Generalized Eruptive Keratoacanthomas Arising in the Setting of Anti-Cancer Therapy: An Illustrative Case with Spontaneous Resolution

Pembrolizumab is a long-awaited drug for the treatment of metastatic urothelial carcinoma. It is an immune checkpoint inhibitor, which has been shown to trigger new autoimmune disorders. We report a case of pembrolizumab-induced myasthenia gravis that occurred in an 84-year-old Japanese female with metastatic urothelial carcinoma in multiple organs. She developed right ptosis 3days after the second pembrolizumab treatment. Although prednisolone was administered, her symptoms did not change and dysphagia appeared. She needed the steroid pulse therapy for treatment eventually. On the other hand, 9weeks after the first pembrolizumab treatment, reductions in the sizes of liver and adrenal metastases was observed. However, unfortunately, the severe immune-related adverse events did not allow her to continue the administration of pembrolizumab for the treatment of multiple metastatic urothelial carcinoma. To our knowledge, this is the first case of myasthenia gravis associated with pembrolizumab treatment against metastatic urothelial carcinoma. In this case, a relationship between immune-related adverse events associated with myasthenia gravis and tumor responses to pembrolizumab was suspected, because marked reductions in the sizes of some metastatic lesions were observed after the administration of only two courses of pembrolizumab.

Traitement chirurgical du carcinome urothélial de vessie métastatique : revue du Comité de cancérologie de l’Association française d’urologie

1764P The vanishing clinical value of PD-L1 status as predictive biomarker in first-line treatment of urothelial carcinoma of the bladder

Survival after Metastasectomy for Metastatic Urothelial Carcinoma: A Systematic Review and Meta-Analysis

Rationale and Outcomes for Neoadjuvant Immunotherapy in Urothelial Carcinoma of the Bladder

Platinum-based combination chemotherapy has been the standard of care in the first-line treatment of metastatic urothelial carcinoma (mUC). Treatment of metastatic disease following progression on platinum-based regimens has evolved significantly in the last few years. Clinical trials are currently ongoing to determine how best to use and sequence these treatments. In this minireview, we will review current first-line treatment options in both cisplatin fit and cisplatin unfit patients and advances in first- and second-line treatments including chemotherapy and immunotherapy. This review reports key findings from the clinical trials especially highlighting the importance of PD-1 and PD-L1 inhibitors in the treatment of bladder/urothelial carcinomas.

<h3>Objective:</h3> Characterization of polyneuropathy in patients receiving enfortumab vedotin (EV) for the treatment of metastatic urothelial carcinoma. <h3>Background:</h3> EV is an antibody-drug conjugate where the antibody binds to nectin-4, an adhesion molecule highly expressed on urothelial carcinomatous cells, and drug monomethyl auristatin E (MMAE) acts as a microtubule inhibitor. Polyneuropathy is reported in 40–50% of treated patients and is the most common side effect necessitating dose reduction. In prior studies, 5% of enrolled subjects had to stop treatment due to polyneuropathy. Sensory polyneuropathy was reported three times more common than motor polyneuropathy. Neuropathy was primarily characterized on clinical grounds, with absence of electrodiagnostic studies and work up for potential other contributing factors. Aim of this study is to further describe polyneuropathy based on detailed neurological examination, electrodiagnostic testing and labs for assessment of any other contributing factors. <h3>Design/Methods:</h3> This is a retrospective case series study. Patients treated with EV were referred for neurological evaluation at onset of neuropathy symptoms and underwent detailed neurological history, examination, electrodiagnostic testing and serological testing for other potential contributors for neuropathy. Data will be collected from 10 patients who were followed at the University of California, Irvine neuromuscular clinic from January 2018 to September 2022. <h3>Results:</h3> Neuropathy types included length-dependent and non-length-dependent sensory and sensorimotor neuropathy. Contributing factors other than EV exposure were identified in some patients (e.g. vitamin B12 deficiency) and correction resulted in improvement in neuropathy with allowance for continuation of chemotherapy. Dose reduction or treatment “holiday” was done at the discretion of the treating oncologist and resulted in stabilization of symptoms in some. Descriptions of polyneuropathy subtypes, diagnostic work up, treatment and follow up will be presented. <h3>Conclusions:</h3> Our cohort provides details on the variability of neuropathy seen in patients treated with EV and provides insights into the electrophysiology, time course and progression of the neuropathy. <b>Disclosure:</b> Dr. Badii has nothing to disclose. Dr. Mar has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Seattle Genetics/Astellas. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for argenx. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Immunovant. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for UCB. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NIH/NINDS. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for argenx. The institution of Dr. Habib has received research support from Alexion. The institution of Dr. Habib has received research support from RA pharmaceuticals. The institution of Dr. Habib has received research support from Immunovant. The institution of Dr. Habib has received research support from UCB. The institution of Dr. Habib has received research support from argenx. The institution of Dr. Habib has received research support from CabalettaBio. The institution of Dr. Habib has received research support from Genentech. The institution of Dr. Habib has received research support from Regeneron.

6639 Background: Despite early promising results, IMvigor211 failed to demonstrate an overall survival benefit for atezolizumab, compared to chemotherapy, in the second-line treatment of metastatic urothelial carcinoma. However, given improvements in adverse events (AE) and quality of life with atezolizumab, there may still be investment value. We conducted a cost-utility analysis (CUA) of atezolizumab compared to chemotherapy from a public-payer healthcare perspective. Methods: We developed a partitioned survival model to evaluate atezolizumab versus chemotherapy (i.e. docetaxel, paclitaxel or vinflunine). IMvigor211 informed rates of treatment receipt (initial and subsequent), AE, effectiveness and utility estimates. Cost for treatment, AE and death were based on published literature (adjusted to 2018 Canadian dollars). Per health state, cost of treatment (initial and subsequent) and AE were incorporated. Outcomes included quality-adjusted life-years (QALY), cost per treatment, and incremental cost-effectiveness ratio (ICER). QALY and cost were discounted at 1.5% (Canadian guidelines). Parameter uncertainty was assessed through one-way and scenario analyses. Time horizons of 2 (within trial) and 5 years (extrapolated lifetime) were evaluated. Results: QALY of atezolizumab and chemotherapy over 2 years (lifetime) were 0.65 (0.93) and 0.58 (0.64), respectively. Cost of atezolizumab and chemotherapy over 2 years (lifetime) was $77,614.64, ($92,484.34), and $62,212.35 ($67,606.65), respectively. ICER over 2 years and lifetime was $220,032.71/QALY and $85,785.14/QALY. Scenario analysis from a North American perspective with only taxane chemotherapy with and without third line immunotherapy (IO) revealed an ICER of $80,144.90/QALY, $125,332.76/QALY over a lifetime horizon, respectively. Conclusions: The difference in ICER dependent on time horizon, driven by extrapolated survival benefits, highlights the importance of long-term follow-up to examine whether early evidence for durable response translates into long-term survival and improvements in cost-effectiveness. Thus, CUA of IO require careful interpretation and warrant dynamic assessment as new data becomes available.

Read the full review for this Faculty Opinions recommended article: Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, phase 2 study.

Metastatic urothelial carcinoma of the bladder is a rarely curable disease. Patients receive systemic therapy with limited response rates and survival benefits. The rescue regimens of these patients who have failed first-line treatment had remained problematic until the recent advances. Several trials with novel regimens, including immune checkpoint inhibitors and targeted therapy, to salvage relapsed urothelial carcinoma of the bladder have recently been published. However, the choice of an optimal treatment regimen remains challenging in the absence of randomized trials comparing regimen sequences. Daily clinical cases provoke the question of whether there is a preferred second-line regimen. This paper provides an overview of recent trials and proposes a management algorithm based on subgroup analyses and prognostic features.

e15027 Background: Cisplatin-based chemotherapy is the first-line treatment standard for metastatic urothelial carcinoma, though carboplatin-based chemotherapy is frequently substituted for reasons of improved tolerability and ease of administration. Because comparative effectiveness in clinical outcomes of cisplatin- versus carboplatin-based chemotherapy is lacking, a meta-analysis of published randomized trials was performed. Methods: PubMed was searched for articles published in the English language from 1966 until 2010. Eligible studies included prospective randomized trials evaluating cisplatin- versus carboplatin-based regimens in patients with metastatic urothelial carcinoma. Individual patient data were not available and progression and survival data were inconsistently reported. Therefore, the analysis focused on overall (OR) and complete response (CR). The Mantel-Haenszel method was used for combining trials and calculating pooled risk ratios (RR). Results: A total of 286 patients with metastatic urothelial carcinoma from 4 randomized trials (3 phase 2 and 1 phase 3 trial) were included. Cisplatin-based chemotherapy was associated with a significantly higher likelihood of achieving a CR (RR = 3.54; 95% CI: 1.48, 8.49; p = 0.005) and OR (RR = 1.34; 95% CI: 1.04, 1.71; p=0.02). Survival endpoints could not be adequately assessed due to inconsistent reporting among trials. Conclusions: Cisplatin-based, as compared with carboplatin-based, combination chemotherapy significantly increases the likelihoods of both OR and CR in patients with metastatic urothelial carcinoma. The impact of improved response proportions on survival endpoints could not be assessed. In the absence of definitive phase 3 trials, these results lend further support to the use of cisplatin-based combination chemotherapy as the preferred first-line treatment of metastatic urothelial carcinoma.

To summarize and evaluate immunotherapy agents targeting programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) recently approved for the treatment of metastatic urothelial carcinomas (UC). A literature review was performed using PubMed (2012 to June 2017), the American Society of Clinical Oncology abstract databases (2012 to June 2017 Annual Meetings/symposia), and the America Association for Cancer Research symposia (2012 to June 2017). A search using clinicaltrials.gov was conducted to identify studies for atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab. English language phase I to III studies assessing PD-1 and PD-L1 in UC were incorporated. Atezolizumab, avelumab, durvalumab, nivolumab, and pembrolizumab have demonstrated clinical efficacy with tolerable toxicities in patients with metastatic UC with disease progression following platinum-based chemotherapy. Anti-PD-1/PD-L1 therapies may provide overall survival advantage; these are currently being evaluated in ongoing phase 3 studies. Greater objective response rates seem to be observed in PD-L1-positive patients versus PD-L1-negative patients, but methodologies in this assessment differ among clinical trials. The identification of biomarkers that provide greater insight into patients who positively respond to PD-1/PD-L1 therapies are needed. Treatment options for metastatic UC have expanded to include PD-1/PD-L1 therapies. These agents should be strongly considered as second-line therapy over single-agent chemotherapy for patients who fail or progress after platinum-based treatment.

521 COMPARATIVE EFFECTIVENESS OF GEMCITABINE/PACLITAXEL VERSUS BEST SUPPORTIVE CARE IN PATIENTS WITH METASTATIC UROTHELIAL CARCINOMA WHO ARE RESISTANT TO PREVIOUS PLATINUM-BASED CHEMOTHERAPY

e16550 Background: Numerous randomized trials have illustrated the survival advantages of immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma. However, the application of ICI varies in different trials, encompassing first-line, second-line, monotherapy, combination with chemotherapy, or maintenance therapy. Real-world clinical practices often diverge from trial criteria. This study aims to evaluate the effectiveness of any ICI regimen in treating metastatic urothelial carcinoma using real-world data. Methods: This retrospective comparative study included patients diagnosed with locally advanced or metastatic urothelial carcinoma between January 2015 and July 2023, sourced from the Taiwan Upper Tract Urothelial Cancer and Bladder Cancer Collaboration Database. Patients with prior neo-adjuvant or adjuvant systemic therapy were excluded. Results: Among 427 patients, 152 (35.6%) who received any ICI as the first-line or second-line regimen constituted the ICI group, while the remaining 275 (64.4%) patients receiving only chemotherapy formed the chemotherapy group. Within the ICI group, 55 (36.2%) patients received monotherapy, 49 (32.2%) received combination therapy with chemotherapy, and 4 (2.6%) received maintenance therapy as the first-line regimen. The remaining 44 (28.9%) patients received ICI as the second-line regimen. No significant differences were observed in age, sex, performance status, renal function, tumor site, ratio of locally advanced disease, ratio of visceral metastasis, and ratio of previous radical surgery between the two groups. Median overall survival (OS) from the start of the first-line therapy was 15.8 months in the ICI group and 10.2 months in the chemotherapy group. Kaplan-Meier curves demonstrated that the ICI group exhibited superior OS and cancer-specific survival compared to the chemotherapy group (log-rank p= 0.009 and 0.004, respectively). In the multivariable analysis, the ICI group also demonstrated favorable outcomes in OS [hazard ratio (HR) 0.726, p=0.011] and cancer-specific survival (HR 0.67, p=0.004). Conclusions: Our study confirms the clinical efficacy of ICI in metastatic urothelial carcinoma. The use of ICI monotherapy or combination in the first-line or second-line regimen for metastatic urothelial carcinoma improves patient survival. [Table: see text]

BackgroundFor locally advanced or metastatic urothelial carcinoma, cisplatin-based chemotherapy is the standard regimen. Nevertheless, almost all responding patients experience recurrence within the first year. When patients who have received prior cisplatin-based therapy become resistant, combination therapy with gemcitabine and paclitaxel has been reported. Few published case reports have addressed the utility of paclitaxel/cisplatin/gemcitabine combination therapy as second-line chemotherapy for advanced or metastatic urothelial carcinoma. This is the first report describing paclitaxel/cisplatin/gemcitabine combination therapy for metastatic urothelial carcinoma arising in a transplanted renal allograft and leading to a successful outcome.Case presentationWe present a case of metastatic urothelial carcinoma of a renal allograft in a 32-year-old Japanese man with a history of kidney transplantation ten years prior. Because the patient’s serum creatinine increased, hemodialysis was resumed, and the surgical allograft was removed. Multiple lung metastases were resistant to gemcitabine/cisplatin adjuvant chemotherapy, so paclitaxel/cisplatin/gemcitabine combination chemotherapy was instituted. After paclitaxel/cisplatin/gemcitabine chemotherapy, all pulmonary metastatic tumors disappeared. The patient has survived without disease progression for more than four years since treatment.ConclusionPaclitaxel/cisplatin/gemcitabine combination therapy may be effective and lead to a survival advantage in patients with locally advanced or metastatic urothelial carcinoma when used as second-line chemotherapy following cisplatin-based therapy. However, further investigations may be required to confirm and evaluate the significance of this treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s13104-015-0982-6) contains supplementary material, which is available to authorized users.