Failure Of Platinum-based Chemotherapy Research Articles

Abstract B117: Phase II study of brentuximab vedotin and bevacizumab in GCT

Abstract Background: Outcomes in refractory germ cell tumors (GCT) after failure of platinum-based chemotherapy are poor with complete responses with salvage chemotherapy being rare and short-lived. Patients progressing after ≥2 lines of chemotherapy have a dismal prognosis and die from disease. Novel therapies and combination strategies are urgently needed. Cluster of Differentiation antigen-30 (CD30) is expressed in embryonal carcinoma, implicating CD-30 as a target in CD-30+ GCT. Brentuximab vedontin (BV) is an antibody-drug conjugate that combines mono-methyl auristatin E (MMAE) with a CD-30 specific monoclonal antibody, and has shown promising activity in CD30+ GCT. VEGF is involved in tumor development, angiogenesis, and metastasis in GCT, and anti-VEGF monoclonal antibody, bevacizumab, has shown activity in GCT. BV and bevacizumab may be synergistic in refractory CD30+ GCT with no potentially overlapping toxicities. Methods: This is a multicenter phase II study of BV and bevacizumab for the treatment of refractory CD-30+ GCT after disease progression on imaging and/or tumor marker progression with serially rising AFP or bHCG. Patients must have received ≥ 2 lines of platinum-based chemotherapy, but only 1 prior line will be allowed if the patient is ineligible or refuses further platinum-based chemotherapy. For primary mediastinal GCT, failure of 1st-line chemotherapy is allowed. Expression of CD-30 (1% or more) in archival or fresh biopsy is required for eligibility. Primary objective is objective response rate. Secondary objectives are safety and tolerability, PFS, and OS. Exploratory objectives include correlation of clinical outcomes with CD-30 expression in tumors and blood and VEGF level in blood, and presence of circulating tumor cells (CTCs) and correlation with clinical outcomes. BV and bevacizumab will be given every 21 days at doses of 1.8 mg/kg and 15mg/kg, respectively, until disease progression or unacceptable toxicity; intrapatient dose reduction of BV to 1.2 mg/kg will be allowed. A total of 21 patients will be enrolled and results from this study will provide an insight into the safety and efficacy of this combination in refractory CD-30+ GCT. (NCT02988843) Citation Format: Shilpa Gupta, Benjamin L. Maughan. Phase II study of brentuximab vedotin and bevacizumab in GCT [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B117.

Atezolizumab in invasive and metastatic urothelial carcinoma

ABSTRACTIntroduction: Until recently, there has been little advancement in the management of invasive and metastatic urothelial cancer in over 30 years, and outcomes with cisplatin-based chemotherapy remain unchanged. Inhibitors targeting PD-1 signaling on cytotoxic T-cells have revolutionized bladder cancer therapy leading to durable responses. Atezolizumab is an engineered humanized anti-PD-L1 monoclonal antibody that inhibits PD-L1 binding to PD-1 and B7.1, enhancing immune-mediated tumor killing and is currently approved as second-line treatment after failure of platinum-based chemotherapy as well as first-line in cisplatin-ineligible patients.Areas covered: This article summarizes all reported phase I, II and III clinical trials that assessed the safety and efficacy of atezolizumab in the treatment of locally advanced and metastatic urothelial carcinoma.Expert commentary: Treatment with atezolizumab showed durable response and a toxicity profile that appears favorable to cytotoxic chemotherapy historically in the treatment of metastatic urothelial cancer among individuals who had progressed after prior platinum-based therapy and among those ineligible for treatment with first-line cisplatin. PD-L1 expression and tumor mutation load associate with response, however further research is needed to identify additional markers to improve prediction of response to atezolizumab.

P2.04-019 A Peripheral Immune Signature Associated with Clinical Activity of Sunitinib in Thymic Carcinoma: Topic: Thymic Malignancies Clinical and Translational

We have previously reported an objective response rate of 26% and disease stabilization in 65% of patients with advanced thymic carcinoma (TC) treated with the multi kinase inhibitor sunitinib after failure of platinum-based chemotherapy. The current study investigates the impact of sunitinib on systemic immunity in patients with thymic epithelial tumors with an aim to discover blood-based, predictive immune biomarkers. Patients with thymoma and TC received sunitinib at a dose of 50 mg once daily in 6-week cycles consisting of 4 weeks of treatment followed by 2 weeks without treatment. Results from 15 patients with TC are reported here. Blood samples were collected before initiation of sunitinib therapy (Cycle 1 day 1; C1D1), and prior to treatment on day 1 of cycles 2 and 3 (C2D1; C3D1). Multiparameter flow cytometry was used to study T-cell subsets with immune checkpoint expression, four phenotypes of myeloid-derived suppressor cells (MDSCs) with CD40, and CD14+ monocytes with HLA-DR expression. Expression of 730 immune-related genes in peripheral blood was analyzed by NanoString technology. Differences in paired markers or changes in markers between two time points was evaluated by the Wilcoxon signed rank test. The Kaplan-Meier method was used to obtain estimates of progression-free survival (PFS) and overall survival (OS). Immunosuppressive Tim-3-positive Tregs declined after 2 cycles of sunitinib (p=0.024). A decrease in granulocytic MDSCs (p=0.012), lineage negative (CD3-CD19-CD56-) MDSCs (p=0.013), and immature MDSCs (p=0.01) but not monocytic MDSCs was observed after 1 cycle of sunitinib. TC patients with no objective response to sunitinib had a higher baseline immature MDSC level than responders (p=0.0044). Greater than median declines in granulocytic MDSC CD40 (C2D1 p=0.027, C3D1 p=0.0046) and lineage-MDSC CD40 (C3D1, p=0.0046) after sunitinib therapy was associated with improved PFS. Similarly, a greater than median decline in CD14+HLA-DRlo/neg monocyte levels on C2D1 was associated with longer PFS (p=0.020). Among the immune genes examined, higher baseline FEZ1 expression was associated with improved PFS and OS. Our findings suggest significant interplay between sunitinib and systemic immunity impacts therapeutic outcome in TC. Monitoring CD40 expression on specific MDSC phenotypes and FEZ1 gene expression may predict a survival benefit after treatment with sunitinib. These results, if validated in larger studies, can serve as potential blood-based predictive biomarkers in TC patients treated with sunitinib.

Preface on "Emerging treatment options for brain metastases from non-small cell lung cancer".

Significant progress in the treatment of advanced non-small cell lung cancer (NSCLC) became first evident with the recognition that certain molecular subtypes (e.g., EGFR-mutant or ALK-rearranged tumors) could tremendously benefit from sequential treatment with small molecules tyrosine-kinase inhibitors (TKIs). In fact, an unprecedented median survival of more than 24 months has been reported in patients with oncogene-addicted disease when appropriate targeted therapies are used (1,2). More recently, the introduction of immunotherapy for use after failure of platinum-based chemotherapy has significantly improved the survival of some patients with no identifiable driver mutations (3), and future treatment landscape is rapidly evolving in order to incorporate immunotherapy in the front-line setting (4,5). Having made this preliminary remark, the downside of the improved survival experienced by patients has led to a significant increase in the spread of the disease to the brain, a phenomenon which already affects nearly one third of advanced NSCLCs at diagnosis. On the other hand, frequent use of serial CT scan or MRI of the brain for tumor (re-) staging has significantly contributed to the increased detection of brain metastases (BMs), especially when asymptomatic. Once developed, BMs predictably represent an important cause of morbidity and mortality in NSCLC patients, and counteracting strategies against BMs are crucial in this context.

Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial

Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0-464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0-470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0-288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. Bristol-Myers Squibb.

From Clinical Trials to the Front Line: Vinflunine for Treatment of Urothelial Cell Carcinoma at the National Cancer Institute of Naples.

Background: The efficacy of Vinflunine, after failure of platinum-based chemotherapy in patients with metastatic or recurrent Transitional Cell Cancer of the Urothelial Tract, TCCU, has been demonstrated in an international, randomized, phase III trial comparing Vinflunine plus Best Supportive Care, BSC, with BSC alone. On the basis of that study vinflunine has been approved by the European Medicine Association, EMA, for treatment of TCCU patients after failure of a platinum treatment. However, since data in clinical trials often differ from routine clinical practice due to unselected population and less strict monitoring, “real life” experiences are very helpful to verify the efficacy of a new therapy.Methods: This was a spontaneous, observational, retrospective study involving 43 patients with metastatic TCCU treated with vinflunine at our cancer center, data about demographics, disease characteristics, and previous treatments were collected and outcome and toxicities of vinflunine were analyzed.Results: 41 of 43 patients were eligible for RR analysis, the Overall RR was 12%, the Disease Control Rate was 29%; when including only patients treated in II line the DCR rose to 33%; the median PFS and the median OS were 2.2 and 6.9 months, respectively.Conclusion: Our findings were consistent with the outcome data emerged in the phase III randomized trial and in the other observational studies conducted all around Europe in the last 2–3 years. This experience supports the use of vinflunine in patients with advanced TTCU as effective and manageable antineoplastic drug.

Phase II study of gemcitabine plus S-1 chemotherapy in recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy

No standard salvage regimen has been established for patients with recurrent and metastatic nasopharyngeal carcinoma (NPC) and disease progression after prior platinum-based chemotherapy. This phase II study was designed to evaluate the efficacy and safety of gemcitabine plus S-1 (GS) chemotherapy as a remedial regimen in this setting. In this multicenter phase II study, 49 patients with recurrent and metastatic NPC who failed previous platinum-based chemotherapy received gemcitabine (1.0 g/m(2) on days 1 and 8) plus oral S-1 chemotherapy (twice daily from day 1 to 14). Each cycle was repeated every 3 weeks for two cycles at least. The dose of S-1 was determined according to the body surface area (BSA): 40 mg twice a day for BSA <1.25 m(2); 50 mg twice a day for 1.25 m(2) ⩽ BSA <1.5 m(2); and 60 mg twice a day for BSA ⩾1.5 m(2). Treatment was generally well-tolerated. A total of seven patients (14.3%) had grade 3 toxicities and the main toxicity was myelosuppression, whereas the nonhematology adverse events were minimal. There were 3 complete responses (6.4%), 17 partial responses (36.2%), and the overall response rate was 42.6% (95% confidence interval: 27.3-61.2). Median time to progression was 5.8 months and median survival was 14.8 months. The 1- and 2-year survival rates were 64% and 30%, respectively. Gemcitabine plus S-1 offers a satisfactory clinical activity and an acceptable safety profile for recurrent and metastatic NPC patients after failure of platinum-based chemotherapy.

PLUTO: A randomised phase II study of pazopanib versus paclitaxel in relapsed urothelial tumours.

430 Background: Two previous single arm trials have drawn conflicting conclusions regarding pazopanib in urothelial bladder cancers (UBC) after failure of platinum-based chemotherapy. PLUTO is a randomized phase II trial to compare the efficacy of pazopanib with paclitaxel in this setting. Methods: It was planned for 140 patients with progressive, advanced UBC (with at least a component of transitional cell carcinoma) who had previously received a single prior platinum containing chemotherapy regimen for advanced UBC to be randomised(1:1). Patients in arm A received weekly paclitaxel 80mg/m2 and those in arm B received pazopanib (800mg once daily) until progression. The primary endpoint was overall survival analysis of which would occur after 110 events. The efficacy was assessed by an independent data monitoring committee during the trial. Results: Between Aug 2012- Oct 2014, 131 patients were randomised. 74.0% of patients had visceral metastases. The study was terminated early by the IDMC due to futility of pazopanib. Final analysis after 110 deaths occurred in July 2015. The median number of cycles of paclitaxel received was 4 (12 weeks). The median time on pazopanib was 11 weeks. Median overall survival was 8.0 months for paclitaxel [80% confidence interval (CI) 6.9 to 9.7 months] and 4.7 months for pazopanib [80% CI 4.2 to 6.4 months]. The hazard ratio (HR) adjusted for baseline stratification factors was 1.25 [80% CI 0.96 to 1.63; 1-sided p = 0.86] in favour of paclitaxel. Median progression free survival was 3.2 months for paclitaxel [80% CI 2.9 to 5.0 months] and 3.1 months for pazopanib [80% CI 2.7 to 3.8 months]. The adjusted HR for PFS was 1.06 [80% CI 0.83 to 1.36; 1-sided p = 0.62] (in favour of paclitaxel). Discontinuations for toxicity occurred in 6.3% and 20.0% for paclitaxel and pazopanib respectively. VHL, HIF1alpha, VEGFR2 and PD-L1 expression were measured from archived tissue and correlated with outcome. Conclusions: Pazopanib does not have greater efficacy than paclitaxel in the second line treatment of UBC. There is a trend towards superior OS with paclitaxel. Clinical trial information: NCT00949455.

Фармакоэкономический анализ лекарственного средства жавлор (винфлунин) у больных с уротелиальным переходноклеточным раком, резистентных к режимам на основе платины

Фармакоэкономический анализ лекарственного средства жавлор (винфлунин) у больных с уротелиальным переходноклеточным раком, резистентных к режимам на основе платины

Efficacy and safety evaluation of gemcitabine combined with ifosfamide in patients with advanced nasopharyngeal carcinoma after failure of platinum-based chemotherapy

To evaluate the efficacy and safety of gemcitabine combined with ifosfamide (GI regimen)in patients with recurrent or metastatic nasopharyngeal carcinoma after failure of platinum-based chemotherapy. The clinical data of 27 nasopharyngeal carcinoma patients, who received GI regimen between April 2005 and March 2014 after failure of prior platinum-based chemotherapy, were retrospectively reviewed,and relevant prognostic factors were explored. All patients were evaluable for efficacy and toxicity. No patient achieved complete response (CR). Partial response (PR) was achieved in ten patients, stable disease (SD) in thirteen patients, progressive disease (PD) in four patients, with a response rate of 37.0% and an overall disease control rate (PR+SD) of 85.2%. For ten PR patients, the median duration of response was 5.5 months. The median progression-free survival of the whole group was 6.7 months, and the Kaplan-Meier estimate of median overall survival was 17.4 months. The 1-year survival rate was 72.6%. Toxicity was mainly hematological: Grade III or IV anemia, neutropenia and thrombocytopenia were found in 3.7%, 37.0% and 18.5% of all patients, respectively. Univariate and multivariate analyses indicated that dose intensity of gemcitabine was a significant prognostic factor for PFS, whereas salvage treatment after failure of GI regimen was a significant prognostic factor for OS. Gemcitabine and ifosfamide combination is effective and well tolerated by patients with advanced nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Further clinical study is warranted.

Second-Line Treatment of Advanced Urothelial Cancer with Paclitaxel and Everolimus in a German Phase II Trial (AUO Trial AB 35/09)

Objective: The efficacy of second-line treatment after failure of platinum-based chemotherapy in patients with advanced urothelial cancer is limited. Based on encouraging preclinical and clinical phase I data, we evaluated the safety and efficacy of the combination of paclitaxel and everolimus in these patients. Methods: In this trial, patients having failed to respond to prior platinum-based combination treatment of urothelial cancer were treated with paclitaxel (175 mg/m² i.v., 3-weekly) and the mTOR-inhibitor everolimus (10 mg p.o., once daily). The patients were treated until tumor progression or until a maximum of 6 cycles was completed. A one-stage design was used to evaluate the objective response rate (ORR) as the primary endpoint. Results: A total of 27 patients (67% male; median age 63 years) were enrolled. The most frequent grade III/IV toxicities were anemia (28%), peripheral neuropathy (28%), and fatigue (24%). No treatment-related deaths were reported. Complete and partial remissions were observed in 0/24 and 3/24 patients eligible for efficacy analysis, respectively (ORR 13%). Progression-free survival was 2.9 months [95% confidence interval (95% CI) 1.9-4.2], and the median overall survival was 5.6 months (95% CI 4.8-10.2). Conclusion: The combination of paclitaxel and everolimus has not achieved the expected efficacy in second-line treatment of urothelial cancer and should not be further explored.

Amrubicin monotherapy for patients with platinum-refractory gastroenteropancreatic neuroendocrine carcinoma.

328 Background: Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, because studies on salvage chemotherapy are limited, its role remains unknown. This study aimed to analyze the efficacy and safety of amrubicin monotherapy in patients with platinum-refractory gastroenteropancreatic NEC. Methods: Among 22 patients with advanced gastroenteropancreatic NEC, 10 received amrubicin monotherapy between September 2006 and May 2014 after failure of platinum-based chemotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively. Results: Eight males and two females ((median age, 67 years (range, 52–78)) received platinum-based chemotherapy, including cisplatin plus irinotecan (n = 7, 70%), cisplatin plus etoposide (n = 2, 20%), and carboplatin plus etoposide (n = 1, 10%) before amrubicin therapy. A total of 30 cycles of amrubicin was administered in 10 patients, with a median number of cycles per patients was 2.5 (range, 1-7). Median progression-free survival (PFS) and overall survival after amrubicin therapy were 2.6 and 5.0 months, respectively. Two patients had partial response (20% response rate), and their PFS were 6.2 months and 6.3 months, respectively. Two patients with partial response had characteristics of NEC with a high Ki-67 index (99% and 89%, respectively) and had received cisplatin and irinotecan as first-line treatment. Grade 3–4 neutropenia and anemia were observed in four (40%) and five (50%) patients, and they were manageable in all cases by careful monitoring of myelosuppression and appropriate dose reduction of amrubicin. Conclusions: Amrubicin monotherapy appears to be potentially active and well-tolerated for platinum-refractory gastroenteropancreatic NEC.

Sunitinib in patients with chemotherapy-refractory thymoma and thymic carcinoma: an open-label phase 2 trial

No standard treatments are available for advanced thymic epithelial tumours after failure of platinum-based chemotherapy. We investigated the activity of sunitinib, an orally administered tyrosine kinase inhibitor. Between May 15, 2012, and Oct 2, 2013, we did an open-label phase 2 trial in patients with histologically confirmed chemotherapy-refractory thymic epithelial tumours. Patients were eligible if they had disease progression after at least one previous regimen of platinum-containing chemotherapy, an Eastern Cooperative Oncology Group performance status of two or lower, measurable disease, and adequate organ function. Patients received 50 mg of sunitinib orally once a day, in 6-week cycles (ie, 4 weeks of treatment followed by 2 weeks without treatment), until tumour progression or unacceptable toxic effects arose. The primary endpoint was investigator-assessed best tumour response at any point, which we analysed separately in thymoma and thymic carcinoma cohorts. Patients who had received at least one cycle of treatment and had their disease reassessed were included in the analyses of response. The trial was registered with ClinicalTrials.gov, number NCT01621568. 41 patients were enrolled, 25 with thymic carcinoma and 16 with thymoma. One patient with thymic carcinoma was deemed ineligible after enrolment and did not receive protocol treatment. Of patients who received treatment, one individual with thymic carcinoma was not assessable because she died. Median follow-up on trial was 17 months (IQR 14.0-18.4). Of 23 assessable patients with thymic carcinoma, six (26%, 90% CI 12.1-45.3, 95% CI 10.2-48.4) had partial responses, 15 (65%, 95% CI 42.7-83.6) achieved stable disease, and two (9%, 1.1-28.0) had progressive disease. Of 16 patients with thymoma, one (6%, 95% CI 0.2-30.2) had a partial response, 12 (75%, 47.6-92.7) had stable disease, and three (19%, 4.1-45.7) had progressive disease. The most common grade 3 and 4 treatment-related adverse events were lymphocytopenia (eight [20%] of 40 patients), fatigue (eight [20%]), and oral mucositis (eight [20%]). Five (13%) patients had decreases in left-ventricular ejection fraction, of which three (8%) were grade 3 events. Three (8%) patients died during treatment, including one individual who died of cardiac arrest that was possibly treatment-related. Sunitinib is active in previously treated patients with thymic carcinoma. Further studies are needed to identify potential biomarkers of activity. National Cancer Institute (Cancer Therapy Evaluation Program).

Amrubicin Monotherapy for Patients with Platinum-Refractory Gastroenteropancreatic Neuroendocrine Carcinoma.

Objective. Patients with gastroenteropancreatic neuroendocrine carcinoma (NEC) have a poor prognosis. Platinum-based combination chemotherapy is commonly used as first-line treatment; however, the role of salvage chemotherapy remains unknown. This study aimed to analyze the efficacy and safety of amrubicin monotherapy in patients with platinum-refractory gastroenteropancreatic NEC. Methods. Among 22 patients with advanced gastroenteropancreatic NEC, 10 received amrubicin monotherapy between September 2007 and May 2014 after failure of platinum-based chemotherapy. The efficacy and toxicity of the treatment were analyzed retrospectively. Results. Eight males and two females (median age, 67 years (range, 52–78)) received platinum-based chemotherapy, including cisplatin plus irinotecan (n = 7, 70%), cisplatin plus etoposide (n = 2, 20%), and carboplatin plus etoposide (n = 1, 10%) before amrubicin therapy. Median progression-free survival and overall survival after amrubicin therapy were 2.6 and 5.0 months, respectively. Two patients had partial response (20% response rate), and their PFS were 6.2 months and 6.3 months, respectively. Furthermore, NEC with response for amrubicin had characteristics with a high Ki-67 index and receipt of prior chemotherapy with cisplatin and irinotecan. Grade 3-4 neutropenia and anemia were observed in four and five patients, respectively. Conclusion. Amrubicin monotherapy appears to be potentially active and well-tolerated for platinum-refractory gastroenteropancreatic NEC.

868P - Effectiveness of Combination Gemcitabine/Paclitaxel After Failure of Platinum-Based Chemotherapy for Metastatic Urothelial Cancer

ABSTRACT Aim: For patients with metastatic urothelial cancer, overall survival is poor after progression from first-line chemotherapy (CT). In Europe, vinflunine is the only approved drug for second-line treatment – however, in Portugal, it has not been approved for reimbursement. Several phase II studies using gemcitabine and paclitaxel (GPac) have shown it to be an active and well tolerated second-line regimen. Our aim is to assess the effectiveness of the GPac regimen after failure of platinum-based CT. Methods: Consecutive series of patients with metastatic urothelial cancer, who experienced progression during or after platinum-based CT and were subsequently treated with GPac, at our center, from January 2007 to December 2013. Data on demographics, prognostic factors, response, survival and toxicity were extracted from clinical files. Results: Twenty five patients were included. Baseline characteristics: median age 63 years (range 48 – 78), 96% males, 12% ECOG performance status (PS) 0 and 88% PS 1 or 2, 20% hemoglobin level 24 months. Of known prognostic factor, only presence of liver metastasis was a predictor of a poorer prognosis. Grade 3–4 toxicity was identified in 88% of patients: neutropenia (60%), thrombocytopenia (56%), anemia (16%) and sepsis (12%). Conclusions: GPac was active, with 8% complete responses and durable remissions in 24% of patients. Toxicity, although high, was manageable. Disclosure: All authors have declared no conflicts of interest.

Safety and efficacy of S-1 chemotherapy in recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy: multi-institutional retrospective analysis.

PurposeThis retrospective study evaluates the efficacy and safety of S-1 chemotherapy for recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy.Patients and methodsThirty-nine patients with recurrent and metastatic nasopharyngeal carcinoma who failed previous platinum-based chemotherapy received oral S-1 chemotherapy (twice daily from day 1 to 14) every 3 weeks. The dose of S-1 was determined according to the body surface area (BSA): 40 mg twice a day for BSA <1.25 m2; 50 mg twice a day for 1.25 m2 ≤BSA<1.5 m2; and 60 mg twice a day for BSA ≥1.5 m2.ResultsTreatment was well tolerated. Most adverse events were mild. Grade 3 hematological toxicity occurred in 7.7%. There was one complete response (2.6%) and 12 partial responses (30.7%), giving an overall response rate of 33.3% (95% CI [confidence interval], 21.7–50.8). Median time-to-progression was 5.6 months, and median survival was 13.9 months. One- and 2-year survival rates were 60% and 26%, respectively.ConclusionS-1 monotherapy is considered a safe and effective treatment option for recurrent and metastatic nasopharyngeal carcinoma patients after failure of platinum-based chemotherapy.

Survival analysis of platinum-refractory patients with advanced esophageal cancer treated with docetaxel or best supportive care alone: a retrospective study.

The survival benefit of second-line chemotherapy with docetaxel in platinum-refractory patients with advanced esophageal cancer (AEC) remains unclear. A retrospective analysis of AEC patients with Eastern Cooperative Oncology Group performance status (PS)≤2 was performed, and major organ functions were preserved, who determined to receive docetaxel or best supportive care (BSC) alone after failure of platinum-based chemotherapy. The post-progression survival (PPS), defined as survival time after disease progression following platinum-based chemotherapy, was analyzed by multivariate Cox regression analysis using factors identified as significant in univariate analysis of various 20 characteristics (age, sex, PS, primary tumor location, etc) including Glasgow prognostic score (GPS), which is a well-known prognostic factor in many malignant tumors. Sixty-six and 45 patients were determined to receive docetaxel and BSC between January 2007 and December 2011, respectively. The median PPS was 5.4 months (95% confidence interval [CI] 4.8-6.0) in the docetaxel group and 3.3 months (95% CI 2.5-4.0) in the BSC group (hazard ratio [HR] 0.56, 95% CI 0.38-0.84, P=0.005). Univariate analysis revealed six significant factors: treatment, PS, GPS, number of metastatic organs, liver metastasis, and bone metastasis. Multivariate analysis including these significant factors revealed three independent prognostic factors: docetaxel treatment (HR 0.62, 95% CI 0.39-0.99, P=0.043), better GPS (HR 0.61, 95% CI 0.46-0.81, P=0.001), and no bone metastasis (HR 0.31, 95% CI 0.15-0.68, P=0.003). There was a trend for PPS in favor of the docetaxel group compared with patients who refused docetaxel treatment in the BSC group (adjusted HR 0.61, 95% CI 0.29-1.29, P=0.20). Docetaxel treatment may have prolonged survival in platinum-refractory patients with AEC.

Phase II trial of sunitinib in patients with thymic epithelial tumors (TET).

7525 Background: There are no standard treatments for patients with advanced TETs after failure of platinum-based chemotherapy. In thymic carcinoma, KIT over-expression and mutations are found in a...

Mesothelin expression in thymic epithelial tumors (TETs).

7607 Background: Mesothelin (meso) is overexpressed in many solid tumors and has been used as a target for anticancer therapy. Limited data is available on meso expression in TETs and its clinical correlates. Standard treatments have limited efficacy for patients with advanced TETs, especially thymic carcinoma (TC) after failure of platinum-based chemotherapy. There is an urgent need to identify novel therapeutic targets. In view of early results demonstrating benefit in therapeutic targeting of meso, we characterized meso expression in TETs. Methods: Patients with histologically confirmed thymoma (T) or TC and available tumor tissue who were enrolled in clinical trials at the National Cancer Institute between December 2007 and December 2013 were included. Meso expression was assessed by immunohistochemistry (IHC) using monoclonal antibody 5B2 (Novocastra/Leica, Bannockburn, IL) by a pathologist who was blinded to histological subcategory (T vs. TC) and clinical outcome. IHC staining of > 50% was labeled as positive and ≤ 50% was considered negative. Associations between meso expression and patient characteristics were assessed. Results: 71 cases (42 TC; 29 T consisting of 3 WHO subtype AB, 2 B1, 13 B2 and 11 B3) were included in this series. Meso expression localized to tumor cell membrane was observed in 19 (45%) TC and 1 (3%) T. Median age and gender distribution of meso-positive vs. meso-negative TC was: 55 (21-73) vs. 50 (20-74) years and 11M/8F vs. 10M/5F respectively. Meso-expressing TC included 12 of 16 (75%) poorly differentiated carcinomas, 3 of 11 (27%) squamous cell carcinomas, 1 of 2 (50%) basaloid cancers and 0 of 8 neuroendocrine tumors (including atypical carcinoids). Median overall survival was significantly higher in meso-positive TC compared to meso-negative TC (not reached vs. 48 months; p=0.03). Extra-thoracic metastases were present in 13 of 19 (68%) meso-positive TC and 17 of 23 (74%) meso-negative TC. Conclusions: This is the largest series of meso expression in TC. Meso expression was detected in 45% of TC and associated with a significantly higher overall survival. Further studies are needed to assess the role of meso as a potential therapeutic target in TC.

Prospective, noninterventional study of vinflunine treatment in advanced urothelial cell carcinoma (UCC) in routine clinical practice.

e15505 Background: Vinflunine is recommended by the European guideline for the treatment of UCC after failure of platinum-based chemotherapy. In a prospective, non-interventional study (NIS) we inv...