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This is the first case report of a non-small-cell lung cancer (NSCLC) patient harboring HIP1-ALK (H28:A20) and CTNNB1 p.S45del treated with first-line alectinib. Approximately 5% of NSCLC patients are reported to have anaplastic lymphoma kinase (ALK) rearrangements, and among these EML4-ALK is the most frequent fusion variant. However, in recent years the use of next-generation sequencing (NGS) in clinical laboratories has become increasingly widespread, identifying a lot of new ALK fusion partners as well as a large quantity of co-occurring genomic alterations. Unfortunately, the growing number of genomic alterations detected by NGS does not always correspond to adequate knowledge of their clinical significance, often resulting in an empiric treatment of patients harboring uncommon mutations., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Background: Mesenchymal-epithelial transition (MET) exon 14 (METex14) skipping mutation is a rare alteration in non-small-cell lung cancer (NSCLC), occurring in about 3%-4% of cases. Here we report disease and patient characteristics, and efficacy and tolerability of MET inhibitors among advanced METex14 NSCLC patients from the Italian real-world registry ATLAS., Materials and Methods: Clinical-pathological and molecular data, and treatment efficacy/tolerability outcomes were retrospectively collected from the ATLAS registry., Results: From July 2020 to July 2023 a total of 146 METex14 advanced NSCLC patients were included across 27 Italian centers. Median age was 74 years, and most patients were male (52%), with an Eastern Cooperative Oncology Group performance status < 2 (72%) and adenocarcinoma subtype (83%). One hundred and twenty-five out of 146 (86%) patients received at least one line of systemic anticancer therapy. Fifty-six (38%) were treated with capmatinib and 34 (23%) with tepotinib. 29% and 52% of them received targeted treatment in the first and second line, respectively. In the cohort of patients treated with MET inhibitors, the response rate (RR) was 37% (33% in previously treated patients and 46% in treatment-naïve) with a disease control rate of 62%. With a median follow-up of 10.8 months, progression-free survival was 6.6 months [95% confidence interval (CI) 4.3-8.3 months] and overall survival was 10.7 months (95% CI 7.2-19.3 months). In patients with measurable brain metastases (17 cases), the intracranial RR was 41%. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 12% of patients with grade 3 peripheral edema in 7% of cases. A fatal adverse reaction occurred in one patient due to pneumonitis. TRAEs-related dose reduction and discontinuation were reported in 6% and 8% of cases, respectively., Conclusion: Capmatinib and tepotinib represent an effective treatment option in NSCLC patients with METex14. Real-world efficacy outcomes are worse than those reported in prospective clinical trials. Their activity is more pronounced in the treatment-naïve population, suggesting that this is the right setting in the management of patients with METex14., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: To date, precision medicine has revolutionized the clinical management of Non-Small Cell Lung Cancer (NSCLC). International societies approved a rapidly improved mandatory testing biomarkers panel for the clinical stratification of NSCLC patients, but harmonized procedures are required to optimize the diagnostic workflow. In this context a knowledge-based database (Biomarkers ATLAS, https://biomarkersatlas.com/) was developed by a supervising group of expert pathologists and thoracic oncologists collecting updated clinical and molecular records from about 80 referral Italian institutions. Here, we audit molecular and clinical data from n = 1100 NSCLC patients collected from January 2019 to December 2020., Methods: Clinical and molecular records from NSCLC patients were retrospectively collected from the two coordinating institutions (University of Turin and University of Naples). Molecular biomarkers (KRAS, EGFR, BRAF, ROS1, ALK, RET, NTRK, MET) and clinical data (sex, age, histological type, smoker status, PD-L1 expression, therapy) were collected and harmonized., Results: Clinical and molecular data from 1100 (n = 552 mutated and n = 548 wild-type) NSCLC patients were systematized and annotated in the ATLAS knowledge-database. Molecular records from biomarkers testing were matched with main patients' clinical variables., Conclusions: Biomarkers ATLAS (https://biomarkersatlas.com/) represents a unique, easily managing, and reliable diagnostic tool aiming to integrate clinical records with molecular alterations of NSCLC patients in the real-word Italian scenario., Competing Interests: Declaration of competing interest Umberto Malapelle has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientific, Eli Lilly, Diaceutics, GSK, Merck and AstraZeneca, Janssen, Diatech, Novartis and Hedera for work performed. Francesco Passiglia Francesco declared consultant/advisory fee from Astrazaneca, Janssen, Amgen, Sanofi, Brystol Myer Squibb, Merck Sharp and Dohne, Roche, Beigene, Novartis, Thermofisher Scientific. Pasquale Pisapia reports speaking fees from Novartis outside the submitted work. Diego Cortinovis has received personal fees (as consultant and/or speaker bureau) from Advisory Amgen, AstraZeneca, BMS, MSD, Novartis, Roche, Jannsen, Sanofi Genzyme.Domenico Galetta has received personal fees (as consultant and/or speaker bureau) from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, MSD, Novartis, Amgen, Roche for work performed outside of the current study. Paolo Graziano has received personal fees (as consultant and/or speaker bureau) from: Amgen, AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Roche, Pfizer, Boehringer Ingelheim unrelated to the current work. Fabio Pagni has received personal fees (as consultant and/or speaker bureau) from Novartis, Roche, MSD, Amgen, GSK and AstraZeneca, for work performed outside of the current study. Giulia Pasello has received personal fees (as consultant and/or speaker bureau) from: Amgen, AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Roche, Jannsen, AstraZeneca, Roche unrelated to the current work. Sara Pilotto reports personal fees (invited speaker, advisory board) from AstraZeneca, Eli-Lilly, Novartis, AMGEN, Takeda, Sanofi, Bristol Myers Squibb, MSD and Roche; and research grants from AstraZeneca, Bristol Myers Squibb and Roche outside the submitted work. Marcello Tiseo reports personal fees (as consultant and/or speaker bureau) from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck, Sanofi. M.T. He received institutional research grants from Astra-Zeneca, Boehringer Ingelheim un related to the current work. Luisella Righi declared consultant/advisory fee from AstraZeneca, Novartis, Roche, Eli Lilly and Boehringer Ingelheim. Giancarlo Troncone reports personal fees (as speaker bureau or advisor) from Roche, MSD, Pfizer and Bayer, unrelated to the current work. Silvia Novello reports personal fees (as speaker bureau or advisor) from Eli Lilly, MSD, Roche, BMS, Takeda, Pfizer, Astra Zeneca and Boehringer Ingelheim, unrelated to the current work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Recently, the fifth edition of the WHO classification recognized the thoracic SMARCA4 -deficient undifferentiated tumor (SMARCA4-UT) as a separate entity from conventional non-small cell lung cancer with SMARCA4 deficiency because of the different clinicopathological characteristics of these two diseases. SMARCA4-UT mainly occurs in young to middle-aged adults and involves a large mass compressing the tissues surrounding the mediastinum and lung parenchyma. Unfortunately, SMARCA4-UT shows a high probability of recurrence after upfront surgery as well as radiotherapy resistance; moreover, chemotherapy has low efficacy. Moreover, given the recent classification of SMARCA4-UT, no data concerning specific clinical trials are currently available. However, several case reports show immunotherapy efficacy in patients with this disease not only in a metastatic setting but also in a neoadjuvant manner, supporting the development of clinical trials. In addition, preclinical data and initial clinical experiences suggest that inhibiting pathways such as CDK4/6, AURKA, ATR, and EZH2 may be a promising therapeutic approach to SMARCA4-UT.

Background: Sotorasib showed a significant improvement of progression free survival (PFS), safety and quality of life over docetaxel in patients with KRASp.G12C-mutated advanced non-small-cell lung cancer (NSCLC) within the CodeBreak-200 study. Here we report real-world efficacy and tolerability data from NSCLC patients who received sotorasib within the Italian expanded access program (EAP)., Methods: Sotorasib (960 mg, orally, once daily) was available on physician request for KRASp.G12C mutant advanced NSCLC patients. Clinical-pathological and molecular data were collected from the Italian ATLAS real-world registry. Patients underwent CT-scan and responses were evaluated by RECIST criteria. Efficacy and tolerability outcomes have been assessed., Results: A total of 196 advanced NSCLC patients were treated across 30 Italian centers. Median age was 69 years old (range 33-86). Most patients were male (61 %), former (49 %) or current smokers (43 %), with ECOG-PS 0/1 (84 %) and adenocarcinoma subtype (90 %). 45 % and 32 % of patients received sotorasib in 2nd and 3rd line, respectively. Overall, response rate was 26 % and the median duration of response was 5.7 months (95 % CI: 4.4-7.0). Median PFS and OS were 5.8 months (95 % CI: 5 - 6.5) and 8.2 months (95 % CI: 6.3 - 9.9). Grade 3-4 TRAEs occurred in 16.5 % of patients, with Grade ≥ 3 liver enzyme increase and TRAEs-related discontinuation reported in 12 % and 4.6 % of cases., Conclusion: Real-world data from the Italian EAP confirm the tolerability and effectiveness of sotorasib in patients with KRASp.G12C-mutated advanced NSCLC and highlight the value of the national ATLAS network as source of real-world evidence driving the clinical management of NSCLC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Medical treatment has changed drastically in recent years, especially for advanced stages of non-small-cell lung cancer (NSCLC), for which the development of immunotherapy and molecular targeted therapy significantly increased survival and quality of life. This single-center retrospective study aimed to analyze the outcome predictors, the surrogate outcomes, and the patient-reported outcomes after neoadjuvant immunotherapy for initially unresectable NSCLC. Patients affected by an initially unresectable NSCLC and identified between March 2014 and December 2021 who received immunotherapy alone or in combination with platinum-based chemotherapy and/or radiotherapy were collected. Overall survival (OS) and disease-free survival (DFS) were estimated according to the Kaplan-Meier method. Patient-reported outcomes were recorded using the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life (QoL) Group questionnaire-Lung Cancer 29 Module to compare differences in symptoms and QoL at two different times, 30 days and 1 year after surgery. Surgical, pathological records, and patient-reported outcomes (at 30 days and 1 year after surgery) were reviewed. Complete pathological remission was achieved in 7 patients (36.8%) and major pathological remission in 3 patients (15.7%). The median overall survival in the study group is 19 months (range: 2-57.4). Of 19 patients, 16 (84.2%) are alive to date, of which 2 (10.5%) have a local recurrence. At 30 days from surgery, the main symptoms reported by EORTC Module were coughing, shortness of breath, the side effect of treatment, fear of progression, and surgery-related problems. Induction immunotherapy with or without chemotherapy can be considered for unresectable locally advanced NSCLC, and after the downstaging, the possibility of surgery could be re-evaluated in a multidisciplinary setting with high rates of R0 resection. In this selected and highly motivated group of patients, the QoL and symptoms after salvage surgeries are acceptable and even better than those reported in the literature., (© 2023. Italian Society of Surgery (SIC).)

Non-Small cell lung cancer (NSCLC) is one of the most dangerous cancers, with 85% of all new lung cancer diagnoses and a 30-55% of recurrence rate after surgery. Thus, an accurate prediction of recurrence risk in NSCLC patients during diagnosis could be essential to drive targeted therapies preventing either overtreatment or undertreatment of cancer patients. The radiomic analysis of CT images has already shown great potential in solving this task; specifically, Convolutional Neural Networks (CNNs) have already been proposed providing good performances. Recently, Vision Transformers (ViTs) have been introduced, reaching comparable and even better performances than traditional CNNs in image classification. The aim of the proposed paper was to compare the performances of different state-of-the-art deep learning algorithms to predict cancer recurrence in NSCLC patients. In this work, using a public database of 144 patients, we implemented a transfer learning approach, involving different Transformers architectures like pre-trained ViTs, pre-trained Pyramid Vision Transformers, and pre-trained Swin Transformers to predict the recurrence of NSCLC patients from CT images, comparing their performances with state-of-the-art CNNs. Although, the best performances in this study are reached via CNNs with AUC, Accuracy, Sensitivity, Specificity, and Precision equal to 0.91, 0.89, 0.85, 0.90, and 0.78, respectively, Transformer architectures reach comparable ones with AUC, Accuracy, Sensitivity, Specificity, and Precision equal to 0.90, 0.86, 0.81, 0.89, and 0.75, respectively. Based on our preliminary experimental results, it appears that Transformers architectures do not add improvements in terms of predictive performance to the addressed problem., (© 2023. The Author(s).)

Background: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients., Patients and Methods: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks., Results: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002)., Conclusions: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted., Competing Interests: Disclosure BB: research funding, institution: Abbvie, Amgen, AstraZeneca, Chugai pharmaceutical, Daiichi-Sankyo, Ellipse pharma, EISAI, Genmab, Genzyme Corporation, Hedera Dx, Inivata, IPSEN, Janssen, MSD, Pharmamar, Roche-Genentech, Sanofi, Socar research, Taiho Oncology, Turning Point Therapeutics. EF: consulting or advisory role, personal: Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Lilly, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Pfizer, Sanofi, Takeda, Peptomyc, Daiichi Sankyo Europe GmbH, F. Hoffmann LaRoche, Merck Sharp & Dohme; speakers’ bureau, personal: AstraZeneca, Bristol-Myers Squibb, Lilly, Medscape, Merck Sharp & Dohme, PeerVoice, Pfizer, Takeda, Amgen, F. Hoffmann LaRoche, Janssen, Medical Trends, Merck Serono, Sanofi, Touch ONCOLOGY; other relationship, personal: GRIFOLS; research funding, institution: Merck, Merck KGaA. RGC: consulting or advisory role, personal: Roche/Genentech, MSD Oncology, AstraZeneca, Bristol-Myers Squibb, Pfizer, Novartis, Takeda, Boehringer Ingelheim, Janssen Oncology; speakers’ bureau, personal: Roche, AstraZeneca, Bristol-Myers Squibb, Pfizer, Novartis, Takeda, Boehringer Ingelheim, MSD Oncology, Sanofi/Aventis, Janssen Oncology, Amgen, Lilly; travel, accommodations, expenses, personal: Roche/Genentech, MSD Oncology, Pfizer. CM: consulting or advisory role, personal: Roche, Sanofi, Takeda, Pfizer, Bristol-Myers Squibb, MSD, AstraZeneca, Kephren, AMGEN, Janssen, GlaxoSmithKline; honoraria, personal: Roche, AstraZeneca, Kephren, Bristol-Myers Squibb, Pfizer, Sanofi, MSD, Takeda, Janssen; travel, accommodations, expenses, personal: MSD; other, uncompensated relationships: Boehringer Ingelheim. FC: consulting or advisory role, personal: Roche/Genentech, AstraZeneca/MedImmune, Pfizer, Bristol-Myers Squibb, Takeda, Lilly, MSD Oncology, Bayer, Amgen, Sanofi, PharmaMar, Novocure; honoraria, personal: Pfizer, Roche/Genentech, AstraZeneca/MedImmune, Lilly, MSD Oncology, Bristol-Myers Squibb, Takeda, Bayer, Amgen, Sanofi, PharmaMar, Novocure; travel, accommodations, expenses, personal: OSE Immunotherapeutics. WH: consulting or advisory role, personal: AstraZeneca, Janssen; honoraria, personal: MSD Oncology. FD: consulting or advisory role, institution: SIVAN Innovation; honoraria, personal: AstraZeneca, MSD, Ipsen, Roche Belgium, Pfizer/EMD Serono, Takeda; stock and other ownership interests, institution: Kelindi; other relationship, personal: Takeda, Novartis, Ipsen, Janssen-Cilag, Merck Serono, Chugai Pharma, Ferring. SV: consulting or advisory role, personal: Roche; company: Bristol-Myers Squibb, Janssen, Takeda, Reddy Pharma Iberia, Merck KGaA, Puma Biotechnology; speakers’ bureau, personal: Bristol-Myers Squibb, Roche, MSD, AstraZeneca Spain; travel, accommodations, expenses, personal: Roche, MSD, Merck KGaA. DD: consulting or advisory role, personal: BMS, OSE Immunotherapeutics, Amgen, AstraZeneca; honoraria, personal: AstraZeneca, BMS, Janssen, Amgen, Novartis, Sanofi Aventis, Ipsen, MSD, GSK, Hoffmann-La Roche, Pfizer, OSE Immunotherapeutics; research funding, institution: AstraZeneca, Chugaï, Hoffmann-La Roche, Lilly, BMS, MSD, Boehringer-Ingelheim, Pfizer, Takeda, Bayer, Janssen, Sanofi-Aventis; travel, accommodations, expenses, personal: Amgen, BMS, AstraZeneca, MSD, Novartis, Roche, Pfizer, Janssen, Takeda. DG: consulting or advisory role, personal: Eli Lilly, Novartis, AZ, BMS, Pfizer; speakers’ bureau, personal: Eli Lilly, Takeda, Novartis, BMS, MSD, Roche; travel, accommodations, expenses, personal: Amgen. GR: consulting or advisory role, personal: MSD, Astra Zeneca, BMS; honoraria, personal: Roche, MSD, Astra Zeneca; research funding, institution: Roche; travel, accommodations, expenses, personal: Roche, MSD, Astra Zeneca. MM: consulting or advisory role, personal: Alfasigma, Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Incyte, Lilly, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi; honoraria: Alfasigma, Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, SciClone; stock and other ownership interests: Epigen Therapeutics, Theravance. AD: consulting or advisory role, personal: Novartis, Pfizer, Immunocore; research funding, institution: MSD; travel, accommodations, expenses, personal: MSD. BR: consulting or advisory role, personal: Amgen, AstraZeneca, BMS, Chugaï, Lilly, Roche, Takeda; speaker’s bureau: BMS, Roche; travel, accommodations, expenses, personal: BMS, Amgen, MSD, Roche, Novartis. WS: consulting or advisory role, personal: Roche, MSD, Novartis; honoraria, personal: Roche, MSD, Novartis. AZ: consulting or advisory role, personal: Boehringer Ingelheim, Roche, MSD, Oncotest/Rhenium, Lilly; honoraria, personal: MSD, Roche, AstraZeneca, Takeda, Novartis; stock and other ownership interests, personal: Nixio; research funding, institution: Bristol-Myers Squibb; travel, accommodations, expenses, personal: AstraZeneca, MSD, Roche. DC: employment, personal: OSE Immunotherapeutics; leadership, personal: OSE Immunotherapeutics; stock and other ownership interests, personal: OSE Immunotherapeutics. BV: employment, personal: OSE Immunotherapeutics; patents, royalties, other intellectual property, personal: uses of anti-SIRPa antibodies in the treatment of cancer; stock and other ownership interests, personal: OSE Immunotherapeutics. RD: consulting or advisory role, personal: Regeneron, Karyopharm Therapeutics; honoraria, personal: Roche/Genentech, Novartis, Pfizer, Bristol-Myers Squibb, Takeda, AstraZeneca, MSD Oncology, Boehringer Ingelheim, Seattle Genetics; travel, accommodations, expenses, personal: Roche, AstraZeneca. GG: consulting or advisory role, personal: Daiichi Sankyo, Novartis, Radiomics, Janssen Oncology, Sanofi, Eisai, Spectrum Pharmaceuticals, Sanofi/Regeneron; research funding, institution: MedImmune, Karyopharm Therapeutics, Cantargia AB; starting in September 2022, employee of Amgen. All other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Immune checkpoint inhibitors (ICIs) represent the cornerstone of the current treatment of non-small cell lung cancer (NSCLC). However, the occurrence of concomitant infections might hamper success. All consecutive patients with advanced NSCLC who started ICIs as a first- or second-line therapy from January 1, 2017 to June 30, 2020 were retrospectively evaluated. The occurrence of infectious events during ICIs was correlated with clinical characteristics, including previous Cytotoxic Chemotherapy (CC), occurrence of immune-related-adverse-events (irAEs). A total of 211 patients were included, 46 (22%) females, with a median (q1-q3) age of 69 (62-76) years. Overall, 85 patients (40%) received ICIs as a first treatment line and 126 (60%) as a second line; 40 patients (19%) had at least one infection during ICIs, and 17 (8%) more than one. Notably, autoimmune diseases (P < .005), neutropenia (P = .001) or infections during previous CC (P = .001), irAEs (P = .006), or steroid therapy for irAEs (P < .001) were associated with infection development. By multivariate Cox-regression, autoimmune diseases (aHR = 6.27; 95%CI = 2.38-16.48; P < .001) and steroid therapy for irAEs (aHR = 2.65; 95%CI = 1.27-5.52; P < .009) were associated with a higher risk of infection during ICIs. Interestingly, autoimmune diseases were confirmed as risk factors in patients treated with ICIs as a first line, while previous infections were the only independent predictor of infections in patients treated with ICIs as a second line. Patients with NSCLC treated with ICIs with concurrent autoimmune disease, receiving steroid therapy for management of irAEs, or having a history of previous infections during CC should be actively monitored for the risk of developing infectious complications., (© 2023 The Authors. Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Non-small cell lung cancer (NSCLC) represents 85% of all new lung cancer diagnoses and presents a high recurrence rate after surgery. Thus, an accurate prediction of recurrence risk in NSCLC patients at diagnosis could be essential to designate risk patients to more aggressive medical treatments. In this manuscript, we apply a transfer learning approach to predict recurrence in NSCLC patients, exploiting only data acquired during its screening phase. Particularly, we used a public radiogenomic dataset of NSCLC patients having a primary tumor CT image and clinical information. Starting from the CT slice containing the tumor with maximum area, we considered three different dilatation sizes to identify three Regions of Interest (ROIs): CROP (without dilation), CROP 10 and CROP 20. Then, from each ROI, we extracted radiomic features by means of different pre-trained CNNs. The latter have been combined with clinical information; thus, we trained a Support Vector Machine classifier to predict the NSCLC recurrence. The classification performances of the devised models were finally evaluated on both the hold-out training and hold-out test sets, in which the original sample has been previously divided. The experimental results showed that the model obtained analyzing CROP 20 images, which are the ROIs containing more peritumoral area, achieved the best performances on both the hold-out training set, with an AUC of 0.73, an Accuracy of 0.61, a Sensitivity of 0.63, and a Specificity of 0.60, and on the hold-out test set, with an AUC value of 0.83, an Accuracy value of 0.79, a Sensitivity value of 0.80, and a Specificity value of 0.78. The proposed model represents a promising procedure for early predicting recurrence risk in NSCLC patients., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bove et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Potential relationships with the prognosis of patients with extensive-stage non-small cell lung cancer (ES-SCLC) have been investigated without valid results., Methods: A retrospective analysis of real-world data of consecutive patients with ES-SCLC admitted to our Medical Thoracic Oncology Unit was carried out from 2010 to 2020, focusing on identification of prognostic factors. Kaplan-Meier analysis was used to represent progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox models were used to investigate prognostic factors., Results: The analysis included 244 patients. The median OS was 8 months (95% confidence interval [CI]: 8-10) and the median PFS was 5 months (95% CI: 5-6). The univariable analysis showed that factors associated with shorter OS were older age (p = 0.047), TNM stage 4 versus 3 (p < 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 and 2 versus 0 (p < 0.001), and >2 metastatic sites (p = 0.004). Mediastinal radiotherapy (RT) (p < 0.001), >1 irradiated site (p = 0.026), 3 and 4 chemotherapy (CT) lines versus 1 (p = 0.044 and 0.001, respectively), prophylactic cranial irradiation (PCI) (p < 0.001), and surgery (p = 0.001) correlated with longer OS. The multivariable analysis revealed statistically significant associations for TNM, ECOG PS 2 versus 0, number of CT lines, PCI, and surgery. A total of 23 patients (9.4%) survived ≥24 months, 39% of whom had received four CT lines and 48% had mediastinal RT., Conclusions: Our data suggest that tumor burden, PS, and mediastinal RT strongly correlate with outcome. With the addition of immunotherapy to CT, the identification of new biomarkers as predictive factors is urgently required., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Mast cells (MCs) are multifunctional immune cells implicated in both physiological and pathological processes. Among the latter, MCs play a crucial role in cancer. Many studies have shown a correlation between MCs and tumor progression in several solid and hematological malignancies. In particular, MCs can directly promote tumor growth via c-kit/stem cell factor-dependent signaling and via the release of histamine, which modulate tumor growth through H1 and H2 receptors. At the same time, MCs can increase tumor progression by stimulating angiogenesis via both proangiogenic cytokines stored in their cytoplasm, and by acting on the tumor microenvironment and extracellular matrix. With regard to NSCLC, the role of MCs has not yet been established, with studies showing a correlation with a poor prognosis on the one hand and suggesting a protective effect of MCs on the other hand. These controversial evidences are at least, in part, due to the heterogeneity of the studies exploring the role of MCs in NSCLC, with some studies describing only the MC count without specification of the activation and degranulation state, and without reporting the intratumoral localization and the proximity to other immune and cancer cells. A better knowledge of the role of MCs in NSCLC is mandatory, not only to define their prognostic and predictive proprieties but also because targeting them could be a possible therapeutic strategy., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Introduction: Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non-small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist., Methods: A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes., Results: Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi., Conclusion: Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This case series aimed to analyze the outcomes of patients referred for salvage pulmonary resections after treatment with chemotherapy and immunotherapy for previously metastatic or unresectable tumors.From October 2016, after multidisciplinary board discussion, eight patients (median: 67 years, range: 52-78 years) underwent medical treatment due to advanced-stage diseases (stage cIIIA-cIVa). Four patients underwent cisplatin-based chemotherapy and, due to progression, were moved to an immunotherapy second line (nivolumab: two patients and pembrolizumab: two patients). Instead, four patients underwent combined cisplatin-based chemotherapy and immune checkpoint inhibitors (atezolizumab: two patients and pembrolizumab: two patients). After a multidisciplinary evaluation for salvage surgery, six patients underwent lobectomies, one patient underwent left pneumonectomy, and one patient underwent upper right lobectomy enlarged to the posterior arches of four ribs. The median duration of surgery was 179 minutes (range: 122-246 minutes). At the final pathological stage, three patients showed a complete major response (ypT0 ypN0), one patient was ypT1a ypN0, one ypT3 ypN0, 2 ypT3 ypN1, and one ypT4 ypN0. The hospital length of stay was 6 days (range: 3-23 days). Two patients had a postoperative complication. At the time of follow-up (median: 15.3 months [range: 1-32 months]), six patients were alive without evidence of the recurrence. Two patients died due to recurrence progression (N3 lymph nodes involvement) of the disease after 6 and 32 months.In stage IIIB-IVA nonsmall cell lung cancer, salvage lung surgeries after chemotherapy and immunotherapy are feasible, with high rates of R0 resection. Surgery can be technically tricky without significant morbidity and encouraging outcomes (even with a short-interval follow-up)., Competing Interests: None declared., (Thieme. All rights reserved.)

Epidermal growth factor receptor (EGFR) exon 20 insertions occur rarely among different cancer types, with the highest frequency reported among non-small-cell lung cancer (NSCLC) patients, particularly adenocarcinomas (ADCs). Exon 20 insertions fall back in the tyrosine kinase domain, and can be clustered into two principal groups represented by in frame insertions and three to 21 bp (corresponding to 1-7 amino acids) duplications within amino acids 762 and 774. The identification of these alterations is key for an adequate management of NSCLC patients due to the possibility to treat these patients with specific targeted therapies. Next generation sequencing (NGS) technology, able to detect several hotspot gene mutations for different patients simultaneously, is the best detection approach due to its higher sensitivity and specificity compared to other techniques. Here we reviewed the principal biological characteristics, the main detection technologies and treatment options for NSCLC patients harbouring EGFR exon 20 insertions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Importance: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population., Objective: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer., Design, Setting, and Participants: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021., Main Outcomes and Measures: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs., Results: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti-programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non-small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged <85 vs ≥85 years). Among all 928 patients, 383 (41.3%) experienced ≥1 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued due to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P = .008)., Conclusions and Relevance: The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age.

Introduction: The efficacy of immune checkpoint inhibitors in patients with brain metastases (BMs) from non-oncogene addicted non-small cell lung cancer (NSCLC) is under investigation. Here, we sought to determine the optimal management of NSCLCs with PD-L1 ≥ 50% and asymptomatic BMs who were treated with first-line pembrolizumab., Methods: Thirty patients from 15 institutions with PD-L1 ≥ 50% NSCLC had asymptomatic BMs, and met inclusion criteria. Patients were classified based on whether they had undergone upfront local radiotherapy for BMs as well as on the type of brain radiotherapy received., Results: Nine patients were treated with upfront pembrolizumab alone, 8 patients with whole-brain radiotherapy (WBRT) followed by pembrolizumab and 13 patients with stereotactic radiosurgery (SRS) followed by pembrolizumab. Patients' characteristics were similar among the three groups of patients except for a higher number of BMs ≥ 3 in the WBRT group. One complete and 4 partial intracranial responses were observed with upfront pembrolizumab alone. The median survival was not reached for the pembrolizumab and WBRT (n = 8) groups, and it was 7.6 months for the SRS (n = 13) group (P = 0.09), with 12-month survival rates being 55.5%, 62.5%, and 23.0%, respectively. Salvage WBRT was delivered in 1 patient in the upfront pembrolizumab group and in 4 patients in the SRS group., Conclusions: Upfront pembrolizumab showed efficacy in selected patients with PD-L1 ≥ 50% non-oncogene addicted NSCLC and asymptomatic BMs. Prospective studies should address whether pembrolizumab alone, and deferral of radiotherapy, could be pursued in this patient population., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

Objectives: Pleomorphic lung carcinoma (PLC) is a rare histotype of non-small cell lung cancer (NSCLC) characterized by aggressive clinical course, poor response to therapy and poor prognosis. Therefore, aim of our study is to analyze with 18F-FDG PET/CT a subset of patients affected by PLC to evaluate their metabolic characteristics in terms of SUVmax, MTV and TLG, in order to correlate them with overall survival (OS) and disease-free survival (DFS)., Material and Methods: We retrospectively analyzed 49 consecutive patients with histologically defined PLC occurred to our Institution between 2003 and 2014. All patients underwent F18-FDG PET-CT before surgery and primary tumor was automatically segmented using an isocontour threshold method. SUV threshold for tumor segmentation was defined as the 41 % of lesion SUVmax. Total volume of the segmented VOI (MTV, centimeters cubed) and average SUV (SUVavg, grams per milliliter) in the segmented VOI were measured., Results: In our population men were significantly more affected than women (42:7). According to Youden criteria, SUVmax, MTV41 and TLG41 best cut-off values to predict 2-year mortality were, 18.95, 27.89 and 290.45, respectively, with TLG41 showing best specificity (85 %) and positive predictive value (82.4 %). As concerning 2-year recurrence, SUVmax, MTV41 and TLG41 best cut-off values were 10.08, 27.89 and 134.85, with SUVmax showing best sensitivity (96.7 %) and negative predictive value (85.7 %). ROC curves confirmed that SUVmax, MTV41 and TLG41 were equally accurate to predict 2-year mortality and 2-year recurrence in our population., Conclusion: Metabolic biomarkers such as SUVmax, MTV and TLG can be used as a prognostic index for disease progression, recurrence and death in patients with PLC, independently from other clinical/pathological prognostic elements., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Real-world data have suggested a detrimental effect of steroid use in patients with advanced non-small-cell lung cancer (NSCLC) receiving immunotherapy. However, previous studies included heterogeneous cohorts of patients receiving different lines of treatment with several immuno-oncology agents and various combinations of chemotherapy and immuno-oncology agents., Patients and Methods: A comprehensive clinicopathologic database of patients with NSCLC and programmed cell death ligand 1 >50% treated with frontline pembrolizumab monotherapy was constructed in 14 centers in Italy, Spain, Greece, and Switzerland. A multivariate analysis adjusting for the established prognostic factors was performed using a Cox regression model., Results: For the 265 eligible patients, the median age at diagnosis was 67 years, 66% were male, 90% were current or former smokers, 18% had had an Eastern Cooperative Oncology Group performance status of 2 or 3. Of the NSCLC subtypes, 64% were adenocarcinoma and 25% were squamous cell. Of the patients, 18% had had brain metastases at diagnosis and 24% had received steroids before or during pembrolizumab treatment. The median time to progression was 4.4 months with and 13.7 months without steroid use (hazard ratio [HR], 2.55; 95% confidence interval [CI], 1.69-3.85; log-rank P < .001). The median survival was 22.5 months for the whole cohort, 7.7 months for the steroid group, and not reached for the non-steroid group (HR, 3.64; 95% CI, 2.34-5.68; log-rank P < .001). On multivariate analysis accounting for all established prognostic variables, steroid use was still independently associated with a high risk of progression (HR, 1.864; 95% CI, 1.179-2.949; P = .008) and death (HR, 2.292; 95% CI, 1.441-3.644; P < .001) CONCLUSIONS: In patients with advanced NSCLC and programmed cell death ligand 1 expression > 50% receiving frontline pembrolizumab monotherapy, any use of steroids before or during treatment was associated with an 86% increase in the risk of progression and a 2.3-fold increase in the risk of death, even accounting for palliative indication-related bias, including the presence of central nervous system metastasis. The use of steroids for palliative indications should be restricted to absolutely necessary for patients receiving immuno-oncology monotherapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction . RET rearrangements have been recently aroused growing interest, due to the availability of target therapies increasingly active and safe. The search for these oncogenic alterations in patients with advanced lung adenocarcinoma has become an integral part of the biomolecular tumoral assessment, in order to possibly provide a selective therapeutical option also for rare subgroups of patients, but belonging to lung cancer that is considered a "big killer", representing the most frequent cause of cancer-related death worldwide. Following to the introduction of modern biomolecular techniques, such as the comprehensive genome profiling (CGP), that has been added to the immunohistochemistry (IHC) and the "in situ fluorescent ibridation" (FISH), the availability of techniques based on genomic sequencing such as the next generation sequencing (NGS), achievable either on tumoral tissue or on plasma, has made it easier to identify oncogenic alterations that, although rare, are potentially treatable with molecularly targeted drugs. A complete molecular assessment should preferable be obtained at the first diagnosis, in order not to neglect the possibility of using target drugs if indicated, but it is possible and desiderable to complete or to re-determine the biomolecular profile also during the clinical course, due to the possibility of spontaneous or drug-induced resistance mechanisms that can modify the biomolecular tumoral characteristics; this reassessment is achievable both through tissutal rebiopsy and by plasma test, the so-called "liquid biopsy". Clinical case . In this report, we describe the case of a patient with advanced lung adenocarcinoma, pretreated with multiple chemo- and immuno-therapic lines of treatment; at baseline, the biomolecular profile was not complete, as well as during the clinical course through repeated re-biopsies. Conclusions . At the time of further disease progression, a liquid biopsy with NGS revealed the presence of a RET rearrangement. This clinical case underscores the importance of a complete biomolecolar assessment in order to identify target linked to effective and innovative treatment options; it is also highlighted the usefulness of the modern CGP techniques, applicable to tumoral tissue and plasma.

Modern gene profiling techniques have allowed in recent years considerable progresses in the knowledge of molecular alterations in the context of non-small cell lung cancer (NSCLC). In some cases, these alterations have been recognized as having a pathogenic role and targeted therapies capable of inhibiting tumor proliferation by selective and specific blocking of the enzymatic activity of the related abnormal proteins have been developed. This has made it possible to improve the effectiveness of the treatments by minimizing toxicity. Today it is essential to apply Comprehensive Genomic Profiling methods also in clinical practice, in order to allow the best treatment available for each patient, possibly also in the context of clinical trials. Below we report the clinical history of a patient with advanced stage adenocarcinoma of the lung with molecular diagnosis of RET fusion, treated with pralsetinib with excellent clinical and radiological response and good tolerability. This clinical case emphasizes the importance of the broader molecular profiling in patients with advanced NSCLC (especially for non-squamous histology) from the diagnosis before starting first-line treatment.

Background: The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%., Patients and Methods: We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes., Results: A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P < .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P < .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P < .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P < .0001), single-site irAEs (P < .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival., Conclusions: This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%., Methods: We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naïve NSCLC and a PD-L1 expression of ≥ 50%., Results: One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2-49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9-9.5; 599 events) and 17.2 months (95% CI 15.3-22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis., Conclusion: Pembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. Questions regarding the effectiveness in clinical subgroups, such as patients with poorer PS and with liver/bone metastases, still remain to be addressed. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.

The authors conducted a multicenter retrospective study on the outcome of programmed death-ligand 1 tumor proportion score≥50% advanced non-small cell lung cancer patients treated with first-line pembrolizumab according to the presence/absence of brain metastases. A total of 282 patients were included, of whom 56 had brain metastases that were treated with upfront local radiation therapy in 80.3% of cases. The overall response rate was 39.2% and 44.4% in patients with and without brain metastases (P=0.48), respectively, while intracranial response rate and intracranial disease control rate were 67.5% and 85.0%, respectively. The median time-to-treatment failure (TTF) and overall survival (OS) were 4.2 and 9.9 months versus 10.8 and 26.5 months for patients with and without brain metastases (P=0.06 and 0.05, respectively). Drug discontinuation rate due to treatment-related adverse events was 10.7% and 10.2% in patients with and without brain metastases, respectively. Multivariate analysis showed that baseline steroids was an independent predictor for a worse OS (P<0.001), while performance status (PS)≥2 was an independent predictor for a poorer TTF (P<0.001) and OS (P<0.001). In patients with brain metastases, only PS ≥2 was predicted for a worse TTF (P=0.02) and OS (P=0.03). Pembrolizumab has activity against brain metastases from non-small cell lung cancers with programmed death-ligand 1≥50%. Presence of brain metastases per se does not appear to be prognostic, and PS ≥2 seems to be the only factor associated with a worse outcome in patients with brain metastases.

Background: Other than the programmed cell death ligand 1 (PD-L1) value, oncologists have only the clinical characteristics of patients with advanced non-small-cell lung cancer (aNSCLC) to determine candidates for immunotherapy. A clinical prognostic score composed of the Eastern Cooperative Oncology Group performance status, sex, histologic type, stage, platinum-based first-line therapy, and response to first-line therapy has categorized 3 prognostic groups for patients undergoing second-line chemotherapy. We sought to validate the same score for patients with aNSCLC treated with second- or further-line immunotherapy., Materials and Methods: We collected data from 2 Italian centers. A score was generated to divide patients into 3 prognostic groups: best, score < 5; intermediate, score 5 to 9; and worst, score > 9. Overall survival (OS) and progression-free survival (PFS) were the endpoints., Results: A total of 347 patients were included for analysis. Their median age was 66 years (range, 30-88 years), most were aged < 70 years (67.5%), 70.7% were men, 79.5% were smokers, and 74.6% had had adenocarcinoma. The Eastern Cooperative Oncology Group performance status was 0 for 23%, 1 for 54.5%, and 2 for 22.5%. Of the 347 patients, 28% were in the best prognosis, 51% in the intermediate, and 21% in the worst prognosis group, respectively. The median OS was 18.0 months for the best, 8.5 months for the intermediate (hazard ratio [HR] vs. best, 1.83; 95% confidence interval [CI], 1.35-2.47; P < .001) and 2.6 months for worst (HR vs. best, 5.77; 95% CI, 3.99-8.33; P < .001) group. The median PFS was 3.4 months for the best, 3.7 months for the intermediate (HR vs. best, 1.35; 95% CI, 1.03-1.77; P = .032), and 1.9 months for the worst (HR vs. best, 2.51; 95% CI, 1.80-3.50; P < .001) group., Conclusions: The prognostic score was able to predict the outcomes of patients with aNSCLC who had received immunotherapy. The worst category showed a dismal life expectancy and probably would not benefit from active systemic therapy. Thus, for these patients, best supportive care could be the best choice., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: We retrospectively analysed patients with advanced non-small-cell lung cancer (NSCLC) harbouring high PD-L1 expression (>50%) and treated with front-line pembrolizumab, comparing outcomes of patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to those with PS 0-1. Methods: Data were collected by 16 participating centres. All patients with NSCLC and high PD-L1, treated with first-line pembrolizumab were included. We collected medical data from patient files, pathology and laboratory reports. Patient characteristics, comorbidities, PS, and tumour characteristics were reported. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were calculated. Results: 302 patients were included, 246 with PS 0-1, 56 with PS 2. RR was 72% among patients with PS 0-1 compared to 45% with PS2 (odds ratio (OR) 0.31 (95% CI: 0.17-0.57), p  < .001). Median PFS was 2.6 months (95% CI: 1.9-5.1) among patients with PS2 and 11.3 months (95% CI: 8.5-14.4) among those with PS 0-1. Median OS was 7.8 months (95% CI: 2.5-10.7) in the PS2 group, not reached in the PS 0-1 group. PS 2 remained predictive of poor outcomes in multivariate analysis. Conclusion: PS 2 is a strong independent predictor of poor response and survival in NSCLC patients with high PD-L1, treated with front-line pembrolizumab. Prospective randomised trials comparing immunotherapy to chemotherapy in this population would be welcome.

Background: Results of resection of lung cancer invading left atrium (T4atrium) without cardiopulmonary bypass (CPB) remain controversial. We reviewed our experience analyzing surgical results and postoperative outcomes., Methods: Patients who underwent extended lung resection for T4atrium without CPB between 1998 and 2018 were retrospectively reviewed using a prospective database., Results: The study included 44 patients (34 males and 10 females; median age: 63 years). Twenty-five patients underwent preoperative mediastinal staging and 27 received induction treatment (IT). Surgery included 40 (90.9%) pneumonectomies, 3 (6.8%) lobectomies, and 1 bilobectomy (2.3%). Pathological nodal status was N0 in 10 patients (22.7%), N1 in 18 (40.9%), and N2 in 16 (36.4%). Four patients receiving IT had a complete pathological response (9.1%). Eight (18.2%) patients had microscopic tumor evidence on atrial resected margins. Mortality was nil. The major complication rate was 11.4%, including one bronchopleural fistula, one cardiac herniation, and three hemothoraces, all requiring reintervention. The minor complication rate was 25.5%. After a median survival of 37 months (range: 1-144 months), 20 (45.4%) patients were alive. Five-year survival rate and disease-free interval were 39 and 45.8%, respectively. Patients with N0 and R0 disease had a best prognosis (log-rank test: p  = 0.03 and p  = 0.01, respectively). IT neither influenced survival nor postoperative complications. On multivariate analysis, pN0 ( p  = 0.04 [95% confidence interval [CI]: 0.65-9.66] and negative atrial margins ( p  = 0.02 [95% CI: 0.96-8.35]) were positive independent prognostic factors., Conclusions: T4atrium is technically feasible without mortality and acceptable morbidity. Patients with N2 cancers should not be operated. T4atrium should not be systematically considered as a definitive contraindication to surgery., Competing Interests: None., (Thieme. All rights reserved.)

Background: Second-line immunotherapy (IO) has shown an overall survival benefit. However, only 18% to 20% of patients with advanced non-small-cell lung cancer (aNSCLC) will respond, with a median progression-free survival (PFS) of 2 to 4 months. Thus, biomarkers to select those patients most likely to benefit from IO are greatly needed., Patients and Methods: We conducted a retrospective analysis of 154 patients with aNSCLC who had received anti-programmed cell death 1 therapy as second line or further treatment. We assessed the absolute neutrophil, lymphocyte, monocyte, and eosinophil counts at baseline (T0) and the second (T1) and third (T2) cycles. The neutrophil/lymphocyte ratio (NLR), derived-NLR (dNLR), lymphocyte/monocyte ratio (LMR), and their percentage of change at T1 and T2 compared with T0 were evaluated. The clinical characteristics and lactate dehydrogenase (LDH) level were also considered. Univariate and multivariate analyses were performed. Significant biomarkers for PFS on multivariate analysis were combined in a prognostic score., Results: For overall survival, the negative prognostic biomarkers were Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2, NLR at T0, and dNLR at T1; the LMR at T0, T1, and T2 was identified as a positive prognostic biomarker. For PFS, the negative prognostic biomarkers were ECOG PS 2, liver metastases, NLR at T0, dNLR at T1 and T2, and ≥ 30% increase of NLR from T0 to T1; the positive prognostic biomarkers were heavy smoking, LDH, and LMR at T2. The ≥ 30% increase of LMR from T0 to T1 and T0 to T2 correlated with the overall response rate. A prognostic score (EPSILoN score; smoking, ECOG PS, liver metastases, LDH, NLR) identified 3 prognostic groups (median PFS, 10.2, 4.9, and 1.7 months, respectively; P < .001)., Conclusions: The EPSILoN score combines 5 baseline clinical and blood biomarkers and can help to identify patients with aNSCLC who will most likely benefit from second-line IO. Further studies are warranted., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In most cases, T790M EGFR-positive NSCLC patients receiving osimertinib developed "non-drugable" progression, as the patients with common EGFR-sensitizing mutations were treated with first-line osimertinib. In both settings, chemotherapy represents the standard treatment and local ablative treatments (LATs) are potential useful options in the case of oligo-progression., Methods: We conducted a study on "post-progression" (pp) outcomes of T790M EGFR-positive NSCLC patients treated with osimertinib, according to the therapeutic strategy applied: osimertinib beyond progression (± LATs), "switched therapies" or best supportive care only (BSC)., Results: 144 consecutive patients were evaluated: 53 (36.8%) did not received post-progression treatments (BSC), while 91 (63.2%) patients received at least 1 subsequent treatment; 50 patients (54.9%) received osimertinib beyond disease progression [19 (20.9%) of them with adjunctive LATs] and 41 (45.1%) a switched therapy. Median ppPFS (progression-free survival) and median ppOS (overall survival) of patients who received osimertinib beyond progression vs. switched therapies were 6.4 months vs. 4.7 months, respectively [HR 0.57 (95% CI 0.35-0.92), p = 0.0239] and 11.3 months vs 7.8 months, respectively [HR 0.57 (95% CI 0.33-0.98), p = 0.0446]. Among patients who received osimertinib beyond progression with and without LATs median ppPFS was 6.4 months and 5.7 months, respectively [HR 0.90 (95% CI 0.68-1.18), p = 0.4560], while median ppOS was 20.2 months and 9.9 months, respectively [HR 0.73 (95% CI 0.52-1.03), p = 0.0748]. At the univariate analysis, the only factor significantly related to the ppPFS was the therapeutic strategy in favor of osimertinib beyond progression (± LATs). Moreover, the only variable which was significantly related to ppOS at the multivariate analysis was osimertinib beyond progression (± LATs)., Conclusion: Our study confirmed that in clinical practice, in case of "non-druggable" disease progression, maintaining osimertinib beyond progression (with adjunctive LATs) is an effective option.

Objectives: A few studies have already demonstrated survival benefits for local treatment in solitary metastatic non-small-cell lung cancer (NSCLC). The aim of this study is to retrospectively investigate the role of surgery in patients with oligometastatic (OM) NSCLC., Methods: Between January 1998 and December 2018, 57 patients with OM stage IV NSCLC (1 or 2) underwent a multidisciplinary approach including lung cancer surgery, local treatment of the distant metastasis (DM) and systemic medical treatments., Results: All patients had DM synchronous to lung cancer. Fifty-one (90%) patients had a single DM whereas 6 (11%) patients had 2 DMs. Forty-eight (84%) patients underwent induction chemotherapy. We performed 47 (82%) lobectomies, 4 (7%) segmentectomies and 6 (11%) pneumonectomies. Pathological lymph node involvement was evident in 28 (49%) patients. Adjuvant chemotherapy was administered in 20 (35%) patients. Forty-six (81%) patients had local treatment of the DM before lung resection, and 11 (19%) patients had after lung resection; 6 (11%) patients had both treatments. The median overall survival (OS) was 30 months, with the 2-, 3- and 5-year OS of 57%, 50% and 30%, respectively. OS was significantly related to lymph node involvement (P = 0.04), size of the primary tumour (P < 0.001), neoadjuvant chemotherapy (P = 0.02) and the time period between metastasis diagnosis and primary tumour removal (P = 0.04)., Conclusions: Multidisciplinary approach is the gold standard in OM patients. Patients with no lymph node involvement are the best candidates, with an acceptable OS. Thus, patients with OM-NSCLC should not be excluded from surgery as a matter of principle., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: The aim of this study was to assess the postoperative outcomes of robotic-assisted lobectomy in obese patients to determine the impact of the robotic approach on a high-risk population who were candidates for major pulmonary resection for non-small-cell lung cancer (NSCLC)., Methods: Between January 2007 and August 2018, we retrospectively reviewed the medical records of 224 obese patients (body mass index ≥ 30) who underwent pulmonary lobectomy at our institution via robotic-assisted thoracic surgery (RATS, n = 51) or lateral muscle-sparing thoracotomy (n = 173)., Results: Forty-two patients were individually matched with those who had the same pathological tumour stage and similar comorbidities and presurgical treatment. The median operative time was significantly longer in the RATS group compared to that in the thoracotomy group (200 vs 158 min; P = 0.003), whereas the length of stay was significantly better for the RATS group (5 vs 6 days; P = 0.047). Postoperative complications were significantly more frequent after open lobectomy than in the RATS group (42.9% vs 16.7%; P = 0.027). After a median follow-up of 4.4 years, the 5-year overall survival rate was 67.6% [95% confidence interval (CI) 45.7-82.2] for the RATS group, and 66.1% (95% CI 46.8-79.9) for the open surgery group (log-rank P = 0.54). The 5-year cumulative incidence of cancer-related deaths was 24.8% (95% CI 9.7-43.5) for the RATS group and 23.6% (95% CI 10.8-39.2) for the open surgery group (Gray's test, P = 0.69)., Conclusions: RATS is feasible and safe for obese patients with NSCLC with advantages compared to open surgery in terms of early postoperative outcomes. In addition, the long-term survival rate was comparable to that of the open approach., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: Anaplastic lymphoma kinase (ALK) rearrangement confers sensitivity to ALK inhibitors (ALKis) in non-small-cell lung cancer (NSCLC). Although several drugs provided an impressive outcome benefit, the most effective sequential strategy is still unknown. We describe outcomes of real-life patients according to the treatment strategy received., Patients: We retrospectively collected 290 ALK rearranged advanced NSCLC diagnosed between 2011 and 2017 in 23 Italian institutions., Results: After a median follow-up of 26 months, PFS for crizotinib and a new generation ALKis were 9.4 [CI 95% 7.9-11.2] and 11.1 months [CI 95% 9.2-13.8], respectively, while TTF were 10.2 [CI 95% 8.5-12.6] and 11.9 months [CI 95% 9.7-17.4], respectively, being consistent across the different settings. The composed outcomes (the sum of PFS or TTF) in patients treated with crizotinib followed by a new generation ALKis were 27.8 months [CI 95% 24.3-33.7] in PFS and 30.4 months [CI 95% 24.7-34.9] in TTF. The median OS from the diagnosis of advanced disease was 39 months [CI 95% 31.8-54.5]. Patients receiving crizotinib followed by a new generation ALKis showed a higher median OS [57 months (CI 95% 42.0-73.8)] compared to those that did not receive crizotinib [38 months (CI 95% 18.6-NR)] and those who performed only crizotinib as target agent [15 months (CI 95% 11.3-34.0)] (P < 0.0001)., Conclusion: The sequential administration of crizotinib and a new generation ALKis provided a remarkable clinical benefit in this real-life population, being an interesting option to consider in selected patients.

Objectives: Molecular diagnostics and care of non-small cell lung cancer (NSCLC) are continuously evolving. Few data document the current strategies to manage advanced NSCLC patients beyond progression in clinical practice., Patients and Methods: Be-TeaM is an Italian multi-center observational study conducted on consecutive EGFR-mutated stage IV NSCLC patients, progressed during/after a first-line EGFR-TKI. It consists of a retrospective phase, from first-line EGFR-TKI therapy start until study entry (i.e. beginning of the diagnostic process), and a prospective phase, until treatment choice or for 3 months if no therapy was prescribed. Primary objective was to describe the diagnostic and therapeutic approaches adopted after progression in a real-world setting., Results: Of 308 patients enrolled in 63 centers from July 2017 to June 2018, 289 were included in the analysis. In first line, 53.3 % received gefitinib, 32.5 % afatinib and 14.2 % erlotinib. The testing rate (i.e. rate of all patients undergone any biopsy -liquid and/or tissue- for the T790 M detection) was 90.7 %, with liquid biopsy being the most frequently executed. Of 262 biopsied patients, 64.5 % underwent only 1 liquid biopsy, 10.7 % only 1 tissue biopsy and 18.3 % >1 biopsy, both liquid and solid in 85.4 %. The T790M positivity rate was 45.3 %; of 166 patients undergone only a liquid biopsy and tested for the mutation, 39.8 % were T790M+ and 60.2 % T790M-/undetermined. By the observation end, 87.9 % patients had a post-progression treatment chosen, osimertinib being the most frequent among the T790M+., Conclusion: Be-TeaM provides the first snapshot of current practices for the management of NSCLC patients beyond progression in Italy; in clinical practice, assessing the T790M status is not always feasible., (Copyright © 2019. Published by Elsevier B.V.)

Background: Patients with cancer are at increased risk for venous thromboembolism (VTE), and 8% to 15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE event during the course of their disease. The incidence of VTE in molecularly defined NSCLC subgroups is still unclear. In this study, we investigated the incidence and the clinical correlates of VTE in patients with ROS1-rearranged NSCLC enrolled in the METROS trial (NCT02499614)., Patients and Methods: The METROS trial is a prospective phase II study designed to assess efficacy, safety, and tolerability of crizotinib in patients with pre-treated metastatic NSCLC ROS1 rearrangement (cohort A) or with MET amplification or MET exon 14 mutation (cohort B). Patients with ROS1-rearranged NSCLC enrolled within cohort A and the expansion cohort of the trial were included in the primary analysis., Results: Among 48 patients with ROS1-rearranged NSCLC enrolled in the METROS study, 20 (41.6%) of 48 had at least 1 VTE event. Among them, 7 (35%) of 20 patients had ≥ 2 VTE events. VTE events consisted of pulmonary embolism (46.4%), deep vein thrombosis (39.2%), renal vein thrombosis (7.1%), internal jugular thrombosis (3.5%), and peripheral inserted central catheter-related thrombosis (3.5%). VTE events occurred at disease progression in 35.7% of cases, at diagnosis in 32.1% of cases, and during chemotherapy or crizotinib in 17.8% and 14.2%, respectively., Conclusion: The incidence of VTE is 3- to 5-fold higher in patients harboring ROS1-rearrangment than previously observed for the general population with NSCLC. Larger studies are warranted to confirm our findings and determine whether the molecular profile of NSCLC should be incorporated into a risk-stratification tool and decision-making algorithm for VTE diagnosis and prophylaxis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: MET -deregulated NSCLC represents an urgent clinical need because of unfavorable prognosis and lack of specific therapies. Although recent studies have suggested a potential role for crizotinib in patients harboring MET amplification or exon 14 mutations, no conclusive data are currently available. This study aimed at investigating activity of crizotinib in patients harboring MET or ROS1 alterations., Patients and Methods: Patients with pretreated advanced NSCLC and evidence of ROS1 rearrangements (cohort A) or MET deregulation (amplification, ratio MET/CEP7 >2.2 or MET exon 14 mutations, cohort B) were treated with crizotinib 250 mg twice daily orally. The coprimary endpoint was objective response rate in the two cohorts., Results: From December 2014 to March 2017, 505 patients were screened and a total of 52 patients (26 patients per cohort) were enrolled onto the study. At data cutoff of September 2017, in cohort A, objective response rate was 65%, and median progression-free survival and overall survival were 22.8 months [95% confidence interval (CI) 15.2-30.3] and not reached, respectively. In cohort B, objective response rate was 27%, median progression-free survival was 4.4 months (95% CI 3.0-5.8), and overall survival was 5.4 months (95% CI, 4.2-6.5). No difference in any clinical endpoint was observed between MET -amplified and exon 14-mutated patients. No response was observed among the 5 patients with cooccurrence of a second gene alteration. No unexpected toxicity was observed in both cohorts., Conclusions: Crizotinib induces response in a fraction of MET -deregulated NSCLC. Additional studies and innovative therapies are urgently needed., (©2019 American Association for Cancer Research.)

Background: Bone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy., Methods: Pretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM., Results: Cohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p <  0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p <  0.0001; Cohort B: 2.7 versus 5.2 months, p <  0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p <  0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78)., Conclusions: BoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy.

Background: Nivolumab has shown a survival benefit compared with docetaxel as second-line treatment for patients with previously treated advanced squamous non-small cell lung cancer (NSCLC) in a randomized phase III trial. The experiences of patients and physicians in routine clinical practice are often different from those in a controlled clinical trial setting. We present data from the entire Italian cohort of patients with squamous NSCLC enrolled in a worldwide nivolumab NSCLC expanded access program., Patients and Methods: Patients with pretreated advanced squamous NSCLC received nivolumab 3 mg/kg every 2 weeks for up to 24 months. Safety was monitored throughout; efficacy data collected included objective tumor response, date of progression, and survival information., Results: The Italian cohort comprised 371 patients who received at least one dose of nivolumab. In the overall population, the objective response rate (ORR) was 18%, the disease control rate (DCR) was 47%, and median overall survival (OS) was 7.9 months (95% confidence interval 6.2-9.6). In subgroup analyses, ORR, DCR, and median OS were, respectively, 17%, 48%, and 9.1 months in patients previously treated with two or more lines of therapy ( n = 209) and 8%, 40%, and 10.0 months in patients treated beyond disease progression ( n = 65). In the overall population, the rate of any-grade and grade 3-4 adverse events was 29% and 6%, respectively. Treatment-related adverse events led to treatment discontinuation in 14 patients (5%). There were no treatment-related deaths., Conclusion: To date, this report represents the most extensive clinical experience with nivolumab in advanced squamous NSCLC in current practice outside the controlled clinical trial setting. These data suggest that the efficacy and safety profiles of nivolumab in a broad, real-world setting are consistent with those obtained in clinical trials., Implications for Practice: Nivolumab is approved in the U.S. and Europe for the treatment of advanced non-small cell lung cancer (NSCLC) after failure of prior platinum-based chemotherapy. In this cohort of Italian patients with previously treated, advanced squamous NSCLC treated in a real-world setting as part of the nivolumab expanded access program, the efficacy and safety of nivolumab was consistent with that previously reported in nivolumab clinical trials., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Background:  This study analyzed the short- and long-term outcomes of robotic-assisted thoracic surgery (RATS) for early stage non-small cell lung cancer (NSCLC)., Methods:  From November 2006 to December 2016, we performed 363 RATS procedures. This study retrospectively reviewed 339 patients who underwent RATS for clinical stages I ( n  = 318) or II ( n  = 21) NSCLC., Results:  Twenty-nine patients underwent segmentectomy, 307 lobectomy, and 3 pneumonectomy. Conversion occurred in 22 patients (6.5%): 15 (4.4%) due to technical issues, 4 (1.2%) for oncological reasons, and 3 (0.9%) for bleeding. The median number of N1 and N2 stations resected was 2 and 3, respectively, and the median number of N1 and N2 lymph nodes resected was 9 and 6, respectively. Median operative time was 192 minutes for lobectomy, 172 minutes for segmentectomy, and 275 minutes for pneumonectomy. Median length of hospital stay was 5 days (2-191). The most common postoperative complication was prolonged air leak (12.1%). Major complications occurred in eight patients (2.4%). The 30-day and 90-day operative mortality was 0% and 0.3%, respectively. Two and 5-year cancer-specific survival rate was 96.1% and 91.5%, respectively. Five-year survival rate was 96.2% for patients who underwent segmentectomy, and 89.1% for lobectomy. All three patients who underwent pneumonectomy were alive at 5 years with no disease., Conclusions:  Besides the well-known short-term outcomes showing very low morbidity and mortality rates, mediastinal lymph node dissection during RATS adequately assesses lymph node stations detecting occult lymph node metastasis and leading to excellent oncologic results. However, these results await longer follow-up studies., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Despite the scant docetaxel's tolerability, second-line association with nintedanib still represents a standard-of-care for non-squamous non-small cell lung cancer (nsNSCLC), giving to rapidly-progressing patients the greatest survival advantage. The SENECA trial is a phase IIb, open-label, study evaluating whether nintedanib/docetaxel can be equally effective and safe regardless docetaxel schedule., Materials and Methods: Recurrent nsNSCLC patients were stratified into cohort 1 and 2, according to relapse-time (within or over 3 months) from end of first-line chemotherapy. They were treated with docetaxel (T1: 33 mg/mq on days 1 and 8 in a 21-days cycle; T2: 75 mg/mq q3wks) plus nintedanib, allowing maintenance in case of disease-control. Primary endpoint was progression-free survival (PFS) by investigator's assessment; secondary endpoints: overall survival (OS), safety and quality-of-life., Results: Between January 2016-April 2018, 212 patients were evaluated: 30 resulted screening-failures, 12 were excluded for lack of compliance. According to investigator's choice, 85 patients received T1 docetaxel and 85 T2; 138 (81.2%) were stratified in C1, 32 (18.8%) in C2, with a median relapse-time of 0.54 and 9.29 months, respectively. Baseline characteristics were balanced between groups. After 35.5 months follow-up, no survival differences appear between cohorts and treatments; toxicity seems to be slightly higher in T2, especially for chemotherapy-related events. Perception of quality-of-life remains stable and docetaxel schedule doesn't modify patients' load., Conclusion: The SENECA trial confirms efficacy of second-line nintedanib/docetaxel for nsNSCLC, regardless time of recurrence and docetaxel schedule; higher toxicities for q3wks docetaxel, without alterations in quality-of-life, have been described, underling the possibility, adopting the weekly schedule, to maintain efficacy with better tolerability., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Testing for circulating biomarkers in lung cancer is hampered by the insufficient specificity. We aimed to assess the relative diagnostic accuracy of pro-gastrin-releasing peptide (ProGRP) for the differential diagnosis of small cell lung cancer and compare it with more conventional biomarkers., Methods: We enrolled a cohort of 390 patients with a clinical suspicion of lung cancer and for whom a histologic assessment was available. Serum or plasma samples were assessed for ProGRP, carcinoembryonic antigen, CYFRA 21-2, and neuron-specific enolase. The performance of each biomarker in discriminating the small cell lung cancer and squamous cell carcinoma/adenocarcinoma from non-malignant lung disease, and small cell lung cancer from squamous cell carcinoma/adenocarcinoma, was assayed by receiver operating characteristic curve analysis., Results: At the cut-off levels suggested by the manufacturers, ProGRP and neuron-specific enolase showed an almost identical sensitivity of 55.2% and 55.6%, respectively, in discriminating small cell lung cancer with respect to non-malignant lung disease. In order to quantify the added value of ProGRP to other conventional markers, we ran a multivariable logistic regression analysis, but the results showed that no markers improve the performance of ProGRP., Conclusions: ProGRP and neuron-specific enolase individually appear more accurate than other conventional biomarkers for small cell lung cancer, but the union of two markers does not increase the accuracy. The very small target group of patients with small cell lung cancer is a limitation of this study, which can explain why ProGRP alone does not show a sensitivity higher than neuron-specific enolase, as reported by other authors.

Background: Owing to the expected poor long-term outcomes and high postoperative morbidity and mortality, patients with stage IIIA-N2 tumors candidate to pneumonectomy (PN) are usually excluded from surgery. This study aims to analyze the outcome of patients who underwent PN to prove its safety and feasibility., Patients and Methods: We retrospectively analyzed data from 233 patients who underwent PN for N2 non-small-cell lung cancer (NSCLC) between 1998 and 2015. Eighty-five patients were occult N2 disease (group 1), whereas 148 patients underwent induction therapy (IT) for stage IIIA-N2 (group 2)., Results: Overall morbidity, postoperative mortality, and 90-day mortality rates were 46.8%, 2.6%, and 8.6%, respectively. The 2 groups (group 1 vs. 2) had similar postoperative and 90-day mortality rates: 2.4% versus 2.7% (P = 1.00), and 9.4% versus 8.1% (P = .81), respectively. The incidence of major morbidity was higher and statistically significant in group 2 compared with group 1: 23% versus 12.9% (P = .1). Postoperative bronchopleural fistula occurred in 4.7% (4/85) of patients with occult N2 (group 1) and in 10.1% (15/148) of patients undergoing IT (group 2) (P = .10). Median overall survival (OS) was 2.2 years, with a 3 and 5-year OS of 43.4% and 31.6%, respectively. Disease-free survival (DFS) was 1.5 years, with 3 and 5-year DFS of 41.6% and 32%, respectively; no difference in OS and DFS between the 2 groups was found., Conclusions: Considering the acceptable morbidity and mortality rate and the long-term survival, PN should not be excluded for selected patients with stage IIIA-N2 NSCLC as a matter of principle., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations., Methods: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events., Results: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively., Conclusions: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.

Introduction: Nivolumab is the first checkpoint inhibitor approved for the treatment of nonsquamous NSCLC. We report results from the nivolumab Italian expanded access program focusing on never-smokers and patients with EGFR-mutant nonsqamous NSCLC., Methods: Nivolumab (3 mg/kg intravenously every 2 weeks) was administered upon physicians' request to patients who had relapsed after one or more prior systemic treatments for stage IIIB/IV nonsquamous NSCLC. Efficacy and safety were evaluated in patients who received at least one dose of nivolumab., Results: Of 1588 patients with nonsquamous NSCLC, 305 (19.2%) were never-smokers. EGFR status was available for 1395 patients. Of the 102 patients (6.4%) with EGFR mutation-positive tumors, 51 (50%) were never-smokers. The objective response rate was significantly higher in patients with wild-type EGFR than patients with EGFR-mutant tumors (19.6% versus 8.8% [p = 0.007]), in former and current smokers than in never-smokers (21.5% versus 9.2% [p = 0.0001]), and in never-smokers with wild-type EGFR than in never-smokers with mutant EGFR (11.0% versus 1.9% [p = 0.04]). There was no significant difference in objective response rate between smokers with wild-type EGFR and smokers with mutant EGFR (22.0% versus 20.6%). There was no statistically significant difference in median progression-free survival or in median overall survival. The median overall survival times were 11 months in patients with EGFR wild-type tumors versus 8.3 months in patients with EGFR-mutant tumors, 11.6 months in smokers versus 10.0 months in never-smokers, 11.0 months in never-smokers with EGFR wild-type tumors versus 5.6 months in never-smokers with EGFR-mutant tumors, and 14.1 months in smokers with EGFR-mutant tumors versus 11.3 months in smokers with EGFR wild-type tumors., Conclusions: The data on the Italian expanded access program in populations with nonsquamous NSCLC suggest that subgroups of patients could benefit differently from nivolumab according to their EGFR mutational status and smoking habits. These results warrant further investigation., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: The role of induction therapy (IT) and its effects on morbidity and mortality of patients receiving tracheal sleeve pneumonectomy (TSP) are unclear. We evaluated early and long-term outcomes of patients who underwent TSP after IT., Methods: From 1998 to 2015, 32 patients (26 men; median age, 63 years) underwent TSP. Twenty-two patients (69%) received IT (cisplatin-based chemotherapy). The TSPs were all right sided and included three completion pneumonectomies. Superior vena cava resection was combined with TSP in 15 cases. Diaphragmatic and vertebral resection was also associated in 1 case each., Results: Operative mortality was nil. Thirty-day mortality was 9% (n = 3). Major complications occurred in 7 patients (21.8%): bronchopleural fistulas in 3; acute respiratory distress syndrome in 2; cardiac hernia in 1; and empyema in 1. The IT had no significant effects on morbidity and mortality. Resection was complete in 31 patients (97%). Pathologic N status was N0 in 2 cases, N1 in 17, and N2 in 13. Nodal downstaging was diagnosed in 13 of 22 patients (59.1%) who received IT (11 passed from N2 to N1, and 2 to N0). Mean survival was 36 months (range, 1 to 181). Overall 5-year survival and disease-free survival were 30.3% and 27.7%, respectively. Patients receiving IT had a poor survival (p = 0.03). At multivariate analysis, nodal downstaging and adjuvant treatment significantly affected survival (p = 0.035 and p = 0.007, respectively)., Conclusions: Tracheal sleeve pneumonectomy is a feasible but technically challenging surgical procedure and provides acceptable results in terms of early and long-term outcomes. Induction therapy did not significantly affect morbidity and mortality., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Aim: Ceritinib was evaluated within a compassionate use program of Italian patients., Patients & Methods: 70 patients with anaplastic lymphoma kinase-positive crizotinib-refractory advanced non-small-cell lung cancer received ceritinib., Results: Overall response was 40.6%, median progression-free survival was 8.2 months and median survival was 15.5 months. Dose reduction due to treatment-related adverse events occurred in 50.8% of patients starting at 750 mg/day. No significantly different progression-free survival was observed between patients who underwent any time dose reduction (n = 38) versus those who remained on the recommended dose of 750 mg/day (n = 32; p = 0.07)., Conclusion: The efficacy of ceritinib compassionate use program resembled that of clinical trials. Dose reductions and adjustments did not appear to negatively affect clinical outcome.

Background: Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a "real-life" Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study., Patients and Methods: Data of advanced NSCLC patients with uncommon EGFR mutations who received first-line first-generation EGFR-TKIs in 24 Italian Hospitals were collected. In this analysis we aimed to evaluate overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of EGFR-TKIs in NSCLC patients harboring uncommon EGFR mutations., Results: Thirty-five patients harboring uncommon EGFR mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) were included of the original 312 EGFR-mutated cases. Most of them were female (n = 20, 57.1%), former smokers (n = 23, 65.7%), with adenocarcinoma (n = 31, 88.6%). The most frequent EGFR mutations were G719X (n = 6, 17.2%) and L861Q (n = 5, 14.2%). The population presented an ORR of 25.7%, a median PFS of 5.19 months, and a median OS of 14.49 months. When stratified according to type of EGFR mutation, median OS ranged from 3.65 months for unspecified mutations to 21.29 for double EGFR mutations. Median PFS ranged from 1.77 months for unspecified mutations to 20.83 months for concomitant EGFR-anaplastic lymphoma kinase alteration. ORR varied from 0% in exon 18, 20 and double gene alteration to 66.6% in exon 19., Conclusion: Our study supports the existence of a strong outcome heterogeneity within patients harboring uncommon EGFR mutations, which needs to be clarified to achieve a real personalized treatment strategy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Molecular profiling of advanced non-small-cell lung cancer (NSCLC) is recommended according to European and Italian guidelines. However, molecular routine assessment remains still heterogeneous. This observational study aimed to take a picture of the real clinical practice in molecular testing and therapeutic choices in advanced Italian NSCLCs., Materials and Methods: This study prospectively enrolled newly diagnosed advanced or recurrent NSCLCs referred to 38 Italian centres, from November 2014 to November 2015. Information regarding molecular profiling and treatment choices were collected. Description of patients' outcome included overall survival (OS), progression-free survival in first (PFS1) and second-line (PFS2)., Results and Conclusion: Among 1787 patients enrolled, 1388 (78%) performed at least one molecular analysis during the history of disease: 76% were tested for EGFR, 53% for ALK, 27% for KRAS, 16% for ROS1, 14% for BRAF, 5% for HER2, 4% for MET and 1% for FGFR. The remaining 399 patients (22.3%) did not receive any molecular test. Among patients receiving at least one molecular analysis, 583 (42%) presented a molecular alteration. Considering EGFR mutated and/or ALK rearranged patients (402), for which target agents were routinely reimbursed at time of study in Italy, the 86% received a personalized treatment as first and/or second line: the 90% (286) of EGFR mutants received an EGFR tyrosine kinase inhibitor, mostly gefitinib (41.1%) or afatinib (36.4%) while 74% (62) of ALK translocated patients received an ALK inhibitor, mostly crizotinib (64%). Median OS was 9.34 months (95% CI 8.62-10.0), median PFS1 was 4.61 months (95%CI 4.31-4.84) and median PFS2 was 2.76 months (95%CI 2.57-3.19). In the Italian clinical practice, routine molecular assessment was largely applied in NSCLC patients, according to national guidelines, but a low level of ALK test was reached. Most of EGFR mutants an ALK rearranged patients received a personalized treatment as first and/or second line., (Copyright © 2017 Elsevier B.V. All rights reserved.)