chemotherapy response, progression-free survival (PFS), overall survival (OS) and stage 3-4 toxicity were registered. RESULTS: Ninety-seven patients were included: 8 (8%) declared to be non-smokers, 56 (58%) current smokers and 33 (34%) former smokers at diagnosis. At the first tumor evaluation, 24 (25%) self-reported as active smokers and 73 (75%) as non-smokers; overall response rate (ORR) was respectively 38% and 48% (p = 0.373). Fifty-four patients had a plasmatic cotinine evaluation at the first tumor evaluation. Seventeen patients (32%) had a positive cotinine rate (median 108ng/mL, IQR 31-236). Six patients (35%) had positive cotinine rate whereas declaring to be non-smokers at the first tumor evaluation. ORR was 18% in case of positive cotinine rate, and 57% when negative (p = 0.007). Regardless of the method for smoking status evaluation, PFS, OS and grade 3-4 toxicities were similar between smoker and non-smoker patients at the first tumor evaluation. CONCLUSION: Smoking continuation during platinum-based chemotherapy, reflected by positive plasma cotinine rate, was associated with a poor ORR.

Predictive role of plasmatic biomarkers in advanced non-small cell lung cancer treated by nivolumab.

Immune checkpoint inhibitors, as nivolumab, are used in advanced non-small cell lung cancer (NSCLC). However, no associated biomarker is validated in clinical practice with this drug. We investigated herein immune-related blood markers in patients with advanced NSCLC treated with nivolumab. Plasma of 43 consecutive patients were prospectively collected at time of the diagnosis of cancer, at the initiation of nivolumab and at the first tumour evaluation (2 months). Concentrations of PD-L1 (sPD-L1), soluble PD-L2 (sPD-L2), Interleukine-2 (sIl-2), Interferon-gamma (sIFN-γ), and Granzyme B (sGranB) were quantified by ELISA. Cell free RNA was quantified by Reverse Transcriptase -PCR), and plasmatic microRNAs (miRNAs) were evaluated by targeted sequencing. Expression of PD-L1 on tumour biopsies was performed by immunohistochemistry using E13LN. High sPD-L1 at 2 months and increase of sPD-L1 concentrations were associated with poor response and absence of clinical benefit (nivolumab treatment less than 6 months). The variation of sPD-L1 concentrations were confirmed by RNA quantification. sPD-L1 concentrations were not correlated with PD-L1 expression on corresponding tumour samples. Low sGranB at nivolumab initiation was also associated with poor response. High sPD-L1 and low sGranB were associated with poor progression-free survival (PFS) and overall survival (OS). Low sPD-L2, low sIl-2 and high sIFN-γ were associated with grade 3-4 toxicities. Finally, miRNA screening showed that patients with clinical benefit (n = 9) had down-expression of miRNA-320b and -375 compared to patients with early progression at 2 months (n = 9). In conclusion, our results highlight the interest of circulating biomarkers in patients treated with nivolumab.

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

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