Ongoing Research Pushes for Neoadjuvant Alternatives to Chemotherapy in MIBC

Although neoadjuvant platinum-based chemotherapy has been the standard of care for patients with muscle-invasive bladder cancer (MIBC), remaining unmet needs in the space, such as patients who are platinum-ineligible, have prompted the exploration of alternative strategies using checkpoint inhibitors and antibody-drug conjugates (ADCs), such as enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda), to further enhance treatment options and outcomes for patients with early-stage disease.

“There have been tremendous advancements in the management of MIBC, clearly proving that the treatment strategy has now moved to a multimodality approach. It is truly a team sport now managing these patients,” Bernard H. Bochner, MD, FACS, explained in an interview with OncLive^®. “Along with that has come some great advances and tremendous excitement in the field—advances of the like that I haven't seen in the last 40 years—which are translating into better outcomes for patients and more people are surviving their disease.”

In the interview during the 17th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies, an event hosted by Physician’s Education Resource (PER^®), Bochner highlighted research integrating checkpoint inhibitors and other agents into earlier treatment settings for MIBC and ongoing research in this space. Bochner is a urologic surgeon and the Sir Murray F. Brennan Chair in Surgery at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: Could you elaborate on the need for a multimodality approach in MIBC?

Bochner: A multimodality approach, when it comes with respect to surgery, involves either preoperative or postoperative treatment regimens. In the past, it was platinum-based chemotherapy, which was the mainstay in improving outcomes. This was based on a variety of studies that were performed throughout the 1990s and early 2000s, which demonstrated that the [chance] of somebody surviving their bladder cancer was improved by up to a third if they received platinum-based chemotherapy prior to having the bladder removed for a muscle-invasive, otherwise localized tumor.

The problem had been that many patients were not eligible for platinum-based chemotherapy–up to approximately 40% of patients with MIBC–due to either renal dysfunction, sensory neural hearing loss, or cardiovascular issues. Due to [those limitations], we were looking for help with other agents. The other issue with giving [platinum-based chemotherapy] in the neoadjuvant setting is that, by definition, we do tend to overtreat some patients; we don't know who has micrometastatic disease, and we don't know who has platinum-sensitive disease either. As a result, there was overtreatment.

There was a lot of interest and excitement in trying to test whether giving adjuvant chemotherapy would have an equal benefit as in the preoperative setting. Those studies did struggle to accrue over time, but the meta-analyses do demonstrate that there [most likely] is a similar benefit [with adjuvant chemotherapy]. However, the studies were somewhat small and the data were not quite as robust. Again, [adjuvant chemotherapy] does require patients to be platinum eligible.

What unmet needs have persisted in the treatment landscape of this disease and how are they being addressed?

We know that patients who have bladder cancer tend to have tumors with a whole variety of genetic abnormalities. A tremendous amount of work has demonstrated the heterogeneity within a bladder tumor or within the group of bladder tumors that we have seen. This has opened up some interesting opportunities for alternative strategies.

Bladder cancer tends to have a very high tumor mutational burden. There's been good evidence in other tumor types that [patients with] high tumor mutational burden respond better to checkpoint inhibition, for instance. Checkpoint inhibitors have been tested in the neoadjuvant setting [of MIBC], both in patients who were platinum-ineligible and in patients who were platinum-eligible patients. [By] combining [checkpoint inhibition] with standard chemotherapy, we tried to improve the fraction of patients who are developing downstaging or pathologic complete responses [pCRs]. Some of those studies have demonstrated some nice outcomes, suggesting that there is activity with checkpoint inhibition in the neoadjuvant setting.

This all stems from a tremendous amount of work being done in patients with more advanced disease, establishing the role of checkpoint inhibition in high-grade metastatic disease. Now that we've seen [checkpoint inhibition] move into the earlier treatment phases, there is a lot of excitement. This is seen with single agents; combined checkpoint inhibition with PD-1 and CTLA-4 inhibitors, for instance; or combinations with standard chemotherapy, demonstrating nice responses within the primary tumor with respect to downstaging.

Are there any ongoing areas of research in the bladder cancer space that you are intrigued by?

Some of the most exciting data has come with the advent of ADCs. Enfortumab vedotin plus pembrolizumab has been established as the new standard of care in the first-line treatment for patients with metastatic disease, and this has allowed us to move these drugs up earlier again in the staging and treatment of patients. There are some excellent studies that are going head-to-head with standard chemotherapy and enfortumab vedotin/pembrolizumab in the neoadjuvant setting prior to surgery to establish a new paradigm in that arena, as well.

On the flip side of treatment, we know that patients do receive platinum-based chemotherapy but still have high-risk disease present within the bladder, and that can be defined as anybody with residual muscle-invasive disease or greater; [these patients] have a pretty guarded outcome, [as] recurrence rates are exceedingly high in that setting. We've been looking for agents to help [patients] in that particular state of disease.

There have been 3 adjuvant checkpoint inhibitor studies in this setting of high-risk patients who have either having [progressed on] prior neoadjuvant therapy with high-risk residual disease, or patients who are ineligible for neoadjuvant therapy who have non–platinum-exposed but high-risk pathology, [meaning patients with] pT3/pT4 node-positive [disease]. We know in that particular group of patients, there's a very high recurrence risk, and now we have good evidence from 2 studies, using either nivolumab [Opdivo] or pembrolizumab, [showing] that the disease-free [survival (DFS) can be significantly improved in patients who receive adjuvant checkpoint inhibition.

We're excited that there is now the ability to offer adjuvant therapy based on level 1 evidence. The overall survival [OS] data are still immature, and we don't have that data available quite yet. However, we all suspect given the DFS data, that this is going to translate into an OS advantage over time as well.

How do you foresee the future treatment of this patient population progressing with ongoing treatment initiatives and research?

We now have several opportunities to offer advances to patients with muscle-invasive disease, [For] people who are headed for surgery, the standard remains platinum-based chemotherapy prior to surgery. However, we're testing whether some of the new combinations such as enfortumab vedotin/pembrolizumab are going to be able to add survival advantage beyond what we see with chemotherapy. For those patients who don't have a complete response to chemotherapy in that [neoadjuvant] setting, we're now seeing checkpoint inhibitors making their way into the adjuvant setting. Again, we are fortunate in that we have significant improvements in those patients with respect to their outcomes, as well.

I hope that this is all going to eventually lead to improved bladder preservation rates as we begin to start identifying those patients who have pathologic complete responses [pCRs], whether that’s to standard chemotherapy or some of the newer agents. Perhaps that will provide some opportunities for bladder preservation [by] selecting patients who are likely to have pCR to systemic therapy alone, who can then undergo close surveillance and perhaps avoid surgery. If we could safely demonstrate sparing the bladder in this setting is achievable, we certainly wish to offer that.