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Purpose:We assessed the immunogenicity and safety of the BNT162b2 vaccine in a large cohort of patients with cancer (CP).Experimental Design:From March 1, 2021 to March 20, 2021, this prospective cohort study included 816 CP afferent to our institution and eligible for the vaccination. A cohort of 274 health care workers (HCW) was used as age- and sex-matched control group. BNT162b2 was administered as a two-dose regimen given 21 days apart. Blood samples to analyze anti-Spike (S) IgG antibodies (Ab) were collected prevaccination [timepoint (TP) 0], and at 3 weeks (TP1) and 7 weeks (TP2) after the first dose.Results:Patients characteristics: median age 62 (range, 21–97); breast/lung cancer/others (31/21/48%); active treatment/follow-up (90/10%). In the whole CP cohort, the serologic response rate (RR) and the titre of anti-S IgG significantly increased across the TPs; at TP2, the responders (IgG >15 AU/mL) were 94.2%. Active chemotherapy and chronic use of steroids were independent predictors of lower RR. Adverse events (AE) after the booster predicted higher likelihood of response (OR, 4.04; 95% confidence interval, 1.63–9.99; P = 0.003). Comparing the matched cohorts, the responders were significantly lower in CP than in HCW at TP1 (61.2% vs. 93.2%) and TP2 (93.3% vs. 100%), while the geometric mean concentration of IgG did not significantly differ at TP2 being significantly lower in CP (23.3) than in HCW (52.1) at TP1. BNT162b2 was well tolerated in CP; severe-grade AEs were 3.5% and 1.3% after the first and second doses, respectively.Conclusions:BNT162b2 assures serologic immunization without clinically significant toxicity in CP. The second dose is needed to reach a satisfactory humoral response.

We previously reported on the immunogenicity and safety of BNT162b2 in a large cohort of patients with cancer after the first and second doses (Di Noia et al., 2021) [1]. Herein, we present result after six months of follow-up.This prospective study included patients affected by solid tumors and afferent to our institution who received two doses of BNT162b2 vaccine. A cohort of vaccinated healthcare workers (HCW) was used as control-group. Both cohorts were evaluated for the titer of anti-Spike (S) IgG at prefixed time-points (TPs). Time-point 4 was scheduled at 24-26 weeks after the second dose.In the current analysis, 400 patients and 232 healthcare workers were evaluated. Responders (IgG15 AU/mL) in patients group were 86.5% compared with 94.4% among healthcare workers. Also the IgG titer at TP4 was significantly inferior in patients than in healthcare workers (70.81 vs 134.64 AU/ml, p 0.001). There was a more rapid decline of the antibody level from TP3 to TP4 in patients than in healthcare workers (1.78 vs 1.3 fold). The estimated IgG half-life was significantly shorter for patients (73 days) than in healthcare workers (118 days) as well as the time to reach negative serological status (340 vs 532 days).The decline of humoral response to the vaccine observed in patients with solid cancer after six months from the first dose support the urgent need of an early additional dose.

Background Improved outcome in tobacco smoking patients with non‐small cell lung cancer (NSCLC) following immunotherapy has previously been reported. However, little is known regarding this association during first‐line immunotherapy in patients with high PD‐L1 expression. In this study we compared clinical outcomes according to the smoking status of two large multicenter cohorts. Methods We compared clinical outcomes according to the smoking status (never smokers vs. current/former smokers) of two retrospective multicenter cohorts of metastatic NSCLC patients, treated with first‐line pembrolizumab and platinum‐based chemotherapy. Results A total of 962 NSCLC patients with PD‐L1 expression ≥50% who received first‐line pembrolizumab and 462 NSCLC patients who received first‐line platinum‐based chemotherapy were included in the study. Never smokers were confirmed to have a significantly higher risk of disease progression (hazard ratio [HR] = 1.49 [95% CI: 1.15–1.92], p = 0.0022) and death (HR = 1.38 [95% CI: 1.02–1.87], p = 0.0348) within the pembrolizumab cohort. On the contrary, a nonsignificant trend towards a reduced risk of disease progression (HR = 0.74 [95% CI: 0.52–1.05], p = 0.1003) and death (HR = 0.67 [95% CI: 0.45–1.01], p = 0.0593) were reported for never smokers within the chemotherapy cohort. After a random case–control matching, 424 patients from both cohorts were paired. Within the matched pembrolizumab cohort, never smokers had a significantly shorter progression‐free survival (PFS) (HR = 1.68 [95% CI: 1.17–2.40], p = 0.0045) and a nonsignificant trend towards a shortened overall survival (OS) (HR = 1.32 [95% CI: 0.84–2.07], p = 0.2205). On the contrary, never smokers had a significantly longer PFS (HR = 0.68 [95% CI: 0.49–0.95], p = 0.0255) and OS (HR = 0.66 [95% CI: 0.45–0.97], p = 0,0356) compared to current/former smoker patients within the matched chemotherapy cohort. On pooled multivariable analysis, the interaction term between smoking status and treatment modality was concordantly statistically significant with respect to ORR (p = 0.0074), PFS (p = 0.0001) and OS (p = 0.0020), confirming the significantly different impact of smoking status across the two cohorts. Conclusions Among metastatic NSCLC patients with PD‐L1 expression ≥50% receiving first‐line pembrolizumab, current/former smokers experienced improved PFS and OS. On the contrary, worse outcomes were reported among current/former smokers receiving first‐line chemotherapy., Improved outcome in tobacco smoking NSCLC patients following treatment with immune checkpoint inhibitors (ICIs) has previously been reported. Little is known regarding this association during first‐line immunotherapy in patients with high PD‐L1 expression. Clinical outcomes according to the smoking status of two large multicenter cohorts were compared in this study. Smokers with high PD‐L1 expression ≥ 50% experienced improved progression‐free survival (PFS) and overall survival (OS) with first‐line pembrolizumab. The opposite trend was found in NSCLC patients treated with first‐line platinum‐based chemotherapy.

No standard treatment option is available for patients with unresectable malignant pleural mesothelioma (MPM) progressing after upfront chemotherapy. We aimed to explore the role of focal radiotherapy (FRT) as a treatment modality for oligo-progressive MPM.In this retrospective study, consecutive patients pretreated with ≥1 lines of chemotherapy were included. Oligo-progressive MPM was defined as an unresectable disease with radiological progression at ≤3 sites according to a chest-abdominal contrast-enhanced computed tomography. Patients were treated with either stereotactic body radiotherapy (SBRT, ≥5 Gy per fraction) or hypo-fractionated radiotherapy (hypoRT,5 Gy per fraction). Time to further systemic therapy (TFST) and local control (LC) after FRT were the primary endpoints. Biologically effective dose (BED) was calculated using three different alpha/beta models (1.5 Gy, 3 Gy and 10 Gy).From April 2006 to March 2019, 37 patients were treated on 43 pleural lesions; 16/37 (43 %) had undergone upfront multimodality treatment (MMT) including surgery. FRT was given in 22/37 (59.5 %) after one line of chemotherapy. SBRT was delivered for 26/43 lesions (60.5 %), hypoRT for 17/43 (39.5 %). Median TFST was 6 months (95 % CI 4.9-7.1). LC at 6 months and 1 year was 84 % and 76 %, respectively. Median TFST was longer in patients treated after 1 vs1 line of chemotherapy (9 vs 4 months, p = 0.001) and in patients pretreated with MMT (6 vs 3 months, p = 0.021). Six-month LC was better in patients treated with a BED 100 using alpha/beta 1.5 and 3. No ≥ G3 acute or late toxicities were reported.FRT was feasible in selected patients with oligo-progressive MPM, allowing delay of further systemic therapies, with no severe toxicity. FRT was more effective when performed at progression after one line of systemic therapy. Our results suggest a radio-resistant behavior of MPM.

The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%.We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes.A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P .0001), single-site irAEs (P .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P .0001), single-site irAEs (P .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival.This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting.

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.

Purpose: We assessed the immunogenicity and safety of the BNT162b2 vaccine in a large cohort of patients with cancer (CP). Experimental Design: From March 1, 2021 to March 20, 2021, this prospective cohort study included 816 CP afferent to our institution and eligible for the vaccination. A cohort of 274 health care workers (HCW) was used as age- and sex-matched control group. BNT162b2 was administered as a two-dose regimen given 21 days apart. Blood samples to analyze anti-Spike (S) IgG antibodies (Ab) were collected prevaccination [timepoint (TP) 0], and at 3 weeks (TP1) and 7 weeks (TP2) after the first dose. Results: Patients characteristics: median age 62 (range, 21–97); breast/lung cancer/others (31/21/48%); active treatment/follow-up (90/10%). In the whole CP cohort, the serologic response rate (RR) and the titre of anti-S IgG significantly increased across the TPs; at TP2, the responders (IgG >15 AU/mL) were 94.2%. Active chemotherapy and chronic use of steroids were independent predictors of lower RR. Adverse events (AE) after the booster predicted higher likelihood of response (OR, 4.04; 95% confidence interval, 1.63–9.99; P = 0.003). Comparing the matched cohorts, the responders were significantly lower in CP than in HCW at TP1 (61.2% vs. 93.2%) and TP2 (93.3% vs. 100%), while the geometric mean concentration of IgG did not significantly differ at TP2 being significantly lower in CP (23.3) than in HCW (52.1) at TP1. BNT162b2 was well tolerated in CP; severe-grade AEs were 3.5% and 1.3% after the first and second doses, respectively. Conclusions: BNT162b2 assures serologic immunization without clinically significant toxicity in CP. The second dose is needed to reach a satisfactory humoral response.

Aim: The association of tyrosine kinase inhibitors (TKIs) and local radiotherapy in EGFR-mutated non-small-cell lung cancer patients experiencing disease progression under TKIs could be a valid an option. Patients & methods: We included 131 patients experiencing disease progression during first-line TKI. In group A, patients received TKI beyond progression and site(s) of progression were irradiated; in group B, patients remained on TKI alone beyond progression; and group C stopped TKI at first disease progression. Results: Median overall survival resulted longer in group A versus B and C (p

Lung neuroendocrine tumours (LNET) include an extremely heterogeneous group of malignancies, whose spectrum of either morphological or clinical characteristics varies from well-differentiated and indolent to poorly differentiated and fatal diseases. In the last decades, the increase in LNET incidence was probably related to an improvement in diagnostic tools (especially histology and immunohistochemistry) and lung cancer awareness, as well as to the wider diffusion of screening programs.

Patients with cancer have an increased risk of complications from coronavirus disease 2019 (COVID-19) infection, including death, and thus, they were considered as high-priority subjects for COVID-19 vaccination. We report on the compliance with the COVID-19 vaccine of patients affected by solid tumours.Patients with cancer afferent to Medical Oncology 1 Unit of Regina Elena National Cancer Institute in Rome were considered eligible for vaccination if they were receiving systemic immunosuppressive antitumor treatment or received it in the last 6 months or having an uncontrolled advanced disease. The Pfizer BNT162b2 vaccine was proposed to all candidates via phone or during a scheduled visit. The reasons for refusal were collected by administrating a 6-item multiple-choice questionnaire.From 1st March to 20th March 2021, of 914 eligible patients, 102 refused vaccination (11.2%, 95% confidence interval [CI] 9.1-13.2). The most frequent (10%) reasons reported were concerns about vaccine-related adverse events (48.1%), negative interaction with concomitant antitumor therapy (26.7%), and the fear of allergic reaction (10.7%). The refusal rate (RR) after 15th March (date of AstraZeneca-AZD1222 suspension) was more than doubled compared with the RR observed before (19.7% versus 8.6%, odds ratio [OR] 2.60, 95% CI 1.69-3.99; P 0.0001). ECOG-PS 2 was associated with higher RR compared with ECOG-PS 0-1 (OR 2.94, 95% CI 1.04-8.34; P = 0.04). No statistically significant differences in RR according to other clinical characteristics were found.Our experience represents the first worldwide report on the adherence of patients with cancer to COVID-19 vaccination and underlines how regulatory decisions and media news spreading could influence the success of the campaign.

Giving the potential contribute in cancer initiation and progression, lung microbiota represents a promising topic in cancer research, although still unexplored. We performed a systematic literature search to identify clinical studies evaluating lung microbiota composition, its correlation with lung cancer patients' clinico-pathological features and prognosis. Of the identified 370 studies, 21 were eligible and included. Although studies were heterogeneous, lung cancer resulted to be enriched in peculiar microbial communities, with differences in composition and diversity according to clinico-pathological parameters. Few studies explored how lung microbiota influences cancer outcome. In light of these findings and borrowing the suggestions coming from gut microbiota, we speculate that respiratory microbiome may influence pathogenesis, progression and outcome of lung cancer. Taking advantage of the experience of chronical lung diseases, prospective studies should be designed to evaluate lung microbiota changes throughout any phase of lung cancer course, particularly with the advent of immunotherapy as pivotal treatment.

Rapid disease progression of patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) has been recently associated with tumor heterogeneity, which may be mirrored by coexisting concomitant alterations. The aim of this analysis was to investigate the correlation between loss of function of PTEN and the efficacy of tyrosine kinase inhibitors in this population.Archival tumor blocks from patients with EGFR-mutant NSCLC who were administered upfront tyrosine kinase inhibitors were retrospectively collected. The status of 4 genes (PTEN, TP53, c-MET, IGFR) was evaluated by immunohistochemistry, and it was correlated with overall response rate, overall survival (OS), and progression-free survival (PFS).Fifty-one patients were included. In multivariate analysis, PTEN loss (hazard ratio [HR], 3.46; 95% confidence interval [CI], 1.56-7.66; P = .002), IGFR overexpression (HR, 2.22; 95% CI, 1.03-4.77; P = .04), liver metastases (HR, 3.55; 95% CI, 1.46-8.65; P = .005), and Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 1 (HR, 2.57; 95% CI, 1.04-6.34; P = .04) were significantly associated with shorter PFS. Patients with PTEN loss had a median PFS of 6 months (2-year PFS, 11.6%), whereas patients without PTEN loss had a median PFS of 18 months (2-year PFS, 43.6%) (log-rank P .005). In the multivariate analysis, PTEN loss (HR, 5.92; 95% CI, 2.37-14.81; P .005), liver metastases (HR, 2.63; 95% CI, 1.06-6.51; P = .037), and ECOG PS ≥ 1 (HR, 2.80; 95% CI, 1.15-6.81; P = .024) were significantly associated with shorter OS. Patients with PTEN loss had a median OS of 6 months (2-year OS, 12.2%), whereas in patients without PTEN loss, OS was not reached (2-year OS, 63.9%) (log-rank P .0005).A low-cost and reproducible immunohistochemistry assay for PTEN loss analysis represents a potential tool for identifying tumor heterogeneity in patients with advanced EGFR-mutant NSCLC.

BackgroundSingle agent pembrolizumab represents the standard first line option for metastatic non-small-cell-lung-cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%.MethodsWe conducted a multicenter study aimed at evaluating the clinicopathologic correlates of pembrolizumab efficacy in patients with treatment-naïve NSCLC and a PD-L1 TPS ≥ 50%.Results1026 consecutive patients were included. ECOG-PS ≥ 2 (p < 0.0001) and bone metastases (p = 0.0003) were confirmed to be independent predictors of a worse ORR. Former smokers (p = 0.0002), but not current smokers (p = 0.0532) were confirmed to have a significantly prolonged PFS compared to never smokers at multivariate analysis. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a worse PFS. Previous palliative RT was significantly related to a shortened OS (p = 0.0104), while previous non-palliative RT was significantly related to a prolonged OS (p = 0.0033). Former smokers (p = 0.0131), but not current smokers (p = 0.3433) were confirmed to have a significantly prolonged OS compared to never smokers. ECOG-PS (p < 0.0001), bone metastases (p < 0.0001) and liver metastases (p < 0.0001) were also confirmed to be independent predictors of a shortened OS. A PD-L1 expression of ≥ 90%, as assessed by recursive partitioning, was associated with significantly higher ORR (p = 0.0204), and longer and OS (p = 0.0346) at multivariable analysis.Conclusionspembrolizumab was effective in a large cohort of NSCLC patients treated outside of clinical trials. We confirmed that the absence of tobacco exposure, and the presence of bone and liver metastasis are associated with worse clinical outcomes to pembrolizumab. Increasing levels of PD-L1 expression may help identifying a subset of patients who derive a greater benefit from pembrolizumab monotherapy.

Before the introduction of tyrosine kinase inhibitors (TKIs) for a particular subgroup of patients, despite platinum-based combination chemotherapy, the majority of patients affected by non-small-cell lung cancer (NSCLC) did not live longer than one year. With deeper understanding of tumor molecular biology, treatment of NSCLC has progressively entered the era of treatment customization according to tumor molecular characteristics, as well as histology. All this information allowed the development of personalized molecular targeted therapies. A series of studies have shown that, in some cases, cancer cells can grow and survive as result of the presence of a single driver genomic abnormality. This phenomenon, called oncogene-addiction, more often occurs in adenocarcinoma histology, in non-smokers (except BRAF mutations, also frequent in smoking patients), young, and female patients. Several different driver mutations have been identified and many studies have clearly shown that upfront TKI monotherapy may improve the overall outcome of these patients. The greater efficacy of these drugs is also associated with a better tolerability and safety than chemotherapy, with fewer side effects and an extremely good compliance to treatment. The most frequent oncogene-addicted disease is represented by those tumors carrying a mutation of the epidermal growth factor receptor (EGFR). The development of first, second and third generation TKIs against EGFR mutations have dramatically changed the prognosis of these patients. Currently, osimertinib (which demonstrated to improve efficacy with a better tolerability in comparison with first-generation TKIs) is considered the best treatment option for patients affected by NSCLC harboring a common EGFR mutation. EML4-ALK-driven disease (which gene re-arrangement occurs in 3–7% of NSCLC), has demonstrated to be significantly targeted by specific TKIs, which have improved outcome in comparison with chemotherapy. To date, alectinib is considered the best treatment option for these patients, with other newer agents upcoming. Other additional driver abnormalities, such as ROS1, BRAF, MET, RET and NTRK, have been identified as a target mirroring peculiar vulnerability to specific agents. Oncogene-addicted disease typically has a low early resistance rate, but late acquired resistance always develops and therefore therapy needs to be changed when progression occurs. In this narrative review, the state of art of scientific literature about targeted therapy options in oncogene-addicted disease is summarized and critically discussed. We also aim to analyze future perspectives to maximize benefits for this subgroup of patients.

Single-agent pembrolizumab represents the standard first-line option for metastatic non-small-cell lung cancer (NSCLC) patients with a PD-L1 (programmed death-ligand 1) expression of ≥ 50%. We conducted a multicenter retrospective study aimed at evaluating the clinicopathologic correlates of pembrolizumab effectiveness in patients with treatment-naive NSCLC and a PD-L1 expression of ≥ 50%. One thousand and twenty-six consecutive patients were included. The objective response rate (ORR) was 44.5% (95% CI 40.2–49.1), while the median progression free survival (PFS) and overall survival (OS) were 7.9 months (95% CI 6.9–9.5; 599 events) and 17.2 months (95% CI 15.3–22.3; 598 censored patients), respectively. ECOG-PS ≥ 2 (p

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

BackgroundThe association between obesity and outcomes in patients receiving programmed death-1/programmed death ligand-1 (PD-L1) checkpoint inhibitors has already been confirmed in pre-treated non-small cell lung cancer (NSCLC) patients, regardless of PD-L1 tumor expression.MethodsWe present the outcomes analysis according to baseline body mass index (BMI) and BMI variation in a large cohort of metastatic NSCLC patients with a PD-L1 expression ≥50%, receiving first line pembrolizumab. We also evaluated a control cohort of metastatic NSCLC patients treated with first line platinum-based chemotherapy. Normal weight was set as control group.Results962 patients and 426 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Obese patients had a significantly higher objective response rate (ORR) (OR=1.61 (95% CI: 1.04–2.50)) in the pembrolizumab cohort, while overweight patients had a significantly lower ORR (OR=0.59 (95% CI: 0.37–0.92)) within the chemotherapy cohort. Obese patients had a significantly longer progression-free survival (PFS) (HR=0.61 (95% CI: 0.45–0.82)) in the pembrolizumab cohort. Conversely, they had a significantly shorter PFS in the chemotherapy cohort (HR=1.27 (95% CI: 1.01–1.60)). Obese patients had a significantly longer overall survival (OS) within the pembrolizumab cohort (HR=0.70 (95% CI: 0.49–0.99)), while no significant differences according to baseline BMI were found in the chemotherapy cohort. BMI variation significantly affected ORR, PFS and OS in both the pembrolizumab and the chemotherapy cohorts.ConclusionsBaseline obesity is associated to significantly improved ORR, PFS and OS in metastatic NSCLC patients with a PD-L1 expression of ≥50%, receiving first line pembrolizumab, but not among patients treated with chemotherapy. BMI variation is also significantly related to clinical outcomes.

Cytological endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimens of mediastinal lymph node metastasis are frequently used to perform concomitant diagnosis, staging and genetic testing in non-small-cell lung cancer (NSCLC). The purposes of this single-center retrospective study were to evaluate EBUS-TBNA samples’ adequacy for molecular testing of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), and to analyze the concordance between the cell block method and liquid-based cytology (LBC) in appraising the sample cellularity and in detecting EGFR mutation. We retrospectively examined 82 patients who underwent EBUS-TBNA from October 2012 to September 2015 and received a confirmed diagnosis of lymph node metastasis of lung adenocarcinoma. Each sample was processed using both cell block and LBC to carry out DNA analysis (adequacy criterion: tumor cell percentage > 25%) and EGFR mutation testing. Fifty-four patients were male, 66 were current or former-smokers, and the median age was 67 years. The median size of sampled lymph nodes was 14.8 mm. Seventy-one and 66 samples were adequate to perform cell block and LBC, respectively. The κ-statistic (0.78) showed an excellent concordance. EGFR mutation was detected in eight patients using cell block and in seven using LBC, with a simple percentage agreement of 87.5%. ALK translocation was found in two patients. This study demonstrates the feasibility of EGFR mutation analysis with both cell block and LBC, with an excellent concordance between the two methods. Considering that the majority of advanced NSCLCs are diagnosed on cytology specimens, LBC is feasible and needs to be implemented for ancillary tests (immunocytochemistry, molecular analysis).

Over the last decade, epidermal growth factor receptor (EGFR) signaling was investigated as a potential target for tyrosine kinase inhibitors in the treatment of non-small-cell lung cancer (NSCLC). Necitumumab is a fully humanized IgG1 monoclonal antibody directed against the binding domain of EGFR, approved in combination with cisplatin-gemcitabine for the first-line treatment of squamous NSCLC. Areas covered: The purpose of this manuscript is to systematically review the state of the art of necitumumab for the treatment of metastatic NSCLC, focusing on predictive factors, cost-effectiveness, and future potential combinations with additional agents. Expert opinion: Despite recent therapeutic advances, platinum-based chemotherapy still represents the most widely used first-line treatment for advanced NSCLC, particularly for the squamous histotype. Necitumumab is nowadays the first targeted agent providing an (statistically significant) additional survival gain to squamous NSCLC patients when combined with first-line chemotherapy at the cost of an increased (although manageable) toxicity, as shown in the SQUIRE trial. Hopefully, improvement in patients' selection by identifying reliable predictive markers and the combination with new agents may help to maximize the benefit of this targeted treatment, which is currently limited by a not optimal cost-benefit ratio.

Erlotinib is approved for the treatment of patients with EGFR mutation positive, metastatic NSCLC. It is also approved as second/third line therapy for EGFR mutation negative patients, but in this setting the benefit of erlotinib is modest and there is no validated biomarker for selecting EGFR wild-type patients who may benefit the most from the treatment. We retrospectively assessed EGFR and K-RAS mutational status, and EGFR, c-MET and IGF1-R expression in tumor samples of 72 patients with metastatic NSCLC treated with erlotinib after at least one prior line of chemotherapy, from 2008 to 2012. We analyzed the association between biomarkers and outcome (RR, PFS, and OS). EGFR mutated patients achieved a better RR (56% vs 8%, p = .002), PFS (10 vs 3 months, HR 0.53, p = 0.48) and OS (20 vs 6 months, HR 0.55, p = .07), compared to EGFR wild-type patients. Among 63 EGFR wild-type patients, those with EGFR high-expression had a better outcome in terms of RR (40% vs 2%, p = .002), PFS (7.5 vs 2 months, HR 0.45, p = .007) and OS (30 vs 5 months, HR 0.34, p

Background: We present immunogenicity data 6 months after the first dose of BNT162b2 in correlation with age, gender, BMI, comorbidities and previous SARS-CoV-2 infection. Methods: An immunogenicity evaluation was carried out among health care workers (HCW) vaccinated at the Istituti Fisioterapici Ospitalieri (IFO). All HCW were asked to be vaccine by the national vaccine campaign at the beginning of 2021. Serum samples were collected on day 1 just prior to the first dose of the vaccine and on day 21 just prior to the second vaccination dose. Thereafter sera samples were collected 28, 49, 84 and 168 days after the first dose of BNT162b2. Quantitative measurement of IgG antibodies against S1/S2 antigens of SARS-CoV-2 was performed with a commercial chemiluminescent immunoassay. Results: Two hundred seventy-four HWCs were analyzed, 175 women (63.9%) and 99 men (36.1%). The maximum antibody geometric mean concentration (AbGMC) was reached at T2 (299.89 AU/mL; 95% CI: 263.53–339.52) with a significant increase compared to baseline (p < 0.0001). Thereafter, a progressive decrease was observed. At T5, a median decrease of 59.6% in COVID-19 negative, and of 67.8% in COVID-19 positive individuals were identified with respect to the highest antibody response. At T1, age and previous COVID-19 were associated with differences in antibody response, while at T2 and T3 differences in immune response were associated with age, gender and previous COVID-19. At T4 and T5, only COVID-19 positive participants demonstrated a greater antibody response, whereas no other variables seemed to influence antibody levels. Conclusions: Overall our study clearly shows antibody persistence at 6 months, albeit with a certain decline. Thus, the use of this vaccine in addressing the COVID-19 pandemic is supported by our results that in turn open debate about the need for further boosts.

Unresectable or relapsed malignant pleural mesothelioma (MPM) has dismal prognosis. First-line combination therapy with pemetrexed and a platinum analog allows a modest survival benefit, while no clear therapeutic options exist for the second-line therapy. In this setting, pemetrexed seems to be the most active drug; however, the inclusion in front-line treatment limits its use in further lines. Nevertheless, rechallenge with one or both drugs used in first-line remains a feasible strategy for responder patients. Alternatively, only few cytotoxic drugs have demonstrated a mild activity in refractory MPM. Among other options, targeted therapy has unfortunately produced disappointing results as salvage treatment probably due to the lack of a clear understanding of the tumor biology. In contrast, recent data suggest moderate efficacy and mild toxicity of immunotherapy also for the treatment of MPM. The combination of checkpoint inhibitors with chemotherapy or other immunological agents seems promising and could really “raise the bar” in this setting.

Patients affected by non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations derive a dramatic and essential clinical benefit from EGFR tyrosine kinase inhibitors (TKIs) therapy in terms of activity, efficacy and quality of life (1,2). Nevertheless, besides the important therapeutic impact of these targeted agents, EGFR -addicted diseases typically develop resistance under the selective pressure of TKIs, usually within 1 year of treatment.

Lung cancer is one of the deadliest and most common malignancies in the world, representing one of the greatest challenges in cancer treatment. Immunotherapy is rapidly changing standard treatment schedule and outcomes for patients with advanced malignancies. However, several ongoing studies are still attempting to elucidate the biomarkers that could predict treatment response as well as the new strategies to improve antitumor immune system response ameliorating immunotherapy efficacy. The complex of bacteria, fungi, and other microorganisms, termed microbiota, that live on the epithelial barriers of the host, are involved in the initiation, progression, and dissemination of cancer. The functional role of microbiota has attracted an accumulating attention recently. Indeed, it has been demonstrated that commensal microorganisms are required for the maturation, education, and function of the immune system regulating the efficacy of immunotherapy in the anticancer response. In this review, we discuss some of the major findings depicting bacteria as crucial gatekeeper for the immune response against tumor and their role as driver of immunotherapy efficacy in lung cancer with a special focus on the distinctive role of gut and lung microbiota in the efficacy of immunotherapy treatment.

Aim: With the final aim to explore the first-line treatment options for non-small-cell lung cancer (NSCLC) patients, we performed a systematic review and literature-based meta-analysis of available clinical trials exploring immunotherapy in combination versus standard histology-based chemotherapy. Materials & methods: We evaluated interactions according to type of treatment-add-on strategy: immunotherapy in combination versus standard chemotherapy-based regimens. Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS) were extracted and cumulated. Results: Seven trials (4278 patients) were included. The addition of immunotherapy to standard chemotherapy-based regimens significantly increased OS (HR 0.74; p = 0.001) and PFS (HR 0.61; p

9598 Background: Identifying the patients who may benefit the most from immune checkpoints inhibitors remains a great challenge for clinicians. The tumor-derived Serum Amyloid A (SAA) inhibits the immune-response in melanoma patients. Here we present the early results of FoRECATT study investigating on blood SAA as biomarker of response to upfront pembrolizumab in patients with advanced non-small-cell lung cancer (NSCLC). Methods: In this prospective study, patients with PD-L1 ≥ 50% receiving upfront pembrolizumab (P cohort) and with PD-L1 0-49% treated with chemotherapy (CT cohort), were evaluated for blood SAA and radiological response at baseline and every 9 weeks. Primary endpoint was response rate (RR) according to Response Evaluation Criteria in Solid Tumors 1.1; secondary endpoints were progression-free (PFS) and overall survival (OS). The most accurate SAA cut-off to predict response was established with ROC-analysis in the P cohort. Results: In the P Cohort (n = 42), the overall RR was 38%. After a median follow-up of 18.5 months (mo), baseline SAA ≤ the ROC-derived cut-off (29.9 mg/L; n = 14/42, 33%) was significantly associated with higher RR (53.6 versus 7.1%; OR 15, 95%CI 1.72-130.7, P= 0.009), longer PFS (17.4 versus 2.1 mo; P< 0.0001) and OS (not reached versus 7.2 mo; P< 0.0001) compared with SAA > 29.9 mg/L. In multivariate analysis, low SAA positively affects PFS ( P= 0.001) and OS ( P= 0.048) irrespective of ECOG PS, number of metastatic sites and pleural effusion. SAA monitoring (n = 40) was also significantly associated with survival endpoints: median PFS 17.4 versus 2.1 mo and median OS not reached versus 7.2 mo when SAA remained low (n = 14) and high (n = 12), respectively. In the CT Cohort (n = 30), RR was not significantly affected by SAA level, while low SAA at baseline (n = 17) was associated with better PFS (HR = 0.42, 95%CI 0.16-1.10, P= 0.02) and OS (HR = 0.16, 95% CI 0.04-0.55, P= 0.0004). Conclusions: Low SAA predicts a higher likelihood of response to upfront pembrolizumab only and good survival outcomes irrespective of treatment in advanced NSCLC patients. Therefore, a simple blood test might be useful to identify patients likely to derive better outcomes from immunotherapy. A further study (FoRECATT-2) is ongoing to confirm the results in a larger validation cohort and to assess the potential effect of SAA on immune response in vitro assays.

This paper has been written because we have a differing idea concerning the suspected negative interference between oxaliplatin and anti-EGFR therapies in cancer patients. Several multicenter, randomized, controlled clinical trials investigated whether the efficacy of oxaliplatin-based chemotherapy is improved by the addition of anti-EGFR therapies in patients affected by KRAS wild-type advanced colorectal cancer. Results of these trials have produced puzzling findings, with some studies demonstrating improved survival and other studies showing no differences in overall survival between experimental and control arms. Moreover, a detrimental effect has been demonstrated in some settings. Nevertheless, the extent of this interaction remains uncertain. Some physicians proposed personal interpretations. This paper describes our hypothesis.

Background Common epidermal growth factor receptor (EGFR) mutations in non–small-cell lung cancer (NSCLC) predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs), with exon 19 deletions being associated with better outcome compared to L858R mutations. We aimed to investigate the impact of different exon 19 deletions on patient outcome in EGFR-mutant NSCLC treated with first-line TKIs. Patients and Methods In this retrospective analysis, 106 patients with metastatic NSCLC harboring EGFR exon 19 deletions and treated with first-line TKIs were included. The primary end point was overall survival (OS), the secondary end point progression-free survival (PFS). Analyses were performed by grouping exon 19 deletions according to 2 models: we compared different type of deletion (delE746_A750 vs. deletions other than delE746-A750, defined as “uncommon”) or different starting codon of deletion (E746 vs. L747). Results The frequency of uncommon deletions of exon 19 was 36%. When delE746_A750 (n = 68) was compared to the other deletions in exon 19 (n = 38), no differences were found, either in terms of OS (P = .65) or PFS (P = .65). Similarly, no difference in OS (P = .74) or PFS (P = .99) emerged when comparing the E746 group (n = 81) to the L747 group (n = 25). On multivariate analysis including clinical characteristics and type of deletions (delE746_A750 vs. uncommon deletions or E746 vs. L747), only the presence of brain metastases at diagnosis or during TKI treatment was associated with shorter PFS but not with worse OS. Conclusion Different exon 19 deletions are equally sensitive to first-line EGFR-TKIs in EGFR-mutant NSCLC.

The RAINBOW Phase III study established the efficacy of the combination of paclitaxel and ramucirumab, a monoclonal antibody targeting VEGF receptor-2 (VEGF-R2), as second-line therapy. We retrospectively analyzed the data of patients treated with ramucirumab plus paclitaxel at our Institution to evaluate the impact of clinical heterogeneous figures on the efficacy and safety of this combination paclitaxel/ramucirumab in a real- life cohort of patients. After a median follow-up of 10.74 months, the median progression-free survival (PFS) was 5.8 months (95% CI: 3.04 - 5,63). Disease control rate (DCR) was 61% and the median duration of response (DOR) was 5.8 months. Median overall survival (OS) was 8.3 months. A trend toward better outcome was observed in HER2 positive patients. In multivariate analysis, nutritional status (p = 0.0001) and number of metastatic sites (p = 0.0266) resulted significantly related with longer PFS. Our analysis confirmed the efficacy and safety of the combination of ramucirumab with paclitaxel also in the real-life practice and the median PFS is significantly longer than that reported for Western population in previous studies. Subgroup analysis confirms the key-role of nutritional status as prognostic factor and suggests a possible interaction between EGF and angiogenesis pathways that deserves further investigations.

Aim: This single institution Phase II study evaluated drug-eluting beads loaded with irinotecan (DEBIRI) plus capecitabine in pretreated patients with colorectal cancer liver metastases. Patients & methods: Forty patients with liver-limited or liver-dominant disease, who have failed at least two previous lines of chemotherapy, underwent either four DEBIRI at 2-week interval or two DEBIRI every 4 weeks for bilobar or single-lobe metastases, respectively. Capecitabine was given at 1000 mg/m2 twice-daily on days 1–14 every 3 weeks. Results: Seven partial responses and 12 stable diseases were observed, achieving a disease control rate of 47.5%. Median progression-free survival and overall survival resulted 4 and 8 months, respectively. Grade 3 adverse events occurred in 6/40 points (15%) of patients. Conclusion: DEBIRI plus capecitabine is a valid treatment option for heavily pretreated patients with colorectal cancer liver metastases.

To compare transfemoral approach (TFA) and transradial approach (TRA) in patients undergoing hepatic chemoembolization in terms of safety, feasibility, and procedural variables, including fluoroscopy time, radiation dose (reference air kerma [RAK]), and patient preference.A single-center prospective intrapatient comparative study was conducted with 42 consecutive patients with hepatic malignancies who received 2 consecutive treatment sessions of unilobar hepatic chemoembolization within a 4-week interval over a 6-month period with both TRA and TFA. All procedures were performed by 1 interventional radiologist who assessed the eligibility of patients for inclusion in the study. The primary endpoint was intraprocedural conversion rate. Secondary endpoints were access site complications, angiographic and procedural variables, and evaluation of patient discomfort and preferences.A 100% technical success rate and a crossover rate of 0% were recorded. There were no major vascular complications and similar rates of minor complications (4.8% for TRA, 7.1% for TFA; P = .095), which were self-limited and without any clinical sequelae. TRA treatments required a significantly longer preparation time for the procedure (P = .008) with no significant differences for other procedural variables. Greater discomfort at the access route and patient inability to perform basic activities after the procedure were recorded for TFA (P.001). TRA was preferred by 35 patients (35/42) for potential future transarterial procedures.TRA is safe and feasible for transarterial hepatic chemoembolization, with high technical success, low overall complications, and improved patient comfort.

Oesophageal gastrointestinal stromal tumors (GISTs) are rare neoplasms (about 2% of all GISTs); radical surgery is the standard treatment of all GISTs but in case of locally advanced and unresectable disease no clear treatment guide lines are available. Studies including neoadjuvant imatinib mesylate (IM) are relatively recent, includes small sample size of heterogeneous patients and do not report a standardized duration of neoadjuvant treatment. The main question still remains whether surgery after neoadjuvant IM gives a survival benefit in locally advanced disease. A 46-year-old man with locally advanced unresectable oesophageal GIST harboring KIT exon 11 mutation was treated in our institution for 12 months with neoadjuvant IM; a reduction of 83% of tumor volume was obtained in 9-month of neoadjuvant IM, but in the last 3 months no further response was seen. After neoadjuvant therapy, patient underwent radical surgery and adjuvant IM, which is still ongoing. Since no definitive data are available about survival benefit of surgery after neoadjuvant IM in locally advanced GISTs, a careful balance between morbidity and mortality derived from surgery should be considered and more studies are needed to better define the utility and the optimal duration of neoadjuvant treatment.

// Sabrina Rossi 1 , Ettore D’Argento 1 , Giovanni Schinzari 1 , Vincenzo Dadduzio 1 , Vincenzo Di Noia 1 , Alessandra Cassano 1 and Carlo Barone 1 1 Department of Medical Oncology, Catholic University of Sacred Heart, Largo A. Gemelli, Rome, Italy Correspondence to: Ettore D’Argento, email: // Keywords : gefitinib; afatinib; elderly; concomitant medications; efficacy; Gerotarget Received : March 17, 2016 Accepted : April 22, 2016 Published : May 17, 2016 Abstract Background: Epidermal Growth Factor Receptor (EGFR) tyrosine-kinase inhibitors (TKIs) have changed treatment strategies for patients with advanced non-small-cell lung cancer (NSCLC) harbouring mutations in EGFR gene. This retrospective analysis assessed efficacy and safety of TKIs in elderly compared to younger patients. Patients and methods: 49 patients with advanced NSCLC and mutations in exon 19 or 21 receiving a first-line therapy with TKIs were included and divided into patients aged

e20608 Background: Common Epidermal Growth Factor Receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict sensitivity to EGFR tyrosine-kinase inhibitors (TKIs), with exon 19 deletions being associated with better outcome when compared to L858R mutations. We aimed to investigate the impact of different exon 19 deletions on patient outcome in EGFR-mutant NSCLC treated with first-line TKIs. Methods: In this retrospective analysis we included 98 patients with metastatic NSCLC and EGFR exon 19 deletions, treated with first-line EGFR TKIs (gefitinib or afatinib) in 3 Italian centers between 2011 and 2016. The primary endpoint was overall survival (OS), the secondary endpoint progression free survival (PFS). Analyses were performed by grouping exon 19 deletions according to two different models: type of deletion (delE746-A750 vs other) and starting codon of deletion (E746 vs L747). Kaplan-Meier method, the log-rank test and multivariate Cox regression models were used to estimate survival outcomes. Median follow-up time was 40 months. Results: All groups resulted well balanced in terms of patients’ characteristics but the percentage of patients treated with gefitinib was significantly superior in E746 group compared to L747 (p = 0.02). In the whole cohort median OS was 24.6 months [95%CI 21.9 – 33.1] while median PFS was 13.7 months [95%CI 11.6 – 15.9]. When delE746-A750 (n = 60) was compared to the other deletions in exon 19 (n = 38), no differences were evidenced either in terms of OS (24.1 vs 26.0 months; HR 0.80 [95%CI 0.5 – 1.4]; p = 0.42) or PFS (13.9 vs. 12.8 months; HR 0.99 [95%CI 0.6 – 1.6]; p = 0.97). Similarly, no difference in OS or PFS emerged comparing E746 (n = 73) versus L747 group (n = 25) (OS:24.6 and 26.0 months, respectively, HR 0.79 [95%CI 0.4 – 1.4; p = 0.45; PFS 13.9 vs 12.9 months, respectively (HR 0.87 [95%CI 0.5 – 1.4] p = 0.57). On multivariate analysis including age, sex, smoking history, deletions (delE746-A750 vs others or E746 vs L747), presence of brain metastases at diagnosis or during TKI treatment, no variable resulted associated with longer OS or PFS. Conclusions: Different exon 19 deletions are equally sensitive to first-line EGFR TKIs in EGFR-mutant NSCLC.

e20662 Background: Continuation of EGFR TKIs with or without local ablative treatments in patients with metastatic EGFR-mutant NSCLC experiencing disease progression under TKIs is feasible and may be associated with improved outcomes. Methods: The retrospective analysis includes 130 patients with advanced EGFR-mutant NSCLC experiencing RECIST disease progression under first-line gefitinib or afatinib, treated in 3 Italian centers between 2011 and 2016. In group 1 (n = 99, 76.2%) patients stopped TKI treatment at first RECIST-confirmed progression while in group 2 (n = 31, 23.8%) TKIs were continued and sites of progression were irradiated. The primary endpoint was overall survival (OS). Progression-free survival (PFS) and time to treatment failure (TTF) were calculated from the start of first-line TKIs. Kaplan-Meier method, the log-rank test and multivariate Cox regression models were used to estimate outcome endpoints. Median follow-up time was 40 months. Results: Median OS, PFS and TTF in the whole cohort were 22.4, 11.1 and 13.0 months, respectively. The two groups resulted well balanced in terms of patients’ characteristics and TKI administered. Median OS was significantly longer in group 2 (37.3 vs 15.6 months; HR 0.33; 95%CI 0.22-0.50; p < 0.0001), as well as median PFS (13.8 vs 8.9 months; HR 0.60; 95%CI 0.42-0.86; p = 0.01) and median TTF (29.3 vs 10.4 months; HR 0.30; 95%CI 0.21-0.44; p < 0.0001). Ten out of 31 (32.3%) patients underwent radiotherapy in ≥2 sites of progressive disease; the most frequently irradiated site was bone (n = 16), followed by brain (n = 9), lung (n = 8) and lymph nodes (n = 6). On multivariate analysis including age, sex, smoking history, mutant exon, presence of brain metastases, TKI administered and treatment strategy at progression, only TKI continuation with radiotherapy was independently associated with all outcome endpoints (OS: p = 0.0007, PFS: p = 0.004; TTF: p < 0.0001). Conclusions: In EGFR-mutant NSCLC progressing under first-line TKIs continuation of TKI in association with local ablative radiotherapy is associated with prolonged OS, PFS and TTF. Whether the improved outcome is a result of treatment strategy or more indolent disease remains unclear.

e15155 Background: Biliary tract cancers (BTC) are composed by a heterogeneous and rare group of malignant tumors with poor prognosis. Surgical resection is the only potentially curative treatment....

e17577 Background: Cancer patients (pts) present often with acute syndromes requiring an urgent management. This scenario has dramatically changed during the last years due to the higher prevalence...

724 Background: Treatment options for metastatic colorectal cancer (mCRC) patients refractory to chemotherapy are limited and clinical outcome is poor. In mCRC patients with liver-dominant disease hepatic locoregional therapy might be a treatment option. In this pilot study we evaluated the safety, tolerance, and efficacy of drug-eluting beads irinotecan (DEBIRI) in combination with capecitabine in the treatment of patients with mCRC with predominally liver disease. Methods: Twenty patients affected by liver metastasis of colorectal cancer were included in this study. All patients had progression of disease after two or more lines of chemotherapy and liver was the major or the predominant site of disease. DEBIRI, beads loaded with 100 mg irinotecan, was administered biweekly via hepatic artery. All patients assumed capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks, until disease progression. Primary endpoints were safety, tolerance and overall responce rate (ORR); secondary endpoints were progression free servival (PFS) and overall survival (OS). Results: Twenty patients underwent a total of 54 DEBIRI treatments of the 66 planned; the median number was 3 (range 2-4) administrated for patients. Grade 1-2 toxic effects included fatigue (70%), diarrhea (45 %), anemia (45%), elevated liver enzymes (45%), nausea (40%), neutropenia (35%) and thrombocytopenia (25%). One grade 3 diarrhea and a case of acute vasospastic angina were observed and required patient hospitalization, but no deaths at 30 days post occurred. Two partial responses were reported (10%) with ORR of 60%. PFS and OS were 4 and 7, 3 months respectively. Univariate analysis showed that patients with KRAS wild-type, good ECOG performance status and single lobe metastases have a better prognosis. Multivariate analysis confirmed that only the good clinical conditions represent an important positive prognostic factor (p=0.03). Conclusions: DEBIRI with capecitabine seem to be a safe, technically feasible and well-tolerated treatment in chemotherapy refractory mCRC with prevalently liver metastases. It has a moderate but not negligible activity in this heavily treated group of patients and deserves further studies in a larger series.