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Introduction: Immune checkpoint inhibitors (ICIs) became the standard of care for several solid tumors. A limited fraction of patients (pts) achieves a long-term benefit. Plasmatic and intracellular cholesterol levels have emerged as promising biomarkers. The aim of the present study was to determine whether cholesterol efflux capacity (CEC), mediated by serum transporters (ABCA1 and ABCG1) and passive diffusion (PD), impacts on clinical outcome of advanced non-small cell lung cancer (NSCLC) and metastatic renal cell carcinoma (mRCC) pts treated with ICIs. Material and methods: We retrospectively enrolled advanced NSCLC and mRCC pts consecutively treated with ICIs between October 2013 and October 2018. CEC and cholesterol loading capacity (CLC) were assessed by well-established specific cell models. As primary endpoint, CEC, PD and CLC were correlated with overall survival (OS) while the effects of these parameters on progression-free survival (PFS) and clinical benefit (CB), defined as complete/partial response or stable disease, represented secondary endpoints. Results: NSCLC accounted for 94.2% of 70 enrolled cases, and serum sample suitable for CEC and PD determination was available in 68. Blood cholesterol and serum ABCA1, ABCG1, PD and CLC were associated with outcomes (OS, PFS and CB) at univariate analysis. At the multivariate analysis, only PD confirmed its positive prognostic value in terms of OS, PFS and CB. Conclusion: The favorable impact of cholesterol PD on clinical outcome might reflect its main conformation in mature HDL particles which potentially shape an inflamed context, ultimately promoting ICI efficacy. Further prospective studies are needed to support our findings and uncover targetable pathways.

Small cell lung cancer (SCLC) arises in peribronchial locations and infiltrates the bronchial submucosa, including about 15% of lung cancer cases. Despite decades of research, the prognosis for SCLC patients remains poor because this tumor is characterized by an exceptionally high proliferative rate, strong tendency for early widespread metastasis and acquired chemoresistance. Omics profiling revealed that SCLC harbor extensive chromosomal rearrangements and a very high mutation burden. This led to the development of immune-checkpoint inhibitors as single agents or in combination with chemotherapy, which however resulted in a prolonged benefit only for a small subset of patients. Thus, the present review discusses the rationale and limitations of immunotherapeutic approaches, presenting the current biological understanding of aberrant signaling pathways that might be exploited with new potential treatments. In particular, new agents targeting DNA damage repair, cell cycle checkpoint, and apoptosis pathways showed several promising results in different preclinical models. Epigenetic alterations, gene amplifications and mutations can act as biomarkers in this context. Future research and improved clinical outcome for SCLC patients will depend on the integration between these omics and pharmacological studies with clinical translational research, in order to identify specific predictive biomarkers that will be hopefully validated using clinical trials with biomarker-selected targeted treatments.

Additional file 1. Supplementary materials.

Supplemental material, sj-doc-5-tmj-10.1177_03008916211014954 for PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors by Roberta Minari, Francesco Bonatti, Giulia Mazzaschi, Alessandra Dodi, Francesco Facchinetti, Francesco Gelsomino, Gloria Cinquegrani, Anna Squadrilli, Paola Bordi, Sebastiano Buti, Melissa Bersanelli, Alessandro Leonetti, Agnese Cosenza, Leonarda Ferri, Elena Rapacchi, Federico Quaini, Andrea Ardizzoni and Marcello Tiseo in Tumori Journal

Supplemental material, sj-pdf-2-tmj-10.1177_03008916211047888 for Transient asymptomatic pulmonary opacities and interstitial lung disease in EGFR-mutated non-small cell lung cancer treated with osimertinib by Gianluca Taronna, Alessandro Leonetti, Filippo Gustavo Dall’Olio, Alessandro Rizzo, Claudia Parisi, Sebastiano Buti, Paola Bordi, Stefano Brocchi, Rita Golfieri, Andrea Ardizzoni, Nicola Sverzellati and Marcello Tiseo in Tumori Journal

Supplemental material, sj-docx-1-onc-10.1177_11795549211043427 for Clinical Impact of COVID-19 Outbreak on Cancer Patients: A Retrospective Study by Sebastiano Buti, Fabiana Perrone, Teresa Zielli, Giulia Mazzaschi, Chiara Casartelli, Alessandro Leonetti, Gianluca Milanese, Mario Silva, Roberta Eufrasia Ledda, Antonino Musolino, Francesca Pucci, Melissa Bersanelli and Marcello Tiseo in Clinical Medicine Insights: Oncology

Supplemental material, sj-docx-1-onc-10.1177_11795549211043427 for Clinical Impact of COVID-19 Outbreak on Cancer Patients: A Retrospective Study by Sebastiano Buti, Fabiana Perrone, Teresa Zielli, Giulia Mazzaschi, Chiara Casartelli, Alessandro Leonetti, Gianluca Milanese, Mario Silva, Roberta Eufrasia Ledda, Antonino Musolino, Francesca Pucci, Melissa Bersanelli and Marcello Tiseo in Clinical Medicine Insights: Oncology

Supplemental material, sj-pdf-1-tmj-10.1177_03008916211047888 for Transient asymptomatic pulmonary opacities and interstitial lung disease in EGFR-mutated non-small cell lung cancer treated with osimertinib by Gianluca Taronna, Alessandro Leonetti, Filippo Gustavo Dall’Olio, Alessandro Rizzo, Claudia Parisi, Sebastiano Buti, Paola Bordi, Stefano Brocchi, Rita Golfieri, Andrea Ardizzoni, Nicola Sverzellati and Marcello Tiseo in Tumori Journal

Supplemental material, sj-docx-1-tmj-10.1177_03008916211000808 for Validation of a radiomic approach to decipher NSCLC immune microenvironment in surgically resected patients by Francesca Trentini, Giulia Mazzaschi, Gianluca Milanese, Claudio Pavone, Denise Madeddu, Letizia Gnetti, Caterina Frati, Bruno Lorusso, Costanza Anna Maria Lagrasta, Roberta Minari, Luca Ampollini, Roberta Eufrasia Ledda, Mario Silva, Nicola Sverzellati, Federico Quaini, Giovanni Roti and Marcello Tiseo in Tumori Journal

Supplemental material, sj-pdf-2-tmj-10.1177_03008916211047888 for Transient asymptomatic pulmonary opacities and interstitial lung disease in EGFR-mutated non-small cell lung cancer treated with osimertinib by Gianluca Taronna, Alessandro Leonetti, Filippo Gustavo Dall’Olio, Alessandro Rizzo, Claudia Parisi, Sebastiano Buti, Paola Bordi, Stefano Brocchi, Rita Golfieri, Andrea Ardizzoni, Nicola Sverzellati and Marcello Tiseo in Tumori Journal

Supplemental material, sj-doc-3-tmj-10.1177_03008916211014954 for PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors by Roberta Minari, Francesco Bonatti, Giulia Mazzaschi, Alessandra Dodi, Francesco Facchinetti, Francesco Gelsomino, Gloria Cinquegrani, Anna Squadrilli, Paola Bordi, Sebastiano Buti, Melissa Bersanelli, Alessandro Leonetti, Agnese Cosenza, Leonarda Ferri, Elena Rapacchi, Federico Quaini, Andrea Ardizzoni and Marcello Tiseo in Tumori Journal

Supplemental material, sj-docx-1-tmj-10.1177_03008916211000808 for Validation of a radiomic approach to decipher NSCLC immune microenvironment in surgically resected patients by Francesca Trentini, Giulia Mazzaschi, Gianluca Milanese, Claudio Pavone, Denise Madeddu, Letizia Gnetti, Caterina Frati, Bruno Lorusso, Costanza Anna Maria Lagrasta, Roberta Minari, Luca Ampollini, Roberta Eufrasia Ledda, Mario Silva, Nicola Sverzellati, Federico Quaini, Giovanni Roti and Marcello Tiseo in Tumori Journal

Supplemental material, sj-pptx-3-tmj-10.1177_03008916211000808 for Validation of a radiomic approach to decipher NSCLC immune microenvironment in surgically resected patients by Francesca Trentini, Giulia Mazzaschi, Gianluca Milanese, Claudio Pavone, Denise Madeddu, Letizia Gnetti, Caterina Frati, Bruno Lorusso, Costanza Anna Maria Lagrasta, Roberta Minari, Luca Ampollini, Roberta Eufrasia Ledda, Mario Silva, Nicola Sverzellati, Federico Quaini, Giovanni Roti and Marcello Tiseo in Tumori Journal

Supplemental material, sj-pdf-1-tmj-10.1177_03008916211047888 for Transient asymptomatic pulmonary opacities and interstitial lung disease in EGFR-mutated non-small cell lung cancer treated with osimertinib by Gianluca Taronna, Alessandro Leonetti, Filippo Gustavo Dall’Olio, Alessandro Rizzo, Claudia Parisi, Sebastiano Buti, Paola Bordi, Stefano Brocchi, Rita Golfieri, Andrea Ardizzoni, Nicola Sverzellati and Marcello Tiseo in Tumori Journal

Supplemental material, sj-doc-4-tmj-10.1177_03008916211014954 for PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors by Roberta Minari, Francesco Bonatti, Giulia Mazzaschi, Alessandra Dodi, Francesco Facchinetti, Francesco Gelsomino, Gloria Cinquegrani, Anna Squadrilli, Paola Bordi, Sebastiano Buti, Melissa Bersanelli, Alessandro Leonetti, Agnese Cosenza, Leonarda Ferri, Elena Rapacchi, Federico Quaini, Andrea Ardizzoni and Marcello Tiseo in Tumori Journal

Supplemental material, sj-doc-1-tmj-10.1177_03008916211014954 for PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors by Roberta Minari, Francesco Bonatti, Giulia Mazzaschi, Alessandra Dodi, Francesco Facchinetti, Francesco Gelsomino, Gloria Cinquegrani, Anna Squadrilli, Paola Bordi, Sebastiano Buti, Melissa Bersanelli, Alessandro Leonetti, Agnese Cosenza, Leonarda Ferri, Elena Rapacchi, Federico Quaini, Andrea Ardizzoni and Marcello Tiseo in Tumori Journal

Supplemental material, sj-doc-2-tmj-10.1177_03008916211014954 for PD-L1 SNPs as biomarkers to define benefit in patients with advanced NSCLC treated with immune checkpoint inhibitors by Roberta Minari, Francesco Bonatti, Giulia Mazzaschi, Alessandra Dodi, Francesco Facchinetti, Francesco Gelsomino, Gloria Cinquegrani, Anna Squadrilli, Paola Bordi, Sebastiano Buti, Melissa Bersanelli, Alessandro Leonetti, Agnese Cosenza, Leonarda Ferri, Elena Rapacchi, Federico Quaini, Andrea Ardizzoni and Marcello Tiseo in Tumori Journal

Supplemental material, Figure_A2 for CEA and CYFRA 21-1 as prognostic biomarker and as a tool for treatment monitoring in advanced NSCLC treated with immune checkpoint inhibitors by Filippo G. Dall’Olio, Francesca Abbati, Francesco Facchinetti, Maria Massucci, Barbara Melotti, Anna Squadrilli, Sebastiano Buti, Francesca Formica, Marcello Tiseo and Andrea Ardizzoni in Therapeutic Advances in Medical Oncology

Supplemental material, Supplementary_Material_-_online_only for Symptomatic COVID-19 in advanced-cancer patients treated with immune-checkpoint inhibitors: prospective analysis from a multicentre observational trial by FICOG by Melissa Bersanelli, Diana Giannarelli, Ugo De Giorgi, Sandro Pignata, Massimo Di Maio, Elena Verzoni, Alberto Clemente, Valentina Guadalupi, Diego Signorelli, Marcello Tiseo, Raffaele Giusti, Marco Filetti, Marilena Di Napoli, Lorenzo Calvetti, Alessandro Cappetta, Paola Ermacora, Diego Zara, Fausto Barbieri, Cinzia Baldessari, Vieri Scotti, Francesca Mazzoni, Antonello Veccia, Pamela Francesca Guglielmini, Marco Maruzzo, Ernesto Rossi, Francesco Grossi, Chiara Casadei, Alessio Cortellini, Francesco Verderame, Vincenzo Montesarchio, Mimma Rizzo, Manlio Mencoboni, Fable Zustovich, Lucia Fratino, Saverio Cinieri, Giorgia Negrini, Maria Banzi, Mariella Sorarù, Paolo Andrea Zucali, Gaetano Lacidogna, Antonio Russo, Nicola Battelli, Giuseppe Fornarini, Claudia Mucciarini, Sergio Bracarda, Andrea Bonetti, Debora Pezzuolo, Lucia Longo, Donata Sartori, Mauro Iannopollo, Luigi Cavanna, Fausto Meriggi, Davide Tassinari, Claudia Corbo, Angela Gernone, Veronica Prati, Simona Carnio, Pasqualina Giordano, Angela Maria Dicorato, Claudio Verusio, Francesco Atzori, Francesco Carrozza, Stefania Gori, Antonino Castro, Sara Pilotto, Vanja Vaccaro, Elisabetta Garzoli, Francesco Di Costanzo, Evaristo Maiello, Roberto Labianca, Carmine Pinto, Michele Tognetto and Sebastiano Buti in Therapeutic Advances in Medical Oncology

Supplemental material, figure_A3 for CEA and CYFRA 21-1 as prognostic biomarker and as a tool for treatment monitoring in advanced NSCLC treated with immune checkpoint inhibitors by Filippo G. Dall’Olio, Francesca Abbati, Francesco Facchinetti, Maria Massucci, Barbara Melotti, Anna Squadrilli, Sebastiano Buti, Francesca Formica, Marcello Tiseo and Andrea Ardizzoni in Therapeutic Advances in Medical Oncology

Supplemental material, Supplementary_data_PDF for CEA and CYFRA 21-1 as prognostic biomarker and as a tool for treatment monitoring in advanced NSCLC treated with immune checkpoint inhibitors by Filippo G. Dall’Olio, Francesca Abbati, Francesco Facchinetti, Maria Massucci, Barbara Melotti, Anna Squadrilli, Sebastiano Buti, Francesca Formica, Marcello Tiseo and Andrea Ardizzoni in Therapeutic Advances in Medical Oncology

Supplemental material, Figure_A1 for CEA and CYFRA 21-1 as prognostic biomarker and as a tool for treatment monitoring in advanced NSCLC treated with immune checkpoint inhibitors by Filippo G. Dall’Olio, Francesca Abbati, Francesco Facchinetti, Maria Massucci, Barbara Melotti, Anna Squadrilli, Sebastiano Buti, Francesca Formica, Marcello Tiseo and Andrea Ardizzoni in Therapeutic Advances in Medical Oncology

Additional file 9. Univariate and multivariate analyses for ORR in cohorts A and B combined.

List of oncological institutions of the study. (DOCX 15 kb)

Additional file 2. Efficacy according to clinical characteristics in cohorts A.

Additional file 7. Efficacy according to clinical characteristics in cohorts B.

Additional file 10. Outcome to nivolumab in BOM+ patients according to prior RT.

Additional file 8. Univariate and multivariate analyses for PFS in cohorts A and B combined.

Additional file 3. PFS and OS in Cohort A and B according to bone and brain metastases.

Additional file 11. Early death and early progression in the whole study population according to bone metastases (BoM) and to prior palliative radiotherapy (RT) and in the METROS cohort.

Additional file 12. Treatment related adverse events in cohorts A and B.

Additional file 6. PFS and OS in patients treated with nivolumab in second-line in cohort B.

Univariate and multivariate analyses with logistic regression of Objective Response Rate. (DOC 49 kb)

Supplemental material, Supplementary_table_1 for KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC by Marika Cinausero, Noemi Laprovitera, Giovanna De Maglio, Lorenzo Gerratana, Mattia Riefolo, Marianna Macerelli, Michelangelo Fiorentino, Elisa Porcellini, Vanessa Buoro, Francesco Gelsomino, Anna Squadrilli, Gianpiero Fasola, Massimo Negrini, Marcello Tiseo, Manuela Ferracin and Andrea Ardizzoni in Therapeutic Advances in Medical Oncology

Immune-related adverse events of any grade and G3/G4 immune-related adverse events. (DOCX 15 kb)

Additional file 4. PFS and OS in patients treated in second-line in Cohort A.

Additional file 1. PFS in Cohort A and B according to bone metastases (A,B) and considering prognostic variables (C-F).

Additional file 5 PFS and OS in patients harboring EGFR mutations in Cohort A.

Le neoplasie polmonari rappresentano la prima causa di morte per cancro al mondo; la loro incidenza e mortalità sono pressoché sovrapponibili ad indicare una scarsa curabilità di questo tipo di neoplasia. Nella maggior parte dei casi, si presentano alla diagnosi in stadio localmente avanzato o metastatico e pertanto non passibili di chirurgia. Circa l’80-85% di queste neoplasie rientrano nella categoria istologica “non a piccole cellule (NSCLC)”. Le neoplasie polmonari non a piccole cellule si presentano nel 50% dei casi in stadio avanzato alla diagnosi e, pertanto, trattabili con il solo trattamento medico. Negli ultimi anni sono aumentate le conoscenze circa la biologia del NSCLC che hanno portato a sviluppare nuove strategie terapeutiche, sia con nuovi farmaci chemioterapici sia con farmaci a target molecolare. Sebbene notevoli progressi siano stati fatti negli ultimi anni nel trattamento del NSCLC, questa malattia risulta ancora legata a cattiva prognosi nella maggior parte dei pazienti. Negli ultimi anni, in relazione al progressivo incremento delle conoscenze ed anche grazie all’introduzione delle terapie biologiche, sempre più si è andato ad affermando il concetto di personalizzazione del trattamento, secondo il quale una determinata terapia andrebbe somministrata ad un dato paziente a seconda delle caratteristiche specifiche della neoplasia di cui è affetto e delle caratteristiche proprie di quell’individuo. Nella pratica clinica, un dato schema terapeutico viene scelto tenendo conto di alcuni fattori come l’età, il performance status, la presenza di co-morbidità e valutando i profili di tossicità dei vari regimi, lontani quindi da una situazione di specifica individualizzazione. In quest’ottica, recenti evidenze suggeriscono la possibilità di individuare sottopopolazioni di pazienti che possono beneficiare di uno specifico trattamento rispetto ad altre. Proprio in questo ambito si inserisce il progetto che ho sviluppato in questi 4 anni, volto ad identificare fattori predittivi di risposta ai diversi tipi di trattamento (chemioterapico e biologico) impiegati nella terapia del NSCLC avanzato. Il mio progetto si è articolato in quattro sottoprogetti relativi a quattro differenti tipi di terapie impiegate nelle varie fasi del NSCLC avanzato. I quattro sottoprogetti sviluppati sono stati i seguenti: 1. Panel di marcatori molecolari predittivi nel trattamento con gefitinib di pazienti affetti da tumore polmonare non a piccole cellule in stadio avanzato; 2. Espressione immunoistochimica di ERCC1/BRCA1 e polimorfismi dei geni di riparo del DNA quali fattori predittivi nel trattamento chemioterapico a base di platino dei pazienti affetti da tumore polmonare non a piccole cellule in stadio avanzato; 3. Correlazione dei polimorfismi e della attività della citidina deaminasi con l’outcome dei pazienti affetti da carcinoma polmonare non a piccole cellule avanzato trattati con platino-gemcitabina; 4. Fattori biologici predittivi nel trattamento chemioterapico con pemetrexed nella neoplasia polmonare non a piccole cellule in stadio avanzato. Nel primo sottoprogetto è stato valutato il ruolo predittivo di un gruppo di marcatori molecolari comprendente le mutazioni dei geni codificanti per EGFR e per K-ras, l’amplificazione dei geni per EGFR ed HER2, l’espressione proteica della proteina EGFR ed i polimorfismi dell’introne 1 del gene EGFR, in 91 pazienti affetti da NSCLC in fase avanzata trattati con gefitinib, inibitore dell’attività tirosino-chinasica di EGFR. Il sesso (p = 0.005), lo stato di non fumatore (p = 0.010), la tossicità cutanea (p = 0.020), mutazioni del gene EGFR (p < 0.001) e la positività per EGFR FISH (p = 0.016) sono risultati associati alla risposta a gefitinib. La mutazione di K-ras è stata rilevata in soli 7 pazienti non-responder. La sopravvivenza mediana è stata di 10 mesi. Solo lo stato di non fumatore e il polimorfismo dell’introne 1 di EGFR hanno mostrato una correlazione statisticamente significativa con la sopravvivenza (p = 0.031 e 0.044, rispettivamente). In conclusione, abbiamo confermato il ruolo della mutazione del gene EGFR come fattore predittivo di risposta agli inibitori dell’attività tirosino-chinasica di EGFR. Inoltre, il numero di copie del gene EGFR e, potenzialmente, anche il polimorfismo dell’introne 1 di EGFR potrebbero aiutare a predire la responsività agli inibitori dell’attività tirosino-chinasica di EGFR nel NSCLC avanzato. Il secondo sottoprogetto è uno studio retrospettivo condotto su materiale istologico di archivio relativo a pazienti affetti da NSCLC in stadio IIIB-IV trattati in I linea all’interno del protocollo di chemioterapia FAST. Con tale studio si sono analizzati su 110 campioni tumorali fattori potenzialmente predittivi di risposta al cisplatino, quali l’espressione immunoistochimica di EGFR e BRCA1 e i polimorfismi di ERCC1, XPD, XRCC1 e 3. La casistica del protocollo FAST ha consentito valutare tali fattori in gruppo di pazienti che ha ricevuto chemioterapia a base di cisplatino ed in un gruppo che è stato trattato senza cisplatino. L’espressione immunoistochimica di ERCC1 e BRCA1 sono risultate positive in 58 e 56 pazienti, rispettivamente. Nel complesso, i pazienti ERCC1-negativi hanno mostrato un migliore tasso di risposta (p = 0.0015), più lunghe sopravvivenza libera da progressione (p = 0.023) e sopravvivenza globale (p = 0.012) rispetto a quelli positivi, con una interazione con il trattamento solo in termini di tasso di risposta (test di interazione, p = 0.076). Nel complesso, i pazienti BRCA1 positivi hanno mostrato un migliore outcome anche se in maniera non statisticamente significativa. I polimorfismi dei geni di riparo del DNA non hanno mostrato associazioni statisticamente significative con l’outcome dei pazienti. Questo studio dimostra il ruolo prognostico dell’espressione immunoistochimica ERCC1 in pazienti con NSCLC avanzato trattati con chemioterapia; tuttavia, l'espressione di ERCC1/BRCA1 e specifici polimorfismi dei geni di riparo del DNA non sembrano influenzare il beneficio clinico derivante dall’uso del cisplatino. La gemcitabina è un analogo della deossicitidina con provata attività nei confronti di un ampio spettro di tumori; la doppietta gemcitabina-cisplatino è uno dei regimi più ampiamente utilizzati nel trattamento del NSCLC in stadio avanzato. La citidina deaminasi (CDA) è il principale enzima inattivante di gemcitabina e il suo ruolo fondamentale nelle attività/tossicità della gemcitabina è stata dimostrata da diversi studi pre-clinici e clinici. L'obiettivo di questo terzo sottostudio è stato di valutare se tre polimorfismi a singolo nucleotide (SNP) nella regione codificante del CDA (CDA 79A>C, 208G>A, e CDA 435C>T) cosi come l’attività enzimatica potessero influenzare l’outcome di un gruppo di 126 pazienti con NSCLC trattati con chemioterapia a base di gemcitabina-platino. I pazienti con genotipi CDA A79A/A79C hanno mostrato un tempo alla progressione di malattia (6.0 vs 3.0 mesi, p = 0.001) e una sopravvivenza globale (11.0 vs 5.0 mesi, p = 0.001) significativamente più lunghi rispetto ai pazienti con genotipo C79C. I pazienti portatori dei genotipi CDA C435C/C435T hanno avuto una più lunga sopravvivenza globale (p = 0.025), ma non sono state osservate correlazioni con il tempo alla progressione di malattia. Al contrario, i pazienti con bassa attività CDA hanno mostrato un tasso di risposta (37.7% vs 13.8%, p = 0.006) e un beneficio clinico (91.8% vs 51.7%, p < 0.001) significativamente più alti, così come migliori tempo alla progressione (8.0 vs 3.0 mesi p < 0.001) e sopravvivenza globale (19.0 vs 6.0 mesi, p < 0.001). Inoltre, l'attività enzimatica è emerso come fattore indipendente del rischio di morte/progressione all'analisi multivariata. In conclusione, l'attività enzimatica di CDA sembra essere un fattore predittivo forte di attività e di efficacia di una chemioterapia a base di gemcitabina. Questo quarto sottostudio biologico rappresenta un’indagine di ricerca traslazionale condotta al fine di identificare gruppi di pazienti che presentano beneficio differente con trattamento a base di pemetrexed. E’ stato valutato il ruolo dei polimorfismi dei geni TS, MTHFR, RFC, GGH nel predire l’efficacia e la tossicità nei confronti del trattamento con pemetrexed in 208 pazienti affetti da NSCLC avanzato. Questo studio ha evidenziato una correlazione significativa fra l’allele MTHFR 677T e una maggiore sopravvivenza in pazienti trattati con pemetrexed. Tale differenza è risultata clinicamente rilevante dato che i pazienti con genotipo TT, che sono però solo il 17% della popolazione in studio, hanno mostrato sopravvivenze libera da progressione e globale quasi doppie rispetto ai pazienti con genotipo eterozigote o wild-type. In assenza di un gruppo di controllo non trattato con pemetrexed, non è possibile tuttavia definire il ruolo prognostico o predittivo del beneficio con pemetrexed di tale polimorfismo. In conclusione, questo progetto ha consentito di identificare alcuni fattori potenzialmente utili nel predire l’outcome dei pazienti con NSCLC avanzato. Le mutazioni di EGFR, come riscontrato anche nel primo sottostudio, rappresentano attualmente un fattore determinante nella scelta terapeutica del NSCLC. ERCC1 ha sicuramente un ruolo prognostico, come evidenziato nel secondo sottostudio, ma non può essere utilizzato come fattore predittivo nella comune pratica clinica. Visti gli interessanti risultati ottenuti, studi clinici prospettici dovrebbero essere condotti al fine di validare l’attività di CDA e il polimorfismo MTHFR 677T quali potenziali marcatori predittivi del trattamento con gemcitabina e pemetrexed rispettivamente nel NSCLC avanzato.

The development of targeted therapies has improved survival rates for patients with advanced non-small cell lung cancer (NSCLC). However, tissue biopsy is unfeasible or inadequate in many patients, limiting biomarker testing and access to targeted therapies. The increasing numbers of established and emerging biomarkers with available targeted treatments highlights the challenges associated with sequential single-gene testing and limited tissue availability. Multiplex next-generation sequencing (NGS) offers an attractive alternative and represents a logical next step, and in cases where the tumour is inaccessible, tissue biopsy yields insufficient tumour content, or when the patient’s performance status does not allow a tissue biopsy, liquid biopsy can provide valuable material for molecular diagnosis. Here, we explore the role of liquid biopsy (i.e., circulating cell-free DNA analysis) in Europe. Liquid biopsies could be used as a complementary approach to increase rates of molecular diagnosis, with the ultimate aim of improving patient access to appropriate targeted therapies. Expert opinion is also provided on potential future applications of liquid biopsy in NSCLC, including for cancer prevention, detection of early stage and minimum residual disease, monitoring of response to therapy, selection of patients for immunotherapy, and monitoring of tumour evolution to enable optimal adaptation/combination of drug therapies.

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.

Purpose Considering promising results in phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line cisplatin plus etoposide for treatment of extensive-disease (ED) small-cell lung cancer (SCLC). Patients and Methods Treatment-naive patients with ED-SCLC were randomly assigned to receive either cisplatin plus etoposide (arm A) or the same regimen with bevacizumab (arm B) for a maximum of six courses. In the absence of progression, patients in arm B continued bevacizumab alone until disease progression or for a maximum of 18 courses. The primary end point was overall survival (OS). Results Two hundred four patients were randomly assigned and considered in intent-to-treat analyses (103 patients in arm A and 101 patients in arm B). At a median follow-up of 34.9 months in arm A and arm B, median OS times were 8.9 and 9.8 months, and 1-year survival rates were 25% and 37% (hazard ratio, 0.78; 95% CI, 0.58 to 1.06; P = .113), respectively. A statistically significant effect of bevacizumab on OS in patients who received maintenance was seen (hazard ratio, 0.60; 95% CI, 0.40 to 0.91; P = .011). Median progression-free survival times were 5.7 and 6.7 months in arm A and arm B, respectively ( P = .030). Regarding hematologic toxicity, no statistically significant differences were observed; for nonhematologic toxicity, only hypertension was more frequent in arm B (grade 3 or 4, 1.0% v 6.3% in arms A v B, respectively; P = .057). Conclusion The addition of bevacizumab to cisplatin and etoposide in the first-line treatment of ED-SCLC had an acceptable toxicity profile and led to a statistically significant improvement in progression-free survival, which, however, did not translate into a statistically significant increase in OS. Further research with novel antiangiogenic agents, particularly in the maintenance setting, is warranted.

Introduction: A prospective investigation of the circulating immune profile in NSCLC patients receiving nivolumab was performed to identify potentially predictive parameters. Methods: Flow Cytometry of peripheral blood (PB) CD3+, CD8+, CD4+, NK, Treg and MDSCs was prospectively performed in 31 consecutive advanced NSCLC patients at baseline (T0) and after 2 (T1) and 4 (T2) cycles of bi-weekly nivolumab. Functional molecules (PD-1, CD3ζ Granzyme B, Perforin), cell proliferation (Ki67) and NK receptors (NKG2 A, NKG2D, NKp30) were also explored. The immunohistochemical evaluation of PD-L1 and TILs was restricted to available tumor biopsies. Tissue and circulating parameters were correlated to clinico-pathological features and treatment outcomes. Results: KRAS mutations, active smoking, COPD and steroid treatment conditioned a different distribution of circulating phenotypes. At baseline, clinical benefit (CB, n = 19) group displayed higher number of phenotypically active NK and PD-1+CD8+ cells (p < 0.01) compared to non-responders (NR, n = 12). Prolonged survival outcomes (p < 0.01) were recorded in cases with high baseline circulating NK and PD-1+CD8+ cells. At tissue level, low PD-1 expression in CD8 + TILs was a positive prognostic feature (p < 0.001). Strikingly, high circulating NK and PD-1+CD8+ cells combined with low PD-1/CD8+ ratio in TILs characterized a privileged context able to provide a significantly prolonged (p < 0.01) progression-free survival (PFS). During PD-1 blockade, NKs progressively raised in CB while declined in NR (p < 0.05) and this phenomenon was counterbalanced by parallel changes in Treg. Conclusion: The functional pool of circulating NKs associated with a divergent PD-1 expression in blood and tissue CD8+ lymphocytes portrays an immune profile predictive of anti-PD1 treatment efficacy.

Background Neoangiogenesis is particularly abundant in small-cell lung cancer (SCLC) and is associated with poor prognosis. As a result of the promising nature of phase II studies, a randomized phase III trial was designed to assess the efficacy of adding bevacizumab to first-line chemotherapy with cisplatin-etoposide for treatment of extensive disease SCLC. We present the treatment rationale and study design of GOIRC trial (FARM6PMFJM study), a multicenter randomized phase III study, supported by AIFA (Agenzia Italiana del Farmaco). Patients and Methods Patients are randomized to receive either cisplatin 25 mg/m2 and etoposide 100 mg/m2 intravenously on days 1 to 3 (control arm) or the same chemotherapy combined with bevacizumab 7.5 mg/kg intravenously on day 1 (experimental arm). Treatment is repeated every 3 weeks and for a maximum of 6 courses. Patients randomized to the experimental arm in the absence of disease progression after 6 cycles continue bevacizumab alone until progression or for a maximum of 18 courses. Tumor assessment is done every 3 cycles. Major eligibility criteria are: age ≥ 18 years; histologically or cytologically documented extensive disease SCLC; Eastern Cooperative Oncology Group performance status ≤ 2; adequate hematological, hepatic and renal functions; no history of grade 2 or higher hemoptysis; and no evidence of tumor cavitation. The primary end point of this study is overall survival. Secondary end points include response rate, time to progression, and toxicity. Conclusion An interim futility analysis was performed by an Independent Data Monitoring Committee in September 2013 and the trial obtained approval to continue. As of July 31, 2014, 171 patients of 206 planned have been randomized.

Objectives: An association between skin toxicity and outcome has been reported for NSCLC patients treated with erlotinib. Several explanations have been suggested, including pharmacokinetic and pharmacogenomic variability. The purposes of this study were to characterize erlotinib pharmacokinetic and to correlate drug serum and urine levels to toxicity and outcomes in advanced NSCLC patients. Methods: Patients with stage IV NSCLC consecutively treated with erlotinib in second- or third-line were enrolled. Biological samples (blood, urine and tumor specimens) were collected. Erlotinib levels in serum and urine samples of all patients after 7 (T1) and 30 (T2) days of treatment were quantified by LC-MS/MS analysis, along with urinary 6β-hydroxycortisol/cortisol ratio, as marker of metabolic phenotype of the CYP3A4/5 enzyme. Results: 56 patients were recruited and for 46 all samples were available. At T1 erlotinib levels were 3.90 [2.13]. μmol/l and 0.37 [2.90]. μmol/mol creat in serum and urinary samples, respectively; at T2 drug concentrations were significantly lower (2.02 [4.05]. μmol/l and 0.23 [4.47]. μmol/mol creat, respectively). Patients with grade 3 skin toxicity showed serum T1 drug levels significantly higher than those with grade 0-2 (6.84 [2.28] vs. 3.08 [1.97]. μmol/l, respectively, p=. 0.004) and had longer progression-free and overall survival. An inverse correlation between erlotinib serum levels and urinary 6β-hydroxycortisol/cortisol ratio was observed in patients with grade 3 skin toxicity. Conclusions: These findings suggest that the pharmacokinetics and metabolism of erlotinib are related to skin toxicity and may support further studies where erlotinib dosing is tailored according to pharmacokinetic parameters. © 2013 Elsevier Ireland Ltd.

Hyponatremia frequently occurs in patients with cancer and is mostly due to a syndrome of inappropriate antidiuresis caused by ectopic secretion of antidiuretic hormone (SIADH). Small cell lung cancer presents with SIADH in approximately 11%-15% of cases. Recently, a new class of drugs, vasopressin V2-receptor antagonists (vaptans), emerged as a promising treatment for SIADH, but efficacy and safety data in cancer patients are lacking. We present a case of SIADH, heralding small cell lung cancer and persisting after apparent complete remission of primary tumor following chemotherapy/radiotherapy, in a patient who underwent long-term treatment with tolvaptan without any serious adverse effects.