Clinical and Translational Oncology (2019) 21:64–74 https://doi.org/10.1007/s12094-018-02001-x CLINICAL GUIDES IN ONCOLOGY SEOM clinical guideline for treatment of muscle‑invasive and metastatic urothelial bladder cancer (2018) A. González del Alba1 · G. De Velasco2 · N. Lainez3 · P. Maroto4 · R. Morales‑Barrera5 · J. Muñoz‑Langa6 · B. Pérez‑Valderrama7 · L. Basterretxea8 · C. Caballero9 · S. Vazquez10 Received: 23 November 2018 / Accepted: 26 November 2018 / Published online: 18 December 2018 © The Author(s) 2018 Abstract The goal of this article is to provide recommendations about the management of muscle-invasive (MIBC) and metastatic bladder cancer. New molecular subtypes of MIBC are associated with specific clinical–pathological characteristics. Radical cystectomy and lymph node dissection are the gold standard for treatment and neoadjuvant chemotherapy with a cisplatin- based combination should be recommended in fit patients. The role of adjuvant chemotherapy in MIBC remains controversial; its use must be considered in patients with high-risk who are able to tolerate a cisplatin-based regimen, and have not received neoadjuvant chemotherapy. Bladder-preserving approaches are reasonable alternatives to cystectomy in selected patients for whom cystectomy is not contemplated either for clinical or personal reasons. Cisplatin-based combination chemotherapy is the standard first-line protocol for metastatic disease. In the case of unfit patients, carboplatin–gemcitabine should be con- sidered the preferred first-line chemotherapy treatment option, while pembrolizumab and atezolizumab can be contemplated for individuals with high PD-L1 expression. In cases of progression after platinum-based therapy, PD-1/PD-L1 inhibitors are standard alternatives. Vinflunine is another option when anti-PD-1/PD-L1 therapy is not possible. There are no data from randomized clinical trials regarding moving on to immuno-oncology agents. Keywords Bladder cancer · Cystectomy · Chemotherapy · Immune checkpoint inhibitors Introduction Cigarette smoking is the main risk factor for urothelial bladder with 50% of bladder cancer cases attributable to According to GLOBOCAN, 2018 will witness some 549,000 smoking in both sexes (ever-smokers have a 2.5 times higher new bladder cancer diagnoses and 200,000 bladder cancer risk of developing this tumor versus never-smokers). The deaths worldwide, making it the 10th most common type of second most important risk factor is occupational exposure cancer for both genders [1]. It is approximately four times to aromatic amines, polycyclic aromatic hydrocarbons, and more common in males as opposed to females, with inci- chlorinated hydrocarbons [3]. dence and mortality rates of 9.6 and 3.2 per 100,000, respec- tively, in men. Europe has one of the highest incidence rates of blad- Methodology der cancer in the world. According to cancer registry data, incidence rates in both sexes are highest in Southern Europe The SEOM guidelines have been elaborated with the con- (Greece, having the highest incidence rate; Italy and Spain, sensus of ten genitourinary cancer oncologists from Spanish with a total of 21,093 estimated new cases in 2015 [2]; West- Society of Medical Oncology (SEOM) and Spanish Oncol- ern Europe (The Netherlands and Belgium) and Northern ogy Genitourinary Group (SOGUG). To assign a level of America. evidence and grades of recommendation, we have used Table 1. Statements without grading were deemed justified standard clinical practice by the SEOM/SOGUG faculty and experts. * A. González del Alba aranzazu.gonzalezalba@salud.madrid.org Extended author information available on the last page of the article 13 Vol:.(1234567890) Clinical and Translational Oncology (2019) 21:64–74 65 Table 1  Levels of evidence/ grades of recommendation Levels of evidence (I) Evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses of well-conducted randomized trials without heterogeneity (II) Small randomized trials or large randomized trials with a suspicion of bias (lower methodological qual- ity) or meta-analyses of such trials or of trials with demonstrated heterogeneity (III) Prospective cohort studies (IV) Retrospective cohort studies or case–control studies (V) Studies without control group, case reports, expert opinions Grades of recommendation (A) Strong evidence of efficacy with a substantial clinical benefit; strongly recommended (B) Strong or moderate evidence of efficacy but having limited clinical benefit; generally recommended (C) Insufficient evidence of efficacy or benefit; does not outweigh risk or disadvantages; optional (D) Moderate evidence against efficacy or of adverse outcome; generally not recommended (E) Strong evidence against efficacy or of adverse outcome; never recommended Molecular biology and classification be associated with mutation signatures for an endog- enous mutagenic enzyme, APOBEC cytidine deami- Urothelial bladder cancer is a heterogeneous epithelial nase [6]. Neoantigen load displays a correlation with malignancy with variable clinical outcomes. From a nor- mutation burden and has been linked survival [7, 8]. mal urothelium, loss of heterozygosity (LOH) of chromo- • FGFR3-TACC3 was the most common gene fusion some 9 has been associated with most urothelial cancers reported [9]. [4] with two main pathways for their development: • Epigenetic changes were observed in nearly 90% of tumors. • Non-muscle-invasive urothelial carcinomas character- ized by activation of the receptor tyrosine kinase-Ras mRNA expression‑based molecular subtypes pathway, activating mutations in HRAS or fibroblast growth factor receptor 3 (FGFR3) genes. FGFR3 and Several studies have proposed a molecular classification of HRAS mutations are not generally present within the bladder cancer based on the whole genome mRNA expres- same cancer. sion profile. The molecular subtypes identified in bladder • Muscle-invasive urothelial carcinoma characterized cancer reveal significant similarities with the molecular clas- by alterations in the p53 and retinoblastoma (RB1) sification previously established in breast cancer [10]. pathways. These genes interact with the Ras-mitogen- activated protein kinase (MAPK) signal transduction • The University of North Carolina group reported a clas- pathways. sification of high-grade, muscle-invasive bladder tumors, in which they detected two main subtypes:(KRT5/6 and The most comprehensive molecular analysis of muscle- CD44) and luminal (PPARG, GATA3, KRT20, and UPK2). invasive bladder cancer has been provided by The Can- A 47-gene signature (BASE 47) classified high-grade blad- cer Genome Atlas Project (TCGA), which has recently der cancer in luminal and basal-like tumors [11]. updated the study with 412 cases [5]. Tumors were cat- • The MD Anderson group identified three distinct clus- egorized histologically and evaluated via whole genome ters: basal, luminal, and p53-like tumors [12]. sequencing, whole exome sequencing, DNA copy number, • The Lund group identified two major molecular subtypes, complete mRNA and microRNA expression, DNA meth- designated MS1 and MS2, displaying differences in the ylation, protein expression, and phosphorylation. number of genomic alterations, including FGFR3 and TP53 mutations [13]. • Fifty-eight genes were significantly mutated; these • The TCGA study identified five expression subtypes [5]: genes included TP53, KTDM2D, KDM6A, PIK3CA, RB1, and FGFR3. Mutations in the p53/RB tumor sup- • Luminal-papillary enriched with FGFR3 alterations; pressor pathway were seen in nearly 90% of tumors papillary histology. and alterations in the PI3K/AKT/mTOR and RTK/ • Luminal-infiltrated characterized by the presence of RAS signaling pathways were observed in 71%. MIBC lymphocytic infiltrates and chemoresistance. These exhibits high overall mutation rates, which appears to tumors had increased expression of several immune 13 66 Clinical and Translational Oncology (2019) 21:64–74 markers, including PD1/PDL1. The wild-type p53 is were identified based on the presence of zero, one, two, or also present in this subgroup. three adverse prognostic factors; the median OS times for • Luminal highest expression levels of several uroplak- these groups were 14.2, 7.3, 3.8, and 1.7 months (p < 0.001), ins. respectively [20]. Additionally, shorter interval from prior • Basal-squamous basal and stem-like markers and chemotherapy appears to be an independent unfavorable squamous differentiation markers. More common in prognostic factor [21]. females. Emerging data exploring the programmed cell death-1 • Neuronal high expression of neuronal differentiation protein (PD-1)/PD-1 ligand (PDL-1) checkpoint inhibitors and development genes. have shown that ECOG PS 0 and 0 visceral metastases could be predictive for response to immune checkpoint inhibitors In conclusion, the TCGA study confirmed the exist- [22]. ence of luminal (KRT20+, GATA3+, FOXA1+) and basal (KRT5,6,14+, GATA3−, FOXA1−) transcriptional sub- Recommendations types, as well as identifying luminal and neuronal subtypes. The subtypes were associated with overall survival. Intrinsic Use of prognostic classification in first-line chemotherapy: subtypes in MIBC patients are associated with specific clini- Level of evidence II. Grade of recommendation B. cal–pathological characteristics. Use of prognostic classification in second-line chemo- therapy: Level of evidence II. Grade of recommendation: B. Clinical prognostic factors Neoadjuvant and adjuvant treatment Prognostic factors generally reflect tumor biology and the extent of disease and can be used to guide treatment The gold standard for patients with MIBC is radical cys- decisions. For patients with non-muscle invasive bladder tectomy (RC) with extended lymphadenectomy and ortho- cancer, tumor histological grade is the single most impor- topic urinary diversion [23, 24]. Nevertheless, some 50% tant prognostic factor [14]. In MIBC, prognosis is derived of patients with MIBC will develop metastatic disease after from staging; i.e., whether the tumor is organ-confined undergoing RC, and only 25–35% with pT3–pT4 tumors (≤ T2) or non-organ-confined (≥ T3 and N +). Pathologi- (and/or with malignant lymph node involvement) are still cal stage establishes different prognostic categories for alive 5 years after surgery. The goal of perioperative chemo- those undergoing radical cystectomy. The 5-year overall therapy is to treat micrometastatic disease and avoid relapse. survival (OS) for ≤ T1 and pT1 tumors was 85% and 76%, respectively, while individuals with MIBC pT2, pT3a/pTb, Neoadjuvant treatment and pT4 lymph node-negative tumors had 5-year OS rates of 77%, 64/49%, and 44%, respectively. Thus, 5-year OS Several randomized trials have explored the benefit of neo- of subjects with lymph node-negative tumors was signifi- adjuvant chemotherapy, although some of them have failed cantly higher than those with positive lymph nodes (69% vs to show a clear benefit of this strategy [25]. Two large, ran- 31%, P < 0.001) [15]. Furthermore, complete pathological domized trials have exhibited survival benefit with cisplatin- response following neoadjuvant chemotherapy is associated based combination chemotherapy compared to surgery alone with improved OS [16]. in patients with clinical stage cT2-T4aN0M0 who are can- The presence of visceral metastases (i.e., pulmonary, didates for RC or definite radiotherapy [16, 26]; moreover, liver, bone) and poor performance status (Karnofsky Perfor- two meta-analyses have confirmed this advantage, with a mance Status of ≤ 80%) were independent prognostic factors 13% reduction of risk of demise and a 5% absolute survival of poor OS following treatment with MVAC (methotrexate, benefit at 5 years [27, 28]. There is no evidence that favors vinblastine, doxorubicin, and cisplatin) in the first-line set- a single superior cisplatin-based neoadjuvant regimen. The ting for advanced/metastatic disease. Median OS for patients two largest randomized trials used CMV (cisplatin, metho- who had zero, one, or two negative prognostic factors were trexate, and vinblastine) or MVAC (cisplatin, methotrex- 33, 13.4, and 9.3 months, respectively [17]. These factors ate, adriamycin, and vinblastine) [16, 26]. Two prospective have also been validated for newer combination chemother- phase II trials have evaluated dose-dense (ddMVAC) in the apy regimens [18, 19]. neoadjuvant setting with encouraging results [29, 30]. In ret- Similar to the first-line setting, the presence of liver rospective studies, CG (cisplatin/gemcitabine) has demon- metastases, hemoglobin levels < 10 g/dl, and ECOG PS > 0 strated complete pathological response (pCR) rates similar appear to predict worse outcomes in the second-line therapy to those of MVAC, albeit with a better toxicity profile [31], for advanced/metastatic bladder cancer. Four subgroups and ddMVAC provides higher (pCR) and improved survival 13 Clinical and Translational Oncology (2019) 21:64–74 67 rates with respect to CG [32]. A comparative effectiveness yet no data with respect to other chemotherapy regimens for study conducted by Galsky et al., found no significant differ- individuals who are unfit for cisplatin. ences in pCR rates between CG, MVAC, and ddMVAC [33]. There is insufficient data with any other cisplatin chemother- Recommendations apy regimens for unfit patients in the neoadjuvant setting. For patients with high-risk MIBC (pT3–pT4 and/or lymph Recommendations node involvement), who are able to tolerate a cisplatin-based regimen, and have not received neoadjuvant chemotherapy, Neoadjuvant chemotherapy with cisplatin-based combina- adjuvant therapy with cisplatin-based chemotherapy after tion chemotherapy is recommended for T2-T4aN0M0 blad- radical cystectomy is recommended: Level of evidence I. der cancer: Level of evidence I. Grade of recommendation Grade of recommendation A. A. For patients unfit for cisplatin, adjuvant chemotherapy Data concerning individuals who are unfit for cisplatin is not recommended: Level of evidence I. Grade of recom- are insufficient to provide a recommendation; therefore, mendation A. in these patients, neoadjuvant chemotherapy is not recom- mended: Level of evidence I. Grade of recommendation A. Bladder‑sparing treatments Adjuvant treatment Bladder-preserving approaches are reasonable alternatives to The role of adjuvant chemotherapy in MIBC remains con- cystectomy for patients who are medically unfit for surgery troversial. Few randomized studies have addressed this issue and those who wish to avoid radical surgery. and the vast majority of trials that have included a small Although there are no absolute criteria, key factors for number of patients, were prematurely closed due to slow identifying candidates for bladder preservation include accrual or had methodological flaws. Four recent randomized urothelial histology, unifocal tumors < 5 cm, the absence of trials have compared adjuvant chemotherapy with observa- carcinoma in situ, maximal transurethral resection of bladder tion after RC in cases of MIBC. The first study looked at tumor (TURBT, early tumor stage (T2–T3a), no hydrone- 114 patients with p53-altered pT1-T2N0 MIBC treated with phrosis, and good bladder function and capacity. Advanced MVAC. Neither the prognostic value of p53 nor the ben- age is not a contraindication for a multi-modality approach efit of MVAC chemotherapy in patients with p53-positive [39]. tumors was confirmed [34]. An Italian study included 194 An appropriate alternative to cystectomy is TURBT fol- pT2-grade 3 or pT3–T4 patients and examined the effect of lowed by radiation therapy with concurrent chemotherapy. CG, but was underpowered to demonstrate a benefit in OS No definitive randomized trials have been completed that or progression-free survival (PFS) [35]. The third trial, con- compare bladder-preserving trimodality treatment (TMT) ducted by SOGUG, appraised 142 subjects treated with CGP with radical cystectomy [40]. A meta-analysis based upon (cisplatin/gemcitabine/paclitaxel) and displayed a difference data from 9000 patients in eight studies found no signifi- in 5-year survival favoring the chemotherapy arm (60% vs cant difference in overall survival, disease-specific survival, 31%; p < 0.001) [36]. Finally, the European Organization for or progression-free survival at 5 or 10 years [41]. Other Research and Treatment of Cancer (EORTC) 30994 study approaches include TURBT alone, TURBT followed by included 284 high-risk patients, who were randomized to chemotherapy, TURBT followed by radiotherapy, and par- receive adjuvant chemotherapy either immediately after RC tial cystectomy. However, none have an established role in or deferred until relapse. PFS was longer with immediate muscle-invasive bladder cancer. versus deferred adjuvant chemotherapy [Hazard ratio (HR): TMT includes maximal TURBT followed by concur- 0.54; p < 0.001], but no differences in OS were observed rent chemoradiotherapy, radiation (40–45 Gy to the pelvis) (HR 0.78; p = 0.13) [37]. with concurrent radiosensitizing chemotherapy and an addi- A recent systematic review, including a meta-analysis of tional radiation boost to the bladder (20–25 Gy), if complete nine randomized trials with a total of 945 patients, dem- response is documented on repeat biopsy. If residual disease onstrated a benefit in OS for adjuvant chemotherapy over is present at response evaluation, surgical consolidation (sal- placebo (HR 0.77; p = 0.05). A benefit was also detected vage cystectomy) is recommended. for relapse-free survival (HR 0.66; p = 0.01) that was even The benefit of adding chemotherapy to RT compared to more evident in patients with lymph node involvement [38]. RT alone is supported by two randomized trials. In the first A combined analysis of this meta-analysis with the results randomized, phase III trial conducted in 360 patients, radio- of the EORTC study confirms this benefit in OS (HR 0.77; therapy with concurrent mitomycin C and 5-FU improved p = 0.002) favoring adjuvant chemotherapy [37]. There is as 2-year locoregional disease-free survival (DFS) from 54% 13 68 Clinical and Translational Oncology (2019) 21:64–74 (radiotherapy alone) to 67% (HR 0.68), and 5-year OS from the ORR was 62% and 50%, respectively (p = 0.06). PFS was 35 to 48% (HR 0.82), without increasing grade 3–4 acute significantly better with HD-MVAC (9.1 vs 8.2 months). An or late toxicity [42]. The second study of 99 patients rand- update at a median follow-up of 7.3 years reported that the omized to receive radiation with or without cisplatin dem- HD-MVAC regimen was associated with improved OS (HR, onstrated a statistically significant decrease in the incidence 0.76; 95% CI 0.58–0.99; p = 0.042). It seems reasonable to of first recurrence in the pelvis with the addition of cispl- reserve HD-MVAC for good prognosis and fit patients and atin [43]. The optimal chemotherapy regimen had not been when a rapid tumor response is needed. defined in adequately powered randomized clinical trials. Another combination therapy often used to treat advanced Neoadjuvant chemotherapy in TMT has not been shown urothelial cancer (UC) in the first-line setting is gemcitabine to improve survival. A phase III trial compared the efficacy and cisplatin (GC), which was evaluated in a multicenter, of two cycles of CMV followed by concurrent chemora- randomized, phase III trial that compared GC with the diotherapy vs concurrent chemoradiotherapy alone. No MVAC regimen in 405 patients with advanced or meta- difference in complete clinical response or 5-year OS was static bladder cancer. GC yielded response rates, time-to- observed [44]. progression, and OS (HR 1.09; 95% CI 0.88–1.34; p = 0.66) RTOG pooled analysis has demonstrated the effectiveness that were similar to MVAC [48], although GC had a better of this approach. This analysis included 468 patients who safety profile and was better tolerated than MVAC. It there- had clinical T2 to T4a tumors and a median follow-up of fore tends to be the preferred choice for first-line therapy. 4.3 years. The main results included [45]: In a randomized phase III trial, the combination of pacli- taxel, cisplatin, and gemcitabine (PCG) was compared with • 5-year and 10-year OS rates of 57 and 36%, respectively. GC. PCG did not show statistically significant differences • Complete response rate following chemoradiotherapy in PFS or OS, and was associated with higher toxicity [49]. was 69%. • Of the 205 patients alive at 5 years, 80% had an intact Recommendations bladder. For first-line fit patients, both CG and MVAC are considered Recommendations standard options. CG is preferred over MVAC, mainly due to its better safety profile: Level of evidence 1. Grade of TURBT alone or radiotherapy alone cannot be recom- recommendation A. mended as standard treatment: Level of evidence: II. Grade Early palliative care is strongly recommended. of recommendation: B. TMT is an alternative in well-informed and compliant First‑line therapy for unfit patients patients for whom cystectomy is not considered for clinical or personal reasons: Level of evidence: I. Grade of recom- A significant percentage of patients with advanced UC are mendation: A. considered ‘‘unfit’’ for cisplatin-based chemotherapy. Given the great variability in the definition of “unfitness for cis- platin”, it has been suggested that the definition adopted Treatment of locally advanced or metastatic in clinical trials should be: ECOG PS 2, or Karnofsky PS bladder cancer of 60–70%, creatinine clearance < 60 mL/min, audiomet- ric hearing loss, and/or peripheral neuropathy ≥ grade 2, CTCAE version 4.0, or NYHA class III heart failure [50]. First‑line therapy for fit patients An EORTC randomized phase II/III trial comparing the combination of carboplatin and gemcitabine (GCa) with Cisplatin-based combination chemotherapy represents the methotrexate, carboplatin, and vinblastine (M-CAVI) in standard of care for patients with metastatic disease. Com- 238 unfit patients, found similar efficacy for the two regi- bination therapy is more effective than single-agent cisplatin mens with a median OS of 9.3 and 8.1 months, respectively therapy alone. In a prospective randomized trial, MVAC was (p = 0.64), and lower toxicity for GCa (9.3% vs 21%) [19]. superior to single-agent cisplatin with respect to RR, dura- KEYNOTE-052 [51] is a single-arm, phase II, multi- tion of remission, and OS (12.5 vs. 8.2 months; p = 0.002) center trial of pembrolizumab in 370 treatment-naïve, cispl- [46]. atin-ineligible, subjects with locally advanced or metastatic The EORTC conducted another randomized trial [47] that UC. The ORR was 29%. Median OS was 11.5 months (95% assessed the efficacy of a high-dose intensity MVAC regi- CI 10.0–13.3) Overall, 67.6% of patients reported AEs of men with a classic MVAC regimen. There were 21% CRs on any grade. Most common AEs were fatigue (18.1%) and the HD-MVAC arm and 9% on the MVAC arm (p = 0.009); 13 Clinical and Translational Oncology (2019) 21:64–74 69 pruritus (17.8%). Immune-mediated AEs occurred in 24.6% nivolumab and pembrolizumab for the treatment of locally of the sample. advanced or metastatic urothelial cell carcinoma that has The IMvigor 210 is a phase II, single-arm, two-cohort, progressed during or after platinum-based chemotherapy multicenter trial of atezolizumab in locally advanced and regardless of PD-L1 expression levels. metastatic UC: cohort 1 comprised patients ineligible for An open-label, randomized, phase III trial compared cisplatin-based chemotherapy as first-line treatment. After pembrolizumab versus standard chemotherapy (paclitaxel, a median follow-up of 17.2 months, ORR was 23% for docetaxel, or vinflunine) in 542 patients with advanced the entire cohort (28% for IC 2/3 group). Responses were urothelial carcinoma that recurred or progressed after plati- durable with median duration of response (DOR) was not num-based chemotherapy and revealed longer median OS for reached. Median PFS was 2.7 months, while median OS pembrolizumab-treated patients compared to chemotherapy was 15.9 months. AEs were reported in 66% of patients; (10.3 vs. 7.4 months; p = 0.002). Furthermore, fewer grade 16% exhibited grade 3–4 AEs. The most common AEs were 3, 4, or 5 treatment-related adverse events (AEs) ensued in fatigue (30%), diarrhea (12%), and pruritus (11%) [52]. the group that received pembrolizumab with respect to those Preliminary data from two phase III clinical trials (Key- treated with chemotherapy (15.0% vs 49.4%) [58]. note-361 and IMvigor130) show reduced survival with A phase II trial in locally advanced or metastatic urothe- pembrolizumab and atezolizumab when used as first-line lial carcinoma that progressed after at least 1 platinum-con- treatments for UC in patients with low levels of PD-L1. taining regimen reported an overall objective response in Atezolizumab and pembrolizumab should only be used for 52 of 265 patients (19.6%; 95% CI 15.0–24.9) after treat- first-line treatment of UC in patients with high PD-L1 levels ment with nivolumab. Median OS was 8.74 months (95% CI [53, 54]. 6.05–not yet reached). Based on PD-L1 expression of < 1% and ≥ 1%, OS was 5.95 and 11.3 months, respectively [59]. Recommendations Data from a 2-cohort, multicenter, phase II trial that eval- uated atezolizumab in 310 patients with metastatic urothelial For first-line treatment in unfit patients, GCa should be con- carcinoma post-platinum treatment yielded a significantly sidered the preferred chemotherapy treatment option: Level improved overall response rate compared to historical con- of evidence 1. Grade of recommendation A. trols (15% vs. 10%; p = 0.0058); at median follow-up of Pembrolizumab and atezolizumab could be considered 11.7 months, these responses have shown to be durable with in patients with high PD-L1 expression levels: Level of evi- good tolerability [60]. The phase III IMvigor211 study that dence 3. Grade of recommendation B. appraised atezolizumab compared with standard chemo- Early palliative care is strongly recommended. therapy failed to meet its primary endpoint of OS in cases of high expression of PD-L1 by IHQ (2–3 immunoscore) Second‑line therapy although it did so in the ITT population. However, the study showed that the median duration of response (mDOR), a Until relatively recently, we have had limited treatment secondary endpoint, for those receiving atezolizumab options for this scenario. Most of chemotherapy agents was 21.7 months (95% CI 13.0, 21.7) in the overall study have been tested in phase II studies. Paclitaxel, docetaxel, population, compared to 7.4 months (95% CI 6.1, 10.3) for oxaliplatin, pemetrexed, nab-paclitaxel, ifosfamida, among those receiving chemotherapy. At the time of data cutoff, others, have a response rate of around 20%, without provid- the majority (63%) of the subjects who responded to treat- ing benefit in overall survival [55]. The use of a combination ment with atezolizumab continued to respond, versus 21% of chemotherapy agents increases response rates and DFS, of those treated with chemotherapy [61]. albeit but not OS [56]. Vinflunine, a third-generation vinca alkaloid, demonstrated an OS benefit in eligible subjects Recommendations during a phase III study, compared to the best supportive care (BSC). The results showed modest activity (overall In cases that progress following platinum-based therapy, response rate was 8.6%), a clinical benefit with a favorable PD-1/PD-L1 inhibitors are standard options: pembroli- safety profile, and survival benefit in favor of vinflunine with zumab (level of evidence: 1. Grade of recommendation: A) median OS of 6.9 vs 4.3 month. VFL reduced the risk of and nivolumab or atezolizumab (Level of evidence: 2. Grade death by 22% compared to BSC (HR 0.78) (although not in of recommendation: A). the intended treatment population) and it has been approved Treatment with vinflunine is an alternative for patients by the European Medicines Agency (EMA) for this indica- in whom anti PD-1/PD-L1 therapy is not possible: Level of tion [57]. evidence: 1. Grade of recommendation: B. In the last 2 years, the EMA has approved the PD-L1 Early palliative care is strongly recommended. inhibitor atezolizumab, as well as the PD-1 inhibitors 13 70 Clinical and Translational Oncology (2019) 21:64–74 Treatment after failure to respond FGFR alterations (mutation in FGFR3 or fusion in FGFR2 to immune checkpoint inhibitors or FGFR3). There was a 42% confirmed ORR (3% CR, 39% PR) and 80% disease control rate (CR + PR + SD). Similarly, Several immune checkpoint inhibitors have been approved among patients with prior immune checkpoint inhibitors for metastatic urothelial carcinoma over the last two years, (ICI) (n = 21), ORR was 70%. Preliminary data from the trial both in platinum-refractory patients and in first line for cis- indicate a median overall survival of 13.8 months. Based on platin-unfit population, on the basis of phase II and phase these outcomes, erdafitinib received breakthrough therapy III clinical trial results [51, 52, 58–61]. However, despite designation by the FDA in June 2018. A Phase III is ongoing some exceptional responders who appear to derive long-term (THOR study: NCT02365597). benefit, most will progress. Others FGFR inhibitors are being tested in phase I/ No randomized data exist regarding patients progressing II clinical trials for advanced or metastatic UC alone or to immune-oncology (IO) agents. The only data published in combination with chemotherapy or ICI (Rogaratinib, are from a small, retrospective dataset with 62 patients [62] B-701, AZD4547, BGJ398, Debio 1347, INCB054828, and and reveal that a mere one-third of the cases with advanced LY3076226) UC are able to receive systemic therapy after PD-1/PD-L1 Tumor angiogenesis as an antineoplastic target for resist- inhibitors. However, it must be pointed out that these sub- ant UC is an old, but good treatment approach. In a phase jects achieve similar outcomes to those historically observed III clinical trial, ramucirumab, a human IgG1 VEGFR-2 in patients who had not received prior treatment with antagonist, plus docetaxel was compared to docetaxel plus immune checkpoint inhibitors. Moreover, some patients placebo in 530 patients with advanced or metastatic UC who show excellent radiological responses to chemotherapy progressed during or after platinum-based chemotherapy [63], suggesting that at least a subset of cases will benefit [66]. The primary endpoint, PFS, was prolonged signifi- from further treatment with chemotherapy after failing on cantly in patients assigned to ramucirumab plus docetaxel IO agents. versus placebo plus docetaxel [median 4.07 months (95% CI 2.96–4.47]) vs 2.76 months (2.60–2.96); HR 0.757; 95% Recommendations CI 0.607–0.943; p = 0.0118]. A blinded independent cen- tral analysis was consistent with these results. Objective Close follow-up is imperative to initiate chemotherapy response was achieved by 53 (24.5%; 95% CI 18.8–30.3) rapidly in those patients. If IO has been used in first-line, of 216 patients assigned to receive ramucirumab and 31 systemic therapy should follow the same rules as for treat- (14.0%, 95% CI 9.4–18.6) of 221 assigned to placebo. ment naïve patients, with cisplatin-based chemotherapy as Antibody–drug conjugate (ADC) is a new therapeutic the cornerstone of therapy. If administered in second line, approach that combines the specificity of monoclonal anti- vinflunine-based chemotherapy seems adequate if available; bodies, that recognized specific antigens on the tumor cell otherwise taxane-based chemotherapy: Level of evidence: II. surface, and the cell-killing power of potent cytotoxic agents Level of recommendation: A. to treat cancer. In a phase I (EV-101) study, 155 patients with metastatic UC treated with ≥ 1 prior chemotherapy or who were ineligible for cisplatin received enfortumab New drugs in research vedotin (EV), an ADC that delivers a microtubule-disrupt- ing agent (monomethyl auristatin E: MMAE) to tumors The signaling component of the Fibroblast Growth Factor expressing Nectin-4, a protein overexpressed in most UCs. (FGF) family comprised of eighteen secreted proteins that Updated results presented at the 2018 ASCO Congress [67], interact with four signaling tyrosine kinase FGF receptors confirmed CR and PRs in 3 and 34 patients, respectively; (FGFRs1-4). Activated FGFR phosphorylate-specific tyros- ORR = 33% (95% CI 24.7–42.9). Overall median duration of ine residues that mediate interaction with cytosolic adaptor response was 24.3 weeks (95% CI 16.3–47.3) and PFS was proteins and the RAS-MAPK, PI3K-AKT, PLC, and STAT 23.1 weeks (95% CI 20.1–24.1). Median OS was 12.5 month intracellular signaling pathways. Aberrant activity of the (95% CI 8.1–14.8) with 76 patients (68%) censored and an pathway is associated with developmental defects that dis- OS rate at 6 months of 75.1%. Based on these results, enfor- rupt organogenesis, impair the response to injury, and result tumab vedotin received breakthrough therapy designation in metabolic disorders, and cancer [64]. by the FDA in June 2018. A Phase III is ongoing (EV-301 In the open-label, phase II study BLC2001 presented at study; EudraCT: 2017-003344-21). the 2018 ASCO Annual Symposium [65], erdafitinib, an oral Another several ADCs against different UC surface pan-FGFR tyrosine kinase inhibitor, was tested in 96 patients markers are in the pipeline, but the ones that are furthest with metastatic or unresectable urothelial carcinoma and along include sacituzumab govitecan (IMMU-132: an anti- Trop-2 mAb conjugated with SN-38, the active metabolite of 13 Clinical and Translational Oncology (2019) 21:64–74 71 irinotecan), ASG-15ME (composed of a SLITRK6-specific 2. Galceran J, Ameijide A, Carulla M. Cancer incidence in Spain, human gamma 2 antibody conjugated to MMAE, a microtu- 2015. Clin Transl Oncol. 2017;19:799–825. 3. Lazaro M, Gallardo E, Domenech M. SEOM Clinical Guideline bule-disrupting agent) for advanced UC, and oportuzumab for treatment of muscle-invasive and metastatic urothelial bladder monatox (an anti-EpCAM humanized single-chain variable cancer (2016). Clin Transl Oncol. 2016;18:1197–205. fragment linked to a truncated form of Pseudomonas exo- 4. Pollard C, Smith SC, Theodorescu D. Molecular genesis of non- toxin A) for early UC. muscle-invasive urothelial carcinoma (NMIUC). Expert Rev Mol Med 2010;12:e10. https​://doi.org/10.1017/S1462​39941​00014​07. 5. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cher- niack AD, et al. Comprehensive molecular characterization of Author contributions All the authors have contributed equally in the muscle-invasive bladder cancer. Cell. 2017;171(3):540–56.e25. writing of the manuscript. 6. Roberts SA, Lawrence MS, Klimczak LJ, Grimm SA, Fargo D, Stojanov P, Kiezun A, Kryukov GV, Carter SL, Saksena G, Compliance with ethical standards Harris S, Shah RR, Resnick MA, Getz G, Gordenin DA (2013) An APOBEC cytidine deaminase mutagenesis pattern is wide- spread in human cancers. Nat Genet 45(9):970–976. https​://doi. Conflict of interest AG reports Advisory Board, consultancy and org/10.1038/ng.2702 speaker honoraria/travel support from Pierre Fabre, Roche, Bristol- 7. Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis Myers Squibb, MSD, Pfizer, Novartis, Bayer, Janssen, Sanofi Astellas, K, Sivachenko A, et al. Mutational heterogeneity in can- EUSA pharma and EISAI, outside the submitted work. Research fund- cer and the search for new cancer-associated genes. Nature. ing from Astellas. GDV reports advisory board, consultancy, speaker 2013;499(7457):214–8. honoraria and travel support from Pierre Fabre, Roche, Bristol-Myers 8. Schumacher TN, Schreiber RD. Neoantigens in cancer immuno- Squibb, Pfizer, Ipsen, Novartis, Bayer, Astellas, EUSA pharma and Ei- therapy. Science. 2015;348(6230):69–74. sai, outside the submitted work. Research funding from Roche, Pierre 9. Williams SV, Hurst CD, Knowles MA. Oncogenic FGFR3 gene Fabre, Ipsen and Pfizer. NL reports personal fees from Pfizer, Sanofi, fusions in bladder cancer. Hum Mol Genet. 2013;22(4):795–803. Pierre Fabre, Roche, Ipsen, PharmaMar, BMS, Bayer, Astra Zeneca, 10. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees Astellas, MSD, outside the submitted work. PM reports Advisory CA, et al. Molecular portraits of human breast tumours. Nature. Board from Roche. RM reports speaker honoraria or travel support 2000;406(6797):747–52. from Bayer, Roche, Astellas, Janssen-Cilag, MSD and Sanofi-Aventis. 11. Damrauer JS, Hoadley KA, Chism DD, Fan C, Tiganelli CJ, JML has nothing to disclose. BPV reports honoraria from Pierre Fa- Wobker SE, et al. Intrinsic subtypes of high-grade bladder cancer bre, Astellas Pharma, Novartis, Bristol-Myers Squibb and Ipsen. Con- reflect the hallmarks of breast cancer biology. Proc Natl Acad Sci sulting or advisory role from Astellas Pharma, Novartis, Pfizer, Pierre USA. 2014;111(8):3110–5. Fabre, Bayer, Sanofi, Bristol-Myers Squibb, Roche and Ipsen. Travel, 12. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Cen- accommodations and expenses from Janssen-Cilag and Bristol-Myers sits J, et al. Identification of distinct basal and luminal subtypes Squibb. LB reports personal fees from Roche, MSD, Bristol-Myers of muscle-invasive bladder cancer with different sensitivities to Squibb, outside the submitted work. CC Reports advisory Board, frontline chemotherapy. Cancer Cell. 2014;25(2):152–65. consultancy, speaker honoraria and travel support from Pierre Fabre, 13. 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Bellmunt J, Theodore C, Demkov T, Komyakov B, Sengelov jurisdictional claims in published maps and institutional affiliations. L, Daugaard G, et al. Phase III trial of vinflunine plus best sup- portive care compared with best supportive care alone after a Affiliations A. González del Alba1 · G. De Velasco2 · N. Lainez3 · P. Maroto4 · R. Morales‑Barrera5 · J. Muñoz‑Langa6 · B. Pérez‑Valderrama7 · L. Basterretxea8 · C. Caballero9 · S. Vazquez10 G. De Velasco P. Maroto gdvelasco.gdv@gmail.com jmaroto@santpau.cat N. Lainez R. Morales‑Barrera nuria.lainez.milagro@cfnavarra.es rmorales@vhio.net 13 74 Clinical and Translational Oncology (2019) 21:64–74 4 J. Muñoz‑Langa Medical Oncology Department, Hospital de la Santa Creu i munyoz_joslan@gva.es Sant Pau, Barcelona, Spain 5 B. Pérez‑Valderrama Medical Oncology Department, Vall d’Hebron Institute bperezv@gmail.com of Oncology, Vall d’ Hebron University Hospital, Barcelona, Spain L. Basterretxea 6 laura.basterrechea@osakidetza.net Medical Oncology Department, Hospital Universitari I Politècnic la Fe, Valencia, Spain C. Caballero 7 caballero_cri@gva.es Medical Oncology Department, Hospital Universitario Virgen del Rocio, Sevilla, Spain S. Vazquez 8 sergio.vazquez.estevez@sergas.es Medical Oncology Department, Hospital Donostia-Donostia Ospitalea, Donostia, Spain 1 Medical Oncology Department, Hospital Universitario 9 Medical Oncology Department, Ciberonc, Centro de Puerta de Hierro-Majadahonda, Joaquin Rodrigo 2, Investigación Biomédica en Red Cáncer. Hospital General 28222 Majadahonda, Madrid, Spain Universitario de Valencia, Valencia, Spain 2 Medical Oncology Department, Hospital Universitario Doce 10 Medical Oncology Department, Hospital Universitario Lucus de Octubre, Madrid, Spain Augusti, Lugo, Spain 3 Medical Oncology Department, Complejo Hospitalario de Navarra, Pamplona, Spain 13