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Introduction: Lanreotide autogel (LAN) and temozolomide (TMZ) are guidelines-recommended monotherapies for thoracic neuroendocrine tumors (carcinoids; T-NETs), but prospective data for both combined and monotherapies are lacking. ATLANT (NCT02698410) evaluated efficacy and safety of LAN/TMZ in progressive T-NETs. Methods: ATLANT was a 12-month, Italian, phase 2, single-arm, open-label, multicenter pilot study. Eligible patients had unresectable, locally advanced/metastatic, well-/moderately differentiated T-NETs with radiological progression. Patients received subcutaneous LAN 120 mg every 28 days and oral TMZ 250 mg/day for 5 consecutive days every 28-day cycle. Main endpoints are disease control rate (DCR) at 9 months (primary; investigator-assessed), median progression-free survival (PFS), biomarkers, and safety. Results: The number of patients was 40; 60% were male. Primary tumor site was lung (90%) and thymus (10%). Carcinoid type was typical (20.0%) and atypical (52.5%). DCR at 9 months was 35.0% (95% confidence interval (CI) 20.63–51.68; nonacceptability threshold ≤10%, p < 0.0001; not significantly above clinically relevant threshold ≥30%, p = 0.2968). DCR between 7.5 and 10.5 months (sensitivity analysis) was 45.0% (95% CI: 29.26–61.51) and clinically relevant (p = 0.0320 at ≥30% threshold). Median PFS was 37.1 (95% CI: 24.1–52.9) weeks. No association was observed between biomarker variations (chromogranin A, neuron-specific enolase, somatostatin receptor type-2, Ki-67, 6-O-methylguanine-DNA-methyl-transferase) and DCR or PFS. Most patients (97.5%) had treatment-emergent adverse events (TEAEs); 72.5% had treatment-related TEAEs. TEAEs were mainly grade 1/2. No unanticipated TEAEs were reported. Conclusions: This study showed that the LAN/TMZ combination has promising efficacy in progressive T-NETs, and was well tolerated. Larger studies are warranted to support the clinical benefits of LAN/TMZ in patients with T-NETs.

Purpose: No evidence exists as to whether type 2 diabetes (T2DM) impairs clinical outcome from Immune Checkpoint Inhibitors (ICI) in patients with solid tumors. Experimental Design: In a large cohort of ICI recipients treated at 21 institutions from June 2014 to June 2020, we studied whether patients on glucose lowering medications (GLM) for T2DM had shorter OS and PFS. We used targeted transcriptomics in a subset of patients to explore differences in the tumor microenvironment of patients with/without diabetes. Results: A total of 1395 patients were included. Primary tumors included NSCLC (54.7%), melanoma (24.7%), renal cell (15.0%) and other carcinomas (5.6%). Following multivariable analysis, patients on GLM (n=226, 16.2%) displayed an increased risk of death (HR 1.29, 95%CI:1.07-1.56) and disease progression/death (HR 1.21, 95%CI:1.03-1.43) independent of number of GLM received. We matched 92 metformin exposed with 363 controls and 78 patients on other oral GLM or insulin with 299 control patients. Exposure to metformin, but not other GLM was associated with an increased risk of death (HR 1.53, 95%CI:1.16-2.03) and disease progression/death (HR 1.34, 95%CI:1.04-1.72). T2DM patients with higher pre-treatment glycaemia had higher neutrophil-to-lymphocyte ratio (p=0.04), while exploratory tumoral transcriptomic profiling in a subset of patients (n=22) revealed differential regulation of innate and adaptive immune pathways in T2DM patients. Conclusions: In this study patients on GLM experienced worse outcomes from immunotherapy, independent of baseline features. Prospective studies are warranted to clarify the relative impact of metformin over a pre-existing diagnosis of T2DM in influencing poorer outcomes in this population.

Background: Immune checkpoint inhibitors (ICIs) represent the standard therapy for malignant melanoma. However, a number of patients do not respond to ICIs and biomarker development remains challenging. Methods: This single cohort observational study investigates the association between mRNA levels of programmed cell death-1 (PD-1) ligand 1 (PD-L1), interferon-gamma (IFN-γ), and transforming growth factor-β (TGF-β) in circulating extracellular vesicles (EVs) in 30 patients with metastatic melanoma treated with first line anti-PD-1 antibodies. Blood samples were collected at baseline and RNA extracted from EVs. The RNA levels of PD-L1, IFN-γ, and TGF-β were analysed by digital droplet PCR (ddPCR). A biomarker-radiomic analysis was performed in a subset of patients.Results: Patients with high TGF-β expression (cut-off fractional abundance [FA] >0.19) at baseline had longer median progression-free survival (8.4 vs 1.8 months; p=0.006) and overall survival (17.9 vs 2.63 months; p=0.0009). Moreover, radiomic analysis demonstrated that patients with high TGF-β expression at baseline had smaller lesions (2.41 ± 3.27 ml vs 42.79 ± 101.08 ml, pConclusions: These results provide evidence that high TGF-β expression in extracellular vesicles at baseline is associated with a better response to immunotherapy. Further investigation on a larger patient population is needed to validate the predictive power of this potential biomarker of response to ICIs.

In patients with B-RAF-mutated cutaneous melanoma, targeted therapies are the treatment of choice to achieve a rapid response. In this multicentric, prospective, observational study, patients with B-RAF-mutated cutaneous melanoma who were treated with dabrafenib and trametinib were categorized in two cohorts (cohort A: limited disease (n = 104) and cohort B: bulky disease (n = 97)) according to lactate dehydrogenase levels. The primary endpoint was the progression pattern; the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety data. From baseline to time of progression, there was a progression from nodal to other sites of disease in cohort A and from skin and nodal to other sites in cohort B. In both the cohorts, the number of involved organs and metastases at each location decreased. The median OS was 32.4 months (95% CI: 20.1 months (not estimable)) for cohort A, and 10.5 months (95% CI: 8.3–14.4 months) for cohort B; median PFS was 12.4 months (95% CI: 10.9–17.0 months) for cohort A, and 8.1 months (95% CI: 6.3–9.4 months) for cohort B. No new safety signals were reported. This study describes the patterns of first-line treatment progression with dabrafenib and trametinib in Italian clinical practice. The effectiveness and safety data were consistent with previous trials and extended to a real-world heterogeneous population.

Advanced age is associated with comorbidities and immune system impairment, which may influence the efficacy and tolerability of immune checkpoint inhibitors. There is evidence that anti-PD1 antibodies in advanced melanoma are equally effective in patients65 years. However, data on patients75 years are lacking as co-morbidities and logistics often exclude them from clinical trials.We retrospectively reviewed the clinical records of older patients with advanced melanoma undergoing any-line treatment with an anti-PD1 (nivolumab/pembrolizumab) to investigate its clinical effectiveness and toxicity in a real-life setting. Clinical response was assessed using RECIST criteria and toxicity was evaluated according to CTCAE 4.0. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and the Cox model was used to assess potential prognostic factors.174 patients were considered; 59.2% males, median age 79 years (range 75-93). The majority had a performance status of 0 and normal lactate dehydrogenase (LDH) levels (55.2% and 52.4%, respectively). 69.1% had multiple co-morbidities. 56.9% received nivolumab. 36.7% of cases showed an objective response and the disease control rate was 56.3%. Median OS was 17.2 months [95% CI: 8.87-not reached] and a better prognosis was observed for patients with normal LDH (p .001) and lower performance status (p .001). Treatment was well tolerated, only 11 patients experiencing severe (grade 3/4) toxicity. There were no treatment-related deaths. Adverse events were managed with corticosteroids and additional immunosuppressive agents were unnecessary.Anti-PD1 antibodies appear effective and well tolerated in older patients with advanced melanoma.

Several studies have found an association between higher body mass index (BMI) and improved clinical outcomes in cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors. In a previous study, we found that overweight/obese patients were significantly more likely to experience any grade immune-related adverse events (irAEs) compared to non-overweight patients.We conducted a 'real-life', multi centre, retrospective observational study aimed at comparing the incidence of irAEs among cancer patients treated with PD-1/PD-L1 inhibitors according to baseline BMI.One thousand and seventy advanced cancer patients were evaluated. The median age was 68 years (range: 21-92), male/female ratio was 724/346. Primary tumours were: non-small-cell lung carcinoma (NSCLC) (653 patients), melanoma (233 patients), renal cell carcinoma (RCC) (152 patients) and others (29 patients). Median BMI was 25 (13.6-46.6); according to World Health Organisation (WHO) classification, 44 patients (4.1%) were defined as underweight, 480 patients (44.9%) as having a normal weight, 416 patients (38.9%) as overweight and 130 patients (12.1%) as obese. Higher BMI was significantly related to higher occurrence of any grade immune-related adverse events [irAEs] (p 0.0001), G3/G4 irAEs (p 0.0001) and irAEs leading to discontinuation (LTD) (p 0.0001). Overweight and obesity were confirmed predictors for irAEs of any grade at both univariate and multivariate analysis. The adjusted odds ratios (ORs) (compared to normal-weight) were 10.6; 95% confidence interval (95%CI): 7.5-14.9 for overweight, and 16.6 (95%CI: 10.3-26.7) for obese patients. Obesity was the only factor significantly related to a higher incidence of G3/G4 irAEs (OR = 11.9 [95%CI: 6.4-22.3], p 0.0001) and LTD irAEs (OR = 8.8 [95%CI: 4.3-18.2], p 0.0001). Overweight and obese patients experienced a significantly higher occurrence of cutaneous, endocrine, gastro-intestinal (GI), hepatic and 'others' irAEs, compared to normal-weight patients. Only obese patients experienced a significantly higher occurrence of pulmonary and rheumatic irAEs, compared to normal-weight patients.Considering the previously evidenced association between higher BMI and better outcome, the current finding about the relationship between BMI and irAEs occurrence can contribute to consideration of these findings as the upside of the downside, which underlies an 'immunogenic phenotype'.

Background Real-world data on extended follow-up of patients with BRAF V600-mutant metastatic melanoma are limited. We investigated dabrafenib plus trametinib (dab + tram) outside of a clinical trial setting (Individual Patient Program; DESCRIBE Italy). Objective To describe the baseline features, treatment patterns, efficacy, and safety outcomes in patients with BRAF V600-mutant unresectable or metastatic melanoma who had received dab + tram as part of the Managed Access Program (MAP) in Italy. Patients and methods An observational, retrospective chart review was conducted in Italian patients with BRAF V600-mutant unresectable stage III/IV melanoma receiving dab + tram as part of the MAP. Baseline features, treatment patterns, efficacy, and safety outcomes were evaluated. Results Overall, 499 patients were included in this analysis. BRAF V600E mutation was seen in 81.4% of patients. Overall response rate achieved in 243 of the 390 evaluable patients was 62.3% (95% CI 57.5–67.1). Median progression-free survival (PFS) was 9.3 months (95% CI 8.6–10.6). Subgroup analyses revealed that patients with normal lactate dehydrogenase (LDH) and ≤ three metastatic sites without brain metastases at baseline had better outcomes. With normal LDH at baseline, median PFS for patients with one or two metastatic sites other than cerebral was 18 months. No new safety signals were observed. Treatment was permanently discontinued because of treatment-emergent adverse events (TEAEs) in 9.2% of patients, and pyrexia (27.3%) was the most common TEAE, with a lower incidence than that in the phase 3 studies of dab + tram. Conclusion Treatment of BRAF V600E-mutant metastatic melanoma with dab + tram in the real-world setting was effective and safe, including the unselected population with several patients having a high tumor burden – concordant with the results of the pivotal phase 3 studies of dab + tram. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-021-00850-1.

Cutaneous Melanoma (CM) is an aggressive cancer whose incidence is increasing worldwide. However, the knowledge of its biology and genes driving cell growth and survival allowed to develop new drugs that have improved PFS and OS of advanced disease. Both BRAF targeting agents and immune checkpoint inhibitors (ICIs) have been adopted for the treatment of metastatic disease and the adjuvant setting. Several melanoma patients show innate or acquired drug-resistance and thus new strategies are required for overcoming this complication. New ICIs have been developed, and strategies of combination or sequencing are under investigation in ongoing clinical trials. In addition, pre-clinical data have demonstrated that many strategies induce the release of neoantigens within the tumor microenvironment, thus suggesting the combination of new agents with ICIs. Here, we review the ongoing strategies in advanced CM including a dedicated section on treatment of brain metastases.

The prognostic relevance of early immune-related adverse events (irAEs) in patients affected by non-small cell lung cancer (NSCLC) upon immunotherapy is not fully understood. The Leading to Treatment Discontinuation cohort included 24 patients experiencing severe irAEs after one of two administrations of single anti-PD-1/PD-L1 in any line setting for metastatic NSCLC between November 2015 and June 2019. The control cohort was composed of 526 patients treated with single anti-PD-1/PD-L1 in any line setting with no severe irAE reported. The primary end points were median progression-free survival, overall survival, objective response rate, risk of progression of disease and risk of death. The correlation of clinic pathological features with early severe irAEs represented the secondary end point. Median PFS was 9.3 and 8.4 months, median OS was 12.0 months and 14.2 months at a median follow-up of 18.1 and 22.6 months in the LTD cohort and in the control cohort, respectively. The ORR was 40% (95% CI 17.2–78.8) in the LTD cohort and 32.7% (95% CI 27.8–38.2) in the control cohort. The risk of disease progression was higher in the LTD cohort (HR 2.52 [95% 1.10–5.78], P = .0288). We found no survival benefit in LTD cohort compared to the control cohort. However, early and severe irAEs might underly an immune anti-tumor activation. We identified a significant association with first-line immune checkpoints inhibitors treatment and good PS. Further studies on risk prediction and management of serious and early irAEs in NSCLC patients are needed.

Background The favourable safety profile and the increasing confidence with immune checkpoint inhibitors (ICIs) might have boosted their prescription in frail patients with short life expectancies, who usually are not treated with standard chemotherapy. Methods The present analysis aims to describe clinicians’ attitudes towards ICIs administration during late stages of life within a multicenter cohort of advanced cancer patients treated with single agent PD-1/PD-L1 checkpoint inhibitors in Italy. Results Overall, 1149 patients with advanced cancer who received single agent PD-1/PD-L1 checkpoint inhibitors were screened. The final study population consisted of 567 deceased patients. 166 patients (29.3%) had received ICIs within 30 days of death; among them there was a significantly higher proportion of patients with ECOG-PS ≥ 2 (28.3% vs 11.5%, p Conclusion Our results confirmed a trend toward an increasing ICIs prescription in frail patients, during the late stages of life. Caution should be exercised when evaluating an ICI treatment for patients with a poor PS and a high burden of disease.

Neuroendocrine carcinomas (NECs) are a rare subgroup of neuroendocrine neoplasms that occasionally originate from gastro-entero-pancreatic (GEP) tract. Evidence of the effectiveness of chemotherapy is scarce. Platinum plus Etoposide regimens are currently the standard treatment in first-line, while little data are available on second-line treatments. The aim of this study is to evaluate the efficacy and safety of irinotecan (IRI)-based chemotherapy in a series of extrapulmonary NECs. Patients with NEC diagnosis treated at University Hospitals of Modena, Florence, Pisa, and European Institute of Oncology of Milan with an IRI-based regimen (FOLFIRI or XELIRI) after progression to a first-line platinum-based therapy were enrolled. Objective responses were assessed according to RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were calculated. Thirty-four patients, 16 males, and 18 females, median age of 59 years (range 32–77), with metastatic NEC were included. Twenty-seven patients had Ki-67 ≥ 55% and four patients Ki-67 of

Background Cutaneous squamous cell carcinoma (cSCC) has an overall favourable outcome, except for patients with an advanced stage disease. The programmed death protein-1 (PD-1) inhibitor cemiplimab has been approved for use in advanced cSCC. We report clinical outcomes from the named patient programme-compassionate use of cemiplimab for patients with advanced cSCC in Italy. Methods This is a retrospective, observational, multicentre study. We analysed medical records of patients with advanced cSCC treated with cemiplimab between May 2019 and February 2020 in 17 referral Italian centres. We assessed the safety profile according to the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v 5.0), the clinical activity in terms of response rate, clinical benefit and duration of response and baseline clinical-pathologic characteristics associated with response. Results 131 patients were included, with a median age of 79 years. Of them, 9.2% had a concurrent chronic lymphoproliferative disease and 8.5% a concomitant autoimmune disease. Some 42.7% of the total patients had at least one treatment-related adverse events (AEs); out of above, 9.2% had grade 3–4 adverse events, and there were two fatal adverse events. The overall response rate (ORR) was 58%, and the disease control rate (DCR) was 71.7%. Cutaneous squamous cell carcinomas (cSCCs) arising on the head and neck area (p = 0.007) and haemoglobin values in normal range (p = 0.034) were significantly associated with a better response, while cSCCs on the genitalia (p = 0.041), treatment with any systemic antibiotic within 1 month of cemiplimab initiation (p = 0.012), performance status ≥1 (p = 0.012), chronic corticosteroids therapy (p = 0.038), previous radiation therapy to lymph nodes (p = 0.052) and previous chemotherapy (p = 0.0020) were significantly associated with a worse response. Conclusions Our real-world study showed safety and effectiveness results comparable to those obtained in clinical trials. We identified some clinical and biochemical factors potentially associated with response to cemiplimab.

Purpose: Temozolomide (TEM) has been reported to be active alone or in combination with capecitabine (CAP) in patients with neuroendocrine neoplasms (NENs). We retrospectively evaluated activity and toxicity of TEM-based chemotherapy in patients with advanced NENs and explored the potential correlation with clinical/biological factors. Methods: Patients received oral TEM alone or in combination with CAP. Objective response rate (ORR) [complete response + partial response (PR)], median progression-free survival (mPFS), and toxicity were calculated. The O6-methylguanine-DNA-methyltransferase (MGMT) gene inactivation status in tumor tissue was evaluated by pyrosequencing. Results: From September 2008 to April 2020, 170 patients (84% progressive on different therapies) were consecutively treated, 114 (67%) patients received TEM-CAP and 56 (33%) TEM alone. Primary tumor sites were: pancreas 98 (58%), gastrointestinal tract 21 (12%), lung 35 (21%), and unknown 16 (9%). The ORR was 28% for the whole population (33% for TEM-CAP and 18% for TEM as single agent). The median OS (mOS) and mPFS of the whole population were 35.6 months (32.6–48.7) and 14.7 months (10.1–18.3), respectively. There were 48% PR in the MGMT hypermethylated, mainly in pancreatic NENs. Vomiting and leukopenia were the most frequent grade 3/4 toxicity. Conclusions: This large retrospective analysis suggested that a TEM-based chemotherapy is active in advanced, pretreated NEN patients. It generated solid hypotheses that warrant a future prospective study in a biological homogeneous NEN population and clinical setting.

// Riccardo Marconcini 1 , Francesco Spagnolo 2 , Luigia Stefania Stucci 3 , Simone Ribero 4 , Elena Marra 4 , Francesco De Rosa 5 , Virginia Picasso 2 , Lorenza Di Guardo 6 , Carolina Cimminiello 6 , Stefano Cavalieri 6 , Laura Orgiano 7 , Enrica Tanda 2 , Laura Spano 2 , Alfredo Falcone 1 and Paola Queirolo 2 for the Italian Melanoma Intergroup (IMI) 1 Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy 2 Department of Medical Oncology, IRCCS AOU San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy 3 Medical Oncology Unit, Department of Biomedical Sciences and Clinical Oncology, University of Bari, Bari, Italy 4 Dermatologic Clinic, Department of Medical Sciences, University of Turin, Turin, Italy 5 Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRST IRCCS, Meldola, Italy 6 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 7 AOU Cagliari, Department of Medical Oncology, University of Cagliari, Cagliari, Italy Correspondence to: Riccardo Marconcini, email: marconcini.riccardo@gmail.com Keywords: melanoma; immunotherapy; ipilimumab; pembrolizumab; nivolumab Received: April 23, 2017 Accepted: November 03, 2017 Published: January 03, 2018 ABSTRACT Metastatic melanoma was the first malignancy in which immune checkpoint inhibitors demonstrated their successful efficacy. Currently, the knowledge on the interaction between the immune system and malignant disease is steadily increasing and new drugs and therapeutic strategies are overlooking in the clinical scenario. To provide a comprehensive overview of immune modulating drugs currently available in the treatment of melanoma as well as to discuss of possible future strategies in the metastatic melanoma setting, the present review aims at analyzing controversial aspects about the optimal immunomodulating treatment sequences, the search for biomarkers of efficacy of immunocheckpoint inhibitors, and innovative combinations of drugs currently under investigation.

Neuroendocrine tumors (NETs) arise from the cells present throughout the diffuse endocrine system. These neoplasms were previously regarded as rare, but in fact are increasing in incidence (3.65/100 000 individuals/y). Enhancer of zeste homolog 2 (EZH2) plays a crucial role in cell cycle regulation, and it was reported to be overexpressed in several tumors. The aim of the study was to investigate EZH2 expression, also related with proliferation rate, and p53 expression in NETs of the intestine encompassing a group of tumors primary to the stomach, appendix, small intestine, and colon. The specimens from 33 patients with neuroendrocrine tumors were investigated by immunohistochemistry for EZH2, p53, and Ki-67. Only 10 of 33 (30.3%) cases showed high EZH2 expression. High EZH2 levels significantly associated with elevated proliferation rates (P=0.0012) and with elevated percentage of positive cells for p53 (P=0.011). Our results suggest an association between p53 and the EZH2 pathway in NETs. EZH2 could represent a potential target antigen in cancer immunotherapy.

BACKGROUND. Patients with a history of autoimmune diseases (AIDs) have not usually been included in clinical trials with immune checkpoint inhibitors. MATERIALS AND METHODS. Consecutive patients with advanced cancer, treated with anti‐programmed death‐1 (PD‐1) agents, were evaluated according to the presence of pre‐existing AIDs. The incidence of immune‐related adverse events (irAEs) and clinical outcomes were compared among subgroups. RESULTS. A total of 751 patients were enrolled; median age was 69 years. Primary tumors were as follows: non‐small cell lung cancer, 492 (65.5%); melanoma, 159 (21.2%); kidney cancer, 94 (12.5%); and others, 6 (0.8%). Male/female ratio was 499/252. Eighty‐five patients (11.3%) had pre‐existing AIDs, further differentiated in clinically active (17.6%) and inactive (82.4%). Among patients with pre‐existing AIDs, incidence of irAEs of any grade was significantly higher when compared with patients without AIDs (65.9% vs. 39.9%). At multivariate analysis, both inactive (p = .0005) and active pre‐existing AIDs (p = .0162), female sex (p = .0004), and Eastern Cooperative Oncology Group Performance Status

Background Recent evidence suggested a potential correlation between overweight and the efficacy of immune checkpoint inhibitors (ICIs) in cancer patients. Patients and methods We conducted a retrospective study of advanced cancer patients consecutively treated with anti-PD-1/PD-L1 inhibitors, in order to compare clinical outcomes according to baseline BMI levels as primary analysis. Based on their BMI, patients were categorized into overweight/obese (≥ 25) and non-overweight (

The aim of the present study was to evaluate clinical activity, and the pharmacodynamic and pharmacokinetic profiles, of oral metronomic vinorelbine (VNR) plus dexamethasone (DEX) in metastatic castration-resistant prostate cancer (mCRPC) patients. Fourty-one patients (92 % chemotherapy-resistant) received 30 mg/day VNR p.o. thrice a week plus 1 mg/day DEX p.o. until disease progression. Plasma soluble B cell antigen 7 homolog 3 (sB7-H3), vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1), were measured by ELISA. Plasma VNR was detected using a LC-MS-MS system. The fraction of patients free of progression, defined by criteria of the Prostate Cancer Clinical Trials Working Group 2, at 3 months was 61 %. PSA decrease ≥50 % from baseline was observed in 35 % of patients. Median PFS and OS were 4 months (95 % CI, 2.8–6.9) and 17.5 months (95 % CI, 10.8–24.5), respectively. Toxicity was mild, and no grade 4 toxicities were found. The mean plasma VNR Cmax ranged from 1 to 2.7 ng/ml (Tmax 1.1 h) and no evidence of drug accumulation was found. A moderate relationship was found between plasma sB7-H3 and PSA values (r = 0.565; P = 0.0094) at the baseline. Increased PFS (11.3 vs. 2.8 months; P = 0.0298) was observed in patients with sB7-H3 levels

BackgroundConcomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors.MethodsWe conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, β-blockers, metformin and other oral antidiabetics, opioids.ResultsFrom June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), pConclusionWe confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.

The role of vitamin D in melanoma is still controversial. Although several Authors described a correlation between vitamin D deficiency and poor survival in metastatic melanoma patients, clinical trials exploring the effects of vitamin D supplementation in this clinical setting were mostly inconclusive. However, recent evidence suggests that vitamin D exerts both anti-proliferative effects on tumor cells and immune-modulating activities, that have been widely explored in auto-immune disorders. On the one hand, vitamin D has been shown to inhibit T-helper17 lymphocytes, notoriously involved in the pathogenesis of immune-related adverse events (iAEs) which complicate immune-checkpoint inhibitor (ICI) treatment. On the other hand, vitamin D up-regulates PDL-1 expression on both epithelial and immune cells, suggesting a synergic effect in combination with ICIs, for which further investigation is needed.

Background: PD-L1 expression in tumour tissues is widely used to select patients to receive anti-PD-1/PD-L1 antibodies, but data are lacking on the correlation of plasma PD-L1 levels with the effect of treatments. Methods: To investigate the association between PD-L1 mRNA in plasma-derived exosomes and response to nivolumab and pembrolizumab in patients with melanoma (n=18) and NSCLC (n=8), blood was obtained at time point 0 and after 2 months. Exosomal PD-L1 mRNA was measured by digital droplet PCR. Results: The mean±s.e.m. PD-L1 levels in patients with complete and partial responses were 830.4±231.3 and 242.5±82.5 copies per ml at time 0 vs 2 months, respectively (P=0.016). In patients with stable disease the mean±s.e.m. values were 298.8±97.2 vs 247.5±29.8 copies per ml (P=0.586), while in progressive disease, PD-L1 mRNA levels were 204.0±68.8 vs 416.0±87.8 copies per ml at time 0 vs 2 months, respectively (P=0.001). Conclusions: This study demonstrates that exosomal PD-L1 is significantly associated with response to treatment.

As for all types of cancer, the incidence of melanoma increases with age. However, naevus counts (the principal risk factor for melanoma) decrease with age; hence the relationship between ageing and melanoma is complex. Subjects who maintain a high naevus count after the age of 50 years are more likely to be affected by melanoma, as their lesions do not senesce. Longer telomere length, which is strongly related to age, is linked to high naevus counts/melanoma risk; thus melanoma biology is influenced by factors that slow down ageing. Age is also an important prognostic factor in melanoma. Increasing age leads to worse survival in stages I, II and III. Sentinel lymph node (SLN) status, which is a strong predictor of melanoma survival, is also affected by age, as SLN positivity decreases with age. However, the prognostic value of SLN on survival increases with age, so, again, these relationships are complex. In patients with stage IV melanoma, age impacts on survival because it affects responses to treatment. This review examines the effects of age on melanoma risk, prognostic factors and responses to treatment.

No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS ≥70%; (II) intermediate risk group: 30% ≤ 10-year OS

BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Background The BRAF K601E mutation occurs in 5% of patients with melanoma, and is the third most common type of BRAF mutation. However, treatment with BRAF and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors is only approved in patients with BRAF V600-positive melanoma, and patients with K601E-mutated melanoma do not have access to such drugs. Case presentation A female patient was diagnosed with high tumor burden metastatic melanoma harboring the BRAF K601E mutation. After chemotherapy failure, she underwent compassionate treatment with trametinib. Trametinib showed good activity and efficacy, with 48% shrinkage of a metastatic lymphadenopathy after 4 months’ treatment. However, the patient reported treatment-related skin toxicity that required dosage reduction and a personalized intermittent trametinib dosing schedule. After over 36 months from the first trametinib administration, and resection of a metastatic lymphadenopathy, the patient experienced complete response. Conclusions This case report shows that trametinib could be a valid therapeutic option in patients with metastatic melanoma harboring the rare BRAF K601E mutation.

BACKGROUND Docetaxel plus prednisone is currently the standard first-line treatment in metastatic castration-resistant prostate cancer (mCRPC). The aim of this study was to assess the clinical activity and pharmacodynamic/pharmacogenetic profile of docetaxel plus prednisone in combination with metronomic cyclophosphamide in mCRPC patients. METHODS Forty-one chemotherapy-naive patients received docetaxel (60 mg/m2 intravenously every 3 weeks up to 12 cycles) and, from day 2, prednisone 10 mg/day, celecoxib 400 mg/day, and metronomic cyclophosphamide 50 mg/day, continuously. Plasma VEGF and bFGF were detected by ELISA. Real-time PCR-SNP analysis of VEGF gene was performed using an ABI PRISM 7900HT SDS and TaqMan SNP genotyping. RESULTS Eighty-seven percent of patients were free of progression at 6 months. A decrease in prostate-specific antigen ≥50% was observed in 82% of 39 evaluable patients, with a median time to progression of 12.3 months. Grade 3 adverse events were neutropenia (5%), thrombocytopenia, diarrhea, and stomatitis (2.5%). Median PFS and OS were 14.9 months (95% CI, 9.2-15.3 months) and 33.3 months (95% CI, 23-35.6 months), respectively. Of 11 patients (28%) with evaluable disease, 5 (44%) achieved a complete response, 2 (11%) a partial response, and 2 (11%) stable disease, whereas 2 showed disease progression. The −1154A/G VEGF polymorphism, plasma VEGF, and bFGF after the first cycle of chemotherapy may represent useful pharmacodynamic markers to predict better outcomes. CONCLUSIONS The combination of docetaxel and oral metronomic chemotherapy is effective and well tolerated in mCRPC patients and may deserve further evaluation. Cancer 2014;120:3923–3931. © 2014 American Cancer Society.

Background Ipilimumab (Ip) is an option in Metastatic Melanoma (MM) patients (pt) in case of disease progression after antiPD1 (AP) treatment and BRAF+MEK inhibitors (BMi) administration (for BRAF mutated melanoma). Clinical trial are evaluating potential Ip-based combinations in 2nd/3rd line setting. Many studies underline the role of some parameters (as LDH, ECOG PS, Neutrophile/Leucocyte ratio) as progostic factors for immunotherapy used in first-line. We evaluate the prognostic role of some relevant clinical or laboratoristic parameters for Ip used in late line after AP, Bmi, in order to define pt that benefit most from Ip monotherapy in this setting. Methods A retrospective multicenter study was conducted in 8 Italian Oncology Centers, evaluating MM pt treated with Ip after AP and/or BMi. Endpoints were OS and PFS, Kaplan Mayer and Cox regression were applied for survival analysis. Results Among 200 pt that received AP or Bmi, 48 were eligible for Ip administration in 2nd/3rd line. Before Ip treatment, ECOG PS was 0 in 21 pt, number of metastatic sites was less then 3 in 14 pt, LDH was within normal range in 19 pt, NLR ratio (= baseline neutrophils/total leukocytes) was less then 0.7 in 28 pt: in univariate analysis, only ECOG PS and NLR resulted significantly associated with better PFS and OS. For pt with ECOG PS 0 or 1 medianPFS was 3.2, 2.3 month respectively (p value 0.0066; HR 0.377 IC95% 0.186-0.762), median OS was 12.1, 4.0 respectively (p value 0.0016 HR 0.287 IC95% 0.132-0.622). For pt with NLR 0,7 medianPFS was 3.2, 2.0 month respectively (p value 0.002 HR 0.241 IC95% 0.0978-0.593), median OS was 7.63, 2.67 respectively (p value 0.0037 HR 0.251 IC95% 0.0986-0.0637) A score was counted for each pt considering the number of favorable basal factors present (ECOG PS 0, NLR Conclusions ECOG PS 0, NLR Legal entity responsible for the study Italian Melanoma Intergroup. Funding Has not received any funding. Disclosure R. Marconcini: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: La Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen. All other authors have declared no conflicts of interest.

Background: No data are available on the pharmacogenetics of metronomic chemotherapy in prostate cancer. The aim of this study was to evaluate the association between VEGF-A sequence variants and prostate-specific antigen (PSA) progression, progression-free survival (PFS) and overall survival (OS), in advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide (CTX), celecoxib and dexamethasone. Methods: Forty-three patients were enrolled, and genomic DNA was extracted. VEGF-A gene SNPs (−2578A/C, −634C/G, +936C/T) were analysed using TaqMan PCR assays. Hardy–Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated by Fisher's exact test. PFS and OS were analysed with GraphPad Prism software, using the product limit method of Kaplan and Meier, and comparing survival curves using both the log-rank test and the Gehan–Wilcoxon test. We used Bonferroni correction to account for multiple testing, and a two-tailed P-value of

10038Background: advanced age is associated with comorbidities and impairment of the immune system: these aspects may influence efficacy and tolerability of immune checkpoint inhibitors. Limited da...