How Immunotherapy Is Transforming Bladder Cancer Treatment

Bladder cancer affects an estimated 550,000 people worldwide each year, including 80,000 in the U.S. Most cases of bladder cancer are caught early and are treatable with a bacteria-based immunotherapy called Bacillus Calmette-Guérin, or BCG, as well as traditional treatments like surgery and chemotherapy.

Historically, advanced bladder cancer has been harder to treat, but recently immunotherapy has made progress here, too. The FDA has approved five checkpoint immunotherapies that target the PD-1/PD-L1 pathway—which can suppress T cell activity—for patients with advanced bladder cancer who don’t respond to prior treatment. More importantly, clinical trials continue to explore a number of promising immunotherapies, both alone and in combination with other treatments. As of May 2020, there were more than 150 active immunotherapy clinical trials for bladder cancer patients.

To get a better idea of the current immunotherapy landscape in bladder cancer and how these immune-based strategies are starting to improve care for some patients, we spoke with Arjun V. Balar, MD, who serves as the director of the genitourinary medical oncology program at NYU Langone Health’s Perlmutter Cancer Center and is a leader in bladder cancer clinical trials.

Arthur N. Brodsky, PhD:

Immunotherapy has been used to treat bladder cancer for a while now, starting with the approval of BCG in 1990 for patients with early-stage disease. Over the past several years, some checkpoint immunotherapies have been approved for more advanced bladder cancer, too. How would you describe the state of immunotherapy in bladder cancer right now?

Arjun V. Balar, MD:

In advanced bladder cancer, immunotherapy’s benefits are very well established. Several trials have consistently demonstrated that checkpoint inhibitors are active in advanced disease, with response rates ranging from 15 to 30 percent depending on the study and the line of treatment. Checkpoint inhibitors have also improved survival in the second-line setting, meaning patients whose cancer persisted or progressed after prior platinum-based chemotherapy treatment. This also appears promising as a first-line approach in previously untreated patients who are cisplatin-ineligible, where response rates approach 30 percent.

In the first-line setting in particular, patients whose tumors express high levels of the PD-L1 biomarker clearly benefit more, and is beginning to challenge some existing standard treatments, like platinum-based chemotherapy, in advanced disease.

In localized disease, we have had an FDA approval of a PD-1 antibody pembrolizumab in BCG unresponsive non-muscle invasive bladder cancer and there are still a number of ongoing studies in both muscle-invasive and non-muscle invasive disease that will further clarify immunotherapy’s role here.

In muscle-invasive disease, there are ongoing studies looking at the benefits of immunotherapy, either alone or in combination with chemotherapy, prior to cystectomy. There are also trials combining checkpoint immunotherapy with chemoradiation as an alternative to cystectomy, allowing patients to keep their bladder. That's probably one of the important impacts in changing bladder cancer care that I envision over the next several years. People with bladder cancer are desperate for options that avoid bladder removal, which is a devastating surgery and permanently impacts quality of life. Trials are now addressing ways we can add immunotherapy to bladder preservation therapy to improve outcomes and I hope is going to become an option we rely on more often.

In non-muscle invasive bladder cancer, there was a recent FDA approval in January for pembrolizumab, a PD-1 checkpoint immunotherapy, and I believe it's going to be the first of many other novel agents in this space. Once again, treatment in these patients is geared toward looking to avoid a radical cystectomy.  The standard of care in high-risk cases at initial presentation is intravesical BCG which is instilled via a catheter into the bladder.

As you've mentioned, it's the first and most well-established immunotherapy for bladder cancer, going back to the 1970s. Interestingly, it’s made of weakened bacteria that induce a localized immune response, so it is highly effective against cancer that hasn’t spread yet and is confined to the bladder lining. Although 70 to 80 percent of patients will experience complete eradication of their tumors, about half of these patients will experience a recurrence after an initial response.

For these patients, we have considered radical cystectomy to be the next standard of care, which means that if BCG doesn't work, the bladder should just come out. The cure rate with a cystectomy in that setting is extremely high, around 95 percent.

While cystectomy is a tough standard to beat in terms of effectiveness, it is not a tough standard to beat in terms of safety and quality of life. Two-thirds of patients have at least some form of complication during or after the operation. Infections and re-hospitalizations are very common, and about four percent of patients don’t’ survive the surgery.

It was in this context that pembrolizumab was tested in the Keynote-052 trial for which I was the overall lead investigator. Ultimately, what the study showed is that about 40 percent of patients can have their cancer eradicated with PD-1 immunotherapy, and about half of those responses last more a year. There's clearly a group of patients where this treatment is active and helps us avoid cystectomy, especially for those who adamantly don't want it or aren't good candidates for surgery. And that's also not a trivial number.

So that's where we are now. A number of other combinations involving PD-1 immunotherapies are also being tested to see if we can improve responses further. One is the combination of dual checkpoint immunotherapy targeting the PD-1 and CTLA-4 pathways.

What we have learned recently with respect to response rates is that the dose of the anti-CTLA-4 immunotherapy really does matter: with the higher dose, you see a higher response rate. So, after we realized that the higher the dose of anti-CTLA-4 drug matters, we are now testing a new dosing strategy for this combination checkpoint immunotherapy and it could be a new standard of care, at least for some patients in the first-line setting.

In the future, you're going to see other novel agents like viral-based gene therapies that can also induce the localized immune response. One called nadofaragene firadenovec is currently being considered for approval by the FDA. The product is a attenuated adenovirus that is encoded with interferon-Alpha 2b and infects tumors cells to then generate a localized immune response.  It is administered via catheter once every three months, so it's attractive for patients with localized disease who want to avoid a cystectomy.

Arthur N. Brodsky, PhD:

It’s easy to understand why that would be such a huge benefit for those patients. Obviously, immunotherapy isn't without its side effects, and patients have got to weigh the potential benefits against the possible risks.

Relatively speaking, advanced bladder cancer responds pretty well to immunotherapy, and that appears to fit with a trend that’s been observed where cancers with higher levels of mutations are more likely to be responsive to immunotherapy.

What do we know about the role of mutations in bladder cancer immunotherapy?

Arjun V. Balar, MD:

Yes, we have generally considered the most immune responsive cancers—like melanoma, some types of lung cancer, bladder cancer, and head and neck cancer—to be associated with higher levels of tumor mutations. These are often linked to specific factors—carcinogens—that cause mutations to accumulate over a long period of time during carcinogenesis. On average, bladder cancer has more mutations compared to other cancer types.

The logic goes that the more mutations you have, the more likely one of those mutations will generate an anti-tumor immune response because it will be recognized as foreign by the person’s immune system. I think that's the fundamental basis for the majority of responses in people with bladder cancer who respond to checkpoint inhibitor immunotherapy.

Still, even within bladder cancer there is wide variability. Some tumors will have fewer mutations. Others will have very high levels of mutations, like people whose cancers have high microsatellite instability, or MSI-high, which reflects cells’ inability to repair their DNA and is often linked with an inherited genetic condition known as Lynch syndrome.

This leads to extremely high mutation rates, sometimes as more than one thousand mutations might be found in a single tumor. It isn’t clear, though, what the optimal cutoff for defining a “highly mutated” cancer is, and that’s one of the issues we’re trying to address with respect to treatment decisions because those patients are most at risk and most likely to be in that 30 percent who respond to checkpoint immunotherapies.

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Arthur N. Brodsky, PhD:

Moving forward, as you alluded to, the goal is to figure out novel approaches that can help the other 70 percent of patients. Can you talk a bit more about some of the promising combination strategies involving PD-1 immunotherapy that are currently being explored in clinical trials?

Arjun V. Balar, MD:

Of course, I’ll highlight a few that I think are exciting. One involves an antibody drug conjugate called enfortumab vedotin (Padcev^TM) that was approved by the FDA in December 2019. It targets nectin-4, which is a cell adhesion molecule that's expressed at abnormally high levels in bladder cancer, among other cancers. So, while one end of the molecule targets nectin-4, the other end is tagged to a toxic payload that is delivered to kill the cancer cell.

In the trials that supported its approval, responses were seen in 44 percent of patients with advanced bladder cancer that didn’t respond to either platinum-based chemotherapy or checkpoint immunotherapy. And about 85 percent of patients had at least some measure of tumor shrinkage.

We saw activity across different groups of patients, including those with liver metastases where we saw a similar response rate of around 44 percent. That's noteworthy because we know that these patients generally have the worst prognosis once the initial treatment proves unsuccessful. To see activity in this population was really striking.

Having treated many patients on the initial pivotal study that supported approval, I can tell you that this drug is extremely active and it’s very effective in getting cancer under control, especially when they are not responding at all to PD-1 immunotherapy.

As the benefits of this antibody-drug conjugate became clear, naturally we wanted to test it in earlier disease as well as in combinations. Some of us investigators on the initial study noted that we had started observing what we thought was evidence of immune synergy between the combination of checkpoint immunotherapy and the antibody-drug conjugate. First, we noticed that patients who were initially resistant to anti-PD-1 immunotherapy responded to re-challenge with immunotherapy after enfortumab vedotin..

So, we had kind of a smattering of evidence from various investigators. We were excited about this combination of enfortumab and anti-PD-1 therapy, so we launched a phase one study in the first-line setting in cisplatin-ineligible patients. Of the 45 patients treated in this small study, 73 percent have obtained an objective response,  over 90 percent had at least some measure of tumor shrinkage, and more than 10 percent saw their tumors completely disappear.

These were extraordinarily striking numbers. Numbers that you can't ignore, even in a small study like this. You can clearly see that there might be substantial synergy between these two drugs. Obviously, we need to test this further, so we’ve launched two studies, one of which also incorporates chemotherapy into the combination.

These studies are poised to answer multiple questions, including some related to the immune synergy that we're seeing. If these data hold, it's possible that this combination becomes the standard of care for every patient, whether they're cisplatin-eligible or not. So that's something to look out for.

The other studies that I think are also potentially practice-changing involve a drug called NKTR-214, which is designed to activate the interleukin 2, or IL-2, pathway. Targeting this pathway in the form of high-dose IL-2, promotes broad T cell proliferation and activity, and has already been established as a curative treatment for advanced kidney cancer as well as melanoma.

High-dose IL-2 therapy had a harsh toxicity profile though, meaning you had to be hospitalized in an ICU-level setting. And so while it was curative in advanced kidney cancer, it was really limited to a subset of young and healthy patients who could adequately handle it.

But this new molecule, NKTR-214, is engineered with several special properties, including the capacity to time-release into the body, so it can be given at lower doses with potentially fewer side effects. It's thought to synergize well with PD-1 blockade, because on-treatment biopsies from a previous study showed an up-regulation of PD-L1 expression in tumors.

A phase 2 study (PIVOT-10) is on-going and is investigating this in combination with PD-1 immunotherapy as a first-line treatment for cisplatin-ineligible patients with advanced bladder cancer. The safety profile is similar to IL-2, but kind of like IL-2-lite. That’s probably the best way I can describe it.

The side effects are largely manageable in the outpatient setting as long as patients are hydrating really well. In addition to these two studies, there are first-line randomized phase III combination studies of anti-PD-1 plus CTLA-4 that are on-going.  The first, DANUBE was reported as negative in a press-release, however the dose of CTLA-4 in that trial may not have been optimized.  A more recently activated trial and currently accruing is CHECKMATE-901 and is testing iplimumab and nivolumab, but with a higher dose (3 mg/kg) of ipilimumab which may be more promosing.  There are also other, more speculative studies that are looking at inhibitors of the IDO immune checkpoint. These are still being tested in both localized non-muscle invasive and muscle-invasive bladder cancer. There are also a number of studies looking at other immune checkpoints such as KIR, but those are probably still very early in development and are not poised to change standards of care anytime soon.

Arthur N. Brodsky, PhD:

With respect to the newer, next generation immunotherapy approaches, cellular therapies like CAR T cells come to mind. Are there any ongoing studies exploring cell-based immunotherapies in bladder cancer?

Arjun V. Balar, MD:

There are. CAR T cell therapies targeting the MAGE-A3 antigen are being developed, and they’re in phase 1 testing for patients whose tumors overexpress the MAGE-A3 antigen.

Arthur N. Brodsky, PhD:

Compared to a decade or two ago, it's really amazing how much we have learned about the immune system and how patients can benefit from immunotherapy. Obviously, much work remains to be done to help more patients. To that end, what are some of the most pressing questions right now in the field of bladder cancer immunotherapy that, if answered, might help provide more cures for more patients?

Arjun V. Balar, MD:

With respect to our current understanding and the treatments that we're using now, what we need to understand is whether or not combining chemotherapy and immunotherapy is a good idea as an up-front, first-line treatment. We were lured into that notion from the studies in advanced lung cancer that combined chemo plus immunotherapy and showed fairly dramatic improvement in survival. But, so far, we are not seeing that in advanced bladder cancer, so we have to ask why? We need to better understand how chemotherapy and immunotherapy work together, especially if there are differences when they’re given sequentially versus simultaneously.

So, that's one of the most pressing questions. Another is, in the future, are we still going to still use cisplatin chemotherapy eligibility as a major determinant for how we approach drug-development and in the clinic, how we treatment make treatment decisions? We have historically used cisplatin-eligibility as a framework for drug development in the first-line setting, however this may need to be revisited given the exciting data we are seeing with enfortumab and pembrolizumab. We also have important biomarker studies looking at genomics and tumor mutational burden, among other factors, that may be more relevant in helping us decide what treatments patients should receive rather than whether they're eligible for cisplatin chemotherapy or not. We need to break down some of those barriers.

From a clinical standpoint, we also need to know whether or not every patient with localized bladder cancer, especially muscle-invasive bladder cancer, needs a cystectomy. And is that necessarily the best treatment for patients? Can we achieve similar cure rates with bladder-preserving treatments, either for non-muscle-invasive or muscle-invasive bladder cancer? I think that's the most pressing question for patients.

Looking more long-term, we need to understand bladder cancer immune biology better. In particular—and this is relevant across different tumor types—we need to know how to convert so-called “cold” tumors (those that are less likely to attract the immune system’s attention) into more immune-responsive tumors. And the way we're probably going to drive immune responses is to target some of those mechanisms of suppression, via treatments that target pathways like TGF beta. Some studies are already targeting TGF beta in combination with checkpoint immunotherapy. We're going to need to look at these other combinations to help get immunotherapy-resistant tumors to become more responsive.

And the only way we can do it is through clinical trials. We use preclinical studies to give us an inkling of what direction we're headed in, but ultimately we have to test these strategies through trials that are robust and scientifically driven.

Arthur N. Brodsky, PhD:

Unfortunately, fewer than ten percent of cancer patients enroll in clinical trials. Now, that may be due in part to some of the misconceptions that exist surrounding clinical trials. Patients might think that they’re only last resort or they're going to get a placebo. What do you say to a patient who's considering a clinical trial but might be hesitant?

Arjun V. Balar, MD:

There are misconceptions about clinical trials. Some of the big fears that patients have about trials are: Am I being experimented upon? Am I a guinea pig? Is there a risk that I'm going to get the placebo and not the treatment?

And my answers to those questions are that, first, clinical trials are very ethically designed today. You can never receive anything less than the standard of care in a clinical trial.

Most importantly, trials are now the way to access the newest and most promising treatments. I tell patients all the time that the best treatments in cancer are not from ten years ago, five years ago or, heck, even two or three years ago. The best treatments in cancer are now. Which means they are just now entering the clinic based on robust science and some of the best compounds with probably better safety profiles and perhaps even improved effectiveness. In general, the best access to new treatments is through trials, and very often a patient’s best treatment option is a clinical trial.

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