Platinum Failure Research Articles

PD11-11 INTERIM RESULTS FROM PURE-01: A PHASE 2, OPEN-LABEL STUDY OF NEOADJUVANT PEMBROLIZUMAB (PEMBRO) BEFORE RADICAL CYSTECTOMY FOR MUSCLE-INVASIVE UROTHELIAL BLADDER CARCINOMA (MIUC)

You have accessJournal of UrologyBladder Cancer: Invasive I1 Apr 2018PD11-11 INTERIM RESULTS FROM PURE-01: A PHASE 2, OPEN-LABEL STUDY OF NEOADJUVANT PEMBROLIZUMAB (PEMBRO) BEFORE RADICAL CYSTECTOMY FOR MUSCLE-INVASIVE UROTHELIAL BLADDER CARCINOMA (MIUC) Andrea Necchi, Alberto Briganti, Daniele Raggi, Patrizia Giannatempo, Marco Bianchi, Luigi Mariani, Antonella Messina, Andrea Anichini, Massimo Freschi, Maurizio Colecchia, Roberto Salvioni, Renzo Colombo, Andrea Gallina, and Francesco Montorsi Andrea NecchiAndrea Necchi More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , Daniele RaggiDaniele Raggi More articles by this author , Patrizia GiannatempoPatrizia Giannatempo More articles by this author , Marco BianchiMarco Bianchi More articles by this author , Luigi MarianiLuigi Mariani More articles by this author , Antonella MessinaAntonella Messina More articles by this author , Andrea AnichiniAndrea Anichini More articles by this author , Massimo FreschiMassimo Freschi More articles by this author , Maurizio ColecchiaMaurizio Colecchia More articles by this author , Roberto SalvioniRoberto Salvioni More articles by this author , Renzo ColomboRenzo Colombo More articles by this author , Andrea GallinaAndrea Gallina More articles by this author , and Francesco MontorsiFrancesco Montorsi More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.634AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES MIUC is an aggressive disease and >40% of patients (pts) will develop recurrence after radical cystectomy (RC). Cisplatin-based neoadjuvant chemotherapy (CT) yields Level 1 evidence, but it is administered in a minority of pts. Pembro is an EMA and FDA-approved therapy for metastatic UC after platinum failure or for cisplatin-ineligible pts. METHODS PURE-01 (NCT02736266) is an open-label, single-arm, phase 2 study to evaluate the activity, medical and surgical safety, and immune modulatory effects of pembro administered before RC. Inclusion criteria: predominant UC histology and </=T3bN0 stage, regardless of eligibility to cisplatin-based CT. Pts received 3 cycles of pembro 200mg 3 weekly before RC. CT scan, FDG-PET/CT scan, and bladder multiparametric MRI (mpMRI) were done during screening and before RC. No additional anti PD-1/PD-L1 therapy was allowed post-operatively. Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be included in the ITT analysis. The H1 is ypT0 >/=20% and H0 ypT0</=10%. In a 2-stage design, 90 pts overall will be accrued (80% power and a 2-sided alpha at 10%). CTCAE v4.03 will be used to grade adverse events (AE), and immune-related AE (irAE). The associations of an 18-gene expression profile and IHC PD-L1 combined positive score (CPS) with pathologic response will be evaluated. TURB specimens from all pts will be also analyzed with FoundationOne test. A first interim analysis for safety is presented. RESULTS From 02-11/2017, 24 pts were enrolled (22M, 2F). 17 had cT3, 7 cT2, 6 had hydronephrosis. 20 pts are evaluable for safety: 1 pt (5%) had G3 irAE (ALT increase) and suspended pembro; 3 (15%) had reversible G2 irAE. There were 3 IIIa and 1 IIIb complications according to Clavien-Dindo classification. At the time of data analysis, 14 pts are evaluable for the primary endpoint. There were 4/14 ypT0 (28.6%) and 3 ypTa/is (total ypT</=2 rate: 50%). Median n. of removed lymph nodes was 27. 19 pts had MRI-evaluable response: baseline median tumor thickness was 10mm vs 5mm after pembro, coupled with significant mpMRI changes. CONCLUSIONS According to the first presented data on the preoperative use of immune-checkpoint inhibitors before major surgery, pembro was safe and endowed with a potent effect in MIUC. Activity results and full translational findings in the first 20 pts will be presented. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e238 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Andrea Necchi More articles by this author Alberto Briganti More articles by this author Daniele Raggi More articles by this author Patrizia Giannatempo More articles by this author Marco Bianchi More articles by this author Luigi Mariani More articles by this author Antonella Messina More articles by this author Andrea Anichini More articles by this author Massimo Freschi More articles by this author Maurizio Colecchia More articles by this author Roberto Salvioni More articles by this author Renzo Colombo More articles by this author Andrea Gallina More articles by this author Francesco Montorsi More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Interim results from PURE-01: A phase 2, open-label study of neoadjuvant pembrolizumab (pembro) before radical cystectomy for muscle-invasive urothelial bladder carcinoma (MIUC).

TPS533 Background: MIUC is an aggressive disease and &gt; 40% of patients (pts) will develop recurrence after radical cystectomy (RC). Despite cisplatin-based neoadjuvant chemotherapy yields Level 1 evidence, it is administered in a minority of pts worldwide. Pembro is an EMA and FDA-approved standard therapy for metastatic UC after platinum failure or for cisplatin-ineligible pts. Our hypothesis was that pembro, given neoadjuvantly, could downstage MIUC and reduce recurrence. Methods: PURE-01 (NCT02736266) is an open-label, single-arm, phase 2 study to evaluate the activity, medical and surgical safety, and immune modulatory effects of pembro administered as a short window-of-opportunity course of therapy preceding RC. Eligibility criteria included: T2-T4aN0 stage, and residual disease after transurethral resection of the bladder (TURB, surgical opinion, cystoscopy or radiological presence). The study includes cisplatin eligible- and ineligible pts. Pts receive 3 cycles of pembro 200mg 3 weekly before RC (planned &lt; 3 weeks of the last dose). Computed tomography (CT) scan, FDG-PET/CT scan, and bladder multiparametric magnetic resonance imaging (mpMRI) are done during screening and before RC. Radiologically non responders to pembro (per investigator decision; i.e., study failures) are given 3 additional courses of dose-dense MVAC chemotherapy. After RC, pts are managed according to local guidelines (adjuvant chemotherapy vs observation). Further anti PD-1/PD-L1 therapy will not be given post-operatively. Pathologic complete response (pT0) is the primary endpoint. All pts enrolled who receive at least 1 cycle of study drug will be included in the ITT analysis. The H1 is pT0 ≥20% and H0 pT0≤10%. In a 2-stage design, 90 pts overall will be accrued (80% power and a 2-sided test of significance at the 10% level). A first interim analysis for safety is planned after 18 patients enrolled and treated (by December 1st, 2017). Activity results and early translational findings (immune-cell profiling) will be added, and may be regarded to as first data of preoperative immunotherapy before major surgery. Clinical trial information: NCT02736266.

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial

The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. Merck KGaA, and Pfizer Inc.

Budget Impact of Atezolizumab for The Treatment of 2nd Line Non-Small Cell Lung Cancer (NSCLC) After Failure with Platinum Containing Chemotherapy in Greece

Lung cancer is the leading cause of death from cancer. Greece is the EU country with the highest incidence of lung cancer under the age of 45. Non-small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. The purpose of this analysis was to estimate the potential budgetary impact of introducing Atezolizumab as a 2nd line treatment for NSCLC patients in Greece, after failure with platinum-containing chemotherapy. The analysis was based on a budget impact model considering the market shares and price of Azetolizumab as a 2nd line treatment approach in NSCLC patients. Published literature was the source of data used regarding the clinical effectiveness of each intervention. The model was populated with epidemiological and clinical effectiveness data from the literature and Greek-specific inputs on health resource use, based on an expert panel of 10 oncologists. The analysis follows a third party payer perspective (Greek Social Insurance). The Incremental Annual Budget Impact of the gradual introduction of Azetolizumab (first year market shares 5% and fifth year 27%) as a 2nd line treatment for NSCLC patients is projected to be €1,483,155, €3,377,747, €4,328,746, €4,421,391 and €5,016,492 for year one to five respectively. The uptake of Atezolizumab is estimated to result in an incremental cumulative budget impact of €18,627,531 for the five year time horizon of the analysis. The analysis is sensitive to the price of Atezolizumab (and its comparators) and the projected market shares. Based on the available epidemiological data for Greece, 2,504 patients with NSCLC move to 2nd line treatment after the failure of platinum containing chemotherapy making them eligible for Atezolizumab. Owing to the projected market shares for Atezolizumab the budgetary impact of its gradual uptake is of moderate size.

5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) as a third-line chemotherapy treatment in metastatic gastric cancer, after failure of fluoropyrimidine, platinum, anthracycline, and taxane.

Studies on the effects of third-line chemotherapy (CT) in advanced gastric cancer (GC) patients are still scarce. The aim of this study was to evaluate the efficacy and safety of the modified 5-fluorouracil, leucovorin, and irinotecan (mFOLFIRI) regimen as a third-line CT in metastatic GC patients, after failure of fluoropyrimidine, platinum, anthracycline, and taxane. After failure of first- and second-line therapies, 42 patients received third-line FOLFIRI (180 mg/m² irinotecan and 400 mg/m² leucovorin administered concomitantly as a 90-minute intravenous (IV) infusion on day 1, followed by a 400 mg/m² 5-fluorouracil IV bolus then 2600 mg/m² continuous infusion over 46 hours), between January 2009 and December 2015. FOLFIRI was administered for a median of 6 cycles (range 4-12 cycles). Eight patients achieved partial response, while 13 patients showed stable disease, resulting in the overall response rate (ORR) of 19% and disease control rate (DCR) of 50%. The most frequent grade 3-4 hematological and non-hematological toxicities were neutropenia (14.2%) and diarrhea (7.1%). The median progression-free survival (PFS) and overall survival (OS) from the start of third-line CT were 3.8 months (95% confidence interval [CI], 3.0-4.5) and 6.8 months (95% CI, 5.6-7.9), respectively. According to the multivariate analysis, two factors were independently predictive of the poor OS: >2 regions of metastasis (relative risk [RR], 2.6; 95% CI, 1.3-5.4) and a high level of carcinoembryonic antigen [CEA] (RR, 3.4; 95% CI, 1.6-7.4). In conclusion, FOLFIRI was well tolerated as third-line CT and showed promising PFS and OS in advanced GC patients, after failure of fluoropyrimidine, platinum, anthracycline, and taxane.

Characterization of potential predictive biomarkers of response to nivolumab in CheckMate 141 in patients with squamous cell carcinoma of the head and neck (SCCHN).

6050 Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs 5.1 months) and improved response (13.3% vs 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n = 36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs 13%; P&lt; 0.05). Interestingly, PD-1+ CD8+ and PD-1+ CTLA-4+ CD8+ effector T cells (likely exhausted T cells) decreased about 2-fold following nivolumab in both responders and non-responders ( P&lt; 0.05), whereas, the decrease in CTLA-4+ CD8+ effector T cells following nivolumab was significant in responders only (8% vs 5%; P&lt; 0.05). Levels of PD-1+ TIM-3+ CD8+ effector cells decreased following nivolumab in non-responders only (11% vs 7%; P&lt; 0.05), a similar non-significant reduction was observed in responders. Levels of PD-1+ Tregs were lower in responders than non-responders at baseline (19% vs 33%; P&lt; 0.01), and following nivolumab (12% vs 20%; P&lt; 0.001). As in T-effector cell populations, PD-1+ Tregs decreased about 1.6-fold after nivolumab in both responders and non-responders ( P&lt; 0.01). Interestingly, baseline Ki67+ Treg levels were lower in non-responders (28% vs 17%; P&lt; 0.05). Conclusions: Response to nivolumab may be associated with higher levels of CD8+ T cells and CTLA-4+ CD8+ effector T cells, and lower PD-1+ CD8+ effector T cells and PD-1+ Tregs at baseline. Targeting both PD-1 and CTLA-4 axes is warranted in SCCHN to overcome suppressive signals in CD8+ effector T cells and in Treg cells expressing both checkpoint receptors. Clinical trial information: NCT02105636.

Characterization of potential predictive biomarkers of response to nivolumab in CheckMate-141 in patients with squamous cell carcinoma of the head and neck (SCCHN).

5 Background: Nivolumab, an anti-programmed death-1 (PD-1) monoclonal antibody, demonstrated longer median overall survival (7.5 vs. 5.1 months) and improved response (13.3% vs. 5.8%) versus investigator choice chemotherapy (ICC) in patients with recurrent SCCHN after platinum failure in CheckMate 141 (NCT02105636), a randomized, open-label Phase 3 trial. We screened peripheral blood lymphocytes (PBL) to identify biomarkers which may predict response to nivolumab. Methods: Paired baseline (day 1) and on treatment (day 43) PBL samples (n=36; 24 nivolumab; 12 ICC) were analyzed using multicolor flow cytometry and a non-competing anti-PD-1 antibody. Results were correlated with clinical outcome: responders (complete/partial response) and non-responders (stable or progressive disease). Results: Levels of CD8+ T cells at baseline and on treatment were higher in nivolumab responders compared to non-responders (23% vs. 13%; p&lt;0.05). Interestingly, PD-1+ CD8+ and PD-1+ CTLA-4+ CD8+ effector T cells (likely exhausted T cells) decreased about 2-fold following nivolumab in both responders and non-responders (p&lt;0.05), whereas, the decrease in CTLA-4+ CD8+ effector T cells following nivolumab was significant in responders only (8% vs. 5%; p&lt;0.05). Levels of PD-1+ TIM-3+ CD8+ effector cells decreased following nivolumab in non-responders only (11% vs. 7%; p&lt;0.05), a similar non-significant reduction was observed in responders. Levels of PD-1+Tregs were lower in responders than non-responders at baseline (19% vs. 33%; p&lt;0.01), and following nivolumab (12% vs. 20%; p&lt;0.001). As in T effector cell populations, PD-1+ Tregs decreased about 1.6-fold after nivolumab in both responders and non-responders (p&lt;0.01). Interestingly, baseline Ki67+ Treg levels were lower in non-responders (28% vs. 17%; p&lt;0.05). Conclusions: Response to nivolumab may be associated with higher levels of CD8+ T cells and CTLA-4+ CD8+ effector T cells, and lower PD-1+ CD8+ effector T cells and PD-1+ Tregs at baseline. Targeting both PD-1 and CTLA-4 axes is warranted in SCCHN to overcome suppressive signals in CD8+ effector T cells and in Treg cells expressing both checkpoint receptors. Clinical trial information: NCT02105636.

P1.07-014 Impact of Chemotherapy for Small Cell Lung Cancer in the Third Line and beyond, a SEER-MEDICARE Analysis

While there is no approved third line chemotherapy option for small cell lung cancer (SCLC), empiric use of chemotherapy is common in this setting in the absence of supporting prospective data. In order to assess the potential benefit and predictors of chemotherapy use beyond the second line setting in SCLC, we analyzed the SEER-MEDICARE database. We employed data of SCLC patients diagnosed between 1985 and 2005. Univariate (UVA) association of line of chemotherapies with covariates was examined with Wilcoxon rank-sum test, chi-square or Fisher’s exact test. Multivariable (MVA) logistic regression analysis for line of therapy was conducted using the following covariates: year of diagnosis, age, gender, race, Medicare status, urban/rural location, and radiation. Survival functions were estimated by the Kaplan-Meier method and the log-rank test was used to assess for difference in overall survival (OS) stratified by line of therapy. UVA and MVA survival analyses were carried out using the Cox proportional hazards model. To further balance confounders between patients receiving different lines of therapy, propensity scores were estimated using a MVA logistic regression model to predict the receipt of 3rd line chemotherapy based on relevant covariates. Propensity score analysis was further conducted by including the estimated propensity score as a covariate in a Cox proportional hazards model. All analyses were done using SAS 9.3 with two-sided tests and a significant level of 0.05. There were 47,351 patients with SCLC of which 23,535 (49.7%) received chemotherapy and 10,887 (23%) received platinum-based chemotherapy. Of the platinum-treated patients, 1424 (13.1%) received additional salvage therapy of either topotecan alone (n=801) or topotecan and additional treatments as 3rd line and beyond (n=623). The median OS was 11, 13, 15 and 17 months respectively for patients treated with one, two, three or > 3 lines of chemotherapy respectively. Propensity score analysis showed additional lines of therapy beyond the second line was associated with a reduced risk of death (HR: 0.786; 0.729 - 0.847, p<0.001 and 0.617; 0.564 - 0.675; p<0.001 for 3rd line and > 3 lines of therapy respectively). Age (p=0.043) and year of diagnosis (P<0.001) were significantly associated with treatment beyond 2nd line topotecan on MVA analysis. Salvage chemotherapy is not commonly used following failure of platinum containing chemotherapy in SCLC patients. However, chemotherapy beyond the second line was associated with an incremental survival benefit in US MEDICARE-eligible SCLC patients.

Polymorphisms of Genes Encoding Multidrug Resistance Proteins as a Predictive Factor for Second-Line Docetaxel Therapy in Advanced Non-small Cell Lung Cancer

Multidrug resistance (MDR) remains a substantial problem in chemotherapy. The purpose of the study was to investigate potential factors, including MDR genes polymorphisms, that could be used in qualification for second-line docetaxel therapy in non-small cell lung cancer (NSCLC) patients after failure of platinum based chemotherapy. Study group comprised of 58 Caucasian subjects. Evaluation of Single Nucleotide Polymorphisms (SNPs) of ABCC2/MRP2 and ABCB1/MDR1 genes was performed using the High Resolution Melting (HRM) technique. TUBB3 gene expression was evaluated on RNA isolated from tumor tissue. Results with p value of <0.05 were considered significant. Factors associated with reduced risk of disease progression included good performance status (PS), long period between diagnosis and docetaxel treatment, and smoking for <10 pack-years. Disease control occurred more often in patients with G/G genotype of the ABCC2/MRP2 gene. Median overall survival was 4.25 months. Factors such as: good PS, disease control after docetaxel, long period from diagnosis to docetaxel, lack of significant weight loss, and third-line treatment were associated with prolongation of patients survival. Overall survival probability was significantly lower in patients with significant weight loss, poor PS, lack of disease control after docetaxel, and without third-line treatment. Factors that characterized the highest risk of survival shortening were: inability to apply third-line treatment, lack of best response to first-line therapy, poor PS, and C/G or G/G genotypes of ABCC2/MRP2 gene. We concluded that assessed factors had mainly prognostic and not predictive value. Finding reliable molecular predictors for second line docetaxel therapy requires further clinical trials.

Are immune checkpoint blockade monoclonal antibodies active against CNS metastases from NSCLC?-current evidence and future perspectives.

Brain metastases occur in approximately half of patients with non-small cell lung cancer (NSCLC) and are associated with a poor prognosis and an inferior quality of life. Historically systemic therapy has had a limited role in CNS disease with a reliance placed on local treatments. The emergence of targeted therapies and immune checkpoint inhibitors (ICIs) in recent years has dramatically changed the treatment landscape of NSCLC. Programmed cell death-1 (PD-1) inhibitors have demonstrated efficacy in three randomized trials and now represent standard second line therapy after platinum failure. Trials have largely excluded patients with symptomatic or untreated CNS disease as the brain has been considered an 'immune-privileged' organ. We review the evidence and future prospects of ICIs in treating brain metastases in NSCLC.

Management of patients with recurrent/advanced cervical cancer beyond first line platinum regimens: Where do we stand? A literature review.

Cervical cancer is the fourth most common cancer affecting women worldwide. Despite advances in screening and human papillomavirus (HPV) vaccination, a significant number of women present with or develop advanced disease. Palliative platinum-based chemotherapy (CT) is the standard first-line treatment for metastatic/recurrent cervical cancer. The prognosis remains poor and effective second line options are urgently needed. We searched the English-language medical literature as well as relevant guideline databases, published from January 1981 to December 2015 and identified publications related to cervical cancer and its therapies. Our effort was to highlight the available treatment options in the setting of recurrent/metastatic disease. Although there have been important advances in the management of women with cervical cancer, the optimal treatment for patients with locally recurrent and metastatic disease after platinum failure is still problematic. Overall, there is a trend in terms of longer overall survival (OS) and better quality of life for the combination of cisplatin/paclitaxel (PC) as compared to the doublets of cisplatin/topotecan (TC), cisplatin/vinorelbine (VC), and cisplatin/gemcitabine (GC). Currently available single agents beyond first-line platinum-based therapy have limited efficacy in this setting and include topoisomerase inhibitors, vinca alkaloids, taxanes, alkylating agents and antimetabolites. Several targeted therapies have demonstrated activity in advanced cervical cancer. Bevacizumab has been evaluated in a phase III trial using doublets of cisplatin with paclitaxel or topotecan and has been approved in the first-line setting by the U. S. Food and Drug Administration. Selective targeting of angiogenic kinases by tyrosine kinase inhibitors (TKIs) may represent a novel therapeutic tool in this setting, but its use alone or in combination with CT is still investigational. Early reports have implicated PI3KCA somatic mutations suggesting that mTOR-targeted agents should be explored in this disease. Development of the immune checkpoint programmed cell death 1 (PD-1) and T-lymphocyte-associated molecule-4 (CTLA-4) inhibitors have been of considerable interest, leading to ongoing phase II studies in patients with advanced cervical cancer. Progress in the management of recurrent and advanced cervical cancer patients has been slow and restricted to palliative intent. These patients should be considered for clinical trials of novel targeted agents and/or immunotherapy.

LBA27 - Randomized, open-label, phase III study comparing irinotecan plus S-1 with S-1 alone in patients with advanced esophageal squamous cell carcinoma after failure of prior platinum- or taxane-based chemotherapy: Results of an interim analysis

LBA27 - Randomized, open-label, phase III study comparing irinotecan plus S-1 with S-1 alone in patients with advanced esophageal squamous cell carcinoma after failure of prior platinum- or taxane-based chemotherapy: Results of an interim analysis

Epicure: a European epidemiological study of patients with an advanced or metastatic Urothelial Carcinoma (UC) having progressed to a platinum-based chemotherapy

BackgroundPlatinum-based systemic chemotherapy is considered the backbone for management of advanced urothelial carcinomas. However there is a lack of real world data on the use of such chemotherapy regimens, on patient profiles and on management after treatment failure.MethodsFifty-one randomly selected physicians from 4 European countries registered 218 consecutive patients in progression or relapse following a first platinum-based chemotherapy. Patient characteristics, tumor history and treatment regimens, as well as the considerations of physicians on the management of urothelial carcinoma were recorded.ResultsA systemic platinum-based regimen had been administered as the initial chemotherapy in 216 patients: 15 in the neoadjuvant setting, 61 in adjuvant therapy conditions, 137 in first-line advanced setting and 3 in other conditions. Of these patients, 76 (35 %) were initially considered as cisplatin-unfit, mainly because of renal impairment (52 patients). After platinum failure, renal impairment was observed in 44 % of patients, ECOG Performance Status ≥ 2 in 17 %, hemoglobinemia < 10 g/dL in 16 %, hepatic metastases in 13 %. 80 % of these patients received further anticancer therapy. Immediately after failure of adjuvant/neoadjuvant chemotherapy, most subsequent anticancer treatments were chemotherapy doublets (35/58), whereas after therapy failure in the advanced setting most patients receiving further anticancer drugs were treated with a single agent (80/114). After first progression to chemotherapy, treatment decisions were mainly driven by Performance Status and prior response to chemotherapy (>30 % patients). The most frequent all-settings second anticancer therapy regimen was vinflunine (70 % of single-agent and 42 % of all subsequent treatments), the main reasons evoked by physicians (>1 out of 4) being survival benefit, safety and phase III evidence.ConclusionIn this daily practice experience, a majority of patients with urothelial carcinoma previously treated with a platinum-based therapy received a second chemotherapy regimen, most often a single agent after an initial chemotherapy in the advanced setting and preferably a cytotoxic combination after a neoadjuvant or adjuvant chemotherapy. Performance Status and prior response to chemotherapy were the main drivers of further treatment decisions.

Second-Line Treatment of Non-Small Cell Lung Cancer: New Developments for Tumours Not Harbouring Targetable Oncogenic Driver Mutations.

Platinum-based doublet chemotherapy with or without bevacizumab is the standard of care for the initial management of advanced and metastatic non-small cell lung cancer (NSCLC) without a targetable molecular abnormality. However, the majority of patients with NSCLC will ultimately develop resistance to initial platinum-based chemotherapy, and many remain candidates for subsequent lines of therapy. Randomised trials over the past 10-15years have established pemetrexed (non-squamous histology), docetaxel, erlotinib and gefitinib as approved second-line agents in NSCLC without targetable driver mutations or rearrangements. Trials comparing these agents with other chemotherapy, evaluating the addition of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) to chemotherapy or the addition of another targeted agent to erlotinib or gefitinib have all failed to demonstrate an improvement in overall survival for patients with NSCLC. In contrast, recent data comparing therapy with novel monoclonal antibodies against programmed cell death 1 (PD-1) or PD ligand (PD-L1) pathway versus standard chemotherapy following platinum failure have demonstrated significant improvements in overall survival. Therapy with nivolumab or pembrolizumab would now be considered standard second-line therapy in patients without contraindication to immune checkpoint inhibitors. Atezolizumab also appears promising in this setting.

Tumor's flare-up and patterns of recurrence in patients (pts) with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treated with anti-PD1/PD-L1 inhibitors.

6072Background: About 20% of R/M HNSCC pts have an objective response with anti-PD1/PD-L1 inhibitors after platinum failure. Some pts, however, experience a rapid flare-up during treatment. We eval...

Gemcitabine, Vinorelbine and Dexamethasone (GVDexa) As Second-Line Salvage Regimen in Relapsed and Refractory Hodgkin's Lymphoma

INTRODUCTION: Traditional platinum-based salvage regimens like DHAP, ICE are effective in relapsed Hodgkin's lymphoma (HL), but are more toxic. Gemcitabine based regimens are equally effective in salvage of lymphomas, but are less toxic and allow better stem cell collection for subsequent high dose therapy (HDT). There is limited data on the usefulness of gemcitabine based salvage regimens after the failure of salvage therapies like DHAP and ICE. At our center, we used a combination of gemcitabine, vinorelbine and dexamethasone (GVDexa), a non-platinum containing regimen in those patients who failed DHAP/ ICE based salvage treatment.METHODS: The records of patients with relapsed and refractory Hodgkin's lymphoma, who were treated with GVDexa, were reviewed. The regimen consisted of Gemcitabine 1000mg/m2 IV (D1,8), Vinorelbine 25mg/m2 IV (D1,8) Dexamethasone 40mg oral (D1-4) given as outpatient. It was given for 2-3 cycles until best response or till the patient underwent HDT.RESULTS: Between July 2010 to Jun 2015, 25 patients received GVDexa. The median age was 23 years (Range: 11 to 45 yrs) and 64% were males. Baseline characteristics are summarised in Table 1. Twenty-one patients (84%) had previous exposure to salvage therapy with DHAP/ ICE and GVDexa was given as third line treatment. The overall response rate was 48% (12/25) with complete response in 20% (5/25) and partial response in 28% (7/25). Toxicity: A total of 61 cycles [Median: 2 (Range: 1-6)] were delivered among 25 patients. Grade 3/4 haematological toxicities (neutropenia and thrombocytopenia) occurred in 9/61 (14.7%) cycles and febrile neutropenia occurred in 2 (3.2%) cycles. Grade 3/4 non-haematological toxicities were rare (paralytic ileus in 1 patient). There were no toxic deaths. Stem cell collection: Stem cell harvesting for HDT was attempted in 12 patients and was successful (> 2 million CD34 positive cells/kg) in 8 (67%) patients. Seven of these patients successfully completed HDT. Two patients who failed stem cell collection underwent reduced intensity conditioning allogeneic transplant.CONCLUSIONS: GVDexa, when used as third line therapy in relapsed and refractory HL shows promising response rates, with minimal toxicity. The high response rates achieved despite failure of first line platinum based salvage, points to the potential usefulness of this regimen as first line salvage therapy in refractory HL. GVDexa could emerge as a safe and effective non-platinum containing alternative regimen for second-line therapy in HL.Table 1Baseline characteristics (N=25)PARAMETERNumber (Range/Percentage)Age (median, range)23 yrs (10 to 45 yrs)Male sex16 (64%)Prior exposure to DHAP/ICE chemotherapy21 (84%)Previous lines of chemotherapy (median, range)2 (1 to 4)Time from 1st diagnosis to relapse (median, range)31.5 months (4.3 to 153.7 months)Primary progressivea/refractory13 (52)Stage III/IV at relapse20 (80)Haemoglobin < 10g/dL at relapse12 (48)a. Progressed within 3 months of completion of first line chemotherapy DisclosuresNo relevant conflicts of interest to declare.

Predicting the response of patients with advanced urothelial cancer to methotrexate, vinblastine, Adriamycin, and cisplatin (MVAC) after the failure of gemcitabine and platinum (GP).

BackgroundPlatinum-based systemic chemotherapy is the treatment of choice for patients with advanced urothelial carcinoma (UC). Although no chemotherapeutic regimen is established as a second-line therapy, recent studies reported that methotrexate, vinblastine, Adriamycin and cisplatin (MVAC) elicited a significant response in patients who failed gemcitabine and platinum (GP) chemotherapy. We investigated the clinical factors useful for predicting a favourable response to MVAC in UC patients who failed GP.MethodsForty-five patients with advanced UC who received second-line MVAC chemotherapy after failure with first-line GP chemotherapy were enrolled in this study. Univariate and multivariate analyses based on Cox’s regression were performed to identify independent prognostic factors for progression-free survival (PFS) after second-line MVAC chemotherapy.ResultsThe median follow-up period after the first MVAC administration was 10.0 months. The median PFS and overall survival (OS) were 6.5 months (95 % confidence interval [CI]: 5.1–7.9) and 14.5 months (95 % CI, 7.4–21.4), respectively. The overall response rate was 57.8 %. The response to first-line GP chemotherapy (hazard ratio [HR], 2.500; p = 0.012) and patient age (HR, 1.047; p = 0.033) were predictors of PFS after MVAC chemotherapy.ConclusionsThe response to first-line GP chemotherapy and age were independent predictors of PFS in patients who received second-line MVAC chemotherapy. This report is the first to describe independent predictors of PFS after MVAC chemotherapy.

Phase II study of everolimus as a salvage treatment after failure of fluoropyrimidine and platinum in patients with metastatic gastric cancer positive for pS6Ser240/4 expression.

4057 Background: Everolimus is a macrolide derivative of rapamycin which inhibits mTOR. Our previous phase II study in 2nd line setting showed that everolimus had no significant activity with 1.7 m...

Molecular biology and targeted therapies for urothelial carcinoma.

Metastatic urothelial cancer (UC) is associated with poor prognosis. In the first-line setting, platinum-based chemotherapy is the standard of care but resistance rapidly occurs. With no validated treatment proven to increase survival after platinum failure, there is an urgent unmet medical need to develop new and efficacious cytotoxic agents. A better understanding of the molecular signaling pathways regulating UC has led to the development of new and innovative therapeutic strategies. Despite this, many recent drugs show only modest activity as single agents, and combining them with standard chemotherapy does not seem to enhance efficacy. Ongoing research is producing, however, a generation of new drugs that are showing promising results in clinical trials. This paper aims to review the most important mechanisms in bladder cancer tumorigenesis and describe the new therapeutic options currently undergoing evaluation in clinical trials.

O1-17-5 - Irinotecan as a Third-Line Treatment of Advanced Gastric Cancer After Failure of Fluoropyrimidine, Platinum, and Taxanes

Background: Oral fluoropyrimidine plus platinum regimen as a first-line and weekly paclitaxel monotherapy as a second-line were one of Japanese standard care for advanced gastric cancer. The irinotecan monotherapy has become a common practice as a third-line chemotherapy, though there are few reports regarding the efficacy. The aim of this study was to evaluate the efficacy and safety of irinotecan as a third-line chemotherapy in patients refractory or intorelant to first-line oral fluoropyrimidine plus platinum and second-line taxane.Methods: We retrospectively analyzed 52 patients received irinotecan as a third-line chemotherapy at the National Cancer Center Hospital, between February 2008 and December 2013.Results: The characteristics of the 52 patients were as follows: median age, 65 years (range, 41 to 78); male/female, 41/11; PS 0/1/2, 2/40/10; number of metastatic sites 1/ ≥ 2, 14/38; and peritoneal metastasis; yes/no, 30/22. The median number of irinotecan administration was three (rage, 1 to 25), and 25 patients (48%) had initial dose reduction. Among the 32 patients who had measurable lesions by RECISTv1.1 criteria, one patient achieved confirmed partial response and six patients had stable disease. The overall response rate was 3% and the disease control rate was 21%. The median progression-free survival was 2.3 months (95% confidence interval [CI], 1.8 to 2.8) and median overall survival was 4.0 months (95% CI, 2.5 to 5.5). The adverse events of grade 3/4 included neutropenia in 14 patients (27%), febrile neutropenia in six patients (12%), anorexia in six patients (12%), and diarrhea in three patients (6%), respectively.Conclusion: Irinotecan would be reasonably well tolerated as a third-line therapy regimen for patients with advanced gastric cancer, however the efficacy might be limited.