B2B: Bladder Cancer Summary

The Bench-to-Bedside Uro-Oncology GU Cancer Triad Meeting was organized by the Société Internationale d’Urologie and was held online on May 21st and 22nd, 2021. The session on bladder cancer (BCa) took place on the morning of Friday, May 21st, and was chaired by Dr. Peter C. Black (Canada) and Dr. Ashish Kamat (United States). This session covered practice- changing advances on the horizon for BCa, the use of urine markers in BCa management, evolving therapies for non-muscle-invasive BCa (NMIBC), and recent advances for systemic therapy for muscle-invasive BCa (MIBC) and advanced urothelial carcinoma (UC). The faculty also discussed how to manage immune-related adverse events (AEs).

Dr. Angela Smith (United States) presented five practice-changing advances on the horizon across the disease spectrum of BCa and upper tract UC (UTUC). One of these advances is in the treatment of low-grade intermediate-risk NMIBC [1,2]. These are tumours that have high rates of recurrence but low risk of progres- sion [2]. In this disease setting, transurethral resection of bladder tumour (TURBT) plus intravesical therapy is considered standard of care [1,3], with mitomycin and gemcitabine instillation after TURBT being shown to reduce the risk of recurrence [4,5]. However, repeat TURBTs expose patients to risks of repetitive anesthe- sia and surgically related complications [6].

The use of UGN-102, a thermoreversible hydro- gel containing mitomycin, is being investigated for nonsurgical chemoablation in patients with low-grade intermediate-risk NMIBC in the phase 2b OPTIMA II trial [7]. In an interim analysis, complete response (CR) at 3 months was observed in 65% of patients (95% CI 52%–77%) following treatment with UGN-102. In the safety analysis, 91% of patients experienced ≥1 AE, with the most common AEs occurring in ≥5% of patients related to lower urinary tract symptoms (LUTS), such as dysuria (91%), pollakiuria (41%), and hematuria (19%) [7]. With an estimated durability of response at the 12-month follow-up of 60%, these interim data demonstrate that primary chemoablation of low-grade intermediate-risk NMIBC using UGN-102 results in a significant treatment response and encour- aging durability, and may provide an alternative to TURBT treatment for patients in this disease setting[7]. Chemoablation with UGN-102 vs. TURBT is now being investigated in the phase 3 trial ATLAS [8].

There have been multiple advances in the treat- ment of high-grade bacillus Calmette-Guérin (BCG)- refractory NMIBC, including the U.S. Food and Drug Administration (FDA) approval of pembrolizumab in this setting for carcinoma in situ (CIS) and the recently published results of the novel gene therapy nado- faragene firadenovec in this population [9,10]. Among the developments on the horizon is the investigation of combination intravesical gemcitabine and pembroli- zumab therapy to treat BCG-unresponsive NMIBC in the phase 2 Alliance A031803 trial [11]. This trial is also assessing correlations of tumour genomic aberrations with therapy response, the results of which may assist in future patient selection for treatment.

In the localized MIBC space, RETAIN BLADDER is a phase 2 trial investigating a risk-adapted approach to treatment that may result in bladder preservation [12]. Treatment was determined according to tumour stage and mutation status following neoadjuvant chemo- therapy (NAC) and TURBT. Patients with no residual tumour (cT0) and positive mutations proceeded to active surveillance. In an interim analysis of clinically meaningful endpoints, 39% of patients proceeded to active surveillance. At the data cut-off, 77% of patients on active surveillance were alive, had not developed metastasis, and had not undergone radical cystec- tomy. Based on these favourable results, the phase 2 RETAIN trial was initiated to investigate a risk-enabled treatment approach following neoadjuvant immuno- chemotherapy in MIBC [13].

Dual immunotherapy is showing encouraging results in the first-line treatment of locally advanced or metastatic BCa. In an updated analysis of cispla- tin-ineligible patients in the EV-103 trial, enfortumab vedotin plus pembrolizumab resulted in a 73.3% con- firmed objective response rate (ORR), regardless of programmed death-ligand 1 (PD-L1) expression, and promising 93% tumour reduction [14]. Response to treatment appears to occur relatively quickly, with 88% of patients demonstrating response at first assessment (week 9±1 week). The median progression-free sur- vival (PFS) in this patient cohort was 12.3 months and both median overall survival (OS) as well as duration of response (DOR) have not been reached. In addition to the positive efficacy results, treatment with enfor- tumab vedotin plus pembrolizumab has a favourable toxicity profile, with only 16% of patients experiencing serious treatment-related AEs (TRAEs).

In the UTUC setting, the phase 3 trial PROOF 302 is evaluating the efficacy and safety of infigratinib as adjuvant therapy in patients with high-risk invasive UC and susceptible FGFR3 alterations [15]. As a large proportion of patients with UTUC shows alterations in FGFR3 [16], infigratinib, a fibroblast growth factor receptor (FGFR) inhibitor, may be an attractive thera- peutic agent for this population.

During the Q&A period, Dr. Smith was asked how the toxicities of novel bladder-sparing treatments will compare to those of current therapeutic options.

According to Dr. Smith, patient-reported outcomes will play an important role in the toxicity evaluation of new therapies, which will also impact the treatment selection. As she pointed out, different treatments may differ considerably in terms of patient experience, regardless of similar efficacy. Another important aspect that will affect treatment selection is the frequency of treatment delivery. Therapies that require fewer visits to the hospital may pose a reduced logistical and finan- cial burden that would ultimately benefit the patient.

The following session was a panel discussion hosted by the SIU Innovators and provided insights on the selection and use of urinary biomarkers in the various stages of BCa diagnosis, management, and follow-up. Dr. Sima Porten (United States) moderated the discus- sion with input from a panel of experts comprising Dr. Renu Eapen (Australia), Dr. Carmen Mir (Spain), and Dr. Jeremy Teoh (Hong Kong).

The case was a 50-year-old male who received ini- tial treatment with TURBT with gemcitabine for a low- grade Ta tumour. At the 3-month follow-up, cytology showed atypical urothelial cells (Paris 3 classification), despite no evidence of disease by cystoscopy. The panelists discussed if cytology is commonly per- formed at the time of cystoscopy, the use of the Paris classification by cytopathologists, and whether other urinary biomarkers are routinely used for BCa diag- nosis. The use of cytology at the time of surveillance cystoscopy is variable and not always performed for low-grade tumours, and the Paris classification is not always adopted. While cytology is considered the gold standard in this setting, the panelists highlighted other commercially available urinary biomarker tests that may be used in adjunction. ADXBLADDER™ is an enzyme-linked immunosorbent assay (ELISA) test that detects MCM5 in urine, a known biomarker for bladder tumours [17]. Other options include gene expression analysis with messenger RNA (mRNA)-based tests for BCa biomarkers, such as Xpert® Bladder Cancer Monitor [18] and Cxbladder Monitor™ tests [19]. Another biomarker test is UroVysion™, a multi-colour fluorescence in situ hybridization (FISH) assay to detect chromosome aberrations associated with urothelial tumour cells [20].

The discussion continued on to which steps would be taken following a positive cytology for Paris 4 or Paris 5, which indicate a higher risk for high-grade UC [21]. If no evidence of disease is seen by cystoscopy, enhanced imaging techniques, such as photodynamic diagnosis or narrow band imaging (NBI) [22], should be implemented to evaluate the presence of UC. Random biopsies of the bladder as well as selective upper tract urine cytology may also be considered, particularly in patients with unexplained positive urine cytology. Upper tract urine cytology may be performed by urine aspiration or lavage cytology and has a high sensitivity of up to 69.9% for high-grade UTUC [23].

Next, the case proceeded with the patient being diagnosed with high-risk NMIBC and starting BCG induction. While not routinely used in clinical prac- tice, urinary biomarkers may play an important role in predicting response to BCG therapy and evaluating patient prognosis. UroVysion FISH analysis has been shown to predict disease recurrence and progression in patients receiving BCG [24]. This may be particularly useful for guiding treatment discussions with patients.

Following BCG maintenance, no evidence of disease was found by cystoscopy and cytology was negative during surveillance for the patient case. However, the number of procedures, frequency of hospital visits, and current risk of COVID-19 may pose an important burden on the patient. In this setting, some urinary biomarker tests demonstrate potential for providing a noninvasive alternative to cystoscopy. Bladder EpiCheck is a kit that detects disease-spe- cific DNA methylation patterns in BCa patients with high negative predictive values (NPV) [25]. However, this test is not routinely implemented in the clinical practice. Other options for patient surveillance may include ADXBLADDER [26] and Xpert Bladder Cancer Monitor [27], both of which have shown high NPV. Dr. Porten highlighted the use of Cxbladder Monitor dur- ing the COVID-19 pandemic as an option for patient surveillance at home that has been adopted at the UCSF Medical Center.

In the patient case, surveillance with Cxbladder Monitor showed values above cut-off. Cystoscopy was performed, leading to a diagnosis of MIBC. The patient received NAC followed by radical cystoprostatectomy with lymph node dissection and neobladder diver- sion with favourable pathology. Given the limited evidence for urinary biomarkers in this setting, com- puted tomography (CT) scans and urine cytology are typically the routine options for patient surveillance. However, emerging data may provide new insights on the use of urinary biomarkers for post-urinary diversion surveillance.

Next, Dr. Tilman Todenhöfer (Germany) discussed the evolving treatments for NMIBC by focusing on three main topics: 1) identifying predictive molecular markers of BCG treatment response, 2) emerging treat- ment options for BCG-unresponsive patients, and 3) novel therapy delivery approaches in NMIBC.

Recent studies examining the molecular alterations of NMIBC have led to significant improvements in understanding the disease. In a recent report of the UROMOL project, four molecular subtypes of NMIBC with differing recurrence rates were identified based on the transcriptomic analysis of 834 patients [28]. In the same study, chromosomal instability was also analyzed, leading to the identification of three genomic classes associated with varying risk of disease progression. Both the molecular subtype and genomic class may have important implications for predicting treatment response.

BCG is currently the gold standard for treatment of BCG-naïve NMIBC and results in high rates of high- grade recurrence-free survival (RFS), as demonstrated in a recent retrospective analysis of a contemporary patient cohort [29]. Despite these excellent outcomes, there is an ongoing need for alternative treatment approaches to BCG in NMIBC. First, BCG shortage is an ongoing issue and limits the access of a high proportion of patients to this therapy, leading to sig- nificant impact on patient outcomes [30]. Second, BCG intolerance is an ongoing issue, regardless of recent decreases in treatment discontinuation due to TRAEs. Lastly, many patients with NMIBC do not respond to BCG therapy and require other treatment approaches. Therefore, predicting BCG response is important to guide treatment decisions in NMIBC. Recent studies have further advanced this field by identifying genomic and histological markers for patient stratification and treatment outcome prediction [31,32,33].

Treatment of BCG-unresponsive disease continues to be a major challenge in NMIBC. Novel treatment options under investigation in this setting include intravesical approaches with nadofaragene firad- enovec [34], oportuzumab monatox [35], and N803/ BCG [36], as well as systemic options with immune checkpoint inhibitors (ICIs), such as atezolizumab [37] and pembrolizumab [38]. While all of these agents are showing encouraging outcomes, treatment tolerability in this setting appears slightly improved with intravesi- cal approaches. However, the role of ICI may increase in the NMIBC setting as the results of multiple ongo- ing trials in BCG-naïve high-risk disease (Potomac, Alban, and CREST), BCG induction failure (KN676 and CheckMate 7G8), and BCG-unresponsive NMIBC (CheckMate 9UT and A031803) become available. In addition, a novel approach for ICI therapy was recently presented. In SUBDUE-1, a dose-finding phase 1b trial, intravesical injection of durvalumab is under investiga- tion for patients with NMIBC [39], an approach that has shown promising results in the pre-clinical studies [40].

Several ongoing trials are also investigating the use of targeted systemic therapies, currently approved for metastatic BCa, in patients with BCG-unresponsive disease. A recent study in patients with FGFR-positive NMIBC demonstrated promising efficacy results fol- lowing treatment with infigratinib. However, TRAE in all patients led to discontinuation of treatment [41]. In order to improve tolerability of FGFR-targeted therapy in NMIBC, ongoing trials are evaluating FGFR inhibitor doses lower than those used in the metastatic set- ting. In a current phase 2 trial led by Dr. Noah Hahn at Johns Hopkins, a 9-mg dose of pemigatinib is being investigated to treat patients with NMIBC, which corresponds to only two-thirds of the dose used in metastatic BCa [42].

Other studies are focusing on improving the efficacy and delivery of intravesical chemotherapy. Hyperthermia-induced mitomycin, an approach fre- quently used in centres in Europe, has become the focus of recent investigations. In a retrospective study of patients with BCG-unresponsive NMIBC, conductive chemohyperthermia with mitomycin led to 12-month RFS rates >50% in patients with CIS [43]. Another way of improving the efficacy of intravesical treatment is the use of a slow-delivery device (TAR-200, GemRIS™) that is inserted in the bladder, which allows continuous delivery and exposure to chemotherapy [44]. Two clin- ical trials will evaluate the use of TAR-200 in patients with NMIBC. In an ongoing, prospective, randomized phase 2b trial, treatment delivery with TAR-200 is being compared with standard of care intravesical chemo- therapy in patients with BCG-unresponsive disease as monotherapy or in combination with the ICI cetreli- mab [45]. Another randomized, phase 3 clinical trial will investigate the efficacy of TAR-200 chemotherapy in combination with cetrelimab compared to BCG ther- apy in BCG-naïve NMIBC, with disease-free survival (DFS) as the primary endpoint.

In the Q&A period, Dr. Todenhöfer provided his highlights of treatment advances in NMIBC to look forward to in the next year. One of the highlights is the development of new drug classes that exceed the efficacy of chemotherapy, such as nadofaragene firad- enovec and oportuzumab monatox. According to Dr. Todenhöfer, these therapies may have an important role not only in the treatment of BCG-unresponsive patients, but also in earlier settings. Another highlight is the advance of systemic therapy for NMIBC. As pointed out by Dr. Todenhöfer, these advances will be influenced by important treatment-related toxicities, which may be less tolerable in patients with NMIBC.

The following talk was by Dr. Tian Zhang (United States) who discussed the advances in systemic ther- apy for MIBC and advanced UC in 2021. The current treatment landscape for metastatic UC comprises plat- inum-based chemotherapy as first-line regimen and switch maintenance with the PD-L1 inhibitor avelumab, recently highlighted in the JAVELIN Bladder 100 study [46]. Treatment then may follow with enfortumab vedotin for all patients or erdafitinib for those pre- senting with FGFR2 and FGFR3 genomic alterations. Multiple clinical trials are ongoing and sacituzumab govitecan recently received FDA accelerated approval in the third-line setting [47].

The successful results of different immunothera- peutic agents for metastatic disease have fomented several trials aiming to bring those treatment advances into earlier disease settings. In MIBC, chemotherapy in combination with pembrolizumab was investigated as neoadjuvant therapy prior to radical cystectomy in the LCCC 1520 trial [48]. The primary endpoint has been met, with 56% of patients achieving a down- staging pathologic response rate <pT2N0M0 and 36% having a pathologic CR to treatment, along with a generally safe toxicity profile. A number of clinical trials have been reported in recent years using neo- adjuvant immunotherapy or combination chemoim- munotherapy in MIBC [48,49,50,51,52,53]. Most of these studies have enrolled patients with T2, T3, T4, or N1 disease and demonstrated the effect of immunotherapies on pathologic response at the time of cystectomy. Several trials are ongoing and aim to examine the role of ICIs, antibody-drug conjugates (ADCs), and combination therapy in the neoadjuvant treatment of MIBC.

In the adjuvant setting, the CheckMate 274 trial investigated the role of nivolumab in the treatment of MIBC following cystectomy, in both patients with prior neoadjuvant cisplatin-based chemotherapy and those without NAC and ineligible for adjuvant treatment [54]. Treatment with nivolumab compared to placebo resulted in a significantly longer median DFS, the primary endpoint, in the intent-to-treat (ITT) population (21.0 vs. 10.9 months, HR=0.70 [98.31% CI 0.54–0.89]; P<0.001), as well as in a subset of patients with PD-L1 expression ≥1% (not reached vs. 10.8 months, HR=0.53 [98.87% CI 0.34–0.84]; P<0.001).

Common AEs included pruritus, fatigue, diarrhea, rash, and increased lipase, which are expected reactions from treatment with immunotherapies. Additional tri- als currently enrolling patients to examine the role of adjuvant immunotherapies in MIBC and UTUC include the AMBASSADOR trial (pembrolizumab vs. observa- tion [55]) and, with targeted therapies for FGFR-altered urothelial cancer, the PROOF-302 trial (infigratinib vs. placebo [15]).

Results of the JAVELIN Bladder 100 trial have changed practice in the locally advanced and met- astatic UC setting. In patients with unresectable dis- ease, treatment with avelumab and best supportive care (BSC) resulted in significant improvements in OS (HR=0.69 [95% CI 0.56–0.86]; P<0.001) and PFS (HR=0.62 [95% CI 0.52–0.75]; P<0.001) compared to BSC alone [46]. The benefit of adding avelumab to BSC was observed in patients who had achieved CR, partial response (PR), or stable disease (SD) after initial chemotherapy. While shorter median OS and PFS were observed in patients with PR or SD, additional treat- ment options may be available for this very frail patient population in the post-avelumab setting.

Additionally, in the metastatic UC setting, the posi- tive results of the phase 3 trial EV-301 have cemented enfortumab vedotin for treatment of patients with refractory disease and prior immunotherapy [56]. In the trial, treatment with enfortumab vedotin resulted in sig- nificantly improved OS (12.88 vs. 8.97 months, HR=0.70 [95% CI 0.56–0.89]; P=0.0142) and PFS (5.554 vs. 3.72 months, HR=0.62 [95% CI 0.51–0.75]; P<0.00001) compared to chemotherapy. Among the grade 3 or higher AEs observed in this trial, maculopapular rash occurred more frequently in patients who received enfortumab vedotin (7% vs. 0%), whereas decreased neutrophil count (6% vs. 13%), decreased white blood cell (1% vs. 7%), and febrile neutropenia (1% vs. 5%) were more frequently observed in the chemotherapy group. Other ongoing trials (EV-302 and EV-103) are evaluating the use of enfortumab vedotin alone or in combination with pembrolizumab or chemotherapy as a first-line treatment option for metastatic UC [51,57].

During the Q&A, Dr. Zhang provided her insights on first- and second-line therapy recommendations for metastatic UC. Platinum-based chemotherapy is still the primary option for eligible patients. Once achiev- ing SD, Dr. Zhang recommends that patients undergo maintenance treatment with avelumab. Second-line options will often include enfortumab vedotin for all patients or erdafitinib for patients with FGFR alter- ations. With each line of therapy in metastatic UC, the goal is to extend patient survival while preserving quality of life. She also pointed out that other options may become available in earlier disease settings, as many ongoing clinical trials are evaluating systemic therapy options in the localized and adjuvant settings. In addition, Dr. Zhang addressed the ideal timing to sequence tumour tissue in order to guide treatment decisions in the metastatic setting. She recommends that sequencing be performed following cystectomy, given the amount of tumour tissue available, particu- larly for patients who have residual disease after neo- adjuvant treatment.

The session concluded with a case-based discus- sion on management of immune-related AEs and toxicities, not specifically related to BCa. This was led by Dr. Kilian Gust (Austria), with the discussion based on the input of Dr. Srikala Sridhar (Canada), Dr. Tilman Todenhöfer (Germany), and Dr. Tian Zhang (United States).

The first case was a 54-year-old female initially diag- nosed with and treated for high-risk NMIBC who pro- gressed to MIBC. Following a radical cystectomy, the patient presented with lymph node metastasis in the surgical field. At this time, the patient started treatment with atezolizumab after enrolling in the SAUL trial [58]. After the first treatment cycle, the patient presented with a marked increase in thyroid-stimulating hormone (TSH), characteristic of thyroiditis. This AE is commonly observed in patients receiving immunotherapies. If the patient is asymptomatic or presents mild symp- toms, immune-related thyroid dysfunction does not require immediate management or discontinuation of immunotherapy. Changes in TSH, T3, and T4 hormone levels should be closely monitored. Early referral to an endocrinologist may be considered [59]. The patient continued treatment with atezolizumab and reached CR. Over time, she developed hypothyroidism, which was managed with thyroid hormones. At cycle 49 of atezolizumab, the patient relapsed and was treated with chemotherapy, after which she achieved PR and was put on avelumab maintenance. After receiving the first dose, the patient presented with fever and chills. These infusion reactions are commonly seen with ave- lumab [46] and may be prevented with premedication.

The second case was a 76-year-old male with poor prognosis for MIBC. After the patient refused NAC, he underwent radical cystectomy and recovered well after surgery. Results of CheckMate 274 trial suggest that this patient could benefit from adjuvant treatment with nivolumab [54], which is not yet approved in this setting. Two weeks after receiving the first dose of nivolumab, the patient reported feeling unwell. His blood work showed altered liver function. At this point, it is important to put the immunotherapy treatment on hold, discuss with the patient the possibility of a TRAE, and consider referral to a hepatologist. Management of altered liver function may include prednisolone. If tests do not show improvement, a liver biopsy may be performed to guide alternative management deci- sions [59]. The patient in this case responded well to intravenous methylprednisolone and resumed immu- notherapy with close monitoring of liver function. In an alternative scenario in which the patient had received NAC, it would be important to discuss potential TRAEs prior to starting treatment with nivolumab. Patients in this setting who have no signs of active disease may be less tolerant to AEs resulting from immunotherapy.

The last case was a 67-year-old male with interme- diate-risk renal cell carcinoma (RCC) who underwent cytoreductive nephrectomy prior to enrolling in the phase 3 CLEAR trial, in which the patient received pembrolizumab plus Lenvatinib [60]. At his first visit, the patient presented with grade 1 nausea and grade 1 hypertension. Later, he also developed grade 2 rash on the back of the legs, corresponding to 18% of the body surface area (BSA). In this scenario, manage- ment of rash includes topical steroids, which may be complemented by oral antihistamines. Early referral to a dermatologist is advised [59]. The patient contin- ued combination therapy and started treatment with topical steroids, until developing intense grade 3 rash on the legs, corresponding to a BSA of 36%. In this case, the patient requires management with systemic steroids and a dermatological review is indicated [59]. Therapy should be put on hold and continued only after symptoms have improved. Combination ther- apy was resumed after symptoms had improved, until recurrent grade 3 rash led to permanent discontinu- ation of first pembrolizumab and later lenvatinib, due to tyrosine kinase inhibitor (TKI)-related rash. In some practices, TKI may be discontinued prior to ICI due to its shorter-acting effects. Steroid treatment may be considered if rash persists after TKI discontinuation. If rashes improve after treatment discontinuation, treatment dose reduction may be considered. When evaluating additional treatment options, it is also important to keep the patient’s quality of life, which may be deeply impacted by skin rashes, in mind.

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