Impact of radiation on host immune system in patients treated with chemoradiotherapy and durvalumab consolidation for unresectable locally advanced non-small cell lung cancer.

Background: The optimal modalities of radiotherapy when combining concurrent chemoradiation (CCRT) and immunotherapy (IO) for locally advanced non-small cell lung cancer (LA-NSCLC) remain to be determined. The aim of this study was to investigate the impact of radiation on different immune structures and immune cells in patients treated with CCRT followed by durvalumab. Material and methods: Clinicopathologic data, pre- and post-treatment blood counts, and dosimetric data were collected in patients treated with CCRT and durvalumab consolidation for LA-NSCLC. Patients were divided into two groups according to the inclusion (NILN-R+) or not (NILN-R-) of at least one non-involved tumor-draining lymph node (NITDLN) in the clinical target volume (CTV). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Fifty patients were included with a median follow-up of 23.2 months (95% CI 18.3-35.2). Two-year PFS and 2-year OS were 52.2% (95% CI 35.8-66.3) and 66.2% (95% CI 46.5-80.1), respectively. In univariable analysis, NILN-R+ (hazard ratio (HR) 2.60, p = 0.028), estimated dose of radiation to immune cells (EDRIC) >6.3 Gy (HR 3.19, p = 0.049), and lymphopenia ≤ 500/mm3 at IO initiation (HR 2.69, p = 0.021) were correlated with poorer PFS; lymphopenia ≤ 500/mm3 was also associated with poorer OS (HR 3.46, p = 0.024). In multivariable analysis, NILN-R+ was the strongest factor associated with PFS (HR 3.15, p = 0.017). Conclusion: The inclusion of at least one NITDLN station within the CTV was an independent factor for poorer PFS in the context of CCRT and durvalumab for LA-NSCLC. The optimal sparing of immune structures might help in achieving better synergy between radiotherapy and immunotherapy in this indication.

Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti-PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma.

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology. SIGNIFICANCE: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti-PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799.

Pediatrician intervention impacts parental smoking in cystic fibrosis, diabetes, and bronchiolitis.

BACKGROUND: Child exposure to cigarette smoke is harmful. It should be reduced through parental smoking cessation interventions. The aim of our study was to determine the impact of simple advice provided by the pediatrician on the smoking habits of parents of children with cystic fibrosis (CF), diabetes mellitus (DM), and infants hospitalized for bronchiolitis. METHODS: Parents were interviewed on their smoking habits. Smoking cessation advice was provided by the pediatrician. A new smoking habits assessment was done at 3 months by phone interviews. RESULTS: A total of 260 parents were interviewed (91 in the CF group, 136 in the DM group, and 33 in the bronchiolitis group). A total of 70 parents were active smokers: 33% of parents of children with CF, 23.5% of parents of children with DM, and 24.2% for those with infants hospitalized for bronchiolitis (p = .42). In the CF group, smoking cessation had been significantly more frequently discussed with the medical team previously. A total of 67 smoking parents (95.7%) answered the 3-month assessment: 29.8% reported having started a smoking cessation process; 10.4% had quit smoking. The quitting rate was significantly higher in the groups of patients followed for a respiratory disorder (37.5% for bronchiolitis, 15% for CF vs. 0% for DM, p = .005). CONCLUSION: This study shows the important role that information and simple advice from pediatricians can have in initiating smoking cessation in parents of patients followed in specialized clinics or who are hospitalized, with a greater efficiency in parents of patients suffering from lung disorders.

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

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

Modernizing adverse events analysis in oncology clinical trials using alternative approaches: rationale and design of the MOTIVATE trial.

In oncology clinical research, the analysis and reporting of adverse events is of major interest. A consistent depiction of the safety profile of a new treatment is as crucial in establishing how to use it as its antitumor activity. The advent of new therapeutics has led to major changes in the management of patients and targeted therapies or immune checkpoint inhibitors are administered continuously for months or even years. However, the classical methods of adverse events analysis are no longer adequate to properly assess their safety profile. Indeed, the worst grade method and time-to-event analysis cannot capture the duration or the evolution of adverse events induced by extended treatment durations. Many authors have highlighted this issue and argue that the analysis of safety data from clinical trials should be modernized by considering the dimension of time and the recurrent nature of adverse events. This paper aims to illustrate the limitations of current methods and discusses the value of alternative approaches such as the prevalence function, Q-TWiST, the ToxT and the recurrent event approaches. The rationale and design of the MOTIVATE trial, which aims to model the evolution of toxicities over time using the prevalence function in patients treated by immunotherapy, is also presented ( ClinicalTrials.gov Identifier: NCT03447483; Date of registration: 27 February 2018).

Effectiveness and safety of nivolumab in the treatment of lung cancer patients in France: preliminary results from the real-world EVIDENS study.

EVIDENS is an ongoing, prospective, non-interventional study evaluating the effectiveness and safety of nivolumab in lung cancer patients in France (ClinicalTrials.gov NCT03382496). Adults with a pathologically confirmed diagnosis of lung cancer and initiating treatment with nivolumab were recruited from 146 sites in France. This analysis included only patients with non-small cell lung cancer (NSCLC) who received ≥1 nivolumab infusion, and evaluated patient characteristics at the time of nivolumab initiation and its effectiveness and safety after a median follow-up of 18 months. A total of 1,420 patients with NSCLC were included, most of whom had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 (82.9%), non-squamous histology (69.2%) and stage IV disease (91.4%). Brain metastases were present in 19.9% of patients. Nivolumab was a second-line or ≥third-line regimen in 73.6% and 26.1% of patients, respectively. Almost all patients had prior chemotherapy (99.7%). Median overall survival was 11.2 months (95% confidence interval [CI]: 10.0-12.4). ECOG PS, smoking status, corticosteroids at baseline, epidermal growth factor receptor mutation status, presence of symptomatic brain metastases and treatment-related adverse events (TRAEs) were independent predictors of survival. Grade 3 and 4 TRAEs were reported in 105 (7.4%) and 12 (0.8%) patients, respectively; no treatment-related deaths were reported. Preliminary results of the EVIDENS study confirm the effectiveness and safety of nivolumab, mostly in pre-treated advanced NSCLC patients, with similar benefits to those observed in the phase III randomized clinical trials, despite a broader study population.

Outcome of Patients with Non-Small Cell Lung Cancer and Brain Metastases Treated with Checkpoint Inhibitors.

INTRODUCTION: Although frequent in NSCLC, patients with brain metastases (BMs) are often excluded from immune checkpoint inhibitor (ICI) trials. We evaluated BM outcome in a less-selected NSCLC cohort. METHODS: Data from consecutive patients with advanced ICI-treated NSCLC were collected. Active BMs were defined as new and/or growing lesions without any subsequent local treatment before the start of ICI treatment. Objective response rate (ORR), progression-free survival, and overall survival (OS) were evaluated. Multivariate analyses were performed by using a Cox proportional hazards model and logistic regression. RESULTS: A total of 1025 patients were included; the median follow-up time from start of ICI treatment was 15.8 months. Of these patients, 255 (24.9%) had BMs (39.2% active, 14.3% symptomatic, and 27.4% being treated with steroids). Disease-specific Graded Prognostic Assessment (ds-GPA) score was known for 94.5% of patients (35.7% with a score of 0-1, 58.5% with a score of 1.5-2.5, and 5.8% with a score of 3). The ORRs with BM versus without BM were similar: 20.6% (with BM) versus 22.7% (without BM) (p = 0.484). The intracranial ORR (active BM with follow-up brain imaging [n = 73]) was 27.3%. The median progression-free survival times were 1.7 (95% confidence interval [CI]: 1.5-2.1) and 2.1 (95% CI: 1.9-2.5) months, respectively (p = 0.009). Of the patients with BMs, 12.7% had a dissociated cranial-extracranial response and two (0.8%) had brain pseudoprogression. Brain progression occurred more in active BM than in stable BM (54.2% versus 30% [p < 0.001]). The median OS times were 8.6 months (95% CI: 6.8-12.0) with BM and 11.4 months (95% CI: 8.6-13.8) months with no BM (p = 0.035). In the BM subgroup multivariate analysis, corticosteroid use (hazard ratio [HR] = 2.37) was associated with poorer OS, whereas stable BMs (HR = 0.62) and higher ds-GPA classification (HR = 0.48-0.52) were associated with improved OS. CONCLUSION: In multivariate analysis BMs are not associated with a poorer survival in patients with ICI-treated NSCLC. Stable patients with BM without baseline corticosteroids and a good ds-GPA classification have the best prognosis.

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

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

Safety of oral hydration after cisplatin infusion in an outpatient lung cancer unit.

PURPOSE: Hydration is needed before and after cisplatin infusion for reducing the risk of nephrotoxicity. Even though there is no standard regimen, patients receive mostly intravenous hydration before and after cisplatin leading hospitalization during at least one night. Since the feasibility has been published, oral hydration after cisplatin was implemented in our practice. The safety of this new way of hydration needs to be assessed in clinical practice. METHODS: We collected medical records from patients treated by cisplatin for lung cancer in our unit between 2010 and 2016. We retrospectively analyzed the incidence of cisplatin induced nephrotoxicity between after and before the change of hydration regimen. RESULTS: Our patient cohort included 241 patients hydrated by intravenous regimen (IV/IV group) and 276 patient hydrated by intravenous and oral regimen (IV/PO group). Grade ≥ 1 nephrotoxicity occurred in 39.4 and 25.7% in the IV/IV and IV/PO groups respectively (p = 0.001). Age over 70 at baseline was a predictive factor for nephrotoxicity, but not estimated glomerular filtration rate nor cisplatin-associated drugs. After a multivariate analysis, age remained a predictive factor for nephrotoxicity and IV/PO hydration associated with a decrease in nephrotoxic risk. CONCLUSION: The implementation of oral hydration in our practice was not associated with an increase in nephrotoxicity. Our observation based on large data from clinical practice shows that oral hydration after cisplatin is safe.

Bronchoscopic Multimodal Management of Tracheal Neurofibroma.

Neurofibromas involving airways are rare and their management is usually surgical. Herein, we report the case of an endotracheal polypoid neurofibroma successfully treated by multimodal interventional bronchoscopy and cryotherapy.