EUROPEAN UROLOGY 76 (2019) 368– 380 available at www.sciencedirect.com journal homepage: www.europeanurology.com

Review – Education – Editor’s Choice Safe Use of Inhibitors in the Multidisciplinary Management of Urological : The European Association of Urology Position in 2019

Marc-Oliver Grimm a,*, Axel Bex b,c, Maria De Santis d,e,Bo¨rje Ljungberg f,[7_TD$IF] James W.F. Catto g, Morgan Roupreˆt h, Syed A. Hussain i, Joaquim Bellmunt j,k, Tom Powles l, Manfred Wirth m, Hendrik Van Poppel n a Department of Urology, Jena University Hospital, Jena, Germany; b Specialist Centre for , Royal Free London NHS Foundation Trust, London, UK; c UCL Division of Surgery and Interventional Science, London, UK; d Department of Urology, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany; e Department of Urology, Medical University of Vienna, Austria; f Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå,[8_TD$IF] Sweden; g Academic Urology Unit, University of Sheffield, Sheffield, UK; h Academic Department of Urology, Sorbonne Université, GRC no. 5, ONCOTYPE-URO, Hôpital Pitié-Salpêtrière, Assistance-Publique Hôpitaux de Paris, Paris, France; i Academic Unit of Clinical Oncology, University of Sheffield, Sheffield, UK; j Harvard Medical School, Boston, MA, USA; k Hospital del Mar Medical Research Institute, Barcelona, Spain; l The Royal Free NHS Trust and Barts Cancer Institute, Queen Mary University of London, London, UK; m Department of Urology, Medical Faculty Carl Gustav Carus, Technical University of Dresden, Dresden, Germany; n Department of Urology, University Hospitals Leuven, Leuven, Belgium

Article info Abstract

Article history: Immune checkpoint inhibitors (ICIs) are now used routinely to treat advanced or Accepted May 30, 2019 metastatic urothelial and , among other . Furthermore, multiple trials are currently exploring their role in adjuvant, neoadjuvant, and nonin- Associate Editor: vasive (eg, high-grade non-muscle-invasive ) settings. Consequently, Giacomo Novara urologists are increasingly confronted with patients who are on, have recently received, or will be treated with ICI therapy. The care of these patients is likely to be shared between urologists and medical oncologists, with additional occasional support of other Keywords: medical specialties. Therefore, it is important that urologists have good knowledge of immune-related side effects. Here, we provide advice on prevention, early diagnosis, and ’ Immune checkpoint inhibitors clinical management of the most relevant toxicities to strengthen urologists insight and, thus, role in the multidisciplinary management in the new immunotherapy era. Immune related Patient summary: Immune therapy is a common treatment for many patients with Adverse events advanced cancer. We describe common side effects of this treatment, and advise how they are best prevented and managed. © 2019 Published by Elsevier B.V. on behalf of European Association of Urology.

* Corresponding author. Department of Urology, Jena University Hospital, Am Klinikum 1, Jena 07747, Germany. Tel. +49 3641 9 329901; Fax: +49 3641 9 329902. E-mail address: [email protected] (M.-O. Grimm).

https://doi.org/10.1016/j.eururo.2019.05.041 0302-2838/© 2019 Published by Elsevier B.V. on behalf of European Association of Urology. EUROPEAN UROLOGY 76 (2019) 368– 380 369

1. Introduction This European Association of Urology (EAU) position paper reviews the current status of ICIs in urological cancers Immune checkpoint inhibitors (ICIs) targeting the pro- and provides recommendations for their safe use. This work grammed cell death protein (PD-1)/programmed cell death provides an overview of common and relevant irAEs that ligand (PD-L1) axis are widely used today in a growing require urologists’ particular attention; expert statements number of cancer indications including urothelial cancer on the diagnosis and clinical management of irAEs are (UC) and renal cell carcinoma (RCC) [1–3]. Following their provided as well. development as monotherapies, current treatment strate- gies use ICIs combined with other immune therapies (dual 2. Patient selection checkpoint inhibition with PD-1 and cytotoxic T-lympho- cyte-associated [CTLA-4] antagonists), tyrosine Routine clinical use of ICIs in urological tumors depends on kinase inhibitors, or chemotherapies [1]. local approval and reimbursement status. Three ICIs that act ICIs are being investigated in therapeutic indications on the PD-1/PD-L1 pathway (atezolizumab, nivolumab, and usually led by multidisciplinary teams, with urologists pembrolizumab) are approved for the use in advanced or either actively involved in or even heading such teams. metastatic UC and/or RCC, as summarized in Table 1 Examples include the adjuvant setting in RCC or UC, or [2,3,5]. For advanced RCC, nivolumab is also approved for neoadjuvant treatment prior to cystectomy for bladder use in combination with ipilimumab, an ICI-targeting CTLA- carcinoma as well as high-grade non-muscle-invasive 4 [6]. Detailed staging and consideration of prior treatment bladder cancer (non-MIBC) [2,3]. Therefore, urologists need sequence for advanced disease are essential for deciding on to be well informed about the basic principles, current patients’ eligibility for ICI therapy. Additional immune indications, and special features of ICI therapy. biomarker testing is recommended and even required for ICIs are associated with a specific spectrum of side patient selection only in specific clinical scenarios, for effects, namely, immune-related adverse events (irAEs). example, previously untreated, cisplatin-ineligible UC. This spectrum differs from toxicities known for kinase inhibitors or cytotoxic drugs. The incidence of irAEs varies, 2.1. Renal cell carcinoma depending on the immune checkpoint that is targeted and the combination that is being used. As for any treatment 2.1.1. Statement modality, gains in efficacy must be balanced against the In advanced RCC, nivolumab monotherapy is a standard of frequency and severity of side effects. As delays in care in patients who failed one or two prior lines of vascular identifying and management of side effects might result endothelial growth factor (VEGF)-targeted monotherapy. in symptom worsening and further complications, it is The use of nivolumab plus low-dose ipilimumab in therefore critical that clinicians prescribing ICIs or super- treatment-naïve patients with advanced or metastatic vising patients under or after ICI therapy must be well clear-cell RCC of International Metastatic Renal Cell trained to identify irAEs promptly, monitor patients Carcinoma Database Consortium (IMDC) intermediate adequately, and either treat the side effects correctly or and poor risk is recommended by EAU guidelines [3]. ICI refer the patients instantly to collaborating colleagues or treatment should be prescribed only after a multidisciplin- teams [4]. ary team decision and by physicians experienced in this

Table 1 – PD-1/PD-L1 ICIs for renal and urothelial cancer investigated in phase 3 randomized controlled trials and approved,[2_TD$IF] or requests for approval filed

Cancer Indication Atezolizumab Avelumab Nivolumab Pembrolizumab

RCC Untreated patients Avelumab 10 mg/kg Nivolumab 3 mg/kg + Ipilimumab Pembrolizumab 200 mg (1st line) Q2W + 5 mg 1 mg/kg Q3W Â 4 Q3W + axitinib 5 mg BIDa BIDa followed by Nivolumab 3 mg/kg Q2Wb[3_TD$IF] After prior therapy Nivolumab 240 mg Q2W or 480 mg Q4W UC Untreated (1st line), Atezolizumab 1200 mg Pembrolizumab 200 mg cisplatin ineligible, Q3W (IC score >5%c)[5_TD$IF] Q3W (CPS >10c)[5_TD$IF] PD-L1 positivec[5_TD$IF]4 After platinum-based Atezolizumab 1200 mg Q3W Nivolumab 240 mg Q2W Pembrolizumab 200 mg chemotherapy Q3W

BI = bis in dies (twice per day); CPS = combined positive score; EMA = European Medicines Agency; IC = immune cell; ICI = immune ; IMDC = International Metastatic Renal Cell Carcinoma Database Consortium; PD-1 = programmed cell death protein 1; PD-L1 = programmed cell death ligand 1; RCC = renal cell carcinoma; UC = urothelial cancer.[1_TD$IF] a Request for EMA approval filed. b Approved for intermediate/poor-risk patients according to IMDC. c Restricted indication for patients with PD-L1-positive tumors as defined by either high infiltrating[6_TD$IF]IC status (atezolizumab) or high CPS (pembrolizumab), both markers are correlates for PD-L1 positivity. 370 EUROPEAN UROLOGY 76 (2019) 368– 380 type of therapy. In patients who stopped an ICI due to shown significant prolongation of OS (10.3 vs 7.3 mo; toxicity, a rechallenge with either drug should be under- HR = 0.73 [95% CI 0.59–0.91], p = 0.004) in patients who had taken only with expert guidance and support from a received prior platinum-containing chemotherapy multidisciplinary team. [11]. Compared with standard-of-care chemotherapy, pem- brolizumab also had a favorable toxicity profile resulting in 2.1.2. Background improved quality of life [12]. Atezolizumab, a PD-L1 inhibitor, For patients with advanced RCC with a clear-cell compo- similarly showed favorable efficacy and reduced toxicity nent, the EAU renal cancer guideline recommends the use of compared with chemotherapy, but no OS benefit was nivolumab after one or two lines of VEGF- observed [13,14]. Nivolumab is the third ICI currently in metastatic RCC, based on the results of a phase III trial approved by the EMA in platinum pretreated advanced or [5]. Compared with , a benefit in overall survival metastatic UC patients; its recommendation for use is based (OS; 25.0 vs 19.6 mo, hazard ratio [HR] = 0.73 [98.5% on single-arm phase II trials [15] (evidence level 1B for confidence interval {CI} 0.57–0.93], p < 0.002), improved pembrolizumab, and 2A for atezolizumab and nivolumab quality of life, and fewer grade 3 or 4 adverse events (AEs) according to the EAU guidelines) [8]. were reported for nivolumab. Based on the results from single-arm phase II trials, Strong evidence (grade 1B) also backs the recommenda- pembrolizumab and atezolizumab are also available in tion for the European Union (EU)/US-approved use of the EU for use in UC patients who are not eligible for nivolumab plus low-dose ipilimumab in treatment-naïve platinum-containing first-line therapy [16,17] (evidence patients with clear-cell metastatic RCC of IMDC intermedi- level 2A): up to 50% of patients with locally advanced or ate and poor risk [6]. A phase 3 randomized controlled trial metastatic UC are considered “unfit” for cisplatin-based (RCT) of atezolizumab plus versus chemotherapy [18]. However, the EMA and the US Food demonstrated a progression-free survival (PFS) benefit in and Drug Administration (FDA) recently restricted the use PD-L1-positive patients. However, a later interim analysis of both antibodies to patients with PD-L1-positive did not show an OS benefit and the respective European tumors. Different immunohistochemical evaluations Medicines Agency (EMA) application was withdrawn (companion diagnostic tests) need to be applied to test [7]. Recent and partly preliminary data from phase 3 RCTs PD-L1 positivity for each of these antibodies (see section comparing the combination of the VEGF receptor (VEGFR)- 2.4, Biomarkers). directed tyrosine kinase inhibitor axitinib and either the Recently, encouraging results on PD-1 ICIs in the PD-L1 inhibitor avelumab [8] or the PD-1 antibody neoadjuvant setting prior to cystectomy for MIBC were pembrolizumab [9] with the previous standard sunitinib reported [19,20]. With surgery planned within 3 wk after indicated consistent gains in efficacy across the overall trial the last dose, neither a delay in radical cystectomy nor more population in treatment-naïve advanced RCC with a clear- postsurgical complications were observed [19]. Ongoing cell component. EU approval and US approval are expected phase 3 randomized trials focus on the neoadjuvant and for pembrolizumab and axitinib based on an OS benefit (OS adjuvant settings of MIBC. Furthermore, PD-1 ICIs are benefit still to be demonstrated for avelumab plus axitinib), explored in high-grade non-MIBC, for example, for bacillus introducing a new era in the front-line setting of metastatic Calmette-Guérin (BCG)-refractory and BCG-naïve disease. RCC in which PD-1 or PD-L1 ICIs constitute the backbone of therapy, in combination with low-dose ipilimumab or an 2.3. Prostate cancer anti-VEGFR-directed tyrosine kinase inhibitor, respectively. 2.3.1. Statement 2.2. Locally advanced unresectable/metastatic UC ICIs are not recommended for prostate cancer outside of clinical trials. 2.2.1. Statement PD-1 ICIs are a standard treatment in patients after prior 2.3.2. Background platinum-based chemotherapy (ie, for second-line therapy). In metastatic castration-resistant prostate cancer Among the approved ICIs (pembrolizumab, atezolizumab, (mCRPC), results from two phase III trials investigating and nivolumab), available evidence (OS benefit) is currently the use of ipilimumab were disappointing. In docetaxel- favoring pembrolizumab [10]. pretreated [21] as well as chemotherapy-naïve patients Atezolizumab and pembrolizumab may also be used in [22], CTLA-4 blockade did not prolong survival, but treatment-naïve, cisplatin-ineligible patients with PD-L1- resulted in significant toxicities. However, there were positive tumors. Patients must be properly counseled about signs of activity of ipilimumab, including some excep- the potential risks and benefits as well as about the lack of tional cases with long-term remissions [23].Evidencefor randomized data comparing ICIs with chemotherapy. PD-1 and PD-L1 antagonists is currently limited to early clinical trials and small case series [24,25]. Several phase 2.2.2. Background II but also phase III trials in mCRPC are ongoing. Checkpoint inhibition with PD-1 and PD-L1 inhibitors has Combinations with second-generation nonsteroidal anti- shown significant antitumor activity with acceptable toxic- androgens as well as combinations with various PARP ity and durable responses in patients with locally advanced inhibitors (eg, olaparib and rucaparib) or chemotherapy and metastatic UC. The PD-1 inhibitor pembrolizumab has (docetaxel) are investigated. EUROPEAN UROLOGY 76 (2019) 368– 380 371

2.4. Biomarkers phase 2 trial indicated that response rate, PFS, and OS might be greater in patients with high PD-L1 expression, in the 2.4.1. Statement randomized phase 3 trial, better outcomes were also Prior to counseling cisplatin-ineligible, treatment-naïve observed in the chemotherapy arm, resulting in no OS patients with metastatic UC about ICI treatment options, difference in the PD-L1-positive group [12,13]. immunohistochemical PD-L1 testing shall be performed to However, for the first-line cisplatin-ineligible setting, on determine the combined positive score (CPS; for pembro- June 1, 2018, the EMA restricted the labels of pembrolizu- lizumab) and/or the tumor-infiltrating immune cell (IC) mab and atezolizumab in UC due to efficacy issues, score (for atezolizumab). compared with chemotherapy, identified in ongoing clinical For RCC or previously treated metastatic UC, upfront trials, excluding patients with low PD-L1 expression from biomarker testing is currently not mandatory. However, its use [34]. The US FDA had alerted health care profes- additional biomarkers are under investigation, which might sionals and investigators on May 18, 2018 with become important to guide treatment decisions. the same concerns [35], which arose from interim analyses of the phase III trials, Keynote-361 and IMvigor 130 [36,37], 2.4.2. Background and restricted both labels in August 2018. Therefore, Identification and validation of clinically useful biomarkers treatment is limited to patients with tumors with either to guide therapeutic decisions for patient selection as well a combined (referring to tumor cells and ICs) positive score as for therapy monitoring of ICIs represent a critical issue (CPS) of 10 for pembrolizumab or an IC score of 5% for across all cancer indications. PD-L1 immunohistochemistry, atezolizumab. individual mutational analysis with The Cancer Genome Atlas (TCGA) RNA subtype correlation, determination of 3. Categorization and frequency of ICI therapy- tumor mutational burden, tumor-infiltrating lymphocyte related toxicities counts, or IC gene expression profiling have been investi- gated prospectively and retrospectively to identify potential 3.1. Statement biomarkers [26–29]. PD-L1 positivity, determined by PD-L1 expression with Side effects of ICIs, namely irAEs, may affect any organ different cutoffs, is the most comprehensively studied system. Symptoms are frequently nonspecific, making their biomarker. Its relevance as a biomarker has been highlight- attribution difficult, and the differential diagnosis between ed by the development of several PD-L1 diagnostic tests, the irAEs and infection (eg, pneumonitis vs pneumonia) use of which in the USA—foremost in non-small cell lung imponderable. Urologists involved in the multidisciplinary cancer—is either mandatorily required for certain clinical treatment of renal, bladder, and prostate cancer should be uses (eg, companion diagnostic total performance score aware of irAEs and know how to diagnose them. For the >50% for first-line use of pembrolizumab) or at least management of ICI therapy, close multidisciplinary collab- recommended (complementary diagnostic) by the FDA to oration is mandatory. support physicians’ informed decision making [30–33]. For RCC, testing of PD-L1 status yields conflicting results 3.2. Background as a predictive factor and assessment is not mandatory. However, patients treated with the combination of nivo- Treatment-related toxicities of ICIs comprise two distin- lumab and low-dose ipilimumab having PD-L1-positive guishable sets of adverse drug reactions (ADRs): on the one tumors appear to benefit most with regard to OS (HR 0.45 vs hand, side effects generally associated with pharmacother- 0.73 for PD-L1-negative tumors) and have higher overall apy (ie, due to absorption, distribution, metabolization, and (58% vs 37%) and complete (16% vs 7%) response rates, elimination processes— eg, hepatic or renal toxicities), and respectively. Of note, no benefit in terms of PFS was on the other hand, the partially novel irAEs that are well- observed for PD-L1-negative tumors [4]. PD-L1 status is also known ICI class effects, caused by their direct impact on recorded in many ongoing ICI trials; the recently reported immune regulation. results from the JAVELIN Renal 101 trial [6] provide support The precise pathophysiology underlying irAEs is still that in advanced, clear-cell RCC, therapy outcomes are more unknown, but is thought to be related to the role that favorable in PD-L1-positive patients treated with avelumab immune checkpoints play in immunological homeostasis plus axitinib. In this trial, PFS and OS in PD-L1-positive [38]. It remains unknown to which extent autoantibodies, patients were the coprimary endpoints. However, due to the rather than autoreactive T cells, contribute to irAEs or the so far exploratory nature of PD-L1 tumor expression, the role of cytokines that are thought to be involved in the EAU renal cancer guideline does not recommend the use of pathophysiology of irAEs. Current guidelines for side-effect PD-L1 as a predictive biomarker. As a prognostic factor, PD- assessment, such as Common Terminology Criteria for L1 status may, however, add to the IMDC prognostic criteria. Adverse Events (CTCAE; CTCAE of the U.S. National Cancer Similarly, for the second-line use of pembrolizumab, Institute, V. 4.0: https://evs.nci.nih.gov/ftp1/CTCAE/ atezolizumab, and nivolumab in locally advanced or CTCAE_4.03/Archive/CTCAE_4.0_2009-05-29_Quick metastatic UC—the same applies for the US-registered uses Reference_8.5x11.pdf), are not specific to irAE reporting, of avelumab and durvalumab in this UC setting—testing of and grading of irAEs may be challenging [39]. Currently, PD-L1 expression is not required. While the atezolizumab irAEs are described as AEs that may differ in type, frequency, 372 EUROPEAN UROLOGY 76 (2019) 368– 380 or severity from AEs caused by nonimmunotherapies: (1) are increased for ICIs; of the more general ADRs related to which may require (eg, corticoste- immune activation, only the rates of rash and associated roids) as part of their management, (2) early recognition pruritus are significantly increased for ICIs [39,40]. Data for and management of which may mitigate severe toxicity, and irAE/ADR incidences according to tumor types are incon- (3) for which multiple event terms may be used to describe clusive so far; however, incidences of particular irAEs vary a single type of AE, thereby necessitating the pooling of across different cancers [41]. One review reported that terms for full characterization [40]. An established defini- arthritis and myalgia were more frequent in tion of an irAE is still missing. patients than in patients with RCC in whom pneumonitis Differentiation of AEs (ie, whether treatment related or was more prevalent [44]. Compared with PD-1 monother- not, and if yes, whether immune related or not) sometimes apy, incidences of ADRs and irAEs are clearly augmented for requires a careful differential diagnosis of even nonspecific PD-1/CTLA-4 combined immune checkpoint blockade and low-grade AEs to determine whether tumor progres- (Table 2) [42,45,46]; the rates of certain irAEs (, sion or organ-specific comorbidities or an ADR is the root pneumonitis, increases in transaminases and lipases) cause of an AE. ADRs not specifically related to immune augment substantially—colitis, rash, and hypophysitis are reactions dominate, by their frequency, the AE reporting for more frequent with CTLA-4 than with PD-1 monotherapy ICIs; their incidence (all grades), as summarized from the [43,44]. actual summaries of product characteristics (SmPCs), are listed in Table 2. 4. Clinical diagnosis and management of ICI The overall incidence of AEs (all causes and grades) in therapy-related major toxicities clinical trials of inhibitors of the PD-1/PL-L1 axis was 67.6%; severe (grade 3–4 according to CTCAE) events occurred in Five organ systems are frequently affected by ICI ADRs: skin 11.4% of patients, but these rates were lower than the rates in with exanthema and pruritus, liver with , colon with the chemotherapy control arms (82.9% and 35.7%, respec- diarrhea/colitis, lung with pneumonitis, and the endocrine tively) [41]. The most frequent ADRs are (31.8%), systems. In order to identify irAEs as early as possible, diarrhea (18.5%), arthralgia (12.4%), and back pain (10.9%), patients should regularly be asked for skin, bowel, and/or according to a recent meta-analysis [42]. The incidence of pulmonary symptoms. Regular laboratory analyses should rash, observed with PD-1/PD-L1 inhibitors as well as with include liver and pancreas enzymes as well as creatinine, several tyrosine kinase inhibitors, reaches 10.3%—also the since irAEs at the respective organs do not result in early WHO criteria for “very common” ADRs [40]. Abnormalities in symptoms. Furthermore, thyroid-stimulating hormone laboratory investigations are very common too: reported are (TSH) should be closely monitored to identify hypo- or increases of aspartate transaminase (AST)/alanine transami- hyperthyroidism. In case of unspecific symptoms and/or nase (ALT), hypokalemia, and hyponatremia, or increased deterioration, an irAE of the endocrine system should be alkaline phosphatase, creatinine, lipase, and amylase. Table 2, ruled out by analysis of TSH, (LH), which lists all very common or common ADRs mentioned in follicle-stimulating hormone (FSH), adrenocorticotropic current EU prescribing information text, mirrors these data hormone (ACTH), cortisol, prolactin, and either estradiol or from meta-analyses. testosterone. The diagnosis of an irAE requires exclusion of The overall incidence of treatment-related irAEs, other causes of the respective signs or symptoms, for assessed through a meta-analysis of 46 trials of PD-1/PD- example, by stool culture or hepatitis serology in case of L1 inhibitors reporting 13 000 patients, is 26.8%. Severe diarrhea/colitis and liver ultrasound (cholestasis, progression irAEs occur in 6.1% of patients; the incidence of therapy- of liver metastasis) for rising transaminases [36,43].Early related death is <0.2% [43]. Most frequent irAEs (of any involvement of other relevant disciplines is recommended in grade) are—both common— (5.6%) and order to facilitate optimal management of irAEs. pneumonitis (2.2%); colitis (0.7%), hypophysitis (0.3%), For the overall management of irAEs, which are and hepatitis (0.2%) are uncommon [40]. The only common predominantly inflammatory reactions, interruption of severe irAE is pneumonitis (1.4%); severe colitis (0.5%), therapy or even permanent therapy discontinuation is a hypophysitis (0.2%), hyperthyroidism (0.2%), and hepatitis measure of choice. Generally, in case of grade 4 irAEs, (0.1%) are uncommon [40]. The incidences generally match therapy discontinuation is recommended in line with those reported in the EU prescription information texts, systemic corticosteroid therapy; for grade 2 irAEs, inter- although differences manifest, mainly due to the grouped ruptions of therapy plus corticosteroid use are recom- coding of several symptoms within a given irAE. Hyperthy- mended; and for grade 1 irAEs, ICI therapy can usually be roidism is also considered to constitute a common irAE continued. Drug manufacturers’ recommendations for the (incidence 1.7–3.5%). Further uncommon events (0.1–1.0%) management of grade 3 irAEs are heterogeneous; official are adrenal insufficiency, type I mellitus, pancrea- recommendations for the most clinically relevant (ie, titis, or nephritis; neurological ADRs such as Guillain-Barré frequency, severity, and complexity of event) irAEs are syndrome and meningitis are uncommon too. Other irAEs displayed in Fig. 1. Dose reductions/modifications are such as myasthenic syndrome, encephalitis, or myocarditis generally not recommended for ICIs. occur rarely (incidence <0.1%). For the general AEs related to immune activation, consensus Compared with ADR rates in comparator arms of clinical recommendations provide guidance in relation to the clinical trials (phase II–III) of PD-1/PD-L1 inhibitors, rates of irAEs management of fatigue [47,48],diarrhea[49],nauseaand EUROPEAN UROLOGY 76 (2019) 368– 380 373

Table 2 – Very common and common ADRs of checkpoint inhibitors authorized in the EU for use in urological cancers (frequencies reported according to current SmPCa)

Adverse Reaction (listed according to Standard Organ Class) Atezolizumab Nivolumab Pembrolizumab Nivolumab + ipilimumab

Infections and infestations Upper respiratory tract infections/pneumonia [TD$INLE]/[TD$INLE] */[TD$INLE] [TD$INLE]/**/* Blood and lymphatic system disorders Neutropenia [TD$INLE] & [TD$INLE] & Eosinophilia [TD$INLE] [TD$INLE] [TD$INLE] * Anemia [TD$INLE] && & Thrombocytopenia *&*& disorders Infusion-related reaction/hypersensitivity */**/**/[TD$INLE] */* Endocrine disorders Hypo-, hyperthyroidism/otherb,* */[TD$INLE] */[TD$INLE] &/[TD$INLE] &/* Metabolism and nutrition disorders Decreased appetite &*&& Dehydration [TD$INLE] [TD$INLE] [TD$INLE] * Hypokalemia/hyponatremia */*&/& [TD$INLE] /[TD$INLE] &/& Hyperglycemia/diabetes mellitus [TD$INLE]/[TD$INLE] &/[TD$INLE] [TD$INLE] &/* Nervous system disorders Headache [TD$INLE] *& * Dizziness [TD$INLE] ** * Peripheral neuropathy [TD$INLE] ** * Eye disorders Uveitis*/blurred vision [TD$INLE]/[TD$INLE] [TD$INLE] /[TD$INLE] [TD$INLE] /[TD$INLE] [TD$INLE] /* Cardiac disorders Tachycardia [TD$INLE] [TD$INLE] [TD$INLE] * Hypertension/hypotension [TD$INLE]/**/[TD$INLE] */[TD$INLE] */[TD$INLE] Respiratory, thoracic, and mediastinal disorders Dyspnea/cough &/[TD$INLE] */*&/&*/* Pneumonitis*/pulmonary embolism */[TD$INLE] */[TD$INLE] */[TD$INLE] */* Hypoxia * [TD$INLE] [TD$INLE] [TD$INLE] Gastrointestinal disorders Diarrhea &&&& /vomiting &/&&/*&/&&/& Abdominal pain **&* Stomatitis/colitis*/pancreatitis* [TD$INLE]/*/[TD$INLE] */*/[TD$INLE] [TD$INLE]/*/[TD$INLE] */*/* Dry mouth/dysphagia /**/ */ */ Constipation [TD$INLE] *& * Lipase increased/amylase increased [TD$INLE] /[TD$INLE] &/& [TD$INLE]/*&/& Hepatobiliary disorders Hepatitis* [TD$INLE] [TD$INLE] [TD$INLE] * Liver transaminases increased (ALT/AST) */*&/&*/*&/& Skin and subcutaneous tissue disorders Rash*/urticaria &/[TD$INLE] &/[TD$INLE] &/[TD$INLE] &/* Dry skin/pruritus [TD$INLE]/&*/&*/&*/& /erythema [TD$INLE]/[TD$INLE] */**/* [TD$INLE] /* Alopecia [TD$INLE] ** [TD$INLE] Musculoskeletal and connective tissue disorders Arthralgia &*&& Myositis*/arthritis [TD$INLE]/[TD$INLE] */* [TD$INLE] /* Musculoskeletal pain **&& Renal and urinary disorders Renal failure (including acute kidney injury) [TD$INLE] [TD$INLE] [TD$INLE] * Creatinine increased [TD$INLE] ** * General disorders Pyrexia &*&& Influenza-like illness/chills */* [TD$INLE]/[TD$INLE] */* [TD$INLE]/[TD$INLE] Fatigue &&&& Asthenia & [TD$INLE] & [TD$INLE] Edema [TD$INLE] *& *

ADR = adverse drug reaction; ALT = alanine transaminase; AST = aspartate transaminase; EU = European Union; irAE = immune-related adverse event; SmPC = summary of product characteristics; & = very common (1/10 patients [10%]); * = common (1/100 and <1/10 patients [1% and <10%]); [TD$INLE] = uncommon (1/1000 and <1/100 patients [0.1% and <1%]); [TD$INLE] = rare (1/10 000 and <1/1000 patients [0.01% and <0.1%]);  = very rare (<1/10 000 patients [<0.01%]); [TD$INLE] = not (yet) mentioned; frequency not yet determined. Listed in the table are adverse reactions that are classified as “very common” or “common” for at least one drug regimen approved for use. a SmPC versions: as of April 30, 2019. b Includes (mainly): adrenal insufficiency, hypophysitis, and thyroiditis. * Classified as irAE also. 374 EUROPEAN UROLOGY 76 (2019) 368– 380 [(Fig._1)TD$IG]

Fig. 1 – Recommendations dependent on irAE type/severity for treatment modifications of ICI therapy. Various colors indicate that treatment may be continued (green), should be interrupted (yellow), or should be discontinued permanently (red; assessment based on drug manufacturers’ current prescribing information text according to Table 2). ADR = adverse drug reaction; AE = adverse event; ALT = alanine transaminase; AST = aspartate transaminase Ate = atezolizumab; BILI = bilirubin; CREA = creatinine; CTCAE = Common Terminology Criteria for Adverse Events; ICI = immune checkpoint inhibitor; irAE = immune-related adverse event; Niv = nivolumab; Pem = pembrolizumab; SmPC = summaries of product characteristics; syndr. = syndrome; TSH = thyroid-stimulating hormone.

vomiting [50], infusion-related reactions [51],pain[52],or provided in a specific, novel European Society for Medical cardiotoxicities [53,54]. More specific recommendations for Oncology Clinical Practice Guideline [55]; for the USA, similar the management of immunotherapy-induced toxicities are guidance has been provided by the American Society of Clinical EUROPEAN UROLOGY 76 (2019) 368– 380 375

Oncology [56]. For the most relevant irAEs, specific recom- 4.2.2. Background mendations for their diagnosis and clinical management are ICI-related immune endocrinopathies commonly include given in the subsequent text chapters. thyroid gland disorders (hypothyroidism, and less frequent- ly hyperthyroidism or thyroiditis). Adrenal insufficiency is a 4.1. Skin and mucosal toxicity common disorder too, while hypophysitis is a rather rare event (Table 2). Compared with PD-1 ICI monotherapy, 4.1.1. Statement endocrine toxicities are more frequent under combined Rash and pruritus are the clinically most relevant dermato- immune checkpoint blockade [43]. Owing to their unspe- logical side effects, which are reversible and clinically well cific and often complex symptoms, the diagnostic approach manageable; their predictive value for response/survival might be challenging [59]. requires clarification in larger studies. For CTCAE grading, The pathogenesis of thyroid disorders arising from ICI the affected body surface area is estimated using the “rule of therapy is not yet well understood [36,53]. Regular control of nine” (known from burns). Urologists should consult a TSH—if repeatedly elevated or decreased TSH or if a thyroid dermatologist in case of persisting or recurrent grade 3 dysfunction is suspected, fT3, fT4, and cortisol should be (>30% of body surface area affected) toxicity. measured as well—is helpful to diagnose hypo- or hyperthy- roidism: these toxicities occur rather late after the start of 4.1.2. Background therapy and resolve more slowly than other immune-related Very common skin toxicities include itching (pruritus) and toxicities [43,60]. Substitution with thyroid hormone associated rash, often in maculopapular form, and vitiligo (L-thyroxin, starting dose 50 mg) should be considered if (Table 2), most often in melanoma patients [57]. Widespread hypothyroidism is diagnosed. Mild and asymptomatic rash (exanthema) may occur at the trunk and/or extremi- hyperthyroidism may be initially observed and might ties; treatment modalities include the use of topical eventually turn into hypothyroidism. However, in symptom- corticosteroids (eg, hydrocortisone creams 1%) or moistur- atic patients, beta-blockers might be started [53]; interrup- izing creams or lotions containing urea or glycerine. For tion of ICI therapy until recovery from symptoms is generally continued itching, oral, nonsedative, systematic H1-anti- SmPCs recommended for CTCAE of grade 3 (Fig. 1). histamines might be used. Regular examinations prior to Adrenal insufficiency may manifest with diffuse symp- and during ICI therapy should rule out skin problems of toms including signs of dehydration, electrolyte abnormali- other etiology, such as an infection, vasculitis, or contact ties (hyperkalemia and hyponatremia), hypotension, and/or dermatitis. The association of dermatological AEs and ICI shock, sometimes mild to moderate but occasionally response or survival has been investigated, but its predictive leading to an adrenal crisis [61]. The disorder might also value remains uncertain [58]. develop following (partial) insufficiency of the pituitary For severe rash, treatment interruption (grade 3) or gland and therefore requires a differential diagnosis: permanent discontinuation (grade 4) of ICI therapy is whether the adrenal gland is affected or a hypophyseal recommended (Fig. 1), and patients should immediately be insufficiency is suspected. Corticosteroid replacement may placed under a dermatologist's supervision: this applies be sufficient in patients with moderate symptoms (grade 2), particularly if severe skin reactions, such as Stevens-Johnson but high-dose steroids are required in more severe cases syndrome or toxic epidermal necrolysis, are suspected or (grade 3–4). When symptoms ameliorate, the use of clinically manifest. Treatment consists of intravenous (i.v.) hydrocortisone has been recommended to avoid the (methyl)prednisolone 1–2 mg/kg, with slow tapering and additional use of fludrocortisone as mineral corticoid switching to oral therapy when toxicity resolves to normal [53]. replacement [62]. An endocrinologist should be consulted to supervise/optimize substitution. 4.2. Endocrinological and metabolic toxicities Immune-related inflammation of the pituitary gland may lead to local swelling and hormone dysfunction most 4.2.1. Statement commonly presenting as central adrenal insufficiency. Thus, Thyroid gland disorders are common side effects of ICIs, hypophysitis is diagnosed by the detection of decreased with 5–10% of all patients being affected. Narrow ACTH, LH, FSH, TSH, and prolactin, as well as subsequently monitoring of TSH and a detailed hormone analysis (ACTH, decreased cortisol and gender-dependent estradiol or LH, FSH, prolactin, cortisol, and estradiol/testosterone) for testosterone; magnetic resonance tomography (MRT) of otherwise unspecific symptoms or deterioration are the brain might confirm a swollen or enlarged pituitary required. The onset of immune-related endocrinopathies gland. Symptoms of hypophysitis are generally unspecific is slow; their resolution may last for weeks and is not and include those of adrenal insufficiency (see above) as always reversible. Patients should be informed adequately well as headache, impaired vision, and dizziness. High-dose prior to the initiation of treatment that occurrence of corticosteroids should be given at least in cases with severe endocrinopathies may result in long-lasting or even symptoms (grade 3–4); ICI therapy should be interrupted in permanent hormone replacement therapy. In case of grade 2–3 cases and discontinued for grade 4 cases (Fig. 1): suspected endocrinopathy other than hypo-/hyperthyreo- this irAE may result in continuous hormone (hydrocorti- sis, the patient should be referred early to a specialist with sone) replacement therapy [63]. experience in the management of immune-related endo- Endocrine side effects are reversible in approximately crinopathies. half of all the patients with thyroid or pituitary gland side 376 EUROPEAN UROLOGY 76 (2019) 368– 380 effects, often requiring long-lasting hormone replacement pancreatitis, which is commonly seen with combined therapy. Therefore, all patients should be informed upfront anti-CTLA-4 plus PD-1 ICI therapy (Table 2). Pancreatitis about this potential, aggravating consequence of ICI as well as small bowel enterocolitis may be visible through therapy. computer tomography (CT): if confirmed, discontinuation Type I diabetes mellitus and also diabetes insipidus are of ICI therapy and initiation of immunosuppression uncommon to rare side effects; advice is given to regularly treatment is recommended in symptomatic patients with monitor blood glucose levels, particularly if patients report severe inflammation reactions (Fig. 1) [53]. However, polydipsia or polyuria [43,53]. In severe cases, patients may treatment may be continued in cases of asymptomatic develop ketoacidosis [64] that should be treated according increases of amylase and lipase up to grade 3. to established guidelines. Patients developing diabetes may Narrow monitoring of serum transaminases (AST and require insulin substitution; in metabolically stable ALT) and bilirubin is the key to detect immune-related patients, ICI therapy may be restarted [53,65]. hepatitis and should be carried out prior to each treatment cycle [67]. Loss of appetite, nausea and vomiting, fatigue, 4.3. Gastrointestinal and hepatic toxicities icterus, and frequent hematomas are other unspecific events. As hepatitis is a diagnosis by exclusion, other 4.3.1. Statement causalities—particularly infections including viral hepati- To detect toxicities early, urologists should train and advise tis—must be ruled out [53,63]. Liver sonography to exclude their patients to report any suspicious gastrointestinal and cholestasis or tumor progression and liver biopsy may be bowel symptoms directly to them; regarding hepatic irAEs, considered in assisting in the differential diagnosis of more close monitoring of liver transaminases and bilirubin is a severe hepatic side effects [58]. Treatment of hepatitis key prerequisite. includes the use of corticosteroids and, depending on severity, additive immunosuppressant agents, for example, 4.3.2. Background mycophenolate mofetil (as is hepatotoxic), if Similar to skin and endocrine toxicities, certain gastroin- there is no response to corticosteroids within 2–3 d. ICI testinal side effects (diarrhea, nausea, and vomiting) are therapy should be withheld if transaminases or bilirubin very common. Therapy-induced inflammation reactions reach CTCAE grade 2: this has been recommended already under monotherapy vary from being common to uncom- (Fig. 1). For hepatitis grade 3, all drug manufacturers mon side effects (Table 2); routine monitoring should recommend permanent discontinuation of ICI therapy. encompass events such as stomatitis, colitis, and pancrea- titis as well as hepatitis [66]. Diarrhea, although a rather 4.4. Pulmonary toxicity unspecific adverse reaction, and very frequently observed with chemotherapy or tyrosine kinase inhibitor therapy, is 4.4.1. Statement however categorized as an irAE: its onset and resolution are Pneumonitis, the only severe irAE of common frequency in equated in the official prescribing information with the PD-1 ICI monotherapy (ie, in >1% of patients), has been the onset and resolution of colitis, the most frequent severe ADR associated with the highest number of fatal outcomes gastrointestinal ADR of ICI therapy. Diagnostic workup of in clinical trials and routine use. Treating physicians should colitis symptoms such as diarrhea, mucus or blood in stool, carefully monitor any pulmonary symptoms during or after abdominal pain, or change in bowel habits should include ICI therapy and start differential diagnostic workup (eg, microbiological examination of stool to exclude pathologi- high-resolution thoracic CT) immediately in case of cal intestinal germs. suspected pulmonary inflammation reactions. Therapy of mild to moderate symptoms of colitis include withholding the ICI treatment beginning at CTCAE grade 4.4.2. Background 2 and start of oral corticosteroid therapy: from grade Pneumonitis is one of the most common irAEs and the only 2 symptoms upward, a colonoscopy should be considered. severe irAE of common frequency (1.4%) [40]; numerous For combined immune checkpoint blockade, permanent cases with a fatal outcome are reported (Table 1) therapy discontinuation is recommended for grade 3 or [68,69]. Hence, any pulmonary symptoms during ICI higher cases (Fig. 1); similarly, ICI monotherapy should be therapy should be monitored carefully: in case of upper stopped after a first episode of grade 4 colitis and/or diarrhea. airway infections, cough, hypoxia or dyspnea, use of high- In case of grade 3 diarrhea or colitis, or in case of remaining resolution thoracic CT shall be considered to exclude symptoms after ICI withdrawal, the i.v. application of pneumonitis. Ideally, an infection should be ruled out by corticosteroids is recommended without further delay. bronchoscopy, especially in case of suspected pneumonitis Diarrhea and colitis are more frequent and occur earlier of grade 2 or higher. with CTLA-4 antibodies than with PD-1 or PD-L1 therapy After diagnosis, corticosteroid therapy should be started [42]. In case i.v. administration of corticosteroids does not immediately with close lung function and blood gas control; improve symptoms of a (moderate to) severe colitis, immune thoracic X-ray is required in short intervals to control the suppression should be escalated by using infliximab in cases clinical course of pneumonitis. Exclusion of infection allows that are refractory to steroids after 3–5d[53,58]. introduction of immunosuppressive therapy more safely, as Increased lipase and amylase as well as bowel pain or such medication increases the chance of opportunistic vomiting may indicate moderate to severe forms of infections [53]. However, if the differential diagnosis EUROPEAN UROLOGY 76 (2019) 368– 380 377 between pneumonitis and pneumonia remains uncertain, ICI therapy in case of myocarditis with CTCAE grade 3 and high-dose corticosteroids and antibiotics should be applied even in case of persisting grade 2 toxicity (Fig. 1). simultaneously. Higher-grade pneumonitis leads to permanent discon- 4.7. Neurological toxicity tinuation of ICI therapy; one drug manufacturer has already recommended therapy discontinuation in case of recurrent 4.7.1. Statement grade 2 pneumonitis (Fig. 1). In severe cases, additional Neurological side effects are rare but might result in serious nonsteroidal immune suppression, for example, with outcomes for patients; in case of onset, early therapy mycophenolate mofetil, should be considered. Corticoste- interruption and permanent discontinuation for all severe roids should be tapered over 4–6 wk (or even more slowly) events (grade 3 and higher) are recommended. after recovery. For prophylaxis of opportunistic infections during this time, use of trimethoprim and sulfamethoxazole 4.7.2. Background (eg, 3Â weekly) has been recommended [53,63]. Neurological events are rare and may present in the form of encephalitis, Guillain-Barré syndrome, myasthenic syn- 4.5. Renal toxicity drome, or myasthenia gravis [72–74], or other very rare events [43]; some were recently identified through EMA 4.5.1. Statement routine pharmacovigilance activities. Brain metastasis Routine clinical chemistry (serum sodium, potassium, should be excluded by MRT in case of neurological creatinine, and urea) should be monitored during and after symptoms. As laboratory and other examinations might ICI therapy to monitor for renal dysfunctions. differ from classical diagnostic procedures, a neurologist should be consulted in case of a suspected neurological irAE. 4.5.2. Background Treatment should include high-dose steroids as oral or i.v. Cases of renal dysfunction are common under ICI therapy, prednisolone (1–2 mg/kg) and might be intensified through usually indicated by an asymptomatic increase in creatinine: additional immunosuppressive measures. Permanent dis- the incidence is higher with the combination of nivolumab continuation of ICI therapy is generally recommended for and ipilimumab (Table 2) [4,53]. Diagnostically, serum grade 3 or higher neurological toxicities (Fig. 1). sodium, potassium, creatinine, and urea should be monitored during ICI therapy, and urinalysis (eg, proteinuria) should be 5. Conclusions performed in case of creatinine rise [70,71]. However, histologically proven cases with nephritis are rare. Therefore, Immunotherapy using ICIs plays an important role in the other causes of renal function deterioration (eg, exsiccosis) treatment of patients with advanced urological cancers. In should be excluded and renal biopsy should be considered order to manage patients with ICI treatment safely, prior to start of corticosteroid therapy for potential immune- urologists should be aware of the nature, diagnosis, and related renal inflammation or damage. Beginning with treatment of immune-related AEs. Most toxicities affect the creatinine elevations of grade 2 or higher, therapy should skin with rash and pruritus, the gastrointestinal tract with be withheld; for a grade 3 increase, certain drug manufac- hepatitis and colitis/diarrhea, the endocrine system with turers recommend stopping ICI therapy permanently (Fig.1). thyroid gland disorders, and the lung with pneumonitis. However, immune-related AEs may affect any organ system, 4.6. Cardiac toxicity and should be considered in each patient with current or prior ICI treatment. Immune-related AEs should be graded 4.6.1. Statement according to CTCAE in order to decide about treatment One should be aware of the rare, but potentially life- interruption or discontinuation as well as the initiation of threatening, cardiac irAEs that may result from ICIs. In case corticosteroid therapy. For urologists inexperienced in of doubt, consult a cardiologist early. immunotherapy, early referral for suspected irAEs to specialist care is strongly recommended. For the safe use 4.6.2. Background of ICI therapy, early identification, and management of Immune-related cardiovascular toxicities are rare, but higher, toxicity, close multidisciplinary collaboration is mandatory. with the combination of nivolumab plus ipilimumab. Cardiovascular toxicities can be life threatening and have Author contributions: Marc-Oliver Grimm had full access to all the data caused fatalities; they deserve special attention and early in the study and takes responsibility for the integrity of the data and the consultation with a cardiologist [43]. Onset of cardiotoxicity accuracy of the data analysis. may occur early during treatment, with nonspecific symp- Study concept and design: Grimm, Van Poppel, Wirth. toms such as fatigue or hypotension, or may occur as acute Acquisition of data: Grimm. heart failure directly. Clinical symptoms and elevated Analysis and interpretation of data: Grimm, Bex, De Santis, Ljunberg, creatinine kinase should prompt further diagnostic modali- Catto, Rouprêt, Hussain, Bellmunt, Powles, Wirth, Van Poppel. ties, including echocardiography or cardiac MRT, as well as Drafting of the manuscript: Grimm. cardiac biopsy. High-dose corticosteroids were successful in Critical revision of the manuscript for important intellectual content: some patients, but the course was fatal in others [53].Drug Grimm, Bex, De Santis, Ljunberg, Catto, Rouprêt, Hussain, Bellmunt, manufacturers recommend permanently discontinuation of Powles, Wirth, Van Poppel. 378 EUROPEAN UROLOGY 76 (2019) 368– 380

Statistical analysis: None. [3] Ljunberg B, Albiges L, Bensalah K, et al. EAU guidelines on renal cell Obtaining funding: None. carcinoma. EAU; 2019. Administrative, technical, or material support: None. [4] Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune- Supervision: Grimm, Bex, De Santis, Ljunberg, Catto, Rouprêt, Hussain, checkpoint inhibitors: epidemiology, management and surveil- Bellmunt, Powles, Wirth, Van Poppel. lance. Nat Rev Clin Oncol. In press. http://dx.doi.drg/10.1038/ Other: None. s41571-019-0218-0. [5] Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Financial disclosures: Marc-Oliver Grimm certifies that all conflicts of everolimus in advanced renal-cell carcinoma. N Engl J Med interest, including specific financial interests and relationships and 2015;373:1803–13. affiliations relevant to the subject matter or materials discussed in the [6] Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipili- manuscript (eg, employment/affiliation, grants or funding, consultancies, mumab versus sunitinib in advanced renal-cell carcinoma. N Engl J honoraria, stock ownership or options, expert testimony, royalties, or Med 2018;378:1277–90. patents filed, received, or pending), are the following: Axel Bex reports [7] European Medicines Agency. Withdrawal of application for a participation in advisory boards of Pfizer, BMS, Novartis, Ipsen, and Eusa; change to the marketing authorization for Tecentriq (atezolizu- fees were paid to an institutional account for participation in the mab). EMA/798527/2018. https://www.ema.europa.eu/en/ CheckMate 914 and IMmotion 010 adjuvant trials; research grants were documents/medicine-qa/questions-answers-withdrawal- received from Pfizer for a neoadjuvant phase 2 trial of avelumab and application-change-marketing-authorisation-tecentriq- axitinib in high-risk. Börje Ljunberg has received company speaker atezolizumab_en.pdf. honoraria from GlaxoSmithKline, Roche, Pfizer, and Novartis; has [8] Motzer RJ, Penkov K, Haanen JB, et al. Avelumab plus axitinib versus participated in trials for GlaxoSmithKline, Medivation, Pfizer, and Janssen sunitinib in advanced renal-cell carcinoma. N Engl J Med R&D; and has been on advisory boards for Pfizer and GlaxoSmithKline. 2019;380:1103–15. Hendrik Van Poppel has no conflicts of interest to declare. Joaquim [9] Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus Bellmunt declares payments for advisory boards by , MSD, sunitinib in advanced renal-cell carcinoma. N Engl J Med Pfizer, BMS, Pierre-Fabre, and Janssen; lecture fees by Genentech, MSD, 2019;380:1116–27. Pfizer, BMS, Pierre-Fabre, and Janssen; and research funding by Takeda [10] Witjes JA, Bruins M, Cathomas R, et al. EAU guidelines on muscle- and Pfizer. James Catto has been paid to lecture by Roche, MSD, Nucleix, invasive and metastatic bladder cancer. EAU; 2019. Roche, BMS, and Astra Zeneca; and has received payment for advisory [11] Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second- boards and consultancy from Astra Zeneca, Astellas, and Steba Biotech. line therapy for advanced urothelial carcinoma. N Engl J Med Maria De Santis reports personal financial interests for Amgen, Astellas, 2017;376:1015–26. AstraZeneca, Bayer, Bioclin, BMS, EISAI, ESSA, Ferring, Ipsen, Janssen, MSD, [12] Vaughn DJ, Bellmunt J, Fradet Y, et al. Health-related quality-of-life Merck, Novartis, OncoGenex, Pfizer, Pierre Fabre Oncology, Roche, Sandoz, analysis from KEYNOTE-045: a phase III study of pembrolizumab Sanofi, SeaGen, Synthon, and Takeda; and institutional financial interests versus chemotherapy for previously treated advanced urothelial for Amgen, Astellas, AstraZeneca, Bayer, Bioclin, BMS, EISAI, ESSA, Ferring, cancer. J Clin Oncol 2018;36:1579–87. Ipsen, Janssen, MSD, Merck, Novartis, OncoGenex, Pfizer, Pierre Fabre [13] Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in Oncology, Roche, Sandoz, Sanofi, SeaGen, and Takeda. Marc-Oliver Grimm patients with locally advanced and metastatic urothelial carcinoma reports payments for advisory boards and consultancy from Astellas, who have progressed following treatment with platinum-based AstraZeneca, Bayer Healthcare, BMS, Intuitive Surgical, Ipsen, Janssen chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet Cilag, Merck Darmstadt, MSD, Novartis, Pfizer, and Sanofi Aventis; and 2016;387:1909–20. payment for lectures by Apogepha, Astellas, AstraZeneca, Bayer Health- [14] Powles T, Durán I, van der Heijden MS, et al. Atezolizumab versus care, BMS, GlaxoSmithKline, Ipsen, Janssen Cilag, MSD, Novartis, ONO chemotherapy in patients with platinum-treated locally advanced Pharma, and Pfizer. Morgan Rouprêt reports participation in advisory or metastatic urothelial carcinoma (IMvigor211): a multicentre, boards of MSD, Ferring, Janssen, and Roche; and institutional support open-label, phase 3 randomised controlled trial. Lancet from Roche. Manfred Wirth reports personal fees from Amgen, ABX 2018;391:748–57. Advanced Biochemical Compounds, Apogepha, Astellas, Bayer Vital, [15] Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in meta- Janssen-Cilag, MSD Sharp & Dohme, Novartis, and Pierre Fabre. Syed A. static urothelial carcinoma after platinum therapy (CheckMate Hussain has been paid to lecture by Roche, MSD, AstraZeneca, BMS, Sotio, 275): a multicenter, single-arm, phase 2 trial. Lancet Oncol Janssen, Pierre Fabre, and Pfizer; and has received payment for advisory 2017;388:312–22. boards and consultancy from Roche, MSD, Astra Zeneca, Astellas, BMS, [16] Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab Pierre Fabre, Janssen, Pfizer, and Bayer. Tom Powles reports lecture fees of in cisplatin-ineligible patients with locally advanced and unresect- Genentech, MSD, Pfizer, BMS, AZ, Janssen, and Novartis; research funding able or metastatic urothelial cancer (KEYNOTE-052): a multicentre, by AZ Roche; and payments for advisory boards by Genentech, MSD, single-arm, phase 2 study. Lancet Oncol 2017;18:1483–92. Pfizer, BMS, and AZ. [17] Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line Funding/Support and role of the sponsor: None. treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase Acknowledgments: The authors thank Dr. Markus Hartmann for editorial 2 trial. Lancet 2017;389:67–76. assistance. [18] Galsky MD, Hahn NM, Rosenberg J, et al. Treatment of patients with metastatic urothelial cancer “unfit” for cisplatin-based chemother- References apy. J Clin Oncol 2011;29:2432–8. [19] Necchi A, Anichini A, Raggi D, et al. 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