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Purpose: The aim of this multi-center, retrospective/prospective cohort observational study was to evaluate outcomes in routine clinical practice of first-line chemo-immunotherapy with cis/carboplatin, pemetrexed and pembrolizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in 33 Italian centers., Methods: The outcome measure was to evaluate overall survival (OS) in a real-world patient population. Secondary endpoints were: progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and incidence of treatment-related adverse events (AEs)., Results: 1068 patients were enrolled at the time of data cut-off (January 31st, 2023), and 812 (76.0%) belonged to the retrospective cohort. Median age was 66 years (27-85), ECOG PS was ≥ 2 in 91 (8.6%) patients; 254 (23.8%) patients had brain metastases at baseline; 38 (3.6%) patients had tumor with PD-L1 expression ≥ 50%. After a median follow-up of 17.0 months (95% CI, 16.1-17.9), median OS was 16.1 months (95% CI, 14.4-18.8) and PFS was 9.9 months (95% CI, 8.8-11.2). Median DoR (n = 493) was 14.7 months (95% CI, 13.6-17.1). ORR was 43.4% (95% CI, 40.4-46.4). Any-grade AEs occurred in 636 (59.6%) patients and grade ≥ 3 in 253 (23.7%) patients. Most common grade ≥ 3 AEs were neutropenia (6.3%) and anemia (6.3%)., Conclusions: First-line chemo-immunotherapy was effective and tolerable in this large, real-world Italian study of patients with advanced non-squamous NSCLC. Our results were in line with the KEYNOTE-189 registration study, also considering the low number of PD-L1 ≥ 50% patients included in our study., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lorenzo Belluomini received speakers' fee from Astra-Zeneca, MSD, Roche, BMS, Amgen, Takeda. Emilio Bria has received grants or contracts from Astra-Zeneca, Roche and honoraria for lectures from Merck-Sharp & Dome, Astra-Zeneca, Pfizer, Eli-Lilly, Bristol-Myers Squibb, Novartis, Takeda and Roche. Emilio Bria has been member of Data Safety Monitoring Board or Advisory Board of Merck-Sharp & Dome, Pfizer, Novartis, Bristol-Myers Squibb, Astra-Zeneca, and Roche. Fabrizio Citarella received speakers’ fee from Astra-Zeneca and Novartis. Fabrizio Citarella has received writing support fee from BMS. Alessio Cortellini declares grants for consultancies/advisory boards from MSD, OncoC4, IQVIA, AstraZeneca, Access Infinity, Ardelis Health, Alpha Sight; speaker fees from Astra Zeneca, Eisai, Pierre-Fabre, MSD, Sanofi/REGENERON; writing/editorial activity from BMS and MSD; travel support from Sanofi and MSD. Alain Gelibter has been on advisory board for Astra-Zeneca, MSD, Roche, BMS, Takeda. Alessandro Leonetti received speakers’ fee from Astra-Zeneca, MSD, Roche, Takeda and Sanofi. Alessandro Leonetti has been on advisory board for BeiGene, Sanofi and Novartis. Alessandro Leonetti attended editorial activities sponsored by Roche and Eli Lilly. Alessandro Leonetti received travel support from MSD and Novartis. Francesca Mazzoni has been on advisory board for Roche, MSD, BMS, Astra Zeneca, Takeda, Sanofi and Novartis. Marcello Tiseo received speakers’ and consultants’ fee from Astra-Zeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, Merck, Sanofi. Marcello Tiseo received institutional research grants from Astra-Zeneca and Boehringer Ingelheim. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Gastroesophageal adenocarcinoma (GEA) is one of the principal causes of death related to cancer globally. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor which is found to be overexpressed or amplified in approximately 20% of GEA cases. In GEA, the identification of HER2-positive status is crucial to activate a specific anti-HER2 targeted therapy. The landmark ToGA trial demonstrated the superiority of adding trastuzumab to platinum-based chemotherapy, becoming the first-line standard of treatment. However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions.

Introduction: Despite several therapeutic efforts, lung cancer remains a highly lethal disease. Novel therapeutic approaches encompass immune-checkpoint inhibitors, targeted therapeutics and antibody-drug conjugates, with different results. Several studies have been aimed at identifying biomarkers able to predict benefit from these therapies and create a prediction model of response, despite this there is a lack of information to help clinicians in the choice of therapy for lung cancer patients with advanced disease. This is primarily due to the complexity of lung cancer biology, where a single or few biomarkers are not sufficient to provide enough predictive capability to explain biologic differences; other reasons include the paucity of data collected by single studies performed in heterogeneous unmatched cohorts and the methodology of analysis. In fact, classical statistical methods are unable to analyze and integrate the magnitude of information from multiple biological and clinical sources (eg, genomics, transcriptomics, and radiomics)., Methods and Objectives: APOLLO11 is an Italian multicentre, observational study involving patients with a diagnosis of advanced lung cancer (NSCLC and SCLC) treated with innovative therapies. Retrospective and prospective collection of multiomic data, such as tissue- (eg, for genomic, transcriptomic analysis) and blood-based biologic material (eg, ctDNA, PBMC), in addition to clinical and radiological data (eg, for radiomic analysis) will be collected. The overall aim of the project is to build a consortium integrating different datasets and a virtual biobank from participating Italian lung cancer centers. To face with the large amount of data provided, AI and ML techniques will be applied will be applied to manage this large dataset in an effort to build an R-Model, integrating retrospective and prospective population-based data. The ultimate goal is to create a tool able to help physicians and patients to make treatment decisions., Conclusion: APOLLO11 aims to propose a breakthrough approach in lung cancer research, replacing the old, monocentric viewpoint towards a multicomprehensive, multiomic, multicenter model. Multicenter cancer datasets incorporating common virtual biobank and new methodologic approaches including artificial intelligence, machine learning up to deep learning is the road to the future in oncology launched by this project., Competing Interests: Disclosures Arsela Prelaj certifies that all conflicts of interest reported can be considered outside the present paper: consulting or advisory role for BMS, AstraZeneca; had travel, accommodations, or other expenses paid or reimbursed by Roche, Italfarmaco; principal investigator of Spectrum Pharmaceuticals. Alessandra Laura Giulia Pedrocchi holds shares of Agade srl. Giuseppe Lo Russo has received fees for acting as a consultant from Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, Amgen, Sanofi, Italfarmaco, Pfizer; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Novartis, BMS, MSD, AstraZeneca, Takeda, Amgen, Sanofi, has received support for attending meetings and/or travel from Roche, BMS, MSD; has participated on data safety monitoring board or advisory board for Roche, Novartis, BMS, MSD, AstraZeneca, Sanofi, has acted as principal investigator in sponsored clinical trials for Roche, Novartis, BMS, MSD, AstraZeneca, GSK, Amgen, Sanofi. Rossana Berardi has received fees for acting as a consultant, for lectures and/or for participating to advisory board from BI, EISAI, GSK, Italfarmaco, Otsuka, Lilly, MSD; has received funding to Institution from AZ, BMS, Pfizer, Novartis, Roche; AMGEN. Giulia Galli declares the following conflicts of interest: Italpharma (advisory board); Roche (travel accommodation); Astra Zeneca, BMS, MSD (honoraria for lectures). Federica Bertolini has received consultant fees from MSD, Astra-Zeneca, Lilly, Eisai, Sanofi and speakers fee from BMS, MSD, Astra Zeneca. Filippo de Braud reports a patent for PCT/IB2020/055956 pending and a patent for IT201900009954 pending; and Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini Healthcare Research & Pharmacoepidemiology, Merck Group, Pfizer, Servier, AMGEN, Incyte. No disclosures were reported by the other authors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic horizons of various cancers. However, immune-related adverse events have been reported, including interstitial lung diseases. Our aim was to describe the clinical and radiological features and survival of a multicentre cohort of patients who developed ICI-related lung toxicity., Methods: Six Italian centres were involved in the study. Patients who were treated with anti-PD-1/PD-L1 and CTLA-4 mAbs and developed ICI-related lung toxicity were recruited retrospectively to study clinical, radiological, immunological and survival data., Results: A total of 41 patients (25 males, 66.8 ± 9.9 years) were enrolled. Lung toxicity occurred after 204.3 ± 208.3 days of therapy, with ground glass opacities being the most common HRCT pattern (23 cases). Male sex, lung cancer and acute respiratory failure were associated with a shorter latency of toxicity ( p = 0.0030, p = 0.0245 and p = 0.0390, respectively). Patients who required high-flow oxygen therapy showed significantly worse survival ( p = 0.0028)., Conclusions: Our cohort showed heterogeneous clinical and radiological aspects of ICI-related lung toxicity, with a latency not limited to the first year of treatment. Severity was mainly mild to moderate, although life-threatening events did occur. Our data indicate that strict long-term follow-up is needed to enable early diagnosis and appropriate management.

Based on improved survival from the addition of PD-L1 inhibitors in phase III trials, the combination of immunotherapy and platinum-doublet chemotherapy has become the new standard treatment for extended-stage small-cell lung cancer (ES-SCLC). Furthermore, the antiangiogenetic agent bevacizumab showed a longer progression-free survival by targeting VEGF that has pleiotropic effects, including immunosuppressive ones. We, therefore, hypothesized that targeting angiogenesis would improve the efficacy of chemoimmunotherapy. The CeLEBrATE trial is an open-label, multicenter, phase II study designed to assess the efficacy and safety of the combination of carboplatin and etoposide plus bevacizumab and atezolizumab in treatment-naive patients with ES-SCLC. The primary end point is overall survival rate at 1 year, while secondary end points include overall response rate, progression-free survival and toxicity.

Objectives: In the most of cases, for non-small cell lung cancer (NSCLC) patients who progressed to previous immune checkpoint inhibitors (CKI) administered as first- or as second-line therapy, chemotherapy (CT) remains the only viable options in the absence of "druggable" mutations. We aimed to explore the efficacy of salvage chemotherapy after immunotherapy (SCAI) in advanced NSCLC patients., Materials and Methods: We designed a retrospective, multicenter study, involving 20 Italian centers, with the primary objective of describing the clinical outcome of advanced NSCLC patients treated with SCAI at the participating institutions from November 2013 to July 2019. The primary endpoint of the study was represented by overall survival (OS), defined as the time from CT initiation to death. Secondary outcome endpoints of the SCAI (progression free survival, PFS, objective response rate, ORR and toxicity) and explorative biomarkers (lactate dehydrogenase, LDH, and neutrophil-to-lymphocyte ratio, NLR during immunotherapy) were also analyzed., Results: In our study population of 342 NSCLC patients, SCAI obtained a median OS of 6.8 months (95 % confidence interval, CI 5.5-8.1), median PFS of 4.1 months (95 % CI 3.4-4.8) and ORR of 22.8 %. A "Post-CKI score" was constructed by combining significant predictors of OS at the multivariate analyses (sex, ECOG PS, disease control with prior immunotherapy), Harrell'C was 0.65, (95 % CI:0.59-0.71)., Conclusions: Despite the late-line settings, our findings support the hypothesis that previous immunotherapy might increase the sensitivity of the tumor to the subsequent chemotherapy. The "Post-CKI score" was clinically effective in successfully discriminating three distinct prognostic subgroups of patients after the failure of CKI, representing a possibly useful tool for the tailored decision-making process of advanced treatment-line settings in NSCLC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: The prevalence of Skeletal Related Adverse Events (SREs) in EGFR mutated non-small cell lung cancer (NSCLC) patients with bone metastases, treated with modern tyrosine kinase inhibitors (TKIs), has been scarcely investigated., Materials and Methods: We retrospectively evaluated the data of EGFR mutated NSCLC patients with bone metastases treated with TKIs in 12 Italian centers from 2014 to 2019, with the primary aim to explore type and frequency of SREs., Results: Seventy-seven out of 274 patients enrolled (28%) developed at least one major SRE: 55/274 (20%) bone fractures, 30/274 (11%) spinal cord compression, 5/274 (2%) hypercalcemia. Median time to the onset of SRE was 3.63 months. Nine patients (3%) underwent bone surgery and 150 (55%) radiation therapy on bone. SREs were more frequently observed within the 12 months from TKI start than afterwards (71 vs 29%, p 0.000). Patient Performance Status and liver metastases where independently associated with the risk of developing SREs. Median TKI exposure and overall survival were 11 and 28 months, respectively. Bone resorption inhibitors were associated with a lower risk of death (HR 0.722, 95% CI: 0.504-1.033, p = 0.075) although not statistically significant at multivariate analysis., Conclusion: Bone metastatic NSCLC patients with EGFR mutated disease, treated with EGFR TKIs, have a relatively long survival expectancy and are at high risk to develop SREs. The early SRE occurrence after the TKI start provides the rationale to administer bone resorption inhibitors., (Copyright © 2020 Laganà, Gurizzan, Roca, Cortinovis, Signorelli, Pagani, Bettini, Bonomi, Rinaldi, Berardi, Filetti, Giusti, Pilotto, Milella, Intagliata, Baggi, Cortellini, Soto Parra, Brighenti, Petrelli, Bennati, Bidoli, Garassino and Berruti.)

Background: Early reports on patients with cancer and COVID-19 have suggested a high mortality rate compared with the general population. Patients with thoracic malignancies are thought to be particularly susceptible to COVID-19 given their older age, smoking habits, and pre-existing cardiopulmonary comorbidities, in addition to cancer treatments. We aimed to study the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on patients with thoracic malignancies., Methods: The Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry is a multicentre observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria were the presence of any thoracic cancer (non-small-cell lung cancer [NSCLC], small-cell lung cancer, mesothelioma, thymic epithelial tumours, and other pulmonary neuroendocrine neoplasms) and a COVID-19 diagnosis, either laboratory confirmed with RT-PCR, suspected with symptoms and contacts, or radiologically suspected cases with lung imaging features consistent with COVID-19 pneumonia and symptoms. Patients of any age, sex, histology, or stage were considered eligible, including those in active treatment and clinical follow-up. Clinical data were extracted from medical records of consecutive patients from Jan 1, 2020, and will be collected until the end of pandemic declared by WHO. Data on demographics, oncological history and comorbidities, COVID-19 diagnosis, and course of illness and clinical outcomes were collected. Associations between demographic or clinical characteristics and outcomes were measured with odds ratios (ORs) with 95% CIs using univariable and multivariable logistic regression, with sex, age, smoking status, hypertension, and chronic obstructive pulmonary disease included in multivariable analysis. This is a preliminary analysis of the first 200 patients. The registry continues to accept new sites and patient data., Findings: Between March 26 and April 12, 2020, 200 patients with COVID-19 and thoracic cancers from eight countries were identified and included in the TERAVOLT registry; median age was 68·0 years (61·8-75·0) and the majority had an Eastern Cooperative Oncology Group performance status of 0-1 (142 [72%] of 196 patients), were current or former smokers (159 [81%] of 196), had non-small-cell lung cancer (151 [76%] of 200), and were on therapy at the time of COVID-19 diagnosis (147 [74%] of 199), with 112 (57%) of 197 on first-line treatment. 152 (76%) patients were hospitalised and 66 (33%) died. 13 (10%) of 134 patients who met criteria for ICU admission were admitted to ICU; the remaining 121 were hospitalised, but were not admitted to ICU. Univariable analyses revealed that being older than 65 years (OR 1·88, 95% 1·00-3·62), being a current or former smoker (4·24, 1·70-12·95), receiving treatment with chemotherapy alone (2·54, 1·09-6·11), and the presence of any comorbidities (2·65, 1·09-7·46) were associated with increased risk of death. However, in multivariable analysis, only smoking history (OR 3·18, 95% CI 1·11-9·06) was associated with increased risk of death., Interpretation: With an ongoing global pandemic of COVID-19, our data suggest high mortality and low admission to intensive care in patients with thoracic cancer. Whether mortality could be reduced with treatment in intensive care remains to be determined. With improved cancer therapeutic options, access to intensive care should be discussed in a multidisciplinary setting based on cancer specific mortality and patients' preference., Funding: None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and progression-free survival (PFS) in cancer patients treated with ICIs. Publications that compared steroids with non-steroid users in cancer patients treated with ICIs from inception to June 2019 were identified by searching the EMBASE, PubMed, SCOPUS, Web of Science, and Cochrane Library databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Patients (studies, n = 16; patients, n = 4045) taking steroids were at increased risk of death and progression compared to those not taking steroids (HR = 1.54, 95% CI: 1.24-1.91; p = 0.01 and HR = 1.34, 95% CI: 1.02-1.76; p = 0.03, respectively). The main negative effect on OS was associated with patients taking steroids for supportive care (HR = 2.5, 95% CI 1.41-4.43; p < 0.01) or brain metastases (HR = 1.51, 95% CI 1.22-1.87; p < 0.01). In contrast, steroids used to mitigate adverse events did not negatively affect OS. In conclusion, caution is needed when steroids are used for symptom control. In these patients, a negative impact of steroid use was observed for both OS and PFS., Competing Interests: The authors declare no conflict of interest.

Immune-related adverse events (irAEs) are autoimmune-toxic effects associated with immune checkpoint inhibitors (ICIs) used for the treatment of advanced solid tumors. We performed a systematic review and meta-analysis of the published literature to assess the outcome for cancer patients treated with ICIs who develop irAEs. Two independent reviewers selected prospective or retrospective studies from PubMed, EMBASE, and the Cochrane Library database from their inception to November 2018. Data were pooled using hazard ratios (HRs) for overall survival or progression-free survival or odds ratio for overall response rate of irAEs versus no irAEs according to fixed or random-effect model. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. A total of 30 studies that included a total of 4324 patients treated with ICIs were selected. Patients who developed irAEs presented a reduced risk of death [HR=0.49, 95% confidence interval (CI): 0.38-0.62; P<0.001]. Similarly, the occurrence of irAEs was associated with a reduced risk of progression (HR=0.51, 95% CI: 0.42-0.64; P<0.001). The odds of response was 4.56 (95% CI: 3.72-5.59; P<0.001). In patients treated with ICIs, irAEs predict survival and response. Although this correlation cannot be fully explained, it may be related to the strongest T-cell activation.

Introduction: The hepatocyte growth factor receptor mesenchymal-epithelial transition (MET) is reported to be a negative prognostic marker in EGFR-mutant NSCLC and involved in resistance to EGFR inhibitors. Emibetuzumab, a humanized immunoglobulin G4 monoclonal bivalent MET antibody, blocks ligand-dependent and ligand-independent hepatocyte growth factor/MET signaling. This phase 2 study compared erlotinib with and without emibetuzumab in first-line treatment of EGFR-mutant metastatic NSCLC., Methods: Patients with stage IV EGFR-mutant NSCLC and disease control after an 8-week lead-in with erlotinib (150 mg daily) were randomized to continue taking erlotinib with or without emibetuzumab (750 mg every 2 weeks). The primary end point was progression-free survival (PFS). Additional end points included overall survival, overall response rate, safety, pharmacokinetics, and exploratory analysis of MET expression., Results: No significant difference in median PFS was observed in the intent-to-treat population (9.3 months with emibetuzumab + erlotinib versus 9.5 months with erlotinib monotherapy [hazard ratio (HR) = 0.89, 90% confidence interval (CI): 0.64-1.23]). The median overall survival was 34.3 months with emibetuzumab plus erlotinib versus 25.4 months with erlotinib (HR = 0.74, 90% CI: 0.49-1.11). Emibetuzumab plus erlotinib was well tolerated, with peripheral edema and mucositis as the only adverse events occurring 10% or more frequently relative to erlotinib. Exploratory post hoc analysis showed an improvement of 15.3 months in median PFS for the 24 patients with the highest MET expression (MET expression level of 3+ in ≥90% of tumor cells) (20.7 with emibetuzumab + erlotinib versus 5.4 months with erlotinib [HR = 0.39, 90% CI: 0.17-0.91])., Conclusions: No statistically significant difference in PFS was noted in the intent-to-treat population. Exploratory analysis confirmed that high MET expression is a negative prognostic marker for patients treated with erlotinib, indicating that emibetuzumab plus erlotinib may provide clinically meaningful benefit., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Cytidine deaminase (CDA) plays a crucial role in the degradation of gemcitabine. In our previous retrospective study, CDA enzymatic activity was the strongest prognostic biomarker of the activity and efficacy of platinum/gemcitabine combinations. The aim of this prospective study was to validate the prognostic role of CDA activity in the first-line treatment of advanced non-small-cell lung cancer., Methods: A total of 124 untreated patients received standard doses of platinum/gemcitabine. CDA activity was baseline measured in plasma samples by spectrophotometric assay., Results: Using the median CDA level as cut-off, in the patients with high versus low CDA activity the response rate was 25.0% (95% CI, 14.7-37.8) and 54.1% (95% CI, 40.8-66.9), P = 0.0013; the 6-month progression rate was 34.5% (95% CI, 22.6-46.6) and 54.1% (95% CI, 40.9-65.6), HR = 2.01 (95% CI, 1.32-3.06), P < 0.001; the 1-year survival rate was 23.3% (95% CI, 13.6-34.6) and 57.3% (95% CI, 43.9-68.6), HR = 2.20 (95% CI, 1.46-3.34), P = 0.0002, respectively. CDA activity resulted to be an independent prognostic factor for progression and survival at multivariate analysis., Conclusions: This study validated prospectively the prognostic role of the CDA activity and should prompt larger and adequately designed randomised prospective studies to establish the predictive impact of this test in improving the outcome of selected patients.

Immune checkpoint inhibitors (CKIs) are therapeutic weapons in several advanced malignancies. Performance status is a validated prognostic variable in cancer patients; it possibly affects the efficiency of the immune system. We performed a systematic review and meta-analysis to investigate the predictive role of PS toward treatment with CKIs in cancer patients. Following PRISMA guidelines, an electronic search from PubMed, The Cochrane Library and Embase was performed, from the inception of each database to May 31, 2018. Inclusion criteria were (1) randomized trials comparing CKI with standard therapy for the treatment of patients with solid tumors; (2) information on overall survival (OS) according to PS; (3) full text available; and (4) reported in English language. Data were pooled using HRs for OS according to random effect model. The effect of experimental versus control arms was evaluated in PS = 0 and 1-2 subgroups, and the heterogeneity between the two estimates was assessed using an interaction test. The OS differences between PS = 0 and PS = 1-2 strata were evaluated in all studies and according to predefined subgroups. Eighteen studies were eligible, with 11,354 patients [PS = 0 group 5217 patients (46%); PS = 1-2 group 6137 patients (54%)]. The pooled HR for OS was 0.78 (95% CI 0.69-0.89) in PS = 0 patients. In PS = 1-2 patients, the pooled OS HR was 0.78 (95% CI 0.71-0.86). The OS difference between PS = 0 and PS = 1-2 patients treated with CKI was not significant (P = 0.99). CKI improves survival irrespective of patients' PS. PS should not guide treatment choice for anticancer immunotherapy.

Background: Patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) have a higher risk of developing brain metastases (BMs) than patients with other NSCLC sub-types. ALK inhibitors have activity in BMs due to ALK+ NSCLC. We performed a systematic review of the literature with the aim of assessing the efficacy of ALK inhibitors on BMs., Material and Methods: A systematic search of the literature was performed using the databases Pubmed, EMBASE, Web of Science, The Cochrane Library, and SCOPUS. Relevant publications reporting activity of ALK inhibitors in NSCLC BMs were retrieved. Data were pooled using the number of events/number of evaluable patients according to fixed or random effect models. Intracranial tumour response was assessed through overall response rate (ORR), disease control rate (DCR: ORR + stable disease rate), median progression-free survival (PFS), and overall survival (OS). The primary endpoint was intracranial overall response rate (IC ORR)., Results: A total of 1,016 patients with BMs from 21 studies were analysed. In patients receiving ALK inhibitors in the first line setting, the pooled IC ORR was 39.17% (95%CI 13.1-65.2%), while the pooled IC ORR observed in further lines was 44.2% (95%CI 33.3-55.1%). Intracranial disease control rate (IC DCR) was 70.3% and 78.2% in naïve and pre-treated patients, respectively. Patients who had not received brain radiation attained an IC ORR of 49.0%., Conclusions: Based on these data, ALK inhibitors are effective in both naive and pre-treated patients with similar IC ORR and IC DCR, irrespective of the line of therapy., Competing Interests: The authors have declared that no competing interests exist.

Clinicopathologic and molecular characteristics of non-small-cell lung cancers (NSCLCs) associated with a strong expression of programmed death ligand 1 (PD-L1 + in > 5% of cells) have not been well elucidated. Expression of PD-L1 is a poor prognostic factor, but NSCLCs with higher levels of PD-L1 have greater benefit when treated with immunotherapy. We have performed a systematic review to synthesize the available evidence regarding clinicopathologic and molecular variables associated with PD-L1 expression in NSCLC. PubMed, EMBASE, SCOPUS, Web of Science and Cochrane Library databases were searched for relevant articles assessing predictors of PD-L1 expression in > 5% cells. Data were reported as odds ratio (OR) of events. Fifty-two studies (for a total of 5066 PD-L1 + out of 13,279 NSCLC patients) were included in this meta-analysis. Factors associated with PD-L1 expression were: smoking status (OR 5.48; 95% confidence interval (CI) 2.8-10.4; P < .001), male gender (OR 4.8; 95% CI 3.2-7.2; P < .001), adenocarcinoma histology (OR 2.75; 95% CI, 1.5-4.8; P < .001), Epidermal growth factor receptor (EGFR) wild type (OR 4.83; 95% CI, 2.1-11.1; P < .001), ALK mutation negative (OR 388.6; 95% CI, 222.5-678.7; P < .001), ROS mutation negative (OR 1904.8; 95% CI, 630-5757; P < .001), and KRAS wild type (OR 19.8; 95% CI, 7.6-51.6; P < .001). Conversely higher pT stages (OR 0.16; 95% CI, 0.04-0.7; P = .01), pN+ stages (OR 0.29; 95% CI, 0.17-0.5; P < .001) are inversely associated with PD-L1 expression in > 5% cells. Expression of PD-L1 is more common in male smokers, with adenocarcinoma histology and not carriers of EGFR/ALK/ROS/KRAS mutations. These data could be useful to screening of PD-L1 expression and to select patients for immunotherapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Oligometastatic non-small cell lung cancer (NSCLC), defined as a disease with low metastatic burden and limited organ involvement, is conceived as an intermediate condition between a truly localised disease and a widely metastatic tumour. Traditionally, local ablative therapies (LATs), such as surgery and radiotherapy, have been limited to symptoms' palliation in advanced NSCLC. Several retrospective studies suggest that using local ablative therapy for oligometastatic disease could offer good local control of the disease and improvement in terms of progression-free survival. The first randomised study of local consolidative therapy versus maintenance therapy or observation in oligometastatic NSCLC has been recently published. The results of this phase II trial showed an impressive improvement in median progression-free survival with local therapy and a delay in the appearance of new lesions, suggesting a systemically extended benefit of consolidation therapies. Nevertheless, further confirmation of this evidence with additional future trials is needed to definitively consider the combination of local treatment techniques with novel systemic agents recently approved for NSCLC therapy, such as immune checkpoint inhibitors., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.

Purpose: To evaluate the efficacy and safety of dose-dense TCF in elderly (≥65 years) compared to younger patients., Methods: Safety and efficacy data relative to 119 consecutive patients with locally advanced or metastatic gastric cancer treated at our institution and enrolled in different phase II trials were retrospectively collected. All patients were treatment-naive and received docetaxel 70 mg/m2 day 1, cisplatin 60 mg/m2 day 1, l-folinic acid 100 mg/m2 days 1-2, followed by 5-fluorouracil 400 mg/m2 bolus days 1-2, and then 600 mg/m2 as a 22-hour continuous infusion days 1-2, every 14 days, plus pegfilgrastim 6 mg on day 3. Sixty patients (50%) aged ≥65 years received the same schedule with a dose reduction by 30%., Results: A total of 86% of patients were evaluable for response and all for toxicity. In patients aged ≥65 years, we observed an overall response rate of 51%. Median overall survival was 11.2 (95% confidence interval [CI] 7.3-15.1) and 11.8 months (95% CI 9.2-16.2) in elderly and younger patients, respectively. In the elderly patients, the most frequent grade 3-4 toxicities were neutropenia (13%), leukopenia (7%), thrombocytopenia (18%), anemia (3%), and febrile neutropenia (8%); in the younger patients, neutropenia (56%), leucopenia (31%), thrombocytopenia (22%), anemia (15%), and febrile neutropenia (15%)., Conclusions: Elderly patients can be safely treated with a dose-dense TCF regimen with a 30% dose reduction achieving similar efficacy results as younger patients with lesser toxicity.

Background/aim: The TArceva and docetaxeL In former-Smokers MAle patients with recurrent non-small cell lung cancer (TALISMAN) phase II, open-label randomized trial evaluates the combination of erlotinib with docetaxel in the second-line therapy of ex-smoker males with advanced squamous non-small cell lung cancer (NSCLC)., Patients and Methods: Patients received erlotinib 150 mg/day (arm A; n=36) or docetaxel 75 mg/m 2 on day 1 of each 3-week cycle and erlotinib 150 mg/day on days 2-16 of each cycle (arm B; n=38). The primary end-point was progression-free rate (PFR) at 6 months., Results: The study was prematurely interrupted due to slow enrolment. Three (8.3%) patients in arm A and 3 (8.1%) in arm B remained progression-free at 6 months. Median progression-free survival (PFS) was 2.3 months in arm A and 2.8 months in arm B. Median overall survival (OS) was 5.6 and 8.9 months, respectively. Overall, 77.8% of patients in arm A and 89.2% in arm B experienced treatment-related adverse events (AEs)., Conclusion: Results do not support further investigation of the combination of erlotinib and docetaxel in this setting., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

MicroRNAs (miRNAs) are a class of small non-protein coding RNAs that modulate important cellular functions via their post-transcriptional regulation of messenger RNAs (mRNAs). Recent evidences from multiple tumor types and model systems implicate miRNA dysregulation as a common mechanism of tumorigenesis, cancer progression and resistance to therapy. Several miRNAs are dysregulated in cancers and a single miRNA can have multiple targets involved in different oncogenic pathways. MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), has a central role in lung cancer development and in acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors; it has been predicted and shown to be the target gene of multiple miRNAs, which play a crucial role in controlling its activity in a stimulatory or inhibitory sense. In this review we will focus on the most important and recent studies about the role of miRNAs in the control of MET expression, reporting also the progress made using miRNAs for therapy of lung cancer.

Background: We previously studied a dose-dense TCF (TCF-dd) regimen demonstrating its feasibility and an activity comparable to epirubicin-based chemotherapy and TCF q3w in terms of overall survival and time to progression (TTP). We report here the final results of a phase II study of chemotherapy with a modified TCF-dd regimen in locally advanced or metastatic gastric cancer (MGC)., Methods and Study Design: Patients with histologically confirmed measurable MGC, not previously treated for advanced disease, received docetaxel 70 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, l-folinic acid 100 mg/m(2) days 1 and 2, followed by 5-fluorouracil (5-FU) 400 mg/m(2) bolus days 1 and 2, and then 600 mg/m(2) as a 22-h continuous infusion days 1 and 2, every 14 days, plus pegfilgrastim 6 mg on day 3. Patients aged ≥65 years received the same schedule with a dose reduction of 30 %., Results: Study duration: December 2007-November 2010. Forty-six consecutive patients were enrolled (78 % male, 22 % female; median age, 66 years, range, 38-76 years; ECOG PS: 0, 48 %, 1, 46 %). Primary endpoint was overall response rate (ORR). A median of four cycles (range, one to six) was administered. Forty-three patients were evaluated for response (93.5 %) and all for toxicity: 3 complete response (CR), 25 partial response (PR), 10 stable disease (SD), and 5 progressive disease (PD) were observed, for an ORR by intention to treat (ITT) of 61 % (95 % CI 47-75). Median overall survival (OS) was 17.63 months (95 % CI, 13.67-20.67); median progression-free survival was 8.9 months (95 % CI, 6.5-13.4). Twenty-one patients (46.0 %) were treated at full doses without any delay, thus respecting the dose-dense criterion. Most frequent grade 3-4 toxicities were neutropenia (20 %), leukopenia (4 %), thrombocytopenia (2 %), anemia (2 %), febrile neutropenia (6 %), asthenia (22 %), diarrhea (4 %), nausea/vomiting (11 %), and hypokalemia (6 %). Overall, TCF-dd was shown to be safe., Conclusions: The TCF-dd regimen in locally advanced or MGC is confirmed to be feasible and very active and needs to be further tested in randomized studies.

The activation of lymphocytes by gefitinib treatment has been described. In this phase II pilot trial, we explored the possible synergism between IL-2 and gefitinib for non-small cell lung cancer (NSCLC) treatment. From September, 2003, to November, 2006, 70 consecutive patients with advanced, progressive NSCLC, previously treated with chemotherapy, received oral gefitinib 250 mg daily. The first 39 patients received gefitinib alone (G group). The other 31 also received subcutaneous IL-2 (GIL-2 group): 1 MIU/m2 (Million International Unit/m2)twice a day on Days 1 and 2, once a day on Days 3, 4, 5 every week for four consecutive weeks with a four-week rest period. Median follow-up was 25.2 months. Grade 3-4 toxicity of gefitinib was represented by skin rash (7%), asthenia/anorexia (6%) and diarrhea (7%); patients treated with IL-2 showed grade 2-3 fever (46%), fatigue (21%) and arthralgia (13%). In the GIL-2 group and G-group, we respectively observed: an overall response rate of 16.1% (6.4% complete response) and 5.1% (only partial response); a disease control rate of 41.9% and 41%; a median time to progression of 3.5 (CI 95% = 3.2-3.8) and 4.1 (CI 95% = 2.6-5.7) months; a median overall survival of 20.1 (CI 95% = 5.1-35.1) and 6.9 (CI 95% = 4.9-8.9) months (p = 0.002); and an actuarial one-year survival rate of 54% and 30%. Skin toxicity (p < 0.001; HR = 0.29; CI 95% = 0.16-0.54) and use of IL-2 (p < 0.001; HR = 0.33; CI 95% = 0.18-0.60) were independently associated with improvement of survival. In this consecutive, non-randomized, series of advanced NSCLC patients, the use of IL-2 increased the efficacy of gefitinib.

Background: Cancer patients receiving chemotherapy are at increased risk of thrombosis. Nadroparin has been demonstrated to reduce the incidence of venous and arterial thrombotic events (TEs) by about 50% in cancer outpatients receiving chemotherapy. The aims of this retrospective analysis were to evaluate the thromboembolic risk and the benefit of thromboprophylaxis according to type of chemotherapy., Methods: Cancer outpatients were randomly assigned to receive subcutaneous injections of nadroparin or placebo. The incidence of symptomatic TEs was assessed according to the type of chemotherapy. Results were reported as risk ratios with associated 95% CI and two-tailed probability values., Results: 769 and 381 patients have been evaluated in the nadroparin and placebo group, respectively. In the absence of thromboprophylaxis, the highest rate of TEs was found in patients receiving gemcitabine- (8.1%) or cisplatin-based chemotherapy (7.0%). The combination of gemcitabine and cisplatin or carboplatin increased the risk to 10.2%. Thromboprophylaxis reduced TE risk by 68% in patients receiving gemcitabine; with a further decrease to 78% in those receiving a combination of gemcitabine and platinum., Conclusions: This retrospective analysis confirms that patients undergoing chemotherapy including gemcitabine, platinum analogues or their combination are at higher risk of TEs. Our results also suggest that outpatients receiving chemotherapy regimens including these agents might achieve an increased benefit from thromboprophylaxis with nadroparin., Clinical Trial Registration Number: NCT 00951574.

Purpose: To evaluate a new strategy of two sequential, intensified chemotherapy regimens in metastatic gastric cancer., Patients and Methods: Chemo-naïve patients with metastatic gastric cancer were enrolled to receive 4 cycles of TCF-dd (docetaxel initially 85 mg/m(2) and cisplatin initially 75 mg/m(2) on day 1 [later modified due to toxicity: 70 and 60 mg/m(2) respectively], l-folinic acid 100 mg/m(2) on days 1 and 2, 5-fluorouracil 400 mg/m(2) bolus and then 600 mg/m(2) as a 22 h continuous infusion on day 1 and 2, every 14 days). Subsequently, patients with CR, PR or SD received 4 cycles of COFFI (oxaliplatin 85 mg/m(2), irinotecan 140 mg/m(2), l-folinic acid 200 mg/m(2), 5-fluorouracil bolus 400 mg/m(2) on day 1 followed by 2,400 mg/m(2) as a 48 h continuous infusion, every 14 days). In both regimens pegfilgrastim 6 mg subcutaneously on day 3 was included., Results: Forty consecutive patients were enrolled. TCF-dd regimen achieved an ORR of 55% (95% CI, 40-70). Twenty-three patients proceeded to COFFI. After this regimen the ORR was then increased to 60% (95% CI, 45-75). Among the 21 patients treated with TCF-dd after the protocol amendments, main grade 3-4 toxicities were: neutropenia (29%), thrombocytopenia (19%), asthenia (24%) and diarrhea (14%). COFFI caused grade 3-4 neutropenia (all not febrile) and diarrhea in 35% and 17% of patients respectively., Conclusions: A sequential strategy with TCF-dd followed by COFFI is very active and may be of special interest in selected patients.

Aims and Background: Previous studies have reported that in early breast cancer, lymphomas and advanced bladder cancer, dose-dense chemotherapy may be more effective than conventional treatments. In metastatic gastric cancer, chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TCF) q3w is very active, and, even though there is no international consensus on the subject, it is the regimen of choice of many European centers as first-line chemotherapy in this subset of patients. Based on these studies, we tested for the first time the feasibility and activity of an intensified dose-dense TCF regimen (q2w) modifying the 5-fluorouracil infusion with 1-folinic acid/5-fluorouracil according to the "De Gramont regimen"., Methods and Study Design: Patients with histologically confirmed measurable metastatic gastric cancer, ECOG performance status or=65 years received the same schedule with a dose reduction of 30%., Results: Thirty-two consecutive patients were enrolled (63% male, 37% female); median age, 64 years (range, 40-81). A median of 4 cycles (range, 1-7) per patient was administered. Eleven of 32 patients (34%) required a dose reduction, mostly for hematological grade III-IV toxicity and severe asthenia. Twelve patients (38%) completed the first 4 cycles of therapy within 7 weeks, thereby finishing without delay the initially planned dose-density schedule. Twenty-eight patients were evaluated for response (1 early suspension after the first cycle because of toxicity, 3 deaths before response evaluation due to progression of disease). There were 3 complete responses (9%), 15 partial responses (47%), 7 stable disease (22%) and 3 progression of disease (9%), for an overall response rate, by intention to treat, of 56% (95% CI, 39-73). The most frequent grade 3-4 toxicities were: neutropenia (53%), thrombocytopenia (34%), anemia (16%) febrile neutropenia (22%), asthenia (38%) and diarrhea (19%). Median time to progression was 9.1 months (95% CI, 6.0-12.2); median overall survival was 10.1 months (95% CI, 8.8-12.2)., Conclusions: A dose-dense TCF regimen in metastatic gastric cancer is feasible, with activity comparable to previous results achieved with epirubicin-based chemotherapy and TCF q3wk in terms of overall survival and time to progression, and deserves to be further tested in randomized phase III studies.

Several phase II trials have shown that gemcitabine and fluoropyrimidines have marginal but definite activity in patients with metastatic renal cell cancer (mRCC). We retrospectively analyzed the 193 mRCC patients consecutively seen in our institutions during the last 11 years, of whom 39 were treated with chemotherapy (CT): 16 were treated with CT alone (gemcitabine and 5-fluorouracil) and 23 with the same regimen plus low dose of interleukin-2 and interferon-alpha. The main end point of the analysis was to estimate response rate and time to progression (TTP); the secondary end point was to evaluate overall survival (OS) and toxicity. Overall TTP was 3.2 months (95% confidence interval: 2.22-4.18). Three patients (7.7%) achieved a partial response and 10 (25.6%) stable disease. Median OS was 9.23 months (95% confidence interval: 7.16-11.31) and the 1-year survival rate was 40.6%. Although not statistically significant, the response and disease control rates were better in the pretreated patients (8% vs. 7% and 44% vs. 14%), with a favorable trend for TTP and OS (4.9 vs. 3.2 mo and 12.9 vs. 4.2 mo). Grade 3 to 4 toxicities included hematologic toxicity and depressed mood. OS was strongly influenced by performance status, the presence of brain metastasis, and response after 3 cycles of therapy. In these mRCC patients, both CT and chemoimmunotherapy showed modest but definite activity and a regimen CT-based should be offered to patients with progressive mRCC. The association of these treatments with antiangiogenetic agents should be tested in future trials.

Aims and Background: Previous phase II studies have reported that combinations of oxaliplatin, folinic acid and 5-fluorouracil or irinotecan, folinic acid and 5-fluorouracil are associated with good efficacy and an acceptable safety profile in metastatic gastric cancer. The aim of this study was to evaluate chemotherapy with oxaliplatin, folinic acid, 5-fluorouracil and irinotecan (COFFI regimen) in metastatic gastric cancer., Methods: Patients received oxaliplatin (85 mg/m2 d 1), irinotecan (140 mg/m2 d 1), and L-folinic acid (200 mg/m2 d 1) followed by 5-fluorouracil bolus (400 mg/m2 d 1) and then 5-fluorouracil (2,400 mg/m2 48-h continuous infusion), every 14 days., Results: Seventeen patients with metastatic gastric cancer were enrolled. Eight patients were pretreated for advanced disease. Of the 9 chemo-naïve patients, 8 were evaluated for response (1 patient was lost to follow-up): one complete response, 5 partial responses and 2 progressions of disease occurred, giving an overall response rate, at intention-to-treat analysis, of 67%. Of the 8 pretreated patients, 6 were evaluated for response (2 patients had nonmeasurable disease): one partial response, 2 disease stabilizations and 3 progressions of disease occurred, giving an overall response rate, at intention-to-treat analysis, of 12%. Median progression-free and overall survival in chemo-naïve patients were 8.2 and 10.2 months, respectively, and in pretreated patients 2.7 and 3 months. Grade 3-4 neutropenia occurred in 55% of chemo-naïve patients. Thrombocytopenia, and anemia were observed in 18% and 29%, respectively. Grade 3 nausea/vomiting occurred in 12% and grade 3 diarrhea in 6%., Conclusions: The COFFI regimen is active and well tolerated, therefore phase III studies are warranted.

We report the case of a 64-year-old patient who developed autoimmune hemolytic anemia with thrombocytopenia and acute renal failure shortly after the infusion of the 11th cycle of adjuvant chemotherapy with oxaliplatin, folinic acid and 5-fluorouracil (FOLFOX 4), and was successfully treated by means of plasmapheresis, corticosteroids and dialysis. To the best of our knowledge, only seven other cases have been described in the literature, but we believe this serious adverse event induced by oxaliplatin is more frequent than this would suggest.

The treatment of renal cell carcinoma is rapidly changing as a result of recent evidence concerning the efficacy of biological drugs, antiangiogenetic agents and signal-transduction inhibitors. This paper will provide a critical overview of the use of immunotherapy in renal cell carcinoma and review the available data concerning the efficacy of interferons, interleukin-2 and other forms of immunological treatment, particularly allogenic transplantation and vaccines. Moreover, it will focus on the new mechanisms of regulation of the immune system with a better understanding of the interaction between host and tumor, the role of T regulatory cells, heat-shock proteins and vaccines. The mechanism of action and the results obtained in renal cell carcinoma using the new molecular targeted drugs will be examined, along with the possibility of using immunotherapy combined with the new biological agents. Future research will not only need to make every effort to optimize the use of the new molecules and to define their efficacy precisely, but also to consider how to integrate these drugs with the traditional immunotherapy.