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Rashid Sayyid: Hello, everyone, and thank you for joining us in this special UroToday Journal Club recording where we'll be discussing the recent recommendations from the Society for Immunotherapy of Cancer and the International Bladder Cancer Group. I'm Rashid Sayyid, I'm a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, who's the associate professor and program director of Wellstar MCG Health, we'll be going through these recommendations, looking specifically at every disease site and stage. So, to start off, we'll be discussing patients with low and intermediate-risk non-muscle invasive bladder cancer. By way of an introduction, it's quite clear to the urological oncology community and our listeners in particular, that there is a significant unmet need for new and ineffective treatments for urothelial carcinoma. And in order to move this field forward, clinical trials are of utmost importance. And so, the trial design thus is something that we really need to take into account, knowing that well-designed trials are going to inform practice in a better fashion.

And so, for future trial design, we need to think about rationally selected endpoints, eligibility criteria, how we evaluate patients. We need to think about methodology and statistical analysis, and how we power our studies and design them in this setting. And we need to think about correlative studies in order to push the field forward. And so, the objective of this statement was to provide a consensus statement or agreement from the International Bladder Cancer Group and the Society for Immunotherapy of Cancer to provide guidance to investigators for late-phase clinical trial design, specifically in the bladder cancer space. And so, this panel consisted of 25 members with experience in different domains, a multidisciplinary committee, including those with experience in clinical trial, conduct, urology, surgery in general, medical oncology, radiation oncology, pathology, statistics, and patient advocacy. And this also included member representatives from both the Society of Immunotherapy for Cancer and the IBCG as well.

Importantly, this consensus statement included input from patient advocates. So, we had a patient representative from the Bladder Cancer Advocacy Network that was involved in this publication. In terms of a conflict-of-interest management, this is also an important point because we want to make sure that these statements are not heavily influenced by certain interests that may sway us one way or another. And so, in terms of conflicts of interest, these were individually reported prior to the onset of manuscript development, and 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 of Immunotherapy for Cancer and the IBCG.

In terms of recommendation development, the recommendations were based on the literature evidence and clinical experience, obviously, where appropriate. And the panel members participated in a modified Delphi process in which an initial anonymous survey was administered to identify recommended endpoints. And then, when practice-changing data or clinical trial results became subsequently available, the authors considered and incorporated new evidence into the recommendations. And then, the statement was refined through consensus discussions, and reviewing, and editing of manuscript drafts.

So, let's start with the first disease stage. So, low and intermediate-risk non-muscle invasive bladder cancer. So, in terms of definitions, first of all, establishing that. So, for low-risk non-muscle invasive bladder cancer, this specifically included those patients with small, less than three-centimeter, single, primary, solitary, low-grade Ta tumor. So, a very narrow subset of patients. And then, for the intermediate-risk non-muscle invasive bladder cancer, it was essentially low-grade non-muscle invasive bladder cancer that exhibited additional risk factors, which included multifocality, large size, meaning more than three centimeters diameter, and/or patients with disease recurrence, meaning this was not their primary disease or the primary occurrence of disease. And then, for T1 low-grade tumors, these are rare, but these are still considered part of the intermediate-risk subgroup.
In terms of pathologic considerations, all low-grade Ta tumors are considered similar, and there's no need, based on the consensus, for further subtyping. The panel did recommend that we should exercise caution in the diagnosis of low-grade lesions in the case of incomplete resection. And it's important to know that cytology has low sensitivity and limited specificity for the detection of low-grade tumors. And if a tumor consists of 5% or more high-grade pathology, then by definition, it should be classified as a high-grade lesion. Now, what are the ongoing hypotheses and objectives in this risk subgroup, the low and intermediate-risk non-muscle invasive bladder cancer? So, first of all, is to test the antitumor activity of treatments. And the type of trial design that allows for that is the evaluation of ablative therapy trials, so it's conceptually similar to neoadjuvant trials. And it's also, the second objective is to test the ability of treatments to prevent disease recurrence or progression. So, the adjuvant setting, and thus adjuvant therapy trials.

So, we can think about two big questions in these risk subgroups. First of all, can we find an alternative, or maybe a supplement, to TURBT in medically unfit patients, or those who prefer to forego surgery? And then second of all, can we minimize the chance of recurrence following a TURBT, for example, in this cohort? In terms of statistical considerations, now, for adjuvant therapy trials specifically, the optimal method to detect a difference in treatment efficacy between the arms is at the time to first recurrence, using the log-rank test. This is a survival analysis with an outcome of interest of recurrence. And this time to recurrence comparisons are performed using the log-rank test. And now, for low and intermediate-risk non-muscle invasive bladder cancer trials, the consensus statement notes that muscle-invasive disease progression should be counted as part of recurrence, as well as progression, and then deaths due to unrelated causes prior to recurrence. These should be analyzed as a competing risk in order to not inflate the survival rates in this subgroup.

Now, what are some additional trial design considerations? So, it's hard to pinpoint a specific target for a complete response rate or an improvement of recurrence-free survival, but the panel does suggest that a critical value for ablative trials should be a complete response rate of at least 60%. And they do suggest that for adjuvant trials, any adjuvant therapy should, at the very least, increase or improve the recurrence-free survival by about 10%. And so, they gave us an example of sample size considerations, assuming a two-year recurrence-free survival of 75% of the control arm, the number of patients that you would require to show is superiority. And so, this can be used as a framework for future trial design, considering these benchmarks. At this point, I'll turn it over to Zach to go over the ablative trials and the rest of the nuances in designing these trials in the low and intermediate-risk subgroup patients.

Zach Klaassen: Thanks so much, Rashid, for that great introduction. So let's focus on ablative trials. So, the objective of these trials is to treat existing tumors by means other than surgical resection. And this is furthermore to provide direct evidence for ablative activity as measured by the complete response rate of the investigational agent at an earlier time point. When we talk about the CR rate, this was a primary endpoint that was previously used in phase two trials. And this is defined as the absence of disease at the treated tumor site at three months, as seen on cystoscopy and negative cytology, with the option of surgical sampling of the post-treatment scar. Furthermore, although a three-month CR rate does not necessarily correspond to a durable clinical benefit, historical marker lesion trials have observed CR rates of approximately 60% with intravesical chemotherapy.

When we're talking about further design of ablative trials, so phase ones are single-armed designs or randomized between different agents or different doses of the same agent to assess safety. When we're looking at phase two and three ablative trials, this is to assess activity where we should be able to do dose escalation. And once the recommended phase two doseis determined, agents should be evaluated in expanded phase two studies to further assess CR and other endpoints. Although single-arm trials are allowed in phase two, the assessment of efficacy endpoints is more meaningful in RCTs comparing ablative therapies versus TURBT. Switching to adjuvant trials, this should have a primary endpoint of recurrence, which is defined as the recurrence of non-muscle invasive bladder cancer or disease progression. Secondary endpoints are the ones that we typically look at in these big trials, PFS, DFS, OS, and safety, and the trials should be randomized.

The control should be active surveillance or standardized intravesical chemo. And, in specifically, intermediate-risk patients, this may depend on several additional risk factors. So if the patient has no additional risk factors, they're on the lower end of intermediate risk. A single postoperative dose of intravesical chemo is fine. If they have greater than or equal to one additional risk factors, we should be doing adjuvant induction intravesical chemo in these intermediate-risk patients. What's important with adjuvant therapy trials is the complete TURBT prior to study enrollment, and we should specify which patients received postoperative treatment previously. And this analysis should be stratified by postoperative intravesical therapy usage as well as institution in the setting of multi-center studies because of the variability of treatment that can occur at different sites.

With regards to evaluation and follow-up, we should document an extensive bladder cancer history. So the date of initial diagnosis, the grade, stage, multiplicity, tumor size, the number of prior recurrences, previous treatment history, as well as detailed cystoscopic findings. If advanced cystoscopic techniques are used, such as blue light, they should be used consistently at the baseline and on treatment. So once you start using blue light, continue blue light throughout the time of the trial. Additionally, contrast-enhanced cross-sectional imaging to rule out upper tract disease, lymphadenopathy, or metastatic disease should also be collected. Furthermore, for ablative therapy trials, if residual tumor is present after therapy, standard of care treatment should be instituted. This may include maintenance therapy with the investible agent, which should be allowed in patients that have not had a recurrence. With regards to follow-up, surveillance cystoscopy evaluation and cytology should be conducted at three-to-four-month intervals for the first year, and then every six months thereafter for two years.

So, to summarize, we have a breakdown of what we've just talked about. And so, this is a summary of the low and intermediate-risk patients. Eligibility should be primary, solitary, low-grade Ta and T1 tumors. As we discussed, the ablative trial should be single-arm, non-randomized. Adjuvant trials should be randomized and controlled, and the control arm for adjuvant trials should be active surveillance or intravesical chemotherapy. The primary endpoint for ablative trials should be the CR rate, whereas for adjuvant trials it should be time to first recurrence. And secondary endpoints are a whole host of endpoints including PFS, disease-specific survival, overall survival, translational and biological correlatives, patient-reported outcomes, quality-adjusted life years, objective measures of therapeutic burden, and the total cost of treatment. The primary endpoint assessment for ablative trials should be cystoscopy with photographic documentation and urine cytology at three months after treatment.

We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of non-muscle invasive bladder cancer, low, and intermediate-risk clinical trial design.