Critical Reviews in Oncology / Hematology 174 (2022) 103683 Contents lists available at ScienceDirect Critical Reviews in Oncology / Hematology journal homepage: www.elsevier.com/locate/critrevonc Recent therapeutic advances in urothelial carcinoma: A paradigm shift in disease management Joaquim Bellmunt a, Begoña P. Valderrama b, Javier Puente c, Enrique Grande d, M. Victoria Bolós e, Nuria Lainez f, Sergio Vázquez g, Pablo Maroto h, Miguel Ángel Climent i, Xavier Garcia del Muro j, José Ángel Arranz k, Ignacio Durán l, * a Department of Medical Oncology, Beth Israel Deaconess Medical Center and IMIM-PSMAR Lab, Harvard Medical School, Boston, MA, USA b Department of Medical Oncology, Virgen del Rocío University Hospital, Sevilla, Spain c Department of Medical Oncology, San Carlos Clinic University Hospital, San Carlos Health Research Institute, Madrid, Spain d Department of Medical Oncology, MD Anderson Cancer Center Madrid, Madrid, Spain e Pfizer, Madrid, Spain f Department of Medical Oncology, Navarra University Hospital, Pamplona, Spain g Department of Medical Oncology, Lucus Augusti University Hospital, Lugo, Spain h Department of Medical Oncology, Santa Creu and Sant Pau Hospital, Autonomous University of Barcelona, Barcelona, Spain i Department of Medical Oncology, Valencia Institute of Oncology Foundation, Valencia, Spain j Department of Medical Oncology, Catalan Institute of Oncology, IDIBELL, University of Barcelona, Barcelona, Spain k Department of Medical Oncology, Gregorio Marañón University Hospital, Madrid, Spain l Department of Medical Oncology, Marqués de Valdecilla University Hospital, IDIVAL, Santander, Spain A R T I C L E I N F O A B S T R A C T Keywords: Management of first-line advanced urothelial carcinoma (UC) has consisted during the past three decades in the Urothelial carcinoma (UC) administration of platinum-based chemotherapy followed by observation. Despite moderate to high response Bladder cancer rates to first-line treatment, most patients will relapse shortly after and the outcomes with subsequent therapies Platinum-based chemotherapy are poor with 5-year overall survival rates of 5% in the pre-immunotherapy era. Nonetheless, recent therapeutic Checkpoint inhibitors (CPIs) Avelumab developments including the paradigm shift of first-line maintenance therapy with avelumab after response or Switch maintenance stabilization on platinum-based chemotherapy, along with the incorporation of new drug classes in further lines Antibody drug-conjugate (ADC) of treatment such as antibody drug-conjugates and fibroblast growth factor receptor inhibitors have reshaped the field leading to better outcomes in this patient population. This article reviews the current state of the art with an overview on UC management, recent advances, and the upcoming strategies currently in development in advanced UC with an insight into the biology of this disease. 1. Introduction 90% of UCs originate in the bladder, while the remaining originate in the renal pelvis, ureters, and urethra (National Cancer Institute, 2022). Less Bladder cancer is the tenth most common form of cancer globally, common types of bladder cancer named “variant histological types” are with 573,278 new cases and 212,536 related deaths estimated in 2020 squamous cell carcinoma (3%), adenocarcinoma (2%), and small cell (World Health Organization, 2020). Bladder cancer is almost four times carcinoma (<1%), among others. Mixed histology is often seen, con­ more common in men than in women, being the sixth most common sisting predominantly of UC with areas of other types of variant histol­ tumor and the ninth leading cause of cancer death in men (Bray et al., ogies (Humphrey et al., 2016). 2018). The median age at diagnosis is 73 years, with cigarette smoking UCs are classified into three categories depending on the invasion of increasing the risk of bladder cancer four-fold in western society (Sag­ the bladder wall and the presence of metastasis: non-muscle invasive inala et al., 2020). bladder cancer (NMIBC), that is limited to the urothelium not beyond The most frequent histology of bladder cancer is urothelial carci­ the lamina propria; muscle invasive bladder cancer (MIBC), that grows noma (UC). UC can occur anywhere along the urinary tract. More than in the lamina propria and invades the muscle layer; and unresectable * Correspondence to: Marqués de Valdecilla University Hospital. IDIVAL, Avenida Cardenal Herrera Oria s/n, 39011 Santander, Cantabria, Spain. E-mail address: ignaciojose.duran@scsalud.es (I. Durán). https://doi.org/10.1016/j.critrevonc.2022.103683 Received 13 January 2022; Received in revised form 7 April 2022; Accepted 11 April 2022 Available online 16 April 2022 1040-8428/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/). J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 locally advanced or metastatic UC (mUC), when it has spread to regional for MIBC who are at high risk of recurrence following resection. Whereas lymph nodes, abdominal or pelvic wall or distant sites (Bochner et al., IMvigor-010 trial did not meet its primary endpoint of disease-free 2017). survival (DFS) for atezolizumab compared to observation (Bellmunt At diagnosis, around two thirds of patients present with NMIBC, of et al., 2021), CheckMate 274 has recently demonstrated that adjuvant whom 10–15% will progress to invasive forms, being mainly high-risk nivolumab is associated with both statistically significant and clinically cases. About 30% of the patients are diagnosed with MIBC and meaningful improvement in DFS compared to placebo in patients with 10–15% present initially with locally advanced or metastatic disease. MIBC following radical surgery, both in the intention-to-treat (ITT) Additionally, around 50% of MIBC patients will relapse after radical population and in patients with programmed death-ligand 1 (PD-L1) cystectomy and develop metastasis (National Cancer Institute, 2022; ≥ 1%. OS data is still immature (Bajorin et al., 2021). Adjuvant nivo­ Bajorin, 2016; Bellmunt et al., 2014; Milowsky et al., 2016). lumab has received recent FDA approval in August 2021. Observation Overall survival (OS) at 5 years considering all bladder cancer stages versus placebo used differently in the control arms of these two studies is approximately 77% in the US. However, OS is especially poor in the might potentially explain the differences observed on trial outcome. majority of patients with mUC (4.6% at 5 years in the pre- Results from the Ambassador study with pembrolizumab in this setting immunotherapy era) (Saginala et al., 2020). are still pending at the time of writing this review (NCT03244384). The goal of treatment in NMIBC is to prevent recurrence and/or Furthermore, based on a retrospective biomarker analysis performed on progression to invasive forms. Patients receive complete transurethral the IMvigor010, another phase III trial with atezolizumab as adjuvant resection of the bladder tumor (TURBT). Subsequent treatment could therapy is now accruing in select patients with high-risk MIBC who are include intravesical instillation with mitomycin C or Bacillus Calmette- positive for circulating tumor DNA (ctDNA+) post cystectomy (IMvi­ Guérin (BCG) according to the risk group (Bajorin, 2016; Bellmunt et al., gor011; NCT02302807). 2014; National Cancer Institute, 2022). Treatment of NMIBC remained Treatment in the unresectable locally advanced or metastatic setting unchanged until the introduction of checkpoint inhibitors (CPIs). In a is mainly palliative. For the past almost 30 years, cisplatin-based CT phase II single arm trial (KEYNOTE-057), pembrolizumab in 103 pa­ followed by observation was the SoC for patients who could tolerate tients with BCG-unresponsive carcinoma in situ (CIS) who were ineli­ cisplatin. In patients ineligible for cisplatin, carboplatin-based CT fol­ gible for or declined radical cystectomy showed a complete response lowed by observation was recommended (Bellmunt et al., 2014). (CR) rate at 3 months of 41%, with a median duration of CR of 16.2 First-line platinum-containing CT in metastatic treatment-naïve pa­ months. Forty-six percent of initial responders had a CR that lasted at tients result in objective response rates (ORR) in the range of 40–60% least 12 months (Balar et al., 2021). Based on this trial, pembrolizumab and disease control rates of nearly 80% of patients, however, was granted US Food and Drug Administration (FDA) approval in progression-free survival (PFS) and OS are short because of primary or January 2020 for patients with BCG-unresponsive high-grade NMIBC - acquired CT resistance (von der Maase et al., 2000; Dogliotti et al., 2007; CIS with or without papillary tumors (Food and Drug Administration, de Santis et al., 2012; von der Maase et al., 2005). Real-world studies 2022a). Several trials are underway to evaluate the role of CPIs in the have shown that in the pre-immunotherapy era, a considerable pro­ treatment of naïve NMIBC either alone or combined with BCG (POTO­ portion of mUC patients were not receiving any systemic therapy at the MAC trial, NCT03528694; CREST trial, NCT04165317; ALBAN trial, time of progression, with only 25–55% of patients receiving second-line. NCT03799835; and KEYNOTE-676 trial, NCT03711032), or after BCG In addition, outcomes with second-line therapy remain suboptimal failure (CheckMate 7G8 trial, NCT04149574; KEYNOTE-676 trial, because of rapid disease progression (Cheeseman et al., 2020; Aly et al., NCT03711032; CREST trial, NCT04165317; and ADAPT trial, 2019; Galsky et al., 2018; Fisher et al., 2018; Niegisch et al., 2018; NCT03317158). Intravesical gene therapy with nadofaragene fir­ Flannery et al., 2019; Swami et al., 2021). adenovec also shows efficacy in this therapeutically challenging disease CPIs have shown antitumor activity against locally advanced and state (N = 103; 53% CR at 3 months; 24% CR at 12 months) with not yet mUC and have shaped the management of the disease (Lopez-Beltran regulatory approval (Boorjian et al., 2021). et al., 2021). These drugs were initially assessed as salvage treatment In the MIBC setting, the goal is to increase the potential for cure following progression on platinum-containing CT and showed favorable while minimizing morbidity (Bajorin, 2016). Although bladder preser­ efficacy and safety profiles compared with cytotoxic CT (Plimack et al., vation strategies through trimodality therapy combining complete 2017; Sharma et al., 2017; Rosenberg et al., 2016; Patel et al., 2018; TURBT, radiation, and concurrent chemotherapy (CT) are increasing, Massard et al., 2016). Consequently, five PD-L1/PD-1 inhibitors (ate­ radical cystectomy and pelvic lymph node dissection are still the gold zolizumab, nivolumab, pembrolizumab, avelumab, and durvalumab) standard for the management of MIBC (Gakis et al., 2013; Witjes et al., received FDA approval and three PD-L1/PD-1 inhibitors (atezolizumab, 2021). If the patient is eligible for cisplatin treatment, neoadjuvant nivolumab, and pembrolizumab) received European Medicines Agency cisplatin-based combination CT should be given (Witjes et al., 2021; (EMA) approval for the treatment of advanced UC in this setting. Advanced Bladder Cancer ABC Meta-analysis Collaboration, 2005). With the aim of bringing forward the use of CPIs to the upfront Adjuvant cisplatin CT is not considered as standard of care (SoC) in these setting, numerous therapeutic approaches have been developed, patients, although it is recommended for patients with high-risk tumors including the use of single agent CPI, the upfront combination of CT and who did not receive neoadjuvant CT (Witjes et al., 2021; Leow et al., CPIs, and the switch to a CPI as maintenance after non-progression to 2014). first-line CT. In PD-L1-positive patients ineligible for cisplatin, pem­ The use of CPIs may also change the SoC in the near future for MIBC brolizumab or atezolizumab were a treatment option based on the re­ disease. While promising results have been reported for single arm phase sults of phase II studies (Galsky et al., 2020; Powles et al., 2020; Powles II trials (NABUCCO, PURE-01, ABACUS, MDACC, NCT, and others), et al., 2021; Powles et al., 2020). However, recently, FDA has restricted some neo-adjuvant phase III clinical trials are underway looking to the use of pembrolizumab only to platinum ineligible patients irre­ confirm the benefit in this setting (NIAGARA, NCT03732677; spective of PD-L1 expression. CA017–078, NCT03661320; KEYNOTE-866, NCT03924856; KEYNOTE- The objective of this article is to review latest advances and the B15/EV-304, NCT04700124; CA045–009, NCT04209114) (Rouanne paradigm shift in advanced UC treatment, including the role of immu­ et al., 2020). Additionally, several phase II trials are currently testing the notherapy and the recent approval of avelumab (anti-PD-L1) as first-line combination of CPIs with CT in the neoadjuvant setting and some of maintenance treatment of locally advanced or metastatic UC that has not them have already reported preliminary results (Rose et al., 2021; progressed with first-line platinum-containing CT, the approval of two Martinez Chanza et al., 2021; Gupta et al., 2020; Funt et al., 2021). antibody drug-conjugate (ADC), enfortumab vedotin (EV) and sacitu­ Three randomized phase III trials have investigated the role of CPIs zumab govitecan (SG), after progression on platinum-based CT and CPIs, (atezolizumab, nivolumab, and pembrolizumab) in the adjuvant setting and of erdafitinib in patients with fibroblast growth factor (FGFR) 2 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 mutations or gene fusions in second or subsequent lines. expression status (Food and Drug Administration, 2022b; European Medicines Agency, 2022). Accelerated approvals were initially based on 2. Therapeutic approach for locally advanced or metastatic the single-arm phase II KEYNOTE-052 study (Balar et al., 2017; Vuky disease et al., 2020; O’Donnell et al., 2021) and the IMvigor210 (Balar et al., 2017; Balar et al., 2018; Rosenberg et al., 2021) trials and are contingent 2.1. State of the art of first-line treatment upon confirmation from the first-line phase III studies KEYNOTE-361 (Powles et al., 2021) and IMvigor130 (Galsky et al., 2020). More The standard first-line treatment for advanced or mUC is a platinum- recently, FDA has granted full approval and updated the indication of containing combination (NCCN Guidelines®, 2021; Powles et al., 2021). pembrolizumab restricting its use in first-line for the treatment of pa­ Combinations of gemcitabine and cisplatin (GC) and dose-dense meth­ tients who are not eligible for any platinum-containing CT (Food and otrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) plus gran­ Drug Administration, 2021). ulocyte colony-stimulating factor regimens are accepted options in In KEYNOTE-052, pembrolizumab long-term results after 5 years of patients fit for cisplatin. The triplet combination of paclitaxel, gemci­ follow-up demonstrated an ORR of 28.9% with 9.5% of CRs, with a tabine and cisplatin (PGC) is another option for patients with mUC median duration of response (DOR) of 33.4 months. The median OS was (Bellmunt et al., 2012). In the EORTC-30987 study, an increase in the 11.3 months, with a 24- and 36-month OS rate of 35.3% and 22.1%, ORR, a trend towards an improvement in PFS and a trend towards longer respectively. Patients with a combined positive score (CPS) ≥ 10% had OS (3 months difference) was observed. Interestingly, PGC was associ­ better outcomes than patients with CPS < 10%; (ORR 47.3% vs. 20.7%, ated with a significant improvement in OS among patients with primary and OS 18.5 months vs. 9.7 months, respectively) (O’Donnell et al., bladder cancer compared with GC (median OS: 15.8 versus 12.7 months; 2021). HR 0.85; 95% CI 0.72–1.02; p = 0.075). An increase in febrile neu­ In IMvigor210, atezolizumab long-term results after a minimum tropenia with a lower incidence of thrombocytopenia and bleeding were follow up of 5.8 years showed an ORR of 28% with a 12% CR. The ORR observed in the PCG arm. These results suggest that PGC may be a was 28% in patients with PD-L1 ≥ 5% in tumor-infiltrating immune cells treatment option for patients with mUC and indicate that it should be (IC 2/3) and 22% in patients with PD-L1 < 1% (IC0/1). Median OS was used for those with the bladder as primary origin. First-line GC and 16.3 months, with a 2-year OS rate of 41%. Median DOR was 59.1 ddMVAC provide a median PFS of 7.7 and 9.5 months respectively, a months in the all-comer population and 53.5 months in patients with median OS of 14.0 and 15.1 months and an ORR of 49.4% and 64% PD-L1 IC0/1 tumors (IC2/3 median DOR not yet reached) (Rosenberg respectively (von der Maase et al., 2000; von der Maase et al., 2005; et al., 2021). Sternberg et al., 2006). PCG provides a median PFS of 8.3 months, a Preliminary analyses of the monotherapy arms from the phase III median OS of 15.8 months and an ORR of 56%. trials KEYNOTE-361 (pembrolizumab) and IMvigor130 (atezolizumab) Around half of patients are ineligible or unfit for cisplatin according assessing upfront CPI monotherapy versus platinum-based CT alone in to the “Galsky criteria” (Galsky et al., 2011), because of impaired renal advanced UC, identified a lower OS rate among patients with low PD-L1 function (creatinine clearance < 60 ml/min), Eastern Cooperative expression treated with a CPI alone than among those who received Oncology Group (ECOG) performance status ≥ 2, peripheral neuropathy platinum-based CT (Galsky et al., 2020; Powles et al., 2021). Based on grade ≥ 2, New York Heart Association (NYHA) Class III heart failure, these data, in 2016–2017 both the EMA and the FDA restricted the use of and/or hearing loss grade ≥ 2. In these patients considered unfit, car­ pembrolizumab and atezolizumab to patients with high expression of boplatin and gemcitabine (CbG) combination is a recommended option PD-L1 (Food and Drug Administration, 2022b), based on a predefined with lower activity than what is observed with cisplatin combinations score and specific antibody against PD-L1 biomarker (22C3 or SP142). (41% ORR and a median PFS and OS of 6 months and 9 months, Due to the hierarchical design of both studies, the monotherapy arms respectively) (de Santis et al., 2012). Normally, four to six cycles of were not formally tested, and results of these trials suggest that neither either cisplatin or carboplatin-based CT are given and then treatment is pembrolizumab nor atezolizumab monotherapy improved OS (Galsky discontinued due to the lack of evidence of further treatment benefit and et al., 2020; Powles et al., 2021). concerns about cumulative toxicity impairing patients’ quality of life A recent exploratory analysis from the IMvigor130 trial assessing (von der Maase et al., 2000). efficacy outcomes for the atezolizumab monotherapy arm in cisplatin- The limited long-term benefit obtained with CT led to a search for ineligible patients based on PD-L1 status showed a median OS of 18.6 new strategies to prolong OS in first-line cisplatin-eligible and cisplatin- months for atezolizumab monotherapy (n = 50) versus 10 months for ineligible patients. CPIs have antitumor activity against UC in first-line the CT arm (n = 43) (HR 0.53; 95% confidence interval [CI] 0.30–0.94) cisplatin-ineligible patients and as salvage treatment in platinum- in PD-L1 positive (IC2/3) patients. Despite the exploratory nature of this refractory patients. Switching to maintenance therapy with avelumab analysis, it suggested an improved OS with atezolizumab monotherapy plus best supportive care (BSC) following non-disease progression with versus CT in cisplatin-ineligible PD-L1-positive patients (Galsky et al., platinum-containing CT has demonstrated a statistically significant 2021). improvement in OS over BSC alone and is recommended as the new SoC However, this trend was not observed in a similar exploratory in advanced and mUC patients with CR, partial response (PR) or SD to analysis from KEYNOTE-361 assessing efficacy outcomes for pem­ first-line platinum-containing CT by treatment guidelines in UC (NCCN brolizumab monotherapy versus CT in cisplatin-ineligible patients, Guidelines®, 2021; Powles et al., 2021; Cathomas et al., 2022). Com­ which showed a median OS of 15.6 months for the pembrolizumab arm binations of CPI plus platinum-based CT or CPI plus CPI have not shown (n = 84) and 13.5 months for the CT arm (n = 89) (HR 0.82; 95% CI an OS benefit so far and additional studies are underway, which will be 0.57–1.17) in PD-L1 CPS ≥ 10% patients. Unlike IMvigor130, this discussed later in this review (Galsky et al., 2020; Powles et al., 2020; analysis suggested that the PD-L1 CPS biomarker for pembrolizumab did Powles et al., 2021). not predict outcome with pembrolizumab in cisplatin-ineligible patients (Powles et al., 2021) and these results led the FDA to restrict pem­ 2.1.1. Checkpoint inhibitor monotherapy in first-line cisplatin-ineligible brolizumab to platinum-ineligible patients (Food and Drug Adminis­ patients tration, 2021). Pembrolizumab and atezolizumab single agents were approved in Another recent phase III trial, the DANUBE study, also failed to show 2017 and 2018 by the FDA and the EMA, respectively, in first-line for a statistically significant improvement for durvalumab monotherapy cisplatin-ineligible patients whose tumors express PD-L1. Additionally, versus CT in the upfront setting of patients with high expression of PD-L1 and only in the United States, approval was granted for patients who (14.4 months versus 12.1 months, HR 0.89; 95% CI 0.71–1.11), were not eligible for any platinum-containing CT regardless of PD-L1 although a survival benefit was observed with the combination of 3 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 durvalumab and tremelimumab in PD-L1-positive patients (secondary is critical. It has been hypothesized that a CT-free interval could study endpoint) (Powles et al., 2020). decrease tumor resistance by removing a selective pressure, thereby allowing the re-expression of drug targets and the reversal of genetic and 2.1.2. First-line maintenance approach epigenetic changes, consequently leading to a less heterogeneous tumor and conditioning new sensitivity to the CT (Tonini et al., 2013). 2.1.2.1. The rationale for maintenance therapy. Despite the activity seen Given these premises and the current treatment scenario in mUC, an with first-line platinum-based CT combinations, most patients with attractive strategy seems to be a sequential approach of CT (a highly advanced UC will experience disease progression soon after concluding active induction strategy) followed, in those patients who achieved first-line treatment. Therefore, strategies to extend or improve the initial benefit, by immunotherapy maintenance (active and with low toxicity, benefit achieved with platinum-based CT are required. allowing for long-term administration). Furthermore, there is a biolog­ A possible solution could be the use of maintenance strategies, ical rationale for the sequential approach of these treatment options. On defined as a continuous treatment with a well-tolerated drug or com­ the one hand, CT is known to overcome tumor resistance by different bination of drugs after completing first-line induction therapy. Two mechanisms such as induction of immunogenic cell death, depletion of maintenance approaches can be generally considered for patients who immunosuppressive cell types, increasing the presentation of tumor achieved an initial benefit with first-line treatment: i) a switch mainte­ antigens, or triggering T-cell infiltration towards immunotherapy- nance that means consecutive treatment with a different agent not used resistant tumors. Recent data from IMvigor130 suggests that GC en­ before; and ii) a continuation maintenance or deintensification that re­ hances anti-tumor immunity, particularly when is combined with ate­ fers to the prolongation of one of the agents previously received as part zolizumab, potentially through the induction of immunogenic cell death of the induction treatment (Lee and Chung, 2014). (Galsky et al., 2021). Therefore, administering CT first could modulate When designing a maintenance strategy, few points need to be tumor resistance and eventually potentiate an immunotherapy effect considered. It is critical to carefully select as an induction treatment an (Emens and Middleton, 2015; Pfirschke et al., 2016). On the other hand, agent or combination of agents capable of inducing a relevant degree of there could be a mechanistic explanation to justify this sequential cytoreduction and somehow “priming” the tumor and its microenvi­ approach using as a model, the cancer immunoediting framework, ronment to facilitate the action of a subsequent drug. More importantly, where elimination, equilibrium, and escape represent the different the subsequent regimen should not only be active by extending or stages of the immune system-tumor interaction (Schreiber et al., 2011) increasing previously obtained responses but also should have a favor­ (Fig. 1). able safety profile, allowing long-term administration without impair­ During the escape stage, when the tumor overcomes the immune ment of patients’ quality of life with ideally, an easy administration system and proliferates, the anti-tumor effect of CT could help to restore schedule. Additionally, the timing use of the sequentially utilized agent the equilibrium phase or even lead to an elimination stage by decreasing Fig. 1. Model of the cancer immunoediting framework. 4 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 or eliminating tumor burden. Nevertheless, these chemo-mediated ef­ Table 1 fects may be transitory until tumor cells acquire immune escape Trial design and main clinical outcomes of the maintenance strategy in advanced mechanisms, and so the sequential administration of immunotherapy as UC. a maintenance schedule may be crucial increasing the immune elimi­ Phase III JAVELIN Bladder 100 Phase II HCRN GU14-182 ( nation and/or allowing the immune system to prolong the equilibrium (Powles et al., 2020;European Galsky et al., 2020) phase, thereby delaying disease progression. Medicines Agency, 2022) A switch-maintenance strategy may also enable more patients to N = 700 N = 108 receive a CPI within first-line therapy, rather than reserving it for the Trial design • Phase III • Phase II minority of patients who can receive it in second-line (Galsky et al., • Open label • Double-blinded 2018; Flannery et al., 2019; Simeone et al., 2019). Previous attempts • Avelumab plus BSC vs. BSC • Pembrolizumab vs. exploring the maintenance approach in mUC using sunitinib or lapatinib • Endpoints are measured placebo post-randomization (after • Endpoints are measured in genomically selected patients failed to show any benefit (Powles CT) post-randomization (after et al., 2017; Grivas et al., 2014). Vinflunine in the maintenance setting CT) showed a PFS benefit without survival improvement (García-Donas Crossover • No crossover to avelumab • Crossover to et al., 2017; Bellmunt Molins et al., 2020). allowed pembrolizumab allowed upon progression on placebo 2.1.2.2. First-line maintenance strategy with checkpoint inhibitors. Two Prior CT • 4–6 cycles of induction • ≤ 8 cycles of induction CT randomized trials have been reported showing activity of switch main­ platinum-based CT before before randomization tenance therapy based on CPI upon non-progression from induction with randomization Dosing • Avelumab Q2W • Pembrolizumab Q3W platinum-based CT in the upfront setting of locally advanced or mUC: Primary • OS • PFS by Investigator namely the Hoosier Cancer Research Network GU14–182 (HCRN endpoint GU14–182) trial and the JAVELIN Bladder 100 trial (Powles et al., 2020; Tumor • Every 8 weeks • Every 12 weeks Galsky et al., 2020). Comparative study design and main clinical out­ assessments comes of these two trials are shown in Table 1. Countries / • Global / Industry • US / Investigator Sponsorship The first trial providing data with CPIs in the maintenance setting Median PFS • PFS by IRC • PFS by investigator was the phase II randomized double-blinded investigator-initiated trial (ITT) • Avelumab plus BSC: 3.7 • Pembrolizumab: 5.4 HCRN GU14–182, which compared pembrolizumab maintenance with months months placebo in 108 patients with advanced UC (Galsky et al., 2020). After • BSC alone: 2.0 months (IC • Placebo: 3.0 months 95% 1.9–2.7) • HR 0.65 (Log-rank receiving up to 8 cycles of platinum-based CT upfront, pembrolizumab • Stratified HR 0.62 (95% CI p = 0.04) showed a benefit in terms of PFS versus placebo (HR 0.65; p = 0.04). 0.52–0.75); p < 0.001 However, that difference was not translated into an improvement in OS Median OS (ITT) • Avelumab plus BSC 22.1 • Pembrolizumab: 22 (HR 0.91; 95% CI 0.52–1.59), probably due to the study design with months months small sample size and because of allowing placebo patients to crossover • BSC alone: 14.6 months • Placebo: 18.7 months HR Stratified HR 0.70 (95% CI 0.91 (95% CI 0.52, 1.59) to pembrolizumab (51.9%) (Galsky et al., 2020). 0.564, 0.862) Definitive evidence for the strategy of switch maintenance with CPI Subsequent 43.7% 51.9% in advanced UC came from the phase III JAVELIN Bladder 100 trial treatment (Powles et al., 2020). A total of 700 patients who did not have disease with CPI (%) progression by Response Evaluation Criteria in Solid Tumors (RECIST) Avelumab maintenance in first-line in patients with advanced or metastatic UC criteria after an induction with 4–6 cycles of first-line platinum-based CT that have not progressed with platinum-based CT is the only treatment approved (GC or CbG) and a treatment-free interval (TFI) of 4–10 weeks from the in this setting. last dose of CT, were randomized to receive avelumab at 10 mg/kg every BSC: best supportive care; CI: confidence interval; CPI: checkpoint inhibitor; CT: 2 weeks plus BSC or BSC alone. Randomization was stratified according chemotherapy; HCRN: Hoosier Cancer Research Network; HR: hazard ratio; IRC: to the best response to first-line CT (CR or PR vs. SD) and to the meta­ Independent Review Committee; ITT: intention-to-treat; OS; overall survival; static site when first-line CT was initiated (visceral vs. non-visceral). PFS: progression-free survival; NR: not reached; Q2W: once every 2 weeks; Q3W: once every 3 weeks. Overall, 51% had PD-L1-positive tumors and 27% had upper urinary tract involvement. The primary endpoint was OS, assessed among the entire population and among those with PD-L1-positive tumors. at 12 months was 30% in the avelumab plus BSC versus 13% in the BSC Importantly, all the endpoints were measured post-randomization (after arm (HR 0.62; 95% CI 0.52–0.75); the median PFS was 3.7 versus 2.0 CT). At the prespecified interim analysis, the median follow-up was months in the entire population. In the PD-L1-positive population, the more than 19 months in each treatment arm. OS at 1 year was 71.3% in PFS rate at 12 months was 36% in the avelumab plus BSC arm versus the avelumab group and 58.4% in the control group in the entire pop­ 15% in the BSC arm (HR 0.56; 95% CI 0.431–0.728); the median PFS ulation. The median OS was 21.4 months and 14.3 months, respectively was 5.7 versus 2.1 months, respectively (Powles et al., 2020). (HR 0.69; 95% CI 0.56–0.86). With a longer follow-up of more than 21 The safety profile of avelumab during the maintenance period was months in each arm, the benefit is maintained (median OS 22.1 vs. 14.6 consistent with the previously reported for avelumab monotherapy. months; HR 0.70; 95% CI 0.564–0.862) (European Medicines Agency, Only 10.2% of infusion-related reactions were reported in the avelumab 2022). Clinical impact was also observed when medians of survival were plus BSC arm and none of them were grade ≥ 3. The most frequent compared (7.5 months of median OS increase) despite the fact that up to category of immune-related adverse events was thyroid disorders 43.7% of patients in the BSC group received subsequent treatment with (12.2%) (Powles et al., 2020). Up to 11.9% of patients discontinued an anti-PD-L1/PD-1 agent, favoring a maintenance approach versus avelumab and 9.0% received high doses of steroids due to adverse second-line CPI treatment (Powles et al., 2020; European Medicines events. The tolerability of avelumab plus BSC is supported by a no Agency, 2022). Avelumab significantly prolonged OS in the detrimental impact on clinically relevant patient-related outcomes PD-L1-positive population too; OS at 1 year was 79.1% in the avelumab compared to BSC alone, which is acceptable and reinforces the use of group and 60.4% in the control group (HR 0.56; 95% CI 0.40–0.79) first-line avelumab maintenance as a new SOC for patients with (Powles et al., 2020; European Medicines Agency, 2022). advanced UC whose disease has no progressed with upfront Avelumab maintenance treatment also improved PFS. The PFS rate platinum-containing CT (Powles et al., 2020). Treatment was given until progression. 5 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 Avelumab maintenance therapy showed a consistent trend towards 2020). The second interim OS analysis with a median follow-up of 13.3 improving survival in all subgroups of patients reported in the JAVELIN months did not cross the prespecified interim efficacy boundary for Bladder 100 trial (Powles et al., 2020). OS and PFS were longer with statistical significance (HR 0.84; 95% CI 0.71–1.00; one-sided avelumab maintenance plus BSC versus BSC alone, both in patients who p = 0.026) (Galsky et al., 2021). Longer follow-up is still required for had received first-line GC and in those treated with a CbG. The former final OS analysis. The combination of atezolizumab and CT was in represented 52% and 59% in the experimental and control arm, general well tolerated, with a safety profile consistent with each indi­ respectively, and the latter 42% and 35% in each of the study arms. vidual agent (Galsky et al., 2020). Moreover, the benefit for the maintenance arm with avelumab was in­ KEYNOTE-361 was an open-label three-arm trial that compared dependent of the type of response achieved with first-line CT (around pembrolizumab plus platinum-based CT and pembrolizumab mono­ 72% of patients in each arm showed a PR/CR after CT and 28% SD) therapy versus CT alone (Powles et al., 2021). Randomization was (Powles et al., 2020). This was also irrespective of the duration or stratified by investigator choice of platinum-based CT and the positivity number of cycles of first-line CT received prior to randomization (Loriot for PD-L1 CPS. Co-primary endpoints were PFS and OS, using a hierar­ et al., 2021) and of the length of the TFI from end of CT to the start of the chical strategy: first, testing both PFS and OS for pembrolizumab plus CT maintenance treatment. In the TFI 4 to < 6 weeks subgroup, median OS versus CT alone; and followed by OS for pembrolizumab alone versus CT was 19.9 vs. 13.5 months. In the TFI 6 to < 8 weeks subgroup, median in CPS ≥ 10% and the entire population if the above analysis was OS was 26.1 vs. 21.0 months for avelumab + BSC and BSC alone, positive. respectively (Sridhar et al., 2021). Subgroup analysis (as seen in the The study included 1010 patients. With a median follow up of 31.7 forest plot) might suggest that patients with PD-L1-negative status (OS months, differences in PFS and OS between pembrolizumab plus CT HR 0.86; 95% CI 0.62–1.18; PFS HR 0.64; 95% CI 0.48–0.85) and pa­ versus CT alone did not reach statistical significance according to the tients who achieve CR with CT (25% in each arm) (OS HR 0.81; 95% CI protocol prespecified criteria (one-sided p value boundary for signifi­ 0.47–1.38; PFS HR 0.65; 95% CI 0.45–0.96) could have a reduced degree cance of 0.0019 and 0.0033 for PFS and OS final analysis, respectively). of benefit from avelumab than the overall population in terms of OS, Median PFS for pembrolizumab plus CT and CT alone was 8.3 and 7.1 although the PFS is significatively improved. Moreover, data in the CR months, respectively (HR 0.78; 95% CI 0.65–0.93). Median OS was 17.0 group was not mature and PD-L1 was not an stratification factor, its and 14.3 months, respectively (HR 0.86; 95% CI 0.72–1.02). DOR was value is discussed later on. Patients with visceral metastasis (HR 0.82; 28.2 months versus 6.2 months with CT plus pembrolizumab and CT 95% CI 0.62–1.09; PFS HR 0.73; 95% CI 0.58–0.93), especially those alone, respectively. with liver involvement (OS HR 0.92; 95% CI 0.54–1.56; PFS HR 0.96; 95% CI 0.59–1.55), might also benefit less from maintenance therapy, 2.1.3.2. Two checkpoint inhibitors as first-line combination approach. The although this could reflect the worse prognosis associated with liver combination of two CPIs with different mechanisms of action and acting metastases and is only a hypothesis from the trial results (Grivas et al., at different stages of immune activation is also an interesting approach 2020). Although the treatment sequence after progression to avelumab (Harris et al., 2016). CTLA-4 is thought to regulate T-cell proliferation in maintenance remains to be clarified, data for subsequent lines from the early stages of the immune response, primarily in lymph nodes, JAVELIN Bladder 100 suggest that CT including platinum-based CT whereas PD-1 suppresses T-cells at later stages in peripheral tissues rechallenge and targeted therapies like erdafitinib are treatment options (Buchbinder and Desai, 2016). (Grivas et al., 2021). The DANUBE study is a randomized phase III trial that compared Based on the JAVELIN Bladder 100 results, avelumab received FDA durvalumab, an anti-PD-L1 agent, with or without tremelimumab, an and EMA approvals in June 2020 and January 2021, respectively, for the anti-CTLA-4 agent, administered for up to a total of 4 doses, with stan­ maintenance treatment of patients with locally advanced or mUC who dard CT (GC or CbG) up to a maximum of 6 cycles as first-line treatment have not progressed with first-line platinum-containing CT and was for mUC (Powles et al., 2020). Randomization was stratified based on added as a preferred or recommended treatment in the National cisplatin eligibility, PD-L1 status (high vs. low expression) and pre­ Comprehensive Cancer Network (NCCN) (Category I) and European sence/absence of liver and/or lung metastasis. The co-primary end­ Society for Medical Oncology (ESMO) (category IA) guidelines, respec­ points were OS of durvalumab versus CT for the population with high tively (Powles et al., 2020; NCCN Guidelines®, 2021; Powles et al., expression of PD-L1, and OS for durvalumab plus tremelimumab versus 2021; Food and Drug Administration, 2022c; Inacio, 2022). CT for the entire population. A total of 1032 patients were included. The OS for durvalumab 2.1.3. Other strategies in first-line versus CT in the population with high expression of PD-L1 (tumor cells and/or immune cells [TC/IC ≥ 25]) was not significant (HR 0.89, 95% 2.1.3.1. Checkpoint inhibitor plus chemotherapy as first-line combination CI 0.71–1.11). The OS for durvalumab plus tremelimumab versus CT in approach. Two large phase III randomized studies evaluated this the entire population was 15.1 months versus 12.1 months, respectively approach in first-line advanced or mUC: IMvigor130 and KEYNOTE-361 (HR 0.85; 95% CI 0.72–1.02). Evaluated as a secondary endpoint in the (Galsky et al., 2020; Powles et al., 2021). IMvigor130 was a three-arm PD-L1-high expression population, the combination of durvalumab plus trial that compared atezolizumab plus platinum-based CT and atezoli­ tremelimumab showed a statistically significant improvement for OS zumab monotherapy versus placebo plus platinum-based CT (Galsky versus CT of 17.9 months versus 12.1 months, respectively (HR 0.74; et al., 2020). The selection of GC or CbG in the CT regimen was based on 95% CI 0.59–0.93). Although in the entire population CT had the highest investigator’s choice. Co-primary efficacy endpoints were PFS and OS ORR (49%), in the PD-L1-high expression population (exploratory for atezolizumab plus CT versus CT, and following a hierarchical analysis) durvalumab plus tremelimumab arm had an ORR comparable approach, OS for atezolizumab monotherapy versus CT was analyzed to CT (47%). However, the median DOR was higher for the durvalumab only if OS was positive for the combination arm versus CT. Patients were and durvalumab plus tremelimumab versus CT arm (9.3 vs. 11.1 vs. 5.7 stratified according to PD-L1 immune cell expression status, Bajorin risk months in the entire population, and 18.5 vs. 10.0 vs. 5.8 months in the factor score, and investigator choice of platinum-based therapy (GC or PD-L1-high expression population, respectively) (Powles et al., 2020). A CbG). recent exploratory analysis also suggests a role for the TC/IC ≥ 25 al­ A total of 1213 patients were included. The final PFS analysis gorithm with the Ventana SP263 biomarker assay as a predictor of revealed a statistically significant difference in median PFS of 8.2 longer survival in patients treated with the combination of durvalumab months for atezolizumab plus CT versus 6.3 months for CT (two months’ plus tremelimumab or even durvalumab monotherapy (Bellmunt et al., increase in median PFS; HR 0.82; 95% CI 0.70–0.96) (Galsky et al., 2021). 6 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 Furthermore, the results from the combination arm of nivolumab monotherapy with a CPI in first-line is not the optimal approach in the plus ipilimumab versus CT from the CheckMate 901 trial (Galsky et al., majority of patients (Galsky et al., 2020; Powles et al., 2021). The 2018) are still pending and will provide additional evidence on the role therapeutic strategy that seems to have provided the greatest robustness of the combination of two CPI in this setting. in terms of efficacy correspond to avelumab as first-line maintenance therapy in patients whose disease has not progressed with first-line 2.1.3.3. Checkpoint inhibitor plus antibody-conjugated drug or targeted platinum-based CT, based on the results of the JAVELIN Bladder 100 therapies as first-line combination approach. ADC therapies, such as EV, trial (Powles et al., 2020). Rapid introduction of post-platinum switch have shown promising results in second-line and further survival maintenance therapy with avelumab is the preferred option over treat­ advantage in third-line treatment of mUC and are expected to move to ment break since it delays disease progression and has shown a benefit in upfront lines in combination with CPIs (Rosenberg et al., 2020; Powles OS, with the longest OS ever achieved in a trial for patients with mUC. et al., 2021; Rosenberg et al., 2019; Balar et al., 2021). EV is a Nectin-4 This strategy does not require PD-L1 testing for assessing eligibility for directed ADC comprised of a fully human anti-Nectin-4 IgG1 conjugated avelumab as the benefit is observed regardless PD-L1 status. Therefore, to the small molecule microtubule-disrupting agent, monomethyl auri­ in line with the recent updated ESMO and NCCN guidelines, statin E (MMAE) via a protease-cleavable maleimide caprol platinum-eligibility should guide therapeutic decisions in first-line valine-citrulline linker (Chau et al., 2019; Food and Drug Administra­ advanced UC and platinum-based CT followed by maintenance avelu­ tion, 2019). The antibody binds with high affinity to tumor cells mab is recommended and preferential compared with upfront CPI expressing Nectin-4 that then internalizes and releases the chemother­ monotherapy in cisplatin-ineligible PD-L1 positive patients (Powles apeutic agent, which arrests the cell cycle and induces apoptosis. et al., 2020; NCCN Guidelines®, 2021; Powles et al., 2021; Food and The phase I/II EV-103 study analyzed the combination of EV and Drug Administration, 2022c; Inacio, 2022). The recent FDA label change pembrolizumab as first-line treatment in patients with advanced UC for pembrolizumab reinforces the idea that for cisplatin-ineligible PD-L1 ineligible for cisplatin (Rosenberg et al., 2020; Friedlander et al., 2021). positive patients, CbG followed by avelumab maintenance is the Five patients were included in the dose escalation phase, and 40 were preferred option instead of pembrolizumab upfront. First-line treatment included in the expansion cohort (Rosenberg et al., 2020). At a median with CPI monotherapy could be limited to patients who are follow-up of 24.9 months, confirmed ORR was 73.3%, including 17.8% platinum-ineligible, have high PD-L1 expression and specific clinical CR. The median DOR was 25.6 months. The median PFS was 12.3 characteristics (Table 2). Recent FDA label for pembrolizumab restricts months, and the median OS was not reached, with an OS rate at 24 its use to platinum ineligible without the need of testing for PD-L1 (Food months of 56.3% (Friedlander et al., 2021). The most common and Drug Administration, 2021). Finally, ADCs targeting a highly treatment-related adverse events were peripheral sensory neuropathy expressed tumor protein and conjugated to a CT payload, such as for EV (56%, 4% grade ≥ 3), fatigue (51%, 11% grade ≥ 3), and alopecia (49%) or SG, are emerging as effective therapies for subsequent lines of treat­ (Rosenberg et al., 2020). ment. EV is being developed in a phase III in the upfront setting based on Due to these results, the pivotal phase III EV-302 trial is underway. the promising results from the phase I/II EV-103 study of EV in com­ This trial originally compared EV plus pembrolizumab versus GC/CbG bination with pembrolizumab (Rosenberg et al., 2020; Friedlander et al., versus EV plus pembrolizumab and cisplatin or carboplatin as first-line 2021). treatment for advanced or mUC (NCT04223856). The enrollment of the third arm was discontinued in August 2020. The primary endpoints 2.3. Second and later lines of treatment are PFS and OS. Other ongoing studies include combinations of CPI with targeted A significant proportion of mUC patients do not receive second-line therapies in randomized phase II trials like the NORSE trial therapy due to deterioration or other comorbidities. For patients who (NCT03473743) of erdafitinib or erdafitinib plus cetrelimab for patients receive second-line therapy, survival is progressively worse (Flannery with FGFR alterations; the FORT-2 trial (NCT03473756) of rogaratinib et al., 2019; Simeone et al., 2019). Patients with mUC who have pro­ in combination with atezolizumab in cisplatin-ineligible patients with gressed on first-line treatment with platinum-based CT may choose to be FGFR alterations; or the FIGHT-205 trial (NCT04003610) of pemigatinib treated with different drugs. Traditionally, they have been treated with or pemigatinib plus pembrolizumab for cisplatin ineligible patients with CT based on vinflunine or taxanes (McCaffrey et al., 1997; Vaughn et al., FGFR3 mutation or rearrangement, among others. The phase III trial 2002; Joly et al., 2009; Petrylak et al., 2017; Gómez de Liaño and Durán, LEAP-011 trial (NCT03898180) of lenvatinib and pembrolizumab 2018; de Santis et al., 2009; Sonpavde et al., 2016). Vinflunine showed combination in patients ineligible for platinum-based CT has been an improvement in terms of survival compared to BSC in the eligible recently discontinued for futility (NCT03898180 Cg, 2022). population analysis in a phase III study, while the efficacy of treatment with taxanes was derived from phase II studies (Gómez de Liaño and Durán, 2018; de Santis et al., 2009). 2.2. Comparing different novel first-line therapeutic approaches The good results obtained subsequently with anti-PD-L1/PD-1 drugs led to the approval of 5 different drugs: durvalumab, nivolumab, and Although the role of platinum-based CT remains a critical option in avelumab (based on phase II studies) and atezolizumab and pem­ advanced UC, its administration partially depends on the presence or brolizumab (based on phase III comparative studies to standard CT) absence of medical comorbidities and the criteria for eligibility proposed (Plimack et al., 2017; Sharma et al., 2017; Rosenberg et al., 2016; by Galsky et al. (2011). It is well recognized that the use of cisplatin is Massard et al., 2016; Sharma et al., 2016; Apolo et al., 2017; Bellmunt associated with OS benefit and eligible patients not treated with et al., 2017). The ORR obtained with the different drugs ranged between cisplatin had a shorter median OS (Bamias et al., 2018). In addition, for 13% and 24%, with a PFS between 1.5 and 2.8 months, and an OS be­ patients who are ineligible for standard cisplatin-based CT, pem­ tween 7.7 and 10.3 months. The only phase III study that clearly brolizumab and atezolizumab are alternative choices in EU for patients demonstrated a statistically significant improvement in the OS was with high PD-L1 expression providing an alternative to KEYNOTE-045, which randomly assigned 542 patients with advanced carboplatin-based CT (Food and Drug Administration, 2022b; European UC that recurred or progressed after platinum-based CT to receive Medicines Agency, 2022), although randomized trials have failed to pembrolizumab versus the investigator’s choice of CT with paclitaxel, show significant superiority compared with CT (Galsky et al., 2020; docetaxel, and vinflunine. With a median follow-up of 5 years, median Powles et al., 2021). OS was 10.1 months vs. 7.2 months; (HR 0.71; 95% CI 0.59–0.86). OS Results from first-line chemo-immunotherapy trials in patients with rates at 48 months were 16.7% for pembrolizumab and 10.1% for CT mUC were recently published with disappointing results, suggesting that (Bellmunt et al., 2017). In addition, the ORR was higher in patients who 7 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 Table 2 Comparison between chemotherapy plus immunotherapy trials (KEYNOTE-361 and IMvigor130) and immunotherapy trial DANUBE. Strategy Chemotherapy plus immunotherapy Immunotherapy KEYNOTE-361 (Powles et al., 2021) IMvigor130 (Galsky et al., 2020) DANUBE (Powles et al., 2020) N 1010 1213 ~885 Trial design Open label Double blinded Open label Arms Pembro + GC/CbG (CT) (A) Atezo + CT (A) Durva + treme (A) Pembro (B) Atezo (B) Durva (B) CT (C) Placebo + CT (C) CT (C) Primary PFS, OS (ITT) A vs. C PFS, OS (ITT) A vs. C OS (ITT) A vs. C endpoints OS (ITT) B vs. C only formally tested if above OS is OS (PD-L1 high) B vs. C positive Patient Platinum eligible Platinum eligible Platinum eligible characteristics 47% PD-L1 + 24% PD-L1 + 60% PD-L1 + PembroþCT vs. CT Pembro vs. CT AtezoþCT vs. CTþplacebo Atezo vs. Durvaþtreme vs. CT Durva vs. CT CTþplacebo mOS ITT ¼ 17 vs. 14.3 mo, ITT = 15.6 vs. 2IA mOS (ITT) ¼ 16.1 vs. IA mOS (ITT) = 15.7 ITT ¼ 15.1 vs. 12.1 mo, ITT = 13.2 vs. HR 0.86 not sig ( ± ) 14.3 mo, HR 0.92 13.4 mo, HR 0.84 not sig ( vs. 13.1 mo, HR 1.02 HR 0.85 not sig ( ± ) 12.1 mo, HR not sig ±) Interim mOS (PD- PD-L1 high = 17.9 vs. 12.1 0.99 not sig PD-L1 high = 16.1 L1 +) = NE vs. 17.8 mo, HR 0.74 sig PD-L1 high vs. 15.2 mo, HR mo, HR 0.68 (#) ¼ 14.4 vs. 1.01 not sig 12.1 months, HR 0.89 not sig ( ± ) mPFS ITT ¼ 8.3 vs. 7.1 mo, 3.9 vs. 7.1 mo ITT ¼ 8.2 vs. 6.3 mo, HR ITT = 8.2 vs. 6.3 mo, ITT = 3.7 vs. 6.7 mo ITT = 2.3 vs. HR 0.78 HR 1.32 sig 0.82 sig ( ± ) HR 0.82 PD-L1 high = 4.1 vs. 5.8 6.7 mo not sig ( ± ) PD-L1 high = NE, HR mo PD-L1 high 0.68 = 2.4 vs. 5.8 mo ORR ITT = 54.7% vs. 44.9% ITT = 30.3% vs. ITT = 47% vs. 44% not sig ITT = 23% vs. 44% ITT = 36% vs. 49% ITT = 26% vs. not sig 44.9% not sig PD-L1 high = 47% vs. 48% 49% PD-L1 high = 28% vs. 48% Second-line Pembro þ CT Pembro CT Atezo þ CT Atezo CT Durva þ Treme Durva CT þ placebo Subsequent 35.3% 41% 61.6% 26.2% 39.8% 41% 45% 47% 54% treatment Immunotherapy 6.6% 4.6% 48% 4.6% 2.6% 20.4% 5% 3% 31% (#) Not formally tested. ( ± ) primary endpoint. 2IA: second interim analysis; Atezo: atezolizumab; C: cisplatin; Cb: carboplatin; CT: chemotherapy; Durva: durvalumab; G: gemcitabine; IA: interim analysis; ITT: intention-to-treat; m: median; mo: month; PD-L1: programmed death-ligand 1; Pembro: pembrolizumab; PFS: progression-free survival; sig: statistically significant; Treme: tremelimumab; ORR: objective response ratio; OS: overall survival. received pembrolizumab (21.9% vs. 11%) and median DOR for re­ FGFR aberrations who have progressed after 1 or 2 prior treatments, is sponders was longer for pembrolizumab vs. CT (29.7 months vs. 4.4 currently ongoing, and its results will refine the role of erdafitinib in months) (Bellmunt et al., 2017; Bellmunt et al., 2021). The second study, these patient populations (NCT03390504). the IMvigor211, which randomly assigned 931 patients to atezolizumab Additionally, several other drugs targeting the FGF-FGFR signaling or CT, failed to achieve its primary objective of improving survival in the pathway, including small molecule FGFR tyrosine kinase inhibitors, IC2/3 population (n = 234) in a hierarchical design (median 11.1 FGFR antibodies, FGF ligand traps, and ADCs are being actively tested in months vs. 10.6 months (HR 0.87; 95% CI 0.63–1.21), thus precluding mUC in first and subsequent lines both as single agents or in combina­ further formal statistical analysis. Despite this, atezolizumab maintained tions (Garje et al., 2020). its approval for second-line use (Powles et al., 2018). More recently, the ADC therapies such as EV have shown efficacy in pretreated patients accelerated approvals of atezolizumab and durvalumab were voluntarily with locally advanced or metastatic disease. The phase III trial EV-301 withdrawn by the responsible companies in the United States following randomly assigned 608 patients who had previously received the failure of the confirmatory phase III trials (IMvigor211 and DAN­ platinum-containing CT and whose disease had progressed during or UBE) (Powles et al., 2018; Powles et al., 2020; Slater, 2022; Sternberg, after treatment with an anti-PD-L1/PD-1 to receive EV or investigator of 2022). choice CT (taxanes or vinflunine) (Powles et al., 2021). At the pre­ In addition to immunotherapy treatments, other new drugs are being specified interim analysis, the median follow-up was 11.1 months. The developed. Those directed against FGFR, such as erdafitinib, have ach­ primary OS endpoint was longer in the EV group than in the CT group ieved an ORR of 40% in a phase II study of patients with mUC and FGFR (median OS 12.88 vs. 8.97 months; HR 0.70; 95% CI 0.56–0.89). PFS genetic alterations after treatment with platinum-based CT and, in many was also longer in the EV group than in the CT group (median PFS 5.55 cases, after treatment with CPI (Loriot et al., 2019). Among the 22 pa­ vs. 3.71 months; HR 0.62; 95% CI 0.51–0.75). ORR was also signifi­ tients who had previously received immunotherapy, the ORR was 59% cantly higher in the EV arm (40.6% vs. 17.9%, of which 4.9% and 2.7% (Loriot et al., 2019). In 2019, the FDA granted accelerated approval for were CR, respectively). The incidence of treatment-related adverse erdafitinib in patients with locally advanced or mUC, with susceptible events was similar in the two groups as well as the incidence of events of FGFR3 or FGFR2 genetic alterations, that has progressed during or grade ≥ 3 (Powles et al., 2021). Patients receiving EV had numerically following platinum-containing CT, including within 12 months of neo­ less deterioration and variability in quality of life during the first 12 adjuvant or adjuvant platinum-containing CT (Food and Drug Admin­ weeks of treatment than patients in the CT group (Mamtani et al., 2021). istration, 2022d). A randomized phase III clinical trial to evaluate Additionally, the results from the cohort 2 of the phase II study EV-201, efficacy of erdafitinib versus vinflunine, docetaxel or pembrolizumab which included 89 patients with locally advanced or mUC with pro­ (based on prior CPI treatment) in patients with mUC harboring selected gression on a prior CPI in the upfront setting, showed an ORR of 52% 8 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 with 20% CR and a median DOR of 10.9 months. Median PFS and OS et al., 2017), however the pivotal randomized phase III trial in mUC were 5.8 months and 14.7 months, respectively (Yu et al., 2021). In July platinum-refractory patients (KEYNOTE-045) showed pembrolizumab 2021, the FDA granted regular approval for EV based on the results of OS benefit when compared to CT irrespective of PD-L1 status (Bellmunt the above studies, for adult patients with locally advanced or mUC who et al., 2017). Furthermore, atezolizumab and pembrolizumab were have previously received a PD-L1/PD-1 inhibitor and initially approved in the frontline setting in cisplatin-ineligible platinum-containing CT or are ineligible for cisplatin-containing CT and PD-L1-positive patients. An exploratory analysis of the confirmatory have previously received one or more prior lines of therapy (Food and phase III trial IMvigor130 suggested an improved OS with atezolizumab Drug Administration, 2022e). monotherapy versus CT in cisplatin-ineligible patients PD-L1-positive Another ADC is SG, a Trop-2-directed ADC to a topoisomerase I in­ (Galsky et al., 2021). Conversely, a similar analysis in the hibitor (SN-38). Data from the cohort 1 of the phase II TROPHY-U-01 KEYNOTE-361 trial suggested that PD-L1 CPS did not predict outcome study, which included 113 patients with mUC previously treated with with pembrolizumab in cisplatin-ineligible patients (Powles et al., platinum-based CT and anti-PD-L1/PD-1 therapy, showed an ORR of 2021), leading the FDA to modify the present label for pembrolizumab, 27% (5% had CR). The median PFS was 5.4 months, and the median OS limiting it to platinum ineligible patients independently of PD-L1 was 10.5 months (Loriot et al., 2020). TROPiCS-04 is an ongoing phase II expression. multicenter, open-label, randomized, controlled trial in patients with In the phase III JAVELIN Bladder 100 study, avelumab maintenance locally advanced unresectable or mUC who progressed after prior benefited patients regardless PD-L1 biomarker (40). Furthermore, platinum-based and CPI therapies. Approximately 482 patients will be several exploratory biomarkers were evaluated including PD-L1, tumor randomized to receive SG or CT of choice (Grivas et al., 2021). In April mutational burden (TMB), mutation profile, and genetic signatures 2021, the FDA granted accelerated approval for SG in patients with (Powles et al., 2020). The PD-L1-positive population was investigated as locally advanced or mUC who previously received a a co-primary endpoint in a pre-specified analysis and revealed a platinum-containing CT and either a PD-L1/PD-1 inhibitor (Food and potentially greater benefit for PD-L1 expressing patients (HR 0.56 vs. Drug Administration, 2022f). Table 3 shows a summary of the efficacy 0.69 in the entire population). Nevertheless, PD-L1 expression was data for all these treatments. associated with survival irrespective to the treatment arm and since it was not a stratification factor, further conclusions cannot be reached, 3. Molecular and genetic markers remaining elusive the prognostic value of PD-L1 in this setting. Further analyses also suggest that PD-L1 expression alone did not fully predict In the current treatment scenario of mUC with different drugs OS benefit (Powles et al., 2021). When TMB was analyzed, the median recently approved, the identification of valid predictive biomarkers re­ number of non-synonymous mutations (7.66 mutations/Mb) was used to mains of paramount importance to maximize treatment benefit and define patient subgroups. Patients with TMB above this threshold minimize detrimental effects. showed a greater OS benefit with avelumab despite being PD-L1 nega­ tive (HR 0.44). Conversely, tumors with low TMB but PD-L1 positive benefited from avelumab (HR 0.60). Therefore, it may be concluded that 3.1. Predictive biomarkers for checkpoint inhibitors neither the biomarkers, TMB nor PD-L1 status individually, are suffi­ cient to properly select patients most likely to benefit from therapy. The PD-L1 protein expression in either tumor or immune cells was pro­ type of mutational process (mutational signature) was also analyzed. An posed early on as a potential biomarker of response to CPIs based on the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like mechanisms of action of these drugs. More than 80% of the CPI pivotal (APOBEC) mutational signature that caused a cytosine to thymine trials in different tumors had PD-L1 expression as a correlate. However, transition as well as mutations located in DNA damage response and only 28.9% of the 45 studies confirmed a predictive role for PD-L1 and 9 repair genes, showed greater benefit from avelumab. Furthermore, gene FDA regulatory approvals required companion PD-L1 diagnostic testing expression analysis showed that a higher expression of immune (Davis and Patel, 2019). modulation-related genes related to innate and adaptive effector cells In mUC, the predictive value of PD-L1 expression has been incon­ (CD8, CXCL9, IFNG, LAG3, and TIGIT) correlated with better outcomes sistent. In platinum-refractory patients, higher levels of PD-L1 in infil­ in patients who received avelumab. Lastly, immune gene signatures trating immune cells correlated with better ORR in early studies with previously developed in other tumor types were explored in JAVELIN atezolizumab (Rosenberg et al., 2016; Powles et al., 2014). However, in Bladder 100 patients, which showed some discriminatory capacity and a confirmatory phase III trial (IMvigor211), high PD-L1 expression did were also able to identify alternative mechanisms of resistance that not predict greater benefit of atezolizumab versus CT (Powles et al., might involve a network of tumor supporting pathways, such as tumor 2018). Likewise, the initial development of pembrolizumab focused on growth factor beta and angiogenesis (Powles et al., 2021). Whereas no mUC with PD-L1 expression ≥ 1% in tumor cells or stroma (Plimack Table 3 Current treatments for the second-line approach in locally advanced disease. Drug Trial N Phase Line ORR CRR OS, months Docetaxel (McCaffrey et al., 1997; Petrylak et al., 2017) 30 II ≥ 2nd Line 13% 9 Paclitaxel (Vaughn et al., 2002; Joly et al., 2009) 31 II 2nd Line 10% 7 Vinflunine (de Santis et al., 2009) V vs. BSC 37 III 2nd Line 9% 6.9 Nivolumab (Sharma et al., 2017; Sharma et al., 2016) CheckMate 032 78 I/II ≥ 2nd Line 24% 6% 9.7 CheckMate 275 270 II 2nd Line 20% 3% 8.6 Atezolizumab (Rosenberg et al., 2016; Powles et al., 2018) IMvigor210 310 II ≥ 2nd Line 16% 7% 7.9 IMvigor211 III vs. CT ≥ 2nd Line 13% 3% 8.6 Pembrolizumab (Plimack et al., 2017; Bellmunt et al., 2017) KEYNOTE-012 27 II ≥ 2nd Line 26% 11% 13 KEYNOTE-045 542 III vs. CT ≥ 2nd Line 21.1% 8% 10.3 Durvalumab (Massard et al., 2016) MEDI4736 41 I ≥ 2nd Line 31% NR Avelumab (Apolo et al., 2017) JAVELIN Solid Tumor 249 II ≥ 2nd Line 16% 5% 7.7 Erdafitinib (Loriot et al., 2019) BLC2001 99 II ≥ 2nd Line 40% 3% 13.8 Enfortumab vedotin (Powles et al., 2021) EV301 608 III 3rd Line 40.6% 4.9% 12.9 Sacituzumab govitecan (Loriot et al., 2020) TROPHY-U01 113 II 3rd Line 27% 5% 10.5 BSC: best supportive care; CRR: complete response rate; CT: chemotherapy; OS: overall survival; ORR: objective response rate. 9 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 molecular biomarker has been validated to predict benefit from avelu­ platinum-based CT, maintenance avelumab started within 10 weeks mab maintenance until now, candidate patients were selected by no maximum of completion of CT is recommended (I, A; MCBS 4). Pem­ progression on prior platinum-based CT, which has been proposed as a brolizumab or atezolizumab are alternative choices for the first-line in putative clinical marker to identify a group of patients who may benefit cisplatin-ineligible metastatic patients who are PD-L1-positive (III, B) from avelumab maintenance (Grivas et al., 2021). More recently, The (Powles et al., 2021). Platinum-based CT followed by maintenance Cancer Genome Atlas (TCGA) genomic subgroups have been evaluated avelumab is preferential compared with upfront CPIs in PD-L1 bio­ as potential predictors of benefit in a post-hoc analysis of JAVELIN marker-positive patients. No consensus could be reached for CPIs in Bladder 100 trial. The survival benefit for avelumab was apparent across PD-L1 biomarker-negative patients not eligible for any CT (Powles et al., TCGA subtypes except luminal. Yet, the small sample size and the wide 2021). CI limit any practical conclusion (Powles et al., 2021). In patients with platinum-refractory disease CPIs are standard op­ tions: pembrolizumab (I, A; MCBS 4), atezolizumab (II, B), nivolumab 3.2. Biomarkers to other targeted agents (III, B), avelumab (III, C), and durvalumab (III, C). Treatment with CT is an alternative for patients in whom CPIs are not possible. Vinflunine (II, EV and SG are ADCs that bind proteins Nectin-4 and Trop-2 C), docetaxel (III, C), and paclitaxel (III, C) can be considered. Combi­ respectively, which have been reported to be widely expressed in UC nations with taxanes may be considered as an option only in selected both in bladder cancer and upper genitourinary tract tumors and patients. Erdafitinib (not currently EMA-approved) is an option in therefore no prior testing would be necessary (Stepan et al., 2011; platinum-refractory or platinum- and CPI-refractory UC tumors with Challita-Eid et al., 2016; Rosenberg et al., 2020). Heterogeneity of selected FGFR2 or FGFR3 alterations (III, B). EV is recommended in expression of Nectin-4, Trop-2, and other targets has been reported in patients with platinum- and CPI-refractory UC (I, A; MCBS 4) or after variant histologies (i.e. small cell, carcinosarcoma, etc.) with low or null relapse to first-line CPI (III, B) as alternative to CT (Powles et al., 2021). expression and this may have therapeutic implications (Hoffman-Censits The European Association of Urology (EAU) guidelines, published in et al., 2020). Nectin-4 and Trop-2 expression have been confirmed as September 2021, are in agreement with the above ESMO guidelines negative prognostic biomarkers in several tumors, including UC (Cathomas et al., 2022). (Tomiyama et al., 2020). FGFR could probably be considered the only fully validated predic­ 5. Proposal for a new treatment algorithm for patients with tive biomarker in mUC therapeutics as discussed above. FGFR presents metastatic urothelial carcinoma aberrations in about 15–20% of mUC cases, with these gene abnor­ malities exceeding 40–50% in upper tract UC (Rodríguez-Vida et al., Based on the current evidence, the different therapeutic options for 2015; Li et al., 2016). Recent data from a mUC biomarker driven study the treatment of patients with UC are summarized in Fig. 2. Due to the revealed that tumors with FGFR alterations had a low prevalence of continuous advances in diagnosis, surgical techniques, radiotherapy, PD-L1 expression and TMB. Analysis of mRNA expression revealed an medical treatments and clinical trials, a multidisciplinary approach is increased proportion of the luminal papillary subtype in tumors with recommended to design the most appropriate strategy for every patient, FGFR alterations but not a higher expression of immune-active T-cell taking into consideration the stage of the disease, the comorbidities and signatures (Powles et al., 2021). These findings might have a potential circumstances of the patient, and the resources available in each center. predictive value although data are still not consistent and require further validation. 6. Questions remaining for the future 4. Current treatment guidelines Avelumab first-line maintenance is the new SoC in patients with no progression on platinum-based CT regardless of PD-L1 status. Despite NCCN Guidelines Version 5.2021 recommends first-line cisplatin- the improvement in OS and PFS shown in the JAVELIN Bladder 100 trial, based CT (GC or ddMVAC with growth factor support in selected pa­ 37% of patients had disease progression as best response in the avelu­ tients) followed by avelumab maintenance therapy in those patients not mab plus BSC arm. Novel therapeutic approaches combining avelumab progressing with first-line CT, as the preferred regimen (category 1) with other drugs in the first-line maintenance setting are under devel­ (NCCN Guidelines®, 2021). In cisplatin-ineligible patients, preferred opment (TALASUR study with talazoparib/NCT04678362; MAIN-CAV regimens are CbG followed by avelumab maintenance therapy (category study with cabozantinib/NCT05092958; PRESERVE3 study with trila­ 1) if there is no progression to first-line CT. Atezolizumab is recom­ ciclib/NCT04887831) to further improve the benefit seen in the mended in cisplatin-ineligible patients only if their tumors express JAVELIN Bladder 100 trial. Longer follow-up and additional analysis PD-L1 or if they are not eligible for any platinum-containing CT may provide some information and help to identify those patient pop­ regardless of PD-L1 expression (category 2 A). P(NCCN Guidelines®, ulations who benefit the most from avelumab maintenance. Further­ 2021). more, it remains questioned whether avelumab maintenance may be an For second-line systemic therapy in patients who progress on option for patients with no progression on less than the 4 platinum- platinum-based CT, the preferred regimen is pembrolizumab (category based CT cycles (i.e. ≤ 3 cycles) in the first-line setting. The findings 1). Alternative preferred regimens include other CPIs (nivolumab or from the DISCUS trial will provide some clarity on this regard (Powles, avelumab), erdafitinib or EV (if available) (category 2 A). Other rec­ 2022). Clinical data with avelumab maintenance after prior CPIs in the ommended regimens include paclitaxel, docetaxel or gemcitabine neoadjuvant or adjuvant setting will be interesting to have in the face of (category 2 A). In patients who progress after CPIs, the preferred the arrival of CPIs into the perioperative setting. Another scenario where regimen for cisplatin-ineligible and CT-naïve patients is CbG or EV if no data are available with CPI maintenance is in the second-line setting available (Yu et al., 2021), and for cisplatin-eligible CT naïve patients it after CR, PR, or SD with a platinum-based CT after progression on is GC or ddMVAC with growth factor support (category 2 A) (NCCN frontline CPI monotherapy. The treatment sequence after progression on Guidelines®, 2021). For the next line of systemic therapy in locally avelumab maintenance also remains to be clarified; based on the in­ advanced or metastatic disease, the preferred regimen is EV (category 1) formation of subsequent lines from the JAVELIN Bladder 100 trial, CT, or erdafitinib in patients with susceptible FGFR3 or FGFR2 genetic al­ platinum-based CT rechallenge and targeted therapies can be used terations (category 2 A) (NCCN Guidelines®, 2021). (Grivas et al., 2021). EV and erdafitinib are reasonable alternatives as In the ESMO guidelines, platinum-based CT is recommended for they have already shown efficacy in mUC after progression to advanced or mUC (I, A). GC or CbG are the most widely used regimens. platinum-based CT and/or CPI monotherapy and have also been used as In patients who have not progressed following 4–6 cycles of first-line a subsequent line of therapy after progression on avelumab maintenance 10 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 Fig. 2. Therapeutic options and comprehensive approach for the patient with bladder carcinoma. ACT: adjuvant chemotherapy; BCG: Bacillus Calmette-Guérin; CR: complete response; CT: chemotherapy; CPI: immune checkpoints inhibitors; IT: immunotherapy; NACT: neoadjuvant chemotherapy; NMIBC: non-muscle invasive bladder carcinoma; MIBC: muscle invasive bladder carcinoma; Mito-C: Mitomycin C; PFI: platinum-free interval; PR: partial response; SD: stable disease; TURTB: transurethral resection of bladder tumor. 1. Licensed by FDA for BCG-unresponsive NMIBC patients; 2. For patients who have not received neoadjuvant chemo­ therapy; 3.Nivolumab has been licensed by FDA as adjuvant therapy for MIBC in patients who had pT2-pT4 or pN+ after NACT, or pT3–4a or pN+ after cystectomy without previous NACT, and refuse, or are not eligible for ACT; 4. Pembrolizumab and atezolizumab have been approved by FDA and EMA for patients with PDL1 + expression (see text for details) and may be an option for patients unable to receive CT (pembrolizumab recently restricted by FDA for patients unable to receive CT); 5. Nivolumab and atezolizumab are also approved by EMA, and nivolumab and avelumab by FDA for second-line after platinum-based CT. No data available in patients with prior CPI; 6. FDA and EMA approved; 7. FDA approved; 8. FDA approved in patients with altered FGFR. See text for further details and references. in the pivotal trial. • ADCs such as EV and SG, which target specific proteins expressed in UC cells, have shown promising activity as single agent in subse­ 7. Summary quent lines of treatment. Moreover, the combination of EV with pembrolizumab is being currently tested in a randomized phase III • With the aim of bringing treatment with immunotherapy into earlier study in the upfront setting (EV-302 trial) based on the remarkable lines and offer these active therapies to more patients with advanced activity from the phase I/II trial (EV-103 study). UC, different therapeutic approaches have been developed in the upfront setting, including the use of CPIs as single agents, combi­ Funding nations of CPIs ± CT or ADC and the use of CPIs as maintenance after non-progression with first-line CT. Medical writing support was provided by HealthCo Trials (Madrid, • The phase III JAVELIN Bladder 100 trial was designed with the aim Spain) and was funded by Pfizer as part of an alliance between Pfizer and of extending the initial benefit achieved with first-line platinum- Merck (CrossRef Funder ID: 10.13039/100009945). J.B., B.P.V., J.P., E. based CT by adding avelumab maintenance in patients that had not G., N.L., S.V., P.M., M.A.C., X.G.M., J.A.A., and I.D. received honoraria progressed to CT. from Pfizer for writing and reviewing the manuscript. • According to the NCCN, ESMO and EAU treatment guidelines, rapid introduction of avelumab maintenance in patients that have not Acknowledgements progressed with platinum-based CT is a preferred option over a treatment break or treatment with a CPI in second-line since it has The authors are grateful for the editorial assistance of Fernando shown a statistically significant improvement in OS versus BSC, with Sánchez Barbero of HealthCo Trials (Madrid, Spain) in the production of the longest OS ever achieved in a phase III trial in mUC, and may also this manuscript and for the writing and review of Belén Sanz Castillo of enable more patients to receive a CPI rather than reserving it to the Pfizer SLU (Madrid, Spain). This article is a non-systematic review of second-line. Avelumab maintenance does not require PD-L1 testing published literature and does not contain any original study with human for treatment selection as the benefit is observed regardless of PD-L1 participants or animals performed by any of the authors. status. Based on single-arm phase II trials, first-line treatment with atezolizumab or pembrolizumab are alternatively choices in Europe Conflict of Interest Statement only for cisplatin-ineligible patients with PD-L1 positive tumors or if they are not eligible for any platinum-containing CT (FDA only). Dr. Joaquim Bellmunt has received honoraria from AstraZeneca, Bristol-Myers Squibb, Merck, MSD, Pfizer, Pierre Fabre and Takeda • Unlike other solid tumors such as lung cancer, currently there is no Pharmaceutical Company; consultancy or advisory roles from AstraZe­ evidence supporting the use of the combination of CPIs and CT as neca, Bristol-Myers Squibb, Merck, Pfizer, Pierre Fabre and Hoffmann- first-line therapy in mUC and this strategy is not currently recom­ La Roche; research funding from Pfizer and Takeda Pharmaceutical mended. First-line phase III chemo-immunotherapy trials (IMvi­ Company; travel and accommodations expenses from Pfizer; licensing gor130 and KEYNOTE-361) have recently been published with and royalties from UpToDate Inc. disappointing results. Dr. Begoña P. Valderrama has received honoraria for consultancy or advisory roles from Astellas Pharma, Bristol-Myers Squibb, EUSA 11 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 Pharma, Hoffmann-La Roche, Ipsen Pharma, MSD, Novartis, Pfizer, Dr. Ignacio Durán has received honoraria for consultancy or advisory Pierre Fabre and Sanofi; speaker engagements from Astellas Pharma, roles from Astellas Pharma, Bristol-Myers Squibb, Hoffmann-La Roche, Bayer, Bristol-Myers Squibb, EUSA Pharma, Hoffmann-La Roche, Ipsen Immunomedics Inc., Ipsen Pharma, Merck and MSD; speaker engage­ Pharma, Novartis and Pierre Fabre; travel and accommodations ex­ ments from Astellas Pharma, Bristol-Myers Squibb, EUSA Pharma, Ipsen penses from Astellas Pharma, Bristol-Myers Squibb, Hoffmann-La Pharma, Janssen-Cilag, MSD, Novartis and Pfizer; research funding from Roche, Ipsen Pharma and Pfizer. AstraZeneca; research grants from AstraZeneca and Hoffmann-La Roche; Dr. Javier Puente has received honoraria from Astellas Pharma, travel and accommodations expenses from Hoffmann-La Roche and AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai Co., EUSA Pharma, Pfizer; Ignacio Durán is a member of a SC for a trial sponsored by Hoffmann-La Roche, Ipsen Pharma, Janssen-Cilag, MSD, Pfizer, Pierre Immunomedics Inc., a member of Board Directors of ASEICA as an Fabre and Sanofi; consultancy or advisory roles from Astellas Pharma, external advisor to the board of directors of the Spanish Association of Bayer, Bristol-Myers Squibb, Clovis Oncology, Eisai Co., Hoffmann-La cancer research and the president of GO NORTE, an independent Roche, Ipsen Pharma, Janssen-Cilag, MSD, Pfizer and Sanofi; research cooperative group of GU Oncologist from the north of Spain. funding from Astellas Pharma and Pfizer; travel and accommodations expenses from Bristol-Myers Squibb, Hoffmann-La Roche, Janssen-Cilag, References MSD and Pfizer. 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Bladder GLOBOCAN 2020: Estimated cancer incidence, previously untreated metastatic urothelial carcinoma: 5-year response and survival mortality and prevalence worldwide in 2020. [Available from: 〈https://gco.iarc.fr/ analysis from the phase II IMvigor210 study (cohort 1). Ann. Oncol. 32 (Suppl 5), today/data/factsheets/cancers/30-Bladder-fact-sheet.pdf〉. S678–S724. https://doi.org/10.1016/annonc/annonc675. Yu, E.Y., Petrylak, D.P., O’Donnell, P.H., Lee, J.L., van der Heijden, M.S., Loriot, Y., et al., Rouanne, M., Bajorin, D.F., Hannan, R., Galsky, M.D., Williams, S.B., Necchi, A., et al., 2021. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible 2020. Rationale and outcomes for neoadjuvant immunotherapy in urothelial patients with advanced urothelial carcinoma (EV201): a multicentre, single-arm, carcinoma of the bladder. Eur. Urol. Onco.l 3 (6), 728–738. https://doi.org/ phase 2 trial. Lancet Oncol 22 (6), 872–882. https://doi.org/10.1016/S1470-2045 10.1016/j.euo.2020.06.009. (21)00094-2. Saginala, K., Barsouk, A., Aluru, J.S., Rawla, P., Padala, S.A., Barsouk, A., 2020. Epidemiology of bladder cancer. Med. Sci. https://doi.org/10.3390/ Dr. Joaquim Bellmunt is presently Associate Professor at Harvard Medical School and medsci8010015. Director of Bladder Cancer Program at Genitourinary Oncology Program of Beth Israel de Santis, M., Bellmunt, J., Mead, G., Kerst, J.M., Leahy, M., Maroto, P., et al., 2009. Deaconess Medical Center. He was the former Director of the Bladder Cancer Center at Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/ Dana-Farber Cancer Institute. Clinical expertise focuses on urological diseases, particularly carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for prostate, bladder and kidney cancer. Extensive experience treating prostate and bladder cisplatin-based chemotherapy: phase II–results of EORTC study 30986. J. Clin. cancer patients and he has been a key investigator in several trials conducted in this patient Oncol. 27 (33), 5634–5639. https://doi.org/10.1200/JCO.2008.21.4924. population. He has been involved in the development of immunotherapy in bladder cancer de Santis, M., Bellmunt, J., Mead, G., Kerst, J.M., Leahy, M., Maroto, P., et al., 2012. since its inception. He participated on the two phase I trials with atezolizumab (Nature. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/ 2014) and with pembrolizumab (The Lancet Oncol. 2017) and the phase II atezolizumab carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for (The Lancet 2016) that lead to the FDA approval and that I also co-authored. Along the cisplatin-based chemotherapy: EORTC study 30986. J. Clin. Oncol. 30 (2), 191–199. same line, he has contributed to the development of these agents in unfit bladder cancer https://doi.org/10.1200/JCO.2011.37.3571. patients (The Lancet. 2017). One of his most important contributions in bladder cancer has Schreiber, R.D., Old, L.J., Smyth, M.J., 2011. Cancer immunoediting: integrating been to be the Chair and lead investigator of the phase III randomized study of immu­ immunity’s roles in cancer suppression and promotion. Science 331 (6024), notherapy (pembrolizumab) versus chemotherapy. This is a landmark trial showing sur­ 1565–1570. https://doi.org/10.1126/science.1203486. vival superiority for immunotherapy versus chemotherapy. The results were published in Sharma, P., Callahan, M.K., Bono, P., Kim, J., Spiliopoulou, P., Calvo, E., et al., 2016. the New England Journal of Medicine (Bellmunt J, New Engl J Med 2017). He is also the Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate principal investigator of the study Imvigor 010 (adjuvant atezolizumab in bladder cancer). 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol. He is a member of the American Society of Clinical Oncology (ASCO), the European 17 (11), 1590–1598. https://doi.org/10.1016/S1470-2045(16)30496-X. 15 J. Bellmunt et al. Critical Reviews in Oncology / Hematology 174 (2022) 103683 Society of Medical Oncology (ESMO), the Spanish Society of Medical Oncology (SEOM) Oncology Institute Hospital in 1990. He is currently working at Lucus Augusti University and the Spanish Oncology Genitourinary Group (SOGUG). Hospital where he is Head of Medical Oncology Service and Radiation Oncology Service Coordinator. His main research activities are in Genitourinary cancers and Lung cancers. He is a member of the Spanish Oncology Genitourinary Group (SOGUG), the Spanish Dr. Begoña P. Valderrama was graduated in Medicine and Surgery at the University of Society of Medical Oncology (SEOM) and Oncology Society of Galicia (SOG). Cantabria (Spain) in 2001 and obtained his specialty in Medical Oncology at Virgen del Rocío University Hospital in 2006. She is currently working at Virgen del Rocío University Hospital where she is Senior Staff Physician. Her main research activities are in Genito­ Dr. Pablo Maroto graduated in Medicine and Surgery at the University of Santiago de urinary cancers. She is a member of the Spanish Oncology Genitourinary Group (SOGUG), Compostela (Spain) in 1990 and obtained his specialty in Medical Oncology at Sant Pau and she is part of the Board of Directors. She is member of the Spanish Immuno-biological Hospital in 1996. He is currently working at Sant Pau Hospital (Barcelona) where he is in Cancer Therapies Group (GETICA), the Spanish Society of Medical Oncology (SEOM), the charge of the area of Uro-Oncology. His main research activities are in Genitourinary Andalusian Society of Medical Oncology (SAOM), and the European Society for Medical cancers. He obtained his Ph.D. in 1999. He is a presently the Chair of the European Or­ Oncology (ESMO). ganization for Research and Treatment of Cancer Genito Urinary Cancer Groups (EORTC GUCG), and member of the Spanish Society of Medical Oncology (SEOM), the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology Dr. Javier Puente was born in Madrid (Spain) in 1977. He received his medical degree in (ESMO). Dr. Maroto is also Associate Professor of medicine at the Autonoma University of 2001 at the Complutense University of Madrid (Spain) followed by his fellowship in 2002. Barcelona. Dr. Puente earns his Doctorate in Medicine (Ph.D.) with a mention of “Cum Laude” in 2007. Dr. Puente served as resident in the Medical Oncology Department at San Carlos Clinic Hospital from 2002 to 2006 at which point he became one of the clinical lead and Dr. Miguel Ángel Climent, graduated in Medicine and Surgery at the University of Valencia researcher in the Genitourinary Cancer Unit. Today, he is the Director of the Institute of (Spain) in 1987 and obtained his specialty in Medical Oncology at Santa Creu and Sant Pau Oncology at that hospital and his activities are focused on the management and treatment Hospital in 1992. He is currently working at the Valencian Oncology Institute where he is of patients with all GU tumors. In addition to the Spanish Society of Medical Oncology Medical Oncologist Chief in Genitourinary tumors. His main research activities are in (SEOM) and the Spanish National Cancer Research Center (CNIO), Dr. Puente is also a Genitourinary cancers. He obtained his Ph.D. in Medicine. He is a member of the Spanish member of the Spanish Oncology Genitourinary Group (SOGUG), the American Society of Society of Medical Oncology (SEOM), the Spanish Oncology Genitourinary Group Medical Oncology (ASCO) and the European Society of Clinical Oncology (ESMO). (SOGUG) and the Spanish Germinal Cancers Group. Dr. Enrique Grande graduated in Medicine and Surgery at the Autónoma University of Dr. Xavier García del Muro graduated in Medicine and Surgery at the University of Bar­ Madrid (Spain) in 1999 and obtained his specialty in Medical Oncology at San Carlos Clinic celona (Spain) in 1982 and obtained his specialty in Medical Oncology at San Carlos Hospital of Madrid in 2005. He is currently working at MD Anderson Cancer Center Madrid University Hospital in Madrid in 1988. He is currently working at the Catalan Institute of where he is the Head of the Medical Oncology Department. His main research activities are Oncology in Barcelona where he is Head of the Genitourinary Cancer Unit and Professor of in Genitourinary cancers and Endocrine tumors. He obtained his Ph.D. in Medicine in a the University of Barcelona. His main research activities are in Genitourinary cancer and work of Interactions on the route of drug metabolism of anti-cancer targets, as a strategy to Sarcoma. He obtained his Ph.D. in Medicine in 2004. He is a member of the American reduce the dose and total cost: sunitinib and ketoconazole. He is a member of the American Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO) Society of Clinical Oncology (ASCO), the European Society of Clinical Oncology (ESMO), and the European Organisation for Research and Treatment of Cancer (EORTC). the European Neuroendocrine Tumor Society (ENETS), the American Association of Cancer Research (AACR), the Spanish Neuroendocrine and Endocrine Tumors Group Dr. José Ángel Arranz graduated in Medicine and Surgery at the University of Valladolid (GETNE), the Spanish Oncology Genitourinary Group (SOGUG), the Spanish Group of (Spain) in 1985 and obtained his specialty in Medical Oncology at Gregorio Marañón Infrequent Orphan Tumors (GETHI) and the Spanish Society of Medical Oncology (SEOM). University Hospital in 1991 in Madrid, Spain. He is currently working at Gregorio Marañón University Hospital where he is Head of the Genitourinary Tumors Section. His Dr. M. Victoria Bolós graduated in Biochemistry at the Autónoma University of Madrid main research activities are in Genitourinary and Gynecologic cancers. He obtained his Ph. (Spain) in 2001 and in Molecular Biology in 2003. She has a strong background as a D. in Medicine (Complutense University of Madrid, Spain). He is a member of the Amer­ researcher in translational oncology. She obtained her Ph.D. in biochemistry in 2006 at the ican Society of Clinical Oncology (ASCO), the European Society of Medical Oncology Autónoma University of Madrid (Spain) with the highest commendation after a 5-year pre- (ESMO), the Spanish Society of Medical Oncology (SEOM) and the Spanish Oncology doctoral position at the Spanish National Research Council (CSIC) and then she spent more Genitourinary Group (SOGUG). than 2 years as a post-doctoral researcher at the Spanish National Centre of Biotechnology. She has more than 12-year industry experience in the oncology field. She is currently Dr. Ignacio Durán graduated in Medicine and Surgery at the University of Salamanca working as a Senior Medical Advisor in charge of Genitourinary and Gastrointestinal tu­ (Spain) in 1997 and obtained his specialty in Medical Oncology at Son Dureta University mors as well as Early Drugs at Pfizer Oncology, Madrid (Spain). Hospital in 2002. He is currently working at Marqués de Valdecilla University Hospital in Santander (Spain) where he is the GU Oncology Group Head in the Medical Oncology Dr. Nuria Lainez graduated in Medicine and Surgery at the University of Zaragoza (Spain) Department. His main research activities are in Genitourinary cancers and in clinical and in 1992 and obtained his specialty in Medical Oncology at Sant Joan de Reus Hospital in translational research. He obtained his Ph.D. in Medicine in 2005 at the Complutense 1998. She is currently working at Navarra University Hospital where she is Clinical chief. University of Madrid (Spain) with highest commendation. He is a member of the American Her main research activities are in Genitourinary cancers and Gynecological cancer. She is Society of Clinical Oncology (ASCO), the European Society of Medical Oncology (ESMO), a member of the Spanish Society of Medical Oncology (SEOM), the Spanish Oncology the European Association of Urology (EAU), the European Association of Cancer Research Genitourinary Group (SOGUG), the Spanish Research Group on Ovarian Cancer (GEICO), (EACR) and the Spanish Society of Medical Oncology (SEOM). He serves in the board of the European Organization for Research and Treatment of Cancer Genitourinary Cancer directors of the Spanish Society of Research in Cancer (ASEICA) and of the Spanish Germ Groups (EORTC GUCG) and member of GO Norte. Cell Cancer Group (GG). He is the president and co-founder of GO Norte oncology coop­ erative group since January 2020. Dr. Sergio Vázquez graduated in Medicine and Surgery at the University of Santiago de Compostela (Spain) in 1987 and obtained his specialty in Medical Oncology at Gipuzkoa 16