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Tumour Treating Fields (TTFields) are a regional, antimitotic treatment for solid tumours, which is based on the delivery of low-intensity alternating electric fields. The aim of the STELLAR study was to test the activity of TTFields delivered to the thorax in combination with systemic chemotherapy for the front-line treatment of patients with unresectable malignant pleural mesothelioma. STELLAR was a prospective, single-arm, phase 2 trial done at 12 European academic and non-academic sites (five in Italy, three in Poland, one in France, one in Belgium, one in Spain, and one in the Netherlands) for treatment-naive patients with histologically confirmed unresectable malignant pleural mesothelioma. Patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0–1, and at least one measurable or evaluable lesion according to modified Response Evaluation Criteria in Solid Tumors for mesothelioma. Patients received continuous TTFields at a frequency of 150 kHz to the thorax and concomitant chemotherapy with intravenous pemetrexed (500 mg/m2 on day 1) plus intravenous platinum (either cisplatin 75 mg/m2 on day 1 or carboplatin area under the curve 5 on day 1) every 21 days for up to six cycles. Patients not progressing after completion of chemotherapy received TTFields as maintenance treatment until progression, patient or physician decision, or unacceptable toxic effects. The primary endpoint of the trial was overall survival. Survival analyses were done in the intention-to-treat population, and safety analyses were done in all patients who received at least 1 day of TTFields treatment. This trial is registered with ClinicalTrials.gov, NCT02397928. Between Feb 9, 2015 and March 21, 2017, 80 patients were enrolled in the study. Median follow-up was 12·5 months (IQR 7·4–16·6). Median overall survival was 18·2 months (95% CI 12·1–25·8). The most common grade 3 or worse adverse events were anaemia (nine [11%] patients), neutropenia (seven [9%]), and thrombocytopenia (four [5%]). Skin reaction was the only adverse event associated with TTFields and was reported as grade 1–2 in 53 (66%) patients, and as grade 3 in four (5%) patients. No treatment-related deaths were observed. The trial showed encouraging overall survival results, with no increase in systemic toxicity. TTFields (150 kHz) delivered to the thorax concomitant with pemetrexed and platinum was an active and safe combination for front-line treatment of unresectable malignant pleural mesothelioma. Further investigation in a randomised trial is warranted. Novocure.

An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer. From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m2, intravenously, every 21 days, or docetaxel 75 mg/m2, intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00989690. 142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8–10·9) in the chemotherapy group and 7·7 months (5·9–10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (pinteraction=0·017 when adjusted for stratification factors; pinteraction=0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08–2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77–1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs one [<1%] in the erlotinib group), whereas skin toxicity (one [<1%] vs 22 [16%]) was the most frequent in the erlotinib group. Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib. Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix.

Several non-comparative phase II studies have evaluated metronomic oral vinorelbine (MOV) in metastatic non-small cell lung cancer (NSCLC) but the small size of each study limits their conclusions. To perform an individual patient-data metaanalysis of studies evaluating MOV in metastatic NSCLC in order to measure survival and safety of treatment with this regimen. Studies were selected if (1) administration of oral vinorelbine thrice a week; (2) fixed daily dose comprised between 30 and 50 mg, and; (3) being published before October 4th 2018. Database encompassed 8 variables characterizing disease and demography, 3 informing therapy, and 12 describing survival and toxicity. Nine studies encompassing 418 patients fulfilled the selection criteria, 80% of them having frailty characteristics. Median overall survival (OS) was 8.7 months (95%CI: 7.6-9.5). OSrates at 6 months, one year and at two years after starting vinorelbine were 64%, 30.3% and 8.9%, respectively. In the Cox model, Eastern Cooperative Oncology Group (ECOG) performance status (PS) = 2, and anemia of any grade were significant determinants of shorter OS. Median progression-free survival(PFS) was 4.2 months (95%CI: 3.9-5). At 6 months and at one-year, PFS rates were 35% and 11.9% respectively. In the Cox model stratified for the variable \"study\", PS = 2and stage IV were significant determinants of shorter PFS. No toxicity was reported for 40% of patients, and 66 (15.8%) patients experienced a grade 3-4 toxicity. The most frequent toxicity was anemia of any grade (35.8%) that was higher with the 50 mg dosage. MOV is an active and well-tolerated chemotherapy in metastatic NSCLC and is a manageable therapy in frail patients.

BackgroundUntil now, no robust data supported the efficacy, safety and recommendation for influenza vaccination in patients with cancer receiving immune checkpoint inhibitors (ICIs).MethodsThe prospective multicenter observational INfluenza Vaccine Indication During therapy with Immune checkpoint inhibitors (INVIDIa-2) study investigated the clinical effectiveness of influenza vaccination in patients with advanced cancer receiving ICIs, enrolled in 82 Italian centers from October 2019 to January 2020. The primary endpoint was the time-adjusted incidence of influenza-like illness (ILI) until April 30, 2020. Secondary endpoints regarded ILI severity and vaccine safety.ResultsThe study enrolled 1279 patients; 1188 patients were evaluable for the primary endpoint analysis. Of them, 48.9% (581) received influenza vaccination. The overall ILI incidence was 8.2% (98 patients). Vaccinated patients were significantly more frequently elderly (p<0.0001), males (p=0.004), with poor European Cooperative Oncology Group performance status (p=0.009), affected by lung cancer (p=0.01), and by other non-cancer comorbidities (p<0.0001) when compared with unvaccinated. ILI incidence was not different basing on influenza vaccination: the time-to-ILI was similar in vaccinated and unvaccinated patients (p=0.62). ILI complications were significantly less frequent for patients receiving the vaccination (11.8% vs 38.3% in unvaccinated, p=0.002). ILI-related intravenous therapies were significantly less frequent in vaccinated patients than in unvaccinated (11.8% vs 29.8%, p=0.027). ILI lethality was, respectively, 0% in vaccinated and 4.3% in unvaccinated patients. Vaccine-related adverse events were rare and mild (1.5%, grades 1–2).ConclusionThe INVIDIa-2 study results support a positive recommendation for influenza vaccination in patients with advanced cancer receiving immunotherapy.

Pleural mesothelioma usually presents at an advanced, incurable stage. Chemotherapy with platinum–pemetrexed is a standard treatment. We hypothesised that the addition of pembrolizumab to platinum–pemetrexed would improve overall survival in patients with pleural mesothelioma. We did this open-label, international, randomised phase 3 trial at 51 hospitals in Canada, Italy, and France. Eligible participants were aged 18 years or older, with previously untreated advanced pleural mesothelioma, with an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were randomly assigned (1:1) to intravenous chemotherapy (cisplatin [75 mg/m2] or carboplatin [area under the concentration-time curve 5–6 mg/mL per min] with pemetrexed 500 mg/m2, every 3 weeks for up to 6 cycles), with or without intravenous pembrolizumab 200 mg every 3 weeks (up to 2 years). The primary endpoint was overall survival in all randomly assigned patients; safety was assessed in all randomly assigned patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02784171, and is closed to accrual. Between Jan 31, 2017, and Sept 4, 2020, 440 patients were enrolled and randomly assigned to chemotherapy alone (n=218) or chemotherapy with pembrolizumab (n=222). 333 (76 %) of patients were male, 347 (79%) were White, and median age was 71 years (IQR 66–75). At final analysis (database lock Dec 15, 2022), with a median follow-up of 16·2 months (IQR 8·3–27·8), overall survival was significantly longer with pembrolizumab (median overall survival 17·3 months [95% CI 14·4–21·3] with pembrolizumab vs 16·1 months [13·1–18·2] with chemotherapy alone, hazard ratio for death 0·79; 95% CI 0·64–0·98, two-sided p=0·0324). 3-year overall survival rate was 25% (95% CI 20–33%) with pembrolizumab and 17% (13–24%) with chemotherapy alone. Adverse events related to study treatment of grade 3 or 4 occurred in 60 (27%) of 222 patients in the pembrolizumab group and 32 (15%) of 211 patients in the chemotherapy alone group. Hospital admissions for serious adverse events related to one or more study drugs were reported in 40 (18%) of 222 patients in the pembrolizumab group and 12 (6%) of 211 patients in the chemotherapy alone group. Grade 5 adverse events related to one or more drugs occurred in two patients on the pembrolizumab group and one patient in the chemotherapy alone group. In patients with advanced pleural mesothelioma, the addition of pembrolizumab to standard platinum–pemetrexed chemotherapy was tolerable and resulted in a significant improvement in overall survival. This regimen is a new treatment option for previously untreated advanced pleural mesothelioma. The Canadian Cancer Society and Merck & Co.

The soluble mesothelin-related peptide (SMRP), a candidate marker for screening of subjects with asbestos exposure, is influenced by some individual and clinical factors. The aim of this study was to quantify the role of age, smoking, weight, presence of diseases and exposure to asbestos on serum SMRP levels in a large series of subjects exposed to asbestos, possible candidates for mesothelioma screening. One thousand seven hundred and four participants underwent clinical examination and were interviewed on medical anamnesis, occupation, smoking and weight. SMRP was measured by an ELISA assay. Overall, median SMRP was 0.4 (IQR 25–75: 0.3–0.7) nmol/l. It was higher in current smokers and in subjects with a cumulative asbestos exposure >50 ff/cc/years than in all the other subjects ( p  < 0.001 and p  = 0.002, respectively). SMRP was positively correlated with age (ρ = 0.11, p  < 0.001) and, inversely, with BMI ( ρ  = −0.15, p  < 0.001). SMRP was lower in healthy subjects ( n  = 1,217: median 0.4 nmol/l) than in subjects with malignant tumors ( n  = 118: 0.5 nmol/l; p  = 0.01), asbestos-related pleural lesions (plaques or thickenings, n  = 152: 0.6 nmol/l; p  < 0.001) and other benign diseases ( n  = 182: 0.5 nmol/l; p  = 0.04). Multivariate analysis revealed significant predictors of increased SMRP: age >57 years, current smoking, a positive anamnesis for cancer and for asbestos-related pleural lesions, and BMI < 25. Some clinical and demographic variables are associated with serum SMRP levels. The degree of these associations is low, nevertheless they should be accounted for in the interpretation of SMPR as a candidate marker predictive of mesothelioma. The potential predictive value of serum SMRP in screening/surveillance programs must be validated in prospective studies.

Immunotherapy based on anti PD-1/PD-L1 inhibitors is the new standard of advanced non-small cell lung cancers. Pembrolizumab, nivolumab and atezolizumab are used in clinical practice. The strict eligibility criteria of clinical trials do not allow researchers to fully represent treatment effects in the patients that will ultimately use these drugs. We performed a systematic review and a meta-analysis to evaluate the effectiveness and safety of these drugs, and more generally of ICIs, as second-line therapy in NSCLC patients in real world practice. MEDLINE, PubMed, Scopus and Web of Science were searched to include original studies published between January 2015 and April 2020. A total of 32 studies was included in the meta-analysis. The overall radiological response rate (ORR), disease control rate (DCR), median progression-free survival (PFS) and overall survival (OS) were 21%, 52%, 3.35 months and 9.98 months, respectively. The results did not change when analysis was adjusted for Eastern Cooperative Oncology Group performance status (ECOG PS) and age. A unitary increase in the percent of patients with liver and CNS metastases reduced the occurrence of DCR by 7% (p < 0.001) and the median PFS by 2% (p = 0.010), respectively. The meta-analysis showed that the efficacy and safety of immunotherapy in everyday practice is comparable to that in clinical trials.

Background MAURIS is an Italian multicenter, open-label, phase IIIb ongoing trial, aiming at evaluating the safety and effectiveness of atezolizumab + carboplatin/etoposide in patients with newly diagnosed, extensive-stage small-cell lung cancer (ES-SCLC). The primary objective is the safety evaluation. Materials and Methods Patients received atezolizumab + carboplatin/etoposide Q3W for 4-6 cycles in the induction phase, followed by atezolizumab maintenance Q3W. We presented the interim analysis on safety (referring to the induction phase) and clinical effectiveness, in all patients (N = 154) and in subgroups that received ≤3 (N = 23), 4 (N = 43), and 5-6 cycles (N = 89) of induction. Results At a median follow-up of 10.5 months, 139 patients (90.3%) discontinued treatment. Serious adverse events occurred in 29.9% of patients overall, and the rate was lower in patients with 5-6 cycles (19.1%) than in those with 4 (34.9%) or ≤3 (63.6%) cycles. Immune-mediated adverse events were reported in 14.9%, 15.7%, 11.6%, and 18.2% of patients, overall and by subgroup, respectively. The median overall survival and progression-free survival were 10.7 and 5.5 months, respectively. Overall, 111 patients (71.6%) had a tumor response. Conclusions Interim results provide further evidences about safety and efficacy profile of atezolizumab + carboplatin/etoposide treatment in a ES-SCLC patient population closer to that observed in clinical practice. Clinical Trial Registration Eudract No. 2019-001146-17, NCT04028050. This analysis is based on interim data from the MAURIS study, an Italian multicenter, phase IIIb ongoing trial to evaluate treatment with atezolizumab plus carboplatin/etoposide in patients with newly diagnosed extensive-stage small-cell lung cancer.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm frequently complicated by transfusion dependent anemia. Both anemia and transfusion-dependence are associated with a poor outcome, at least in part because of toxic effects of iron overload (IOL). Iron-chelating therapy (ICT) is increasingly used in order to prevent IOL in this setting. Here, we describe the case of a 73-year-old man affected by PMF and severe transfusion-dependent anemia who experienced a dramatic erythroid response after being treated with deferasirox to prevent IOL.

Radium-223 dichloride (Ra223) represents the unique bone-directed treatment option that shows an improvement in overall survival (OS) in metastatic castrate resistant prostate cancer (mCRPC). However, there is an urgent need for the identification of reliable biomarkers to non-invasively determine its efficacy (possibly improving patients’ selection or identifying responders’ after therapy completion). 18F-Fluorodeoxyglucose (FDG)-avidity is low in naïve prostate cancer, but it is enhanced in advanced and chemotherapy-refractory mCRPC, providing prognostic insights. Moreover, this tool showed high potential for the evaluation of response in cancer patients with bone involvement. For these reasons, FDG Positron Emission Tomography (FDG-PET) might represent an effective tool that is able to provide prognostic stratification (improving patients selection) at baseline and assessing the treatment response to Ra223. We conducted a retrospective analysis of 28 mCRPC patients that were treated with Ra223 and submitted to bone scan and FDG-PET/CT for prognostic purposes at baseline and within two months after therapy completion. The following parameters were measured: number of bone lesions at bone scan, SUVmax of the hottest bone lesion, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). In patients who underwent post-therapy 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT), (20/28), PET Response Criteria in Solid Tumors (PERCIST), and European Organization for Research and Treatment of Cancer (EORTC) criteria were applied to evaluate the metabolic treatment response. The difference between end of therapy and baseline values was also calculated for Metabolic Tumor Volume (MTV), TLG, prostate-specific antigen (PSA), alkaline phosphatase (AP), and lactate dehydrogenase (LDH) (termed deltaMTV, deltaTLG, deltaPSA, deltaAP and deltaLDH, respectively). Predictive power of baseline and post-therapy PET- and biochemical-derived parameters on OS were assessed by Kaplan–Meier, univariate and multivariate analyses. At baseline, PSA, LDH, and MTV significantly predicted OS. However, MTV (but not PSA nor LDH) was able to identify a subgroup of patients with worse prognosis, even after adjusting for the number of lesions at bone scan (which, in turn, was not an independent predictor of OS). After therapy, PERCIST criteria were able to capture the response to Ra223 by demonstrating longer OS in patients with partial metabolic response. Moreover, the biochemical parameters were outperformed by PERCIST in the post-treatment setting, as their variation after therapy was not informative on long term OS. The present study supports the role of FDG-PET as a tool for patient’s selection and response assessment in mCRPC patients undergoing Ra223 administration.