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

Lay abstract Extended-stage small-cell lung cancer (ES-SCLC) is a highly aggressive lung cancer subtype, accounting for 13-15% of all lung cancers. For several years, the standard treatment for this disease was based on polychemotherapy, with a rapid disease response but with an equally rapid disease progression. The new standard treatment has recently been changed, based on the results of two large clinical trials, which showed the efficacy and safety of the combination of chemotherapy with immunotherapy compared to chemotherapy alone. Nevertheless, prognosis of ES-SCLC remains poor, and new treatment strategies are urgently needed. Therefore, we designed the CeLEBrATE trial to investigate whether the combination of chemotherapy with antiangiogenetic therapy and immunotherapy is safe and could improve survival in patients with ES-SCLC.Based on improved survival from the addition of PD-L1 inhibitors in phase III trials, the combination of immunotherapy and platinum-doublet chemotherapy has become the new standard treatment for extended-stage small-cell lung cancer (ES-SCLC). Furthermore, the antiangiogenetic agent bevacizumab showed a longer progression-free survival by targeting VEGF that has pleiotropic effects, including immunosuppressive ones. We, therefore, hypothesized that targeting angiogenesis would improve the efficacy of chemoimmunotherapy. The CeLEBrATE trial is an open-label, multicenter, phase II study designed to assess the efficacy and safety of the combination of carboplatin and etoposide plus bevacizumab and atezolizumab in treatment-naive patients with ES-SCLC. The primary end point is overall survival rate at 1 year, while secondary end points include overall response rate, progression-free survival and toxicity.

Immune checkpoint inhibitors (ICIs) can elicit toxicities by inhibiting negative regulators of adaptive immunity. Sometimes, management of toxicities may require systemic glucocorticoids. We performed a systematic review and meta-analysis of published studies to evaluate the correlation between steroids use, overall survival (OS), and progression-free survival (PFS) in cancer patients treated with ICIs. Publications that compared steroids with non-steroid users in cancer patients treated with ICIs from inception to June 2019 were identified by searching the EMBASE, PubMed, SCOPUS, Web of Science, and Cochrane Library databases. The pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Patients (studies, n = 16; patients, n = 4045) taking steroids were at increased risk of death and progression compared to those not taking steroids (HR = 1.54, 95% CI: 1.24−1.91; p = 0.01 and HR = 1.34, 95% CI: 1.02−1.76; p = 0.03, respectively). The main negative effect on OS was associated with patients taking steroids for supportive care (HR = 2.5, 95% CI 1.41−4.43; p < 0.01) or brain metastases (HR = 1.51, 95% CI 1.22−1.87; p < 0.01). In contrast, steroids used to mitigate adverse events did not negatively affect OS. In conclusion, caution is needed when steroids are used for symptom control. In these patients, a negative impact of steroid use was observed for both OS and PFS.

Immune-related adverse events (irAEs) are autoimmune-toxic effects associated with immune checkpoint inhibitors (ICIs) used for the treatment of advanced solid tumors. We performed a systematic review and meta-analysis of the published literature to assess the outcome for cancer patients treated with ICIs who develop irAEs. Two independent reviewers selected prospective or retrospective studies from PubMed, EMBASE, and the Cochrane Library database from their inception to November 2018. Data were pooled using hazard ratios (HRs) for overall survival or progression-free survival or odds ratio for overall response rate of irAEs versus no irAEs according to fixed or random-effect model. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. A total of 30 studies that included a total of 4324 patients treated with ICIs were selected. Patients who developed irAEs presented a reduced risk of death [HR=0.49, 95% confidence interval (CI): 0.38-0.62; P

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

Background: During COVID pandemic, many cancer patients (pts) refused to come to hospital, suspending therapies, with ominous consequences. Based on positive (+) results of DOMONCOVID, our homecare project for COVID+ cancer pts, we created a new model of assistance, ONCOHOME, delivering cancer care at home to immune-compromised pts. We aim to provide data on feasibility, efficacy and costs of this innovative model. Methods: ONCOHOME is a multicenter project involving 3 Cancer Center (CC) of the North of Italy: National Cancer Institute, San Raffaele in Milan and Cremona CC. We created an organizational homecare model based on a medical and nursing team with a car equipped for home visits and a secretariat managing patient calls, with a dedicated phone number. The team administers cancer care at home and provides pts with the same assistance usually delivered in hospital. Patient-reported outcome (PRO) assessment is performed. Results: From August 3rd 2020 to May 5th 2021, 79 cancer pts were assisted at home by Cremona team, receiving oral (62 pts), subcutaneous (10pts) or intravenous therapy (7 pts). All types of cancer were included. 77% of pts had a metastatic disease, 88% had a PS ECOG 0-1. Median duration of assistance was 126 days [range 2-270 days]. Most of the pts received oral chemotherapy (41pts). TKIs (25 pts), hormonal therapy (12 pts), supportive care with denosumab and zolendronic acid (5 pts ) and immunotherapy (1 patient, pt) were successfully administered at home, too. 13 pts required hospitalization due to clinical complications. In this group, only 2 pts were admitted to hospital due to severe toxicity;in particular, 1 pt treated with trifluridin/tipiracil developed febrile neutropenia and 1 pt treated with gefitinib reported Grade 3 diarrhea. Both pts were discharged and continued to be assisted at home. Conclusions: ONCOHOME showed that inpatient or outpatient cancer drug administration could be successfully replaced by home administration, for appropriate therapies and selected pts. This model is feasible at an affordable cost. The project is ongoing, planning to accrue other 100 pts for each center. ONCOHOME will be implemented with electronic devices for PRO evaluation, certified telemedicine service and non-invasive wearable smart tissue monitoring physiological parameters devices. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

Background: Cancer patients (pts) have higher risk of serious COVID-19 symptoms, morbidity and mortality than general population. SARS-CoV-2 vaccine trials excluded patients with metastatic cancer or undergoing immunosuppressive therapies;therefore, the effectiveness of vaccines are unknown in this population. Hence, there is an urgent need to understand the correlation between cancer type, its treatment and vaccine efficacy. Trial design: Methods: This is a prospective study conducted by the Oncology Unit of Cremona (Cr) Hospital, enrolling pts from Oncology, Hematology, Radiotherapy (RT) and Palliative Care divisions. The trial aims to evaluate effectiveness of mRNA vaccines [BNT162b2 (Pfizer) and mRNA-1273 (Moderna)], incidence of symptomatic COVID-19 infection, antibodies (Abs) response and onset of adverse events (AEs) in a consecutive population of 300 cancer pts, undergoing antiblastic therapies, starting from March 2021. A vaccination point was set up by Cr Hospital, dedicated to cancer pts treated with chemotherapy (CT), TKIs, RT, hormones. Only pts in follow-up or treated with adjuvant hormone are excluded. CT was suspended at least 5 days before and 3 days after vaccination;targeted therapy, immunotherapy and RT are not interrupted. Primary endpoint: Number of symptomatic pts affected by COVID-19, diagnosed 7-60 days after the 2nddose of vaccines. The infection is defined according to the FDA criteria combined with a positive nasopharyngeal swab. Secondary endpoints: Abs variation at different timepoints compared to baseline;vaccine-related adverse events;duration of abs, up to 12 months after 2nd dose;correlation between effectiveness of vaccines and antiblastic treatments, tumor burden, PS ECOG. Statistical analysis: The primary objective will be tested by non-inferiority one-single proportion test, compared with the value of 95% observed in the vaccine registration trials. The hypothesis of vaccine inferiority in the trial population is rejected if a rate of protection conferred by the vaccine is observed in 89% of the sample size. Results Preliminary results will be available in July 2021. Clinical trial identification: NCT04878796. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.

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

Background: At the last update of the TERAVOLT registry, patients with thoracic malignancies and COVID-19 showed a high mortality rate (35.5% overall and 31% due to COVID-19) compared to the general population and to other solid tumors. Major determinants of mortality were age, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), and previous administration of chemotherapy. No cancer-specific data are available with respect to small-cell lung cancer (SCLC) and other rare thoracic malignancies. Methods: TERAVOLT is an international, multicenter observational registry launched to collect data on patients with thoracic malignancies diagnosed with COVID-19 infection. Risk factors for hospitalization and mortality were identified by Wilcoxon rank sum tests (continuous variables) or χ2 tests (categorical variables). Here we present the subgroup analyses of SCLC and other rare thoracic malignancies, including malignant pleural mesothelioma (MPM), thymic carcinoma/thymoma, and carcinoid/neuroendocrine lung tumors. Results: As of June 4th, 2020, a total of 581 patients with COVID-19 and thoracic cancers have been entered; among them, 66 (11%) were SCLC, 22 (4%) were MPM, 18 (3%) were thymic carcinoma/thymoma, 12 (2%) were carcinoid/neuroendocrine lung tumors, and 442 (76%) NSCLC; 21 were an unknown type. Among SCLC patients, 54% were > 65 years old, 56% were males, 98% were current/former smokers, 31% had an ECOG-PS ≥ 2, 67% had stage IV disease, 82% were on current oncologic treatment at the COVID-19 diagnosis, and 58% were receiving chemotherapy alone or in combination with immune checkpoint inhibitors. Among other non-NSCLC patients, 56% were > 65 years old, 56% were males, 69% were current/former smokers, 24% had an ECOG-PS ≥ 2, 50% had stage IV disease, 52% were on current oncologic treatment at the COVID-19 diagnosis, and 37% were receiving chemotherapy alone or in combination with immune checkpoint inhibitors. Overall, 79.7% of the patients required hospitalization, 15.4% were admitted to an ICU, and 39.8% died (36.2% due to COVID-19). Among SCLC patients, 74.2% required hospitalization, 14.3% were admitted to an ICU, and 42.2% died (37.5% due to COVID-19). Among SCLC patients, age > 65 years old (p=0.81), gender (p=0.71), smoking status (p=1.0), ECOG-PS ≥ 2(p=0.17), disease stage of IV (p=0.37), and having received chemotherapy alone or with checkpoint inhibitors (p=0.84) were not associated with mortality. Conclusions: This analysis confirmed that patients with thoracic malignancies have a high mortality and risk for hospitalization due to COVID-19 overall. SCLC patients showed the highest mortality rate among thoracic cancer patients. Citation Format: Alessio Cortellini, Anne-Marie C. Dingemans, Oscar Arrieta, Javier Baena, Matteo Brighenti, Enriqueta Felip, Marina Chiara Garassino, Pilar Garrido, Carlo Genova, Federica Grosso, Leora Horn, Li-Ching Huang, Jan Van Meerbeeck, Solange Peters, Ernest Nadal, Jacobo Rogado, Yu Shyr, Marcello Tiseo, Valter Torri, Annalisa Trama, Heather Wakelee, Jennifer G Whisenant, Giuseppe Viscardi, Fabrice Barlesi, Sanjay Popat. Thoracic cancers international COVID-19 collaboration (TERAVOLT): Small-cell lung cancer and other rare thoracic malignancies [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S12-03.

Background/Aim: The TArceva and docetaxeL In former-Smokers MAle patients with recurrent non-small cell lung cancer (TALISMAN) phase II, open-label randomized trial evaluates the combination of erlotinib with docetaxel in the second-line therapy of ex-smoker males with advanced squamous non-small cell lung cancer (NSCLC). Patients and Methods: Patients received erlotinib 150 mg/day (arm A; n=36) or docetaxel 75 mg/m2 on day 1 of each 3-week cycle and erlotinib 150 mg/day on days 2-16 of each cycle (arm B; n=38). The primary end-point was progression-free rate (PFR) at 6 months. Results: The study was prematurely interrupted due to slow enrolment. Three (8.3%) patients in arm A and 3 (8.1%) in arm B remained progression-free at 6 months. Median progressionfree survival (PFS) was 2.3 months in arm A and 2.8 months in arm B. Median overall survival (OS) was 5.6 and 8.9 months, respectively. Overall, 77.8% of patients in arm A and 89.2% in arm B experienced treatment-related adverse events (AEs). Conclusion: Results do not support further investigation of the combination of erlotinib and docetaxel in this setting Background/Aim: The TArceva and docetaxeL In former-Smokers MAle patients with recurrent non-small cell lung cancer (TALISMAN) phase II, open-label randomized trial evaluates the combination of erlotinib with docetaxel in the second-line therapy of ex-smoker males with advanced squamous non-small cell lung cancer (NSCLC). Patients and Methods: Patients received erlotinib 150 mg/day (arm A; n=36) or docetaxel 75 mg/m2 on day 1 of each 3-week cycle and erlotinib 150 mg/day on days 2-16 of each cycle (arm B; n=38). The primary end-point was progression-free rate (PFR) at 6 months. Results: The study was prematurely interrupted due to slow enrolment. Three (8.3%) patients in arm A and 3 (8.1%) in arm B remained progression-free at 6 months. Median progressionfree survival (PFS) was 2.3 months in arm A and 2.8 months in arm B. Median overall survival (OS) was 5.6 and 8.9 months, respectively. Overall, 77.8% of patients in arm A and 89.2% in arm B experienced treatment-related adverse events (AEs). Conclusion: Results do not support further investigation of the combination of erlotinib and docetaxel in this setting.

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

Background Patients with anaplastic lymphoma kinase rearranged (ALK+) non-small cell lung cancer (NSCLC) have a higher risk of developing brain metastases (BMs) than patients with other NSCLC sub-types. ALK inhibitors have activity in BMs due to ALK+ NSCLC. We performed a systematic review of the literature with the aim of assessing the efficacy of ALK inhibitors on BMs. Material and methods A systematic search of the literature was performed using the databases Pubmed, EMBASE, Web of Science, The Cochrane Library, and SCOPUS. Relevant publications reporting activity of ALK inhibitors in NSCLC BMs were retrieved. Data were pooled using the number of events/number of evaluable patients according to fixed or random effect models. Intracranial tumour response was assessed through overall response rate (ORR), disease control rate (DCR: ORR + stable disease rate), median progression-free survival (PFS), and overall survival (OS). The primary endpoint was intracranial overall response rate (IC ORR). Results A total of 1,016 patients with BMs from 21 studies were analysed. In patients receiving ALK inhibitors in the first line setting, the pooled IC ORR was 39.17% (95%CI 13.1–65.2%), while the pooled IC ORR observed in further lines was 44.2% (95%CI 33.3–55.1%). Intracranial disease control rate (IC DCR) was 70.3% and 78.2% in naive and pre-treated patients, respectively. Patients who had not received brain radiation attained an IC ORR of 49.0%. Conclusions Based on these data, ALK inhibitors are effective in both naive and pre-treated patients with similar IC ORR and IC DCR, irrespective of the line of therapy.

BACKGROUND: Cytidine deaminase (CDA) plays a crucial role in the degradation of gemcitabine. In our previous retrospective study, CDA enzymatic activity was the strongest prognostic biomarker of the activity and efficacy of platinum/gemcitabine combinations. The aim of this prospective study was to validate the prognostic role of CDA activity in the first-line treatment of advanced non-small-cell lung cancer.METHODS: A total of 124 untreated patients received standard doses of platinum/gemcitabine. CDA activity was baseline measured in plasma samples by spectrophotometric assay.RESULTS: Using the median CDA level as cut-off, in the patients with high versus low CDA activity the response rate was 25.0% (95% CI, 14.7-37.8) and 54.1% (95% CI, 40.8-66.9), P = 0.0013; the 6-month progression rate was 34.5% (95% CI, 22.6-46.6) and 54.1% (95% CI, 40.9-65.6), HR = 2.01 (95% CI, 1.32-3.06), P CONCLUSIONS: This study validated prospectively the prognostic role of the CDA activity and should prompt larger and adequately designed randomised prospective studies to establish the predictive impact of this test in improving the outcome of selected patients.

Clinicopathologic and molecular characteristics of non–small-cell lung cancers (NSCLCs) associated with a strong expression of programmed death ligand 1 (PD-L1+ in > 5% of cells) have not been well elucidated. Expression of PD-L1 is a poor prognostic factor, but NSCLCs with higher levels of PD-L1 have greater benefit when treated with immunotherapy. We have performed a systematic review to synthesize the available evidence regarding clinicopathologic and molecular variables associated with PD-L1 expression in NSCLC. PubMed, EMBASE, SCOPUS, Web of Science and Cochrane Library databases were searched for relevant articles assessing predictors of PD-L1 expression in > 5% cells. Data were reported as odds ratio (OR) of events. Fifty-two studies (for a total of 5066 PD-L1+ out of 13,279 NSCLC patients) were included in this meta-analysis. Factors associated with PD-L1 expression were: smoking status (OR 5.48; 95% confidence interval (CI) 2.8-10.4; P 5% cells. Expression of PD-L1 is more common in male smokers, with adenocarcinoma histology and not carriers of EGFR/ALK/ROS/KRAS mutations. These data could be useful to screening of PD-L1 expression and to select patients for immunotherapy.

e14130 Background: irAEs are autoimmune-toxic effects associated with ICIs used for treatment of advanced solid tumors. The correlation of these irAEs with survival is presently unknown. The objective of this meta-analysis is to assess the outcome of cancer patients treated with ICIs who develop irAEs. Methods: Two independent reviewers selected prospective or retrospective studies from PubMed, EMBASE, and the Cochrane library database from their inception to November 2018. Studies were selected if: 1) they reported correlation of irAEs (any) with outcome, 2) they included patients with solid tumors; 3) they included treatment with anti-PD-(L)1 or anti-CTLA-4 agents, 4) patients had no previous history of autoimmune disorders, 5) they were published in English language, and 6) they provided availability of adequate data to calculate hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs). Data were pooled using HRs for overall survival (OS) or progression-free survival (PFS) or ORs for overall response rate (ORR) of irAEs vs no irAEs according to fixed or random effect model. HRs for OS (the primary outcome measure) were pooled to provide an aggregate value. Hazard ratio for PFS and ORs for ORR were secondary endpoints. Results: A total of 29 studies for a total of 4242 patients treated with ICIs were selected. Patients who developed irAEs presented a reduced risk of death (HR = 0.52, p < .001). Similarly, the occurrence of irAEs was associated with a reduced risk of progression (HR = 0.51, p < .001). The combined odds of response was 4.87 (p < .001). Conclusions: In patients treated with ICIs, irAEs predict survival and response. Although this correlation cannot be fully explained, it may be related to the strongest T cell activation. Patients showing any form of irAEs can be informed about the positive prognostic effect, and physicians can detect patients with favorable outcome to ICIs.

e16023 Background: Currently, cisplatin, gemcitabine, paclitaxel (CGP) and MVAC are the most active chemotherapy regimens in mUC. We tested the hypothesis that two sequential non-cross-resistant, dose-dense (DD) regimens may target different cancer cells, avoid drug resistance, and improve response rate. Methods: This is a single institution, explorative trial. The aim is to evaluate the incremental benefit of the two regimens in terms of complete response and long term survival. We treat all consecutive, chemo-naïve mUC patients with 4 cycles of CGP dose-dense every 14 days followed by 4 cycles of MVAC every 14 days. In all cycles we used Pegfilgrastim 6 mg on day 3. Pts were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for 2 years and 6 months thereafter. Results: From 2007 to 2018, 67 consecutive pts were included. Male were 82%; median age 66 years (33-83); Bajorin risk factors was 0 in 31%, 1 in 52%, 2 in 16%. The majority of pts were hospitalized for three days during chemotherapy and received hydration and supportive therapy. After the first 4 cycles of CGP, we observed 7% CR, 46% PR, 31% SD, and 12% PD. After the 4 sequential cycles of MVAC DD we observed a global 25% of CR, 33% PR, 10% SD, and 24% PD. Median TTP was 8.2 months (95% CI, 7.3-10.1) and median OS was 18 months (95% CI, 10.8-26.1). 5 pts are still alive after more than 30 months and maintaining complete response. Main grade 3–4 toxicity included anemia 27%, asthenia 23%, neutropenia 19% (febrile 7%), thrombocytopenia 13%. Conclusions: The sequential use of these two DD regimens is active and leads to an increased number of complete response and possible longer survival. A randomized trial is needed to confirm our results.

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

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

Aims and background Previous studies have reported that in early breast cancer, lymphomas and advanced bladder cancer, dose-dense chemotherapy may be more effective than conventional treatments. In metastatic gastric cancer, chemotherapy with docetaxel, cisplatin and 5-fluorouracil (TCF) q3w is very active, and, even though there is no international consensus on the subject, it is the regimen of choice of many European centers as first-line chemotherapy in this subset of patients. Based on these studies, we tested for the first time the feasibility and activity of an intensified dose-dense TCF regimen (q2w) modifying the 5-fluorouracil infusion with l-folinic acid/5-fluorouracil according to the “De Gramont regimen”. Methods and study design Patients with histologically confirmed measurable metastatic gastric cancer, ECOG performance status ≤1, and not previously treated for advanced disease received docetaxel, 85 mg/m2 (75 mg/m2 after the first 6 patients, 70 mg/m2 after the 19th patient) on day 1, cisplatin, 75 mg/m2 on day 1 (60 mg/m2 after the 19th patient), l-folinic acid, 100 mg/m2 on days 1 and 2, followed by 5-fluorouracil, 400 mg/m2 bolus on days 1 and 2 and then 600 mg/m2 as a 22-h continuous infusion on days 1 and 2, every 14 days, plus pegfilgrastim, 6 mg on day 3. Patients aged ≥65 years received the same schedule with a dose reduction of 30%. Results Thirty-two consecutive patients were enrolled (63% male, 37% female); median age, 64 years (range, 40–81). A median of 4 cycles (range, 1–7) per patient was administered. Eleven of 32 patients (34%) required a dose reduction, mostly for hematological grade III-IV toxicity and severe asthenia. Twelve patients (38%) completed the first 4 cycles of therapy within 7 weeks, thereby finishing without delay the initially planned dose-density schedule. Twenty-eight patients were evaluated for response (1 early suspension after the first cycle because of toxicity, 3 deaths before response evaluation due to progression of disease). There were 3 complete responses (9%), 15 partial responses (47%), 7 stable disease (22%) and 3 progression of disease (9%), for an overall response rate, by intention to treat, of 56% (95% CI, 39–73). The most frequent grade 3–4 toxicities were: neutropenia (53%), thrombocytopenia (34%), anemia (16%) febrile neutropenia (22%), asthenia (38%) and diarrhea (19%). Median time to progression was 9.1 months (95% CI, 6.0–12.2); median overall survival was 10.1 months (95% CI, 8.8–12.2). Conclusions A dose-dense TCF regimen in metastatic gastric cancer is feasible, with activity comparable to previous results achieved with epirubicin-based chemotherapy and TCF q3wk in terms of overall survival and time to progression, and deserves to be further tested in randomized phase III studies.

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

e14532 Background: Biomarkers predicting response to checkpoint inhibitor are needed to better select patients most likely to benefit from treatment. We observed that baseline absolute lymphocyte count (ALC) can predict durable responses to anti-PD-1 antibodies in various malignancies. Methods: This is a retrospective analysis of patients with advanced solid tumors treated with anti-PD-1 antibodies. Pembrolizumab was given at 2 mg/kg every 3 weeks, Nivolumab at 3 mg/kg every 2 weeks. Peripheral ALC and absolute neutrophil count (ANC) from routine safety labs were collected at baseline, cycle 4 and cycle 8. Evaluation of response was based on irRECIST. Neutrophil lymphocyte ratio [NLR = ANC/ALC] was stratified by ≤4 or > 4. The lymphocyte count cutoff was 1000/mm3. Time to progression (TTP) and overall survival (OS) were estimated with the Kaplan-Meier method. Differences between groups were estimated with the log rank test. Results: We have retrospectively evaluated 40 patients with unresectable stage III/IV Non Small Cell Lung Cancer (squamous n. 17; 42.5%, adenocarcinoma n. 7; 17.5%), Malignant Melanoma (n.11; 27.5%), Renal Cell Carcinoma (n.5; 12.5%) treated with anti-PD-1 antibodies. 6 pts (15%) received treatment as 1st line, 14 pts (35%) as 2nd line, 20 pts (15%) as ≥ 3rd line. We observed a 29% partial response (PR), 31% stable disease (SD) and 40% progressive disease (PD). The overall response rate (ORR) was 29% [I.C. 95% 13-42]. Median TTP was 5.5 months [IC 95% 3.3-NR]. Median OS was not reached. Pts with baseline ALC ≥1000/mm3 had significantly longer TTP (median value not reached), compared with those who had ALC < 1000/mm3 (median TTP 2.8 months), p = 0.01. There was also a trend for longer TTP in patients with NLR < 4 vs ≥4 (4.9 vs 10.5 months, p 0.44). Conclusions: In our observation baseline ALC ≥1000/mm3 is a predictive biomarker of prolonged TTP in patients treated with anti-PD-1 antibodies. The potential predictive value of this test should be prospectively validated.

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

e15552Background: TCF is one of the most effective first-line option in metastatic GEC. We previously reported on the promising and high activity of mTCF-dd (Tomasello G et al: Gastric Cancer 2014 ...

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

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

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

303 Background: Currently, cisplatin, gemcitabine, paclitaxel (CGP) and MVAC are the most active regimens in transitional-cell carcinoma (TCC). We tested the hypothesis that two sequential non-cross-resistant, dose-dense (DD) regimens may target different cancer cells, avoid drug resistance, and improve response rate. Methods: This is a phase II, single institutional trial, including patients (pts) with bladder, renal pelvis, or ureteral TCC. Primary end point was the rate of complete response (CR) after two sequential DD regimens. Primary analysis was carried out in the intention to treat (ITT) population.Patients with histological diagnosis of TCC, PS 0–2 (ECOG), adequate organ function and no previous systemic regimens were treated with 4 cycles of CGP DD followed by 4 cycles of M-VAC DD. All received peg-filgrastim after chemotherapy. Pts were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for 2 years and 6 months thereafter. Results: 44 consecutive pts followed in the same oncology institution were included. Males were 73%; median age was 66 years; median PS ECOG was 1; Bajorin risk factors was 0 in 36%, 1 in 48%, 2 in 16%. After the first 4 cycles of CGP DD, we observed 6.8% CR, 43.2% PR, 38.6% SD, and 11.4% PD. After the 4 sequential cycles of M-VAC DD, we observed a global 27.3% of CR, 15.9% of PR, 18.2% of SD, and 13.6% of PD. Median TTP was 9.66 months (95% CI, 6.7-13) and median OS was 18.6 months (95% CI, 12-30). Main grade 3–4 toxicity included asthenia (26%), anemia (26%), neutropenia (9.5%), febrile (7%), thrombocytopenia (12%), and neurological toxicity (5%). No toxic deaths were seen. After a median follow up of 50 months, 4 of 12 patients who obtained a complete response are free of disease since more than 3 years. Conclusions: This sequential use of these two DD regimens leads to a 4-fold increase in CR, an increase in survival, and a possible cure for some patients. A phase III trial is warranted.

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

e15502 Background: mUC is a chemotherapy sensitive tumor. Currently, CGP and MVAC are the most active regimens in this setting. According to Norton and Simon hypothesis, the administration of two sequential non cross-resistant, dose-dense chemotherapy regimens may target different cancer cells, avoid drug resistance, improve response rate and CR. Methods: Patients with histological diagnosis of mUC, PS 0–2 (ECOG), adequate organ function and no previous systemic regimens were treated with 4 cycles of CGP dose-dense (Gemcitabine 1000 mg/m2 d 1, Paclitaxel 140 mg/m2 d 1, Cisplatin 70 mg/m2 d 2 plus PegFilgrastim 6 mg on day 3, every 2 weeks) followed by 4 cycles of M-VAC (Methotrexate 30 mg/m2 d 1,Vinblastine 3 mg/m2 d 2, Doxorubicin 30 mg/m2 d 2, Cisplatin 70 mg/m2 d 2 plus Pegfilgrastim 6 mg on day 3 every 2 weeks). All were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for two years and 6 months thereafter. Metastatic sites included retroperitoneal nodes, lung, liver and bone. Results: From January 2007, 35 consecutive pts followed in the same oncology institution were included. Male were 74%; median age 65 years; median PS ECOG was 1; Bajorin risk factors was 0 in 37%, 1 in 43%, 2 in 20%. All pts were hospitalized for three days and received chemotherapy with hydration and supportive therapy. After the first 4 cycles of CGP we observed 14.3% CR, 48.6% PR, 22.9% SD and 14.3% PD. After the 4 sequential cycles of M-VAC we observed a global 37.1% of CR, 25.7% of PR, 8.6% of SD and 28.6% of PD. Median TTP was 9.9 months ( 95 % CI, 7.53-14.83) and median OS was 24.27 months ( 95 % CI, 10.03-38.43). Main grade 3–4 toxicity included asthenia ( 27%), anemia (21%), neutropenia (12 %), febrile (9%), thrombocytopenia (9%) and peripheral neuropathy (6 %). After a median follow up of 33 months, 6 of 13 patients who obtained a complete response are free of disease. Conclusions: These data confirm that the sequential use of this two dose-dense regimens is very active and 17 % of patients maintained a CR status.

4112 Background: TCF is a standard first line option for GEC. The Norton-Simon hypothesis suggests that chemotherapy efficacy can be enhanced by decreasing intervals between cycles. We previously reported on the high activity of TCF-dd in GEC (Tomasello 2010). The aim of this study is to investigate the efficacy and safety of this intensified dose-dense regimen in a single-center large cohort of patients (pts). Methods: 150 pts with measurable or evaluable GEC, PS 0-2, with adequate organ function, treated in our center from 2004 to 2012 received TCF-dd: Docetaxel (60-85 mg/m2 d 1), Cisplatin (50-75 mg/m2 d 1), l-Folinic Acid (100 mg/m2 d 1-2), 5-FU (400 mg/m2 bolus d 1-2, and 600 mg/m2 as a 22 h continuous infusion d 1-2), plus Pegfilgrastim 6 mg d 3, every 14 days. Pts aged ≥ 65 years received the same schedule with a dose reduction by 30%. Analysis was based on the intention to treat population. Results: At a median follow-up of 44 months, 128 pts were evaluable for response, all for survival. Median age 65 (range 31-81), M:F 112:38. 17 pts (11%) with locally advanced inoperable GEC, 133 pts (89%) with metastatic GEC. Metastatic sites: liver 40%, peritoneum 31%, bone 14%, lung 12%. A median of 4 cycles (range 1-7) per patient was administered. 33% required a dose reduction. 33% were treated without any delay. 10 CR, 74 PR, 24 SD and 20 PD were observed, for an ORR of 66% (95% CI 57-74). Median OS was 13 months (95% CI 9.7-14.2). Most frequent grade 3/4 toxicities: neutropenia (34%), asthenia (28%), thrombocytopenia (17%), hypokalemia (16%), diarrhea (11%), febrile neutropenia (10%), anemia (9%), and stomatitis (4%). 11 pts (7%) [7 metastatic, 4 locally advanced] became operable after TCF-dd and underwent surgery. We identified 12 metastatic pts (8%) with overall survival > 3 years and 7 (5%) still maintaining a long lasting CR at the time of the current analysis. Conclusions: TCF-dd in GEC is very active and may be an option for conversion therapy. Toxicity can be relevant and requires a careful monitoring.

e15086 Background: Gastric cancer is more common in elderly pts with its highest incidence around the seventh decade of life. Most oncologists are reluctant to treat this population with the most active polichemotherapy combinations because of safety concerns. Subgroup analyses of elderly pts enrolled in European studies show limited and conflicting data.We previously reported on the feasibility and high activity of a dose-dense TCF regimen (Tomasello 2010). This is a retrospective analysis of efficacy and safety of this schema in the elderly pts subgroup (≥ 65 years). Methods: From Nov 2004 to Jan 2013, 119 consecutivepts with MGC, PS 0-2, not previously treated, received Docetaxel 70 mg/m2 d1, Cisplatin 60 mg/m2 d1, l-Folinic Acid 100 mg/m2 d1-2, followed by 5-FU 400 mg/m2 bolus d1-2, and then 600 mg/m222 h c.i. d1-2, every 2 weeks, plus Pegfilgrastim 6 mg on day 3. Pts aged ≥ 65 years (60) received the same schedule with doses reducted by 30%. Results: Overall pts characteristics: 76% male, 24% female; median age: 65, range 31-81. A median of 4 cycles was administered. 102 pts were evaluable for response (86%) and all for toxicity. In pts aged ≥ 65 y, we observed 5 CR (8%), 26 PR (43%), 10 SD (17%) and 7 PD (12%); in younger pts: 3 CR (5%), 32 PR (54%), 9 SD (15%) and 10 PD (17%); ORR by ITT was 56% (95% CI 45-64). Median OS was 11,2 months (95% CI 9,4-14,1); in elderly and younger pts was 11,2 (95% CI 7,3-15,1) and 11,8 (95% CI 9,2-16,2), respectively. Out of 48 evaluable pts aged ≥ 65 years, 24 (50%) were treated at full doses without any delay. In the elderly most frequent grade 3-4 toxicities were: neutropenia (13%, p

Background GC is more common in elderly patients (pts). Most oncologists are reluctant to treat this pts population with the most active poli-chemotherapy combinations because of safety concerns. Subgroup analysis of elderly pts enrolled in European studies show limited and conflicting data. We previously reported on the feasibility and high activity of a dose-dense TCF regimen (TCF-dd) (Tomasello 2010). This study aims to evaluate the efficacy and safety of this schema in the elderly pts subgroup (≥ 65 years). Methods From 11/04 to 05/12, 111 consecutive pts with MGC (median age 65, range 31-81) were enrolled in a single-centre phase II study. Pts received Docetaxel 70 mg/m2 d1, CDDP 60 mg/m2 d1, l-AF 100 mg/m2 d1-2 followed by 5-FU 400 mg/m2 bolus d1-2, and then 600 mg/m2 as a 22h c.i. d1-2, q2w, plus G-CSF d3. Pts ≥ 65y (56) received the same schedule reduced by 30%. Results 96 pts evaluable for response and all for toxicity. In pts ≥ 65y we observed 4 CR (7%) 25 PR (45%) 10 SD (18%) 7 PD (13%); in younger pts: 2 CR (4%) 30 PR (55%) 9 SD (16%) 9 PD (17%); ORR by ITT 56% (95% IC 45-64). Median OS was 11.9 months (9,4-14,8); in elderly and younger pts 11,2 (8,4-11,1) and 12,7 (9-16,5) respectively. Out of 48 evaluable pts ≥ 65y, 26 (54%) were treated at full doses without any delay. In the elderly most frequent G3-4 toxicities were neutropenia (14%) thrombocytopenia (15%) febrile neutropenia (7%) asthenia (27%) and hypokalemia (17%); in the younger: neutropenia (56%) thrombocytopenia (21%) febrile neutropenia (16%) asthenia (43%) hypokalemia (21%). Conclusions This study shows that elderly pts can be treated with a TCF-dd regimen reduced by 30% achieving similar efficacy results of younger patients with lesser toxicity. Disclosure All authors have declared no conflicts of interest.

4097 Background: MGC is a chemosensitive tumour. According to the Norton-Simon hypothesis, a reduction of tumor burden could best be achieved by shortening the interval between the cycles, and the resistance might be overcome by switching from initial chemotherapy to a new, non cross-resistant one. We previously reported on the high efficacy of a new strategy using 2 sequential, non cross-resistant chemotherapy regimens in MGC (Cancer Chemother Pharmacol 11 Jan; 67 (1): 41-8). Aim of this study is to evaluate this therapeutic approach in a larger case series. Methods: 43 patients (pts) treated at our centre from November 04 to April 11 were included. All pts were chemo-naïve and received 4 cycles of TCF-dd (see reference above for doses) every 2 weeks. Subsequently and irrespective of their response, they received 4 cycles of COFFI (see reference above ) every 2 weeks. In both regimens pegfilgrastim 6 mg sc on day 3 was included. Results: Median age: 63; 74% male. PS 0-1. After the first regimen (TCF-dd) 43 pts were evaluable for response.We registered 3 CR, 27 PR, 7 SD, 5 PD and 1 not evaluable for an ORR at ITT of 70% (95% CI, 58-85). All pts proceeded to the second regimen (COFFI) and 40 pts were evaluable for response. The 3 CR observed after TCF-dd were maintained. Among the 27 pts with PR after TCF-dd, 2 achieved CR, 14 improved the response, 6 maintained PR, 3 progressed. Among the 7 pts with SD after TCF-dd, 1 achieved CR, 3 achieved PR, 2 progressed and 1 is not valuable. Among the 5 pts with PD after TCF-dd, 1 achieved CR, 4 achieved RP. After COFFI we observed 5 CR, 21 PR, 9 SD and 5 PD. The ORR in the 40 pts was 60% (95% CI, 50-80). Considering both regimen ORR was 93%. mTTP was 12.1 months (95% CI, 8,1-16,2). mOS was 16.1 months (95% CI, 12.7-21.6). At Dec '11, 4 out of 8 pts who achieved CR are alive and disease free. Most frequent G3-4 toxicities were: astenia (32%), neutropenia (35%), anemia (14%), neurotoxicity (21%). Conclusions: The study confirms that a sequential dose-dense strategy using TCF-dd followed by COFFI is feasible and highly effective and deserves to be tested in a randomized study which is on going.

e19612 Background: Five variables (site of cancer, platelet count, haemoglobin level, leukocyte count, and body mass index-BMI) define the Khorana risk score (KS), predicting the high (≥ 3), the moderate (1-2) and the low (0) risk of thromboembolic events (TEs) in cancer outpatients. Nadroparin has been demonstrated to reduce the incidence of TEs by about 50% in cancer outpatients receiving chemotherapy (PROTECHT study) and patients receiving chemotherapy including gemcitabine, platinum analogues or their combination are at higher risk of TEs. Methods: 378 patients enrolled in the PROTECHT study didn’t receive thromboprophylaxis (placebo group) and were evaluable for the KS. The aim of this retrospective analysis was to assess the distribution of the five KS variables and if the replacing of BMI variable, in the KS, with a chemotherapy variable (administration of platinum compound or gemcitabine added 1point and their association 2points) in a PROTECHT score (PrS) could better predict high risk patients. A receiver operating characteristic (ROC) curve has been used to assess the accuracy of both scores. Results: Among patients the five KS variables were distributed as follow: 15% of stomach/pancreas cancer (2points), 33% with lung/gynecologic cancer (1point), 24% with platelet count of ≥350x10^9/L, 7.9% hemoglobin 11x10^9/L (1point each variable) and only 1.3% with BMI ≥ 35 (1point). 15 TEs occurred in the 378 pts, below the TEs distribution according to KS and PrS (see table). The area under the ROC curve was larger with PrS in comparison with KS (0.70 and 0.65 respectively). Conclusions: BMI ≥ 35 seems not to be a predictable factor for TEs in European cancer patients and the use of a chemotherapy variable could be more useful to identify patient at high risk of TE. A formal study is needed to evaluate which score could have a higher predictability to identify high risk patients for TEs. [Table: see text]

471 Background: Oral sunitinib administration at 50 mg daily given for 4 weeks followed by 2 weeks off treatment (4+2 schedule) is a standard first line for mRCC treatment. About 20% of patients had to discontinue treatment permanently and 50% of patients are forced to reduce the doses due to adverse events [Motzer RJ, J Clin Oncol. 2009]. A meta-analysis showed that increase exposure to sunitinib is associated with improved clinical outcome [Houk BE, Cancer Chemother Pharmacol. 2010]. Methods: This is a pilot study in which consecutive mRCC patients admitted to our hospital who had at least a grade 2 toxicity with sunitinib, were switched to a modified schedule maintaining the same dose-intensity of 4+2 schedule: starting on Monday, 1 tablet (50 mg) a day for 5 consecutive days a week for 5 weeks and 1 tablet per day on days 1, 3 and 5 in the sixth week (28 tablets in 6 weeks), until disease progression. Primary end points were toxicity changes assessment and schedule feasibility, secondary end point was overall progression free survival (PFS). Results: Eight nephrectomized patient were enrolled: 6 males; median age 61; 37% good, 50% intermediate and 13% poor MSKCC risk; 3 patient pretreated; 6 clear cell histologies, 1 papillary and 1 undifferentiated histotypes. Median time from start therapy to switch was 7.4 months (range 1.4-16.1). Treatment delays and dose reductions were reduced from 50% to 25% and from 37% to 12% of patients respectively. The table shows the toxicity changes: there were no new toxicities. PFS was 16.3 months (CI 95% 5.6-23.4). Conclusions: This new modified schedule requires and deserves further studies. [Table: see text]

e19551 Background: Cancer and chemotherapy are well recognized risk factors for thromboembolic events (TEs). Nadroparin has been demonstrated to reduce the incidence of TEs by about 50% in cancer o...

4615 Background: Efficacy and tolerability of chemo-immunotherapy plus anti-VEGF therapy is unknown. Aim of this study is to explore the combination of B+IT+C and to correlate its efficacy with the...

e16014 Background: Long-term effects of a combined approach of transurethral resection (TUR) plus chemotherapy (CT) and pelvic radiotherapy (RT) in terms of bladder preservation, survival, QOL are largely unknown. Moreover we investigated whether p53, Ki67, bcl-2, c-erbB-2 protein expression predict the achievement of a complete response (CR). Methods: From March 1994 to June 2000, 75 pts with muscle invasive BC were treated with a bladder sparing approach including an initial TUR, 3 cycles of CT (cisplatin + 5- FU) alternating with pelvic RT (40 Gy). At the response evaluation, pts with biopsy proven residual disease were considered incomplete responders (IR) and underwent immediate cystectomy. Pts with CR were treated with two additional CT cycles plus a bladder RT boost (20- 24 Gy). Paraffin embedded blocks of the primary tumors were collected and Ki67, p53, bcl-2 and c-erbB-2 protein expression were evaluated in a blind fashion. The Expanded Prostate Cancer Index Composite (EPIC) scores for urinary function, (especially storage, voiding symptoms and bowel function) was used to explore QOL in bladder preserved and compared with a group of matched patients treated by radical cystectomy only. Results: Median age was 67 yrs (range 42–80); T2a-T2b: 42%; T3a-T3b: 47%; T4a: 11%; G3: 88%; hydronephrosis: 32%. Overall, 56 (74.7%) pts achieved a CR and the achievement of a CR was significantly related to lower T stage (p= 0.002), high Ki67 (p=0.001), absence of hydronephrosis (p= 0.007) and high p53 overexpression (p=0.007). Multivariate analysis showed that only a low T stage (p=0.002) and high p53 expression (p=0.043) predict the obtaining of a CR. At 5 years of follow-up, 44 (59%) were alive and in 33 of them (75%) bladder was preserved; after 10-years 28 (37.3%) were alive and in 23 of them (82%) bladder was preserved. Analysis of QOL scores is ongoing. Conclusions: This approach induces a long term survival similar to radical cystectomy with a high rate of bladder preservation and represents a valid treatment for muscle invasive BC. Overexpression of p53 is a predictive marker for the obtaining of CR and for bladder preservation. No significant financial relationships to disclose.

5121 Background: B is effective in mRCC and has a synergistic effect with CT in many tumors. The activity of B plus interleukin- 2 (IL-2) and interferon-α (IFN-α) has not been studied. Aim of this ...

4570 Background: In the 2007 ASCO Annual Meeting we reported the high activity of TCF-DD in MGC. Previous phase II trials showed that regimens with O, I, FA, and 5-FU are very active in MGC. Based ...

18042 Background: Previous studies in patients with NSCLC treated with IL-2 reported relatively long survival (Cancer 1994;73:1353–60) and a recent study indicated that lymphocytes are activated by G treatment (J Cancer Res Clin Oncol. 2006;132:719- 725.). In this study we explored the possible synergism between IL-2 and G in terms of response rate, survival and toxicity. Methods: From September 2003 to November 2006, 70 consecutive chemotherapy treated patients with advanced, progressive NSCLC received oral G 250 mg daily in a compassionate use program at a single institution. The first 39 patients included in the study received only G, the others 31 also received subcutaneous IL-2: 1 MUI/m2 twice a day on day 1 and 2, once a day on day 3, 4, 5 every week for 4 consecutive weeks with 4 week rest period. This is a phase II trial combined with a cohort design each having a different outcome event. All the evaluations were made using Recist criteria and according to the intention to treat principle. Results: The main patients characteristics and results are showed in the table below. Fifty-one (73%) patients received one prior chemotherapy regimen, while 17 (24%) received = two prior lines of treatment. *Median, months ±95% CI. §p value [Table: see text] No significant financial relationships to disclose.

15068 Background: Previous studies reported that in lymphomas, early breast and bladder cancer, dose-dense CT is more effective than conventional treatment. We reported for the first time, in 2006 ASCO meeting, the feasibility of an intensified dose-dense TCF regimen (q2w) in MGC. This is the subsequent phase II study. Methods: patients (pts) with histologically confirmed measurable MGC, ECOG PS 0–3, received up to 6 cycles of Docetaxel 85 mg/m2 (75 mg/m2 after first 12 pts, 70 mg/m2 after the 28th patient) day 1, Cisplatin 75 mg/m2 day 1 (60 mg/m2 after the 28th patient) l-Folinic Acid 100 mg/m2 day 1 and 2, followed by 5-Fluorouracil 400 mg/m2 bolus day 1 and 2, and then 600 mg/m2 as a 22 hour continuous infusion day 1 and 2, every 14 days, plus Pegfilgrastim 6 mg on day 3. Pts with a PS > 1 and/or age > 65 years and/or pre-treated for the metastatic disease, received the same schedule with a dose reduction by 30%. Results: 31 consecutive pts were enrolled (81% male, 19% female; median age: 60, range 40–79; median ECOG PS: 1, range 0–3; 3 pts pre-treated). Primary end points were response rate and safety. A median of 4 cycles (range 1–6) per pts were administered. 15 pts (48%) required a dose reduction, mostly because of hematologic toxicity and severe asthenia. 10 pts (32%) were treated with full dose without any delay on at least the first 4 cycles. 25 pts were evaluated for response (3 too early, 1 early suspension because of severe allergic reaction to Docetaxel; 2 early deaths: 1 bowel perforation and 1 sepsis) and 30 for toxicity. 2 CR (multiple liver metastases), 12 PR, 4 SD and 7 PD were observed, for an ORR (RECIST criteria and intention-to-treat principle) of 50% (95% CI 30–65). At a median follow-up of 10 months (range 1–24), overall median survival was 6 months (range 1–20). Frequent grade 3 to 4 toxicities were: neutropenia (65%), thrombocytopenia (31%), anemia (14%) febrile neutropenia (31%), asthenia (62%), diarrhoea (21%) and stomatitis (14%). Conclusions: TCF-DD regimen in MGC is feasible and very active. The recommended dose (with reduction by 30% as above) for further randomised studies comparing TCF-DD with standard TCF is Cisplatin 60 mg/m2 and Docetaxel 70 mg/m2. No significant financial relationships to disclose.