Neoadjuvant and Adjuvant Trials Could Continue to Individualize Treatment in MIBC

Bernard H. Bochner, MD, FACS

Bernard H. Bochner, MD, FACS, a urologic surgeon and the Sir Murray F. Brennan Chair in Surgery at Memorial Sloan Kettering Cancer Center, in New York, New York, shared recent updates in the treatment of muscle-invasive bladder cancer (MIBC) in an interview with OncLive®at the 17th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, an event hosted by Physician’s Education Resource (PER®). He provided an overview of what the impact of these ongoing trials in the neoadjuvant and adjuvant settings could have on the treatment paradigm; and emphasized the importance of global efforts to better identify markers that could help guide therapy decisions for different subsets of patients.

Previously, Bochner provided further insights into the evolving treatment paradigm of MIBC in another interview with OncLive.

OncLive: Are there any ongoing studies looking at potential bladder sparing for patients with MIBC?

Bochner: There are several ongoing studies now looking at chemotherapy alone using molecular markers. For instance, the [phase 2] Alliance A031701 trial [NCT03609216] being headed by Gopa Iyer, MD, [of Memorial Sloan Kettering Cancer Center], is specifically looking at mutations within the DNA damage repair gene apparatus—specific genes that have been validated prospectively to show a very strong correlation with exquisite platinum sensitivity. These are the complete responders that we typically would see.

In this setting, tumors are being sequenced [to see if] they have an eligible mutation, and patients are able to undergo platinum-based chemotherapy. Following the completion of their chemotherapy, if they have a clinical complete response [CR], we are now offering bladder preservation on a trial basis to identify the safety of this approach.

We're hopeful that approaches like this are going to lead to better outcomes for patients who do require surgery and perhaps [help identify the] important subset of patients in whom it may be possible to spare the bladder and still have similar cancer outcomes in the long term.

If data for adjuvant nivolumab (Opdivo) do not show an overall survival (OS) benefit, do you see the disease-free survival (DFS) benefit being convincing enough to justify its use in that setting?

Ultimately, payers are going to be the ones who decide whether these agents are going to be covered. There are some countries right now that are not moving toward approval [of nivolumab] in the adjuvant setting based on a DFS benefit alone, and they are waiting for that OS signal. It's going to be interesting [to see how this plays out] in the long term. Ultimately, the OS advantage is what we want to see.

However, on the flip side, patients who are no longer dying of bladder cancer—a disease-specific survival outcome—is also quite important in maintaining [adjuvant nivolumab’s] use, though [disease-specific survival] may not be [as important] as an OS. We're not trying to make patients live forever. This is [generally] an older [patient population with comorbidities], but we want to prevent them from [dying] of their disease. There is going to be a role for these agents if we can demonstrate that fewer patients are dying of metastatic bladder cancer.

What is the importance of gathering data on the correlation between pathologic CR (pCR) and long-term outcomes for newer agents being evaluated in the neoadjuvant setting?

The coordination of the introduction of neoadjuvant drugs with surgery must be closely [monitored]. The goal would ultimately be to try to offer bladder preservation in the subset of patients who clearly demonstrate CRs. The bladder itself, with every bladder preservation option we've tried, tends to be a source of additional disease over time. Not all of those are invasive tumors, but [approximately] one-third of them are, setting those patients up for the potential of additional metastatic disease. Therefore, [patients with invasive tumors] do need to be followed closely.

We've recognized with chemotherapy that pCR in the primary [tumor] is a very good indicator of long-term outcome. We need to continue to confirm that with newer agents. Is pathologic response in the primary now continuing to correlate with those good long-term disease-free outcomes? I suspect that they will; however, it could be very specific from mechanism to mechanism. That's still something that will need to be validated with some of the newer agents.

For community oncologists who may not routinely see as many patients with MIBC, what would like for them to take away from this conversation that they could potentially apply to their practice?

There is now clear evidence that at least 60% of most bladder cancer populations with muscle-invasive disease are going to be able to tolerate a platinum-based regimen, whether that's gemcitabine or cisplatin. Some of the healthier patients are being pushed toward some of the dose-dense regimens, as well. However, there will be a subset of patients who simply are not going to be eligible for comorbidity reasons.

In that setting, hopefully moving in the future, these large, randomized trials are going to be able to identify whether checkpoint [inhibitor therapy] alone, checkpoint [inhibitor–based combinations], or—what likely will be the outcome—enfortumab vedotin-ejfv [Padcev]/pembrolizumab [Keytruda] or other antibody-drug conjugate/checkpoint [inhibitor] combinations, will continue to get us to that very high downstaging rate. We can hopefully validate this through the continuation of [obtaining] the same good correlation with good outcomes. In the adjuvant setting, there are several options that are available.

While yes, the OS data is still pending, hazard ratios that drop the recurrence risk by 30% or more are quite impressive, particularly in the subset patients with PD-L1–positive [disease]. That must be considered in the discussion with patients. Previously treated patients who still have invasive disease after surgery are at a higher risk for recurrence, as are extra vesicle patients who did not receive neoadjuvant chemotherapy. It is imperative that we [explain to patients at higher risk of recurrence], based on high-level evidence, that a year's worth of checkpoint inhibition may significantly improve their outcome.

How do you interpret the data being seen in the adjuvant setting for the PD-L1–positive population?

[There does] appear [to be a benefit for the PD-L1 population, although] these are subset analyses that are being done. However, for now, in the entire group of intent-to-treat patients, those outcomes are still very positive. There's ongoing interest in identifying markers of patients who are going to show selected benefit or resistance—which probably even more important. [We also need to establish] the whole role of circulating tumor DNA [ctDNA] and where that fits in.

There are great efforts worldwide to try to validate the identification of high-risk patients in whom we need to intensify therapy, and perhaps in ctDNA-negative patients, we can de-escalate therapy, whether by avoiding chemotherapy altogether or potentially avoiding surgery in the post-neoadjuvant treatment setting. There is a lot to learn. Thankfully, with a variety of new agents available, the outcomes in [patients with] bladder cancer are on the rise, and that's very exciting to see.