Emanuele Vita

Scopus Publications

Overcoming amplification-mediated resistance to sotorasib by dose re-escalation in KRAS G12C mutant NSCLC: a case report
Antonio Vitale, Emanuele Vita, Alessio Stefani, Alessandra Cancellieri, Filippo Lococo, Giampaolo Tortora, and Emilio Bria
Oxford University Press (OUP)
Abstract Precision oncology has transformed non-small cell lung cancer (NSCLC) treatment by tailoring therapies to the genomic profile of the disease, significantly improving clinical outcomes. However, acquired resistance to molecularly targeted therapies remains a major challenge. This report details a 69-year-old woman with KRAS G12C-mutant metastatic NSCLC who developed resistance to sotorasib, a KRAS G12C inhibitor. Initially responding to the standard dose of 960 mg, the patient required a dose reduction to 480 mg due to liver toxicity. After 20 months, oligoprogression occurred, managed through surgical resection. Molecular analysis of the resected tissue identified KRAS amplification as a resistance mechanism. Following disease progression, re-escalation of sotorasib to 960 mg led to renewed tumor response without additional toxicity. This case highlights dose re-escalation as a potential strategy to address resistance in selected patients and underscores the critical role of molecular profiling and personalized approaches in optimizing targeted NSCLC treatments.

COVALENCE STUDY: Immunogenicity and Reactogenicity of a COVID-19 mRNA Vaccine in an Open-Label Cohort of Long-Survivor Patients with Metastatic Lung Cancer
Emanuele Vita, Federico Monaca, Luca Mastrantoni, Geny Piro, Giacomo Moretti, Ileana Sparagna, Alessio Stefani, Antonio Vitale, Giovanni Trovato, Mariantonietta Di Salvatore,et al.
MDPI AG
Background: As COVID-19 has become an epidemic, we conducted an open-label study aimed to identify immunogenicity and reactogenicity of boosters of the BNT162b2 vaccine in a real-world cohort of long-survivor metastatic lung cancer patients (LS-mLC pts). Methods and Analysis: According to the timing of the booster dose (BD) and SARS-CoV-2 infection (Cov-I) during anticancer treatment (ACT), between October 2021 and February 2022, we prospectively enrolled 166 cancer patients into five parallel cohorts. The primary endpoints were seroprevalence of IgG Anti-spike-RBD (anti-S IgG) at two pre-defined timepoints (T1: +30–90 days after BD; T2: +6 months +/− 4 weeks after BD). As an exploratory endpoint, we compared the median pre-vaccination value of four cytokines (IL-6, IL-2R, TNF-α, IL-10) with post-BD values in immunotherapy-treated pts (IO-pts). Results: The anti-S IgG seropositivity rate was 100% at T1 and 98.8% at T2. After 6 months, hybrid immunisation was associated with a higher median anti-S IgG titre compared to vaccine-alone-induced seroconversion (p < 0.0001). In uninfected pts, the median anti-S IgG titre was significantly lower in IO-pts compared to non-IO-pts (p = 0.02); no difference was found when comparing myelosuppressive or not ACT. Among the 68 IO-pts, 5 pts (7.3%) showed a significant increase (≥1.5 fold) of at least two cytokines in post-BD samples, without reporting ir-AEs. Conclusions: Boosters of the COVID-19 mRNA vaccine were effective and safe. In IO-pts without recent Cov-I, additional BDs should be considered to prolong serological immunity.

Body composition derangements in lung cancer patients treated with first-line pembrolizumab: A multicentre observational study
Ilaria Trestini, Lorenzo Belluomini, Alessandra Dodi, Marco Sposito, Alberto Caldart, Dzenete Kadrija, Luca Pasqualin, Silvia Teresa Riva, Ilaria Mariangela Scaglione, Daniela Tregnago,et al.
Wiley
AbstractBackgroundWhile immune checkpoint inhibitors (ICIs) are increasingly reshaping the therapeutic landscape of non‐small‐cell lung cancer (NSCLC), only a limited proportion of patients achieve a relevant and long‐lasting benefit with these treatments, calling for the identification of clinical and, ideally modifiable, predictors of efficacy. Body composition phenotypes may reflect aspects of patients' immunology and thereby their ability to respond to ICIs. This study aims to explore the possible association between pre‐treatment body composition phenotypes, tumour response, and clinical outcomes in patients receiving first‐line pembrolizumab monotherapy for advanced NSCLC.MethodsA retrospective review of consecutive patients with treatment‐naïve NSCLC and PD‐L1 expression ≥50% undergoing pembrolizumab at three academic institutions was performed. Pre‐treatment body composition parameters were measured at the third lumbar vertebra level by computed tomography, defined using pre‐established cut‐offs. Primary endpoint was objective response rate (ORR), secondary endpoints progression‐free survival and overall survival (PFS and OS), compared through the log‐rank test and the Cox proportional hazards model.ResultsData from 134 patients (93 males [69.4%] and 41 females [30.6%]) were collected. Median age was 69 years (range 36–85), with a median follow‐up of 12 months (range 1–131). The median body mass index (BMI) was 24.5 (IQR 21.5; 26.1) kg/m2. Overall, 59.0% and 51.5% of patients met established radiographic criteria for evidence of sarcopenia and myosteatosis, respectively, which occur across the BMI spectrum. Multivariate regression analysis, adjusted for co‐morbidities, revealed that sarcopenia (aOR 5.56, 95% CI. 2.46–12.6, P < 0.0001) and low intermuscular adipose tissue (IMAT) area (aOR 1.83, 95% CI. 1.22–2.83, P = 0.001) were associated with a lower rate of ORR (30.4% vs. 70.5%, P < 0.0001 and 30.7% vs. 73.2%, P < 0.0001, respectively). Moreover, both in univariate and multivariate analysis, adjusted for co‐morbidities, low performance status according to the Eastern Cooperative Oncology Group scale (ECOG PS), sarcopenia and low IMAT were significantly related to short PFS (ECOG PS: aHR 2.73, 95% CI 1.60–4.66, P < 0.0001; sarcopenia: aHR 2.24, 95% CI 1.37–3.67, P = 0.001; IMAT depot: aHR 2.26, 95% 1.40–3.63, P = 0.002) and OS (ECOG PS: aHR 3.44, 95% CI 1.96–6.01, P < 0.0001; sarcopenia: aHR 4.68, 95% CI 2.44–8.99, P < 0.0001; IMAT depot: aHR 3.18, 95% 1.72–5.88, P < 0.0001).ConclusionsSkeletal muscle abnormalities, apparently frequent in NSCLC, potentially represent intriguing predictive markers of response to ICIs and survival outcomes. Large prospective trials are needed to validate ICIs responders' clinical biomarkers.

Artificial intelligence applications in personalizing lung cancer management: state of the art and future perspectives
Filippo Lococo, Galal Ghaly, Sara Flamini, Annalisa Campanella, Marco Chiappetta, Emilio Bria, Emanuele Vita, Giampaolo Tortora, Jessica Evangelista, Carolina Sassorossi,et al.
AME Publishing Company

Impact of Comprehensive Genome Profiling on the Management of Advanced Non–Small Cell Lung Cancer: Preliminary Results From the Lung Cancer Cohort of the FPG500 Program
Antonio Vitale, Luca Mastrantoni, Jacopo Russo, Flavia Giacomini, Diana Giannarelli, Simona Duranti, Emanuele Vita, Camilla Nero, Ettore D'Argento, Tina Pasciuto,et al.
American Society of Clinical Oncology (ASCO)
PURPOSE The clinical and research FPG500 program (ClinicalTrials.gov identifier: NCT06020625 ) is currently ongoing at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS to tailor matched targeted therapies (MTTs) according to biomarkers predictive of response identified by comprehensive genome profiling (CGP). MATERIALS AND METHODS The non–small cell lung cancer (NSCLC) cohort results from the FPG500 program are outlined. CGP was performed by TruSight Oncology 500 High Throughput (TSO500HT) assay or Oncomine Focus Assay plus Archer's FusionPlex Lung Panel according to tumor cell content and DNA/RNA quantity. Relevant issues for Molecular Tumor Board (MTB) evaluation included uncommon genomic findings, evaluation for off-label therapies, uncertain result confirmation, and variants of suspect germline origin requiring genetic counseling. Progression-free survival (PFS) and overall survival (OS) for the enrolled patients were assessed using Kaplan-Meier analysis. RESULTS In 2022, 283 patients with NSCLC were considered for sequencing, with 93% meeting eligibility criteria. TSO500HT sequencing was conducted in 76% of patients. Follow-up data were obtained for 187 patients, among whom 81% received treatment. Potential driver alterations were identified in 59% of patients, with 41% receiving MTT: 25% were prescribed approved MTTs, whereas 16% gained access to experimental drugs post-MTB evaluation; of note, 18% did not receive any MTT because the regimen was not yet reimbursed in our country. Median PFS and OS varied among treatment groups, with standard chemotherapy/immunotherapy at 7.7 and 10.7 months, approved tyrosine kinase inhibitors at 18.8 and 23.9 months, and MTT post-MTB discussion at 14 and 23.4 months, respectively. CONCLUSION The early data of the FPG program (NSCLC cohort) support the implementation of CGP and MTB in clinical practice to grant access to patients harboring actionable molecular alterations to the most effective and individualized available treatment options, thus improving their survival outcomes.

Comparative Analysis of Comprehensive Genomic Profile in Thymomas and Recurrent Thymomas Reveals Potentially Actionable Mutations for Target Therapies
Filippo Lococo, Elisa De Paolis, Jessica Evangelista, Andrea Dell’Amore, Diana Giannarelli, Marco Chiappetta, Annalisa Campanella, Carolina Sassorossi, Alessandra Cancellieri, Fiorella Calabrese,et al.
MDPI AG
Molecular profiles of thymomas and recurrent thymomas are far from being defined. Herein, we report an analysis of a comprehensive genetic profile (CGP) in a highly selected cohort of recurrent thymomas. Among a cohort of 426 thymomas, the tissue was available in 23 recurrent tumors for matching the biomolecular results obtained from primary and relapse samples. A control group composed of non-recurrent thymoma patients was selected through a propensity score match analysis. CGP was performed using the NGS Tru-SightOncology assay to evaluate TMB, MSI, and molecular alterations in 523 genes. CGP does not differ when comparing initial tumor with tumor relapse. A significantly higher frequency of cell cycle control genes alterations (100.0% vs. 57.1%, p = 0.022) is detected in patients with early recurrence (<32 months) compared to late recurrent cases. The CGPs were similar in recurrent thymomas and non-recurrent thymomas. Finally, based on NGS results, an off-label treatment or clinical trial could be potentially proposed in >50% of cases (oncogenic Tier-IIC variants). In conclusion, CGPs do not substantially differ between initial tumor vs. tumor recurrence and recurrent thymomas vs. non-recurrent thymomas. Cell cycle control gene alterations are associated with an early recurrence after thymectomy. Multiple target therapies are potentially available by performing a comprehensive CGP, suggesting that a precision medicine approach on these patients could be further explored.

Symptomatic androgen deficiency and sexual dysfunctions in male patients receiving alectinib for ALK-positive advanced nonsmall cell lung cancer
Emanuele Vita, Federico Monaca, Domenico Milardi, Luca Mastrantoni, Alessio Stefani, Edoardo Vergani, Jacopo Russo, Diletta Barone, Ileana Sparagna, Antonio Vitale,et al.
Wiley
ABSTRACTBackgroundIt is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK‐positive cancer and in murine models.MethodsIn this study, three groups, including an experimental group of male patients with ALK‐positive, advanced nonsmall cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK‐positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK‐negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist.ResultsNinety‐five patients were consecutively enrolled onto the study. Among sixty‐eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p = .0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p = .0002) were significantly lower in ALK‐positive ANSCLC patients in cohort A compared with ALK‐negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p = .0059) and LH levels (4.72 vs. 7.49 mUI/ml; p = .0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK‐positive male patients (74.3 vs. 44.24 pg/ml; p = .0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B.ConclusionsSymptoms of androgen deficiency should be tracked in male patients with ALK‐positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate.

Implementation of Artificial Intelligence in Personalized Prognostic Assessment of Lung Cancer: A Narrative Review
Filippo Lococo, Galal Ghaly, Marco Chiappetta, Sara Flamini, Jessica Evangelista, Emilio Bria, Alessio Stefani, Emanuele Vita, Antonella Martino, Luca Boldrini,et al.
MDPI AG
Artificial Intelligence (AI) has revolutionized the management of non-small-cell lung cancer (NSCLC) by enhancing different aspects, including staging, prognosis assessment, treatment prediction, response evaluation, recurrence/prognosis prediction, and personalized prognostic assessment. AI algorithms may accurately classify NSCLC stages using machine learning techniques and deep imaging data analysis. This could potentially improve precision and efficiency in staging, facilitating personalized treatment decisions. Furthermore, there are data suggesting the potential application of AI-based models in predicting prognosis in terms of survival rates and disease progression by integrating clinical, imaging and molecular data. In the present narrative review, we will analyze the preliminary studies reporting on how AI algorithms could predict responses to various treatment modalities, such as surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. There is robust evidence suggesting that AI also plays a crucial role in predicting the likelihood of tumor recurrence after surgery and the pattern of failure, which has significant implications for tailoring adjuvant treatments. The successful implementation of AI in personalized prognostic assessment requires the integration of different data sources, including clinical, molecular, and imaging data. Machine learning (ML) and deep learning (DL) techniques enable AI models to analyze these data and generate personalized prognostic predictions, allowing for a precise and individualized approach to patient care. However, challenges relating to data quality, interpretability, and the ability of AI models to generalize need to be addressed. Collaboration among clinicians, data scientists, and regulators is critical for the responsible implementation of AI and for maximizing its benefits in providing a more personalized prognostic assessment. Continued research, validation, and collaboration are essential to fully exploit the potential of AI in NSCLC management and improve patient outcomes. Herein, we have summarized the state of the art of applications of AI in lung cancer for predicting staging, prognosis, and pattern of recurrence after treatment in order to provide to the readers a large comprehensive overview of this challenging issue.

Real-world outcomes of Italian patients with advanced non-squamous lung cancer treated with first-line pembrolizumab plus platinum-pemetrexed
Alessandro Leonetti, Fabiana Perrone, Matteo Puntoni, Giuseppe Maglietta, Paola Bordi, Emilio Bria, Emanuele Vita, Francesco Gelsomino, Andrea De Giglio, Alain Gelibter,et al.
Elsevier BV

APOLLO 11 Project, Consortium in Advanced Lung Cancer Patients Treated With Innovative Therapies: Integration of Real-World Data and Translational Research
Arsela Prelaj, Monica Ganzinelli, Leonardo Provenzano, Laura Mazzeo, Giuseppe Viscardi, Giulio Metro, Giulia Galli, Francesco Agustoni, Carminia Maria Della Corte, Andrea Spagnoletti,et al.
Elsevier BV

The likelihood of being helped or harmed as a patient-centred tool to assess ALK-Inhibitors clinical impact and safety in ALK-addicted non-small cell lung cancer: A systematic review and sensitivity-analysis
Luca Mastrantoni, Giulia Giordano, Emanuele Vita, Guido Horn, Jacopo Russo, Armando Orlandi, Gennaro Daniele, Diana Giannarelli, Giampaolo Tortora, and Emilio Bria
Elsevier BV

Facial Papulopustular Eruption during the COVID-19 Pandemic in Patients Treated with EGFR Inhibitors
Eleonora De Luca, Pietro Sollena, Lucia Di Nardo, Ettore D’Argento, Emanuele Vita, Giampaolo Tortora, and Ketty Peris
Hindawi Limited
Papulopustular rash (PPR) is the most frequent cutaneous adverse event during treatment with epidermal growth factor receptor inhibitors (EGFRis). Although often mild in severity, it can impair patients’ quality of life and may also be a reason for discontinuing or changing the dose of the antineoplastic treatment. During COVID-19 pandemics, the use of surgical masks drastically increased and it had an impact on the face skin microenvironment, favoring the worsening of dermatological pathologies. We reported the relapse of PPR in patients treated with EGFR inhibitors who consistently wore face masks (>6 hours/day). All the patients developed the PPR within 6 months of starting mask use. Compared to the PPR occurred previously, after mask use, the skin eruption was more severe and affected mainly those regions of the face which came into contact with the mask. Patients received topical or systemic treatment, obtaining complete response in 65.7% of the cases. The establishment of an early treatment for the PPR allows continuing the oncologic treatment, without any suspension which could result in a decreased oncologic outcome. In conclusion, when using these devices, it is recommended to use special precautions, particularly in oncologic patients, by using a daily prophylactic skincare and replacing masks regularly with regular and frequent breaks.

Correction: Lung cancer multi-omics digital human avatars for integrating precision medicine into clinical practice: the LANTERN study (BMC Cancer, (2023), 23, 1, (540), 10.1186/s12885-023-10997-x)
Filippo Lococo, Luca Boldrini, Charles-Davies Diepriye, Jessica Evangelista, Camilla Nero, Sara Flamini, Angelo Minucci, Elisa De Paolis, Emanuele Vita, Alfredo Cesario,et al.
Springer Science and Business Media LLC

Lung cancer multi-omics digital human avatars for integrating precision medicine into clinical practice: the LANTERN study
Filippo Lococo, Luca Boldrini, Charles-Davies Diepriye, Jessica Evangelista, Camilla Nero, Sara Flamini, Angelo Minucci, Elisa De Paolis, Emanuele Vita, Alfredo Cesario,et al.
Springer Science and Business Media LLC
Abstract Background The current management of lung cancer patients has reached a high level of complexity. Indeed, besides the traditional clinical variables (e.g., age, sex, TNM stage), new omics data have recently been introduced in clinical practice, thereby making more complex the decision-making process. With the advent of Artificial intelligence (AI) techniques, various omics datasets may be used to create more accurate predictive models paving the way for a better care in lung cancer patients. Methods The LANTERN study is a multi-center observational clinical trial involving a multidisciplinary consortium of five institutions from different European countries. The aim of this trial is to develop accurate several predictive models for lung cancer patients, through the creation of Digital Human Avatars (DHA), defined as digital representations of patients using various omics-based variables and integrating well-established clinical factors with genomic data, quantitative imaging data etc. A total of 600 lung cancer patients will be prospectively enrolled by the recruiting centers and multi-omics data will be collected. Data will then be modelled and parameterized in an experimental context of cutting-edge big data analysis. All data variables will be recorded according to a shared common ontology based on variable-specific domains in order to enhance their direct actionability. An exploratory analysis will then initiate the biomarker identification process. The second phase of the project will focus on creating multiple multivariate models trained though advanced machine learning (ML) and AI techniques for the specific areas of interest. Finally, the developed models will be validated in order to test their robustness, transferability and generalizability, leading to the development of the DHA. All the potential clinical and scientific stakeholders will be involved in the DHA development process. The main goals aim of LANTERN project are: i) To develop predictive models for lung cancer diagnosis and histological characterization; (ii) to set up personalized predictive models for individual-specific treatments; iii) to enable feedback data loops for preventive healthcare strategies and quality of life management. Discussion The LANTERN project will develop a predictive platform based on integration of multi-omics data. This will enhance the generation of important and valuable information assets, in order to identify new biomarkers that can be used for early detection, improved tumor diagnosis and personalization of treatment protocols. Ethics Committee approval number 5420 − 0002485/23 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS – Università Cattolica del Sacro Cuore Ethics Committee. Trial registration clinicaltrial.gov - NCT05802771.

Leptin-mediated meta-inflammation may provide survival benefit in patients receiving maintenance immunotherapy for extensive-stage small cell lung cancer (ES-SCLC)
Emanuele Vita, Alessio Stefani, Geny Piro, Luca Mastrantoni, Marco Cintoni, Giuseppe Cicchetti, Ileana Sparagna, Federico Monaca, Guido Horn, Jacopo Russo,et al.
Springer Science and Business Media LLC
Abstract Background Only few ES-SCLC patients experience long-term survival benefit by maintenance IT. Adipokines-induced metabolic meta-inflammation has been related to enhanced responsiveness to IT in obese patients; however, their prognostic role in SCLC is currently controversial. Methods Pre-treatment CT scan was used for determining distribution of abdominal adiposity, and blood samples were collected at fasting for measuring glycemia, insulin, ghrelin, leptin and adipokines (TNF-α, IFN-γ, IL-6 and MCP-1). Patients with known history of DM type II or metabolic syndrome with HOMA index > 2.5 were considered insulin resistant (IR). Results In ES-SCLC pts receiving maintenance IT, increased leptin concentration and higher leptin/visceral adipose tissue (VAT) ratio were significantly associated with prolonged PFS. By applying a hierarchical clustering algorithm, we identified a cluster of patients characterized by higher leptin values and lower pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) who experienced longer PFS (13.2 vs 8.05 months; HR: 0.42 [0.18–0.93] p = 0.02) and OS (18.04 vs 12.09 mo; HR: 0.53 [0.25–1.29] p = 0.07). Conclusions Adipokines can play a crucial role to determining effectiveness of anti-cancer immunotherapy. The role of metabolic immune dysfunctions needs further pre-clinical validation and is currently investigated in the larger prospective cohort.

Salvage Surgery After First-Line Alectinib for Locally-Advanced/Metastatic ALK-Rearranged NSCLC: Pathological Response and Perioperative Results
Filippo Lococo, Alessandra Cancellieri, Marco Chiappetta, Alessandro Leonetti, Giuseppe Cardillo, Francesca Zanelli, Giuseppe Mangiameli, Luca Toschi, Gianluca Guggino, Francesco Jacopo Romano,et al.
Elsevier BV

Clinical Stage III NSCLC Patients Treated with Neoadjuvant Therapy and Surgery: The Prognostic Role of Nodal Characteristics †
Marco Chiappetta, Diomira Tabacco, Amedeo Giuseppe Iaffaldano, Jessica Evangelista, Maria Teresa Congedo, Carolina Sassorossi, Elisa Meacci, Ettore D’Argento, Emilio Bria, Emanuele Vita,et al.
MDPI AG
BACKGROUND: The aim of this study is to analyze the prognostic factors in patients that underwent induction therapy and surgery for clinical stage III NSCLC. METHODS: Clinical and pathological characteristics of stage III NSCLC patients for N2 involvement that underwent neoadjuvant treatment (NAD) and surgery from 1/01/1998 to 31/12/2017 were collected and retrospectively analyzed. Tumor characteristics, yClinical, yPathological stage and lymph node characteristics were correlated to Overall Survival (OS). RESULTS: The analysis was conducted on 180 patients. Five-year OS (5YOS) was 50.9%. Univariable analysis results revealed old age (p = 0.003), clinical N2 post-NAD (p = 0.01), pneumonectomy (0.005), persistent pathological N2 (p = 0.039, HR 1.9, 95% CI 1.09–2.68) and adjuvant therapy absence (p = 0.049) as significant negative prognostic factors. Multivariable analysis confirmed pN0N1 (p = 0.02, HR 0.29, 95% CI 0.13–0.62) as a favorable independent prognostic factor and adjuvant therapy absence (p = 0.012, HR 2.61, 95% CI 1.23–5.50) as a negative prognostic factor. Patients with persistent N2 presented a 5YOS of 35.3% vs. 55.8% in pN0N1 patients. Regarding lymph node parameters, the lymph node ratio (NR) significantly correlated with OS: 5YOS of 67.6% in patients with NR < 50% vs. 29.5% in NR > 50% (p = 0.029). CONCLUSION: Clinical response aided the stratification of prognosis in patients that underwent multimodal treatment for stage III NSCLC. Adjuvant therapy seemed to be an important option in these patients, while node ratio was a strong prognosticator in patients with persistent nodal involvement.

Unweaving the mitotic spindle: A focus on Aurora kinase inhibitors in lung cancer
Alessio Stefani, Geny Piro, Francesco Schietroma, Alessandro Strusi, Emanuele Vita, Simone Fiorani, Diletta Barone, Federico Monaca, Ileana Sparagna, Giustina Valente,et al.
Frontiers Media SA
Lung cancer is one of the most aggressive malignancies, classified into two major histological subtypes: non-small cell lung cancer (NSCLC), that accounts for about 85% of new diagnosis, and small cell lung cancer (SCLC), the other 15%. In the case of NSCLC, comprehensive genome sequencing has allowed the identification of an increasing number of actionable targets, which have become the cornerstone of treatment in the advanced setting. On the other hand, the concept of oncogene-addiction is lacking in SCLC, and the only innovation of the last 30 years has been the introduction of immune checkpoint inhibitors in extensive stage disease. Dysregulation of cell cycle is a fundamental step in carcinogenesis, and Aurora kinases (AURKs) are a family of serine/threonine kinases that play a crucial role in the correct advance through the steps of the cycle. Hyperexpression of Aurora kinases is a common protumorigenic pathway in many cancer types, including NSCLC and SCLC; in addition, different mechanisms of resistance to anticancer drugs rely on AURK expression. Hence, small molecule inhibitors of AURKs have been developed in recent years and tested in several malignancies, with different results. The aim of this review is to analyze the current evidences of AURK inhibition in lung cancer, starting from preclinical rationale to finish with clinical trials available up to now.

Role of Peripheral Blood Markers for Detecting Response and Predicting Prognosis in Patients with Non-small-cell Lung Cancer Undergoing Neoadjuvant Therapy and Surgery
Filippo Lococo, Marco Chiappetta, Jessica Evangelista, Isabella Sperduti, Dania Nachira, Venanzio Porziella, Maria Teresa Congedo, Emilio Bria, Emanuele Vita, Alfredo Cesario,et al.
Springer Science and Business Media LLC

Identification of Targetable Liabilities in the Dynamic Metabolic Profile of EGFR-Mutant Lung Adenocarcinoma: Thinking beyond Genomics for Overcoming EGFR TKI Resistance
Anastasios Gkountakos, Giovanni Centonze, Emanuele Vita, Lorenzo Belluomini, Michele Milella, Emilio Bria, Massimo Milione, Aldo Scarpa, and Michele Simbolo
MDPI AG
The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as first-line treatment in patients with lung adenocarcinoma (LUAD) harboring EGFR-activating mutations has resulted in a dramatic improvement in the management of the disease. However, the long-term clinical benefit is inevitably compromised by multiple resistance mechanisms. Accumulating evidence suggests that metabolic landscape remodeling is one of the mechanisms that EGFR-mutant LUAD cells activate, thus acquiring higher plasticity, tolerating EGFR TKI-mediated cytotoxic stress, and sustaining their oncogenic phenotype. Several metabolic pathways are upregulated in EGFR TKI-resistant models modulating the levels of numerous metabolites such as lipids, carbohydrates, and metabolic enzymes which have been suggested as potential mediators of resistance to EGFR TKIs. Moreover, metabolites have been shown to carry signals and stimulate oncogenic pathways and tumor microenvironment (TME) components such as fibroblasts, facilitating resistance to EGFR TKIs in various ways. Interestingly, metabolic signatures could function as predictive biomarkers of EGFR TKI efficacy, accurately classifying patients with EGFR-mutant LUAD. In this review, we present the identified metabolic rewiring mechanisms and how these act either independently or in concert with epigenetic or TME elements to orchestrate EGFR TKI resistance. Moreover, we discuss potential nutrient dependencies that emerge, highlighting them as candidate druggable metabolic vulnerabilities with already approved drugs which, in combination with EGFR TKIs, might counteract the solid challenge of resistance, hopefully prolonging the clinical benefit.

The Renaissance of KRAS Targeting in Advanced Non-Small-Cell Lung Cancer: New Opportunities Following Old Failures
Miriam Grazia Ferrara, Alessio Stefani, Sara Pilotto, Carmine Carbone, Emanuele Vita, Mariantonietta Di Salvatore, Ettore D’Argento, Ileana Sparagna, Federico Monaca, Giustina Valente,et al.
Frontiers Media SA
Non-small cell lung cancer (NSCLC) represents the perfect paradigm of ‘precision medicine’ due to its complex intratumoral heterogeneity. It is truly characterized by a range of molecular alterations that can deeply influence the natural history of this disease. Several molecular alterations have been found over time, paving the road to biomarker-driven therapy and radically changing the prognosis of ‘oncogene addicted’ NSCLC patients. Kirsten rat sarcoma (KRAS) mutations are present in up to 30% of NSCLC (especially in adenocarcinoma histotype) and have been identified decades ago. Since its discovery, its molecular characteristics and its marked affinity to a specific substrate have led to define KRAS as an undruggable alteration. Despite that, many attempts have been made to develop drugs capable of targeting KRAS signaling but, until a few years ago, these efforts have been unsuccessful. Comprehensive genomic profiling and wide-spectrum analysis of genetic alterations have only recently allowed to identify different types of KRAS mutations. This tricky step has finally opened new frontiers in the treatment approach of KRAS-mutant patients and might hopefully increase their prognosis and quality of life. In this review, we aim to highlight the most interesting aspects of (epi)genetic KRAS features, hoping to light the way to the state of art of targeting KRAS in NSCLC.

PTEN Loss as a Predictor of Tumor Heterogeneity and Poor Prognosis in Patients With EGFR-mutant Advanced Non–small-cell Lung Cancer Receiving Tyrosine Kinase Inhibitors
Miriam Grazia Ferrara, Maurizio Martini, Ettore D’Argento, Chiara Forcella, Emanuele Vita, Vincenzo Di Noia, Isabella Sperduti, Mirna Bilotta, Marta Ribelli, Paola Damiano,et al.
Elsevier BV

Early progression in non-small cell lung cancer (Nsclc) with high pd-l1 treated with pembrolizumab in first-line setting: A prognostic scoring system based on clinical features
Antonio Passaro, Silvia Novello, Diana Giannarelli, Emilio Bria, Domenico Galetta, Alain Gelibter, Maria Lucia Reale, Simona Carnio, Emanuele Vita, Alessio Stefani,et al.
MDPI AG
Background: Pembrolizumab is approved in monotherapy for the first-line (1L) of advanced or metastatic NSCLC patients with high PD-L1 (≥50%). Despite a proportion of patients achieve long-term survival, about one-third of patients experience detrimental survival outcomes, including early death, hyperprogression, and fast progression. The impact of clinical factors on early progression (EP) development has not been widely explored. Methods: We designed a retrospective, multicenter study involving five Italian centers, in patients with metastatic NSCLC with PD-L1 ≥ 50%, treated with Pembrolizumab in a 1L setting. EP was defined as a progressive disease within three months from pembrolizumab initiation. Baseline clinical factors of patients with and without EP were collected and analyzed. Logistic regression was performed to identify clinical factors associated with EP and an EP prognostic score was developed based on the logistic model. Results: Overall, 321 out of 336 NSCLC patients treated with 1L pembrolizumab provided all the data for the analysis. EP occurred in 137 (42.7%) patients; the median PFS was 3.8 months (95% CI: 2.9–4.7), and median OS was not reached in the entire study population. Sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), steroids, metastatic sites ≥2, and the presence of liver/pleural metastasis were confirmed as independent factors for EP by multivariate analysis. By combining these factors, we developed an EP prognostic score ranging from 0–13, with three-risk group stratification: 0–2 (good prognosis), 3–6 (intermediate prognosis), and 7–13 (poor prognosis). The area under the curve (AUC) of the model was 0.76 (95% CI: 0.70–0.81). Conclusions: We identified six clinical factors independently associated with EP. We developed a prognostic score model for EP-risk to potentially improve clinical practice and patient selection for 1L pembrolizumab in NSCLC with high PD-L1, in the real-world clinical setting.

Oncological frontiers in the treatment of malignant pleural mesothelioma
Emanuele Vita, Alessio Stefani, Mariantonietta Di Salvatore, Marco Chiappetta, Filippo Lococo, Stefano Margaritora, Giampaolo Tortora, and Emilio Bria
MDPI AG
Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by very poor prognosis and lack of treatment options. Immunotherapy has rapidly emerged as an effective tool for MPM, particularly for tumors of non-epithelioid histology. At the same time, comprehensive genomic sequencing may open the way to new-generation targeted-drugs able to hit specific MPM molecular vulnerabilities. These innovations will possibly enrich, but also dramatically complicate, the elucidation of treatment algorithms. Multidisciplinary integration is urgently needed.

Blood serum amyloid A as potential biomarker of pembrolizumab efficacy for patients affected by advanced non-small cell lung cancer overexpressing PD-L1: results of the exploratory “FoRECATT” study
Vincenzo Di Noia, Ettore D’Argento, Sara Pilotto, Emanuele Vita, Miriam Grazia Ferrara, Paola Damiano, Marta Ribelli, Antonella Cannella, Antonella Virtuoso, Andrea Fattorossi,et al.
Springer Science and Business Media LLC
AbstractBackgroundIdentifying the patients who may benefit the most from immune checkpoints inhibitors remains a great challenge for clinicians. Here we investigate on blood serum amyloid A (SAA) as biomarker of response to upfront pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC).MethodsPatients with PD-L1 ≥ 50% receiving upfront pembrolizumab (P cohort) and with PD-L1 0–49% treated with chemotherapy (CT cohort) were evaluated for blood SAA and radiological response at baseline and every 9 weeks. Endpoints were response rate (RR) according to RECIST1.1, progression-free (PFS) and overall survival (OS). The most accurate SAA cut-off to predict response was established with ROC analysis in the P cohort.ResultsIn the P Cohort (n = 42), the overall RR was 38%. After a median follow-up of 18.5 months (mo), baseline SAA ≤ the ROC-derived cut-off (29.9 mg/L;n = 28/42.67%) was significantly associated with higher RR (53.6 versus 7.1%; OR15, 95% CI 1.72–130.7,p = 0.009), longer PFS (17.4 versus 2.1 mo;p < 0.0001) and OS (not reached versus 7.2mo;p < 0.0001) compared with SAA > 29.9 mg/L. In multivariate analysis, low SAA positively affects PFS (p = 0.001) and OS (p = 0.048) irrespective of ECOG PS, number of metastatic sites and pleural effusion. SAA monitoring (n = 40) was also significantly associated with survival endpoints: median PFS 17.4 versus 2.1 mo and median OS not reached versus 7.2 mo when SAA remained low (n = 14) and high (n = 12), respectively. In the CT Cohort (n = 30), RR was not affected by SAA level (p > 0.05) while low SAA at baseline (n = 17) was associated with better PFS (HR 0.38, 95% CI 0.16–0.90,p = 0.006) and OS (HR 0.25, 95% CI 0.09–0.67,p < 0.001).ConclusionLow SAA predicts good survival outcomes irrespective of treatment for advanced NSCLC patients and higher likelihood of response to upfront pembrolizumab only. The strong prognostic value might be exploited to easily identify patients most likely to benefit from immunotherapy. A further study (FoRECATT-2) is ongoing to confirm results in a larger sample size and to investigate the effect of SAA on immune response in vitro assays.

Emanuele Vita

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