Holistic management of patients with progressive pulmonary fibrosis

Progressive pulmonary fibrosis (PF) is a complex interstitial lung disease that impacts substantially on patients’ daily lives, requiring personalised and integrated care. We summarise the main needs of patients with PF and their caregivers, and suggest a supportive care approach. Individualised care, education, emotional and psychological support, specialised treatments, and better access to information and resources are necessary. Management should start at diagnosis, be tailored to the patient’s needs, and consider end-of-life care. Pharmacological and non-pharmacological interventions should be individualised, including oxygen therapy and pulmonary rehabilitation, with digital healthcare utilised as appropriate. Further research is needed to address technical issues related to oxygen delivery and digital healthcare.</p

Immunosenescence (iSenescence) correlates with progression (PD) to PD-(L)1 inhibitors (IO) and not to platinum-chemotherapy (PCT) in advanced non-small cell lung cancer (aNSCLC) patients (pts)

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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

Circulating Lymphocytes Expressing PD-1 During Lung Cancers, Predictive Impact on Response to PD-1 PD-L1 Inhibitors

Les bloqueurs de point de contrôle de l‘immunité (ICB) de PD-1/PD-L1 sont devenus incontournables dans le traitement des cancers bronchiques non à petite cellule (CBNPC). Cependant une minorité de patients va avoir une réponse clinique majeure liée aux ICB. Actuellement, pour prédire la réponse à ces traitements, seule l’expression de PD-L1 à la surface des cellules tumorales est utilisée en pratique clinique. Ce marqueur est cependant imparfait. D’abord, car il ne permet pas de détecter l’ensemble des répondeurs avec fiabilité. Ensuite, car il nécessite d’avoir accès à une biopsie tissulaire. Une des pistes pour dépasser ces limitations repose sur l’utilisation de biomarqueurs sanguins, dite « biopsie liquide ». Un prélèvement sanguin est en effet plus facile à réaliser, à réitérer et permet d’apprécier l’ensemble de la maladie tumorale tout en évaluant l’immunité de l’hôte. Nous avons choisi de nous intéresser aux lymphocytes circulants. Nous avons d’abord étudié les lymphocytes sénescents. La sénescence a été décrite comme un processus progressif, lié à la persistance de l’exposition antigénique et à l’acquisition d’une différenciation terminale et une faible capacité de prolifération. Nous avons défini en cytométrie de flux un « Senescent immune phenotype » (SIP) en fonction d’une population exprimant CD8+ CD28- CD57+ KLRG-1+. Le SIP+ est associé à une résistance primaire aux ICB en monothérapie chez les patients atteints de CBPNC avancés. La population SIP a des capacités de prolifération faibles tout en sécrétant des cytokines inflammatoires telles que le TNFα et de l’INFγ. Nous avons ensuite exploré un second biomarqueur circulant, le ratio LT CD8+ PD-1+ / LT CD4+ PD-1+, permettant d’apprécier l’impact des LT exprimant PD-1 les uns par rapport aux autres. Le rôle des LT CD8+, en particulier PD-1+, est souvent montré comme central dans le cycle de l’immunité antitumorale. Les LT CD4+ ont aussi un rôle important, à la fois de soutien à la réponse T CD8+ spécifique, mais aussi pour leur action antitumorale directe. Nous avons donc évalué ces deux populations au sein du rapport T CD8+ PD-1+ / T CD4+ PD-1+, le PERLS (PD-1+ Expressing Ratio on Lymphocyte on Systemic sample). Nous montrons dans ce travail que le PERLS est un marqueur associé à la réponse sous ICB. Sur le plan immunologique, le PERLS était significativement associé aux LT CD4+ naïfs circulants pré-thérapeutiques et à l’augmentation des LT mémoires sous traitement. Nous mettons aussi en évidence que l’augmentation de la polyfonctionnalité des LT est corrélée à la réponse ainsi qu’à une différenciation mémoire sous traitement. Ces résultats suggèrent que le PERLS pourrait être un marqueur, avant l’initiation du traitement, de la capacité des LT à se différencier et à devenir polyfonctionnels pendant le traitement. Nous avons obtenu et validé ces résultats pour les biomarqueurs SIP et PERLS, sur deux cohortes indépendantes de patients traités par anti-PD-1/PD-L1. Ces deux biomarqueurs ne permettent pas de prédire la réponse dans une cohorte de patients traités par chimiothérapie, ce qui suggère un rôle prédictif spécifique pour les ICB. Nous avons ensuite évalué un score composite en combinant le PERLS et le SIP avec une amélioration de la capacité à prédire à la fois la résistance primaire et les répondeurs. Conclusion : A travers le PERLS et le SIP nous montrons que l’utilisation de biomarqueurs circulants pré thérapeutiques est pertinente pour prédire l’efficacité des ICB et que ces tests peuvent être combinés. Une meilleure compréhension des mécanismes immunologiques mis en jeu est maintenant nécessaire. L’espoir serait de pouvoir cibler spécifiquement les populations néfastes ou à l’inverse de pouvoir restimuler des populations nécessaires à la réponse via des associations d’immunothérapies. L’exploration de ces biomarqueurs aurait donc à la fois un rôle dans la prédiction des ICB actuels mais aussi dans le développement des thérapeutiques à venir.The immune checkpoints blockers (ICB) of PD-L1/PD-1 became essential in treating most non-small cell lung cancer (NSCLC). However, only a small minority of patients will have a major clinical response to ICB. To predict the response to these treatments, only the expression of PD-L1 on the cancerous cell surface is being used currently. Nevertheless, this marker remains imperfect. First because it is not reliable to detect all the responders. Also, because it shows multiple technical limitations such as variability in results depending on tests being used and the requirement of a tissue biopsy. One possible avenue to overcome these limits is to use blood biomarkers grouped under the general term of liquid biopsy. A blood draw would be easier to do and to repeat during the evolution, while also allowing the assessment of immune status of the patient. We chose to look particularly at circulating lymphocytes. First, we looked at senescent lymphocyte’s populations. Senescence is described as a progressive multistage process linked to a persistent antigenic exposure and the acquisition of terminal differentiation and low proliferation phenotype. We defined by flow cytometry a « Senescent immune phenotype » (SIP) for a CD8+ CD28- CD57+ KLRG-1+ population. SIP+ was associated with primary resistance to monotherapy ICB in advanced NSCLC. This SIP+ population shows low proliferating ability while producing TNFα and INFγ. We then looked at a second circulating biomarker the LT CD8 PD-1+ / LT CD4 PD-1+ ratio. The role of T CD8+ lymphocytes, in particular PD-1+, is often shown as central in the antitumor immunity cycle. However, we also note the role of LT CD4+ as crucial both in initiating and sustaining the lymphocyte T CD8+ specific response and for it’s one direct antitumoral effect. Therefore, we evaluate these two populations in a CD8+ PD-1+ / CD4+ PD-1+ ratio (PD-1+ Expressing Ratio on Lymphocyte on Systemic sample, “PERLS”). We demonstrate in this work that the PERLS+ is associated with response under ICB. From an immunology standpoint PERLS is highly associated to naïve lymphocyte T CD4+ circulating lymphocytes before therapy and with the increase of memory T lymphocytes under treatment. We also show that the increase in polyfunctional lymphocyte T is correlated to response and to memory differentiation under treatment. We obtained and validated these results on 2 independent patient cohorts treated with PD-1 and PD-L1 ICB. These 2 biomarkers do not allow to predict the response in a cohort of patients treated by chemotherapy, thus suggesting a specific predictive role for ICBs. Finally, we created a composite score combining PERLs and SIP which allow a better description of both primary resistance and response under ICB. Conclusion: Through PERLS and SIP we prove that utilizing circulating pre-therapy biomarkers is relevant to predict the efficiency of ICB and that these tests can be combined. A better understanding of the immunology mechanism behind these biomarkers is needed. The hope is to be able to pinpoint the bad populations or conversely, to stimulate the response of other populations through immunotherapy associations. The further exploration of these biomarkers would have an impact on predicting current ICB and in developing upcoming therapie

Monitoring anti-PD-1-based immunotherapy in non-small cell lung cancer with FDG PET: introduction of iPERCIST

Abstract Background Immunotherapy represents a new therapeutic approach in non-small cell lung carcinoma (NSCLC) with the potential for prolonged benefits. Because of the systemic nature and heterogeneity of tumoral diseases, as well as the immune restoration process induced by immunotherapy, the assessment of therapeutic efficacy is challenging, and the role of FDG PET is not well established. We evaluated the potential of FDG PET to monitor NSCLC patients treated with a checkpoint inhibitor. Results This was a retrospective analysis of 28 NSCLC patients treated with nivolumab, a programmed cell death 1 (PD-1) blocker. All patients underwent a PET scan before treatment (SCAN-1) and another scan 2 months later (SCAN-2). Disease progression was assessed by immune PET Response Criteria in Solid Tumors (iPERCIST), which was adapted from PERCIST; and the immune Response Evaluation Criteria in Solid Tumors (iRECIST). iPERCIST is a dual-time-point evaluation of “unconfirmed progressive metabolic disease” (UPMD) status at SCAN-2. UPMD at SCAN-2 was re-evaluated after 4 weeks with SCAN-3 to confirm PMD. Patients with complete/partial metabolic response (CMR or PMR) or stable metabolic disease (SMD) at SCAN-2 or -3 were considered responders. Patients with UPMD confirmed at SCAN-3 were considered non-responders. The Kaplan-Meier method was used to estimate survival. At SCAN-2, we found 9/28 cases of PMR, 4/28 cases of SMD, 2/28 cases of CMR, and 13/28 cases of UPMD. Four of the 13 UPMD patients were classified as responders at SCAN-3 (PMR n = 1, SMD n = 3). The remaining nine UPMD patients were classified as non-responders due to clinical degradation, and treatment was stopped. The median follow-up was 16.7 months [3.6–32.2]. Responders continued treatment for a mean of 10.7 months [3.8–26.3]. Overall survival was longer for responders than that for non-responders (19.9 vs. 3.6 months, log rank p = 0.0003). The 1-year survival rates were 94% for responders and 11% for non-responders. A comparison with iRECIST showed reclassification in 39% (11/28) of patients with relevant additional prognostic information. Conclusions iPERCIST dual-time-point evaluation might be a powerful tool for evaluating anti-PD-1-based immunotherapy, with the ability to identify patients who can benefit most from treatment. The prognostic value of iPERCIST criteria should be confirmed in large prospective multicentric studies

First-line immune-checkpoint inhibitor plus chemotherapy versus chemotherapy alone for extensive-stage small-cell lung cancer: a meta-analysis

Introduction: Platin-based chemotherapy (CT) has long been the first-line standard-of-care for patients with extensive-stage small-cell lung cancer (ES–SCLC). Adding immune-checkpoint inhibitor(s) to CT (ICI+CT) in this setting is an option of interest, although its benefit is apparently modest. Methods: This meta-analysis was conducted on randomized trials comparing first-line ICI+CT versus CT alone for ES–SCLC. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), response at 12 months and adverse events (AEs). Subgroup analyses were computed according to the immunotherapy used, performance status (PS), age, platinum salt, liver metastases and brain metastases at diagnosis. Results: The literature search identified one randomized phase II (ECOG-ACRIN-5161) and four phase III trials (CASPIAN, IMPOWER-133, KEYNOTE-604 and Reck et al. 2016) that included 2775 patients (66% males, 95% smokers, median age: 64 years, PS = 0 or 1). ICI+CT was significantly associated (hazard ratio [95% confidence interval]) with prolonged OS [0.82 (0.75–0.89); p < 0.00001] and PFS [0.81 (0.75–0.87); p < 0.00001], with OS benefits for anti-PD-L1 [0.73 (0.63–0.85); p < 0.0001] or anti-PD-1 [0.76 (0.63–0.93); p < 0.006] but not for anti-CTLA-4 [0.90 (0.80–1.01), p = 0.07]. ORRs for ICI+CT or CT alone were comparable [odds ratio 1.12 (0.97–1.00); p = 0.12], but responses at 12 months favored ICI+CT [4.16 (2.81–6.17), p < 0.00001]. Serious grade-3/4 AEs were more frequent with ICI+CT [odds ratio 1.18 (1.02–1.37); p = 0.03]. Compared with CT, no ICI+CT benefit was found for ES–SCLC with brain metastases at diagnosis [HR 1.14 (0.87–1.50); p = 0.34]. Conclusions: First-line ICI+CT appears to be superior to CT alone for ES–SCLC except for patients with brain metastases at diagnosis

Successful sequential tyrosine kinase inhibitors to overcome a rare compound of EGFR exon 18–18 and EGFR amplification: A case report

Background New mutational detection techniques like next-generation sequencing have resulted in an increased number of cases with uncommon mutation and compound mutations [3%–14% of all epidermal growth factor receptor (EGFR) mutations]. In rare exon 18 mutations (3%–6%), G719X and E709X represent the majority, but CMut associating these exon 18 points mutations are even rarer, making the understanding of the impact of epidermal growth factor receptor tyrosine kinase inhibitors still limited. Three generations of EGFR tyrosine kinase inhibitors (TKIs) are available to target EGFR mutations, but according to the types of mutations, the sensitivity to TKI is different. Afatinib, osimertinib, and neratinib have showed some effectiveness in single exon 18, but no report has precisely described their efficiency and acquired mechanism of resistance in a CMut of exon 18–18 (G719A and E709A). Case presentation We report a case of a 26-year-old woman with bilateral advanced adenocarcinoma of the lung harboring a compound mutation associating G719A and E709A in exon 18, who developed an EGFR amplification as resistance mechanism to osimertinib. She presented a significant clinical and morphological response under sequential TKIs treatment (afatinib, osimertinib, and then neratinib). Conclusion A non-small cell lung cancer (NSCLC) with rare compound mutation exon 18–exon 18 (G719A and E709A) and EGFR amplification can be overcome with adapted sequential second- and third-generation TKIs. This report has potential implications in guiding decisions for the treatment of these rare EGFR mutations

Budget Impact Analysis of Fixed Dose Versus Weight-Based Dosing Regimen of Nivolumab and Pembrolizumab in the Treatment of Non-Small Cell Lung Cancer

In 2018, dosing regimens of the two most prescribed immune check point inhibitors (ICI), nivolumab (Opdivo&reg;) and pembrolizumab (Keytruda&reg;), in the treatment of lung cancer were changed from weight-based dosing to fixed dosing. The aim of this study was to compare the economic impact of this change in our university hospital group and then across Ile-de-France, the most inhabited French region. A budget impact analysis (BIA) has been performed on the French public health insurance data. The duration of treatment and the weight of the patients were calculated using data from the patients treated at our health facility and from clinical studies. The cost of treatment was calculated at the local level of our health facility and then for Ile-de-France. Our model demonstrates an additional cost of &euro;550,115 in our hospital and &euro;9,704,778 in Ile-de-France for a fixed dose prescription in 2018. In 2019, the BIA concluded an additional cost, according to the respective low and high assumptions, of &euro;556,969 and &euro;756,544 locally and &euro; 10,201,027 to &euro;14,486,141 for Ile-de-France for an equivalent efficacy between the two different drug dosing regimens of nivolumab and pembrolizumab. The adoption of the fixed dose regimen would lead, according to the least expensive hypothesis, to an additional cost of 26% for the ICI. These results encourage reflection on the strict adoption of this dosage modification. The option of maintaining the free choice between a prescription adapted to weight or in a fixed dose seems a relevant option and should be considered