First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817

Antigen CTLA-4; Immunoteràpia; Neoplàsies pulmonarsAntígeno CTLA-4; Inmunoterapia; Neoplasias PulmonaresCTLA-4 antigen; Immunotherapy; Lung NeoplasmsBackground CheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (cohort A) and special populations (cohort A1: ECOG PS 2; or ECOG PS 0–1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection). Methods Cohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary endpoint was the incidence of grade 3–4 and grade 5 immune-mediated adverse events (IMAEs; adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoring/intervention, reported between first dose and 30 days after the last dose) in cohort A; efficacy endpoints were secondary/exploratory. In cohort A1, safety/efficacy assessment was exploratory. Results The most common grade 3–4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) in cohort A (N=391) and diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N=198). The most common grade 3–4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively. Conclusions Flat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0–1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate.This work was supported by Bristol Myers Squibb (Princeton, New Jersey, USA)

Survival of patients with non-small cell lung cancer having leptomeningeal metastases treated with immune checkpoint inhibitors

Introduction: Patients with non-small cell lung cancer (NSCLC) experience leptomeningeal metastases (LM) in 3-9% of cases. Because overall survival (OS) and performance status are very poor, they are mostly excluded from clinical trials. Here, we evaluated survival of patients with NSCLC having LM treated with immune checkpoint inhibitors (ICIs).Methods: A prospectively collected list of patients with advanced NSCLC treated with ICIs between November 2012 and July 2018 in 7 European centres was merged. All patients with LM before ICI start were selected, data were retrospectively added and patients were classified according to the National Comprehensive Cancer Network (NCCN) LM prognostic classification (good/poor). Progression-free survival (PFS) and OS on ICIs were evaluated.Results: Nineteen of 1288 (1.5%) patients had LM; 73.7% had synchronous brain metastases; 73.7% had neurological symptoms at the start of ICIs and 52.6% were in the NCCN LM good prognosis group. Programmed death ligand-1 (PD-L1) expression was known for 42.1% of patients (87.5% positive). Median follow-up was 13 months from the start of ICIs, and median (95% confidence interval [CI]) PFS on ICIs was 2.0 (1.8-2.2) months. Six-month PFS rate was 21.0% and was significantly higher in the NCCN good versus poor prognostic group: 40% vs 0% (p = 0.05). Twelve-month PFS rate was 0%. Median (95% CI) OS from the start of ICIs was 3.7 (0.9-6.6) months. Six-month OS rate was 36.8%, and 12-month OS rate was 21.1%; both were not statistically significantly different for the good versus poor NCCN prognostic group (p = 0.40 and p = 0.56, respectively).Conclusion: Some patients with NSCLC having LM do benefit from ICI treatment; specifically, those in the NCCN LM good prognosis group can obtain a long survival. (C) 2019 Elsevier Ltd. All rights reserved.</p

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. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved

Routine molecular profiling of cancer: results of a one-year nationwide program of the French Cooperative Thoracic Intergroup (IFCT) for advanced non-small cell lung cancer (NSCLC) patients.

International audienceBackground: The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute. Methods This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582. Findings 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p&lt;0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2–10·7] vs 7·1 months [6·1–7·9]; p&lt;0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5]; p&lt;0·0001) compared with absence of a genetic alteration. Interpretation Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit

Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non-Small-Cell Lung Cancer in CheckMate 227

[Purpose] We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non–small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status.[Methods] Adults with stage IV/recurrent non–small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life.[Results] At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed.[Conclusion] With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non–small-cell lung cancer.Peer reviewe

Treatment patterns and clinical outcomes of extensive stage small cell lung cancer (SCLC) in the real-world evidence ESME cohort before the era of immunotherapy

International audienceBackground: Small cell lung cancer (SCLC) is a highly aggressive entity of lung cancer with tendency toward early recurrence after first-line treatment. As per recently updated European Society for Medical Oncology recommendations, first-line treatment with up to 4 cycles of platinum-etoposide combined with immune checkpoint inhibitor (ICIs)-targeting PD-L1, is now the standard of care. The purpose of the current analysis is to identify current patient profiles and treatment strategies in real life clinical practice, and report outcomes in Extensive Stage (ES)-SCLC. Methods: Non-interventional, retrospective, multicentre, comparative study was carried out to describe the outcome of ES-SCLC patients included in the Epidémiologie Stratégie Médico–Economique (ESME) data platform for advanced and metastatic lung cancer. Patients were selected from 34 health care facilities between January 2015 and December 2017, before the era of immunotherapy. Results: 1315 patients were identified, including 64% male and 78% under 70 year-old; 24% had at least 3 metastatic sites, mainly liver metastases (43%), bone metastases (36%), brain metastases (32%). 49% received only one line of systemic treatment; 30% and 21% received 2 and 3 lines or more, respectively. Carboplatin was more frequently used than cisplatin (71% and 29%, respectively). Prophylactic cranial irradiation was infrequent (4% of patients), but 16% of patients received thoracic radiation therapy, mainly after the completion of first-line chemotherapy (72% of patients); such strategies were more frequently applied in cisplatin/etoposide than carboplatin/etoposide patients (p = 0.006 and p = 0.015, respectively). After a median follow-up time of 21.8 (95% CI: 20.9–23.3) months, median real-world Progression-Free Survival (rw-PFS) was 6.2 (95% CI: 5.7; 6.9) and 6.1 (95% CI: 5.8; 6.3) months for cisplatin/etoposide and carboplatin/etoposide doublet regimens, respectively; 24-month rwPFS and Overall Survival were 3.2% (95% CI: 2.3; 4;2) and 22.2% (95% CI: 19.4; 25.1) in the whole population, respectively. Conclusion: Our data provide with landmark reference findings on ES-SCLC before the immunotherapy era, and cover many aspects of the treatment strategy, while highlighting on the role of radiotherapy, subsequent lines of therapy, and the outcomes of patients. Generation of real-world data focusing on patients who received platinum-based chemotherapy combined with immune checkpoint inhibitors is under way

Epidemiology and treatment costs of bone metastases from lung cancer: a French prospective, observational, multicenter study (GFPC 0601).

International audienceINTRODUCTION: The aim of this prospective, observational, multicenter study was to examine the epidemiology and management costs of bone metastatic disease (BMD) in patients with lung cancer. METHODS: The analysis included all patients with BMD from lung cancer diagnosed between May 2006 and May 2007 in 40 centers. We analyzed their management and the direct costs of BMD from the health care provider's perspective, using a Markov model. Skeletal-related event (SRE) was defined as pathological fractures, spinal cord compression, or hypercalcemia (clinical SRE [cSRE]) for an initial analysis; a second analysis included palliative radiotherapy and surgery (therapeutic SRE [tSRE]). RESULTS: Among the 554 patients enrolled (62 ± 11 years, 76.5% males, 69.3% performance status 0/1, 91% non-small cell lung cancer), 24.7% had a cSRE and 26.7% a tSRE at baseline and 9% and 39% during follow-up, respectively; 81.8% received at least one chemotherapy cycle. The median survival time was 5.8 months, and the 1- and 2-year survival rates were 22% and 7%, respectively; there was no significant difference in overall survival between the patients with and without SRE at enrollment. The main BMD treatments were opiate therapy (77.7%), biphosphonates (52.3%), radiotherapy (42.1%), and surgery (9.2%). The mean monthly BMD treatment costs in euros were €190, €374, and €4672 for asymptomatic patients, symptomatic patients, and patients with SRE, respectively. The average first-year BMD management cost in euros was €3999 ± 4135 (95% confidence interval: 374-15,886), and 49.5% of this cost was attributable to patients with SRE. CONCLUSIONS: This analysis confirms the poor prognosis of BMD from lung cancer and underlines the burden of SRE in overall treatment costs

Patients with advanced lung cancer harboring oncogenic mutations should be admitted to intensive care units

International audienc