Chemotherapy For Metastatic Urothelial Carcinoma Research Articles

Durable Response to Enfortumab Vedotin Compared to Re-challenging Chemotherapy in Metastatic Urothelial Carcinoma After Checkpoint Inhibitors.

Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has been used for patients with metastatic urothelial carcinoma (mUC) after progressing on checkpoint inhibitors (CPIs). Re-challenging chemotherapy with platinum agents and continuing CPIs beyond progressive disease (PD) have often been chosen following PD on CPIs, and several studies indicate favorable treatment effects of re-challenging chemotherapy. There is little evidence for comparing EV and re-challenging chemotherapy in real-world clinical practice. The aim was to reveal the real-world treatment outcomes of EV, re-challenging chemotherapy, and continuing CPIs beyond PD in mUC patients. A multi-institutional dataset of 350 mUC patients treated with CPIs was utilized. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) were evaluated to compare the treatment arms. One hundred and nine mUC patients were treated with EV with a median follow-up of 6.4months. The ORR and disease control rate (DCR) were 48% and 70%, respectively. The OS from PD on pembrolizumab exhibited significant differences among the three groups, with a median OS of 8, 14, and 29months in continuing pembrolizumab beyond PD, re-challenging chemotherapy, and EV, respectively. When comparing the survival outcomes from the initiation of the treatment, there is neither a difference in OS (p=0.124), PFS (p=0.936), nor ORR (p=0.816) between EV and re-challenging chemotherapy. Notably, the DOR in patients who achieved an objective response was significantly longer in the EV group than the re-challenging chemotherapy group (a median of 11 and 5months, p=0.049). For OS, the difference was not statistically significant (27 and 11months in EV and re-challenging chemotherapy, respectively: p=0.05). A superior effect of EV on patient survival compared to re-challenging chemotherapy and continuing pembrolizumab beyond PD was observed in our real-world analysis, which is attributed to the durable DOR in EV treatment despite the similar ORR to re-challenging chemotherapy.

Real-world retrospective review of monotherapy following platinum-based chemotherapy for metastatic urothelial cancer

To compare estimated survival times of patients who had received maintenance monotherapy with gemcitabine (GEM), or an immuno-oncology (IO) drug (i.e., pembrolizumab or avelumab) or both therapies (one after the other) following platinum-based combination chemotherapy for metastatic urothelial carcinoma (UC) in a real-world setting. For this retrospective study, we included consecutive patients with metastatic UC who had received first-line platinum-based chemotherapy followed by second-line treatment at our centre from March 2008 to June 2020. Of the 74 patients identified, 58 had received monotherapy as second line treatment, and 16 had received combination chemotherapy (i.e., non-monotherapy). The estimated median duration of survival was significantly longer in the monotherapy group compared with the non-monotherapy group (29 vs 7 months). Multivariate analysis showed that the outcome of the first-line chemotherapy treatment was the most important prognostic factor for survival. There was no significant difference in survival times between monotherapy with GEM or IO drugs. In addition, survival was significantly prolonged when GEM therapy was administered following IO drugs compared with GEM therapy alone. Monotherapy following primary chemotherapy for advanced UC significantly prolonged survival times, and IO drug therapy remained effective when followed by GEM single agent maintenance therapy.

A randomised, double blind, phase II clinical trial of maintenance cabozantinib following chemotherapy for metastatic urothelial carcinoma (mUC): Final analysis of the ATLANTIS cabozantinib comparison.

LBA4505 Background: Platinum-based chemotherapy (PBC) is an active first line therapy in mUC, but duration of response is usually short. We hypothesised that switch maintenance therapy with the tyrosine kinase inhibitor cabozantinib, in patients who have derived clinical benefit from PBC, would improve outcomes for mUC. Methods: ATLANTIS is an adaptive, multi-comparison, phase II trial platform. It tests multiple maintenance therapies for mUC patients who complete 4 to 8 cycles of PBC without disease progression. Whilst some patients were selected for randomisation into alternative comparisons in the platform based on putative predictive biomarkers, those who were not selected were randomised 1:1 to commence either cabozantinib 40mg once-daily or matching placebo within 10 weeks of completing PBC until progression. The primary endpoint was progression free survival (PFS) and 114 events in 140 patients (90% power, 20% 1-sided level alpha) were required to target a hazard ratio of 0.67. Due to a change in standard of care (maintenance avelumab), this was modified to 50 events in 57 patients (72.3% power, 20% 1-sided alpha) prior to the study closing early. PFS was compared between trial arms, by intention to treat, within a Cox model incorporating baseline minimisation factors. Secondary endpoints included overall survival (OS), response rate, maximum percentage decrease in measurable disease, safety and tolerability. Results: 30 patients were randomised to cabozantinib and 31 to placebo from 25 sites (Feb 2017-March 2021). Patient characteristics (median age 69.0 years; 75.4% male; 75.4% bladder primary; 67.2% ECOG PS 0; 70.5% prior cisplatin; 36.1% visceral metastases) were balanced by treatment arm. 25 (83.3%) and 26 (83.9%) PFS events had occurred in the cabozantinib and placebo arms. Median PFS was 13.7 weeks (80% confidence interval (CI) 12.1-23.3) with cabozantinib and 15.8 weeks (80% CI 11.3-23.6) with placebo (adjusted hazard ratio 0.89 favouring cabozantinib, 80% CI 0.61-1.3, 1-sided p = 0.35). There was no difference in overall survival (hazard ratio 0.80 (0.52-1.23) p=0.25). In the safety population (n = 61) treatment related adverse events were mostly low grade. The most frequent (all grades), fatigue (56.7% vs 32.2%, p = 0.02), hypertension (43.3% vs 12.9%, p = 0.01), nausea (30% vs 19.4%, p = 0.36) and diarrhea (40.0% vs 6.5%, p < 0.01), were more common with cabozantinib. Overall, cabozantinib was tolerable with median duration of treatment of 13 28-day cycles of cabozantinib or 10 of placebo. 13 (43.%) vs 3 (9.7%) patients required dose reduction in the cabozantinib and placebo arms respectively. Conclusions: Though tolerable, cabozantinib did not show a significant benefit compared to placebo when used in the switch maintenance setting following platinum based chemotherapy. Clinical trial information: ISRCTN25859465.

A retrospective study on optimal number of cycles of the first-line platinum-based chemotherapy for metastatic urothelial carcinoma

Recently, switch maintenance with avelumab has been approved for the treatment of advanced or metastatic urothelial carcinoma (UC), with no progression after four to six cycles of first-line platinum-based chemotherapy. However, the optimal number of cycles of platinum-based chemotherapy has not been determined. To analyze the clinical characteristics of patients with advanced UC who were treated with platinum-based chemotherapy and investigate the association between the number of cycles of the treatment and the patients' overall survival. A total of 124 patients with advanced UC who were treated with first-line platinum-based chemotherapy at Osaka City University Hospital between April 2009 and January 2020 were retrospectively reviewed. Of the 124 patients, clinical information regarding overall survival was available for 115 patients. The median age was 72 years (range, 43-95 years). Only 59 patients (51.3 %) were treated with gemcitabine and cisplatin, and 52 patients (45.2 %) were treated with gemcitabine and carboplatin. The median number of cycles was three (1-8), and the percentage of patients who discontinued chemotherapy due to progressive disease was 80.3%, 64.0%, and 86.4% in those receiving one to three, four, and five or more cycles, respectively. Moreover, no difference in overall survival was observed between patients who received four cycles and those who received five or more cycles at both univariate and multivariate levels. The present study shows that five or more cycles of first-line platinum-based chemotherapy did not prolong overall survival compared with four cycles, suggesting that four cycles of chemotherapy might be sufficient, considering the new treatment strategy involving switch maintenance with avelumab.

Comparative effectiveness analysis of first-line immunotherapy versus chemotherapy in metastatic urothelial carcinoma of the bladder

Clinical trials have not shown a significant overall survival (OS) difference between chemotherapy and immunotherapy as first-line agents in metastatic urothelial carcinoma (UC). However, the generalizability of these findings in a real-world setting has not yet been evaluated in comparative effectiveness studies. To assess the effectiveness of first-line immunotherapy compared with chemotherapy regimens on OS in patients with metastatic UC of the bladder. This retrospective propensity-matched study identified metastatic bladder UC patients in the National Cancer Database from 2014 to 2017 who received either first-line immunotherapy-monotherapy or multi-agent chemotherapy, and who were not treated on a clinical trial protocol. The primary outcome was OS from the date of diagnosis to date of death or censoring at last follow-up. Patients were stratified into first-line immunotherapy and chemotherapy treatment groups. After 1:1 nearest-neighbor caliper-matching of propensity scores, the survival analysis was conducted using Cox regression modeling and Kaplan-Meier estimates. A total of 2,796 patients were included in the final study population, and 960 in the matched cohort (480 per treatment group). Utilization of immunotherapy increased over the time period studied as chemotherapy decreased (Immunotherapy: 3%-37%; Chemotherapy: 97%-63%; P < 0.001). In the overall cohort, patients who received first-line immunotherapy were older and more comorbid than those who received first-line chemotherapy (Age: 73 v. 67, respectively, P < 0.001; Charlson-Deyo score ≥2: 17% v. 11.5%, respectively, P < 0.001). In the matched cohort, patients who were treated with first-line immunotherapy had similar OS to those who were treated with first-line chemotherapy (HR: 0.91, 95CI 0.72-1.15). Due to the retrospective nature of the study, interpretation is limited by potential selection bias from unmeasured confounding. Metastatic bladder UC patients who received first-line immunotherapy had similar OS to those who received first-line chemotherapy.

Tailored immunotherapy approach with nivolumab in advanced transitional cell carcinoma (TITAN-TCC).

441 Background: Nivolumab (nivo) is an approved 2nd line treatment after platinum-based chemotherapy in metastatic urothelial carcinoma (mUC). Recent studies suggest improved outcomes for dual checkpoint inhibition in mUC in particular with higher ipilimumab (ipi) doses (nivo 1mg/kg + ipi 3mg/kg). TITAN-TCC uses a response-based approach starting with 4 doses of nivo (8 weeks) followed by nivo+ipi boosts in non-responders. Here we report cohort 2 of TITAN-TCC applying nivo1/ipi3 boost doses in patients after prior platinum-based chemotherapy (2nd/3rd line). Methods: Between April 2019 and February 2021 83 patients with histologically confirmed mUC (TITAN-TCC cohort 2) started with nivo 240mg Q2W induction. After 4 doses and tumor assessment at week 8 (i) non-responders (stable (SD)/ progressive disease (PD)) received 2-4 doses nivo1+ipi3 while (ii) responders (complete (CR)/ partial response (PR)) continued with nivo maintenance but could receive nivo1+ipi3 for later PD. Primary endpoint was confirmed investigator-assessed ORR per RECIST1.1. Using a Fleming single-stage phase II design 77 evaluable patients would provide a 90% power to reject the null-hypothesis that ORR was ≤20% at a one-sided 5% type I error if the true ORR was ≥35%. Secondary endpoints included activity of nivo monotherapy at week 8, remission rate with nivo+ipi boosts, progression-free survival (PFS), overall survival (OS), and safety. Results: Median follow-up time was 5.6 months. Of the patients, 78 (94%) were 2nd line. Median age was 68 years (range 37-84) and 57 patients (69%) were male. ORR with nivo monotherapy at first assessment (week 8) was 20.5%. Of the patients, 44 and 6 received nivo+ipi boosts after week 8 and for later PD, respectively. Confirmed objective response with nivo induction ± nivo+ipi boosts was achieved in 27/83 (32.5%) of the patients (significant &gt; 20%, p &lt; 0.01). Patients with PD-L1 expression in ≥1% of tumor cells had a numerically higher ORR (46% vs. 24% for PD-L1 negatives). Of the patients with initial SD after nivo induction, 4/13 (31%) achieved response upon boost. Of the patients boosted for PD, 9/37 (24%) improved. Median PFS was 1.9 months (95% CI 1.8-3.2), median OS was 7.6 months (95% CI 5.1-14.9). No new safety signals emerged. Conclusions: In patients after prior platinum-based chemotherapy treatment with nivo and nivo+ipi boosts in non-responders significantly improved ORR compared to the one reported for nivo as 2nd line monotherapy. Patients with PD-L1 positive tumors appear to benefit most. Our study provides further evidence for the added value of high dose (3mg/kg) ipilimumab in mUC. Clinical trial information: NCT0321977.[Table: see text]

A randomized, double blind, biomarker selected, phase II clinical trial of maintenance PARP inhibition following chemotherapy for metastatic urothelial carcinoma (mUC): Final analysis of the ATLANTIS rucaparib arm.

436 Background: A subset of mUC exhibits a DNA repair deficiency (DRD) phenotype predicting benefit from platinum based chemotherapy (PBC). We hypothesised that switch maintenance therapy with the PARP inhibitor rucaparib, in patients who have derived clinical benefit from PBC, would improve outcomes for patients with mUC harbouring a DRD biomarker. Methods: ATLANTIS is an adaptive, multi-comparison, phase II trial platform. It tests multiple biomarker selected maintenance therapies for mUC after 4 to 8 PBC cycles without disease progression. Biomarker allocation to the rucaparib comparison was based on ≥10% genomic loss of heterozygosity (%LOH) and/or somatic alteration in defined DRD associated genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, NBN, PALB2, RAD51, RAD51B, RAD51C, RAD51D, RAD54L) and/or germline BRCA1 or BRCA2 alteration. Biomarker positive patients were randomised (1:1) to maintenance rucaparib 600 mg BID PO, or matched placebo, within 10 weeks of completing PBC, until disease progression. The primary endpoint was progression free survival (PFS). Statistical analysis (data cut 17/Nov/2021) was pre-planned to target a hazard ratio of 0.5. We selected a 20% 1-sided alpha for this signal seeking phase II trial with 85.4% power (requiring 30 PFS events in 40 patients). PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model incorporating baseline minimisation factors. Adverse events (AE) were assessed by CTCAE v4.03. Results: 74 of 279 (26.5%) screened patients were biomarker positive. 40 were randomised within the rucaparib comparison (Dec 2017-Dec 2020). Biomarker positive status was by high %LOH in 22 (55%), DRD gene alteration in 11 (27.5%) and both in 7 (17.5%). Patient characteristics (median age 70.5; 82.5% male; 87.5% bladder primary; 52.5% ECOG PS 0; 62.5% prior cisplatin; 45% visceral metastases) were balanced by treatment arm. 12 (60%) and 20 (100%) PFS events have occurred in the rucaparib and placebo arms respectively (median duration follow up 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% confidence interval (CI) 11.7-35.6) with rucaparib and 15.1 weeks (80% CI 11.9-22.6) with placebo (hazard ratio 0.53, 80% CI 0.30-0.92, 1 sided p = 0.07). In the safety population (n = 39) treatment related adverse events were mostly low grade. Rucaparib was tolerable with a median duration of 10 rucaparib or 6 placebo cycles on treatment. The most frequent treatment related AEs (all grades) of fatigue (63.2% vs 30.0%, p = 0.03), nausea (36.9% vs 5.0%, p = 0.03) and rash (21.1% vs 0%, p = 0.04) were more common with rucaparib respectively. Conclusions: Maintenance rucaparib, following PBC, extended PFS in DRD biomarker selected patients with mUC and is tolerable. Further investigation of PARP inhibition for mUC is warranted. Clinical trial information: 25859465.

Impact of clinicopathological features on immune-based combinations for advanced urothelial carcinoma: a meta-analysis.

Aims: Immune checkpoint inhibitors (ICIs) have recently revolutionized the treatment landscape of metastatic urothelial carcinoma. The authors performed a meta-analysis aiming to evaluate the predictive value of Eastern Cooperative Oncology Group performance status, age, sex, liver metastasis and histology in trials comparing first-line ICI-based combinations with chemotherapy in metastatic urothelial carcinoma patients. Methods: Hazard ratios were analyzed. Results: ICI-based combinations significantly decreased the risk of death in several clinicopathological subgroups, including patients with no liver metastases (hazard ratio: 0.84; 95% CI: 0.74-0.95) and those with an Eastern Cooperative Oncology Group performance status of 0 (hazard ratio: 0.84; 95% CI: 0.72-0.97). Conclusion: The benefit of ICI-based combinations over chemotherapy in metastatic urothelial carcinoma was consistent across several clinicopathological subgroups, although a proportion of patients responded to chemotherapy alone.

Clinical Outcomes of Three or More Courses of First-line Chemotherapy for Metastatic Urothelial Carcinoma.

The current standard of care for first-line treatment of locally advanced or metastatic urothelial carcinoma (UC) is platinum-based combination chemotherapy. Recently, immune checkpoint inhibitors have been reported to be effective for UC. Knowing whether immunotherapy or chemotherapy is suitable as first-line treatment is beneficial for patients. A retrospective study was conducted on the clinical outcomes of Japanese patients who received three or more courses of first-line chemotherapy for metastatic UC to assess the outcome of conventional treatments in real clinical situation. Patients who received first-line chemotherapy between August 2009 and December 2019 were included. Progression-free survival (PFS) and overall survival (OS) were assessed. The median PFS and OS were 7.1 and 27.1 months, respectively, for patients with no disease progression at the end of three courses. Of 28 patients, 25 (89.3%) received second-line drug therapy and 10 (35.7%) received focal therapy for disease control. Patients with focal therapy had significantly longer OS than those without focal therapy (p=0.019, log-rank test). OS of metastatic UC at our Institution is relatively long, suggesting that aggressive second-line drug therapy and focal therapy may have contributed to such result.

Impact of the objective response to and number of cycles of platinum-based first-line chemotherapy for metastatic urothelial carcinoma on overall survival of patients treated with pembrolizumab.

To investigate the impact of the number of cycles and objective response to chemotherapy on overall survival in patients with metastatic urothelial carcinoma treated with pembrolizumab. This multicenter, retrospective study included 755 patients from 59 institutions with advanced, chemoresistant urothelial carcinoma who received pembrolizumab. The associations of the overall survival with the number of cycles and best objective response were investigated using Cox multiple regression analysis. Overall, 391 patients received standard first-line chemotherapy and pembrolizumab as a second-line treatment, and were included in the final analysis. Of the 391 patients, 185 received less than four cycles, 134 received four to six cycles and 72 received more than six cycles of first-line chemotherapy. An objective response (complete or partial response) to chemotherapy was observed in 145 patients (37.1%). Univariate analysis showed that the overall survival of patients who received more than six cycles or responded to chemotherapy (complete or partial response) was significantly longer than that of patients who received less than four cycles or did not respond to chemotherapy (stable or progressive disease). At multivariate levels, no correlations were observed between overall survival and the number of cycles of or the response to chemotherapy. Therapeutic benefit of pembrolizumab can be expected irrespective of the objective response to and number of cycles of platinum-based first-line chemotherapy.

Organ-Specific Therapeutic Effect of Paclitaxel and Carboplatin Chemotherapy After Platinum-Based Chemotherapy and Pembrolizumab for Metastatic Urothelial Carcinoma.

BackgroundTo evaluate the organ-specific therapeutic effect of paclitaxel and carboplatin (TC) chemotherapy in patients who failed platinum-based chemotherapy and pembrolizumab for metastatic urothelial carcinoma (UC).Patients and MethodsWe retrospectively reviewed the data of patients with metastatic UC who had received TC chemotherapy after the failure of platinum-based chemotherapy and pembrolizumab. The RECIST 1.1 criteria were used to assess the objective response to pembrolizumab and TC chemotherapy at tumor sites.ResultsWe analyzed 8 patients (male, n=5; female, n=3; median age, 65 years old). All patients except one had visceral metastasis. The median overall survival for TC was 10.9 months (95% confidence interval, 1.0‑12.7 months), and the objective response rate was 25.0% (partial response [PR]: 2 cases). The metastatic organs were the lymph nodes in 5 cases (number of tumor sites: 8), lung in 4 cases (number of tumor sites: 12), liver in 3 cases (number of tumor sites: 14), bone in 3 cases (number of tumor sites: 12), and primary lesion in 3 cases (number of tumor sites: 3). There were no cases of a complete response or progressive disease in any metastatic organs due to TC chemotherapy. A PR was seen in 2 cases of lymph node metastasis (40.0%), 2 cases of lung metastasis (50.0%), and 2 cases of liver metastasis (66.7%). All 3 cases of bone metastasis showed stable disease, as did all 3 cases of primary lesion. Improvement in the therapeutic effect of TC chemotherapy compared with pembrolizumab was observed in 2 cases (40.0%) of lymph node metastasis, 2 cases (50.0%) of lung metastasis, and 1 case (33.3%) of liver metastasis.ConclusionLymph node, lung, and liver metastases may respond to TC chemotherapy, even if exacerbated with pembrolizumab after platinum-based chemotherapy in metastatic UC.

Five-Factor Prognostic Model for Survival of Post-Platinum Patients with Metastatic Urothelial Carcinoma Receiving PD-L1 Inhibitors.

A prognostic model for overall survival of post-platinum patients with metastatic urothelial carcinoma receiving PD-1/PD-L1 inhibitors is necessary as existing models were constructed in the chemotherapy setting. Patient level data were used from phase I/II trials evaluating PD-L1 inhibitors following platinum based chemotherapy for metastatic urothelial carcinoma. The derivation data set consisted of 2 phase I/II trials evaluating atezolizumab (405). Two phase I/II trials that evaluated avelumab (242) and durvalumab (198) comprised the validation data sets. Cox regression analyses evaluated the association of candidate prognostic factors with overall survival. Stepwise selection was used to select an optimal model using the derivation data set. Discrimination and calibration were assessed in the avelumab and durvalumab data sets. The 5 prognostic factors identified in the optimal model using the atezolizumab derivation data set were ECOG-PS (1 vs 0, HR 1.80, 95% CI 1.36-2.36), liver metastasis (HR 1.55, 95% CI 1.20-2.00), platelet count (HR 2.22; 95% CI 1.54-3.18), neutrophil-to-lymphocyte ratio (HR 1.94, 95% CI 1.57-2.40) and lactate dehydrogenase (HR 1.60, 95% CI 1.28-1.99). There was robust discrimination of survival between low, intermediate and high risk groups. The c-statistic was 0.692 in the derivation and 0.671 and 0.773 in the avelumab and durvalumab validation data sets, respectively. A web based interactive tool was developed to calculate the expected survival probabilities based on risk factors. A validated 5-factor model has satisfactory prognostic performance for survival across 3 PD-L1 inhibitors to treat metastatic urothelial carcinoma after platinum therapy and may assist in stratification, interpreting and designing trials incorporating PD-1/PD-L1 inhibitors in the post-platinum setting.

Influence of pretreatment quality of life on prognosis in patients with urothelial carcinoma.

We investigated the association between the pretreatment quality of life (QOL) and overall survival (OS) in patients with urothelial carcinoma (UC), as the influence of pretreatment QOL on prognosis remains unclear in patients with localized and metastatic UC. Between June 2013 and May 2019, we retrospectively investigated 205 patients with UC who received radical cystectomy or nephroureterectomy for non-metastatic UC (M0 group) or systemic chemotherapy for metastatic UC (M1 group). Patients answered the European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire C30 (QLQ-C30) before the treatments. Patients were stratified into two groups: QOL high and low according to the optimal cutoff scores which were defined by receiver operating characteristic curve. Inverse probability of treatment weighting (IPTW)-adjusted multivariate Cox regression analyses were performed to investigate the clinical implication of pretreatment QOL score on OS in patients with UC. The number of patients in the M0 and M1 groups was 125 and 80, respectively. Optimal cutoff values in global, fatigue, pain, appetite loss, physical, and role scores were < 50, > 33, > 33, > 16, < 80, and < 67, respectively. IPTW-adjusted multivariate Cox regression analyses revealed that appetite loss score indicated a significantly poorer OS in the M1 group. No significant association of QOL with OS was observed in the M0 group. Pretreatment QOL of appetite loss may predict poor prognosis of patients with metastatic UC.

235P - Comparison of cisplatin versus carboplatin chemotherapy for metastatic urothelial carcinoma in patients with stage III chronic kidney disease

235P - Comparison of cisplatin versus carboplatin chemotherapy for metastatic urothelial carcinoma in patients with stage III chronic kidney disease

Prognostic Effect of FGFR Mutations or Gene Fusions in Patients with Metastatic Urothelial Carcinoma Receiving First-line Platinum-based Chemotherapy: Results from a Large, Single-institution Cohort

FGFR gene alterations represent a target for treatment in clinical trials of urothelial carcinoma (UC). Little is known about their prognostic effect in patients with metastatic UC. We analyzed data for 112 patients treated with platinum-based first-line chemotherapy at our center between October 2011 and March 2017 and who were screened for the presence of FGFR mutations or gene fusions within multiple clinical trials with pan-FGFR inhibitors. Centralized targeted exome sequencing analyses were performed to detect multiple FGFR mutations and fusions. Cox regression analyses were performed, adjusting for recognized prognostic factors. Thirty-seven patients (33%) had upper tract UC (UTUC). A total of 22 patients (19.6%) had FGFR alterations and ten (8.9%) received salvage pan-FGFR inhibitor therapy. Thirty-two patients (45.4%) received salvage treatment with an immune checkpoint inhibitor. FGFR alterations were more frequently observed in UTUC versus bladder UC (p=0.017). On multivariable analyses, FGFR alterations were not significantly associated with OS (p=0.860) or PFS (p=0.147) after first-line chemotherapy. Patient summaryIn an original single-center study, FGFR gene alterations were not prognostic for either progression-free survival or overall survival in patients receiving first-line chemotherapy for metastatic urothelial carcinoma. These results will be useful in interpreting findings from future clinical trials.

Analysis of multidrug resistant transporter expression in tumor blood vessels of urothelial carcinoma during chemotherapy.

e23004 Background: ABCB1, a multidrug transporter, is encoded by multidrug resistance (MDR) 1 gene and plays a major role in drug resistance. Recently, we have reported that not only tumor cells, tumor vascular endothelial cells (TECs) also confer cancer drug resistance. We isolated TECs and found that they have various abnormalities such as aneuploidy or stemness characteristics. TECs showed resistance to Paclitaxel (PTX) with ABCB1 up-regulation. Furthermore, their resistance to PTX was abrogated by ABCB1 inhibition of TECs in vivo. In clinical urology, gemcitabine / cisplatin (GC) is standard 1st line chemotherapy for metastatic urothelial carcinoma (mUC). PTX is often selected in 2nd line chemotherapy for GC resistant cases, however the therapeutic outcomes are limited. We hypothesized that ABCB1 inhibitor/PTX combination would be more effective strategy for mUC, if TEC ABCB1 expression is upregulated. In this study, we investigated ABCB1 expression in tumor blood vessels of UC during 1st line chemotherapy. Methods: Paraffin-embedded samples were corrected from 50 patients who were performed tumor resection before and after 1st line chemotherapy. ABCB1 expressions were analyzed by immunohistochemical staining and the ratio of ABCB1 positive (+) vessels in total vessels were quantified. In vitro assays were performed to address how endothelial cells (ECs) are affected by change of tumor microenvironment during chemotherapy. Results: The ABCB1 (+) vessels were 0.00 – 16.80% (Median 0.00%) and 0.00-58.94% (Median 4.49%), before and after chemotherapy, respectively. In 32 of 50 cases (64%), the ratio of ABCB1 (+) vessels increased after 1st line chemotherapy. Additionally, gemcitabine induced MDR1 mRNA expression in ECs via NF-kB activation. Furthermore, gemcitabine and cisplatin induced IL-8 secretion from tumor cells, and MDR1 mRNA expression level was elevated in ECs. Conclusions: It was suggested that conventional chemotherapy may cause inflammatory change in tumor tissues, which causes in ABC transporter induction in tumor blood vessels. It was suggested that inhibition of ABC transporter in TECs is one of important new strategy to overcome cancer drug resistance.

A pilot study of gemcitabine and paclitaxel as third-line chemotherapy in metastatic urothelial carcinoma

Background: We evaluated the effectiveness of gemcitabine and paclitaxel therapy in patients with metastatic urothelial carcinoma for whom two lines of sequential chemotherapy had been unsuccessful.Methods: A total number of 105 patients who had previously received first-line chemotherapy consisting of gemcitabine and cisplatin or carboplatin, were treated with second-line gemcitabine and docetaxel therapy between June 2006 and May 2015. Of these patients, 15 with an Eastern Cooperative Oncology Group Performance Status of 0 or 1 were administered gemcitabine and paclitaxel as third-line treatment from 2013 after failure of the second-line therapy. For each 21-day cycle, gemcitabine (1000 mg/m2) was administered on days 1, 8, and 15, and paclitaxel (200 mg/m2) on day 1. Patients were assessed for each cycle and any adverse events were noted. Furthermore, a Short Form Health Survey questionnaire was used to assess each patient’s quality of life.Results: Third-line gemcitabine and paclitaxel treatment cycles were undertaken for a median of four times (range 2–9). The disease control rate was 80.0%. After second-line gemcitabine and docetaxel therapy was completed, median progression-free survival and median overall survival were determined as 9.8 and 13.0 months, respectively. The only prognostic factor for overall survival, as determined by univariate and multivariate analyses, was third-line gemcitabine and paclitaxel therapy. Neutropenia (66.7%) and thrombocytopenia (53.3%) were noted as the grade 3 treatment-related toxicities. After two cycles of third-line gemcitabine and paclitaxel therapy, the pre- and post-treatment quality of life scores did not differ significantly.Conclusions: Results demonstrate that third-line combination therapy using gemcitabine and paclitaxel is a feasible option for metastatic urothelial carcinoma patients.

Acute Tumor Lysis Syndrome after Cisplatin and Gemcitabine for Treatment of Urothelial Carcinoma of the Renal Pelvis: Case Report and Review of Literature

Tumor lysis syndrome (TLS) is a potentially fatal complication of oncological therapy. It is rarely described in patients with solid tumors, even rare in urological cancer. To the best of our knowledge, there were only two cases describing TLS following chemotherapy for metastatic urothelial carcinoma documented in the literature, although only one occurred after gemcitabine, another case occurred after PD-1 Immunotherapy. Case presentation: We present the case of a 67-year-old female who developed acute renal failure and tumor lysis syndrome after a single infusion of cisplatin and gemcitabine for metastatic renal pelvic urothelial carcinoma. Conclusions: Patients with urothelial carcinoma that are highly proliferative and have high tumor burden are at high risk of developing hyperuricemia and TLS, while undergoing chemotherapy. Although TLS is rare in solid tumor, oncologists should be alert when treating patients at high risk of TLS, and determine appropriate prophylaxis. We also proposed biomarker based risk stratification for patients with high risk for TLS.

Clinical significance of a second-line chemotherapy regimen with paclitaxel, ifosfamide and nedaplatin for metastatic urothelial carcinoma after failure of cisplatin-based chemotherapy.

Cisplatin-based chemotherapy has been commonly used as the first-line chemotherapy for metastatic urothelial carcinoma. However, after failure of the first-line cisplatin-based chemotherapy, there is no established standard second-line chemotherapy. Starting in 2006, paclitaxel, ifosfamide and nedaplatin chemotherapy has been performed as the second-line chemotherapy in our institution. Here, we report the treatment results of paclitaxel, ifosfamide and nedaplatin chemotherapy. From 2006 to 2015, 33 patients with metastatic urothelial carcinoma were treated with paclitaxel, ifosfamide and nedaplatin chemotherapy after failure of first-line cisplatin-based chemotherapy in our institution. We retrospectively examined the treatment outcome and predictive factors for therapeutic effects of paclitaxel, ifosfamide and nedaplatin. The median age, treatment cycle and follow-up period were 62.5 years, 3 cycles and 10.4 months, respectively. The median overall survival and progression-free survival were 10.4and 3.5 months, respectively. Complete and partial responses were found in 3 and 7 patients, respectively, with an overall response rate of 30%. All patients developed grade 3-4 neutropenia, but there was no treatment-related death. In multivariate analysis, the only prognostic factor for progression-free survival was 24-hour urinary creatinine clearance. A paclitaxel, ifosfamide and nedaplatin regimen as second-line chemotherapy for metastatic urothelial carcinoma was effective and tolerable. Moreover, paclitaxel, ifosfamide and nedaplatin chemotherapy may be more effective in patients with satisfactory renal function.

Second-Line Chemotherapy for Metastatic Urothelial Carcinoma: Importance of Lymph Node-Only Metastasis as a Prognostic Factor and Construction of a Prognostic Model

BackgroundA prognostic model for patients with metastatic urothelial carcinoma (UC) progressing after platinum-based therapy was constructed from data from the phase III vinflunine trial. However, prognostic information for patients treated with other regimens is limited. Materials and MethodsWe pooled individual patient data from 7 second-line studies and analyzed the influence of factors of interest on overall survival (OS) through univariate and multivariate analysis. A prognostic model was constructed, and data from an independent series were used for validation. ResultsThe data from 193 patients were pooled. The second-line chemotherapy regimen was single-agent taxane in 54 patients (28%), a platinum-based combination in 47 (24%), and a non-platinum combination in 92 (48%). On multivariate analysis, Eastern Cooperative Oncology Group performance status ≥ 1, hemoglobin < 10 g/dL, and metastatic patterns other than lymph node-only metastasis emerged as independent adverse prognostic factors. Patients with all 3 factors (poor risk), 1 to 2 factors (intermediate risk), and no factors (good risk) had a median OS of 3.1, 8.7, and 16.5 months, respectively (P < .0001). The corresponding median OS for the validation series (n = 44) was 3.3, 8.1, and 13.3 months (P = .023). Furthermore, platinum-based regimens were independently associated with an OS benefit compared with other regimens (hazard ratio, 0.31; 95% confidence interval, 0.18-0.53; P < .0001). ConclusionWe have proposed and validated a prognostic model for patients with metastatic UC who were eligible for second-line therapy. The proposed model could prove helpful for risk stratification. Furthermore, our data suggest that testing second-line platinum-based regimens in randomized trials is warranted.