Matthew Galsky, MD

Patients with muscle-invasive urothelial cancer of the bladder and invasive urothelial cancer of the upper urinary tract are at generally at high risk for metastatic recurrence despite curative intent surgery. A series of clinical trials investigating systemic therapies applied in the adjuvant setting have been performed over the past few decades in an attempt to mitigate this risk.

 Compared with the development of therapeutic approaches in the metastatic setting, the development of therapeutic approaches in the adjuvant setting is potentially more impactful but more complicated. That is, in the metastatic setting, we mainly face the question “Who benefits from treatment?” Whereas in the adjuvant setting, we face both the question “Who needs treatment?” and “Who benefits from treatment?” A large proportion of patients with muscle-invasive urothelial cancer will achieve cure with surgical resection alone. On the other hand, for those patients who harbor micrometastatic disease after surgery, just as in the metastatic setting, not all such cancers will be sensitive to the systemic therapy being applied.

Historically, we have addressed the “Who needs treatment?” question in the adjuvant setting by using pathologic features of the primary tumor and regional lymph nodes to help refine estimates regarding recurrence risk. Such features, in turn, have formed the eligibility criteria for clinical trials. The majority of adjuvant trials in urothelial cancer have enrolled patients with bladder-only primary tumors and have limited enrollment to patients who had not received prior neoadjuvant chemotherapy and had pathologic T3 or higher urothelial cancer or pathologic evidence of regional lymph node involvement. Randomized trials exploring adjuvant cisplatin-based chemotherapy in this context suffered from methodologic flaws and/or closed early due to poor accrual, leaving some doubt regarding the efficacy of this approach despite meta-analyses suggesting a benefit.

Although trials of adjuvant cisplatin-based chemotherapy in high-risk urothelial cancer continued, for a number of reasons, neoadjuvant cisplatin-based chemotherapy became the standard preferred treatment standard supported by level I evidence.

 Therefore, regardless of one’s interpretation of the studies evaluating adjuvant cisplatin-based chemotherapy, additional unmet need populations at high risk for recurrence after surgery arose not addressed by the prior generation of studies: (1) patients with pT3 or higher and/or pN-positive disease who are considered cisplatin ineligible

 and (2) patients with residual ypT3 or higher and/or ypN-positive disease despite having received prior cisplatin-based neoadjuvant chemotherapy. These 2 distinct populations have formed the basis for large phase 3 trials exploring PD-1 and PD-L1 immune checkpoint inhibitors in the adjuvant setting triggered by the safety and efficacy of these therapies in metastatic urothelial cancer.

Three somewhat similarly designed adjuvant trials, with some nuances, have been conducted to test adjuvant PD-1 or PD-L1 blockade. IMvigor010 (NCT02450331) randomized patients with urothelial cancer of the upper tract or bladder at high risk for recurrence (as defined above) after definitive surgery to atezolizumab (Tecentriq) administered for 1 year vs observation.

 This was the first in the series of immune checkpoint blockade adjuvant trials to report and it was presented at the 2020 American Society of Clinical Oncology Annual Meeting, though it has not been published. The trial did not meet the primary end point of improvement in disease-free survival with atezolizumab in the intent-to-treat population, nor was there in an improvement in the subset of patients with tumors harboring increased PD-L1 protein expression.

The Checkmate 274 trial (NCT02632409) employed similar eligibility criteria but randomized patients to 1 year of adjuvant nivolumab (Opdivo) vs placebo (rather than observation).

 This trial, presented at the 2021 Genitourinary Cancers Symposium, met coprimary end points of an improvement in disease-free survival in the intent-to-treat population (HR, 0.70; 95% CI, 0.54-0.89; 

 < .001) and in the subset of patients with tumors harboring increased PD-L1 protein expression (HR, 0.53; 95% CI, 0.34-0.84; 

 < .001). Overall survival, a secondary end point of this study and an event-driven analysis, has not been assessed. A third trial enrolling a similar patient population but randomizing patients to 1 year of adjuvant pembrolizumab (Keytruda) vs observation, dubbed the AMBASSADOR trial (NCT03244384), is still enrolling.

Many questions have arisen regarding the disparate results reported from IMvigor010 and Checkmate 274. Ultimately, these are different drugs explored, employing different PD-L1 biomarkers, in trials that likely enrolled patients with slightly different baseline characteristics and involved some important clinical trial design nuances. For example, the former involving randomization between atezolizumab and observation may have been affected by informed censoring based on the proportion of patients randomized to observation that withdrew early from the study. Checkmate 274 represents the first trial demonstrating an improvement in outcomes with an adjuvant immune checkpoint inhibitor in urothelial cancer, addresses a patient population without previously available systemic therapies to mitigate risk of recurrence, and represents the first big step in a new era of immune checkpoint inhibitor for muscle-invasive urothelial cancer.

is acting chief, Division of Hematology and Medical Oncology, and professor of medicine at Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai in New York City, New York.

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Articles

Recent trial demonstrates an improvement in outcomes with an adjuvant immune checkpoint inhibitor in urothelial cancer.

Adjuvant immune checkpoint blockade in urothelial cancer: A new era?

Bladder cancer is traditionally thought of as almost two distinct cancers, with nearly 80% of newly diagnosed cases being nonmuscle-invasive disease (NMIBC). The challenge of managing patients with NMIBC is predicting which patients are at risk for progression to muscle-invasive bladder cancer (MIBC), where treatment is much more aggressive and life altering, versus those that are at a much lower risk and potentially the surveillance can be altered with a concomitant reduction in costs.

For patients with higher risk NMIBC, the mainstay of therapy has historically been bacillus Calmette–GuÃ©rin (BCG). However, because of the ongoing BCG shortage in addition to the lack of effective alternative drug therapies for patients with BCG-unresponsive disease, a large unmet need exists for these patients and providers. Newer agents are addressing these challenges. 

discusses these therapies, their specific indications, how they are administered, dosing, and side effects.

Dr. Galsky is professor of medicine, director of genitourinary medical oncology, director of the Novel Therapeutics Unit, and co-director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, New York. He was interviewed by 

, chief clinical urologic officer, Integra Connect, West Palm Beach, FL, and clinical associate professor of urology, Vanderbilt University School of Medicine, Nashville, TN.

What are the current challenges associated with the treatment of NMIBC?

There are two major challenges. One is in patients who are treatment naive, and that challenge is that there's a shortage of the standard-of-care treatment for patients with high-risk nonmuscle-invasive disease, which is BCG. That creates some challenges in terms of clinical management, but it also creates challenges in terms of clinical trials in that if you don't have the standard of care as a control treatment, then it's difficult to run clinical trials that are randomized or with combination therapies, etc.

The second major challenge has existed for a bit longer, and that's how we optimally manage patients who have BCG-unresponsive carcinoma in situ, ie, patients who have not adequately responded to treatment with BCG. We know that the standard of care in that context is radical cystectomy, but that's a treatment many patients would like to avoid if possible. That's led to a long history of studies seeking to determine whether or not there are medical treatments that can be used to avoid cystectomy, ideally, or at the very least, delay it.

Please discuss developments that will address one or both of those challenges. What do you anticipate will be approved for the management of NMIBC over the next 12 months, especially in the BCG non-responsive patient?

Pembrolizumab (KEYTRUDA), the PD-1 inhibitor, has already been approved for the treatment of BCG-unresponsive disease. That approval was based on a single-arm study that involved two cohorts. We only have the results of one of those cohorts-patients with BCG-unresponsive disease who had carcinoma in situ with or without papillary disease-so that was the basis for the approval. Pembrolizumab is the first systemic treatment approved in this context.

The second cohort included patients with only papillary disease, either high-grade Ta disease or T1 disease, and we don't have the results from that cohort yet. That's potentially an important point that's often missed in clinical situations as medical oncologists like myself get some referrals for patients with nonmuscle-invasive disease who don't specifically meet the eligibility criteria that were the basis for the approval of pembrolizumab. 

Incidentally, another systemic therapy, atezolizumab, which is a PD-L1 inhibitor, was being studied in a similar context in SWOG-1605, and that trial closed prematurely. It failed to meet the threshold for which it was likely to be a successful trial. We don't fully understand the results of that study yet and the nuances of pembrolizumab versus atezolizumab in this setting.

There are also two intravesical treatments that are being reviewed by the FDA, and the expectation is that one or both of these drugs will likely become available as well. These agents include nadofaragene firadenovec (Instiladrin), which is an interferon-alpha expressing-adenovirus, and that has been studied in nonmuscle-invasive BCG-unresponsive disease and led to a 12-month complete response rate of 24%, which is encouraging in this context, particularly based on the route and frequency of administration.

A second intravesically administered drug is called Vicinium, which is a fusion protein consisting of an epithelial cell adhesion molecule (EpCAM) that is fused to a Pseudomonas exotoxin, essentially delivering this exotoxin to EpCAM-expressing cells. Vicinium has been studied in a single-arm study with a 12-month complete response rate of 17%.

The 12 month-complete response rates with pembrolizumab, nadofaragene, and Vicinium-even though these cohorts are not exactly the same and there are some nuances in terms of study eligibility-line up fairly well at between 17% and 24%.

How are these three therapies administered?

Pembrolizumab is administered intravenously every 3 weeks. In the clinical trial that led to its approval, it was administered for up to 2 years as long as there wasn't evidence of recurrence or progression. Nadofaragene is administered intravesically every 3 months for up to 4 years. Vicinium is administered intravesically one to two times a week for 12 weeks, and then every 2 weeks for 2 years.

Will the approvals be for high-grade TA, T1 disease, and carcinoma in situ?

As I mentioned, the approval for pembrolizumab was based on one of the two cohorts that were explored in that study, and that was a cohort of patients with carcinoma in situ with or without papillary disease (Ta or T1 disease). Results for Cohort B, which was in patients with papillary disease, are not available yet. So far, the approval of pembrolizumab is in patients with carcinoma in situ, and we'll have to see if that's extended based on the initial results.

In the nadofaragene and the Vicinium trials, if these therapies are indeed approved, it will be interesting to how restricted the label might be with regard to the type of NMIBC.

Will these agents be approved for primary therapy, given the current BCG shortage?

I don't suspect they'll be approved as primary therapy in the near term, even with the BCG shortage. I think the question, though, is will they be used in the absence of BCG? When there are drug shortages in other disease states, we see some extrapolations of data, so it wouldn't be a surprise to me if we start to see some of these drugs being used in that context if BCG can't be obtained.

In the longer term, whether or not these therapies have the potential to be compared to BCG in randomized studies and ultimately replace BCG remains to be seen. We know there are studies with immune checkpoint blockade in combination with BCG aimed at potentially finding a drug to replace maintenance BCG, which could certainly lighten the load in terms of the need to source BCG. Those studies are probably coming in the future, but I don't suspect the approvals will be for that use in the short term.

For the immunologic agents, will there be both induction and maintenance dosing?

There isn't induction and maintenance dosing per se, but there is long-term treatment, at least based on the initial study. With pembrolizumab, the treatment is administered for up to 2 years in the absence of recurrence or progression. The dosing, though, is the same, and the schedule is the same. Unlike with BCG, where the schedule changes with maintenance, pembrolizumab is administered potentially for a long term, but with the same dosing schedule. The optimal duration of immune checkpoint inhibitors, even in the metastatic setting, remains unclear.

How do you anticipate that medical oncologists, who have historically not managed nonmuscle-invasive bladder cancer patients, and urologists will use these newer agents?

That's going to be an evolving question, at least in part based on longer term follow-up data from these studies and, of course, the pending approvals of Vicinium and nadofaragene. The reason I say that is, if you look across the studies with those three agents-and again, it's somewhat dangerous to do that because they're not randomized and the eligibility doesn't exactly line up-the proportion of patients who have a complete response at 12 months is pretty similar.

Then you need to think about other factors to help make the decision about choice of treatment, which include the potential side effects of treatment, the mode of administration, the frequency of administration, and potentially the cost. One can develop a scorecard of those items for each of these individual therapies. If there's an intravesical treatment that works potentially just as well, spares systemic side effects, and is administered less frequently, then that may be a preferable treatment from the standpoint of patient and physician.

However, one also need to consider the long-term follow-up data from these trials. The goal of giving these treatments is really to avoid cystectomy ideally more so than delay cystectomy. If our goal is to avoid cystectomy, then we are looking for treatments that are potentially curative in at least a subset of patients. If there is a subset of patients who are cured with these treatments, rather than just experiencing a delay in recurrence or progression, then the value proposition of that treatment changes a bit. So if immune checkpoint blockade given for a fixed period of time, say 2 years, leads to eradication of cancer and durable remission in a subset of patients, that might balance against the inconvenience of intravenous administration and the risk for systemic side effects. So, treatment paradigms are in evolution based on all of these considerations.

What are the side effects of the three agents you discussed?

The side effect profile of pembrolizumab is pretty well defined based on its approval in metastatic cancers. Pembrolizumab and other immune checkpoint inhibitors are widely approved in various solid tumors and hematologic malignancies as well, so we have a pretty good understanding of the potential side effects, which don't seem to differ in the NMIBC patient population. Based on the KEYNOTE study that led to the approval of pembrolizumab, there was a 13% likelihood of having treatment-related moderate to severe (grade 3 to 5) side effects. Those side effects include the potential for inflammation of various parts of the body: colitis, pneumonitis, dermatitis, hepatitis, etc.

When those side effects occur, they often resolve with simply stopping the medication. Sometimes steroid medications are required to help resolve those side effects.

With nadofaragene and Vicinium, there are side effects similar to other local therapies. Grade 3 to 5 side effects in the trials of those drugs were in the 4% range. We do see a different side effect profile when treatments are administered into the bladder versus when they're administered systemically.

What is the role of chemoradiation in chemoradiation for high-grade T1 bladder cancer?

That is one topic that often gets left out of the conversation. We know that chemoradiation has a role for muscle-invasive bladder cancer. Its role in T1 high-grade disease, particularly post-BCG, is not entirely well defined.

There was a fairly large study looking at chemoradiation for BCG-naive, high-grade T1 disease that showed reasonable bladder-intact outcomes. That concept is being explored in an RTOG study in patients who have already received BCG. It is an option that we think about for T2 disease, but oftentimes we don't think about it for T1 disease, possibly because of the absence of data in this in the post-BCG setting.

What is the status of molecular markers for NMIBC?

The major molecular marker that's potentially relevant is a mutation in a gene called fibroblast growth factor receptor 3, or FGFR3. We know that FGFR3 is mutated in a large subset of low-grade, nonmuscle-invasive bladder cancers, but it's mutated in a smaller subset of high-grade cancers as well. Erdafitinib (BALVERSA) is an orally bioavailable, small-molecule inhibitors of this receptor that is now approved by the FDA for the treatment of metastatic bladder cancer.

Thus, a logical question is whether or not those treatments can be effective in patients who have FGFR3-mutated nonmuscle-invasive bladder cancer. Some pilot studies have suggested intriguing results, but there are large studies that have just been initiated with more definitive endpoints, trying to determine whether or not this could be the first "precision medicine-based" approach for nonmuscle-invasive disease.

Systemic and intravesical therapies are changing the landscape of BCG-unresponsive disease, according to Matthew Galsky, MD.

Matthew Galsky, MD

Articles

Adjuvant immune checkpoint blockade in urothelial cancer: A new era?

How new agents may address NMIBC treatment challenges