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Rashid Sayyid: Hello everyone, and thank you for joining us for this special UroToday Journal Club recording. I'm Rashid Sayyid, a Urologic Oncology Fellow at the University of Toronto, along with Zach Klaassen, Associate Professor and Program Director at Wellstar MCG Health. We'll be discussing the recent recommendations from the Society for Immunotherapy of Cancer and the International Bladder Cancer Group, specifically looking at definitions, endpoints, and clinical trial designs for bladder cancer. This will be a four-part series Journal Club, and in the prior recordings we've discussed the recommendations for low and intermediate-risk non-muscle invasive, high-risk non-muscle invasive, and muscle-invasive bladder cancer subgroups. And in this recording, we'll be discussing the locally advanced and metastatic urothelial carcinoma recommendations. This consensus statement was published in the Journal of Clinical Oncology with Dr. Ashish Kamat as the lead author.

So we know that there's a significant unmet need for new and effective treatments for urothelial carcinoma and in order to move this field forward, future trial design and conduct is of utmost importance. So we need to consider rationally selected endpoints in this subgroup. What are the appropriate eligibility criteria? How do we evaluate these patients? Considerations for statistical analysis, particularly with regards to adequate powering for the study endpoints, and also correlative studies that push the field forward. And so the objective was to provide a consensus statement from both the International Bladder Cancer Group and the Society for Immunotherapy of Cancer to provide guidance to investigators for late phase clinical trial design.

This panel consisted of 25 members with multidisciplinary experience in clinical trial design, in conducting urology surgery, medical oncology, radiation oncology, pathology, statistics, and patient advocacy. It also included member representatives from both the Society of Immunotherapy for Cancer and the International Bladder Cancer Group. And importantly, it included a patient representative from the Bladder Cancer Advocacy Network or BCAN, which is important in order to ensure that our patients get a voice when considering these recommendations.

In terms of conflicts of interest, these are critical to the conduct of these statements in making sure these are well-controlled. And so the COIs were individually reported prior to the onset of manuscript development. No members with industry employment were eligible to serve on the panel, and the financial support for the development of this guideline was provided solely by the Society for Immunotherapy for Cancer and the IBCG. In terms of recommendation development. These were based on literature evidence and clinical experience where appropriate. Panel members participated in a modified Delphi process in which an initial anonymous survey was administered to identify recommended endpoints. And when practice-changing data or clinical trial results became available, authors considered and incorporated new evidence into the recommendations. And these were subsequently refined through consensus discussions and reviewing and editing of manuscript drafts.

What is the definition of metastatic urothelial carcinoma? So per the panel, advanced urothelial carcinoma includes either locally advanced disease, meaning T4B disease invading the pelvic sidewall, or in the case of females, the uterus, and or clinical node II or III disease that is not amenable to curative intent therapy, or patients with metastatic disease. It's important to note that this may develop either as de novo disease, so metastatic at initial presentation, or more commonly as progressive disease in patients with localized muscle invasive bladder cancer. And this includes primary tumors originating from either the bladder, the urethra, or the upper tract.

In terms of pathologic considerations, what is the main challenge? Is the lesion from a metastasis from a known primary urothelial carcinoma or is it from somewhere else? So patients are often treated without a biopsy, and based on imaging alone. Often, tumor tissue from a metastasis changes differentiation as to not resemble the primary tumor. And this is going to be important with regards to genetic subtypes and treatment considerations in the setting, particularly with regards to personalized treatment approaches. And if a primary tumor is available, comparison may be helpful, but does not always resolve the diagnostic problem in the setting of metastatic disease. Presence of histologic subtypes in a primary tumor or metastasis should not exclude participation in a clinical trial with the exception of two subtypes, small cell histology and neuroendocrine histology. And more than 50% of histologic subtype should be reported as a stratification factor for this subgroup.

Now, what is the research hypothesis for patients in this setting with muscle-invasive disease? And so the hypothesis for clinical trials evaluating novel agents or combinations of agents for the treatment of these patients is that an investigational regimen will prolong survival or improve objective response rates compared with the historic standard of care of platinum-based chemotherapy. In terms of study objectives in the treatment-naive advanced urothelial carcinoma, the primary endpoints for randomized clinical trials should include PFS and/or overall survival. And then PFS may be considered in randomized phase II, immunotherapy-based combination trials. And secondary endpoints should include objective response rate, the durability of response among responders, safety-toxicity outcomes, and evaluation of biomarkers for treatment response, safety, etc., and quality of life and patient-reported outcomes assessment.

In terms of study objectives in the progressive disease subgroup, so single-arm phase II trials may be conducted per the panel using RECIST version 1.1, with objective response rate for signal finding. And then an objective response rate as a primary endpoint is important to note and often excludes patients with evaluable yet non-RECIST measurable disease such as patients with bone-only metastasis. Prognostic estimates of the trial population-baseline characteristics may be exploratory but should be avoided as the primary endpoint in single-arm trials. At this point, I'll turn it over to Zach to discuss statistical considerations for RCTs in this setting, as well as other considerations for clinical trial design in the MIBC disease space.

Zach Klaassen: Thanks so much, Rashid, for that great introduction. So when we're looking at statistical considerations for randomized trials, Kaplan-Meier and cumulative incidence function curves should provide the best estimate of an event-free rate at a given point in time. It also allows for proper consideration of competing risks and censoring of patients. Except for the comparison of response rates, comparisons in RCTs should be based on time-to-event analyses using the log-rank test, and this includes endpoints such as time to progression, progression-free survival, as well as overall survival. Finally, percent event-free at a given time point may be reported, such as a landmark analysis, but this should not be used for sample size computations.

With regards to additional statistical considerations, single-arm trials have the advantage of a two-stage design. First, the trial may be stopped early if the investigational treatment shows less activity than expected in an initial, smaller sample of patients, and the total maximum sample size is increased because there's an initial cohort of N1 of patients and an expansion cohort of N1 patients that may be required. When we look at the critical value for effect size or response threshold. When we look at advanced metastatic urothelial carcinoma in the first-line setting, this should be a 15% increase in overall survival. In the subsequent line, this should be a three-month overall survival improvement compared with the control. For sample size considerations, assuming a two-year overall survival rate of 45% in the control arm, 164 events are required for a hazard ratio of 0.64 and an alpha of 0.05 and a beta of 0.20.

For study design, RCTs, the primary endpoint should be overall survival, estimated using the Kaplan-Meier method. And patients in this disease state should be categorized into two groups, including chemotherapy-naive, and those that have previously received platinum-based chemotherapy. The appropriate control arm in RCTs of first-line trials should be platinum-based chemotherapy combinations followed by switch maintenance avelumab. However, as we know from the recent ESMO 2023 presentation, enfortumab vedotin plus pembrolizumab as a first-line comparator may be acceptable based on the results versus first-line platinum-based chemotherapy. So depending on guideline recommendations and approval, the first-line treatment of cisplatin-eligible patients may be changing to a new standard of care. So the guideline and the panel do recommend that we have to be paying attention to these future recommendations.

Furthermore, for patients progressing after immune checkpoint inhibitor therapy, enfortumab vedotin is the standard of care and an appropriate control arm in patients assessing therapies in patients progressing despite prior platinum-based chemotherapy and immune checkpoint inhibitor therapy. Furthermore, single-agent sacituzumab govitecan or erdafitinib in select patients or taxanes or vinflunine is an adequate control group in RCTs testing novel agents after progression on enfortumab vedotin, which is essentially third-line treatment.

With regards to the duration of therapy, first-line platinum-based chemotherapy does have a finite number of cycles, which is typically six cycles of platinum-based therapy. However, the optimal duration of immune checkpoint blockade remains unknown, and many studies do treat patients until radiographic progression. In clinical practice or in the real world, therapy is sometimes discontinued in patients who achieve a complete response or partial response after two years of therapy. But there are several important questions we may be able to answer in clinical trials, such as what is the optimal duration of immune checkpoint inhibitor therapy? Are we able to re-challenge patients at the time of progression if immune checkpoint inhibitor therapy is stopped early?

With regards to biomarkers, there's been a huge amount of data in the last couple of years and a big push for the stratification of patients and personalization of medicine with biomarkers, and certainly, these should be integrated into clinical trial design. The nature of the endpoint should be based on preliminary data, pre-analytical features, and validity. The following box shows several definitions of types of biomarkers. So first, integral biomarkers are essential to conducting the study, i.e., for randomization and treatment allocation and must be analyzed in real time. Secondly, integrated biomarkers are dispensable to conducting the study yet also associated with a high-priority scientific question that can be tested statistically with pre-specified protocols for specimen collection, testing, and analysis. Finally, exploratory biomarkers are all other biomarkers that do not fit into the aforementioned two definitions.

With regards to the study population, receipt of, and time from platinum chemotherapy until the time of recurrence needs to be considered. If it's greater than one year, patients may be re-challenged with platinum chemotherapy. The re-challenge, though, does depend on the pathological response to prior neoadjuvant chemo, tolerance and toxicity, performance status, comorbidities, organ function, the availability of other therapies, as well as clinical trials. Patients with active autoimmune conditions or those requiring systemic immunosuppression should be excluded from trials evaluating immune checkpoint inhibitors. We should also consider several stratification factors in the first-line setting, and this should include visceral metastasis and ECOG performance status. And it may also include albumin or neutrophil-lymphocyte ratio depending on the sample size of the trial.

For the evaluation of follow-up, surveillance scans including the chest, abdomen, and pelvis, should be obtained at routine intervals. And the initial and follow-up imaging should be the same modality. So if you start with a CT scan of the chest, abdomen, and pelvis, these patients should subsequently be scanned with CTs of the chest, abdomen, and pelvis. Although FDG-PET/CT could be valuable, it should not be used as the primary mode of response assessment. And finally, baseline staging should be obtained within four weeks before starting new therapy to ensure accurate radiological assessment of the tumor burden.

So in summary, we look at the tabular summary of what we've just discussed and highlight that again. Eligibility includes locally advanced disease, i.e., T4B and/or N-I to N-III that is not amenable to curative intent therapy or metastatic M1 disease. For the study design, first, second, and third-line trials should have randomized controlled trials, subsequent line. So after third-line, single-arm trials are appropriate. For the control arms in the first-line, platinum-eligible, cisplatin-based combination chemotherapy, followed by maintenance of avelumab in patients who respond or have stable disease at chemotherapy, should be used. In the first-line platinum-ineligible, this should be pembrolizumab. In the second line, this should be enfortumab vedotin. In the third line, this can be sacituzumab govitecan or erdafitinib. And for the primary endpoint in first-line trials, this should be PFS and overall survival. And in subsequent-line trials, this could be objective response rate and overall survival.

Secondary endpoints should include toxicity, quality of life, patient-reported outcomes, and cost. And the primary endpoint assessment for advanced trials should be scans every two to three months for two years and then every six months for up to five years. But thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of clinical trial design for metastatic and locally advanced urothelial carcinoma.