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Rashid Sayyid: Hello, everyone, and thank you for joining us in this special UroToday Journal Club recording. I'm Rashid Sayyid, an Urological 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 the definitions, endpoints, and clinical trial design recommendations for bladder cancer. This is going to be a four-part series recording, and in this segment, we'll be discussing the recommendations specifically for muscle-invasive bladder cancer. These consensus statement recommendations were published in the Journal of Clinical Oncology with Dr. Ashish Kamat as the lead author.

So, by way of introduction, we know that there's a significant unmet need for new and effective treatments for urothelial carcinoma, and clinical trial design and conduct is going to be the platform that allows us to push for such new and effective treatments, and so their design is of utmost importance. So, we need rationally selected endpoints. We need to consider appropriate eligibility criteria, how to evaluate patients, statistical analyses, particularly with regards to the study endpoints, and powering for them, as well as correlative studies to push the field forward. So, the objective was to provide a consensus statement from the IBCG 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 and conduct, in urology, surgery, medical oncology, radiation oncology, pathology, statistics, and patient advocacy. It included also member representatives from both the Society for Immunotherapy of Cancer and the IBCG, or the International Bladder Cancer Group. Importantly, this panel included a patient representative from the Bladder Cancer Advocacy Network, ensuring that our patients' voices were heard in putting these consensus statements together.

In terms of conflicts of interest, always important when considering these statements, these were individually reported prior to the onset of manuscript development. No members with industry employment were eligible to serve on the panel, and financial support for the development of this guideline was provided solely by the Society for Immunotherapy of Cancer and the International Bladder Cancer Group.

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. Then, when practice-changing data or clinical trial results subsequently became available, authors considered and incorporated new evidence into the recommendations. These were subsequently refined through consensus discussions and reviewing and editing of manuscript drafts.

Now let's talk about the definition of muscle-invasive bladder cancer, particularly in the neoadjuvant setting. So, this is defined by the panel as a clinical T2-T4A, node-negative, without evidence of metastasis, disease. This, as you may note, excludes patients with local invasion, such as into the pelvic sidewall or, in females, the uterus. So, it includes patients with clinical T4B disease. It excludes patients with surgically unresectable disease and those with metastatic disease. So, you'll also note that the AJCC Stage IIIa tumors should be included within the MIBC group for trial design and conduct purposes. This includes patients with node-positive disease, specifically the N1 tumor subgroup.

It's important to note that in this group, there's a high risk of understaging patients, particularly with regards to the presence of more aggressive, potentially locally advanced, or metastatic disease. So, we need to standardize bimanual examinations under anesthesia, the performance, and quality, and extent of TURBTs, and also incorporating high-quality MRI or CT as part of the staging workup. Neoadjuvant chemo can be in the form of systemic or other therapy prior to the definitive local therapy, and this definitive local therapy can either be a radical cystectomy or radiation with concurrent sensitizing chemotherapy.

What about some definitions in the adjuvant setting for the MIBC group? These should be considered for patients with T3-T4 disease, with or without node-positive disease, in a cystectomy specimen, in the absence of prior neoadjuvant chemo. Now, among those who have received neoadjuvant chemo, and these are the ypT2, or worse, with or without pathologic nodal involvement, these can also be considered for adjuvant treatment. We note the Y notation to denote that patients with such a distinction have received neoadjuvant chemo, and these pathologic evaluations are in the context of knowing that these patients had received the neoadjuvant chemo. Now, the panel was split on whether to include patients in adjuvant trials with lymph nodes outside the true pelvis, and so that's to be determined. The panel did note that these trials may include patients with upper tract urothelial cancer, as we've seen in previous trials, but it's important to cap the enrollment at 20-25% in order to create a more generalizable cohort, concurrent with what we see in clinical practice.

Now, in terms of baseline staging and stratification, enrolled patients with clinical T2 disease alone may be capped to allow for the accrual of patients with higher-stage disease such as T3-T4a, or other high-risk features. A lot of these trials are driven by the number of events and not just the number of patients, and so we expect recurrence, progression, or mortality events to occur more frequently in patients with higher-stage disease. So, that provides the rationale for not over-enriching these trials with the lower-risk patients, such as T2, and making it more balanced, including more T3-T4a patients, who are more likely to have the events of interest, and thus allow for a more practical conduct of these trials. It's important to note that patients with extensive, diffuse, or multifocal CIS and poor baseline bladder function are not ideal candidates for trimodality therapy.

They note also that all patients with at least a predominant conventional urothelial histology of at least 25% should be included in these trials, and to minimize delays to accrual and timelines overall, central pathology review for biomarkers for enrollment should not be mandated. Common stratification variables for enrollment of patients then, for randomization, in order to make sure that the two groups are balanced with respect to these variables, are the T and N stage, and geography, because we know there are geographic variations in the way care is practiced, and importantly, the availability regionally of certain agents and the costs that come with them, as well as histologic subtype. This, again, is to ensure that these are well-balanced across the clinical trial arms and to ensure reproducible data.

Now, in terms of pathologic considerations, the TURBT remains the gold standard for documenting muscle-invasive disease, at least clinical T2, but as we know, TURBT cannot reliably detect more advanced T stages accurately. So, this relies on radiographic findings such as MRI and the VI-RADS, et cetera, in order to at least define the extent of local-regional disease involvement. The pathologic T and N stage, as the name suggests, is only after a cystectomy specimen is evaluated. Small cell or neuroendocrine tumors probably should be considered separately in these clinical trials because of their variable chemotherapy responsiveness and behavior. As we had previously noted, cystectomy specimens after neoadjuvant chemo, the Y designation before the pathologic T stage must be used to emphasize post-treatment staging.

What are some pathology considerations in the adjuvant setting? We do know that it can be difficult to distinguish between muscularis mucosa and muscularis propria, and so as of yet, no immunohistochemical marker exists to confirm the difference, and so that needs to be considered. We must also consider that different subtypes, such as micropapillary, plasmacytoid, pure squamous, or pure adenocarcinoma, may respond differently to adjuvant therapies. In terms of the pathology reports, what is important and what is not, we must detail the presence or absence of lymphovascular invasion, concomitant CIS, depth of invasion, the tumor subtype, and whether lymph nodes were positive or not, and then, if they are, report whether there was extracapsular or extranodal extension. These are important because these are prognostic markers for a worse prognosis, and in certain circumstances, may predict response to treatment, and so it's very important that these are detailed very well.
At this point, I'll turn it over to Zach to go over the research hypothesises that are considered in the muscle-invasive bladder cancer risk subgroup and the remaining of the study design considerations in this group.

Zach Klaassen: Thanks so much for that extensive introduction, Rashid. So, let's talk about the research hypotheses for neoadjuvant chemo. So, the hypothesis for neoadjuvant chemo is that systemic treatment before cystectomy may be better tolerated or more feasible, and offers earlier treatment of micrometastatic disease, and measurement of pathological response to the primary tumor as an intermediate measure of treatment benefit. Additionally, cisplatin-based chemo, as we know, has demonstrated improved overall survival in patients with muscle-invasive bladder cancer, with now 20 years of data supporting this. The rates of metastatic recurrence remain high, and a large portion of patients are cisplatin-ineligible. So, this is a very important disease space for clinical trials.

With regards to adjuvant therapy, this systemic therapy allows treatment decisions to be based on more precise pathological, rather than clinical, staging. Adjuvant systemic therapy can also be used in patients with adverse pathological findings in the cystectomy specimen, despite prior neoadjuvant chemotherapy, and we know that these patients, based on their disease biology, have a very high risk of metastatic recurrence. Finally, a goal for perioperative systemic therapy is to eradicate micrometastases, with the rationale that systemic therapy may improve patient survival, but also has to have an acceptable quality of life.

So, let's talk about study objectives for neoadjuvant chemo. So, the primary objective is, number one, to eradicate micrometastases, and two, decrease primary tumor burden before a consolidated local therapy approach. We know that there are two specific pathological groups that have improved overall survival, and really do very well. These are patients that are ypT0N0, so complete pathological response, as well as those that are ypTcisN0. The recommendation from the panel is that pathological complete response is a primary endpoint in phase three RCTs, but also should be accompanied by a co-primary endpoint, such as event-free survival. For those patients on trials undergoing concurrent chemo-radiation, the panel recommends that using clinical complete response as an intermediate endpoint is feasible, although bladder-intact event-free survival is the primary endpoint of choice.

Looking at secondary endpoints, these include treatment-associated adverse events, overall survival, metastasis-free survival, cystectomy-free survival, preservation of bladder function, and non-muscle-invasive or muscle-invasive recurrence for bladder-preserving strategies. If we look a little bit deeper at treatment-associated adverse events, this has several important points. So, we should be looking at the percentage of patients precluded from cystectomy or precluded from completing planned chemo-radiation, secondary to toxicity. We should be assessing for rates of immune-related adverse events. We should be assessing for delay to cystectomy secondary to adverse events, as well as rates of post-cystectomy or post-radiation complications.

For the objectives of adjuvant trials, the most meaningful primary endpoints are disease-free survival and overall survival. Secondary endpoints include distant metastasis-free survival, which is defined as recurrence outside of the urothelial tract, urothelial recurrence-free survival, which is also important, as well as patient-reported outcomes, quality-adjusted life years, and discontinuation rates for reasons other than recurrence.

Looking at statistical considerations, it's important to assess the critical value for effect size or response rate thresholds. We can see that for trimodal therapy trials, this should be a 10% increase in bladder-intact event-free survival, for neoadjuvant trials, a 10% increase in event-free survival, and for adjuvant trials, a 10% increase in disease-free survival. When looking at sample size calculations, essentially, these are the same for all three cohorts, whether it be trimodal therapy, neoadjuvant, or adjuvant. This is assuming a three-year event-free survival rate of 50% in the control arm with 344 events required to have a hazard ratio of 0.74.

When we look at the study design of neoadjuvant clinical or neoadjuvant chemo trials, these should be phase three RCTs comparing the standard of care versus experimental therapy. This is subsequently followed by cystectomy plus pelvic lymph node dissection or trimodality therapy, depending on the trial design. The standard is to give four cycles of neoadjuvant every three weeks prior to consolidative therapy. It's important to note that there are groups of patients based on their cisplatin and cystectomy eligibility. So, the healthiest patients, these are cisplatin-eligible as well as cystectomy-eligible, then we have the cisplatin-ineligible, cystectomy-eligible, and finally bladder-sparing protocols, including chemo-radiation or intravesical therapy, plus immune checkpoint inhibitor therapy.

For adjuvant trials, these should be prospective randomized controlled trials. Again, there are several important groups amongst these patients. There are cisplatin-eligible patients that did not receive neoadjuvant chemotherapy. Their comparator for these trials should be cisplatin-based adjuvant chemo. For cisplatin-ineligible patients or those who previously received neoadjuvant chemo, their comparator should be adjuvant nivolumab. What's also important, and we've seen emerge over the last couple of years, is ctDNA, and this may be used to stratify patients for micrometastatic disease and should be integrated into clinical trials based on the panel recommendations.

With regards to the study population of neoadjuvant chemotherapy patients, it's important to delineate cisplatin eligibility, and this can be delineated from the Galsky criteria. So, this includes creatinine clearance greater than or equal to 50 to 60 ml per minute, ECOG performance status of less than two, as well as the absence of grade two neuropathy, grade three or four heart failure, or grade two to three hearing loss. Furthermore, immune checkpoint inhibitor therapy adds limited additional risk to patients with well-controlled HIV infection, those that have been treated for hepatitis B or C, and those that have well-controlled autoimmune conditions, and it's important that these patients should not be excluded from these trials based on the recommendations of the panel. For radiotherapy eligibility, this includes patients that have not had prior radiotherapy to the pelvis, as well as those with no additional contraindications to radiotherapy.

For adjuvant patients, these patients should be fit for systemic therapy and have an ECOG performance status of zero to one. There should be adequate tumor tissue for biomarker analysis, and they should have already completed the standard of care treatments, such as cystectomy with extensive pelvic lymph node dissection, used as a stratification factor. For these trials, prior neoadjuvant therapy should be allowed, but noted when discussing sequencing these agents. With regards to prior anti-PD or PD-(L)1 therapy, this may be administered greater than six to 12 months before trial inclusion if nivolumab is the comparator. For those patients with positive surgical margins in their cystectomy specimen, these should be allowed to be included in these trials, but capped at 20 to 25% enrollment, and analyzed as a subgroup analysis. Finally, we should include histological subtypes greater than 50%, but these should be also a stratification factor in these trials.

With regards to evaluation and follow-up of neoadjuvant clinical trials, staging should include a baseline chest CT scan, as well as pelvic MRI or CT urogram, prior to TURBT. Interim cystoscopy before cystectomy is an option, but was not a recommendation by the panel. Finally, patients should be followed for a minimum of three years, with consideration of decreasing scan frequency after the first two years.

For the evaluation and follow-up of adjuvant trials, assessment of clinical recurrence should include physical exams, cross-sectional imaging of the chest, abdomen, and pelvis, as well as possibly including biomarker analysis such as ctDNA. Scan frequency is a little more frequent than in the neoadjuvant trials. It should be every three to six months for the first two years, annually for the next three years, and as clinically indicated at greater than or equal to five years. It's important that, because of the risk of these patients, they should be followed for a minimum of five years.

So, with regards to a summary, let's highlight what we've already discussed, broken down by these three groups, as you can see here. So, eligibility for trimodality therapy includes high-grade, histologically confirmed, clinical T2-4aN0-1M0 urothelial carcinoma, eligibility criteria for neoadjuvant patients includes high-grade, histologically confirmed, clinical T2-4aN0-1M0 urothelial carcinoma, and for adjuvant patients, high-grade pT3-4, and/or pN positive, in the radical cystectomy specimen. For all three groups, we have high-grade, histologically confirmed, clinical T2 to four, in all three cohorts. The study design should be randomized controlled clinical trials. With regards to the control arm for both trimodality therapy and neoadjuvant, this should be guideline-informed standard of care. For adjuvant, the control arm should be cisplatin-eligible, with no prior neoadjuvant chemo. These should receive platinum-based chemotherapy, for those that are cisplatin-eligible with prior neoadjuvant chemo. For those that are cisplatin-ineligible, their comparator should be nivolumab.

Furthermore, when we look at the primary endpoint for trimodality therapy, this is bladder-intact event-free survival. For patients in neoadjuvant trials, it should be pCR rate and event-free survival. For those in concurrent chemo-radiation trials, it should be clinical complete response rate and bladder-intact event-free survival, and for adjuvant trials, it should be disease-free survival and overall survival. The secondary endpoints that you can see listed here include a whole host of endpoints for each of these cohorts. Primarily, this should include overall survival, distant metastasis-free survival, and toxicity is very important, as well as cost and patient-reported outcomes, amongst the others listed in the middle of this table. For the primary endpoint assessment for trimodality therapy, this includes cystoscopy and urine cytology to assess for complete response every three months for two years, and then thereafter, every six months up to five years, and yearly for lifelong surveillance.

For neoadjuvant patients, the primary endpoint assessment should be cystoscopy or rebiopsy and urine cytology to assess for complete response at three or six months, followed by every three to four months for two years, thereafter, every six months for five years, and then lifelong surveillance with scans every three to six months for the first two years, yearly for up to five years after, and then clinically indicated thereafter. Finally, for adjuvant therapy trials, the primary endpoint assessment should be scans every three to six months, and then clinically indicated thereafter, and finally for the first two years, and then yearly scans for up to five years, followed by scans as clinically indicated for lifelong surveillance.

We thank you very much for your attention. We hope you enjoyed this UroToday Journal Club discussion of clinical trial design for muscle-invasive bladder cancer patients.