Characterization of 164 patients with NRAS mutated non-small cell lung cancer (NSCLC).

BACKGROUND: NRAS mutations are observed in less than 1% of non-small cell lung cancer (NSCLC). Clinical data regarding this rare subset of lung cancer are scarce and response to systemic treatment such as chemotherapy or immune checkpoint inhibitors (ICI) has never been reported. METHODS: All consecutive patients with an NRAS mutated NSCLC, diagnosed between August 2014 and November 2020 in 14 French centers, were included. Clinical and molecular data were collected and reviewed from medical records. RESULTS: Out of the 164 included patients, 106 (64.6%) were men, 150 (91.5%) were current or former smokers, and 104 (63.4%) had stage IV NSCLC at diagnosis. The median age was 62 years, and the most frequent histology was adenocarcinoma (81.7%). NRAS activating mutations were mostly found in codon 61 (70%), while codon 12 and 13 alterations were observed in 16.5% and 4.9% of patients, respectively. Programmed death ligand-1 expression level <1%/1-49%/≥50% were respectively found in 30.8%/27.1%/42.1% of tumors. With a median follow-up of 12.5 months, median overall survival (OS) of stage IV patients was 15.3 months (95% CI 9.9-27.6). No significant difference in OS was found according to the type of mutation (codon 61 vs. other), HR = 1.12 (95% CI 0.65-1.95). Among stage IV patients treated with platinum-based doublet (n = 66), ICI (n = 48), or combination of both (n = 10), objective response rate, and median progression free survival were respectively 45% and 5.8 months, 35% and 6.9 months, 70% and 8.6 months. CONCLUSION: NRAS mutated NSCLC are characterized by a high frequency of smoking history and codon 61 mutations. Further studies are needed to confirm the encouraging outcome of immunotherapy in combination with chemotherapy.

Radiomics combined with transcriptomics to predict response to immunotherapy from patients treated with PD-1/PD-L1 inhibitors for advanced NSCLC.

Introduction: In this study, we aim to build radiomics and multiomics models based on transcriptomics and radiomics to predict the response from patients treated with the PD-L1 inhibitor. Materials and methods: One hundred and ninety-five patients treated with PD-1/PD-L1 inhibitors were included. For all patients, 342 radiomic features were extracted from pretreatment computed tomography scans. The training set was built with 110 patients treated at the Léon Bérard Cancer Center. An independent validation cohort was built with the 85 patients treated in Dijon. The two sets were dichotomized into two classes, patients with disease control and those considered non-responders, in order to predict the disease control at 3 months. Various models were trained with different feature selection methods, and different classifiers were evaluated to build the models. In a second exploratory step, we used transcriptomics to enrich the database and develop a multiomic signature of response to immunotherapy in a 54-patient subgroup. Finally, we considered the HOT/COLD status. We first trained a radiomic model to predict the HOT/COLD status and then prototyped a hybrid model integrating radiomics and the HOT/COLD status to predict the response to immunotherapy. Results: Radiomic signature for 3 months' progression-free survival (PFS) classification: The most predictive model had an area under the receiver operating characteristic curve (AUROC) of 0.94 on the training set and 0.65 on the external validation set. This model was obtained with the t-test selection method and with a support vector machine (SVM) classifier. Multiomic signature for PFS classification: The most predictive model had an AUROC of 0.95 on the training set and 0.99 on the validation set. Radiomic model to predict the HOT/COLD status: the most predictive model had an AUROC of 0.93 on the training set and 0.86 on the validation set. HOT/COLD radiomic hybrid model for PFS classification: the most predictive model had an AUROC of 0.93 on the training set and 0.90 on the validation set. Conclusion: In conclusion, radiomics could be used to predict the response to immunotherapy in non-small-cell lung cancer patients. The use of transcriptomics or the HOT/COLD status, together with radiomics, may improve the working of the prediction models.

Occupational asbestos exposure and survival among lung cancer patients.

OBJECTIVE: This study investigated the association between occupational asbestos exposure (OAE) and survival in patients with histologically confirmed lung cancer (LC). METHODS: This monocentric study was conducted in the Comprehensive Cancer Centre Léon Bérard, Lyon, France. A systematic screening has been in place since 2014 for occupational exposure to carcinogens using a self-assessment questionnaire sent to all patients newly diagnosed with histologically confirmed LC identified through the multidisciplinary LC board from 2014 to 2019. When the physician suspected a work-related exposure from the questionnaire including job history, an occupational cancer consultation was carried out to detail carcinogen exposures and assess if the LC was work-related. Demographics, clinical characteristics and survival data were extracted from medical records. The association between asbestos exposure and overall survival (hazard ratio and 95% confidence intervals) was estimated by Cox proportional hazards regression. RESULTS: Overall, 702 patients were eligible to the present study, including 180 patients with OAE. In the crude analysis, LCs assessed as moderately or highly attributable to OAE were associated with decreased overall survival (HR = 1.32, 95 %CI 1.04-1.67) compared to LC without OAE or with a low degree of imputability to OAE (median follow-up 28.8 months). After adjustment for confounding (age at diagnosis, smoking status, stage, brain metastasis at diagnosis, and histology), the association of OAE with overall survival was no longer statistically significant (HR = 1.21, 95 %CI 0.94-1.56). CONCLUSION: Overall survival in occupationally asbestos exposed LC patients may be decreased in comparison with non-exposed LC patients, warranting further investigations in larger studies.

Survival of bronchopulmonary cancers according to radon exposure.

Introduction: Residential exposure is estimated to be responsible for nearly 10% of lung cancers in 2015 in France, making it the second leading cause, after tobacco. The Auvergne-Rhône-Alpes region, in the southwest of France, is particularly affected by this exposure as 30% of the population lives in areas with medium or high radon potential. This study aimed to investigate the impact of radon exposure on the survival of lung cancer patients. Methods: In this single-center study, patients with a histologically confirmed diagnosis of lung cancer, and newly managed, were prospectively included between 2014 and 2020. Univariate and multivariate survival analyses were carried out using a non-proportional risk survival model to consider variations in risk over time. Results: A total of 1,477 patients were included in the analysis. In the multivariate analysis and after adjustment for covariates, radon exposure was not statistically associated with survival of bronchopulmonary cancers (HR = 0.82 [0.54-1.23], HR = 0.92 [0.72-1.18], HR = 0.95 [0.76-1.19] at 1, 3, and 5 years, respectively, for patients residing in category 2 municipalities; HR = 0.87 [0.66-1.16], HR = 0.92 [0.76-1.10], and HR = 0.89 [0.75-1.06] at 1, 3, and 5 years, respectively, for patients residing in category 3 municipalities). Discussion: Although radon exposure is known to increase the risk of lung cancer, in the present study, no significant association was found between radon exposure and survival of bronchopulmonary cancers.

Datasets for gene expression profiles of head and neck squamous cell carcinoma and lung cancer treated or not by PD1/PD-L1 inhibitors.

Identification of tumors harboring an overall active immune phenotype may help for selecting patients with advanced head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC) who may benefit from immunotherapies. In this context, we generated targeted gene expression profiles in three and two independent cohorts of patients with HNSCC or NSCLC respectively, treated or not by PD-1/PD-L1 inhibitors. Notably, we generated two datasets including 102 and 82 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors. Clinical information, including detailed survival raw data, is available for each patient, allowing to test association between gene expression data and patient survival (overall and progression-free survival). Moreover, we also generated gene expression datasets of 27 paired HNSCC samples from diagnostic biopsies and versus surgically resected specimens as well as 33 paired HNSCC samples at initial diagnosis (untreated) and at recurrence. Those datasets may allow to test the stability of a given biomarker across paired samples.

Immunologically active phenotype by gene expression profiling is associated with clinical benefit from PD-1/PD-L1 inhibitors in real-world head and neck and lung cancer patients.

INTRODUCTION: Identification of tumours harbouring an overall active immune phenotype may help for selecting patients with advanced head and neck squamous cell carcinomas (HNSCC) and non-small cell lung cancer (NSCLC) who may benefit from immunotherapies. Our objective was to develop a reliable and stable scoring system to identify those immunologically active tumours. METHODS: Using gene expression profiles of 421 HNSCC, we developed a score to identify immunologically active tumours. Validation of the 'HOT' score was done in 40 HNSCC and 992 NSCLC. Stability of the 'HOT' score was tested in paired HNSCC samples from diagnostic biopsies versus surgically resected specimens, untreated versus recurrent samples, and pre-versus post-cetuximab samples in a total of 76 patients. The association between the 'HOT' score with overall survival (OS) and progression-free survival (PFS) was tested in 184 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors. RESULTS: A 27-gene expression based 'HOT' score was correlated with: (i) PD-L1 and IDO1 expression, (ii) TCD8 infiltrate and (iii) activation of the IFN-γ pathway. The HOT score concordance when comparing diagnostic biopsies and surgically resected specimens was higher than in untreated samples versus recurrent or pre-versus post-cetuximab samples. In 102 and 82 patients with HNSCC or NSCLC treated with PD-1/PD-L1 inhibitors, the HOT score was associated with an improved OS and PFS in multivariate analysis. CONCLUSION: The 'HOT' score is a simple and robust approach to identify real-world patients with HNSCC and NSCLC immunologically active tumours who may benefit from PD-1/PD-L1 inhibitors.

Epithelial-to-mesenchymal transition promotes immune escape by inducing CD70 in non-small cell lung cancer.

INTRODUCTION: Epithelial-to-mesenchymal transition (EMT) is associated with tumor aggressiveness, drug resistance, and poor survival in non-small cell lung cancer (NSCLC) and other cancers. The identification of immune-checkpoint ligands (ICPLs) associated with NSCLCs that display a mesenchymal phenotype (mNSCLC) could help to define subgroups of patients who may benefit from treatment strategies using immunotherapy. METHODS: We evaluated ICPL expression in silico in 130 NSCLC cell lines. In vitro, CRISPR/Cas9-mediated knockdown and lentiviral expression were used to assess the impact of ZEB1 expression on CD70. Gene expression profiles of lung cancer samples from the TCGA (n = 1018) and a dataset from MD Anderson Cancer Center (n = 275) were analyzed. Independent validation was performed by immunohistochemistry and targeted-RNA sequencing in 154 NSCLC whole sections, including a large cohort of pulmonary sarcomatoid carcinomas (SC, n = 55). RESULTS: We uncover that the expression of CD70, a regulatory ligand from the tumor necrosis factor ligand family, is enriched in mNSCLC in vitro models. Mechanistically, the EMT-inducer ZEB1 impacted CD70 expression and fostered increased activity of the CD70 promoter. CD70 overexpression was also evidenced in mNSCLC patient tumor samples and was particularly enriched in SC, a lung cancer subtype associated with poor prognosis. In these tumors, CD70 expression was associated with decreased CD3+ and CD8+ T-cell infiltration and increased T-cell exhaustion markers. CONCLUSION: Our results provide evidence on the pivotal roles of CD70 and ZEB1 in immune escape in mNSCLC, suggesting that EMT might promote cancer progression and metastasis by not only increasing cancer cell plasticity but also reprogramming the immune response in the local tumor microenvironment.

First-Line Treatment of Advanced Non-Small-Cell Lung Cancer with Immune-Checkpoint Inhibitors: New Combinations and Long-Term Data.

Treatment of metastatic non-small-cell lung cancers (NSCLCs) has long been based on cytotoxic chemotherapy. Immune checkpoint inhibitors (ICIs), notably monoclonal antibodies directed against programmed cell death protein-1 (PD-1) or its ligand (PD-L1), have transformed therapeutic standards in thoracic oncology. These ICIs are now the reference first-line therapy, and numerous phase III trials have established their efficacy in treatment-naïve patients. First-line pembrolizumab monotherapy was validated for patients with ≥ 50% of tumor cells expressing PD-L1 and, in the USA, for patients with ≥ 1% PD-L1 positivity. More recently, cemiplimab as monotherapy was also validated for patients whose tumors expressed ≥ 50% PD-L1. Several ICIs (pembrolizumab, atezolizumab, nivolumab, and recently durvalumab) in combination with chemotherapy achieved overall survival gains among "all comers", compared with chemotherapy alone. The results were more contrasting for paired immunotherapies combining anti-PD-L1 and anti-cytotoxic T-lymphocyte antigen-4 agents, with the benefit/risk balance not yet fully established. Recently, nivolumab-ipilimumab and two chemotherapy cycles limited patient exposure to chemotherapy and obtained positive results compared with the latter alone. However, those phase III trials included selected patients in good general condition and without active brain metastases. Little is known about immunotherapy and combination immunotherapy-chemotherapy efficacies in never-smokers or patients with tumors harboring an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation. In this review, we report our analysis of the main results available on first-line ICI use, as monotherapy or combined or in combination with chemotherapy, to treat metastatic NSCLCs in general and also for specific populations: the elderly, never-smokers, patients with brain metastases, and those with an EGFR mutation or ALK translocation.

Response to the Combination of Osimertinib, Dabrafenib, and Trametinib in Leptomeningitis From EGFR-Mutant NSCLC With Acquired BRAF V600E Mutation: A Case Report.

Molecular sequencing after highly potent targeted gene inhibitors have suggested resistant tumors can display substantial heterogeneity. Among these various mechanisms of resistance, secondary mutations on targetable oncogenes have been identified. BRAF V600E, as a bypass mechanism on disease progression while receiving osimertinib therapy, has been reported in 3% of EGFR-mutated patients. Few case reports described the efficacy of the association of osimertinib and dabrafenib plus trametinib. Here, we report, for the first time, a case of a patient treated with this association, with a prolonged response on leptomeningeal metastasis. We also provide a comprehensive overview of the available literature on the efficacy and tolerance of this association.

The safety and efficacy of erlotinib and ramucirumab combination in EGFR-mutant non-small-cell lung cancer.

INTRODUCTION: EGFR-tyrosine kinase inhibitors (TKIs) changed the natural history of EGFR-mutant advanced NSCLC patients, but acquired resistance is inevitable. New strategies are being tested to overcome or prevent the emergence of resistance mechanisms to first-line TKIs, among which combinations of TKIs with antiangiogenic agents. AREAS COVERED: We performed a literature search for preclinical and clinical data on the interplay and dual inhibition of EGFR/VEGF pathways, particularly in EGFR-mutant NSCLC. We then focused on RELAY, a placebo-controlled phase 3 trial evaluating ramucirumab combined to erlotinib in treatment-naïve advanced EGFR-mutant NSCLC patients. This article aims to summarize efficacy and safety of the ramucirumab-erlotinib combination in this setting. EXPERT OPINION: RELAY confirmed the clinical relevance of combining EGFR and VEGF(R)-targeting therapies, previously investigated in smaller phase 2-3 trials of erlotinib and bevacizumab. However, the meaningful PFS benefit observed in the ramucirumab + erlotinib arm is counterbalanced by the toxicity profile of ramucirumab and the need for bimonthly infusions. Pending OS results are, therefore, critical to assess the real benefit from this combination, especially as first-line osimertinib has improved survival in EGFR-mutant NSCLC patients and will probably remain the pivotal EGFR-TKI in this setting. However, its heterogeneous efficacy across subgroups paves the way for osimertinib-based combinations, which are being investigated in ongoing trials.